dissertation on uterine fibroids

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Uterine fibroids: current perspectives

Affiliations.

1 Birmingham Women's Hospital, Edgbaston, Birmingham, UK.
2 Academic Department of Obstetrics and Gynaecology, University of Birmingham, Birmingham, UK.
PMID: 24511243
PMCID: PMC3914832
DOI: 10.2147/IJWH.S51083

Uterine fibroids are a major cause of morbidity in women of a reproductive age (and sometimes even after menopause). There are several factors that are attributed to underlie the development and incidence of these common tumors, but this further corroborates their relatively unknown etiology. The most likely presentation of fibroids is by their effect on the woman's menstrual cycle or pelvic pressure symptoms. Leiomyosarcoma is a very rare entity that should be suspected in postmenopausal women with fibroid growth (and no concurrent hormone replacement therapy). The gold standard diagnostic modality for uterine fibroids appears to be gray-scale ultrasonography, with magnetic resonance imaging being a close second option in complex clinical circumstances. The management of uterine fibroids can be approached medically, surgically, and even by minimal access techniques. The recent introduction of selective progesterone receptor modulators (SPRMs) and aromatase inhibitors has added more armamentarium to the medical options of treatment. Uterine artery embolization (UAE) has now been well-recognized as a uterine-sparing (fertility-preserving) method of treating fibroids. More recently, the introduction of ultrasound waves (MRgFUS) or radiofrequency (VizAblate™ and Acessa™) for uterine fibroid ablation has added to the options of minimal access treatment. More definite surgery in the form of myomectomy or hysterectomy can be performed via the minimal access or open route methods. Our article seeks to review the already established information on uterine fibroids with added emphasis on contemporary knowledge.

Keywords: leiomyoma; menorrhagia; myomectomy; selective progesterone receptor modulators; ultrasonography; uterine artery embolization.

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Article Contents

Introduction, current surgical management strategies, alternatives to surgical intervention, why we need new options, current medical therapy, the future of medical therapy, acknowledgements, authors’ roles, conflicts of interest, uterine fibroid management: from the present to the future.

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Jacques Donnez, Marie-Madeleine Dolmans, Uterine fibroid management: from the present to the future, Human Reproduction Update , Volume 22, Issue 6, 20 November 2016, Pages 665–686, https://doi.org/10.1093/humupd/dmw023

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Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Clinical presentations include abnormal bleeding, pelvic masses, pelvic pain, infertility, bulk symptoms and obstetric complications.

Almost a third of women with leiomyomas will request treatment due to symptoms. Current management strategies mainly involve surgical interventions, but the choice of treatment is guided by patient's age and desire to preserve fertility or avoid ‘radical’ surgery such as hysterectomy. The management of uterine fibroids also depends on the number, size and location of the fibroids. Other surgical and non-surgical approaches include myomectomy by hysteroscopy, myomectomy by laparotomy or laparoscopy, uterine artery embolization and interventions performed under radiologic or ultrasound guidance to induce thermal ablation of the uterine fibroids.

There are only a few randomized trials comparing various therapies for fibroids. Further investigations are required as there is a lack of concrete evidence of effectiveness and areas of uncertainty surrounding correct management according to symptoms. The economic impact of uterine fibroid management is significant and it is imperative that new treatments be developed to provide alternatives to surgical intervention.

There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids due to the use of selective progesterone receptor modulators (SPRMs) such as ulipristal acetate (UPA). The efficacy of long-term intermittent use of UPA was recently demonstrated by randomized controlled studies.

The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now exist, with SPRMs which are proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium, opening up novel strategies for the management of uterine fibroids.

Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors ( Stewart, 2001 ; Donnez and Jadoul, 2002 ; Bulun, 2013 ; Islam et al ., 2013 ; Drayer and Catherino, 2015 ). They are monoclonal tumors of uterine smooth muscle, thus originating from the myometrium ( Kim and Sefton, 2012 ; Bulun, 2013 ; Islam et al ., 2013 ). They are composed of large amounts of extracellular matrix (ECM) containing collagen, fibronectin and proteoglycans ( Parker, 2007 ; Sankaran and Manyonda, 2008 ; Kim and Safton, 2012 ). Leiomyomas occur in 50–60% of women, rising to 70% by the age of 50 ( Baird et al ., 2003 ), and, in 30% of cases, cause morbidity due to abnormal uterine bleeding (heavy menstrual bleeding inducing anemia) and pelvic pressure (urinary symptoms, constipation and tenesmus) ( Donnez and Jadoul, 2002 ; Donnez et al ., 2014a , b ). Clinical presentations of uterine leiomyomas include pelvic masses, pelvic pain, infertility and obstetric complications ( Donnez and Jadoul, 2002 ).

Risk factors

Risk factors for uterine fibroid. These include race, age, delayed pregnancy, early menarche, parity (protective effect), caffeine, genetic alterations, and others, such as obesity and a diet rich in red meat.

Race constitutes an important risk factor for leiomyoma development ( Marshall et al ., 1997 ; Wise et al ., 2004 ; Stewart et al ., 2013 ; El Toukhi et al ., 2014 ). An US study found that the incidence of uterine fibroids was 60% by age 35 among African-American women, increasing to >80% by age 50, while Caucasian women showed a rate of 40% by age 35, increasing to 70% by age 50 ( Baird et al ., 2003 ). Differences in gene expression in uterine fibroids between these two groups may influence these growth rates ( Davis et al ., 2013 ). Nevertheless, it is clear that African-American women have a greater chance of being affected by uterine fibroids, particularly at an earlier age ( Wise et al ., 2004 , 2005 ; Wise and Laughlin-Tommaso, 2016 ). Among women of African origin living in Europe, a similar trend has been observed, with more severe symptoms and surgery required at a younger age. Moreover, recurrence rates after surgery (myomectomy) may be as high as 59% after an interval of 4–5 years ( Malone, 1969 ; Donnez et al ., 2014a , b ) for women of African origin.

Peddada et al . (2008) followed the size of 262 leiomyomas from 72 women for up to 12 months using magnetic resonance imaging (MRI). The average growth rate was 9% over 6 months, but growth rates differed between races when age was taken into account. White women under 35 years of age had faster-growing tumors than white women over 45, who exhibited a comparatively slow growth rate. On the other hand, women of African origin did not show any decrease in myoma growth rates with age.

Moreover, delaying the first pregnancy until the third decade of life also places women at higher risk of uterine fibroids ( Petraglia et al ., 2013 ).

Early menarche

Menarche at an early age increases the risk of developing fibroids and is also considered a risk factor for other hormonally mediated diseases, such as endometrial and breast cancers ( Kim and Sefton, 2012 ; Khan et al ., 2014 ).

Pregnancy has been found to have a protective effect on the development of uterine fibroids, but the mechanism remains unclear. It has been suggested that during post-partum uterine remodeling, small lesions may be subject to selective apoptosis. Furthermore fibroid tissue may be highly susceptible to ischemia during both uterine remodeling and parturition ( Baird and Dunson, 2003 ; Laughlin et al ., 2010 ).

Caffeine and alcohol

An association has been reported between alcohol and caffeine intake and an increased risk of developing uterine fibroids in a study concerning the health of women of African origin ( Wise et al ., 2004 ; Wise and Laughlin-Tommaso, 2016 ).

Genetic factors

Some specific genetic alterations are linked to fibroid growth ( Mäkinen et al ., 2011 ; Eggert et al ., 2012 ; Islam et al ., 2013 ; Mittal et al ., 2015 ; Styer and Rueda, 2015 ). Mehine et al . (2013) performed whole genome sequencing and gene expression profiling of 38 uterine leiomyomas and corresponding myometrium. The common occurrence of chromothripsis in uterine fibroids suggests that it also plays a role in their genesis and progression ( Mehine et al ., 2013 , 2014 ).

Other factors

General health status may also be predictive of leiomyoma growth, with factors such as obesity and high blood pressure playing a role. A diet rich in red meat appears to increase the risk of developing leiomyomas, while smoking decreases the risk, for unknown reasons ( Kim and Sefton, 2012 ; Islam et al ., 2013 ).

Classifications

Numerous classifications of myomas can be found in the literature ( Lasmar et al ., 2005 ; Stamatellos and Bontis, 2007 ). All of them take into account the degree of intramural extension and/or uterine cavity distortion. The fibroid classification adopted by the ESGE (European Society for Gynecological Endoscopy) has the advantage of being very simple (G0 is a pedunculated intrauterine myoma, G1 has its largest part (>50%) in the uterine cavity, and G2 has its largest part (>50%) in the myometrium).

FIGO classification of uterine fibroids according to Munro et al . (2011) . Fibroid types range from 0 to 8. 0 = Pedunculated, intracavitary; 1 = Submucosal, <50% intramural; 2 = Submucosal, ≥50% intramural; 3 = Contact with endometrium, 100% intramural; 4 = Intramural; 5 = Subserosal, ≥50% intramural; 6 = Subserosal, <50% intramural; 7 = Subserosal, pedunculated; 8 = Other (e.g. cervical, parasitic). Where two numbers are given (e.g. 2–5), the first number refers to the relationship with the endometrium, while the second number refers to the relationship with the serosa; e.g. 2–5 = Submucosal and subserosal, each with less than half the diameter in the endometrial and peritoneal cavities respectively. Fibroid classification cartoon republished with permission from Munro et al . (2011) .

Many fibroids are asymptomatic, but in 30–40% of cases, they show a variety of symptoms, depending on the location and size. Fibroids can cause heavy menstrual bleeding with subsequent anemia, which could be life-threatening ( Parker, 2007 ; Nelson and Ritchie, 2015 ). African-American women have more severe symptoms in terms of heavy bleeding and anemia compared to white women ( Stewart et al ., 2013 ). Large fibroids can also result in pressure symptoms (bulk symptoms) that may be responsible for bowel and bladder dysfunction, including urgency, increased daytime urinary frequency and urinary incontinence ( Gupta et al ., 2008 ). Abdominal distention or distortion and pelvic pressure on the ureters (causing hydronephrosis) and pelvic blood vessels (particularly pelvic veins) could also interfere with quality of life (QoL) ( Spies et al ., 2002 ; Donnez et al ., 2014a , b ).

Dysmenorrhea and pelvic pain are frequently encountered, impacting on QoL and impairing daily activities ( Spies et al ., 2002 ). Infertility and recurrent miscarriage may also be symptoms of fibroids, depending on their location and size, especially for submucous and intramural myomas distorting the uterine cavity ( Pritts et al ., 2009 ; Sunkara et al ., 2010 , Yan et al ., 2014 ; Zepiridis et al ., 2015 ).

Fibroids can impair fertility through several possible mechanisms, including: (1) alteration of the local anatomy (anatomic distortion of the uterine cavity), with subsequent alterations to endometrial function ( Somigliana et al ., 2007 ); (2) functional changes, such as increased uterine contractility and impairment of the endometrial and myometrial blood supply ( Donnez and Jadoul, 2002 ) and (3) changes to the local hormone milieu and paracrine molecular changes induced by fibroids, which could impair gamete transport and/or reduce blastocyst implantation ( Sinclair et al ., 2011 ; Galliano et al ., 2015 ).

Moreover, fibroids can affect obstetric outcomes. Inflammatory pathways, associated or not with other reproductive disorders, may impair pregnancy outcomes ( Vannuccini et al ., 2016 ). Fibroids are significantly associated with preterm delivery (<37 weeks), primary cesarean section, breech presentation and lower birthweight infants ( Shavell et al ., 2012 ; Lam et al ., 2014 , Parazzini et al ., 2015 ; Blitz et al ., 2016 ). Very recently, a higher incidence of short cervix was also observed during pregnancy in women with fibroids ( Blitz et al ., 2016 ).

Pelvic examination

Examination of the pelvis may reveal an enlarged uterus or mass. If fibroids are suspected and a woman reports heavy menstrual bleeding, a hemoglobin evaluation will allow detection of iron deficiency anemia.

Ultrasonography

An ultrasound is the gold standard test for uterine fibroids. Its widespread availability enables easy and inexpensive confirmation in almost all instances. Moreover, ultrasonography after infusion of saline into the uterine cavity can delineate submucous myomas and indicate the proximity of intramural myomas to the endometrial cavity ( Seshadri et al ., 2015 ). The advent of 3D imaging technology has seen 3D ultrasound establishes itself as a useful tool for the investigation of myometrial pathology due to its ability to reconstruct the coronal plane of the uterus ( Andreotti and Fleischer, 2014 ; Wong et al ., 2015 ).

Hysteroscopy

A hysteroscopy may be required to differentiate intracavitary myomas and large endometrial polyps ( Bettocchi et al ., 2003 ; Di Spiezio Sardo et al ., 2010 ; Parazzini et al ., 2015 ). Hysteroscopy is usually performed in an outpatient setting and does not require any anesthesia ( Bettocchi et al ., 2003 ). Ultrasonography with saline infusion and diagnostic hysteroscopy should be considered more as complementary examinations when hysteroscopic myomectomy is indicated. Of course, in case of irregular bleeding or if the patient has risk factors for endometrial hyperplasia (obesity, chronic anovulation), hysteroscopy may be combined with an endometrial biopsy.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) of fibroids. Midline sagittal T2-weighted images show different types of myomas according to the FIGO classification ( Munro et al ., 2011 ). Fibroids vary in size, number and site in the uterus. (A) Submucosal type 2 myoma. (B) Large type 2–5 myoma (white arrow): submucosal and subserosal, each with less than half the diameter in the endometrial and peritoneal cavities respectively. Subserosal type 5 myomas (subserosal, > 50% intramural) (black arrows). (C) Submucosal type 2 myoma ( > 50% intramural) (white arrow). Intramural type 4 myoma (arrowhead). Small type 5 myomas (black arrows). (D) Multiple myomas, three of which are type 0 (intracavitary) (white arrows).

As stressed by Stewart (2015) , there are areas of uncertainty surrounding the management of myomas, as only a few randomized trials have compared different therapies for fibroids. Moreover, data on their comparative effectiveness in terms of future fertility are lacking. There are also inadequate data on long-term outcomes in women who have undergone hysterectomy according to indication ( Stewart, 2015 ). Prospective data and studies are essential to compare different options and evaluate long-term outcomes with regard to QoL, recurrence of symptoms (bleeding, bulk symptoms), fertility and even complications.

Indeed, in a cohort study of 30 117 Nurse's Health Study participants undergoing hysterectomy for benign disease, bilateral oophorectomy was found to be associated with increased mortality in patients under 50 years of age who had never used estrogen therapy ( Parker et al ., 2013 ).

While guidelines exist in the literature ( ACOG, 2008 ; ASRM, 2008 ; Marret et al ., 2012 ; Stewart, 2015 ), the risks and benefits of each option should be discussed with the patient. It should also be stressed that many other factors need to be taken into account, including the skill of the surgeons involved, as well as the experience of different centers in the available techniques.

Current surgical and non-surgical management strategies of myomas. Left panel: hysterectomy, laparoscopic myomectomy and hysteroscopic myomectomy are the most widely used surgical interventions for myomas. Right panel: alternatives to surgical intervention include uterine artery embolization (UAE), high-frequency magnetic resonance-guided focused ultrasound surgery (MRgFUS) and vaginal occlusion of uterine arteries.

Hysteroscopic myomectomy

Over the last 30 years, advances in instruments and techniques have promoted hysteroscopic myomectomy to the rank of a standard minimally invasive surgical procedure for submucous myomas. Small fibroids (<2 cm) are now routinely removed in an outpatient setting according to the technique described by Bettocchi ( Bettocchi et al ., 2003 , 2004 ; Di Spiezio Sardo et al ., 2010 ; Casadio et al ., 2011 ; Mazzon et al ., 2015 ; Vilos et al ., 2015 ).

Depending on personal experience and available equipment, the gynecologist has a choice of several alternative procedures.

The first involves cutting the base of pedunculated fibroids with either the resectoscopic loop or laser fiber ( Stamatellos and Bontis, 2007 ; Bettocchi et al ., 2004 ; Di Spiezio Sardo et al ., 2008 ; Tan and Lethaby, 2013 ). The base of the pedicle is cut and the fibroid is extracted by forceps or may be left in place.

The second alternative is a complete excision of fibroids by a one-step procedure ( Di Spiezio Sardo et al ., 2008 , 2015 ). The most commonly used approach is the slicing technique. Repeated and progressive passage of the cutting loop allows the surgeon to cut the myoma into small chips. The operation is considered complete when the fasciculate fibers of the myometrium are visualized ( Donnez et al ., 1990 ; Bettocchi et al ., 2004 ; Di Spiezio Sardo et al ., 2015 ; Mazzon et al ., 2015 ; Saridogan, 2016 ). Hysteroscopic resection is effective and safe and should be considered the technique of choice for type 1 myomas. The development of intrauterine morcellators has facilitated the implementation of hysteroscopic myomectomy ( Lee and Matsuzono, 2016 ; Munro, 2016 ). If the myoma is large (>3 cm in diameter), there is an increased risk of operative complications (perforation, bleeding and fluid intravasation) and damage to surrounding myometrium due to use of electrosurgery. Interestingly, Casadio et al ., (2011 ) demonstrated that during surgery, myometrial thickness increases when myoma slices are removed, leading to protrusion of the intramural component into the uterine cavity.

The third alternative is myomectomy by a two-step procedure (for large type 1–3 myomas of according to the FIGO classification, Munro et al ., 2011 ). After resection or ablation of the protruded portion of the myoma during first-step hysteroscopy, the residual intramural component rapidly migrates to the uterine cavity, with a parallel increase in myometrial thickness, allowing complete and safe myoma excision during second-step hysteroscopy ( Donnez et al ., 1990 ; Bettocchi et al ., 2004 ; Stamatellos and Bontis, 2007 ; Tan and Lethaby, 2013 ; Di Spiezio Sardo et al ., 2008 , 2015 ).

With all the techniques described here, there is risk of fluid (glycine) absorption while using monopolar energy. This risk is avoided by use of bipolar or laser energy with saline solution.

Hysteroscopic myomectomy is effective for control of bleeding, but failures are reported and are often related to growth of fibroids in other sites, association of fibroids with adenomyosis, and incomplete treatment of large intramural (partially submucous) myomas ( Pritts, 2001 ; Pritts et al ., 2009 ; Donnez and Jadoul, 2002 ; Donnez et al ., 2014a ; Parazzini et al ., 2015 ).

In terms of reproductive outcomes, most studies are retrospective ( Bosteels et al ., 2010 , a , b ). They report post-surgery pregnancy rates ranging from 16.7% to 76.9%, with a mean of 45% ( Donnez et al ., 2014a) . Their robustness could be criticized ( Metwally et al ., 2011 , 2012 ), but the authors of a recent review ( Bosteels et al ., 2015 ) acknowledge that the benefits of hysteroscopic removal of submucous myomas for improving the chances of pregnancy ‘cannot be excluded’. In addition, one prospective randomized study ( Casini et al ., 2006 ) has provided good-quality evidence that surgical therapy (hysteroscopic myomectomy) yields higher pregnancy rates than alternative treatments in women with submucous myomas.

Laparoscopic myomectomy

Laparoscopic myomectomy is perceived by many gynecological surgeons to be more difficult, but the advantages are real: less severe post-operative morbidity, faster recovery with laparoscopic procedures and no significant difference between reproductive outcomes after laparoscopic or abdominal myomectomy (by minilaparotomy) ( Donnez et al ., 2014a , b ; Bhave Chittawar et al ., 2014 ; Segars et al ., 2014 ). However, there have been reports of uterine rupture after laparoscopic myomectomy, thus emphasizing the importance of adequate closure of the myometrial defect ( Dubuisson et al ., 2000 ; Parker et al ., 2010 ; Thomas et al ., 2010 ). In a review of nine trials including 808 patients ( Bhave Chittawar et al ., 2014 ), there was no evidence of any difference in recurrence risk between laparoscopy and open myomectomy.

Usually, a 10 mm scope and two or three ancillary ports are used, although some gynecologists prefer a 5-mm scope. Depending on the site of the myoma, either a vertical (longitudinal) or a transversal incision is made. In the majority of cases, a unipolar hook probe is utilized, but CO 2 laser myomectomy is also performed in some departments. In certain cases, uterine artery ligation may be beneficial to reduce intraoperative bleeding ( Hald et al ., 2004 ; Liu et al ., 2007 ; Alborzi et al ., 2009 ; Thomas et al ., 2010 ; Bae et al ., 2011 ; Donnez et al ., 2014a ). Robotic laparoscopic myomectomy has been evaluated in a few retrospective series ( Gargiulo et al ., 2012 ; Pitter et al ., 2013 ; Lewis et al ., 2015 ) but no prospective study has been published yet and considerable scepticism remains about the real advantages of the technique ( Carbonnel et al ., 2014 ).

Leiomyomas are usually removed with a morcellator, although some gynecologists propose vaginal removal through the cul-de-sac of Douglas or minilaparotomy to avoid the risk of dispersing tissue fragments during sarcoma morcellation. The risk of uterine fragment dispersion with the subsequent appearance of pelvic adenomyotic masses and parasitic leiomyomas was described in 2006 ( Donnez et al ., 2006 , 2007 ) and remains a concern. This complication can be avoided by extensive peritoneal lavage and careful removal of all the fragments ( Donnez et al ., 2007 ), even if some authors still have misgivings ( Pereira et al ., 2015 ). Indeed, since their first publication, Donnez et al . no longer encountered this complication in a subsequent series of 400 laparoscopic hysterectomies (LHs), when caution was exercised and attention was paid to examine all areas of the abdominal cavity by placing the patient in the Trendelenburg and anti-Trendelenburg position and by extensive lavage ( Donnez and Donnez, 2010 ). The risk of morcellation of uterine leiomyosarcomas has recently become a ‘hot’ topic, since the Food and Drug Administration (FDA) warned about the use of electromechanical power morcellation ( Ton et al ., 2015 ; Parker et al ., 2015 , 2016 ). It should nevertheless be stressed that the prevalence of sarcoma in leiomyomas is <0.3% and the debate on the use of electric morcellation has probably been overstated, not only because of the fear of medicolegal issues but also due to emotional reasons ( Donnez et al ., 2014a , b ; Parker et al ., 2016 ). In a recent study ( Bojahr et al ., 2015 ), the prevalence of sarcoma was just 0.06% in a series of 10 731 uteri morcellated for myomas during LH. Of course, we should do all we can to improve the diagnosis of sarcoma, but a similar low incidence (1/2000) was observed in a very recent meta-analysis by Pritts et al ., (2015) and in a retrospective study including 4791 women in Norway ( Lieng et al ., 2015 ). Another meta-analysis by Brohl et al . (2015) concluded that leiomyosarcomas are diagnosed unexpectedly after surgery for what are presumed to be benign fibroids in 1 in 340 women, and that risks increase with age from less than one case per 500 women aged under 30 years to 1 in 98 women aged 75–79 years.

The technique of power morcellation in a bag was recently suggested to minimize the risk of inadvertent tissue spread ( Kanade et al ., 2014 ; Kho and Brown, 2015 ; Cholkeri-Singh and Miller, 2015 ), but there is no evidence that this technique will not increase the rate of post-operative complications ( Donnez et al ., 2014a , b ).

Contraindications to laparoscopic myomectomy usually include the presence of an intramural myoma >10–12 cm in size or multiple myomas (≥4) in different sites of the uterus, requiring numerous incisions.

The dimensions and localization of the main myoma are the principal criteria for choosing the laparoscopic approach ( Dubuisson et al ., 2000 ; Alessandri et al ., 2006 ; Palomba et al ., 2007 ; Nezhat et al ., 2009 ; Malzoni et al ., 2010 ; Thomas et al ., 2010 ; Donnez et al ., 2014a , b ; Segars et al ., 2014 ; Parazzini et al ., 2015 ). Thus, depending on the skill of the surgeon and his/her ability to suture the myometrial defect without delay, either laparoscopy or minilaparotomy may be selected.

In terms of infertility, several non-controlled studies have suggested that myomectomy yields a decrease in the miscarriage rate in women with myomas distorting the uterine cavity ( Saravelos et al ., 2011 ; Bernardi et al ., 2014 ; Parazzini et al ., 2015 ).In a review of prospective and retrospective studies, Donnez and Jadoul reported a pooled pregnancy rate of 49% (95% CI 46–52) in patients who underwent laparoscopic myomectomy ( Donnez and Jadoul, 2002 ). In another review by Somigliana et al . (2007 ), the post-operative pregnancy rate was 57%. These post-myomectomy pregnancy rates have been confirmed by other studies, but the lack of randomized trials represents a serious drawback ( Galliano et al ., 2015 ). However, it should be pointed out that there are no significant differences in cumulative pregnancy rates or obstetric or perinatal outcomes when laparoscopic and abdominal myomectomy are compared ( Metwally et al ., 2011 ; Fukuda et al ., 2013 ; Shen et al ., 2015 ; Tian et al ., 2015 ).

Laparoscopic hysterectomy

Hysterectomy has long been considered standard surgical treatment for symptomatic intramural and submucous fibroids, particularly for women not wishing to conceive or those of premenopausal age (40–50 years). In the US, more than 600 000 hysterectomies are performed each year ( Flynn et al ., 2006 ). In Denmark, the overall hysterectomy rate was around 180/100 000 women during the period 1977–2011 ( Lykke et al ., 2013 ).

Fibroids are the main indication for hysterectomy and, in the last decade, LH has become the ideal surgical approach to replace laparotomy. In some departments, the rate of LH exceeds 90% ( Donnez et al ., 2009 ). Vaginal hysterectomy (VH) still remains indicated in some conditions, depending on the skill and habits of the surgeon ( Aarts et al ., 2015 ).

Some studies have reported an increased risk of complications after LH ( Johnson et al ., 2005 ; Aarts et al ., 2015 ), but in a very large series, Donnez et al ., (2009 ) found a similar complication rate after LH, VH and abdominal hysterectomy (0.44% of major complications). In a personal prospective series of 400 cases, no major complications were encountered ( Donnez and Donnez, 2010 ). Of course, as stressed by the authors, uterine volume of ≥13–14 weeks represents a relative contraindication. A very recent study demonstrated that in some conditions, hospitalization for LH could be less than 5 h ( Donnez et al ., 2015c ).

Some ‘in bag’ morcellation techniques, one of them called the Sydney technique, were developed to address the concerns of morcellating large myomatous uteri after total or subtotal hysterectomy ( Mc Kenna et al ., 2014 ) but, as stressed earlier, no large studies have demonstrated any real benefit in terms of general safety. Moreover, the risk of leiomyosarcoma morcellation during LH must be weighed against procedure-related complications associated with laparotomy, including mortality ( Siedhoff et al ., 2015 ).

Laparoscopic cryomyolysis and thermo-coagulation

Both laparoscopic cryomyolysis and thermo-coagulation have the same goal: reduction or suppression of the primary blood supply and induction of myoma shrinkage by causing sclerohyaline degeneration (by very low or very high temperatures).

For cryomyolysis, a cryoprobe is inserted into the myoma and cooled to a temperature of <90°C ( Zupi et al ., 2004 ; Exacoustos et al ., 2005 ). For laparoscopic thermocoagulation, either a monopolar or bipolar probe is inserted into the myoma before delivering the electrical current. In some studies, laser fibers (YAG) have also been used ( Donnez et al ., 2000 ). The limitation of all of these techniques is the lack of histological evaluation of the fibroids ( Zupi et al ., 2015 ).

Laparoscopic occlusion of the uterine arteries

Laparoscopic occlusion of the uterine arteries appears to have no specific advantage over vaginal occlusion, as it requires a laparoscopic approach. Moreover, when compared to UAE, the outcomes were found to be inferior in terms of myoma size reduction and devascularization ( Hald et al ., 2004 ).

The alternatives to surgical interventions are illustrated on the right-hand side of Fig. 4 .

Uterine artery embolization

Although rapidly adopted by enthusiasts, the introduction of UAE has varied widely across the globe ( Moss and Christies, 2016 ). This technique was first used in 1995 ( Ravina et al ., 1995 ) to treat uterine fibroids in women wishing to preserve their uterus.

UAE constitutes complete uterine therapy, as most fibroids are supplied by the uterine arteries. In UAE, percutaneous ablation of the fibromatous uterus is applied to induce ischemic necrosis of the fibroids, while the myometrium revascularizes. Most fibroids are targeted simultaneously. UAE has been shown, in randomized trials, to result in QoL similar to that achieved after surgery, but with a shorter hospital stay and earlier resumption of normal activities ( Gupta et al ., 2012 , 2014 ).

Although UAE is highly effective for treating symptoms (reduction in bleeding and fibroid size), the risk of reoperation is a reality: 15–20% after successful embolization and up to 50% in cases of incomplete infarction ( Kroencke et al ., 2010 ; Gupta et al ., 2014 ; Mara and Kubinova, 2014 ; Vilos et al ., 2015 , Spies, 2016 ). Among possible complications, abdominal pain due to ischemic necrosis of fibroids and risk of infection should not be overlooked ( Goodwin and Spies, 2009 ). The impact of UAE on the ovarian reserve is another concern ( Gupta et al ., 2014 ), but a systematic review of 15 randomized trials and prospective cohort studies demonstrated that loss of ovarian function occurred primarily in women over 45 years of age ( Kaump et al ., 2013 ). In a very recent review, Zupi et al . (2015) clearly detailed the results and complications of UAE. It was emphasized that a desire for future pregnancy is a relative contraindication, as the lack of data in the literature cannot ensure a good pregnancy outcome. In a randomized controlled trial (RCT) comparing UAE and myomectomy, surgical removal had a more favorable outcome than UAE in terms of pregnancy rate (78% vs 50%), delivery rate (48% vs 19%), and abortion rate (23% vs 64%) ( Mara et al ., 2008 ).

Gupta's article in the Cochrane Database of Systematic Reviews ( Gupta et al ., 2014 ) evaluated seven RCTs comparing UAE and surgery (abdominal hysterectomy or myomectomy). The authors clearly stated that there were limitations in the evidence. The main limitations of the studies were a serious lack of precision due to wide confidence intervals, failure to clearly report methods, and the absence of blinding for subjective outcomes. They also estimated that between 15% and 32% of subjects would require further surgery within two years of UAE.

Several trials comparing UAE and myomectomy and UAE with focused ultrasound are currently ongoing, whose outcomes are awaited ( Stewart, 2015 ).

High-frequency magnetic resonance-guided focused ultrasound surgery

High frequency magnetic resonance-guided focused ultrasound surgery (MRgFUS) is thermal ablation using MRI to visualize the myoma and define the target. Ultrasonic energy is directed to a point inside the fibroid and coagulation tissue necrosis is induced in the myoma. In theory, damage to surrounding tissue is minimal ( Clark et al ., 2014 ; Park et al ., 2014 ) but, in fact, the impact on critical neighboring structures cannot be excluded ( Fischer et al ., 2015 ; Kim et al ., 2015 ).

As stressed by Zupi et al . in their review ( 2015 ), hyperintensive MRI images are associated with reduced treatment success compared with hypointensive images of fibroids. The principal limitations to the use of MRgFUS are that (i) only a fraction of patients with fibroids meet the inclusion criteria, (ii) future fertility may be compromised and (iii) the financial burden may be too heavy.

The literature is still scarce on this topic and additional studies are needed to evaluate safety profiles ( Zupi et al ., 2015 ). In a recent study, 30% of women underwent further fibroid surgery or procedures two years after MRgFUS ( Jacoby et al ., 2015 ). Screening and MRI-based prediction models for assessing therapeutic responses may reduce the risk of treatment failure ( Kim et al ., 2016 ). Several non-controlled clinical trials ( Rabinovici et al ., 2010 ; Berman et al ., 2015 ) have reported pregnancies after MRgFUS, but a recent review by Clark et al . (2014) found a high rate of complications in the 34 documented pregnancies.

Vaginal occlusion of the uterine arteries

Occlusion of the uterine arteries with a clamp-like device that remains in place for 6 h leads to myoma ischemia by interfering with the blood supply to the uterus ( Hald et al ., 2004 ). However, this technique is not recommended for women wishing to conceive in the future.

In a study by Vilos et al . (2006) , dominant fibroid volume decreased by 24% and heavy bleeding symptoms decreased by 51%. Here too, research with larger populations is needed to prove the efficacy of the technique.

Fibroids are highly prevalent and represent a high health burden. Indeed, about 30% of women with leiomyomas will request treatment due to morbidities such as heavy menstrual bleeding, abdominal pain, pressure symptoms and/or infertility. Current treatments are mainly surgical and expensive. Among 600 000 hysterectomies performed each year in the USA, 200 000 are for fibroids ( Flynn et al ., 2006 ). In a study by Flynn et al . (2006) , health care costs for the management of leiomyomas were estimated to be over $2 billion per year. There is no doubt that fibroids have a significant economic impact ( Cardozo et al ., 2012 ; Soliman et al ., 2015 ), but the cost of therapy both to the health care system and women with fibroids must be balanced against the cost of untreated disease conditions, as well as the cost of ongoing or repeated investigations and treatment modalities ( Vilos et al ., 2015 ). Despite the lack of relevant medico-economic evaluations of the different therapeutics, it is likely that reducing the number of hysterectomies and other surgical procedures will reduce costs and morbidity. It is therefore necessary to develop and evaluate alternatives to surgical procedures especially when fertility preservation is the goal ( Donnez et al ., 2014 , a , b ).

Two recent Cochrane Reviews on the use of herbal preparations ( Liu et al ., 2013 ) and aromatase inhibitors ( Song et al ., 2013 ) concluded that there was no evidence to support the use of herbal preparations or aromatase inhibitors as medical therapy for treating myomas. However, as reviewed by Islam et al . (2013 , 2014 ), there is evidence to suggest that certain dietary or alternative treatments like phytochemical herbal preparations may be effective. In addition, some synthetic and natural compounds as well as growth factors are now under laboratory investigation ( Islam et al ., 2013 ), while observational data suggest that increased consumption of fruits, vegetables and low-fat dietary products are associated with a reduced risk of developing fibroids ( Wise et al ., 2011 ). Nevertheless, some uncertainty remains due to insufficient high-quality studies with large enough sample sizes.

GnRH agonists

Mode of action of GnRH agonists and SPRMs (Selective Progesterone Receptor Modulators). GnRH agonists have a direct impact on the pituitary. SPRMs have a direct impact on fibroids, endometrium and the pituitary.

Use of GnRH agonist before surgery is still a matter of debate, but a review by Gutmann and Corson ( Gutmann and Corson, 2005 ) reports that ‘preoperative use of GnRH agonist appears to be relevant and beneficial in patients with submucous fibroids’. Benefits include a resolution of preoperative anemia ( Donnez et al ., 1989 ; Lethaby et al ., 2001 ; Stamatellos and Bontis, 2007 ; Doherty et al ., 2014 ); a decrease in fibroid size ( Donnez et al ., 1989 ; Lethaby et al ., 2001 ); a reduction of endometrial thickness and vascularization with subsequently improved visibility and reduced fluid absorption ( Donnez and Jadoul, 2002 ; Metwally et al ., 2011 ; Doherty et al ., 2014 ) and the possibility of surgical scheduling ( Donnez et al ., 1990 ; Donnez and Jadoul, 2002 ; Pritts, 2001 ; Pritts et al ., 2009 ). Conversely, this preoperative treatment is associated with post-injection endometrial bleeding due to the flare-up effect.

Evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids by use of selective progesterone receptor modulators

To date, genetic and epigenetic factors, sex steroids, growth factors, cytokines, chemokines and ECM components have been identified as being implicated in the pathogenesis of leiomyomas ( Bulun, 2013 ; Islam et al ., 2013 ; Marsh et al ., 2015 ; Protic et al ., 2015 ; Yin et al ., 2015 ). Many growth factors and also activin and myostatin play a role in the mechanisms involved in the development of leiomyomas ( Ciarmela et al ., 2011a , b ; Protic et al ., 2015 ). Of course, estrogen and progesterone and their respective receptors also have a very significant impact on leiomyoma growth ( Kim and Sefton, 2012 ). Recently, Wong et al . (2016) demonstrated that testosterone was additionally implicated in the growth of uterine fibroids. In vitro studies have also shown that fibroid development depends on miRNA regulation of gene targets which impact cellular processes ( Karmon et al ., 2014 ). The initial event that triggers the first stages of tumorigenesis nevertheless involves somatic mutations ( Kim and Sefton, 2012 ).

In the past, estrogen was considered to be the major growth factor in myoma development. However, already in the 1990s, a number of studies reported increased the expression of both progesterone receptor A (PR-A) and progesterone receptor B (PR-B) in leiomyoma tissue ( Englund et al ., 1998 ; Nisolle et al ., 1999 ) compared with adjacent normal myometrium. Very recently, Tsigkou et al . showed that PR-B mRNA and PR-A and PR-B proteins were more concentrated in leiomyomas than in matched myometrium ( Tsigkou et al ., 2015 ). Levels of PR-B mRNA in leiomyoma tissue were directly associated with the number of myomas, but inversely correlated with the intensity of symptoms. Moreover, higher proliferative activity, demonstrated by proliferating cell nuclear antigen (PCNA) and the mitotic index, was observed in leiomyomas during the luteal (secretory) phase ( Nisolle et al ., 1999 ). There is evidence from preclinical and clinical trials, as well as from histological and pharmacological studies, that progesterone and its receptors play a key role in uterine fibroid growth ( Bouchard et al ., 2011 ; Bouchard, 2014 ; Chabbert-Buffet et al ., 2011 , 2012 , 2014 ; Kim and Sefton, 2012 ; Bestel and Donnez, 2014 ; Moravek et al ., 2015 ). In a review, Kim and Sefton (2012) described, in detail, the activation of signaling pathways in leiomyomas by both estrogen and progesterone. Progesterone is able to cause rapid, membrane-initiated effects, independent of gene transcription, that alter the production of second messengers involved in cell signaling transduction pathways. The PI3K/AKT pathway is mediated by progesterone which, through its receptors, can quickly activate this pathway, which is increasingly considered to be a potential promoter of leiomyoma growth. PTEN, on the other hand, should be considered as a negative regulator of AKT ( Kim and Sefton, 2012 ). Progesterone and growth factor signaling pathways are interconnected and govern numerous physiological processes such as proliferation, apoptosis and differentiation.

Progesterone can modulate the expression of growth factor signaling proteins and is implicated in the regulation of genes associated with proliferation and apoptosis, but these genes have not yet been fully identified or studied in detail ( Islam et al ., 2013 ; Kim and Sefton, 2012 ; Moravek et al ., 2015 ). There is therefore evidence that progesterone plays a crucial role, but the mechanism by which it promotes proliferation, the repertoire of genes involved, and how it crosstalks with growth factor signaling pathways all need to be investigated in greater depth. The recent discovery of stem cells and their paracrine interactions with more differentiated cell populations within leiomyoma tissue may lead to the development of therapeutics that temper leiomyoma growth as well as those that eradicate them ( Moravek et al ., 2015 ).

Having established the crucial role of progesterone in the growth and development of myomas, we can modulate the progesterone pathway by use of selective progesterone receptor modulators (SPRMs) ( Chabbert-Buffet et al , 2005 , 2011 , 2015 ; Bouchard et al . 2011 ; Bouchard, 2014 ; Kim and Sefton, 2012 ; Bestel and Donnez 2014 ; Donnez et al ., 2012a , b ). SPRMs are synthetic compounds that exert either an agonistic or antagonistic effect on PRs (Fig. 5 ). Their binding allows these receptors to interact with coactivators and/or corepressors, and this is further impacted by the presence of coregulators in a particular cell type, which will dictate whether an SPRM acts more as an agonist or antagonist ( Chabbert-Buffet et al ., 2005 , 2011 ). Hence, the mechanism of action of SPRMs on PRs depends on their structure and how they alter the PR conformation, resulting in exposure or inactivation of particular binding domains. Their activity is also mitigated by tissue types and physiological contexts ( Kim and Sefton, 2012 ; Bouchard, 2014 ; Moravek et al ., 2015 ).

SPRMs and fibroids: what we know so far

Four members of the family of compound SPRMs have been investigated in phase II clinical trials: mifepristone, asoprisnil, ulipristal acetate (UPA) and telapristone acetate ( Spitz, 2009 ; Bouchard et al ., 2011 ; Bouchard, 2014 ; Chabbert-Buffet et al ., 2011 ; Nieman et al ., 2011 ; Shen et al ., 2013 ; Whitaker et al ., 2014 ). All were shown to decrease leiomyoma size and reduce uterine bleeding in a dose-dependent manner. However, although three studies ( Fiscella et al ., 2006 ; Engman et al ., 2009 ; Bagaria et al ., 2009 ) showed a myoma volume reduction of ±30%, a review of the literature by Tristan et al . (2012) (Cochrane Review) found no clear evidence of this. Some follow-up studies have also raised concerns about unopposed estrogenic activity and liver toxicity ( Williams et al ., 2007 ; Spitz, 2009 ; Bouchard et al ., 2011 ; Chabbert-Buffet et al ., 2011 ; Tristan et al ., 2012 ).

The latest antiprogestin to be studied in large clinical trials, UPA, has shown promising results in terms of efficiency and safety. UPA was compared to a placebo and to leuprolide acetate (a GnRH agonist) in two randomized trials ( Donnez et al ., 2012a , b ). In these first clinical studies, uterine bleeding was controlled in more than 90% of patients receiving a three-month course of UPA, and the median times to control bleeding were shorter in the UPA group (5–7 days) than in the GnRH agonist group (21 days). The control of bleeding and subsequent correction of anemia were clinically relevant ( Barlow et al ., 2014 ; Donnez et al ., 2012a , b ). Indeed, it has been well documented that preoperative anemia, even to a mild degree, is associated with an increased risk of morbidity and mortality in patients undergoing surgery ( Mussalam et al ., 2011 ; Richards et al ., 2015 ). UPA was also found to have a sustained effect (up to six months) in women who did not undergo surgery after the three-month study period. By contrast, those treated with GnRH agonist experienced rapid regrowth of their fibroids, whose size reached pre-therapy dimensions by six months post-treatment ( Donnez et al ., 2012a , b ).

Importantly, the induced effects of SPRMs on the endometrium, now described as progesterone receptor modulator (PRM)-associated endometrial changes (PAECs) ( Mutter et al ., 2008 ) (Fig. 5 ), present in almost 70% of patients at the end of treatment, have proved to be benign and reversible, as they disappeared two months after the end of therapy ( Williams et al ., 2012 ; Donnez et al ., 2012a , b ). Safety has also been well documented in pharmacokinetic studies following multiple doses ( Pohl et al ., 2013 , 2015 ).

The mechanism of action by which SPRMs reduce menstrual blood loss in women with fibroids remains unknown ( Wilkens et al ., 2013 ), although a number of possible factors have been proposed by Williams et al . (2007 , 2012 ). Wilkens et al . (2013) reported that uterine NK cells regulate endometrial bleeding and were suppressed by asoprisnil.

Long-term intermittent administration of SPRMs, opening up new treatment perspectives

Because of the sustained effect observed in the first two trials (Donnez et al ., 2012a , b ), additional intermittent (12-week) courses of SPRMs with off-treatment intervals may be an alternative for long-term medical management of fibroids. The results of the first long-term intermittent administration study suggested that more than one course of SPRMs can maximize its potential benefits in terms of bleeding control and fibroid volume reduction ( Donnez et al ., 2014b ).

Effect on fibroid volume reduction after four courses of three months of ulipristal acetate (UPA) 5 mg daily. The off-period between two courses was two natural cycles.

The safety profile of UPA during multiple treatment courses was well documented in this study ( Donnez et al ., 2015 , a , b , c ). Safety assessments, including vital signs, physical examinations and laboratory analyses, as well as reported adverse events (AEs) both on and off treatment, showed repeated intermittent administration of UPA to be well tolerated. The vast majority of AEs (97.6%) were of mild or moderate severity. Headaches and hot flushes were the most frequently reported AEs (less than 11% of subjects in any treatment course), but the frequency of these events decreased with each additional treatment course. Breast pain or discomfort was observed in 3% of subjects. In this series of 451 women ( Donnez et al ., 2015b , c ), serious AEs related to medication included five cases of menorrhagia, one bipolar disorder, one spontaneous myoma expulsion, one abdominal pain and one back pain. No safety concerns were identified from physical examination, vital signs, ovarian ultrasound or electrocardiogram (ECG).

Based on the available data related to endometrial safety after up to four treatment courses, no increased occurrence of more serious conditions of the endometrium, such as hyperplasia with atypia or endometrial carcinoma, was noted. The frequency of SPRM-associated non-physiological endometrial changes (PAEC) did not appear to increase with repeated treatment courses, reaching 13.3% after a fourth treatment course, and returning to pretreatment levels within three months of completion of treatment. These data further confirm the rapid reversibility of PAEC following completion of treatment and subsequent menstruation. It is reassuring that median endometrial thickness (7–8 mm) was similar to screening levels after single and multiple treatment courses and remained stable during post-treatment follow-up (three months after treatment cessation).

A recent study by Courtoy et al . suggested an important role of UPA in collagen degradation induced by matrix metalloproteinase 2 (MMP-2), offering an explanation for the sustained beneficial effect. Indeed, this study strongly points to multifactorial mechanisms of action involving: (1) a persistently low cell death rate; (2) a limited period of cell death and (3) ECM remodeling concomitant with stimulation of MMP-2 expression ( Courtoy et al ., 2015 ).

An in vitro study demonstrated another possible mechanism of action of UPA: inhibition of activin A expression and function in cultured leiomyoma cells ( Ciarmela et al ., 2014 ).

Novel approaches and algorithms, with a special emphasis on infertility

There is a clear need for alternatives to surgery, even the less invasive endoscopic techniques, especially when fertility preservation is the goal ( Donnez et al ., 2014a , b ; Donnez et al . 2015b ). There is no doubt that surgery remains indicated in some instances, but we must now establish whether SPRMs (UPA) allow less invasive surgery or even complete avoidance of surgery. On the other hand, it is clear that long-term intermittent use of UPA will change our approach to the management of uterine fibroids.

To address the question of which therapy to adopt, it is crucial to consider key factors determining the management of uterine fibroids: patient age, severity of symptoms (pain, bleeding and infertility), wish to preserve the uterus and/or fertility, localization of fibroids according to FIGO classification and myoma volume. The approaches described below are according to the FIGO classification ( Munro et al ., 2011 ).

Type 0 myomas

Management of type 0 myomas. Hysteroscopic myomectomy is the most appropriate approach. Fibroid classification cartoon republished with permission from Munro et al . (2011) .

Type 1 myomas

Management of type 1 myomas. Depending on the myoma size, presence of anemia and the surgeon's skill, hysteroscopic myomectomy combined or not with ulipristal acetate(UPA) should be proposed. Fibroid classification cartoon republished with permission from Munro et al .(2011) .

Medical therapy may be given in one or two courses of three months. In the vast majority of cases, type 1 myomas respond to this preoperative therapy and regress in size, enabling an easier hysteroscopic approach in better conditions (recovery of hemoglobin). It should be pointed out that in some cases, myomas regress so much that surgery may be avoided.

Type 2 or type 2–5 myomas (single or multiple) distorting the uterine cavity

Young infertile women of reproductive age and wishing to conceive.

Management in case of myomas or multiple myomas (type 2–5) in women of reproductive age, according to desire for pregnancy. In cases of infertility, two courses of three months are recommended (left panel). Subsequent therapy is determined depending on the response to treatment and restoration of the uterine cavity. If there is no desire to conceive (right panel), long–term (four courses) intermittent therapy may be proposed. In case of a good response in terms of fibroid volume reduction and bleeding, treatment is stopped and only restarted if symptoms recur. Fibroid classification cartoon republished with permission from Munro et al . (2011) .

Considerable shrinkage of all myomas after four courses of intermittent ulipristal acetate (UPA) therapy. A patient aged 30 years presented with heavy menstrual bleedingand an unclear desire for pregnancy. (A) Before treatment, a midline sagittal T2-weighted magnetic resonance image (MRI) demonstrated the presence of multiple myomas: type 2, 3, 4 and 6. (B) Upon completion of treatment (intermittent UPA therapy (four courses of threemonths), the uterine cavity was no longer distorted. (C) One year after delivery of a healthy baby, no fibroid regrowth was observed after delivery.

The least outcome would be that the response to medical therapy is inadequate. In this case, surgery remains indicated.

Young women of reproductive age with symptomatic myomas and wishing to preserve their fertility but having no immediate desire for pregnancy

Important shrinkage of the submucosal myoma was obtained after two courses of three months of intermittent ulipristal acetate (UPA) therapy. (A) Coronal T2-weighted magnetic resonance image (MRI) image illustrated the presence of multiple myomas (type 2, type 2-5) distorting the uterine cavity in a 19-year-old nulligravid patient, who presented to the emergency department, with heavy menstrual bleeding and anaemia (haemoglobin level of 7.4 g/l).The patient received two courses of UPA (5 mg) and iron. (B) At the end of therapy, MRI demonstrated a significant reduction in myoma volume (<50%) and restoration of the uterine cavity. Amenorrhea was achieved, with a haemoglobin level of 11.9 g/l. The patient was free of symptoms and did not wish to conceive; therefore, surgery was avoided.

When there is no immediate wish to conceive, there is no pressing need for surgery (even if the uterine cavity remains distorted and/or large myomas are still present). In some cases, myomas will all but disappear. In case of symptom recurrence, medical therapy may be reinitiated. Myomectomy should only be considered when the patient wishes to become pregnant, and if really necessary according to the localization and volume of the fibroids still present. This is important to take into account, especially for women of African descent. Indeed, African and African-American women have a greater chance of developing symptomatic myomas at an earlier age than Caucasian women ( Baird et al ., 2003 ). It is widely known that the rate of recurrence of myomas after myomectomy can reach almost 60% after an interval of 4–5 years, and that the risk of pelvic adhesions is significantly increased after a repeated myomectomy ( Malone, 1969 ; Donnez et al ., 2014a ). Medical treatment with SPRMs can thus be beneficial, since long-term intermittent therapy (repeated in case of symptom recurrence during the interval) may help to avoid or at least postpone the need for surgery until the patient wishes to conceive (Fig. 11 ).

Surgery therefore remains indicated only when the patient wishes to conceive, and if large myomas (>3–4 cm) distorting the uterine cavity are present, as these could be the cause of her infertility.

Asymptomatic women with myomas and undergoing IVF or oocyte donation

A meta-analysis by Pritts et al . (2009) evaluating 23 studies showed a significant drop in pregnancy and implantation rates in the presence of myomas, especially submucous and/or intramural myomas distorting the uterine cavity. In another meta-analysis, Sunkara et al . (2010) demonstrated their impact on fertility, even in case of intramural myomas not distorting the uterine cavity. A recent study by Yan et al . (2014) confirmed that intramural fibroids >2.85 cm in size significantly decreased the delivery rate of patients undergoing IVF/intracytoplasmic sperm injection (ICSI).

Moreover, some centers have large cohorts of patients of more than 40 years of age in oocyte donation programs ( Cobo et al ., 2015 ). In this group of women, the prevalence of myomas is higher than in women of 30 years of age.

It could be proposed that patients with myomas be treated with one or two courses of SPRMs before IVF or oocyte donation, in order to reduce the size of myomas and restore the uterine cavity and subsequently improve implantation rates. Clinical trials evaluating UPA before IVF or oocyte donation should be initiated to investigate this further.

Premenopausal women presenting with symptomatic myomas and with no desire for pregnancy but a wish to keep their uterus

Management of type 2 to 5 myomas or multiple myomas (type 2–5) in premenopausal women wishing to preserve their uterus. In this case, long-term (four courses of three months) intermittent therapy with SPRMs is proposed. Fibroid classification cartoon republished with permission from Munro et al . (2011 ).

Our latest results ( Donnez et al ., 2015 , a , b , 2016 ) led us to slightly modify previously published algorithms ( Donnez et al ., 2014a , b ) for this group of women. Indeed, in subjects treated with 5 mg UPA for four courses of three months, the percentage of patients with a clinically significant volume reduction increased from 62.3% after 1 course to 78.1% after 4 courses, suggesting increased benefits with repeated courses. The percentage of women showing a clinically significant reduction of >50% also increased from course 1 (37.2%) to course 4 (63.8%). Moreover, the median PBAC score during the off-treatment period decreased with each subsequent course.

In case of a good response (characterized by a clinically significant volume reduction and/or control of bleeding), treatment can be stopped after four courses and the patient is re-evaluated ( Donnez et al ., 2015 , a , b , 2016 ). Repeated therapy may be proposed when the symptoms recur, as no endometrial hyperplasia was diagnosed in subjects who took 5 mg UPA for eight courses of three months. In this context, the goal is to reach menopause without the need for surgery. Data indicating that SPRMs exert an anti-proliferative effect in breast tissue are also reassuring ( Poole et al ., 2006 ; Engman et al ., 2008 ). Some studies reported anti-proliferative effects on the endometrium after SPRM courses of up to six months ( Wilkens et al ., 2009 ).

Uterine fibroid associated pathologies

Endometriosis and adenomyosis are frequently associated with uterine fibroids ( Donnez et al ., 2014a ).

Endometriosis

In theory, induction of amenorrhea in women treated with SPRMs should also relieve endometriosis-associated pain. In mammalian models, SPRMs stop prostaglandin production by endometriotic lesions ( Gemzeel-Danielson and Hamberg, 1994 ; Elger et al ., 2004 ) and this direct effect may also serve to reduce pain.

27 year-old women complaining of heavy menstrual bleeding and pelvic pain. A: Coronal T2-weighted MRI images illustrated the presence of type 2–5 and type 3 myomas distorting the uterine cavity and an endometrioma (indicated by X) of 4.3 cm in size. The white lines represent the diameter of the myomas. This patient received long-term intermittent therapy with 5 mg of UPA (2 courses of 3 months). B: At the end of therapy there was an important reduction in myoma volume, but not endometrioma volume.

The specific effects of SPRMs have yet to be determined in ectopic endometrium. Indeed, PAECs ( Williams et al ., 2007 , 2012 ; Mutter et al ., 2008 ) may be present in lesions, as observed in eutopic endometrium.

Adenomyosis

Adenomyomas and adenomyosis are two distinct clinical entities. Adenomyomas may respond very well to SPRMs, but severe full-thickness adenomyosis, characterized by the presence of numerous sites of ectopic endometrium in the myometrium of an enlarged uterus, is a specific entity that might have a completely different response.

SPRMs will probably be effective in reducing adenomyosis-associated pain by inducing amenorrhea, but are unlikely to be able to significantly reduce the size of the uterus. Clinical trials are ongoing to explore this particular context and the impact of endometrial modifications, as PAECs will also be present in ectopic intramyometrial endometrium.

Future prospectives for medical therapy

SPRMs have opened up new avenues to explore in fibroid medical therapy, to both treat symptoms and postpone or to eliminate the need for surgery. Future clinical trials should focus on prevention strategies, such as preventing occurrence in women genetically predisposed to this condition, and avoiding recurrence after surgery in women at high risk (i.e. those of a young age or with a family history) (Fig. 14 ).

New avenues are emerging in medical fibroid therapy. The first goal of medical therapy is clearly to treat symptoms resulting from the presence of fibroids (heavy menstrual bleeding, pelvic pain, bulk symptoms, infertility, etc.), as well as to postpone or avoid surgery. Further avenues should be investigated by randomized trials, looking to avoid recurrence after surgery in women at high risk of recurrence, and to prevent occurrence of myomas in genetically predisposed women.

On the other hand, the need for medical therapy remains a reality. It is indeed essential that new treatments be developed to be able to offer as there is a pressing need for alternatives to surgical intervention, particularly when fertility preservation is the goal.

GnRH agonists have been used to shrink fibroids and restore hemoglobin levels in symptomatic women, but because of their side effects, they cannot be used for long periods of time. However, there is now growing evidence of the crucial role of progesterone in pathways in the pathophysiology of uterine fibroids by the use of SPRMs. UPA (one member of the SPRM compound family) has been studied in large clinical trials and its long-term intermittent administration has been evaluated, yielding promising results for new treatment perspectives. It was found that more than one three-month course of UPA maximizes its potential benefits in terms of bleeding control and fibroid volume reduction. Hence, depending on age and symptoms (infertility, bleeding, etc.), SPRMs should be considered an alternative to surgical therapy, or at least an adjunct to surgery, in some circumstances, as illustrated in the algorithms.

Surgical, non-surgical and medical therapy for the management of fibroids: the current armamentarium.

The authors thank Dr. Latifa Fellah, MD, for the selection and preparation of MRI images, Mira Hryniuk, BA, for reviewing the English language of the manuscript and Deborah Godefroidt for her administrative assistance.

J.D. and M.M.D. contributed equally to the research and interpretation of data discussed in the manuscript and approved the final version.

No funding was received for this paper.

J.D. has been a member of the Scientific Advisory Board (SAB) of PregLem S.A. since 2007. He held PregLem stocks, related to SAB activities, that he sold in October 2010 upon PregLem's full acquisition by the Gedeon Richter Group. There was no relationship between the stock payment value and future commercial performance of the studied drug.

M.M.D. has no conflict of interest to declare.

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laparoscopy
fibroid tumor
surgical procedures, operative
uterine fibroids
uterine myomectomy
selective progesterone receptor modulator
medical management

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Home > ETD > DISSERTATIONS > AAI3544126

Mapping the cultural and social landscape of uterine leiomyomas: Fibroid tumors as a Black woman's disease

Sydney Janelle Dillard , Purdue University

In this dissertation, I explore a particular health issue called uterine fibroids (uterine leiomyomas), as it has been found to be the most common pelvic tumor occurring in all women in the US. The purpose of the dissertation is to explore how the social and cultural meaning of fibroid tumors are constructed in the narratives of African American women living with it within the localized context of Cook County, IL. Though proven to be prevalent in a large portion of women in the US, uterine fibroids have been found to be most prevalent in African American women and have been reported to be higher than 80%. Moreover, several epidemiological studies have shown that African American women are more likely than Caucasian women to have multiple fibroids, that are larger in diameter, with greater uterine weights, and more severe symptoms. Given this health issues physical, financial, and emotional burden in African American women's lives, my dissertation employs the theoretical framing of the culture-centered approach (CCA). CCA places emphasis on the need for investigating alternative entry points to interpreting health and the ways in which ideas of health are delivered, particularly within marginalized populations. Thus, the dissertation's primary goal is to allow African American women who have or have had the disease to provide alternative understandings of the health issue through their lived experience, thus leading towards change in the research agendas and funding of studies on women's reproductive health and pointing towards structural modifications as articulated by underserved populations.

Dutta, Purdue University.

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Introduction
Conclusions
Article Information

eAppendix. Assay Details for Cardiovascular Biomarkers

eReferences

eFigure 1. Study Timeline and Schematic

eFigure 2. Directed Acyclic Graph (DAG) Showing the Relationships Between Each Confounder, the Exposure (in This Example, Blood Pressure) and the Outcome (Self-Reported Fibroid Diagnosis)

eTable 3. Longitudinal Discrete Survival Models Estimate the Risk of Newly Diagnosed Fibroids Associated With Each Cardiovascular Risk Factor in the Study of Women’s Health Across the Nation (SWAN) Cohort

eTable 4. Longitudinal Discrete Survival Models Estimate the Risk of Newly Diagnosed Fibroids Associated With Each Cardiovascular Risk Factor in the Study of Women’s Health Across the Nation (SWAN) Cohort

eTable 5. Longitudinal Discrete Survival Models Estimate the Risk of Newly Diagnosed Fibroids Associated With Each Cardiovascular Risk Factor in the Study of Women’s Health Across the Nation (SWAN) Cohort

eTable 6. Longitudinal Discrete Survival Models Estimate the Risk of Newly Diagnosed Fibroids Associated With Each Cardiovascular Risk Factor in the Study of Women’s Health Across the Nation (SWAN) Cohort

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Mitro SD , Wise LA , Waetjen LE, et al. Hypertension, Cardiovascular Risk Factors, and Uterine Fibroid Diagnosis in Midlife. JAMA Netw Open. 2024;7(4):e246832. doi:10.1001/jamanetworkopen.2024.6832

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Hypertension, Cardiovascular Risk Factors, and Uterine Fibroid Diagnosis in Midlife

1 Division of Research, Kaiser Permanente Northern California, Oakland
2 Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
3 Department of Obstetrics and Gynecology, University of California Davis School of Medicine, Davis
4 Department of Obstetrics and Gynecology, Kaiser Permanente Northern California, Oakland
5 Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor
6 Brigham and Women’s Hospital, Boston, Massachusetts
7 Department of Psychology and Psychiatry, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
8 Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
9 Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora

Question Are study-measured blood pressure, antihypertensive treatment, and cardiovascular risk factors (anthropometry and biomarkers) associated with incidence of fibroids?

Findings In this cohort study of 2570 individuals at midlife, participants with untreated and new-onset hypertension had increased risk of newly self-reported fibroids, whereas those taking antihypertensive treatment had lower risk. Anthropometric factors and blood biomarkers were not associated with risk of newly reported fibroids.

Meaning These findings motivate investigation into the mechanisms underlying fibroids and may lead to new strategies for their prevention.

Importance Fibroids are benign neoplasms associated with severe gynecologic morbidity. There are no strategies to prevent fibroid development.

Objective To examine associations of hypertension, antihypertensive treatment, anthropometry, and blood biomarkers with incidence of reported fibroid diagnosis in midlife.

Design, Setting, and Participants The Study of Women’s Health Across the Nation is a prospective, multisite cohort study in the US. Participants were followed-up from enrollment (1996-1997) through 13 semiannual visits (1998-2013). Participants had a menstrual period in the last 3 months, were not pregnant or lactating, were aged 42 to 52 years, were not using hormones, and had a uterus and at least 1 ovary. Participants with prior fibroid diagnoses were excluded. Data analysis was performed from November 2022 to February 2024.

Exposures Blood pressure, anthropometry, biomarkers (cholesterol, triglycerides, and C-reactive protein), and self-reported antihypertensive treatment at baseline and follow-up visits were measured. Hypertension status (new-onset, preexisting, or never [reference]) and hypertension treatment (untreated, treated, or no hypertension [reference]) were categorized.

Main Outcomes and Measures Participants reported fibroid diagnosis at each visit. Discrete-time survival models estimated hazard ratios (HRs) and 95% CIs for associations of time-varying hypertension status, antihypertensive treatment, anthropometry, and biomarkers with incident reported fibroid diagnoses.

Results Among 2570 participants without a history of diagnosed fibroids (median [IQR] age at screening, 45 [43-48] years; 1079 [42.1%] college educated), 526 (20%) reported a new fibroid diagnosis during follow-up. Risk varied by category of hypertension treatment: compared with those with no hypertension, participants with untreated hypertension had a 19% greater risk of newly diagnosed fibroids (HR, 1.19; 95% CI, 0.91-1.57), whereas those with treated hypertension had a 20% lower risk (HR, 0.80; 95% CI, 0.56-1.15). Among eligible participants with hypertension, those taking antihypertensive treatment had a 37% lower risk of newly diagnosed fibroids (HR, 0.63; 95% CI, 0.38-1.05). Risk also varied by hypertension status: compared with never-hypertensive participants, participants with new-onset hypertension had 45% greater risk of newly diagnosed fibroids (HR, 1.45; 95% CI, 0.96-2.20). Anthropometric factors and blood biomarkers were not associated with fibroid risk.

Conclusions and Relevance Participants with untreated and new-onset hypertension had increased risk of newly diagnosed fibroids, whereas those taking antihypertensive treatment had lower risk, suggesting that blood pressure control may provide new strategies for fibroid prevention.

Uterine fibroids are benign, hormonally responsive tumors that occur in 70% to 80% of people with uteruses by age 50 years, approximately one-half of whom have clinically relevant disease. 1 A high-risk time for fibroid diagnosis begins around age 40 years. 2 Although fibroids are common and cause debilitating symptoms, including pain and bleeding, 3 no strategies are available to prevent them.

Growing evidence suggests that hypertension and other cardiovascular risk factors (including cholesterol levels, anthropometric measurements, carotid intima-media thickness, ankle-brachial index, and body composition) may be associated with fibroids. 4 However, most studies have been cross-sectional, 5 - 13 precluding analysis of temporality. Evidence from prospective studies is limited. One study 14 reported a positive association between diastolic blood pressure and risk of fibroid diagnosis, whereas another 15 reported that hypertension, but not heart attack or stroke, was associated with greater risk of fibroid surgery. A third study 16 linked untreated hypertension with ultrasonography-confirmed fibroids only and treated hypertension with risk of hysterectomy-confirmed fibroids only. These prior prospective studies used self-reported blood pressure, hypertension diagnosis, and antihypertensive use and, thus, may be subject to reporting errors. If blood pressure affects fibroid risk, hypertension control may have the added benefit of preventing fibroid development or growth.

Prospective longitudinal studies with criterion-standard risk factor ascertainment are needed to elucidate potential associations between hypertension, markers of cardiovascular risk, and fibroids. Using data from a racially and ethnically diverse prospective cohort, Study of Women’s Health Across the Nation (SWAN), we examined whether measured hypertension, antihypertensive treatment, and other cardiovascular risk factors were associated with new fibroid diagnosis in midlife, when fibroids often become clinically apparent.

SWAN is a multisite cohort study that enrolled 3302 participants between 1996 and 1997. 17 Eligible participants had a menstrual period in the 3 months before enrollment, were not pregnant or lactating, were aged 42 to 52 years, were not using hormones, and had a uterus and at least 1 ovary. Recruitment details have been published elsewhere. 18 Protocols were approved by institutional review boards at each participating institution. Participants provided written informed consent at each study visit. This manuscript follows Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline for observational studies.

Fibroid diagnosis was reported at baseline (visit 0, 1996-1997) and longitudinally through visit 13 (2011-2013, at which point nearly all participants were postmenopausal). Follow-up visits occurred approximately once per year from 1998 to 2008 (visits 1-11); visit 12 was in 2010 to 2011. At baseline participants were asked, “Has a doctor, nurse practitioner or other health care provider ever told you that you had fibroids, benign growths of the uterus or womb?” In visits 1 to 13, participants were asked, “Since your last study visit, have you had fibroids (benign growths in the uterus or womb)?” Self-reported fibroid diagnosis has been shown to have high specificity. 19 We excluded participants who reported a history of fibroids at enrollment (670 participants [20.3%]) or were missing baseline fibroid status (62 participants [1.9%]). eTable 1 in Supplement 1 compares participants with and without fibroids at baseline. eFigure 1 in Supplement 1 shows a timeline and sample sizes for each visit.

At each visit, study staff measured blood pressure with a standardized protocol: 2 readings from the right arm after the participant had been seated for 5 minutes. We averaged the measured values. We defined hypertension as study-measured systolic blood pressure 130 mm Hg or higher or diastolic blood pressure 80 mm Hg or higher. 20 Study staff also measured participant waist and hip circumference, height, and weight, and calculated waist-to-hip ratio and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared).

We quantified high-sensitivity C-reactive protein (hsCRP), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides in fasting blood samples (plasma or serum). hsCRP was quantified at baseline and visits 1, visits 3 to 7, and visits 9 to 12. Lipids were quantified at baseline and visits 1, 2 to 7, 9, 12, and 13. The study laboratory changed between visits 7 and 9, so concentrations were calibrated to ensure consistency. Additional details of the assays and calibration procedures are in the eAppendix in Supplement 1 .

We created a 3-category hypertension treatment variable to evaluate associations of fibroid diagnosis risk with treated and untreated hypertension. The hypertension treatment variable was updated at each visit and compared (1) participants with no antihypertensive treatment and measured normotension (no hypertension [reference group]) with (2) participants with no antihypertensive treatment and measured hypertension (untreated hypertension) and (3) participants receiving antihypertensive treatment regardless of measured blood pressure (treated hypertension).

We also created a 3-category, time-varying hypertension status variable to capture associations of fibroid diagnosis risk with hypertension onset. The hypertension status variable used information from current and prior visits and compared (1) participants who had never reported antihypertensive use and never had measured hypertension (ie, systolic blood pressure ≥130 mm Hg and diastolic blood pressure ≥80 mm Hg) (never hypertensive [reference group]) with (2) participants who had reported antihypertensive treatment or had measured hypertension at past visits (preexisting hypertension) and (3) participants who reported antihypertensive treatment or had measured hypertension for the first time at the current visit (new-onset hypertension).

Participants reported all medication used at each visit, and study staff categorized each medication by mechanism. Antihypertensive medications included α-blockers, β-blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, and diuretics. Participants who reported use of antihypertensive medication in the current visit or in a prior visit were considered to be using antihypertensive medication; however, the type of antihypertensive medication used was updated at each visit and reflected current use only.

Models of time-varying antihypertensive treatment vs no treatment were conducted among a subpopulation of participants eligible to be treated with antihypertensives (624 participants at baseline; using antihypertensive medication; having systolic blood pressure ≥140 or diastolic blood pressure ≥90 mm Hg; or having systolic blood pressure ≥130 or diastolic blood pressure ≥80 mm Hg and at least 1 risk factor [age ≥65 years, history of cardiovascular event, 10-year atherosclerotic cardiovascular disease risk score ≥10%, 21 or diabetes]) (eFigure 1 in Supplement 1 ). 20 We also evaluated time-varying treatment with ACE inhibitors specifically, because of evidence suggesting that ACE inhibitors may be associated with lower fibroid incidence 22 (ACE inhibitors were 28%-34% of antihypertensive medications used across visits). eTable 2 in Supplement 1 describes the subpopulation eligible for antihypertensive treatment.

Participants self-reported their age, educational attainment, race and ethnicity, smoking status, and parity. To identify race and ethnicity, participants were asked their primary group and told to choose 1 group if identifying as multiple races and ethnicities. Data on race and ethnicity are included in this analysis because Black women experience elevated risk of both fibroids and hypertension compared with White women. 23 , 24

Because fibroids are diagnosed by radiological tests or physical examinations, they are more likely to be identified in participants with greater health care engagement. We operationalized health care utilization with variables that may reflect healthy behaviors, health care seeking, and health care access, 25 such as multivitamin use, calcium supplementation, annual times spoken to a health care practitioner, and recency of last mammogram. To explore the role of gynecologic symptoms and care on likelihood of fibroid detection, we used recency of last pelvic examination, abnormal bleeding, and pelvic pain. We categorized menopausal status using data on menstrual bleeding patterns, pregnancy and/or breastfeeding, hormone use, and hysterectomy and/or oophorectomy. 26 All variables except baseline age, education, site, and race and ethnicity were updated at each visit.

Data analysis was performed from November 2022 to February 2024. We used discrete-time survival models (with a complementary log-log link) to estimate hazard ratios (HRs) and 95% CIs for the associations of hypertension, anthropometry, blood biomarkers, and new reported fibroid diagnosis. 27 We censored participants at menopause (because it is unusual for fibroids to develop after menopause), 28 hysterectomy, loss to follow-up, or visit 13 (last visit with fibroid data), whichever occurred first. One site paused data collection for several years after visit 5, so we censored participants from that site at the pause. When participants had missing data due to a missed visit or questionnaire changes, we imputed the last observed value. Anthropometry, blood-based biomarkers, and hypertension variables were modeled separately to avoid collinearity.

Confounder selection was based on published literature indicating associations between each covariate and both fibroids and blood pressure and a directed acyclic graph (eFigure 2 in Supplement 1 ). We ran unadjusted models and models adjusted for the baseline value of the exposure, age, 1 study site, educational attainment (less than high school, high school, some college and/or technical school, college graduate, or postgraduate), 28 , 29 self-reported race and ethnicity (Black, Chinese, Hispanic, Japanese, or White), 29 , 30 smoking status (current smoker vs nonsmoker), 31 , 32 menopause status (perimenopausal, premenopausal or pregnant or breastfeeding, or unknown due to hormone use), 30 , 33 parity (0, 1-2, ≥3 births), 30 and BMI (continuous) 34 , 35 (minimally adjusted models). Finally, we ran models including all covariates in the minimally adjusted model plus time-varying health care utilization variables reflecting behavior since the prior visit: times spoken to a health care practitioner (0, 1-2, or ≥3 times), use of multivitamins (yes or no), use of calcium supplements (yes or no), and mammogram (yes or no) (health care–adjusted models).

We further adjusted blood pressure models for antihypertensive medication use, and cholesterol and triglyceride models for statin use. Models of antihypertensive treatment vs no treatment were restricted to participants eligible to receive antihypertensive treatment (eTable 2 in Supplement 1 ).

Consistent with recommendations issued by the American Statistical Association, 36 - 38 we interpret results according to the magnitude and direction of point estimates, width of 95% CIs, and pattern of findings across models, rather than statistical significance testing. Analyses were conducted using SAS statistical software 9.4 (SAS Institute).

In sensitivity analyses, to explore the role of gynecological symptoms or care, we repeated analyses restricted to participants who reported a pelvic examination, abnormal bleeding, or pelvic pain since the prior visit. To assess the effect of carrying forward observations to fill missing values, we repeated the main analysis without filling missing values (complete case analysis). Finally, we repeated analyses without censoring at menopause, and without adjusting for baseline values of exposure variables.

The eligible population of 2570 participants had a median (IQR) age of 45 (43-48) years. With regard to race and ethnicity, 644 (25.1%) were Black, 212 (8.3%) were Chinese, 235 (9.1%) were Hispanic, 223 (8.7%) were Japanese, and 1256 (48.9%) were White. A total of 1079 participants (42.1%) had a college education or greater, and 1398 (54.8%) were premenopausal ( Table 1 ). Compared with participants with a history of fibroids, eligible participants were less likely to be Black (644 participants [25.1%] vs 284 participants [42.4%]), to have BMI 30 or greater (630 participants [25.7%] vs 195 participants [29.8%]), and to use antihypertensive medication (333 participants [13.0%] vs 120 participants [17.9%]) (eTable 1 in Supplement 1 ). Over follow-up, 526 participants (20% of eligible) reported a new diagnosis of fibroids.

We found no association between continuous blood pressure and new reported fibroid diagnosis ( Table 2 ). However, participants with new-onset hypertension had a 45% higher risk of new reported fibroid diagnosis (HR, 1.45; 95% CI, 0.96-2.20) compared with never-hypertensive participants, whereas those with preexisting hypertension did not have higher risk. Similarly, participants with untreated hypertension had a 19% (HR, 1.19; 95% CI, 0.91-1.57) greater risk of new reported fibroid diagnosis compared with those with no hypertension, whereas those with treated hypertension had a 20% lower risk (HR, 0.80; 95% CI, 0.56-1.15).

Participants eligible to use antihypertensive medication were more likely than the overall study population to be non-Hispanic Black and have BMI 30 or higher (eTable 2 in Supplement 1 ). Among participants eligible to use antihypertensive treatment, those using antihypertensive treatment had a 37% lower risk of new reported fibroid diagnosis (HR, 0.63; 95% CI, 0.38-1.05); reduction in risk was especially pronounced among participants using ACE inhibitors compared with those using no antihypertensive treatment (48% lower risk; HR, 0.52; 95% CI, 0.27-1.00) ( Table 2 ).

Anthropometry, lipids, and hsCRP were not associated with risk of new reported fibroid diagnosis. For each 0.1-unit increase in waist-to-hip ratio, the risk of newly developed fibroids increased by 29% (HR, 1.29; 95% CI, 1.02-1.63), but there were no associations with BMI, waist circumference, lipids, or hsCRP ( Table 2 ). In sensitivity analyses, the findings slightly attenuated in models restricted to participants who reported a pelvic examination, abnormal bleeding, or pelvic pain since the prior visit (63%-72% of participants); in models without carried forward observations to fill missing values; in models that did not censor at menopause (postmenopausal participants increased from 2% at visit 1 to 99% at visit 13); and in models without adjustment for baseline exposure values (eTables 3-6 in Supplement 1 ).

In this longitudinal cohort study with repeated measures of both cardiovascular risk factors and self-reported fibroid diagnosis, patients with new-onset hypertension had a 45% increased risk of newly reported fibroids, and those with untreated hypertension had a 19% increased risk. Participants who used antihypertensive medication had lower risks of newly reported fibroids: 20% lower risk compared with participants without hypertension, and 37% lower risk (for ACE inhibitors, 48% lower risk) compared with untreated participants eligible to use antihypertensive medication. These findings suggest that new hypertension is associated with elevated risk of first fibroid diagnosis at midlife, a high-risk time for both fibroid diagnosis and the development of cardiovascular risk.

Our finding that risk of new reported fibroid diagnosis was higher among participants with untreated vs treated hypertension, whereas continuous blood pressure was not associated with risk, adds important new insights to a conflicting literature. Both the Black Women’s Health Study, a prospective cohort of premenopausal Black women, and the Nurses’ Health Study II, a prospective cohort of nurses aged 25 to 42 years at baseline, found that higher blood pressure was associated with greater fibroid incidence regardless of antihypertensive use. 14 , 16 We also found that new-onset hypertension carried greater risk of newly reported fibroids than ongoing hypertension, which differs from prior research suggesting either sustained elevation 14 or no change 16 in fibroid risk after hypertension diagnosis. Our findings may differ from prior literature for many reasons. Importantly, we relied on technician-measured blood pressure to ascertain hypertension status, thereby reducing misclassification; participants with untreated hypertension may not be aware of their hypertension. Also, previous studies less precisely ascertained hypertension onset, which may have attenuated the associations. Finally, prior cohort studies included a wider age range (eg, approximately 20-80 years in some cases 14 - 16 ), possibly diluting associations. Nonetheless, our results add to the prospective evidence linking untreated hypertension to risk of newly clinically apparent fibroids.

Our related finding among participants eligible to use antihypertensive medication that those using antihypertensive medication had a 37% lower risk of newly reported fibroids, and those using ACE inhibitors in particular had 48% lower risk, is consistent with a recent commercial insurance database study that reported that ACE inhibitor use was associated with 32% reduced odds of new fibroid diagnosis. 22 Preliminary evidence suggests that the renin-angiotensin-aldosterone pathway may explain a protective effect of ACE inhibitors: angiotensin II and aldosterone have been shown to cause fibroid cell proliferation in a rat cell line, 39 , 40 and mixed evidence from human genetic studies 41 suggests that fibroid risk is associated with angiotensin II receptor type 1 genetic sequence variants 42 and angiotensin-converting enzyme insertion-deletion genetic sequence variants. 43 , 44 The renin-angiotensin-aldosterone pathway deserves further exploration in light of our findings suggesting reduction of fibroid risk associated with ACE inhibitors.

Alternatively, associations between new-onset hypertension and newly reported fibroid diagnosis may be due to bias. For example, unmeasured comorbidities could increase both blood pressure and health care utilization, leading to incidental fibroid diagnosis; however, results were robust to adjustment for health care utilization and sensitivity analyses restricting to participants with a pelvic examination or symptoms. Reverse causation is also possible: a growing fibroid might increase blood pressure through vascular demands 4 or altered systemic hemodynamics. 45

Although a growing literature links cardiovascular risk factors to prevalent fibroids, nearly all studies have been cross-sectional in design. In this prospective study, we reported null associations between lipids, CRP, anthropometry (except waist-to-hip ratio), and incidence of fibroids. Prior studies have reported mixed findings for the association between cholesterol and fibroids, with some linking fibroids to higher low-density lipoprotein and lower high-density lipoprotein cholesterol, 7 , 11 , 13 , 46 some suggesting the opposite, 47 and others reporting null associations. 5 , 48 , 49 The only prior study to investigate associations between CRP and fibroid prevalence reported null associations. 50 Prior literature has reported nonlinear associations between BMI and fibroids (highest risk for BMI approximately 28-32) and both positive and null associations between waist-to-hip ratio and fibroids. 7 , 34 , 51 - 53 Previous studies varied widely in design, which may also explain heterogeneity; for example, some relied on retrospective analyses (eg, lifetime fibroid occurrence), 5 clinical convenience samples, 11 or surgically confirmed cases. 54 Our null findings in a longitudinal cohort study with criterion-standard biomarker measurements do not support an effect of lipids or CRP on new fibroid diagnosis in midlife participants.

Our analysis benefited from high-quality, repeated measurements of blood pressure, biomarkers, and anthropometry, enabling us to assess exposures independent of health care access. SWAN’s midlife participants and criterion-standard assessment of menopause status allowed us to focus on a high-risk life stage. 55 Finally, we adjusted for a wide range of potential confounding factors, including health care utilization (an especially strong confounder of associations between medication use and fibroid diagnosis).

Our work also has limitations. First, we used self-reported fibroid diagnosis; therefore, asymptomatic fibroids, which may constitute more than one-half of cases, 2 may be missed. Complete fibroid ascertainment (ie, repeated ultrasonography of asymptomatic participants) is difficult, and all prior prospective studies of hypertension and fibroids also relied on self-reported diagnosis. 14 - 16 Self-reported fibroid diagnosis has high specificity 19 ; sensitivity is estimated to be approximately 50% for women aged 35 to 49 years. 19 Because fibroid misclassification is unlikely to vary by study-measured hypertension status and specificity is high, despite lower sensitivity, effect estimates are expected to be unbiased. 56 On the other hand, if participants with study-measured hypertension had lower rates of missed fibroid diagnosis than those with normotension, the magnitude of our associations would be overstated. Second, the eligibility criteria may limit generalizability. Fibroids often develop before midlife, especially for Black women 28 ; in this study, Black participants were more likely to be excluded because of prior fibroids. Findings are most applicable to those with a first fibroid diagnosis in midlife. Fibroids may grow slowly 57 and may have been present but undiagnosed before hypertension onset. However, prospective associations between new-onset hypertension and fibroid diagnosis suggest that high blood pressure plays a role in fibroid growth to the point of clinical recognition. Participants using ACE inhibitors may differ from those using other antihypertensive medications or no medications; further investigation is needed to determine the causal effect of ACE inhibitor use on fibroid risk. Furthermore, we could not rule out unmeasured confounding but were able to adjust for multiple demographic and health care utilization variables.

This study of a midlife cohort found that patients with untreated and new-onset hypertension had increased risk of newly reported fibroid diagnosis, whereas those taking antihypertensive medication had a reduced risk. Investigation into mechanisms and health implications is warranted; if the associations are causal, antihypertensive medication use where indicated may present an opportunity to prevent clinically apparent fibroid development at this high-risk life stage.

Accepted for Publication: February 18, 2024.

Published: April 16, 2024. doi:10.1001/jamanetworkopen.2024.6832

Corresponding Author: Susanna D. Mitro, PhD, Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612 ( [email protected] ).

Author Contributions: Dr Mitro had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Mitro, Zaritsky, Solomon, El Khoudary, Hedderson.

Acquisition, analysis, or interpretation of data: Mitro, Wise, Waetjen, Lee, Zaritsky, Harlow, Thurston, El Khoudary, Santoro, Hedderson.

Drafting of the manuscript: Mitro, Wise, Zaritsky, Harlow, El Khoudary, Santoro.

Critical review of the manuscript for important intellectual content: Mitro, Wise, Waetjen, Lee, Zaritsky, Harlow, Solomon, Thurston, El Khoudary, Hedderson.

Statistical analysis: Mitro, Wise, Santoro.

Obtained funding: Waetjen, Harlow, Thurston, El Khoudary, Hedderson.

Administrative, technical, or material support: El Khoudary, Santoro.

Supervision: Wise, Waetjen, Lee, Zaritsky, Thurston, El Khoudary, Hedderson.

Conflict of Interest Disclosures: Dr Wise reported receiving grants from the National Institutes of Health (NIH), personal fees from The Gates Foundation and Abbvie, Inc, and in-kind donations for primary data collection in a study outside the submitted work from Swiss Precision Diagnostics (home pregnancy tests) and Kindara.com (fertility applications). Dr Waetjen reported receiving grants from Accessa Health Inc outside the submitted work. Dr Solomon reported receiving grants from CorEvitas, Janssen, and Novartis outside the submitted work. Dr Thurston reported receiving personal fees from Astellas Pharma, Bayer, Hello Therapeutics, Happify Health, and Vira Health outside the submitted work. Dr Santoro reported receiving grants from Menogenix, Inc, and personal fees from Astellas Pharma, Ansh Labs, Amazon, and FertilityIQ outside the submitted work. No other disclosures were reported.

Funding/Support: The Study of Women’s Health Across the Nation (SWAN) has grant support from the NIH, Department of Health and Human Services, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR), and the NIH Office of Research on Women’s Health (ORWH) (grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495, and U19AG063720; the SWAN Repository is funded through grant U01AG017719). This publication was supported in part by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH (UCSF-CTSI grant UL1 RR024131). Dr Mitro is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH (award number K12AR084219).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH, or the NIH.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: We thank the study staff at each site and all the women who participated in SWAN. Clinical centers included University of Michigan, Ann Arbor (principal investigators [PIs], Carrie Karvonen-Gutierrez, 2021 to present; Siobán Harlow, 2011-2021; MaryFran Sowers, 1994-2011); Massachusetts General Hospital, Boston (PIs, Sherri-Ann Burnett-Bowie, 2020 to present; Joel Finkelstein, 1999-2020; Robert Neer, 1994-1999); Rush University, Rush University Medical Center, Chicago, Illinois (PIs, Imke Janssen, 2020 to present; Howard Kravitz, 2009-2020; Lynda Powell, 1994-2009); University of California, Davis, and Kaiser Permanente, Oakland, California (PIs, Elaine Waetjen and Monique Hedderson, 2020 to present; Ellen Gold, 1994-2020); University of California, Los Angeles (PIs, Arun Karlamangla, 2020 to present; Gail Greendale, 1994-2020), Albert Einstein College of Medicine, Bronx, New York (PIs, Carol Derby, 2011 to present; Rachel Wildman, 2010-2011; Nanette Santoro, 2004-2010); University of Medicine and Dentistry–New Jersey Medical School, Newark (PIs, Gerson Weiss, 1994-2004); University of Pittsburgh, Pittsburgh, Pennsylvania (PIs, Rebecca Thurston, 2020 to present; Karen Matthews, 1994-2020); NIH Program Office, National Institute on Aging, Bethesda, Maryland (PIs, Rosaly Correa-de-Araujo, 2020 to present; Chhanda Dutta, 2016 to present; Winifred Rossi, 2012-2016; Sherry Sherman, 1994-2012; Marcia Ory, 1994-2001); National Institute of Nursing Research, Bethesda, Maryland, Program Officers; central laboratory, University of Michigan, Ann Arbor (PI, Daniel McConnell; Central Ligand Assay Satellite Services); SWAN repository, University of Michigan, Ann Arbor (PIs, Siobán Harlow, 2013-2018; Dan McConnell, 2011-2013; MaryFran Sowers, 2000-2011), coordinating center, University of Pittsburgh, Pittsburgh, Pennsylvania (PIs, Maria Mori Brooks, 2012 to present; Kim Sutton-Tyrrell, 2001-2012); New England Research Institutes, Watertown, Massachusetts (PI, Sonja McKinlay, 1995-2001), and steering committee (Susan Johnson, current chair; Chris Gallagher, former chair).

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Diagnosis and management of uterine fibroids: current trends and future strategies

Uterine fibroids (UFs), leiomyomas or myomas, are a type of malignancy that affects the smooth muscle of the uterus, and it is most commonly detected in women of reproductive age. Uterine fibroids are benign monoclonal growths that emerge from uterine smooth muscle cells (myometrium) as well as fibroblasts. Uterine fibroid symptoms include abnormal menstrual bleeding leading to anaemia, tiredness, chronic vaginal discharge, and pain during periods. Other symptoms include protrusion of the abdomen, pain during intercourse, dysfunctions of bladder/bowel leading to urinary incontinence/retention, pain, and constipation. It is also associated with reproductive issues like impaired fertility, conceiving complications, and adverse obstetric outcomes. It is the leading cause of gynaecological hospitalisation in the American subcontinent and a common reason for the hysterectomy. Twenty-five percent of the reproductive women experience the symptoms of uterine fibroids, and among them, around 25% require hospitalization due to the severity of the disease. The frequency of the disease remains underestimated as many women stay asymptomatic and symptoms appear gradually; therefore, the condition remains undiagnosed. The exact frequency of uterine fibroids varies depending on the diagnosis, and the population investigated; nonetheless, the incidence of uterine fibroids in reproductive women ranges from 5.4 percent to 77 percent. The uterine fibroid treatment included painkillers, supplementation with iron, vitamin D3, birth control, hormone therapy, gonadotropin-releasing hormone (GnRH) agonists, drugs modulating the estrogen receptors, and surgical removal of the fibroids. However, more research needed at the level of gene to get a keen insight and treat the disease efficiently.

Acknowledgments

Authors are thankful to Professor S.M. Hasan, Dean Faculty of Pharmacy, Integral University, Lucknow for providing technical support and guidance. Thanks to Dean R&D, Integral University for assigning manuscript communication reference IU/R&D/2022-MCN0001405.

Research funding: None declared.

Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

Competing interests: Authors state no conflict of interest.

Informed consent: Informed consent was obtained from all individuals included in this study. Not Applicable

Ethical approval: The local Institutional Review Board deemed the study exempt from review.

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Home > TMC > DISSERTATIONS > Evaluation of current knowledge and education practices regarding uterine fibroids amongst Black women

Evaluation of current knowledge and education practices regarding uterine fibroids amongst Black women

Nickell M Dixon , The University of Texas School of Public Health

Uterine fibroids are currently being studied only in the clinical setting. Although there has not been a cure or even definite etiology found on this issue. If public health addressed this subject it would allow us an opportunity to educate others on what is already known. This dissertation will be the foundation of an intervention to be implemented specifically with Black women, as well as provide information and education to those in leadership positions that are able to create policies and an office geared toward further research and ultimately a cure for this problem. The overall research question for this dissertation is: "In what ways does current knowledge of uterine fibroids affect norms, beliefs, attitudes, and decision making in Black women?" This study began with a systematic review on decision aids to help women make decisions about reproductive health problems. A focus group was then conducted to obtain women's beliefs, attitudes, norms, and decisional regret regarding uterine fibroids and treatment. A fibroid knowledge questionnaire was then develop and piloted containing items related to attitudes, norms, beliefs and knowledge. The systematic review revealed that decision aids that address fibroids or fibroids-related symptoms would be uncommon. Out of the 25 articles found, none were directly about uterine fibroids and most were related to pregnancy. The most common target audience was pregnant women and teenagers. More decision support tools are needed for women of child bearing age in order to make reproductive health decisions that take in consideration preserving fertility. The systematic review also revealed that decision aids targeted to Black women would be rare. Some of the hypotheses were found false via information from Black women in their focus group. Women based their treatment decision based on personal reasons of pain and fertility. Most stated that if pain was the major reason for treatment, the physicians made the major decisions. Women who major factor was fertility tend to do the most research and had the most regret. Surprisingly women in this research project had little to no regret regarding their treatment choices. A lot of women didn't have regret because they had already had children. Regret was stated for women who went thru early menopause or experience problems due to a hysterectomy. It was stated that having fibroids is such a secret that no one is aware who does or doesn't have it until an opportune time. This study was the first to access current knowledge of women with or has had fibroids. The study indicated women are unable to separate facts from opinions regarding prevention and treatment. The study also proved family and religion are not contributors in making treatment decisions.

Subject Area

Behavioral psychology|Public health|Health education

Recommended Citation

Dixon, Nickell M, "Evaluation of current knowledge and education practices regarding uterine fibroids amongst Black women" (2014). Texas Medical Center Dissertations (via ProQuest) . AAI3719054. https://digitalcommons.library.tmc.edu/dissertations/AAI3719054

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A look at the current state of uterine fibroid care

“Over 70% of women are estimated to develop uterine fibroids by age 50,” said senior author Irene Aninye, PhD, chief science officer for the Society for Women’s Health Research (SWHR) in Washington, D.C. “Fibroids are a complex condition that can range from being asymptomatic to having deleterious effects on a woman’s health and quality of life.”

Irene Aninye, PhD, chief science officer for the Society for Women’s Health Research (SWHR) in Washington, D.C.

A review of the current state of research and clinical care for uterine fibroids in the Journal of Women’s Health identified many areas for improvement, calling for increased research investment; improved fibroid assessment via pelvic imaging; addressing factors that contribute to disease disparities—especially among women of color—and developing fertility-friendly treatment options. 1

SWHR assembled an interdisciplinary working group of expert researchers, gynecology-focused health care providers, patients, patient advocates and policy leaders to discuss key deficits within the areas of research, clinical care, and federal policy that are needed from bench to bedside.

During a 2-day roundtable meeting, participants discussed updates on key literature, research, clinical practices, and public health data on uterine fibroids.

Expanding awareness and education of uterine fibroids beyond gynecologic specialists, along with advancing personalized patient care through shared decision-making, were also flagged as ways to address unmet needs in the review.

Additionally, exploring novel non-hormonal medical therapies might lead to fertility-friendly options to treat fibroids. For instance, upregulation of vitamin D could have protective effects against fibroid growth without negatively impacting ovarian function.

“The findings of the working group may not particularly come as a surprise to many clinicians; however, the review’s presentation across research, clinical and policy landscapes offers a vantage point that may be overlooked when professionals are intently working in their respective niches,” Aninye told Contemporary OB/GYN® .

For example, providers routinely ask about gynecological health during a well-woman exam. “We suggest reconsidering a patient’s use of the word ‘normal’ or ‘fine’ when describing menstrual flow or pain because they may not realize that their normal may actually warrant medical concern,” Aninye said. “Quantifying the use of feminine products or the duration of pain and its influence on daily activities is likely to better inform an assessment.”

Furthermore, patient outcomes and personal stories are essential to understanding the full scope of impact that uterine fibroids have on women’s health.

It helps if patients articulate their experiences, “which is important for clinical care and identifying needs that should inform future research focuses and policy interventions,” said Aninye, noting that the disease burden factors in both financial and health data.

The review offers recommendations that individual clinicians can incorporate in their practice. “It also highlights areas and potential solutions that require more systemic attention, such as basic and clinical research investments, addressing stigma and biases that can contribute to delays in diagnosing and treating fibroids, and barriers to accessing care that affect overall and disparate populations of women,” Aninye said.

The working group hopes that the review will shed light on the growing public health burden of uterine fibroids and reinforce the need to address persistent gaps with an interdisciplinary and multisector approach.

“SWHR is committed to building awareness and support for the Stephanie Tubbs Jones Uterine Fibroids Research and Education Act of 2021, and will continue to promote provider, patient and policymaker education so that women are empowered throughout their life-course to live well and manage uterine fibroid disease,” Aninye said.

Aninye IO, Laitner MH. Uterine fibroids: assessing unmet needs from bench to bedside. J Womens Health (Larchmt). 2021 Aug:30(8):1060-1067. doi:10.1089/jwh.2021.0280

Deciding the best treatment for uterine fibroids | Image Credit: jeffersonhealth.org.

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Published: 24 August 2024

Impact of ultrasound-guided high-intensity focused ultrasound for the treatment of uterine fibroids on ovarian reserve and quality of life: a single-center prospective cohort study

Wei Gu 1 , 2 , 4 na1 ,
Jiangjing Yuan 1 , 2 , 4 na1 ,
Yun Zhou 2 , 3 , 4 ,
Yuhong Li 1 , 2 , 4 &
Yudong Wang 1 , 2 , 4

BMC Women's Health volume 24 , Article number: 470 ( 2024 ) Cite this article

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Metrics details

We aimed to evaluate changes in ovarian reserve and quality of life in women treated with ultrasound-guided high-intensity focused ultrasound (USgHIFU) for uterine fibroids.

In this single-center prospective study, a total of 69 patients with uterine fibroids treated with USgHIFU from October 2018 to November 2021 were enrolled. Fibroid volume, anti-Müllerian hormone (AMH) levels, uterine fibroid symptom scores, and uterine fibroid symptoms and quality of life (UFS-QOL) questionnaire scores before and 1, 3, and 6 months after USgHIFU treatment were analyzed. Correlations between AMH levels and age, fibroid type, and fibroid location were assessed.

Data from 54 of the 69 patients included in the present study were analyzed. The UFS-QOL scores at baseline and at 1 month and 6 months after USgHIFU treatment were 70 (50.75–87.50), 57 (44.75–80.00), and 52 (40.75–69.00) points, respectively ( p < 0.001). The rate of fibroid volume reduction increased significantly at the 3-month follow-up compared with the 1-month follow-up ( p < 0.001), and no significant change was observed between the 3-month and 6-month follow-ups ( p > 0.99). The median AMH levels before and at 1, 3 and 6 months after treatment were 1.22 (0.16–3.28) ng/ml, 1.12 (0.18–2.52) ng/ml, 1.15 (0.19–2.08) ng/ml and 1.18 (0.36–2.43) ng/ml, respectively ( p = 0.2). Multivariate linear regression analyses revealed that age was independently associated with AMH levels.

Conclusions

USgHIFU treatment for uterine fibroids can significantly improve quality of life with minimal adverse effects on ovarian function.

Peer Review reports

Introduction

Uterine fibroids are the most common gynecologic neoplasms in women of reproductive age, affecting up to 70% of women worldwide [ 1 ]. Although benign, approximately 30% of uterine fibroids can cause severe symptoms, including menorrhagia, pelvic pain, frequent urination, miscarriage, or infertility [ 2 , 3 ]. Evidence suggests that women with uterine fibroids are at greater risk of experiencing emotional distress, depression, and anxiety, which can affect their health and quality of life [ 4 ].

Common treatment options for symptomatic uterine fibroids include medical treatments (hormonal medications and progesterone receptor modulators), surgical procedures to remove uterine masses (myomectomy and hysterectomy), and nonsurgical treatments (uterine artery embolization and high-frequency focused ultrasound [HIFU]) [ 5 ]. Notably, a differential diagnosis for uterine sarcoma, an aggressive and rare type of uterine neoplasm with a poor prognosis, must be conducted prior to initiating non-surgical treatment. Gold-standard surgical treatment of uterine sarcoma typically involves hysterectomy with bilateral salpingo-oophorectomy, and a fertility-sparing approach is only appropriate for carefully selected patients with strong desire to preserve fertility [ 6 ]. With the American College of Obstetricians and Gynecologists recommending the most minimally invasive approach whenever possible, clinicians have been utilizing less invasive treatments for uterine fibroids [ 7 ]. HIFU is a noninvasive treatment technique performed under the guidance of diagnostic ultrasound or magnetic resonance imaging that uses multiple high-intensity ultrasound waves to induce focal thermocoagulation to ablate fibroid vascularity. This procedure has been widely used in recent decades and has achieved favorable clinical efficacy in the treatment of uterine fibroids [ 8 , 9 , 10 ]. In addition, studies have shown that HIFU treatment is associated with shorter hospital stays, fewer adverse effects, and fewer complications than traditional surgery [ 11 , 12 ]. However, there are still limited data on whether HIFU affects women’s health-related quality of life or causes ovarian dysfunction in the short or long term.

Anti-Müllerian hormone (AMH), a hormone produced by small developing, mostly antral follicles, is not affected by changes in the menstrual cycle. Compared with follicle stimulating hormone (FSH) or inhibin B, AMH is generally considered a good indicator of the ovarian reserve [ 13 , 14 , 15 ]. Therefore, this study was designed to evaluate changes in ovarian function and quality of life in women after USgHIFU treatment for uterine fibroids.

Materials and methods

This single-center prospective study was carried out after approval was obtained from the Ethics Committee of the International Peace Maternity and Child Health Hospital. Written informed consent was obtained from all participating patients.

A total of 69 patients with symptomatic uterine fibroids were enrolled between October 23, 2018, and November 27, 2021. The inclusion criteria for patients were as follows: (1) were > 18 years of age; (2) had imaging-confirmed uterine fibroids 3–8 cm in diameter; (3) were premenopausal; and (4) had symptoms such as abdominal pain, constipation, abnormal uterine bleeding and frequent urination. The exclusion criteria for patients were as follows: (1) had a history of pelvic inflammatory disease, gynecologic malignancy, or endocrine disorders; (2) had contraindications to magnetic resonance imaging, such as metallic implants; (3) had severe fibroid calcifications or abdominal skin scarring along the acoustic pathway; (4) were unable to tolerate USgHIFU or were lost to follow-up; and (5) were suspected of having extensive abdominal adhesions.

Preprocedural preparation and evaluation

Bowel preparation was performed with semiliquid food 3 days before the scheduled procedure. The lower abdominal skin in the acoustic pathway was shaved and degreased to avoid skin burns. HIFU treatment was performed via a system (SUA-I, Shanghai Zhonghui Medical Equipment Co. Ltd., Shanghai, China) with an ultrasound imaging device (Voluson 730, GE Healthcare, IL, USA) for guidance. Preprocedural evaluation included conventional ultrasound, noncontrast T1-weighted and T2-weighted imaging, and contrast-enhanced T1-weighted imaging. Magnetic resonance images were acquired in the axial and sagittal planes with a slice thickness of 5 mm and an interslice distance of 1 mm via a 1.5 T MRI scanner (MAGNETOM Aera, SIEMENS, Erlangen, Germany). The fibroid volume was calculated on contrast-enhanced T1-weighted images according to the ellipsoid calculation formula: V = 0.523×D1×D2×D3, where V is the fibroid volume and D1, D2, and D3 are the fibroid diameters in the longitudinal, anteroposterior, and axial planes, respectively [ 16 ]. Preoperative information, including patient age, height, weight, fibroid location, type, size, and blood supply, was recorded.

The patients were placed in the supine position. After identifying the location of the targeted fibroids, USgHIFU treatment was initiated under the guidance of real-time ultrasound via a 3.5 MHz convex US imaging probe (OPEN 580, Jiangsu Sinoways Medical Technology Co. Ltd., Yangzhou, China). The default acoustic power and periods of pulse-on and pulse-off were 126 W, 500 ms and 1000 ms, respectively. A pulse count of 6 was used for the sonication of each spot. During the procedure, the patients were conscious and able to inform the physician of any pain or discomfort; USgHIFU was stopped in the presence of unbearable pain or successful ablation, as blood flow could not be detected by color Doppler flow imaging and power Doppler imaging. The procedure was performed by the same operator for all patients, and the duration of treatment was carefully recorded and documented. For patients with multiple fibroids, only the largest fibroid was ablated.

Patient quality of life

We used the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire, which is a fibroid-specific health and symptom-related questionnaire, to measure the patients’ quality of life before USgHIFU treatment and at the 1- and 6-month follow-ups after treatment. The original English version of the UFS-QOL questionnaire has been extensively validated and was translated into Chinese for ease of use. This questionnaire consists of 8 items on fibroid-related symptoms and 29 items on health-related quality of life, and the final score is obtained by summing the scores of these 2 domains [ 17 ].

Follow-up evaluation

Complications, such as skin burns, abdominal pain, fever, nausea, vomiting, skin blisters and hematuria, were observed and recorded during and after the USgHIFU procedure. The follow-up evaluation included assessments of hemoglobin levels, AMH levels, and fibroid volume before and at 1, 3, and 6 months after USgHIFU treatment and nonperfused fibroid volume at 1 and 6 months after USgHIFU treatment. The blood samples were subsequently centrifuged at 2000 r/min for 20 min, after which the serum was extracted and stored at -20 °C. AMH levels were measured via an enzyme-linked immunosorbent assay kit (Beckman Coulter Inc., Brea, CA). The magnetic resonance imaging protocol and imaging parameters were the same as those used before USgHIFU. The fibroid volume reduction rate and nonperfused volume ratio were calculated as the ratio of fibroid volume post-USgHIFU/pre-USgHIFU treatment and the nonperfused volume/fibroid volume immediately after USgHIFU treatment, respectively. AMH measurements were performed via an enzyme-linked immunosorbent assay in centrifuged serum from enrolled patients stored at -20 °C.

Statistical analyses

Statistical analyses and figure generation were performed via SPSS version 22.0 and GraphPad Prism software, respectively. Continuous variables were first tested for normality via the Kolmogorov‒Smirnov test. Data are presented as medians (interquartile ranges) for nonnormally distributed data. Comparisons between pre-USgHIFU and post-USgHIFU parameters were performed via the nonparametric Friedman test with post hoc analysis. Multivariate linear regression analysis was used to explore factors influencing AMH levels at different follow-up time points. A two-tailed P value < 0.05 indicated statistical significance.

Patient demographics

A total of 69 patients were enrolled, and data from 54 patients were ultimately analyzed. Data from the other 15 patients were excluded from the final analysis because no measurements of pre- or post-USgHIFU AMH levels ( n = 12) and no post-USgHIFU hemoglobin assessments ( n = 3) were performed. The mean age and median height, weight, and body mass index for the 54 included patients were 41.04 ± 5.26 years, 160 (158–164) cm, 56.8 (52.0–61.3) kg and 21.99 (20.28–23.88) kg/m 2 , respectively. Regarding fibroid type, 37 were anterior fibroids, 8 were posterior fibroids, 7 were lateral fibroids and 2 were fundus fibroids. A total of 21 and 33 patients had subserosal and intramural fibroids, respectively. The median baseline fibroid volumes, as assessed by sonography and magnetic resonance imaging, were 52.03 (35.90–93.78) cm 3 and 56.30 (25.89–82.76) cm 3 , respectively. The median USgHIFU treatment time was 100 (70–140) minutes.

Changes in quality of life, nonperfused volume ratio, and reductions in the treated volume and hemoglobin level over time

As shown in Table 1 ; Fig. 1 (A), the median pretreatment UFS-QOL score was 70 points (50.75–87.50). At 1 month and 6 months after HIFU ablation, the UFS-QOL scores decreased to 57 (44.75–80.00) and 52 (40.75–69.00) points, respectively, and a significant difference in the QOL score after USgHIFU treatment between the 1-month and 6-month follow-ups was observed ( p < 0.001). The rate of fibroid volume reduction was significantly greater at the 3-month follow-up than at the 1-month follow-up, and no significant change was observed between the 3-month and 6-month follow-ups ( p > 0.99). The median nonperfused volume ratio at the 6-month follow-up was lower than that at the 1-month follow-up (82.21% [6.52-100.00%] vs. 91.80% [24.84-100.00%], p = 0.001). Notably, the hemoglobin levels at the 1-, 3- and 6-month follow-ups were not significantly different from those before USgHIFU treatment ( p > 0.05).

Violin plots of the USF-QOL score and AMH level before and after USgHIFU treatment. ( A ). USF-QOL score before and at 1-month and 6-month after treatment showed significant difference ( p < 0.001). ( B-D ). Violin plots comparing AMH at time points in patients stratified by age. ( B ), AMH at different time points for patients aged < 40; ( C ), AMH at different time points for patients aged 40 to 44; ( D ), AMH at different time points for patients aged ≥ 45. No significant change was seen among the three age groups ( p > 0.05). Abbreviations: Pre, before HIFU; Post-1 M, 1 month after HIFU; Post-3 M, 3 months after HIFU; Post-6 M, 6 months after HIFU

AMH level assessment

The median AMH levels before and 1 month, 3 months, and 6 months after treatment were 1.22 (0.16–3.28), 1.12 (0.18–2.52), 1.15 (0.19–2.08) and 1.18 (0.36–2.43) ng/ml, respectively, and the pre-USgHIFU and post-USgHIFU AMH levels were stable without statistically significant changes (Table 2 ). We then explored whether age had an effect on AMH levels. Thus, patients were grouped into the < 45 years group ( n = 41) [< 40 years subgroup ( n = 20), 40–44-year subgroup ( n = 21)] and ≥ 45 years group ( n = 13). As presented in Table 2 ; Fig. 1 (B, C, D), the AMH levels pre-USgHIFU, 1-month post-USgHIFU, 3-month post-USgHIFU and 6-month post-USgHIFU in all the 3 subgroups were statistically insignificant ( p > 0.05).

Factors influencing AMH levels at the 1-, 3-, and 6-month follow-ups

Multivariate linear regression analyses were used to determine the relationships between AMH levels and other variables, which included patient age, treatment time, body mass index, fibroid location, and fibroid type. The results revealed that age was independently associated with AMH levels at the 1-, 3-, and 6-month follow-ups (Table 3 ).

USgHIFU is a safe and reliable noninvasive treatment for uterine fibroids [ 18 , 19 , 20 ]. It has been shown to be effective in reducing the size and symptoms of uterine fibroids, such as heavy menstrual bleeding, pelvic pain, and urinary symptoms. Previous studies reported that the fibroid volume reduction rates at 3, 6, and 12 months after treatment were 58.08%, 66.18%, and 77.59%, respectively [ 21 ]. Others reported that the mean fibroid volume reduction in 36 patients was 17.3% at 1 month, 33.3% at 3 months, and 45.1% at 5 months after HIFU treatment [ 22 ]. The nonperfused volume rate evaluated by magnetic resonance imaging has been used as an important indicator of the success of HIFU ablation for uterine fibroids [ 23 ]. Our study revealed that the 1-month and 6-month nonperfused volume rates were 91.80% and 82.21%, respectively. Even when the nonperfused volume rate was reduced, the fibroids still shrunk: the fibroid volume reduction rates compared with the initial fibroid volume at 1, 3, and 6 months after treatment were 20.03%, 45.58%, and 45.37%, respectively.

The UFS-QOL questionnaire is a validated questionnaire designed to assess the impact of uterine fibroid symptoms on women’s health-related quality of life [ 24 , 25 ]. It assesses the physical, social, and emotional impacts on patients with uterine fibroids, including symptoms such as pelvic pain, bleeding, and urinary problems, as well as the impact on daily activities, emotional well-being, and sexuality. The UFS-QOL questionnaire consists of 31 questions that patients are required to complete before and at 1 and 6 months after USgHIFU treatment. A raw score of 1 ~ 5 points, representing symptoms from mild to severe, is assigned to each of the items, and the final score is obtained by summing the raw scores of related items [ 17 ]. Our results convincingly show that, compared with the initial UFS-QOL score, the UFS-QOL score decreased by 18.57% at 1 month and 25.71% at 6 months after treatment.

As women age, the number and quality of primordial follicles decline, and the ovarian reserve decreases. AMH is a member of the transforming growth factor beta protein family. It is produced by the granulosa cells of the ovarian follicles, and its expression increases as the follicles grow from the primary to the small antral stage [ 26 ]. AMH levels are not affected by the menstrual cycle and are more accurate at reflecting the ovarian reserve than follicle stimulating hormone levels and the antral follicle count are. It is a good indicator of the number of small antral follicles remaining in the ovaries, which is directly related to the ovarian reserve [ 13 , 27 ].

Uterine artery embolization is recommended as another nonsurgical treatment for uterine fibroids in patients who desire uterine conservation. During uterine artery embolization, an embolic agent is delivered through the catheterization of both uterine arteries, blocking blood flow to the fibroids and causing involution. Most studies have shown that women who undergo uterine artery embolization for uterine fibroids have an increased risk of decreased ovarian reserve or premature menopause, depending on factors such as the size and location of the fibroids and the type of particles used in the embolization procedure [ 28 , 29 ]. In contrast, a more recent meta-analysis of 6 studies and 353 participants revealed no effect on ovarian reserve, as measured by AMH and FSH levels at 12 months after the procedure [ 30 ]. The small number of available studies makes it difficult to draw accurate conclusions about ovarian reserve with uterine artery embolization [ 7 ]. During HIFU treatment, high-intensity ultrasound waves are directed to the precise location of the fibroid, causing ablation of the fibroid vascularity. This may be an advantage of HIFU over uterine artery embolization because it does not interfere with ovarian perfusion by blocking the uterine arteries.

In our study, all 69 patients were successfully treated with USgHIFU, and no complications occurred in any of the patients. As shown in Table 2 , there was no change in AMH levels in women who underwent USgHIFU before or six months after treatment. Similarly, several studies have shown that USgHIFU has no effect on the ovarian reserve [ 9 , 31 , 32 ].

AMH levels are known to decrease with age, and the main strength of our prospective study is that we examined possible changes in AMH levels in different age subgroups. The results revealed that there was no change in AMH levels regardless of age (less than 40 years, 40 to 45 years, or 45 years and older). Higher total treatment energy and longer treatment times may be required for larger fibroids, and ovarian function after HIFU treatment may be correlated with the location of fibroids. However, our study revealed that HIFU treatment has no effect on AMH levels regardless of fibroid location, type or treatment time.

The present study has several implications for clinical practice and future research. First, we demonstrated that USgHIFU is safe and effective in improving quality of life. Second, this study also showed that USgHIFU treatment did not have a significant impact on ovarian reserve. This is particularly reassuring for counseling patients, especially relatively young women who are concerned about future pregnancies. Finally, based on our results, future research would be focused on directly assessing whether USgHIFU treatment has a negative impact on maternal and neonatal outcomes.

Compared to previous studies on similar topics [ 31 ], the strength of our study lies in the sequential measurement of AMH at multiple time points after USgHIFU, providing a more nuanced understanding of AMH changes. Although this prospective study may have successfully demonstrated the efficacy and safety of USgHIFU in the treatment of uterine fibroids, there are several limitations to this study. The main limitation of the study is the small sample size. In addition, the follow-up period was only six months. Multicenter, large sample, and randomized controlled trials with more ovarian reserve biomarkers, such as serum follicle-stimulating hormone and serum estradiol, are expected to be conducted in the future. Importantly, USgHIFU does not affect ovarian function; therefore, further research is needed to fully understand the impact of USgHIFU treatment on pregnancy outcomes. At last, comparison of USgHIFU with other fibroid treatment modalities, such as uterine artery embolization, would provide more information on the impact of ovarian reserve.

In conclusion, USgHIFU is an effective and noninvasive procedure for the treatment of uterine fibroids. It has been shown to improve quality of life and has no adverse effects on the ovarian reserve in the short or long term.

Data availability

The data are not publicly available due to privacy or ethical restrictions.

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Acknowledgements

This work was supported by the Program of Shanghai Academic Research Leader (No. 22XD1403500), the Central Guidance on Local Science and Technology Development Fund of Shanghai Province (No. YDZX20223100003006), the Shanghai Municipal Key Clinical Specialty (No. shslczdzk06302), the “Science and Technology Innovation Action Plan” International Science and Technology Cooperation Project (No. 20550760600), and the Shanghai Science and Technology Commission (21Y11906600).

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Wei Gu and Jiangjing Yuan contributed equally to this work.

Authors and Affiliations

Department of Gynecologic Oncology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China

Wei Gu, Jiangjing Yuan, Yuhong Li & Yudong Wang

Shanghai Municipal Key Clinical Specialty, Shanghai, China

Wei Gu, Jiangjing Yuan, Yun Zhou, Yuhong Li & Yudong Wang

Department of Ultrasonography, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China

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YDW was involved in planning and designing the study, interpretation, and manuscript revision and has the final responsibility for the manuscript. WG was involved in planning and designing the study, generating the dataset, manuscript writing, and statistical analyses. JJY was involved in conceiving and designing the study and writing and revising the manuscript; YZ was involved in performing the USgHIFU procedure, data analysis and interpretation. YHL was involved in planning and performing the literature review and editing the manuscript. All authors reviewed the manuscript.

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Correspondence to Yudong Wang .

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This study was approved by the Ethics Committee of the International Peace Maternity and Child Health Hospital (GJEC-A-2017-08-1). All methods were performed in accordance with the relevant guidelines and regulations. All participants provided written consent before participation.

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Gu, W., Yuan, J., Zhou, Y. et al. Impact of ultrasound-guided high-intensity focused ultrasound for the treatment of uterine fibroids on ovarian reserve and quality of life: a single-center prospective cohort study. BMC Women's Health 24 , 470 (2024). https://doi.org/10.1186/s12905-024-03315-5

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Theses & Dissertations

Long term health related quality of life following uterine fibroid embolization at aga khan university hospital, nairobi.

Michael Muthoka Kioko , Aga Khan University

Date of Award

Document type.

Dissertation

Degree Name

Master of Medicine (MMed)

First Supervisor/Advisor

Professor Marleen Temmerman

Second Supervisor/Advisor

Dr. Adelaide Lusambili

Third Supervisor/Advisor

Dr. Timona Obura

Obstetrics and Gynaecology (East Africa)

Background: Uterine Fibroid Embolization (UFE) is one of the effective options available for treatment of symptomatic uterine fibroids with documented improvement in the quality of life and reduction in symptoms. Most of the studies have demonstrated an improvement in the quality of life over a short to intermediate period. We carried out this study to assess the long-term quality of life following uterine fibroid embolization in a predominantly black population. There are no identified studies locally or in Africa addressing this issue whereas studies done elsewhere indicate a probable increased fibroid disease burden among black women.

Objectives: Our objectives in this study were to determine the long-term health related quality of life, symptom severity and follow up procedures after UFE at Aga Khan University Hospital, Nairobi using the Uterine Fibroid Symptom and Quality of life (UFS-QOL) tool.

Methods: This was a retrospective single cohort study that recruited patients who had UFE between 2009-2014. Study participants were sampled consecutively, invited to the study and asked to fill an online general demographic tool and the UFS-QOL. A minimum calculated sample size of 60 was determined adequate to achieve the primary objective. The primary objective was to determine the health related quality of life outcome. The secondary objective was to assess symptom severity among the participants.

Results: Data was obtained from 77 participants. The median duration after the initial UFE was eight years. The median health related quality of life was 88.6 (62.9-98.3). This was statistically significant from baseline median scores of similar studies. The median symptom severity score decreased from a baseline score of 54.7 (43.8-65.6) to 21.9 (6.3-42.2). This decrease was statistically significant (p-value

Conclusion: UFE results in clinically sustained improvement in health related quality of life and symptom control among patients with uterine fibroids.

Recommended Citation

Kioko, M. M. (2020). Long term health related quality of life following Uterine Fibroid Embolization at Aga Khan University Hospital, Nairobi (Unpublished master's dissertation). Aga Khan University, East Africa.

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Uterine Fibroid Research

James h. segars.

1 Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

Uterine fibroids are the most common disease of reproductive-age women, affecting 25% of African American women at the age of 25 1 and up to 80% African American women by the age of menopause. 2 , 3 Although it is clear that uterine fibroids are a health disparity issue 4 , they affect women of all races and add billions of dollars in cost each year to the US health care system. Globally as well, uterine fibroids are among the most significant diseases of reproductive-age women. Despite the magnitude of the problem, nonsurgical and medical options for treatment are extremely limited.

One reason for the limited treatment options is that funding for research on uterine fibroids has been sparse in comparison to the scope of the problem. Uterine fibroids are wholly deserving of research effort because investments will also inform the disciplines and fields of: tumor biology, angiogenesis, mechanical signaling, fibrosis, and genetics. Consider for a moment that uterine fibroids frequently grow many centimeters in size but only very rarely will metastasize. Thus, investment of resources will pay dividends not only for the understanding of uterine fibroids but also for many pathophysiologic states and other fields of medicine. Recently, PCORI has launched an initiative to address this disparity of research funding. This issue of Reproductive Sciences is significant because it reflects a dividend of investment of resources and investigator effort to address this prevalent disease.

Specifically, 5 of the articles in this issue address the disordered pathophysiology of uterine fibroids, the root cause, and/or growth of fibroids. Studies examine collagen-binding α11 integrin, nicotinamide adenine dinucleotide phosphate oxidase, telomerase, PLZF and H1.5, and mechanical signaling. These studies shed light on the disordered mechanisms of this disease. Although the etiology of commonly occurring spontaneous fibroids remains unclear, some tenets have emerged through the lens of current research that begin to provide a view of fibroid formation, albeit “through a glass, darkly.” One factor that likely contributes to the conflicting views of fibroid formation is that all fibroids are not the same: some are growing, some are static, and others are regressing 3 ; a fact that is now clear but is not always considered in the analysis of specimens by investigators.

As noted previously, a particular problem is the absence of medical approaches for treatment. Five of the studies from this issue address the response of fibroids to new treatment strategies, including Paricalcitol, Ulipristal acetate, Fasudil, Flavopiridol, and Celecoxib a cyclooxygenase inhibitor. These innovative studies provide the important and necessary first step in the clinical continuum toward drug development and new therapeutic strategies for the treatment of uterine fibroids. Additionally, 3 of the studies examine diagnosis and clinical manifestations of disease. Proper diagnosis is increasingly important, as illustrated by the current controversy that surrounds morcellation of fibroid tissue.

Thus, this issue of Reproductive Sciences is an important step toward improved care for women with uterine fibroids but more is needed. As scientists, we need to understand the mechanisms involved in fibroid formation and growth, the different types of fibroids and the genetic underpinnings of this disease. As clinicians and researchers, we need to develop robust methods to measure outcomes other than bleeding, currently the primary metric used for approval of drugs for this condition. As a society, we need to go beyond treatment to focus on prevention of uterine fibroids since this is the most effective method, not only from a cost perspective but also for the health of women. As readers of the journal, we celebrate this focused issue and thank the editor and erstwhile renew our continued commitment for additional research for the millions of women affected by this significant and disabling disease.

Author’s Note: The views expressed in this article are those of the author and do not reflect the official policy or position of the US Government.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funded, in part, by ZIA HD008737 to JHS.

Open access
Published: 19 August 2024

Deep learning based uterine fibroid detection in ultrasound images

Haibin Xi 1 &
Wenjing Wang 1

BMC Medical Imaging volume 24 , Article number: 218 ( 2024 ) Cite this article

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Uterine fibroids are common benign tumors originating from the uterus’s smooth muscle layer, often leading to symptoms such as pelvic pain, and reproductive issues. Early detection is crucial to prevent complications such as infertility or the need for invasive treatments like hysterectomy. One of the main challenges in diagnosing uterine fibroids is the lack of specific symptoms, which can mimic other gynecological conditions. This often leads to under-diagnosis or misdiagnosis, delaying appropriate management. In this research, an attention based fine-tuned EfficientNetB0 model is proposed for the classification of uterine fibroids from ultrasound images. Attention mechanisms, permit the model to focus on particular parts of an image and move forward the model’s execution by empowering it to specifically go to imperative highlights whereas overlooking irrelevant ones. The proposed approach has used a total of 1990 images divided into two classes: Non-uterine fibroid and uterine fibroid. The data augmentation methods have been connected to improve generalization and strength by exposing it to a wider range of varieties within the training data. The proposed model has obtained the value of accuracy as 0.99. Future research should focus on improving the accuracy and efficiency of diagnostic techniques, as well as evaluating their effectiveness in diverse populations with higher sensitivity and specificity for the detection of uterine fibroids, as well as biomarkers to aid in diagnosis.

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Introduction

Fibroids are non-cancerous/benign growths that occur in the muscle wall of the uterus of the woman. These Uterine Fibroids (UF) are commonly found in middle-aged and elderly women with an occurrence rate of 20–25% in women over 30 years old. Pelvic pain, infertility and heavy menstrual bleeding are the common symptoms of UF [ 1 ]. However, hormonal imbalances and genetics may be one of the reasons but the accurate cause of UF is unknown. UF can have a substantial impact on women’s reproductive health and quality of life as UFs are a major cause of hysterectomies worldwide, losing their uterus each year due to fibroids [ 2 ]. Ultrasound (US) imaging is a non-invasive and commonly used to diagnose and monitor UF. Initial diagnosis of UF typically involves ultrasound images but treatment depend on the type, size, and location, as well as the symptoms and the reproductive goals. Generally, medications are suggested to reduce fibroid size and to control the symptoms [ 3 , 4 ]. However, manual identification of UFs in the US can be challenging for small or obscured lesions. Therefore, deep learning offers a promising method for automatic classification of UFs in ultrasound images. As per the literature review, it has been observed that deep learning models can achieve high accuracy in classifying non-fibroids and fibroids by surpassing human performance in certain cases. Moreover, it helped in removing human bias and subjectivity from the classification process leading to more consistent results. Automated classification can potentially lead to earlier detection of UFs, allowing for timely intervention and improved patient outcomes by saving radiologists and sonographers valuable time. Therefore, in this proposed work, attention mechanism is combined with EfficientNetB0 model for the uterine fibroids classification from ultrasound images. The chief offerings of the study are as follows:

An attention based fine-tuned EfficientNetB0 model is proposed for the classification of uterine fibroids from ultrasound images. Attention mechanisms, permit the model to focus on detailed parts of an image and improve the model’s performance by enabling it to selectively attend to important features while ignoring irrelevant ones.

The data augmentation techniques have been applied to improve model generalization and robustness by revealing it to a wider range of disparities in the training data.

The rest of the research is shown as: Sect. 2 shows the literature review, followed by dataset description in Sect. 3 , methodology in Sect. 4 followed by results in Sect. 5 , conclusion and future scope in Sect. 6.

Literature review

The researchers had performed work on the classification of UF. They had worked using 3D CNN using a dataset of 3D ultrasound images and had obtained the value of accuracy as 91.3% [ 5 ]. The researchers commended the 3D CNN points of interest over conventional 2D in identifying UF due to its upgraded capacity to seizure spatial information. Authors [ 6 ] attained 98.8% accuracy by employing a pre-trained ResNet50 CNN calibrated on their dataset of 2D ultrasound images. A study [ 7 ] accomplished 96.4% accuracy utilizing the VGG16 model, which was prepared on their ultrasound images dataset. The proposed model extracted highlights from US images employing a grouping of convolutional layers. The proposed model had an accuracy of 97.5%, illustrating the adequacy of DCNNs inside the assurance of UF [ 8 ]. In a study [ 9 ], examiners proposed a cross breed DL illustrated to recognize UF. The ultrasound images were fed into the show, and highlights were removed utilizing a gathering of CNN and dreary neural frameworks. The revelations of the think about show up that the hybrid DL show has the potential for utilize in helpful picture dealing with since the proposed demonstrate accomplished an accuracy of 96.8%. For the location of UF from ultrasound images, another thinks about [ 10 ] proposed a DCNN plan. The proposed shows extricated characteristics from ultrasound images utilizing a combination of convolutional and pooling layers. The proposed demonstration showed up that DCNN can be profitable for recognizing UF with an accuracy of 96.7%. A DL-based system was proposed for programmed UF location from ultrasound pictures in think about [ 11 ] to extricate qualities from the ultrasounds.

Dataset description

Input dataset.

The dataset comprises 1990 images divided into two classes: Non-uterine fibroid (NUF) and uterine fibroid (UF) as shown in Fig. 1 [ 12 ]. The data is split into an 80 − 20 ratio for training and testing, respectively. for the test set, the total NUF is 223 and UF is 173, whereas for the train set, the total NUF is 892 and the total UF is 702. Each image is resized to a uniform size of 224 × 224 pixels. This dataset is crucial for the development and evaluation of deep learning models aimed at the automated detection and classification of uterine fibroids. The class imbalance between the two classes presents a challenge that must be addressed to ensure the model’s robustness and effectiveness. The utilization of such a dataset enables the exploration and implementation of various deep learning architectures and algorithms for improved diagnosis and treatment planning in the context of uterine fibroids.

( a ) Non-Uterine Fibroid (NUF): The red arrow points to the fibroid mass located outside the uterus. ( b ) Uterine Fibroid (UF): The blue arrow points to the fibroid mass within the uterus. The dataset

Data augmentation

Information increase could be a vital strategy in machine learning for misleadingly growing a dataset by making altered adaptations of images [ 13 ]. This process makes a difference move forward demonstrate generalization and robustness by uncovering it to a wider range of varieties within the training data, such as rotations, translations, flips, and changes in brightness or contrast. By augmenting the dataset, the model learns to recognize objects in various positions, orientations, and lighting conditions, making it more effective when applied to real-world data.

Random Rotation: Randomly rotates the image by a factor of up to 0.15, introducing variations to the orientation of the images.

Random Translation: Randomly translates the image horizontally and vertically by up to 10% of the image height and width, respectively, adding positional variance.

Random Flip: Randomly flips the image horizontally or vertically, augmenting the dataset with mirror images.

Random Contrast: Randomly adjusts the contrast of the image by a factor of up to 0.1, modifying the intensity of pixel values.

These augmentation methods offer assistance to avoid overfitting and move forward the model’s generalization by exposing it to a more extensive extend of varieties inside the dataset, eventually upgrading the model’s execution on unseen information. After the application of information augmentation procedures presently the image count expanded to 10,000. Out of which 8000 images are taken for training and 2000 images are taken for testing reasons.

Methodology

The Fig. 2 has outlined the process of developing a deep learning model for ultrasound image classification. The specific task here is to distinguish between uterine fibroids (UF) and non-uterine fibroids (NUF) in ultrasound images. The process started with a data source of ultrasound images. Subsequently, data augmentation has been applied to enhance the robustness of the model by including some operations like random rotations, translations, flips and contrast adjustments. Following the augmentation, the data has been fed into a pre-trained EfficientNetB0 model, which is a kind of convolutional neural network (CNN) architecture that has been specifically a kind of artificial neural network suggested to analyse visual images. EfficientNetB0 model has acted as a feature extractor by learning patterns from the data. Furthermore, an attention mechanism has been incorporated to the EfficientNetB0 model which has allowed the proposed model to focus on relevant aspects of the input data that are most relevant to the task. Afterward, the global average pooling layer was employed to sum up the features that have been extracted by the EfficientNetB0 model [ 14 ], which were afterward followed by a dropout layer that randomly dropped out a specified percentage of neurons during the training to mitigate the overfitting. Henceforth, the data has been served to a dense layer with a softmax activation function. The softmax function has generated a probability distribution over two set of classes that is Uterine Fibroid (UF) or Non-Uterine Fibroid (NUF).

Proposed methodology

Lastly, the hyperparameters such as learning rate, optimizer, and batch size of the model have been tuned to manage the learning process of the model. Tuning of these hyper-parameters has involved setting of their values to accomplish optimal model performance. This optimization process is normally concerned the evaluation of the model’s performance on a validation set with diverse combinations of hyperparameter values. The objective is to determine the set of hyperparameters that has obtained the best balance between efficiency and accuracy.

EfficientNetB0 model

EfficientNetB0 is a CNN architecture that has been proposed to obtain the balance between the state-of-the-art performance and computational efficiency. Scaling approach has been employed that allowed the EfficientNet model to get better performance as compared to existing models while being more efficient in terms of computational resources in terms of width, depth and resolution. EfficientNetB0 has achieved better performance by scaling these dimensions in a organized way than the other models that only scale one or two dimensions while claiming computational efficiency. EfficientNetB0 has appeared to realize state-of-the-art execution on different picture classification assignments while being more proficient in terms of show measure and computational assets compared to other models. EfficientNetB0 has scaled the width by increasing the number of channels in each layer, the depth of the network by increasing the number of layers and the resolution by increasing the input image size. This multi-dimensional scaling approach has contributed to the model’s superior performance. It is efficient on resource-constrained gadgets such as portable phones or implanted frameworks, where computational assets are constrained [ 15 ]. In this work, the EfficientNetB0 model has been optimized through fine-tuning which entailed freezing the weights of the pre-trained base model (base_model) while adding new layers (GlobalAveragePooling2D, Dropout, Dense) on top of it for a new classification task. The frozen base model has acted as a feature extractor by capturing general features from the input images. The new added layers are then trained to learn task-specific features from these extracted features to enhance the model’s performance.

Fine-tuning is performed because pre-trained models like EfficientNetB0 have already learned rich representations from a large dataset (e.g., ImageNet) and can generalize well to new tasks with less data. Instead of training a model entirely from scratch, the power of fine-tuning has been employed. This process has taken a pre-trained model, that is EfficientNetB0, which has already learned valuable features from a massive dataset. These learned features have been adapted to the specific task by fine-tuning for the classification of uterine fibroids. This scheme has offered several benefits. Fine-tuning has led to faster progress as the model does not need to re-learn the elementary image recognition skills which permitted it to focus on the unique characteristics of fibroids in ultrasound images resulting in quicker training times. While dealing with the limited data, fine-tuning has improved the performance. The pre-trained model has acted as a strong basis and fine-tuning has aided it in adapting to the specific patterns in the fibroid classification dataset. This is very helpful when the dataset is fairly small as there is less information for the model to learn from scratch. Finally, fine-tuning has aided in avoiding the overfitting. The pre-trained weights were performed as a method of control which prevented the model from learning specific details in the training data that might not generalize well to unseen images. Moreover, fine-tuning has permitted the model to transfer knowledge acquired from the pre-trained model’s substantial dataset, even if the unfamiliar fibroid dataset is lesser.

Proposed attention mechanism based EfficientNetB0 method

In this research work, a new model named as Attention based EfficientNetB0 has been developed where EfficientB0 is a CNN architecture known for its performance and efficiency which has been improved by the addition of attention mechanisms. The attention mechanism has allowed the model to prioritize the precise areas of an image that are most appropriate for the desired task. This has improved the performance of the model by allowing it to select the significant features while ignoring the inappropriate ones. In the context of EfficientNetB0, attention mechanisms have been typically applied in the form of attention layers, which are added at the several phases of the network. These layers have enhanced the capability of model to capture fine-grained details and long-range dependencies within an image which lead to better generalization and improve feature representation.

Therefore, attention mechanisms have been incorporated to further enhance the capabilities of the model. The integration of attention mechanisms has significantly enhanced the performance of EfficientNetB0 by capturing crucial dependencies and contextual information from images by mimic the human visual focus that allowed the model to highlight specific image regions which are most relevant to the task. There are two main types of attention mechanisms that can be beneficial: Self-Attention has enabled the EfficientNetB0 to capture long-range dependencies and contextual information within the image. It has essentially allowed different regions of the image to communicate with each other that lead to more comprehensive understanding of the content. By employing self-attention, EfficientNetB0 has effectively learned the global dependencies within an image. This attention mechanism has aided in identifying relationships between distant image elements for improving performance in various tasks. Another Spatial Attention mechanism has focused on specific locations within the image. It has focused on specific image regions highlighting the areas of interest while suppressing non-relevant ones in tasks where spatial information is essential, such as object detection and segmentation. Integrating attention mechanisms into EfficientNetB0’s architecture has involved the addition of attention layers. A prevalent approach is to integrate the self-attention through the transformer mechanism which has enhanced the model’s ability to extract relevant information from images by boosting its performance in computer vision tasks.

Hyperparameter tuning

In this work, proposed model has been trained using four distinct hyperparameters named as batch size, optimizer, learning rate and epochs.

It determined the number of training examples used in a single update of the model’s internal parameters during gradient descent. It could be a vital hyperparameter in deep learning models that influences both the training speed and the quality of the model. Choosing a suitable batch estimate depends on the particular dataset size, model complexity, and available resources. Batch size is regularly tuned along with other hyperparameters to optimize the execution of the demonstrate. Batch size is related to the training set size (N) and the number of iterations per epoch (M) by the given formula.

Where N is the total number of training examples. M is the number of iterations per epoch.

Nadam Optimizer is an optimization algorithm in place of the Adam optimizer that has combined the benefits of Nesterov accelerated gradient (NAG) descent and Adam. By integration of the NAG technique, Nadam is the modification over Adam by enabling more precise and stable convergence. It has integrated the NAG technique to adjust the update direction based on momentum with adaptive learning rates for each parameter. This integration has permitted Nadam to offer steadier and more effective optimization in comparison to the other optimizers. It is helpful in providing training to deep neural networks where fast convergence and robustness to noisy data are crucial. Nadam’s adaptive learning rate method has assisted in navigating complex loss settings which makes it a widespread selection for various deep learning tasks.

An epoch is represented as a single training cycle where the entire dataset is fed through the model once. During each epoch, the model has renewed its internal parameters (weights and biases) based on the errors (loss) it has faced in the training. Training for more epochs has permitted the model to learn from the data multiple times to improve its performance. However, it may lead to overfitting. Overfitting occurs when a model has memorized the training data too well, losing its ability to generalize to unseen data. It’s a balancing act: train for too few epochs and the model might underfit (fail to learn the patterns in the data), train for too many and you risk overfitting. Epochs are related to the batch size ( B ), the total number of training examples ( N ), and the number of iterations per epoch ( M ) by the formula:

Learning rate

The learning rate is a hyperparameter in deep learning that controls the step size during optimization. The learning rate is typically set before training and can be fixed or adjusted dynamically during training using techniques like learning rate schedules or adaptive learning rate methods. In this work, the learning rate is set to 0.00005. Lower learning rates often result in a more stable optimization process, as the updates to the parameters are smaller and less likely to lead to divergence. With a lower learning rate, the optimization algorithm takes smaller steps toward the minimum point, potentially allowing it to find a more precise solution.

Accuracy and loss analysis

The Fig. 3 represents the accuracy metrics of a model trained over multiple epochs. Each row corresponds to an epoch number, and the columns indicate the accuracy achieved on the training data (Accuracy) and the validation data (Val_Accuracy) at that epoch. The accuracy values show a clear trend of improvement over epochs for both the training and validation sets. Initially, at epoch 1, the model started with a relatively low training accuracy of 56.11% on the training data and an even lower 34.85% validation accuracy, indicating that the model is not performing well and likely underfitting. However, as the training progresses, the model’s performance has been improved significantly. By epoch 4, the model has achieved a high training accuracy of 96.70% on the training data and 86.11% validation accuracy on the validation data, indicating that the model is learning the underlying patterns in the data well. Towards the later epochs, the model’s performance has continued to improve, with accuracy values nearing 100% on both the training and validation sets. From these experiments, it has been observed that the model has learned the dataset’s features effectively and is performing very well, likely indicating that it has reached a point of overfitting, especially as the validation accuracy started to plateau.

Proposed Attention based fine-tuned EfficientNetB0 model’s accuracy

Figure 4 displays the loss metrics of a proposed model trained over ten epochs, showing both training loss (Loss) and the validation loss (Val_Loss) at each epoch. At initial state, during epoch 1, both the training and validation losses are relatively high, which indicated that the model has not performed well and likely has high error rates.

Loss of Attention based fine-tuned EfficientNetB0 model

However, as the training progressed, the losses steadily has decreased which indicated that the model has improved its performance by learning the dataset’s patterns. By epoch 4, the losses have reduced significantly, indicating that the model has become more accurate by making fewer errors. This trend continued with the losses decreasing further in each subsequent epoch. Towards the later epochs, the model’s performance has continued to improve, with the losses approaching very low values. This suggested that the model has learned the dataset well and has performed well at a high level of accuracy, especially as the validation loss closely tracked the training loss, indicating that the model did not have any overfitting issue.

State-of-art comparative analysis

The table has listed a comparative analysis of various techniques and their corresponding accuracy rates. Table 1 , it has shown that Dilna et al. [ 11 ] have achieved an accuracy of 95.1% in classifying ultrasound scanned uterus images indicating the effectiveness of their classification method. Furthermore, Behboodi et al. [ 10 ] have utilized UNet-based networks for US diagnostic imaging and have achieved an accuracy of 86.2% with the consideration of the utility of this architecture for medical image analysis. Besides, Li et al. [ 16 ] have used deep learning on the ChEMBL dataset by achieving an accuracy of 85% which shows the potential of deep learning for pharmaceutical research. Moreover, Tang et al. [ 17 ] has introduced the AR-Unet Network and has achieved an impressive accuracy of 94.56% on the AR-Unet dataset which indicated the robustness of approach. Then, Yang et al. [ 18 ] utilized neural networks on an ultrasound image and achieved an accuracy of 88.5% which demonstrated the effectiveness of deep learning for medical image analysis. Girija et al. [ 19 ] has employed various data mining techniques on 450 patients with an accuracy of 89.54% which has illustrated the importance of data mining in healthcare research. Additionally, Huo et al. [ 20 ] have used a Deep learning-based method on a dataset of 3870 ultrasound images with an accuracy of 87.45%. Overall, the accuracies attained by these studies have displayed the efficiency of different methods and procedures in healthcare with each approach showcasing its strengths in diverse perspectives.

Conclusion and future scope

Fibroids in the uterine are a gynaecological disorder that can substantially influence the health of women and their quality of life. Fibroids can impede the implantation of a fertilized egg or interrupt the blood flow to the uterus which may lead to recurrent miscarriages or infertility. Thus, early detection of uterine fibroids (UF) is essential for maintaining the fertility. By early treatment of fibroids, these risks can be reduced, and women can have a better chance of conceiving and carrying a pregnancy. Though, all fibroids don’t cause any symptoms or require any form of treatment, therefore, detection of those that are likely to cause problems can help in providing treatment plans to individual needs. This can lessen the use of unnecessary treatments and minimize the impact of fibroids. Another challenge is the lack of reliable diagnostic tests for uterine fibroids. Therefore, in this work, for the early detection of fibroids in the uterine, an attention mechanism based fine-tuned EfficientNetB0 model has been proposed for the classification of uterine fibroids and non-fibroids from ultrasound images.

Future research directions include the use of biomarkers that can specify the occurrence of fibroids at an early stage or predict their growth and progression at diverse stages. Biomarkers such as specific proteins or genetic markers could help to improve the accuracy of diagnosis and guide in treatment decisions. This will help to ensure that new diagnostic techniques are applicable and accessible to a wide range of women, regardless of their age, ethnicity, or socioeconomic status.

Data availability

Dataset of Fibroid is publicly available at https://data.mendeley.com/datasets/n2zcmcypgb/2 .

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Department of Obstetrics and Gynecology, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Xinghualing District, Taiyuan City, 030001, Shanxi Province, China

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Haibin Xi and Wenjing Wang participated in the design of this study, and Haibin Xi performed the statistical analysis. Haibin Xi and Wenjing Wang carried out the study and collected background information. Haibin Xi drafted the manuscript. All authors read and approved the final manuscript.

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Xi, H., Wang, W. Deep learning based uterine fibroid detection in ultrasound images. BMC Med Imaging 24 , 218 (2024). https://doi.org/10.1186/s12880-024-01389-z

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Risk factors

Early menarche

Caffeine and alcohol

Genetic factors

Other factors

Classifications

Pelvic examination

Ultrasonography

Hysteroscopy

Magnetic Resonance Imaging

Hysteroscopic myomectomy

Laparoscopic myomectomy

Laparoscopic hysterectomy

Laparoscopic cryomyolysis and thermo-coagulation

Laparoscopic occlusion of the uterine arteries

Uterine artery embolization

High-frequency magnetic resonance-guided focused ultrasound surgery

Vaginal occlusion of the uterine arteries

GnRH agonists

Evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids by use of selective progesterone receptor modulators

SPRMs and fibroids: what we know so far

Long-term intermittent administration of SPRMs, opening up new treatment perspectives

Novel approaches and algorithms, with a special emphasis on infertility

Type 0 myomas

Type 1 myomas

Type 2 or type 2–5 myomas (single or multiple) distorting the uterine cavity

Young women of reproductive age with symptomatic myomas and wishing to preserve their fertility but having no immediate desire for pregnancy

Asymptomatic women with myomas and undergoing IVF or oocyte donation

Premenopausal women presenting with symptomatic myomas and with no desire for pregnancy but a wish to keep their uterus

Uterine fibroid associated pathologies

Endometriosis

Adenomyosis

Future prospectives for medical therapy

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Mapping the cultural and social landscape of uterine leiomyomas: Fibroid tumors as a Black woman's disease

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Evaluation of current knowledge and education practices regarding uterine fibroids amongst Black women

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A look at the current state of uterine fibroid care

Impact of ultrasound-guided high-intensity focused ultrasound for the treatment of uterine fibroids on ovarian reserve and quality of life: a single-center prospective cohort study

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Preprocedural preparation and evaluation

Patient quality of life

Follow-up evaluation

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Changes in quality of life, nonperfused volume ratio, and reductions in the treated volume and hemoglobin level over time

AMH level assessment

Factors influencing AMH levels at the 1-, 3-, and 6-month follow-ups

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