Summary
Contents showUterine leiomyomas are the most common benign tumor in women of reproductive age. Uterine leiomyomas are produced by the clonal expansion of myometrial stem cells under certain circumstances.
Patients with uterine leiomyomas could present with nonspecific symptoms or be otherwise asymptomatic. Among those presenting with complaints, common manifestations include abnormal genital bleeding, abdominal or pelvic pain, dyspareunia, dysmenorrhea, and symptoms due to local compression of viscera (bladder and rectum).
Diagnostic strategies include anamnesis and physical examination, diagnostic imaging (ultrasound and MRI), and laboratory studies. Treatment of uterine leiomyomas depends upon the type and location of leiomyoma(s) (FIGO classification), which could involve medical or surgical therapy.
Introducing Uterine Leiomyomas (Uterine Fibroid)
It is the most frequent benign estrogen-dependent mesenchymal tumor affecting fertile women.
Uterine leiomyomas (UL) could be symptomatic or not and may vary in number and size.
Women who are symptomatic have an alteration in their quality of life, and in a great number of cases, the resolution may involve surgery and even hysterectomy (1). Based on this and the consequences that they can generate, it is very important to know how to diagnose and treat accordingly.
Definition of Uterine Leiomyoma
Uterine leiomyomas, also called myoma, leiomyoma, leiomyoma uteri, myoma uteri, and uterine fibroid. Leiomyoma is the most accurate term because it emphasizes the muscular origin. (1, 2)
UL originates from myometrium cells and comprises smooth muscle type of cells and fibroblasts, and is very rich in extracellular matrix (3). Due to the arrangement of its muscle fibers, it is a well-defined tumor, but it is not encapsulated (2).
Risk Factors for Uterine Leiomyoma Development
- The most important risk factors are age and ethnicity. UL are frequently seen among women of reproductive age (4, 5). African American women are more frequently associated with UL, but this could be due to some differences in lifestyle, diet, psychosocial stress, and environmental exposure (6-8).
- Menarche is associated with increased levels of estradiol which can lead to increased muscular growth, and there is a higher association when menarche is at an early age (< 10 years of age) (9). In addition, prenatal exposure to diethylstilbestrol (a non-steroidal estrogen analog) is also related (10).
- A diet poor on fruits and vegetables has been described as having an association with UL (11). Also, the increased consumption of caffeine and alcohol, especially beer, are associated with UL development risk (12).
- When we talk about obesity as a risk factor, we should remark that there is a complex relationship that could be related to changes in body habitus as an adult. Moreover, the increment of estrogens generated by the aromatization of androgens in fat tissue might play a role (13-15). Some authors also state that the risk of UL increases by 21% per 10 kg of overweight (16).
- Hypertension has been associated with UL diagnosis (17-19) and is hypothesized to be related to Angiotensin receptor activity.
- Vitamin D deficiency, which is also more frequent among women of African descent, has been related to leiomyoma production (20).
- Some environmental exposures like phthalates, polychlorinated biphenyl, and bisphenol seem to be linked to an increased risk linked by endocrine disruption (21).
Protective Factors
Prepubertal and menopause stages are related to less risk of UL (22). Also, exposure to long-acting progestins (depot medroxyprogesterone) might exert protective properties (23, 24).
In reference to food habits, a diet based on high consumption of green vegetables and fruits is protective (25). A study also mentioned that dairy consumption decreases the risk in a dose-response fashion; women who reported consuming ≥4 servings of dairy per day had a 33% decrease in the risk of leiomyomas compared with women who consumed <1 serving per day (26).
Dietary vitamin A from animal sources may also be associated with a decreased risk (27).
The presence of human papillomavirus has been reported in three cohorts as having some protector effect (28-30).
Epidemiology of Uterine Leiomyoma
UL are the most common pelvic tumors in women of reproductive age, affecting 1 in 4 adult women. They are the primary cause of hysterectomies in the United States and are a leading cause of hospitalizations for gynecologic conditions unrelated to pregnancy.
The individual and societal economy is affected by absence from work and healthcare costs associated with surgery, hospital admissions, outpatient visits, and medications. Black women suffer disproportionately from fibroids, with a prevalence 2–3 times higher than the one reported in white women. (31)
Pathophysiology of Uterine Leiomyoma Formation
The traditional description is that UL are composed of clonal smooth muscle cells that are steroid dependent and have characteristic chromosomal rearrangements underlying their development (32). A defining characteristic is an overproduction and the disorganized fibrous nature of the extracellular matrix (ECM). This matrix is basically composed of collagen, fibronectin, and proteoglycans. (33)
There is one cell, the myometrial stem cell, which can transform into a fibroid progenitor cell and start a proliferation process, which is thought to be a paracrine mechanism mediated by the WNT–β-catenin pathway, in addition to estrogen and progesterone (34). Because of this, stem cells seem to have low or absent levels of sex steroid hormone receptors but require these steroids for growth. This pathway can stimulate the expression of transforming growth factor-β3, which induces fibronectin, an ECM protein, expression, and cell proliferation (35).
In the beginning, it does not have blood vessels, but during the growth process, it drags connective and vascular elements to be independent of the normal myometrium. As expansive growth occurs and upon reaching a certain size, the UL displaces the normal muscle fibers, which, together with the connective tissue, are stratified in the form of concentric sheets, constituting a capsule around it and losing direct contact with normal muscle tissue. In this way, there would only be a macroscopic differentiation between the two that would make it possible to easily enucleate the tumor during surgical resection. (1)
Classification of Uterine Leiomyomas
UL are commonly classified into three subgroups based on their location: subserosal, projecting outside the uterus; intramural, within the myometrium; and submucosal, projecting into the cavity of the uterus. A more detailed classification system has been described by the International Federation of Gynecology and Obstetrics (FIGO) (36). This classification makes reference to the location of leiomyomas based on the uterine thickness they compromise (mucosal, serosal, or intramural) and does not indicate anything about size or symptoms. Both of these are relevant as well and are considered for choosing the correct treatment.
FIGO CLASSIFICATION
| Type 0 | Pedunculated leiomyoma, which is localized in the submucosa and extends inside the uterine cavity |
| Type 1 | Submucosal leiomyoma, with <50% in an intramural location |
| Type 2 | Submucosal leiomyoma, with ≥50% in an intramural location |
| Type 3 | Contacts the endometrium, with 100% in an intramural location |
| Type 4 | Intramural leiomyoma |
| Type 5 | Subserosal leiomyoma, with ≥50% in an intramural location |
| Type 6 | Subserosal leiomyoma, with <50% in an intramural location |
| Type 7 | Subserosal pedunculated leiomyoma |
| Type 8 | Other (for example, cervical or parasitic) |
Clinical Manifestations of Uterine Leiomyoma
- The uterine leiomyomata could be asymptomatic, or it could generate symptoms, including abnormal uterine bleeding. This bleeding could be intermenstrual or postmenopausal; therefore, it is very important to rule out other diagnoses (37). Based on these different types of bleeding, iron deficiency anemia can happen (38).
- Other symptoms that may occur are menstrual cramps and dysmenorrhea, which could be correlated with the amount of menstrual flow and or passages of clots. Also, pelvic pressure or bulk symptoms are mentioned by some patients; these could be related to the enlargement of the uterus and the irregularly shaped this can acquire, causing some symptoms related to the organ that is affecting, for example, the urinary tract or bowel obstruction, or venous compression (39).
- In some cases, dyspareunia is present. This is more frequently seen when the UL is located anterior or in the fundus (40). In addition, the serous-bloody vaginal discharge could also happen due to an ectropion of endocervical mucosa or necrobiosis and erosions of submucosal UL (1).
- Regarding reproductive dysfunction, infertility or obstetric complications such as preterm delivery, premature rupture of membranes, fetal malformation, cesarean section, postpartum hemorrhage, and miscarriage are some of the complications that can occur in pregnant women with UL (41-45).
- An infectious syndrome could also happen as a result of a degenerative process or infective process compromising UL. Cases of necrosis present with pain of rapid onset and moderate fever but without repercussions on the general condition. These symptoms are probably due to the reabsorption of the decomposition products of UL. Sudden and high fever, accompanied by chills, tachycardia, vomiting, and malaise, is almost always caused by a submucous myoma in the process of sloughing, which is accompanied by uterine bleeding and fetid vaginal discharge. (1)
- Endocrine effects are rare, but they are reported. Some UL can secrete ectopic hormones such as erythropoietin, causing polycythemia (46); parathyroid hormone-related protein causing hypercalcemia (47); and hyperprolactinemia (48).
Diagnosis of Uterine Leiomyomas
It is based on performing a complete evaluation of the patient, including anamnesis, evaluation of vital signs, and performance of an appropriate pelvic and abdominal examination. Sometimes the physical examination could be affected by patient factors, such as obesity in patients with small UL (< 3 cm). Abdominal palpation should aim at finding abnormalities, such as deformities or changes in consistency, followed by speculoscopy to look for bleeding or cervical lesions to rule out differential diagnoses or instances where the UL is protruding from the cervix.
Gynecological Examination
Vaginal examination helps in corroborating the uterus size or detecting if there is some mass effect. In case of identifying a mass, check its mobility. The diagnostic accuracy of bimanual examination is around 17%, and it increases to almost 26% when a transvaginal or abdominal ultrasound is done (49). Among women who presented with heavy menstrual bleeding (approximately 25 % of all cases), the probability of a diagnosis of UL by transvaginal ultrasound was 73,3 % (50).
Transvaginal Ultrasound
Transvaginal ultrasound had a 90% of sensitivity and 87% specificity. These could be improved with the addition of sonohysterography (that is, instilling saline into the uterine cavity), up to 100% and 98%, respectively (51, 52). The characteristic ultrasound image generally consists of a solid hypoechoic mass with regular contours and variable size. The use of standard transvaginal ultrasonography is limited when the uterus extends beyond the pelvis, a common problem with this disease. Thus, abdominal ultrasonography with proper bladder filling is required for the diagnosis.
Hysteroscopy
Hysteroscopy is used for diagnosed UL classified as 2 and 3 by the FIGO classification, and it is also the best option for evaluating these. This study allows evaluation of the cavity, identification of submucosal fibroids, and definition of the degree of intramural involvement. (1)
Magnetic Resonance Imaging
MRI is the most accurate study, with a sensitivity and specificity close to 100 % in assessing the fallopian tubes and ovaries (53). Also, it is useful for uterine evaluation because it provides information about the size, location, number, and perfusion of leiomyomas, as well as the presence of other uterine pathology (54-56). Although it is more expensive than ultrasonography, MRI is usually required for accurate diagnosis in a minority of patients, such as women with a larger body habitus, who have had prior surgery or do not tolerate either the transvaginal probe or the transvaginal instillation of contrast media.
Furthermore, the additional information gained might be useful for planning complex surgery or procedures that require visualization of fibroid vascularization and precise volume determination (57). Priority should be given to sagittal and coronal sections that allow a better evaluation of the uterine silhouette and the nodular imprint of leiomyomas (1).
Urodynamic Studies
Excretory urogram is indicated for cases where the tumor reaches a considerable volume and compresses the ureters. It is observed more frequently in those located in the broad ligament and in the cervical ligament. Knowing an extrinsic compression before surgery helps to define the approach.
Laboratory Studies
Laboratory test help rules out differential diagnoses. It is very important to know if the patient is pregnant or not, so a human chorionic gonadotropin is usually required; hemoglobin and hematocrit levels, as well as the coagulation studies, aim at preoperative evaluation and in the diagnosis of anemia. And following some rare endocrinological manifestations, calcium and prolactin levels might need to be evaluated. (1)
Differential diagnosis
Polyp, adenomyosis, endometriosis, pregnancy, endometrial hyperplasia, ovary tumor, adnexal inflammation, and malignancy (endometrial stromal sarcoma). (1, 2)
Treatment Strategies
The therapeutic approach is determined by various clinical factors: age, fertility, symptoms, general condition, and factors related to the fibroid, such as size, quantity, location, and exaggerated growth, among others.
Observation
There are situations in which it is advisable to carry out a periodic control every 4 to 6 months in order to monitor the evolution or seek the stability of the process. Examples include asymptomatic fibroids regardless of size (except when exaggerated growth occurs), small fibroids (<4-5 cm) with few symptoms, and asymptomatic fibroids in postmenopausal women. About 3% to 7% of untreated UL in premenopausal women regress over six months to three years, and most decrease in size at menopause (4).
Medical Treatment
- Medical treatment can be used in cases of acute abnormal uterine bleeding as an initial measure. Medical treatment also plays a role in cases of chronic disorders that cause heavy menstrual bleeding and for cases in which surgery is contraindicated due to comorbidities such as hypertension, diabetes, arrhythmias, obesity, etc. (1)
- NSAIDs have been shown to reduce the painful menses and heavy menstrual bleeding associated with UL compared with placebo treatment but to a lesser extent than with the use of hormonal medications (58). They are indicated to treat symptoms, although it has no relationship to effects on the tumor size (1, 59).
- Tranexamic acid, an antifibrinolytic drug, is often used as a first-line therapy, as it was shown to cause a significant reduction in menstrual blood loss when compared with a placebo group. Moreover, it is well tolerated and has a favorable safety profile (60, 61). Both NSAIDs and antifibrinolytics reduce fibroid-associated heavy menstrual bleeding, although they do not alter the size of fibroids.
Hormonal Therapy
- Contraceptives containing synthetic analogs of estrogen and progesterone are the most widely used for menstrual bleeding abnormalities and pelvic pain, associated or not with leiomyomas. It is advisable that when initiating hormone therapy, it is maintained for 4 to 6 months to assess tumor and uterine size.
- Progestin-containing levonorgestrel intrauterine device has proven efficacy for the control of abnormal uterine bleeding and decreases leiomyoma volume with minimal systemic effects (1, 62). Unfortunately, there is an increased risk of expulsion of the levonorgestrel intrauterine device in women with leiomyomas (12–16% over up to 3 years) (63, 64).
- GnRH analogs (Leuprolide, Goserelin, Triptorelin) utilization has been shown to reduce the size of leiomyomas in a range of 35 to 65% after three months of treatment. In small fibroids, an almost complete reduction and a decrease in uterine size have also been seen. However, their effect is temporary, with a gradual recurrence to the original size after treatment. Some advantages are decreased blood loss, and operative and recovery time. (65)
- GnRH analogs use to generate a hypoestrogenism that is associated with pseudomenopause, which makes it impossible to carry out prolonged treatments. Adding therapy with low-dose estrogen and progestin can be considered to minimize the symptoms observed when long-term therapy is required (1, 66). Because of these, they are useful preoperatively to shrink fibroids and to reduce anemia related to uterine bleeding (1, 67, 68).
- Progesterone receptor modulators (PRMs) such as Mifepristone and Ulipristal act on the progesterone receptors that are found in high concentration in the leiomyomatous uterus. Rapidly becoming the standard medical option when bulky symptoms are happening, as well as for preoperative treatment. They have a rapid onset of action and are effective at reducing both leiomyoma and uterine volume, in addition to heavy menstrual bleeding, anemia, and pain. (69-71)
- During PMR therapy, amenorrhea is observed in 90% of cases with stable bone density. The most observed adverse effects are headache, breast tenderness, endometrial hyperplasia without atypia (14-28%), and a transient increase in transaminase levels (4%); therefore, liver function monitoring should be performed. (1, 72)
Surgical Treatment
There are circumstances in which surgical treatment is indicated: when the size of the fibroid causes discomfort, pelvic pain, intestinal transit disorders, and compression of the ureters with urinary symptoms. Abnormal uterine bleeding compromises the general condition of the patient; rapid growth is diagnosed in clinical and imaging controls; when a secondary alteration in the evolution of the UL is suspected or detected, such as infection, necrobiosis, torsion of the pedicle, sarcomatous degeneration, or the UL determines an alteration in the reproductive function, surgical treatment is considered.
- For women with menstrual bleeding and a FIGO type 0 or type 1 UL, the preferred therapeutic option is hysteroscopic myomectomy. In addition, this therapeutic approach could also be made for FIGO type 2 by an expert surgeon (73-77).
- For women with symptomatic UL classified as FIGO types 3–8 who do not wish to become pregnant, medical management is the first line of treatment. If this does not function, surgical therapy is the best option.
- Vaginal myomectomy is indicated in cases of nascent or cervical submucous leiomyomas, with or without a visible pedicle. (1)
- Uterine artery embolization is a valid option for women who wish to preserve their uterus or avoid surgery because of medical comorbidities or personal preference. (78) It is an interventional procedure in which occluding agents are injected into one or both of the uterine arteries, limiting blood supply to the uterus and UL.
- Myolysis is a minimally invasive procedure targeting the destruction of leiomyoma via a focused energy delivery system such as heat, laser, or magnetic resonance–guided focused ultrasound surgery (MRgFUS). Overall, this procedure is well tolerated, although risks include localized pain and heavy bleeding. (1, 79)
- Hysterectomy provides definitive treatment for women with symptomatic UL who do not wish to preserve fertility, resulting in complete resolution of symptoms and improved quality of life. It is the most effective treatment. (80)
Disclosures
The author does not report any conflict of interest.
Disclaimer
This information is for educational purposes and is not intended to treat disease or supplant professional medical judgment. Physicians should follow local policy regarding the diagnosis and management of medical conditions.
See Also
Diagnosis and Management of Vulvovaginitis
References
1- Gori J, castaño R, Lorusso M. Miomatosis Uterina. Ginecologia de Gory. 3ra edicion. Ciudad autónoma de Buenos Aires. Panamericana. 2016. p 645-666
2- Roberts CP, Kawwass JF. Leiomiomats uterinos y miomectomia. Te Linde, Ginecologia Quirúrgica. 11 edicion. Philadelphia. Wolters Kluwer. 2017. p 656-697
3- Stewart, E. A. Uterine Fibroids: the Complete Guide (Johns Hopkins Univ. Press, 2007).
4- Laughlin, S. K., Baird, D. D., Savitz, D. A., Herring, A. H. & Hartmann, K. E. Prevalence of uterine leiomyomas in the first trimester of pregnancy: an ultrasound-screening study. Obstet. Gynecol. 113, 630–635 (2009).
5- Marsh, E. E. et al. Racial differences in fibroid prevalence and ultrasound findings in asymptomatic young women (18–30 years old): a pilot study. Fertil. Steril. 99, 1951–1957 (2013).
6- Boynton-Jarrett R, Rich-Edwards JW, Jun HJ, Hibert EN, Wright RJ. Abuse in childhood and risk of uterine leiomyoma: the role of emotional support in biologic resilience. Epidemiology. 2011 Jan;22(1):6-14.
7- Wise LA, Palmer JR, Rosenberg L. Lifetime abuse victimization and risk of uterine leiomyomata in black women. Am J Obstet Gynecol. 2013 Apr;208(4):272.e1-272.e13. doi: 10.1016/j.ajog.2012.12.034. Epub 2013 Jan 4.
8- Wise LA, Palmer JR, Cozier YC, Hunt MO, Stewart EA, Rosenberg L. Perceived racial discrimination and risk of uterine leiomyomata. Epidemiology. 2007 Nov;18(6):747-57.
9- Hodge JC, T Cuenco K, Huyck KL, Somasundaram P, Panhuysen CI, Stewart EA, Morton CC. Uterine leiomyomata and decreased height: a common HMGA2 predisposition allele. Hum Genet. 2009 Apr;125(3):257-63.
10- Huyck, K. L. et al. Baird, D. D. & Newbold, R. Prenatal diethylstilbestrol (DES) exposure is associated with uterine leiomyoma development. Reprod. Toxicol. 20, 81–84 (2005).
11- Wise, L. A. et al. Intake of fruit, vegetables, and carotenoids in relation to risk of uterine leiomyomata. Am. J. Clin. Nutr. 94, 1620–1631 (2011).
12- Wise LA, Palmer JR, Harlow BL, Spiegelman D, Stewart EA, Adams-Campbell LL, Rosenberg L. Risk of uterine leiomyomata in relation to tobacco, alcohol and caffeine consumption in the Black Women’s Health Study. Hum Reprod. 2004 Aug;19(8):1746-54. Risk of uterine leiomyomata in relation to tobacco, alcohol and caffeine consumption in the Black Women’s Health Study – PMC (nih.gov)
13- Sato F, Nishi M, Kudo R, Miyake H. Body fat distribution and uterine leiomyomas. J Epidemiol. 1998 Aug;8(3):176-80. Body Fat Distribution and Uterine Leiomyomas (jst.go.jp)
14- Wise LA, Palmer JR, Spiegelman D, Harlow BL, Stewart EA, Adams-Campbell LL, Rosenberg L. Influence of body size and body fat distribution on risk of uterine leiomyomata in U.S. black women. Epidemiology. 2005 May;16(3):346-54. Influence of Body Size and Body Fat Distribution on Risk of Uterine Leiomyomata in U.S. Black Women – PMC (nih.gov)
15- Marshall LM, Spiegelman D, Manson JE, Goldman MB, Barbieri RL, Stampfer MJ, Willett WC, Hunter DJ. Risk of uterine leiomyomata among premenopausal women in relation to body size and cigarette smoking. Epidemiology. 1998 Sep;9(5):511-7. Risk of uterine leiomyomata among premenopausal women in relation to body size and cigarette smoking. – Abstract – Europe PMC
16- Flake GP, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environmental health perspectives. 2003 Jun;111(8):1037-54. Etiology and pathogenesis of uterine leiomyomas: a review. | Environmental Health Perspectives | Vol. 111, No. 8 (nih.gov)
17- Faerstein E, Szklo M, Rosenshein NB. Risk factors for uterine leiomyoma: a practice-based case-control study. II. Atherogenic risk factors and potential sources of uterine irritation. Am J Epidemiol. 2001 Jan 1;153(1):11-9. Risk factors for uterine leiomyoma: a practice-based case-control study. II. Atherogenic risk factors and potential sources of uterine irritation – PubMed (nih.gov)
18- Fischer NM, Nieuwenhuis TO, Singh B, Yenokyan G, Segars JH. Angiotensin-Converting Enzyme Inhibitors Reduce Uterine Fibroid Incidence in Hypertensive Women. J Clin Endocrinol Metab. 2021 Jan 23;106(2):e650-e659. doi: 10.1210/clinem/dgaa718. Angiotensin-Converting Enzyme Inhibitors Reduce Uterine Fibroid Incidence in Hypertensive Women – PubMed (nih.gov)
19- Stewart EA, Borah BJ. Uterine Fibroids and Hypertension: Steps Toward Understanding the Link. J Clin Endocrinol Metab. 2021 Jan 23;106(2):e1039-e1041. Uterine Fibroids and Hypertension: Steps Toward Understanding the Link | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic (oup.com)
20- Paffoni A, Somigliana E, Vigano’ P, Benaglia L, Cardellicchio L, Pagliardini L, Papaleo E, Candiani M, Fedele L. Vitamin D status in women with uterine leiomyomas. The Journal of Clinical Endocrinology & Metabolism. 2013 Aug 1;98(8):E1374-8. Vitamin D Status in Women With Uterine Leiomyomas | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic (oup.com)
21- James-Todd TM, Chiu YH, Zota AR. Racial/ethnic disparities in environmental endocrine disrupting chemicals and women’s reproductive health outcomes: epidemiological examples across the life course. Curr Epidemiol Rep. 2016 Jun;3(2):161-180.
22- James-Todd TM, Chiu YH, Zota AR. Racial/ethnic disparities in environmental endocrine disrupting chemicals and women’s reproductive health outcomes: epidemiological examples across the life course. Curr Epidemiol Rep. 2016 Jun;3(2):161-180.
23- Lumbiganon, P. et al. Protective effect of depot- medroxyprogesterone acetate on surgically treated uterine leiomyomas: a multicentre case–control study. Br. J. Obstet. Gynaecol. 103, 909–914 (1996).
24- Wise, L. A. et al. Reproductive factors, hormonal contraception, and risk of uterine leiomyomata in African-American women: a prospective study. Am. J. Epidemiol. 159, 113–123 (2004).
25- L. A. et al. Intake of fruit, vegetables, and carotenoids in relation to risk of uterine leiomyomata. Am. J. Clin. Nutr. 94, 1620–1631 (2011).
26- Wise, L. A., Radin, R. G., Palmer, J. R., Kumanyika, S. K. & Rosenberg, L. A prospective study of dairy intake and risk of uterine leiomyomata. Am. J. Epidemiol. 171, 221–232 (2010).
27- Wise LA, Radin RG, Palmer JR, Kumanyika SK, Boggs DA, Rosenberg L. Intake of fruit, vegetables, and carotenoids in relation to risk of uterine leiomyomata. Am J Clin Nutr. 2011 Dec;94(6):1620-31.
28- Laughlin, S. K., Schroeder, J. C. & Baird, D. D. New directions in the epidemiology of uterine fibroids. Semin. Reprod. Med. 28, 204–217 (2010).
29- Faerstein, E., Szklo, M. & Rosenshein, N. Risk factors for uterine leiomyoma: a practice-based case–control study. I. African-American heritage, reproductive history, body size, and smoking. Am. J. Epidemiol. 153, 1–10 (2001).
30- Moore, K. R., Smith, J. S., Laughlin-Tommaso, S. K. & Baird, D. D. Cervical neoplasia-related factors and decreased prevalence of uterine fibroids among a cohort of African American women. Fertil. Steril. 101, 208–214 (2014).
31- Holly R. Harris, Jessica L. Petrick, Lynn Rosenberg. The epidemiology of uterine fibroids: Where do we go from here?. Fertility and sterility. Asrm. VOL. 117 NO. 4. April 2022
32- Stewart EA, Laughlin-Tommaso SK, Catherino WH, Lalitkumar S, Gupta D, Vollenhoven B. Uterine fibroids. Nat Rev Dis Primers. 2016 Jun 23;2:16043.
33- Walker CL, Stewart EA. Uterine fibroids: the elephant in the room. Science. 2005; 308(5728):1589– 1592.
34- Ono, M. et al. Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth. Proc. Natl Acad. Sci. USA 110, 17053–17058 (2013).
35- Zhou, S. et al. Proteomics identification of annexin A2 as a key mediator in the metastasis and proangiogenesis of endometrial cells in human adenomyosis. Mol. Cell. Proteomics 11, M112.017988 (2012).
36- Munro MG, Critchley HO, Broder MS, Fraser IS. The FIGO Classification System (“PALM-COEIN”) for causes of abnormal uterine bleeding in non-gravid women in the reproductive years, including guidelines for clinical investigation. Int J Gynaecol Obstet 2011;113:3–13.
37- Fraser IS, Critchley HO, Munro MG, Broder M; Writing Group for this Menstrual Agreement Process. A process designed to lead to international agreement on terminologies and definitions used to describe abnormalities of menstrual bleeding. Fertil Steril. 2007 Mar;87(3):466-76.
38- Committee on Practice Bulletins—Gynecology. Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012 Jul;120(1):197-206.
39- Soliman AM, Margolis MK, Castelli-Haley J, Fuldeore MJ, Owens CD, Coyne KS. Impact of uterine fibroid symptoms on health-related quality of life of US women: evidence from a cross-sectional survey. Curr Med Res Opin. 2017 Nov;33(11):1971-1978.40- 44- Ferrero S, Abbamonte LH, Giordano M, Parisi M, Ragni N, Remorgida V. Uterine myomas, dyspareunia, and sexual function. Fertil Steril. 2006 Nov;86(5):1504-10.
41- Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril. 2009 Apr;91(4):1215-23.
42- Kramer, M. et al. Incidence, risk factors, and temporal trends in severe postpartum hemorrhage. Am J. Obstet. Gynecol. 209, 449.e1–449.e7 (2013).
43- Stout, M. J. et al. Leiomyomas at routine second- trimester ultrasound examination and adverse obstetric outcomes. Obstet. Gynecol. 116, 1056–1063 (2010).
44- Ciavattini, A. et al. Number and size of uterine fibroids and obstetrics outcomes. J. Matern. Fetal Neonatal Med. 28, 484–488 (2014).
45- Ferreira, J. et al. The evolution of fetal presentation during pregnancy: a retrospective, descriptive cross sectional study. Acta Obstet. Gynecol. Scand. 94, 660–663 (2015).
46- Yoshida M, Koshiyama M, Fujii H, Konishi M. Erythrocytosis and a fibroid. Lancet. 1999 Jul 17;354(9174):216.
47- Ravakhah K, Gover A, Mukunda BN. Humoral hypercalcemia associated with a uterine fibroid. Ann Intern Med. 1999 Apr 20;130(8):702.
48- Cordiano V. Complete remission of hyperprolactinemia and erythrocytosis after hysterectomy for a uterine fibroid in a woman with a previous diagnosis of prolactin-secreting pituitary microadenoma. Ann Hematol. 2005 Mar;84(3):200-2.
49- Myers, E. et al. Management of Uterine Fibroids (Agency for Healthcare Research and Quality, 2001).
50- Fonseca-Moutinho, J. A., Barbosa, L. S., Torres, D. G. & Nunes, S. M. Abnormal uterine bleeding as a presenting symptom is related to multiple uterine leiomyoma: an ultrasound-based study. Int. J. Women’s Health 18, 689–694 (2013). 51- Cicinelli, E. et al. Transabdominal sonohysterography, transvaginal sonography, and hysteroscopy in the evaluation of submucous myomas. Obstet. Gynecol. 85, 42–47 (1995).
52- Becker, E. Jr et al. The added value of transvaginal sonohysterography over transvaginal sonography alone in women with known or suspected leiomyoma. J. Ultrasound Med. 21, 237–247 (2002).
53- Adusumilli S, Hussain HK, Caoili EM, Weadock WJ, Murray JP, Johnson TD, et al. MRI of sonographically indeterminate adnexal masses. AJR Am J Roentgenol 2006;187:732–40.
54- Dueholm M, Lundorf E, Hansen ES, Ledertoug S, Olesen F. Accuracy of magnetic resonance imaging and transvaginal ultrasonography in the diagnosis, mapping, and measurement of uterine myomas. Am J Obstet Gynecol 2002;186:409–15.
55- Omary RA, Vasireddy S, Chrisman HB, Ryu RK, Pereles FS, Carr JC,
et al. The effect of pelvic MR imaging on the diagnosis and treatment of women with presumed symptomatic uterine fibroids. J Vasc Interv Radiol 2002;13:1149–53.
56- Stamatopoulos CP, Mikos T, Grimbizis GF, Dimitriadis AS, Efstratiou I, Stamatopoulos P, et al. Value of magnetic resonance imaging in diagnosis of adenomyosis and myomas of the uterus. J Min Invas Gynecol 2012:19:620–6.
57- Dudiak, C. M. et al. Uterine leiomyomas in the infertile patient: preoperative localization with MR imaging versus US and hysterosalpingography. Radiology 167, 627–630 (1988).
58- Lethaby, A., Duckitt, K. & Farquhar, C. Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst. Rev. 1, CD000400 (2013).
59- Lethaby A, Duckitt K, Farquhar C. Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst Rev. 2013;(1):CD000400.
Lukes, A. S. et al. Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial. Obstet. Gynecol. 116, 865–875 (2010).
Eder, S., Baker, J., Gersten, J., Mabey, R. G. & Adomako, T. L. Efficacy and safety of oral tranexamic acid in women with heavy menstrual bleeding and fibroids. Womens Health (Lond. Engl.) 9, 397–403 (2013).
62- Sayed GH, Zakherah MS, El-Nashar SA, et al. A randomized clinical trial of a levonorgestrel-releasing intrauterine system and a low-dose com- bined oral contraceptive for fibroid-related menorrhagia. Int J Gynaecol Obstet. 2011;112(2):126-130.
63- Sangkomkamhang, U. S., Lumbiganon, P., Laopaiboon, M. & Mol, B. W. Progestogens or progestogen-releasing intrauterine systems for uterine fibroids. Cochrane Database Syst. Rev. 2, CD008994 (2013).
Lethaby, A. E., Cooke, I. & Rees, M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst. Rev. 4, CD002126 (2005).
65-Lethaby A, Vollenhoven B, Sowter M. Efficacy of preoperative gonado- trophin hormone releasing analogues for women with uterine fibroids undergoing hysterectomy or myomectomy. BJOG. 2002;109(10): 1097-1108.
66-Kamath, M. S., Kalampokas, E. E. & Kalampokas, T. E. Use of GnRH analogues preoperatively for hysteroscopic resection of submucous fibroids:
a systematic review and meta-analysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 177, 11–18 (2014).
67- Vercellini P, Crosignani PG, Mangioni C, Imparato E, Ferrari A, De Giorgi O. Treatment with a gonadotropin releasing hormone agonist before hysterectomy for leiomyomas: results of a multicentre, randomized controlled trial. Br J Obstet Gynaecol 1998;105:1148–54.
68- Friedman AJ, Hoffman DI, Comite F, Browneller RW, Miller JD. Treatment of leiomyomata uteri with leuprolide acetate depot:a double-blind, placebo-controlled, multicenter study. The Leuprolide Study Group. Obstet Gynecol 1991;77:720–5.
Donnez, J. et al. Long-term treatment of uterine fibroids with ulipristal acetate. Fertil. Steril. 101, 1565–1573.e18 (2014).
70- Stewart, E. A. Clinical practice. Uterine fibroids. N. Engl. J. Med. 372, 1646–1655 (2015). This is an updated review of the clinical diagnosis and treatment of fibroids.
Donnez, J. et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N. Engl. J. Med. 366, 409–420 (2012).
72- Donnez J, Tatarchuk TF, Bouchard P, et al. Ulipristal acetate ver- sus placebo for fibroid treatment before surgery. N Engl J Med. 2012;366(5):409-420.
73- Marret, H. et al. Therapeutic management of uterine fibroid tumors: updated French guidelines. Eur. J. Obstetr. Gynecol. Reprod. Biol. 165, 156–164 (2012).
Perez-Lopez, F. R. et al. EMAS position statement: management of uterine fibroids. Maturitas 79, 106–116 (2014).
Laughlin, S. K., Hartmann, K. E. & Baird, D. D. Postpartum factors and natural fibroid regression. Am. J. Obstet. Gynecol. 204, 496.e1–496.e6 (2011).
Flake, G. P. et al. The natural history of uterine leiomyomas: morphometric concordance with concepts of interstitial ischemia and inanosis. Obstet. Gynecol. Int. 2013, 285103 (2013).
Wamsteker, K., Emanuel, M. H. & de Kruif, J. H. Transcervical hysteroscopic resection of submucous fibroids for abnormal uterine bleeding: results regarding the degree of intramural extension. Obstet. Gynecol. 82, 736–740 (1993).
78- Vilos GA, Allaire C, Laberge PY, et al. The management of uterine leio- myomas. J Obstet Gynaecol Can. 2015;37(2):157-181.
79- Stewart EA, Gostout B, Rabinovici J, et al. Sustained relief of leiomy- oma symptoms by using focused ultrasound surgery. Obstet Gynecol. 2007;110(2 pt 1):279-287.
80- Aarts JW, Nieboer TE, Johnson N, et al. Surgical approach to hysterectomy for benign gynaecological disease. Cochrane Database Syst Rev. 2015;(8):CD003677.