Benign Uterine Diseases




Abstract


The traditional concept of the uterus is that the endometrium is the dynamic tissue, providing an intricate set of functions throughout the menstrual cycle—a process that rarely culminates in implantation and pregnancy. The myometrium has been viewed as an inert tissue, chiefly important during pregnancy and, when abnormal, providing the surgical livelihood of clinical gynecologists. To understand both the physiology of menstruation and the pathophysiology of abnormal uterine bleeding (AUB), both the myometrial and the endometrial layers of the uterus are important. This chapter covers both myometrial disease (adenomyosis and leiomyomas) and endometrial diseases (polyps, AUB, intrauterine adhesions, and dysmenorrhea). The objective is to provide the reader with an understanding of the various clinical presentations as well as the molecular pathophysiology of the disease process and to enlist various therapeutic options for these benign uterine diseases.




Keywords

Uterine fibroids, leiomyoma, myomectomy, uterine artery embolization, magnetic resonance–guided focused ultrasound surgery, adenomyosis, endometrial polyps, abnormal uterine bleeding, intrauterine adhesions, Asherman syndrome, dysmenorrhea

 




Uterine Leiomyomas




  • ◆

    Uterine leiomyomas are very common benign clonal smooth muscle cell tumors that have increased prevalence in black women.


  • ◆

    Gonadal steroids, fibrotic and angiogenic factors, as well as cytogenic and molecular genetic factors play a role in the pathogenesis and growth of uterine leiomyomas.


  • ◆

    Therapeutic options for uterine leiomyomas can range from observation to medical management, surgical resection as well as the newer interventional radiologic procedures that include uterine artery embolization (UAE) and magnetic resonance–guided focused ultrasound surgery (MRgFUS).



Epidemiology


Uterine leiomyomas, frequently termed myomas or fibroids, are benign clonal smooth muscle cell tumors ranging in size from several millimeters to many centimeters ( Fig. 26.1 ). Clinically, fibroids are appreciated in approximately 25% of all women, and in black women they appear to have a threefold increased incidence and relative risk. Careful pathologic study of surgical specimens suggests that greater than 80% of black and 70% of white women have detectable leiomyomas, which parallels the lifetime incidence of the clinical disease. Thus it appears that there is little occult disease in black women. This suggests that in this group, growth acceleration of transformed myocytes into clinical fibroids may be ubiquitous. Black women are not only significantly more likely than white women to have leiomyomas but also to be younger at the time of diagnosis and hysterectomy. They also have more severe diseases and are 2 to 3 times more likely to have hysterectomy for leiomyomas and sixfold more likely to have a myomectomy ( Table 26.1 ).




FIGURE 26.1


A T 2 -weighted fast-spin echo sagittal image of a leiomyomatous uterus with multiple type 2 submucosal fibroids.

This sagittal image allows the endometrial cavity to be visualized from the fundus to the cervix, indicating that these fibroids are not displacing the cavity laterally. This series of images is typically best for visualizing clinically important submucous fibroids. Visualization of the sacrum and coccyx, bladder, and rectum allows assessment of bulk effects of the fibroid in the pelvis.


Table 26.1

Increased Burden of Fibroid Disease in Black Women




































Fibroid Characteristic Black Versus White Women Reference Number
Incidence of uterine fibroids Threefold increase
Relative risk Threefold increase
Age at diagnosis 3–5 years younger
Severity of disease Fivefold increase
Fibroid growth at older age (≥45 years) Sevenfold to Eightfold increase
Myomectomy risk Sixfold increase
Hysterectomy risk Twofold to threefold increase


Known risk factors do not adequately explain this racial disparity. Newly discovered genetic polymorphisms that include abnormal transcriptional factors, increased aromatase activity, and signal transduction genes may dictate a more severe phenotype of the disease in black women. Polymorphism of catechol-O-methyltransferase (COMT), an essential enzyme for estrogen metabolism, has been shown to be linked to fibroid formation and is more common in black women. Vitamin D has been shown to inhibit fibroid proliferation via the COMT pathway ; it also reduces fibrosis caused by transforming growth factor-β3 (TGF-β3). The role of vitamin D has been reproduced in the Eker mouse model, where supplementation with 1,25 dihydroxyvitamin D3 at 0.1 and 1 µM for 24 hours led to reduced myoma size compared with controls. Studies in black women correlate fibroid risk with polycystic ovarian syndrome, history of physical and/or sexual abuse, and self-reported experiences of racism. An understanding of the unique genetic and environmental factors leading to an increased risk for black women is a key research agenda for leiomyomas. There are mixed data regarding fibroid risk in Latina women.


Reproductive factors affect the risk of leiomyomas. Numerous studies have shown that parity is associated with decreased fibroid risk. One hypothesis is that the remodeling of the postpartum uterus can clear nascent fibroids. In one of these reports of women who had fibroids at the beginning of pregnancy, 36% had no identifiable lesion on ultrasonography postpartum and 79% of the remaining fibroids had decreased in size. Progestin use in the postpartum period was the only significant risk factor for the limited regression of fibroids postpartum. The fact that this study contrasts with previous reports (i.e., that progestin-only injectable contraceptives are associated with decreased fibroid risk and that these contraceptives are widely used by breastfeeding women) makes it critical that this area be explored further. Although clinical dogma traditionally suggested that oral contraceptives (OCs) were contraindicated for women with myomas, OCs instead appear to protect against clinically evident fibroids, with the caveat that timing of use may be important. Exposure to OCs between ages 13 and 16 for women in the Nurses’ Health Study led to an increased relative risk of leiomyomas, while later OC use was protective in direct proportion to duration of use. Recent work has proposed an increase in vitamin D levels in women who are using OCs as a means of protection against leiomyomas. Postmenopausal hormone replacement therapy (HRT) has been associated with a higher likelihood of having fibroids on pathology after surgery in one report, although this may have been due to bias, since HRT may have inhibited normal postmenopausal fibroid regression. Early menarche is also associated with increased risk of developing fibroids ; this may explain earlier disease in black women, in whom menarche is earlier than in white women.


Environmental and dietary habits also appear to influence the risk of myoma formation. Decreased vegetable and fruit intake, especially citrus fruits, increased dietary long-chain omega-3 fatty acids, specifically marine fatty acids, and significant consumption of red meats or ham were all associated with an increased relative risk of developing fibroids. The consumption of green vegetables was associated with a decreased risk of myomas. Reduced dairy consumption, use of hair relaxer, and increased intake of alcohol, especially beer, appear to increase the risk in black women. An association of fibroid risk with a high alcohol intake has also been reported in Japanese women. No one, however, has demonstrated that dietary intervention leads to changes in the incidence, symptomatology, or regression of fibroids. Major life events and stress as well as a history of abuse in childhood have been linked to the presence of uterine fibroids. In utero exposure to diethylstilbestrol (DES) in animals and humans as well as consumption of soy formula in infancy, low childhood socioeconomic status, early gestational age at birth, and maternal prepregnancy or gestational diabetes have all been associated with a greater risk of fibroid development. Caffeine consumption was not noted to be a risk factor. Smoking is considered protective through an unknown mechanism, although recent work has challenged this and has shown environmental tobacco smoke exposure as a risk factor for the late diagnosis of incident fibroids in women undergoing menopausal transition. Dietary vitamin A from animal sources appears to be protective.


Increased body mass index (BMI) or weight gain since age 18 also appears to influence myoma risk in some cohorts. A high dietary glycemic index and glycemic load and decreased physical activity are also risk factors. Finally, women with leiomyomas appear to be more likely to have hypertensive disease than control women. It is unclear whether this commonality is due to a common underlying mechanism, since leiomyomas have been shown to share pathogenic features with the development of metabolic syndrome.


Finally, uterine infections appear to be associated with an increased risk of leiomyomas, yet factors associated with cervical neoplasia are associated with a decreased risk. Additional study is needed regarding infectious agents and leiomyoma risk.


Pathophysiology


Leiomyomas have a median of 9% change, generally an increase in volume in a 6-month period. Growth appears to be race related. Black and white women had similar growth until 35 years of age, after which growth rates declined for white women. It has also been shown that the growth of a fibroid is not dependent on its position in the uterus. The size of fibroids may be important, as lesions greater than 5 cm in diameter have less short-term change.


Gonadal Steroids: Estrogen and Progesterone


There are substantial in vitro data supporting major roles for both estrogen and progesterone in the biology of uterine leiomyomas. The role of progesterone in myoma growth has moved beyond the simplistic concept of increasing mitosis to include inhibition of the apoptosis pathway via the induction of β-cell lymphoma 2 (Bcl 2). The apoptotic inhibitor Bcl2 is present in leiomyomas but is largely undetectable in myometrium. The role of Kruppel-like transcription factor 11 (KLF11) in integrating progesterone-mediated myoma cell signaling and proliferation has been shown. Likewise, regarding estrogen action, local action is likely key via an upregulation of the enzyme aromatase P450 and its gene CYP19 . Other elements of estrogenic response in myomas can also come into play, as myoma cells have a modest increase in type I isotype of 17β hydroxysteroid dehydrogenase.


Modulation of steroid receptors is also important. Leiomyomas have increased amounts of both estrogen and progesterone receptor (ER and PR) messenger ribonucleic acid (mRNA) compared with normal myometrial tissue. Both the A- and the N-terminally truncated B-isoforms of the PR appear to be present in both leiomyomas and myometrium; however, the A-isoform predominates. Similarly, ER-α rather than ER-β appears to be the predominant form in leiomyomas.


In addition to the direct action of ovarian steroids on the uterus, it is possible that the reproductive axis may also influence uterine metabolism through the direct action of pituitary gonadotropins. Gonadotropin-releasing hormone (GnRH), which is clinically used to reduce myoma size, abolishes differences in gene expression between normal myometrium and myomas. The placental glycoprotein chorionic gonadotropin (hCG) has been shown by several laboratories to have direct actions on myometrial metabolism. Additionally, work has shown that follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and their common α-subunit can all have stimulatory effects on uterine prolactin production. There appears to be a variant LH/hCG receptor present in human uterine tissue that may modulate this action. LH has also been associated with myoma formation but not growth independent of the patient’s age. Genome-wide microarray studies have shown a strong role of glucocorticoids in the pathogenesis of fibroids. There are new data suggesting that the Nr4A nuclear receptor, which does not have a ligand, may be playing a role in fibroid pathogenesis. This receptor family is important because of its regulation of the profibrotic/extracellular matrix (ECM) pathways. Finally, there is increasing evidence that stem cells may be playing a key regulatory role in leiomyoma biology.


Fibrotic Factors


Leiomyomas can also be viewed as fibrotic tumors with a dynamic ECM playing an important role in their pathophysiology ( Fig. 26.2 ). This hypothesis dates back to the 1990s where experiments demonstrated that the ECM characterizing fibroids contains significant amounts of collagen types I and III protein, and that upregulation of mRNA levels occurs during the proliferative phase of the menstrual cycle in leiomyomas but not in myometrium. Other matrix components including matrix metalloprotease stromelysin 3 (MMP 11) and dermatopontin (a collagen-binding protein, also having decreased expression in keloid scars) have also been shown to be dysregulated in leiomyomas. Morphologic arrangement of extracellular proteins is also abnormal in myomas, and increased stiffness of these ECM alterations leads to altered gene expression through solid-state signaling. These modified mechanical stresses on cells lead to the activation of Rho-dependent signaling. Activation of this solid-state signaling and altered state of stress may also contribute to fibroid growth.




FIGURE 26.2


Histologic evaluation of fibroid using hematoxylin and eosin staining highlights both cellular bundles and the acellular extracellular matrix.

The extracellular matrix not only contains significant amounts of collagen type I and III but can also act as a reservoir for growth factors such as basic fibroblast growth factor.


The TGF-β system also appears to be involved in the pathophysiology of leiomyomas as in other fibrotic processes. A complete review of this topic is beyond the scope of this chapter. Leiomyomas appear to have higher levels of TGF-β and particularly TGF-β3 mRNA and protein; this, in turn, affects cellular proliferation. Vitamin D supplementation has been shown to reverse TGF-β3–induced fibrosis in fibroids. Additionally, granulocyte-macrophage colony-stimulating factor (GM-CSF), connective tissue growth factor (CTGF), TGF-β4 (also known as lefty or ebaf, endometrial bleeding-associated factor), the sma- and mad-related (SMAD) family of transcriptions factors, and the mitogen-activated protein kinase (MAPK) signaling pathway appear to be part of the fibrotic pathway that is dysregulated in myomas, or in the myometrium or endometrium of the uterus in women with leiomyomas or abnormal uterine bleeding (AUB).


Angiogenesis


Angiogenesis, the formation of new blood vessels, is physiologic in the female reproductive tract as opposed to most other tissues, where it is pathologic. Abnormalities in uterine blood vessels and angiogenic growth factors also appear to play a role in the pathobiology of myomas. The myomatous uterus shows increased numbers of arterioles and venules as well as venule ectasia. These changes are not confined to the leiomyoma itself but also involve the myometrium and the endometrium. Although such venous abnormalities were originally postulated to be the result of physical compression of the vascular structures by bulky myomas, it is likely that molecular alterations are actually responsible for increased vessel numbers or abnormal function.


The process of angiogenesis involves interactions with specific components of the ECM, such as collagens type I and III, that are dysregulated in fibroids. There are also conflicting data regarding whether the resident immune cells (especially mast cells) contribute to the physiology of myomas by modulating angiogenesis.


The basic fibroblast growth factor (bFGF) receptor/ligand system appears to be a significant factor in the pathophysiology of leiomyomas. In addition to promoting angiogenesis, bFGF is a smooth muscle cell mitogen and acts similarly to estradiol on leiomyoma smooth muscle cells. Leiomyomas have increased levels of bFGF mRNA compared with matched myometrium, a reservoir of bFGF protein in the ECM, and dysregulation of the endometrial type I bFGF receptor.


Cytogenetic and Molecular Genetics


There appear to be multiple genetic pathways to the phenotypic leiomyomas. Leiomyomas are monoclonal, and each tumor is an independent clonal event. Although this fact was originally investigated using G6PD polymorphisms, androgen receptor polymorphism studies concur.


Second, certain cytogenetic rearrangements characterize leiomyomas. Although 40% of fibroids have 46,XX karyotypically normal cells, there are specific karyotypic abnormalities that have been consistent in a number of studies: t(12;14) translocations between chromosomes 12 and 14; trisomy 12; rearrangements of 6p, 10q, and 13q; and deletion of 3q, 7q, and 1p. There is evidence that karyotypic evolution is a late event in the pathogenesis of leiomyomas. There is also some evidence that genotype is related to both fibroid size and location and that specific karyotypic groups have specific gene expression profiles. Thus many of the characteristics we attribute to submucous fibroids, for example, may be related to genotype; therefore the clinical heterogeneity we see may be more intelligible when genotypic information is available. A genomewide association study (GWAS) from Japan determined significant associations with uterine fibroids in three chromosomes 10q24.33, 22q13.1, and 11p15.5. Subgroup analyses revealed a strong association of marker single nucleotide polymorphisms (SNPs) with uterine fibroids regardless of the presence or absence of heavy or painful menstrual bleeding, suggesting that these SNPs are associated with predisposition genes.


Hierarchical gene clustering has revealed at least four key pathogenic subgroups of fibroids, depending on somatic mutations or chromosomal alterations in key genes: the mediator complex subunit 12 (MED12) group, the high-mobility group AT-hook2 (HMG2), the fumarate hydratase (FH) group, and a rare group associated with deletion of collagen IV α5 (COL4A5) and COL4A6. It now appears that chromothripsis, a global event causing multiple chromosome rearrangements at once, may also play a role in leiomyomas. MED12 is a transcriptional factor, a mediator of both global and specific gene transcription located on chromosome Xq13.1 that has been described in the pathogenesis of uterine fibroids. MED12 was altered in 70% of tumors from 80 patients studied in this report from Scandinavia, and pathway analysis suggested that ECM-receptor interaction, Wingless family (Wnt) signaling, and focal adhesion pathways were altered by this change. Whole-genome sequencing has shown MED12 mutations to be present frequently in fibroids in racially and ethnically diverse American women, confirming its importance as a key molecule in fibroid pathobiology. There is increasing evidence that the downstream Wnt/β-catenin signaling pathway may also play a key role in fibroid pathogenesis.


High-mobility-group protein A2 (HMGA2, formerly called HMGI-C) is an architectural transcription factor located on chromosome 12 that is involved in the pathogenesis of fibroids with t(12;14). The dysregulation of HMGA2 might be associated with fibroid growth by the increased expression of CDKN2A (which encodes ARK[p14]). Intact ARF (p14) maintains senescence in fibroids.


The mutation of tumor repressor REST and activation of the mammalian target of rapamycin (mTOR) signaling pathway may also play a key role. The Eker rat model for leiomyomas has a germline defect in the tuberous sclerosis complex 2 (Tsc-2) tumor suppressor gene. Tsc-2 also activates mTOR , which makes the latter a particularly interesting gene in the pathogenesis of leiomyomas.


A significant limitation of genetic studies is that they have largely been conducted in areas where white people predominate and may not accurately reflect the karyotypes seen in black women. Given the different clinical behavior of myomas in black women, it is reasonable to believe that unique genes may be contributing to this risk. Association of a polymorphism in the COMT gene, seen more frequently in African-American women, was linked to leiomyoma risk. In vitro work also suggests that there may be differences in growth-factor regulation in leiomyomas from African-American women. Linkage analysis for FH in nonsyndromic leiomyomas has demonstrated a significant effect of race, with linkage only seen in white women and a negative relation in black patients.


Genetic Influences: Clinical


There are several lines of evidence that suggest that fibroids have a genetic component. First, monozygotic twins have twice the rate of concordance for hysterectomy as compared with dizygotic twins. There is also familial clustering, with a two- to sixfold increased risk of a woman having fibroids if she has an affected first-degree relative. Finally, there are also specific syndromes that have a demonstrated genetic component and whose phenotype includes uterine leiomyomas in association with other specific lesions:


Hereditary Leiomyomatosis and Renal Cell Cancer (Mendelian Inheritance in Man 605839) *

* The following website contains the full online catalog of these genetic disorders: http://www-ncbi-nlm-nih-gov.easyaccess1.lib.cuhk.edu.hk/omim/


This syndrome is autosomal dominant, and affected families manifest cutaneous leiomyomas and papillary renal cell carcinoma (RCC). Affected women can have uterine leiomyomas as well as uterine leiomyosarcomas. Both malignancies (sarcomas and RCCs) are atypical in their presentation compared with their sporadic counterparts; uterine sarcomas can appear in young premenopausal women, and the papillary RCC is often metastatic at presentation and more likely to be seen in women. Two other syndromes with cutaneous and uterine leiomyomas have been described, but lessons from molecular genetics suggest that these are incomplete forms of the hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome and should be of historical interest only (Reed syndrome or multiple cutaneous and uterine leiomyomas [MCUL], Mendelian Inheritance in Man [MIM] 150800).


FH, an enzyme that is part of the Krebs tricarboxylic acid cycle, is the gene mutation at 1q 42-43 responsible for HLRCC syndrome. Germline mutations appear to result in absent or nonfunctional proteins; thus FH appears to act as a tumor suppressor. FH appears to play a role in a small percentage of nonsyndromic leiomyomas seen in white women.


Although work on elucidating the pathogenesis of the HLRCC syndrome continues, FH mutations appear to induce a change toward a hypoxic phenotype. Thus the hypothesized relationship between hypoxia and the pathogenesis of myomas appears linked to this subset of leiomyomas.


Currently the identification of women at higher risk for malignancy due to the HLRCC syndrome is an important clinical task, as is the identification of women whose families carry the breast cancer (BRCA) gene mutations. However, in the future, individualized therapy will likely be possible based on genotype and underlying predispositional genes.


Cowden Disease (MIM 158350 )


This disease is a type of hamartomatous polyposis syndrome characterized by leiomyomas as well as other benign tumors, including lipomas and hamartomas. It is autosomal dominant in inheritance and involves the candidate gene phosphatase and tensin homologue (PTEN) . Patients with Cowden disease are at increased risk for endometrial, thyroid, kidney, and colorectal cancers. Around 40% of women with Cowden disease are reported to have fibroids.


Finally, deletions of collagen genes COL4A5 and COL4A6 have also been shown to be associated with a familial syndrome known as diffuse leiomyomatosis with Alport syndrome and rarely with nonsyndromic fibroids. There may be a synergistic effect between the inactivation of COL4A5, COL4A6 , and insulin receptor substrate 4 (IRS4) underlying the pathogenesis of Alport syndrome.


Other Influences


Epidermal growth factor (EFG) is a growth factor mitogenic for smooth muscle cells. EGF mRNA is upregulated in leiomyomas only in the secretory phase of the cycle. Receptor levels appear to be similar in leiomyomas and myometrium. The latest work concentrates on the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase–derived reactive oxygen species (ROS) for signaling EGF and the platelet-derived growth factor (PDGF) signaling pathway, leading to myomatous cell proliferation.


Heparin-binding growth factors are important biologic regulators in leiomyomas since they can be secreted and bound to the reservoir of heparin sulfate proteoglycans filling the leiomyomatous ECM. Heparin-binding epidermal growth factor (HBEGF), vascular endothelial growth factor (VEGF), PDGF, hepatoma-derived growth factor (HDGF), and the previously described basic FGF are all found in myomas. Many have also been documented to be stored in the ECM.


Insulin-like growth factors (IGFs) can act as smooth muscle cell mitogens and were originally shown to have greater binding to leiomyomas as compared with myometrium. However, assessment of mRNA levels suggests that gene expression has differed among studies. Later studies suggested specific modulation of the IGF-binding proteins. Recent work has demonstrated the role of activation of tyrosine kinases and especially the IGF-1 signaling pathway in fibroids. Regulation of these factors following GnRH-agonist treatment has also been reported. There may also be increased prevalence of leiomyomas in women with acromegaly.


Prolactin also appears to play an important role in myoma pathogenesis. In vitro studies suggest that it is mitogenic for leiomyoma and myometrial smooth muscle cells and that the prolactin receptor is present in these tissues, setting up an autocrine or local endocrine system. Additionally, agents that appear to cause clinical regression of uterine leiomyomas also appear to decrease prolactin production in vitro.


The resident immune cells also appear to influence leiomyoma biology. Mast cells have been implicated in leiomyoma pathobiology, given that they are generally uniformly distributed in myometrium but highly variable in leiomyomas. Recent work has suggested a correlation of mast cell number with vasculature. A number of cytokines have also been shown to be differentially regulated in leiomyomas and myometrium. Interleukin 8 (IL8) has decreased expression of both the ligand and its receptor in myometrium compared to leiomyomas. The functional significance of this is shown by the fact that neutralizing antibody to IL8 decreases cellular proliferation in vitro. Monocyte chemotactic protein-1 (mcp1) is largely undetectable in normal samples of leiomyoma and myometrium but is increased significantly following GnRH-agonist therapy.


Wnt 7a , the human homologue of the wingless Drosophila genes involved in anteroposterior (AP) axis formation and smooth muscle cell patterning, appears to be suppressed in leiomyomas as compared with normal myometrium and to be inversely related to ER-α expression. In contrast, secreted frizzled related protein 1 (sFRP1), a modulator of Wnt signaling, is increased in leiomyomas (particularly in the late proliferative phase) and increased by estradiol treatment and hypoxia. HOX gene expression does not appear to differ between leiomyomas and myometrium. The mRNA for protooncogenes cfos and cjun is also overexpressed in leiomyomas compared with normal myometrium.


Parathyroid hormone–related peptide (PTHrP) mRNA is also overexpressed in leiomyomas compared with normal myometrium. Serum overexpression of this protein originating from a fibroid simulating the hypercalcemia of malignancy has been reported in the literature.


Micro-RNAs


Micro-RNAs (mi-RNAs) are small noncoding RNAs that generally inhibit gene expression and appear to have a key role in the pathogenesis of leiomyomas. Although early studies showed differential expression of specific miRNAs between leiomyomas and normal myometrium and an association of key miRNAs with leiomyoma size and patient race, more recent studies have started to define the key regulatory pathways that are influenced by mi-RNAs.




Principles of Treatment




  • ◆

    An initial assessment of whether bleeding, bulk-related symptoms, or both are prompting therapy helps to guide appropriate therapeutic options. Additionally, desire for future fertility can further refine the available options.


  • ◆

    Surgical therapies primarily include hysterectomy and myomectomy. Both options can be offered using various surgical approaches (open vs. laparoscopic vs. robot assisted).


  • ◆

    Uterine artery embolization is being used increasingly as the first-line alternative to hysterectomy for women with bulk-related symptoms and no desire for future pregnancy.


  • ◆

    MRI guided focused ultrasound surgery provides a noninvasive FDA approved ablation method for uterine leiomyomas.


  • ◆

    Medical therapies that include oral contraceptives, progestins, nonsteroidal antiinflammatory drugs, antifibrinolytic agents, and progestin-loaded IUDs are all used for heavy menstrual bleeding associated with leiomyomas. There is, however, a lack of randomized trials that demonstrate their effectiveness in the medical management of fibroids.


  • ◆

    Progesterone receptor modulators like Ulipristal acetate have shown promising results from European reports.


  • ◆

    Other therapeutic agents like gonadotropin-releasing hormone agonists and antagonists and androgenic compounds also have a role in medical management of uterine fibroids.



Uterine leiomyomas do not always necessitate treatment. In general, expectant management is appropriate until the woman develops enough symptoms that she requests treatment. The US Agency for Healthcare Research and Quality on comparative management of fibroids has noted the lack of published data that examines the effectiveness of treatment strategies. There are two important caveats to this generalization. First, although bleeding symptoms are usually evident, bulk symptoms can be insidious in their onset and are often attributed to other processes such as aging. An initial assessment of whether bleeding, bulk-related symptoms, or both are prompting therapy helps to guide appropriate therapeutic options. Women not electing therapy cannot reflexively be termed asymptomatic; they may have substantial symptoms but view the therapies they are offered as worse than the disease. As a second step, assessing the patient’s desire regarding reproduction helps refine the available options. In general women with complaints of heavy menstrual bleeding (HMB) alone tend to have more options for therapy (e.g., endometrial ablation, hysteroscopic myomectomy, and hormonal therapy including a progestin-containing intrauterine device [IUD]) than women with concurrent bulk-related symptomatology.


Finally, menopause can be a cure for women with myomas. Clearly HMB ceases with the onset of menopause. However, not all women have enough volume reduction to alleviate their symptoms. In addition, bleeding symptoms may continue for women who elect postmenopausal HRT, and studies have suggested that myomas continue to grow in women who take HRT.


Surgical Therapies


Hysterectomy provides the only cure for fibroids and will remain a viable treatment option for the near term. In addition, short-term outcome studies suggest that women with myomas experience an improved quality of life following hysterectomy. Hysterectomy also eliminates concomitant conditions including adenomyosis, endometrial polyps, and abnormal pap smears. Observational data suggest that women who have undergone hysterectomy have an improved quality of life over the next 1 to 10 years. Unlike the case in hysterectomy for endometriosis, the ovaries can be retained without losing therapeutic efficacy. Generally women weigh the risk of menopausal symptoms against the risk of ovarian tumors in making this decision. The attention paid to the ovary’s production of androgens in the postmenopausal period and their possible importance in mood and libido appears to be leading to an increase in the number of women who retain their ovaries even if they are perimenopausal. The fact that hysterectomy, even without oophorectomy, decreases the risk of ovarian cancer may also affect decision making on this issue. Laparoscopic rather than open hysterectomy, if possible, should be a goal if this treatment modality is chosen. As robot assistance has shown a reduction in the likelihood of conversion to laparotomy at the time of hysterectomy, there may be hidden potential in this modality compared with traditional aggressive surgery. However, this benefit must be weighed against the risk of dissemination of undiagnosed cancer when power morcellation is used for specimen removal, given concern regarding peritoneal dissemination and its effect on survival. Although the magnitude of this risk is debated, recent guidance from the US Food and Drug Administration (FDA) recommends limiting the use of power morcellation to hysterectomy in premenopausal women who are not candidates for en bloc resection and counseling all women about the risks of power morcellation. Despite definitive treatment, hysterectomy alone (without oophorectomy) has been linked to an increased incidence of cardiovascular morbidity, prolapse, and worsening cognitive function, including Alzheimer and Parkinson diseases. These long-term adverse outcomes should be kept in mind in recommending hysterectomy as a surgical therapy.


Finally, the use of supracervical or subtotal hysterectomy in women with leiomyomas is debated. The fact that 7% of women in an unselected population have cyclic bleeding following this type of hysterectomy deserves further study to see whether these women had bleeding complaints and/or fibroids prior to hysterectomy. Women may also run the theoretical risk of forming cervical fibroids following supracervical hysterectomy. Finally, accumulating data suggest that, at least in the short term, sexual functioning is not improved with supracervical hysterectomy.


Nonetheless, as women seek less invasive options and the health care system seeks less costly ones, alternatives to hysterectomy will become more widely used. All surgical alternatives to hysterectomy, however, share the risk of new myoma formation (what is commonly but incorrectly termed fibroid recurrence ). Unlike the similar phenomenon after surgery in malignant disease, this is unlikely to be persistence of the same tumor but instead growth of additional tumors that may have been missed, not treated, resistant to treatment, or not yet present at the time of initial therapy. Thus, following a variety of techniques including abdominal myomectomy and UAE, the risk of subsequent procedures is significant.


Since the 1930s, abdominal myomectomy ( ) has been the traditional alternative to hysterectomy because it preserves the uterus and allows childbearing. However, open myomectomy does have morbidity similar to that of hysterectomy and poses a significant risk of subsequent surgery. Myomectomies are now increasingly being performed laparoscopically, with or without robotic assistance. Rates of conversion to laparotomy have been reported to be as low as 2% after laparoscopic myomectomy, and the procedure has shown fewer complications as compared with open myomectomy. Patients undergoing traditional myomectomy via laparotomy, compared with robot-assisted myomectomy, had more estimated blood loss and a longer length of stay in the hospital. When outcomes from robot-assisted laparoscopic myomectomy, standard laparoscopic myomectomy, and open myomectomy were compared, patients with laparoscopic and robot-assisted procedures had similar blood loss and length of stay, both of which were reduced compared with the open procedure. Short-term surgical outcomes are similar after robot-assisted myomectomy and standard laparoscopic myomectomy. Reports have shown increased operating time with robotic procedures, but the rate of complications is low compared with open surgery. However, recent safety concerns regarding the use of power morcellation and the need for having a larger abdominal wall incision for the delivery of surgical specimens intact has made conventional abdominal myomectomy relevant again. Using single-port laparoscopy or laparoendoscopic single-site surgery (LESS) has led to success for myomas; however, since this is the newest form of laparoscopic innovation, data are limited.


Abdominal myomectomy permits healthy pregnancies after surgery and pregnancy rates have been reported to be in the range of 50% to 60%. Uterine rupture following myomectomy is very rare, at 0.5% to 1%; it is suggested that this may be related to surgical technique. The common clinical practice of counseling women who have had a myomectomy with a transmural uterine incision to undergo an elective cesarean section is based on this risk of uterine rupture following classical cesarean delivery. However, there is no evidence they are analogous situations. There is enough evidence to question the rationale for the conventional practice and recommendation of cesarean delivery after myomectomy, even if the endometrial cavity has been breached.


Although laparoscopic myomectomy involves much smaller incisions and a quicker recovery, it does require a surgeon skilled in laparoscopic suturing, and not all women have the number and size of fibroids amenable to this technique. Whereas updated series suggest that the risk of uterine rupture is low following laparoscopic myomectomy, rare cases continue to be reported. Because these uterine ruptures typically occur remote from term, appropriate counseling for patients contemplating pregnancy is important, especially if devascularization with cautery occurs intraoperatively. Data are very limited on obstetric outcomes following robot-assisted myomectomy, but the few reports that are available have been reassuring.


Myolysis is a variation on the technique of laparoscopic myomectomy in which the leiomyoma tissue is coagulated rather than removed. Although this technique is easier to master than laparoscopic morcellation or suturing, localized destruction without repair may also increase the chance of uterine rupture and adhesion formation. A laparoscopically deployed radiofrequency ablation device for fibroids is now approved by the FDA, and concomitant use of intraperitoneal ultrasound diagnosis with this technique can optimize the detection of fibroids. In a single randomized trial, radiofrequency ablation resulted in a shorter length of stay and less blood loss compared with laparoscopic myomectomy.


For women with submucous myomas, the use of hysteroscopic myomectomy ( ) has distinct advantages. With their accessible location, type 0 and 1 (European Society of Hysteroscopy classification) myomas can be resected with an intrauterine operative endoscope with good long-term results. Although this procedure requires a highly skilled practitioner, it can be done as outpatient surgery, often with a regional or local anesthetic and sedation that eases recuperation. Symptomatic relief is good, with fewer than 16% of women in one large series who were treated for menorrhagia reporting second surgeries after 9 years. Fertility rates after hysteroscopic myomectomy appear excellent, and there have been no case reports of uterine rupture after uncomplicated hysteroscopic myomectomy.


For women who have completed childbearing and for whom bleeding is the primary problem, endometrial ablation, either alone or in combination with hysteroscopic myomectomy, may give relief with minimal invasiveness. Increasingly, a levonorgestrel IUD can be used to implement a “reversible endometrial ablation.” In addition to providing effective control of bleeding, it provides contraception for women in this premenopausal age group, in contrast to surgical endometrial ablation, which leaves women at risk for tubal and cervical and cervical ectopic pregnancies.


Uterine Artery Embolization


Transcatheter arterial embolization has long been an effective percutaneous technique for controlling bleeding in a wide variety of disorders. Its use for the treatment of leiomyomas was first reported in 1995. Although initially used as an alternative for patients who were felt to be poor surgical candidates, the resolution of symptoms in the initial cohort encouraged the use of this technique as a primary therapy.


UAE is increasingly the first-line alternative to hysterectomy for women with bulk-related symptoms and no desire for future pregnancy ; it has been recommended by the American College of Obstetrics and Gynecology (ACOG) as a safe and effective form of uterus-preserving treatment for fibroids. The procedure can be completed in 98% to 100% of patients. It provides a decrease in HMB in 85% to 94%, improves dysmenorrhea in 77% to 79%, and improves bulk-related symptoms in 60% to 96% of women, whereas mean uterine volume reduction is seen in 30% to 60% of women. The largest reported series of 1278 patients 3 years after UAE reported improvement of symptoms and quality of life in 95% of women. A rate of amenorrhea of 29% after procedures for fibroids was seen in 14.4% of women (hysterectomy 9.8%, myomectomy 2.8%, repeat UAE 1.8%). In other reports, the need for a second form of intervention after UAE was noted to be somewhere between 9% and 32%. Series with follow-up over 5 years report higher rates of secondary intervention. Although 75% of women continue to report normal or improved bleeding, approximately 20% report having undergone a second procedure in the form of hysterectomy, myomectomy, or a repeat UAE procedure. Previously thought of as a contraindication, fibroids greater than 10 cm in diameter have been shown to be treated successfully with UAE.


A series of randomized clinical trials and systematic reviews have compared UAE to surgery (hysterectomy and myomectomy). These reports have noted a shorter duration of hospitalization at initial treatment for patients undergoing UAE compared with surgery. Additionally, patients after UAE had similar improvement of symptoms at 5 years as compared with surgery.


It is relatively common for submucous myomas to be expelled vaginally after treatment ; thus most hysteroscopically resectable fibroids are still approached surgically. Similarly, the presence of pedunculated subserosal fibroids has historically been considered a relative contraindication to UAE therapy, although no cases of intraperitoneal expulsion have been reported. There are some data suggesting that UAE can still be performed in cases of pedunculated fibroids. A laparoscopic approach is generally preferred in such patients. Studies also suggest that high T2 signals predict greater volume reduction and complete devascularization predicts outcome at 5 years.


Most patients develop significant pain and some vaginal discharge following the procedure and usually require intravenous narcotics for pain control. Postembolization syndrome, defined as the combination of diffuse abdominal pain, mild fever, and mild leukocytosis, is common and can occur in 30% to 40% of patients; it gradually improves over a week. Serious complications after UAE are rare but are more likely when there is a single large leiomyoma. Since preoperative imaging and endometrial biopsies cannot distinguish between benign leiomyomas and myometrial neoplasms of low- or high-grade malignancy (e.g., leiomyosarcoma), a misdiagnosed sarcoma may be treated with UAE rather than surgical resection. Fortunately, given the rarity of these tumors, a review of the literature has noted only six cases (out of 8084 procedures) where women with uterine sarcomas underwent UAE. In such cases UAE did not seem to spread the disease, but it impaired prognosis by delaying diagnosis. Because the risk of leiomyosarcoma increases with age, UAE is not recommended for menopausal women with new onset or worsening symptoms related to presumed leiomyomas.


It is important to assess the effects of UAE on the ability of women to become pregnant subsequently or to carry a pregnancy to term. Thus far, there are a number of reported patients who became pregnant following UAE. Although no difference in intrapartum adverse outcomes was noted when patients after UAE were compared with patients after myomectomy, cesarean delivery rate was increased in both groups. Pregnancy clearly can and does occur following UAE with success rates reported from 20% to 60% ; however, the risk of spontaneous miscarriage in these women has been noted to be higher compared with women with fibroids who had not undergone UAE treatment. There are two major areas of caution for women wishing to optimize their fertility potential: effects on ovarian function and myometrial wall integrity. Because of increased placental implantation issues after UAE, close monitoring of placental status has been recommended. In one series, approximately 13% of women who were nulliparous and had no other risk factors had some form of placenta previa or accreta.


The early data on ovarian damage used amenorrhea as the indicator of perturbed ovarian function. It is clear that amenorrhea risk is age-related, with women under age 40 years having a 3% risk and women over age 50 years a 41% risk. Newer studies evaluate FSH and anti-müllerian hormone (AMH) levels to detect more subtle damage. Although studies with short-term outcomes may not show impact, most have shown an age-dependent risk, with risk increasing more after age 45 years. Compared with hysterectomy, UAE causes more of a decrement in AMH levels after a 2-year follow-up. However, it is often overlooked that surgery also has an adverse impact on ovarian reserve. A putative mechanism is suggested in another report indicating significantly increased FSH levels following UAE in patients with uteroovarian vascular anastamoses.


Focused Ultrasound—Noninvasive Treatment


MRgFUS provides a noninvasive ablation method that has been FDA-approved for the treatment of uterine fibroids since 2004. Although it was pioneered for the treatment of uterine fibroids, this modality can be used to treat multiple diseases and may prove to be the next step in surgical innovation from open to minimally invasive to noninvasive approaches.


Just as a laser amplifies and collates light into a therapeutic modality, focused ultrasound (FUS) can deliver a large amount of energy to target tissues in a noninvasive way. Treatment is accomplished by placing a transducer against the abdomen and targeting an intraabdominal myoma without breaching the skin. The intensity of FUS used for treatment is significantly higher than that used in diagnostic ultrasound and can rapidly increase temperature at the focal point in excess of 70°C. At this temperature, coagulative necrosis will occur. The procedure is performed under conscious sedation. After T2-weighted images are obtained (to develop a treatment plan), FUS sonications are targeted at the fibroid while MRI provides continuous thermal feedback.


It is not typically size alone that limits treatment, but size, vascularity, access, and other factors also play major roles. The strongest predictor of MRgFUS success is the nonperfused volume (NPV) or the area devascularized by treatment that is nonperfusing in posttreatment gadolinium imaging. In one of the pivotal trials, 71% of women reached a target symptom reduction score on the uterine fibroid symptom and quality-of-life (UFS-QOL) questionnaire at 6 months, and 51% maintained this at 12 months. In newer studies, as higher NPV rates were achieved, quality of life improved. Volume reduction is again proportional to NPV achieved after treatment. Up to 40% reduction in volume has been noted in fibroids after MRgFUS treatment. When low NPV (of around 26%) was achieved, 28% of patients ended up with an alternative form of treatment at 12 months after MRgFUS. Newer reports with higher NPV achieved (around 60% to 80%) led to failure of treatment in only 8% to 12% of women.


Complications from MRgFUS are very rare. The most common complication is skin burns. These can occur because of poor coupling or abdominal scars on the patient that are encountered within the FUS beam pathway. An early trial reported around 5% risk of burns. Only one case of extensive skin burns has been reported. Use of acoustic reflectors (like cork or foam) and an energy-blocking patch on scars has shown success in preventing burns.


A parallel enrollment trial compared MRgFUS with abdominal hysterectomy and recorded significant clinical complications on the short-form health survey (SF-36) at 1, 3, and 6 months. Clinically significant complications were lower in the MRgFUS group, with SF-36 scores improved in both arms at 6 months. However, scores were significantly better in the hysterectomy group. There is currently a randomized clinical trial funded by the National Institutes of Health (NIH) comparing MRgFUS with UAE (NCT00995878, clinicaltials.gov ), which should provide important information. Studies have also shown MRgFUS to be in the range of currently accepted criteria for cost-effectiveness.


Subsequent pregnancy-related complications after MRgFUS treatment are minimal; it is possible that MRgFUS could be the treatment of choice for patients desiring future fertility. Around 100 cases of pregnancies after MRgFUS have shown no impact on the rate of miscarriage or other obstetric parameters. In the only published series, 45 pregnancies in 51 women were reported. A live birth rate of 41%, mean birth weight of 3.3 kg, spontaneous abortion rate of 28%, and term delivery rate of 93% were noted. At least one patient with a fibroid impinging on the cavity and unexplained infertility conceived spontaneously after MRgFUS treatment.


Ultrasound-guided FUS (typically referred to as high-intensity focused ultrasound [HIFU]) has been used to treat several solid tumors outside the United States. Since feasibility studies showed promising results for the use of ultrasound-guided HIFU for uterine fibroids, larger studies have been reported. These reports have not only demonstrated safety and efficacy of ultrasound guided-HIFU for treatment of uterine fibroids, but one report also showed safety of pregnancy within 1 year of treatment.


Medical Therapies


There is a lack of randomized trials to demonstrate effectiveness of medical management of fibroids. Oral contraceptive pills (OCPs), progestins, nonsteroidal antiinflammatory drugs (NSAIDs), antifibrinolytic agents, androgenic compounds, and progestin-loaded IUDs, all of which are useful in the treatment of idiopathic HMB, have not been studied with leiomyoma-related bleeding. Nonetheless, they are widely used and are likely effective in at least a subset of women with fibroids. A systematic review reports that in trials where women were assigned to medical therapy, at least 60% underwent surgery by 2 years.


Progesterone Modulators


Clinical data regarding the efficacy of progesterone modulators have confirmed the importance of progesterone in myoma biology. A concern of paramount importance in using progesterone receptor modulators (PRMs) is the potentially increased risk of endometrial hyperplasia or cancer. Pathologists have, however, shown a unique histologic pattern in patients on these medications : simple endometrial cystic dilation. These PRM-associated endometrial changes do not have the typical molecular signatures of malignant progression ; however, long-term data are still lacking.


Ulipristal acetate is a PRM that is approved for both preoperative and intermittent repeated courses of therapy in the European Union under Conformité Européene marking; it is also undergoing further evaluation in other countries. Ulipristal has been compared with placebo at 5 or 10 mg once daily for 13 weeks in a randomized controlled trial. Treatment with this medication has resulted in the resolution of HMB and a significant reduction in fibroid volume in women with uteri of less than 16 weeks’ gestational size. No findings of endometrial hyperplasia were associated with its use. In another noninferiority trial, ulipristal was compared with GnRH agonists, at 5 or 10 mg a day for 13 weeks. Both arms had comparable rates of resolution of HMB. The ulipristal arm had more rapid induction of ammenorrhea; however, smaller reduction in myoma size was noted in this group compared to GnRH agonist arm. Data from the supplementary appendix of these studies suggest that PRMs provide more prolonged volume reduction after treatment is discontinued compared with GnRH agonists. Endometrial biopsies from women on ulipristal revealed a carryover effect of this medication after 3 months of therapy, which lasted up to 6 months. The use of ulipristal use has been reported for up to four 3-month courses separated by a spontaneous menstrual flow upon withdrawal or one brought on by norethindrone acetate. No cases of endometrial hyperplasia or cancer were noted in either group. A sustained long-term effect of 3 to 12 months of treatment with ulipristal on fibroid volume reduction and menstrual bleeding has been suggested from a series of 18 successful pregnancies occurring for up to 6 years following completion of therapy. A longer duration of treatment has not yet been evaluated. However, given these reassuring data, women with symptomatic fibroids may have the option of a unique intermittent therapy with this medication. Unfortunately the available FDA-approved formulation (30-mg tablet) makes off-label use of ulipristol for fibroids problematic in the United States.


Mifepristone (RU486) is a steroidal derivative of norethindrone; it acts primarily as an antiprogestin. It has, at high doses (50 mg/day), shown a reduction in myoma size comparable to that produced by GnRH agonists. Thus the clinical benefit was equivalent to that seen with GnRH agonists, yet follicular levels of estradiol were maintained to support bone mass and provide symptomatic relief. Identical results were found with a reduction in dose to 25 mg/day ; however, with a dose of 5 mg/day, although acyclicity was maintained, volume reduction was reduced to 30%. More recent studies suggest that daily doses of 5 and 10 mg produce volume reduction equivalent to that elicited by the higher doses, but they produced amenorrhea in only 60% to 65% of women while also resulting in less menstrual blood loss. Nonetheless, this regimen provides significant symptomatic improvement. Mifepristone has mild side effects compared with GnRH agonists. Adverse effects included mild and infrequent hot flashes in approximately 20% of patients during the first month of treatment only with higher doses; however, more persistent symptoms appeared in another study. Mifepristone is not approved for use by the FDA. A major impediment to off-label use is the fact that the currently available dose of RU486 is not appropriate (200 mg once for pregnancy termination vs. 5 to 10 mg/day for fibroid treatment for 6 months).


A unique pattern of endometrial changes has been observed following treatment with PRMs termed progesterone receptor modulator–associated endometrial changes (PACESs). The clinician should be aware of these cystic glandular changes causing thickening of the endometrium. True endometrial hyperplasia and atypical hyperplasia have not been observed following PRM therapy, and no woman has developed endometrial carcinoma.


Gonadotropin-Releasing Hormone Agonists


Since the action of native GnRH depends on its pulsatile release, the effects of GnRH agonists depend upon their continuous presence. They first cause a time-limited increase in gonadotropin release, termed the flare . This subsequently leads to receptor downregulation, followed 1 to 3 weeks later by a hypogonadotropic hypogonadal state. It is this downregulated phase that is useful clinically in the treatment of myomas. Alterations of the GnRH molecule, typically at positions 6 and 10 of the two glycine (G) residues, produce a longer half-life and are more useful for clinical purposes.


Many studies have focused on the efficacy and benefits of treatment with a GnRH agonist in women with fibroids. Most women experience a substantial reduction in mean uterine volume of 30% to 60% over 3 to 6 months of therapy. However, there is a wide range of responsiveness, with rare individuals achieving no volume reduction. Both the estradiol levels at week 12 and the woman’s weight are correlated with the degree of uterine shrinkage.


The other primary benefit of treatment with a GnRH agonist is the induction of amenorrhea. Menses typically return 4 to 10 weeks following the end of treatment. Fibroid and uterine volume usually returns to pretreatment size within 3 to 4 months. The rapid return of ovarian steroidogenesis, coupled with an increase in the concentration of ERs in fibroids recently treated with GnRH agonists, may contribute to the rapid regrowth of these tumors.


GnRH agonists can have significant adverse effects, the most important of which is bone loss. Six months of GnRH-agonist treatment can cause a 6% loss in trabecular bone, not all of which is reversible on discontinuation of therapy. Symptomatic side effects of GnRH-agonist therapy are common. Hot flashes are universal in women undergoing treatment. Other less common side effects include sleep disturbance, irregular vaginal bleeding, vaginal dryness, headache, depression, hair loss, and musculoskeletal symptoms.


Because of the concerns regarding bone loss with GnRH agonists, clinical use of these drugs is typically confined to use as preoperative therapy or in women for whom a short period of treatment will be effective. The GnRH agonist leuprolide is FDA-approved in conjunction with iron administration for the presurgical treatment of uterine fibroids and to correct anemia. This is the only medical treatment approved by the FDA for the treatment of this disease.


Administration prior to either hysterectomy or myomectomy is the most common current use of these agents. Length of therapy varies from 1 to 6 months, depending on the surgical and hematologic goals and the planned procedure. The amenorrhea induced by GnRH therapy leads to improved hemoglobin concentrations, which permits women who are anemic to correct this problem and potentially to donate their own blood for transfusion. Preoperative GnRH therapy has also been shown to reduce intraoperative blood loss significantly. Although current guidelines from ACOG suggest that the use of GnRH agonists is beneficial preoperatively, they also state that for each individual the benefit must be weighed against the cost and the side effects.


Gonadotropin-Releasing Hormone Agonist Therapy With an Estrogen/Progestin Add-Back Regimen


For many women, 3 to 6 months of symptomatic relief from leiomyomas will not allow them to avoid surgery but it does afford them the opportunity to prepare themselves optimally for an operation. Therefore the concept of adding additional therapy to minimize the side effects of prolonged therapy was developed, the so-called add-back regimen. The goal of this approach was to achieve a window of therapeutic efficacy during which side effects would be lessened or eliminated yet no regrowth of the myomas would occur.


Studies have used one of two treatment strategies: simultaneous and sequential administration. With simultaneous treatment regimens, both the GnRH agonist and the add-back regimen are started at the same time. In sequential treatment regimens, the GnRH-agonist is given alone for up to 6 months before steroid hormone treatment is added, reducing a period of hypoestrogenism before steroid add-back therapy is started. Studies have suggested that sequential treatment is superior for therapeutic efficacy in the treatment of fibroids.


Gonadotropin-Releasing Hormone Antagonists


GnRH antagonists have also been studied in the treatment of uterine leiomyomas. The lack of flare effect and rapid onset of action give them an advantage over GnRH agonists. Although they are not FDA-approved for this indication, they have several significant advantages over GnRH agonists. However, in the United States, these agents are marketed for use of ovulation induction, and long-term preparations are not available. This could make the treatment of fibroids with GnRH antagonists cumbersome.


Aromatase Inhibitors


Aromatase inhibitors have been shown to decrease symptoms from fibroids and to effect shrinkage in size when given to women that were pre- or perimenopausal. A randomized trial compared letrozole at 2.5 mg/day to triptorelin (3.75 mg/month) for 12 weeks in 70 women with a single fibroid 5 cm or greater size. A statistically significant volume reduction in myoma size was noted in the letrozole group versus the triptorelin arm (45% vs. 33%). Serum hormone levels were also significantly reduced in the triptorelin arm versus the letrozole group. Extensive data regarding the safety, efficacy, and cost-effectiveness of this class of medications as medical therapy for uterine fibroids are still lacking.


Selective Estrogen-Receptor Modulators


Selective estrogen-receptor modulators (SERMs), which exhibit tissue-specific agonist or antagonist activity, appear to work better in animal models of myomas than in clinical trials. Studies have examined both tamoxifen and raloxifene. Clomiphene has not been studied and has been reported to cause growth of a myoma in a single case report. Despite promising results in animal models, clinical studies have had less impressive results. However, in premenopausal women, raloxifene alone or when combined with GnRH agonists demonstrated little efficacy despite use at three times the conventional dose.


Androgens


Danazol, an androgenic steroid most commonly used for the medical treatment of endometriosis, can be used to induce amenorrhea to control anemia due to fibroid-related HMB. A second androgenic steroid, gestrinone, has been shown to cause volume reduction and amenorrhea in women with myomas. A great advantage of this drug is that, after it is discontinued, there is a carryover effect like that of PRMs; in one study, 89% of the women maintained a decreased uterine volume 18 months after cessation of therapy. Unfortunately gestrinone is not available in the United States. However, androgenic side effects including acne, hirsutism, and irreversible deepening of the voice have limited its clinical use.


Future Directions for Medical Therapy


Growth Factor–Directed Treatments


Particular factors that appear to be relevant to leiomyoma biology include basic fibroblast growth factor (bFGF), which is angiogenic; TGF-β, which is fibrotic; and insulin-like growth factors I and II (IGF-I and -II), which mediate the effects of growth hormone (GH). These molecules, as well as other growth factors, are likely to be targets for leiomyoma treatment in the future.


Growth Hormone- and Insulin-Like Growth Factor–Directed Therapy


Both GH and the IGFs appear to have metabolic effects on uterine leiomyomas and the surrounding myometrium. Because women with acromegaly (an excess of GH) have a high incidence of leiomyomas, researchers decided to test the hypothesis that interfering with the GH axis might work as a treatment for leiomyomas. Lanreotide (a long-acting somatostatin analogue) has been used in seven premenopausal women with uterine myomas in a pilot study in Italy. Over the 3 months of treatment, both uterine volume and the volume of the largest leiomyoma were significantly reduced by 24% and 42%, respectively. Three months following the discontinuation of therapy, there was some regrowth, but a significant reduction in uterine volume persisted at 17% and 29%, respectively. Levels of estradiol were not affected by this treatment, although both plasma GH and IGF-I levels were significantly reduced, suggesting that additional pathologic modulators may be effective.


Antiangiogenic Therapies


There is significant evidence that the angiogenic factor bFGF and its type I receptor are important in the pathogenesis of leiomyoma-related bleeding. In a variety of systems, interferons (IFNs)-α or -β antagonize the effects of bFGF and have proven clinically useful in the treatment of a variety of vascular tumors. In vitro studies of leiomyomas demonstrate that IFN-α is an effective inhibitor of serum-stimulated and bFGF-stimulated DNA synthesis in both leiomyoma and normal myometrial cells as well as in endometrial cells. A case report also raises the possibility that IFNs may provide effective treatment for fibroids. A premenopausal woman who was treated with IFN-α for hepatitis C was noted to have significant shrinkage of a leiomyoma after 7 months of interferon therapy. Tranilast (N-[3′4′-dimethoxycinnamonyl] anthranilic acid [N-5′]), a drug currently used in the treatment of a variety of allergic conditions, has been shown in vitro to decrease leiomyoma cellular proliferation by arresting cells at the transition from G0 to G1 phase. Although this drug acts as an angiogenesis inhibitor, it also works as a mast cell stabilizer and a fibrosis inhibitor, which may have relevance for leiomyomas.


Current research also involves work on the role of retinoic acid, vitamin D, and green tea components in preventing fibroid formation.




Adenomyosis




  • ◆

    Adenomyosis is a very common benign uterine disease associated with increased parity.


  • ◆

    Although the pathophysiology of the disease process is not well understood, gonadal steroids and the physiology of the uterine junctional zone may play a key role in the disease process.


  • ◆

    Typically diagnosed by histology on posthysterectomy specimens, adenomyosis can now be diagnosed by transvaginal ultrasonography (TVS) and MRI.


  • ◆

    Hysterectomy is considered the definitive therapy; the role of uterus-sparing surgery is still undetermined.



Adenomyosis, formerly termed endometriosis interna, is a benign uterine disease characterized by the presence of ectopic endometrial glands and stroma within the myometrium ( Fig. 26.3 ). Furthermore, the surrounding myometrium is usually altered to produce hypertrophy. Disease ranges from grossly visible nodules, termed adenomyomas , which can clinically resemble leiomyomas, to disease that is detectable only by microscopy. Definitions vary for the abnormal presence of glands within the stroma, with most settling on a definition of glands found one to three low-power fields from the endomyometrial junction. Clearly differences in definition will lead to differences in perceived rates of occurrence.




FIGURE 26.3


A T 2 -weighted fast-spin echo image of the adenomyotic uterus.

Adenomyosis is characterized by the proliferation of glandular elements of the uterus so that bright (white) areas similar in intensity to the endometrial cavity are seen deep within the uterine wall. The uterine wall in adenomyosis can also be asymmetrical. In this image, the posterior wall is markedly thicker than the anterior wall. Thickening of the junctional zone, another characteristic of adenomyosis, is not seen in this image.


Classically, an adenomyotic uterus is termed boggy, globular, and symmetrically enlarged . However, this disease coexists with many other uterine conditions. One study has argued that adenomyosis is not indeed a true disease but a variant of the norm as women have had similar symptoms for hysterectomy with and without adenomyosis. Most women in this study were perimenopausal, which could have been a major selection bias.


Adenomyosis can affect around 20% to 65% of women, although the accuracy of these numbers can be questioned, since diagnosis can be made with certainty only by microscopic examination of the uterus typically after a hysterectomy. In another series of hysterectomies, adenomyosis appeared in about one quarter of all uterine specimens, but it is no more likely to coexist with symptomatic leiomyomas (23.3%) than with endometrial cancer (28.2%) or ovarian cancer (28.1%).


Unlike leiomyomas, adenomyosis is associated with increasing parity. It is estimated that at least 80% of women with this disorder are parous. However, this may be a confounding variable, since women with a history of multiple pregnancies may simply have had more indications and/or inclination to proceed to hysterectomy, during which the diagnosis could be made. Studies suggesting the presence of adenomyosis with imaging modalities rather than histopathology have suggested the presence of this disease process in adolescents as well. The California Teachers Study noted clinical differences in women with endometriosis and adenomyosis. Women with adenomyosis were older, had higher parity, early menarche, and shorter menstrual cycles, and were more obese compared with women with endometriosis. Another study compared women with fibroids and adenomyosis with women who had fibroids only. Women with both fibroids and adenomyosis had more pelvic pain and dysmenorrhea, higher parity, a history of previous uterine surgery and more clinical depression compared with those who had fibroids only. Women with histopathology-proven adenomyosis were more likely to have a history of previous uterine surgery in several reports. Data regarding smoking as a risk factor for adenomyosis are controversial.


Clinically, adenomyosis has similarities to leiomyomas in that its peak incidence is in women from 40 to 50 years of age, with approximately 60% of women reporting AUB, chiefly HMB. The clinical presentation of adenomyosis is heterogeneous, with AUB (classified as AUB from adenomyosis, or AUB-A type of bleeding ; see section on AUB later in this chapter) and dysmenorrhea being the two most commonly reported symptoms. Abnormal distribution of thick and dilated vessels in the endometrium, particularly in the secretory phase of the menstrual cycle, is one explanation for heavy menstrual flow in such women. Dysmenorrhea, occurring in approximately one quarter of all cases, has been correlated with deep penetration and/or a high density of endometrial glands within the myometrium.


The most widely quoted hypothesis regarding the pathogenesis of adenomyosis is that invasion of the myometrium by the endometrium induces hypertrophy and hyperplasia of the myometrium. Proponents of this theory often quote the association of parity with adenomyosis to suggest that disruption of the layers of the uterus at the time of pregnancy and cesarean delivery may predispose to this condition. However, experimental evidence indicates instead that adenomyosis can be a metaplastic process or a developmental defect. First, adenomyosis has been diagnosed in a woman with Rokitansky–Kuster–Hauser syndrome who lacked eutopic endometrium. Additionally, studies comparing the molecular expression of growth factors show distinct differences between ectopic and eutopic endometrium. Factors that appear common to the pathogenesis of leiomyomas and adenomyosis include angiogenic factors such as bFGF, fibrotic factors including GM-CSF, the gonadotropin receptor LH, and resident immune cells. The efficacy of some conventional and investigational therapies may be mediated through these systems.


The junctional zone of the myometrium may also play a role in the disease process. This structurally distinct region appears as a dark band on T2-weighted MRI and separates the subendometrial myometrium from the outer myometrium. Ultrastructural changes and differential growth factor expression in this region may influence disease physiology.


Gonadal steroid hormones also play a role in the pathophysiology of adenomyosis. Adenomyotic implants express higher aromatase and estrone sulfatase activity, and also have polymorphisms in estrogen receptors (ERs). In vitro studies have shown normalization of aromatase activity by GnRH agonists and danazol, but there is a lack of data to show these effects in vivo. The role of estrogen and ERs in adenomyotic implants is further supported by the fact that endometrial hyperplasia was more prevalent in women with adenomyosis in one report. A murine model of adenomyosis also supports this, as early tamoxifen exposure in these mice led to the development of adenomyosis and abnormal myometrium.


Interestingly, another murine model of adenomyosis was developed by placing a graft of pituitary tissue in a uterine horn. Prolactin appears to be the key pathogenic agent in this model: the mice have elevated levels of plasma prolactin, and administration of bromocriptine prevents the development of adenomyosis. In this model, there does appear to be endometrial cell invasion due to degeneration of myometrial cells. Indirect exposure of the uterus due to hyperprolactinemia secondary to treatment with selective serotonin reuptake inhibitors (SSRIs) can also induce adenomyosis. This theory is further strengthened by work showing both clinical depression and antidepressant use to be increased in women with adenomyosis. A second model using the FORKO (follitropin receptor knockout) mouse suggests that the rising levels of FSH seen with aging may also play an important pathogenic role in this disease.


Although a definitive diagnosis of adenomyosis requires histology, imaging techniques are increasingly able to suggest the appropriate diagnosis. Both TVS and MRI, especially T2-weighted images, are used for this purpose. MRI is a better imaging modality for adenomyosis, but it is expensive. It can also differentiate very well between an adenomyoma and a fibroid. Visual evidence of adenomyosis with TVS includes (1) asymmetric thickening of the myometrium (with the posterior uterine wall typically thicker), (2) myometrial cysts, (3) linear striations radiating out from the endometrium, (4) loss of a clear endomyometrial border, and (5) increased myometrial heterogeneity. With MRI, adenomyosis can be diagnosed with accuracy when the maximal junctional zone thickness is 12 mm or greater; a maximal junctional zone thickness of 8 mm or less usually rules out adenomyosis. Although TVS is a less expensive imaging technique, it is known to be operator-dependent. Three-dimensional (3D) TVS can allow better visualization of the junctional zone compared with standard TVS and hence may be more advantageous. A review of 23 articles comparing the sensitivity and specificity MRI and TVS revealed both techniques to have similar sensitivity (0.72 for TVS and 0.77 for MRI) and specificity (0.81 for TVS and 0.89 for MRI). Computed tomography has no role in the diagnosis of adenomyosis, and needle biopsy should be reserved for cases where malignancy must be ruled out.


The only definitive treatment for adenomyosis is total hysterectomy. GnRH-agonist treatment has been shown to produce amenorrhea, a transient decrease in uterine size, and even in the ability to conceive. Other medical therapies include use of a levonorgestrel-releasing IUD ; there is also a single case report of a danazol containing IUD. Unfortunately resumption of pretreatment uterine size and recurrence of symptoms are usually documented within 6 months of cessation of therapy.


Data regarding conservative surgery (if an adenomyoma is present) are scarce. The absence of a surgical plane separating adenomyotic tissue from normal myometrium makes adenomyomectomy difficult. Furthermore, the consistency of the adenomyotic uterus is described as “woody,” and suturing is difficult in this environment. Adenomyomectomy has been reported to improve the symptoms of adenomyosis, and one study reports conservative surgery and GnRH medical therapy following treatment to be superior to surgery alone. Other reported techniques include endomyometrial ablation and laparoscopic myometrial electrocoagulation, which, on the basis of 3 years of follow-up data, appear to decrease symptoms in more than half of patients.


Both UAE and MRgFUS have been reported for the treatment of adenomyosis. Several studies show small case series with symptomatic adenomyosis diagnosed by MRI or TVS. A review article found that in 511 women from 15 studies, UAE led to improvement of symptoms in 75.5% of patients after a median follow-up of 26.9 months. In another report, after a median follow-up of 58 months, around 18% of women ended with a hysterectomy; however, 73% of women were completely asymptomatic. There has been limited experience with treatment outcomes following MRgFUS for adenomyosis. The largest study to date included 20 patients with a 6-month follow-up and indicated safe and effective MRgFUS therapy in all subjects enrolled. Another MRgFUS case reports a spontaneous pregnancy with full-term delivery after treatment. Ultrasound-guided high-intensity focused ultrasound ablation has also been studied in one report, wherein 78 patients with adenomyosis were enrolled. After a mean follow-up of 24 months, around 90% of the patients had complete relief of symptoms. Based on these findings, hysterectomy still appears to be the treatment of choice for women with significant symptoms who have completed childbearing. Exploration of uterine-sparing alternative treatments for symptomatic relief is warranted.


As imaging techniques get better, adenomyosis is being diagnosed with increasing frequency in women of reproductive age. Data on these women are limited to small case series. Evidence shows a link between adenomyosis and infertility ; however, there is no direct link. There is currently no consensus regarding the impact of adenomyosis on embryo implantation potential. Although some studies have identified alterations in the endometrial milieu in adenomyosis patients that may impact implantation, others have shown no such impairment. Increased risk of preterm birth and preterm premature rupture of membranes in women with adenomyosis (diagnosed with TVS or MRI) is noted in certain reports.




Endometrial Polyps




  • ◆

    Endometrial polyps arise from the endometrium, causing AUB.


  • ◆

    Most polyps are benign, although malignant transformation has been noted in certain high-risk women.


  • ◆

    Polyps can be diagnosed by imaging in the form of TVS, saline infusion sonograms, hysterosalpingograms, or hysteroscopy.


  • ◆

    Polypectomy under hysteroscopic guidance is the recommended treatment.



Endometrial polyps, as their name suggests, arise from the endometrial layer of the uterus. They are characterized by glandular proliferation surrounding a central core of prominent blood vessels in the stroma. Polyps are associated with AUB, particularly spotting and irregular bleeding, but the underlying mechanism has not been articulated. Several mechanisms are thought to play a role in development of endometrial polyps. These include overexpression of endometrial aromatase activity ; monoclonal endometrial hyperplasia ; genetic factors, particularly cytogenetic rearrangements of chromosomes 6p, 12q, and 7q ; and alterations in endometrial levels of matrix metalloproteinases and cytokines. Other work has also shown the role of increased TGF-β, VEGF, and bcl-2 in the pathogenesis of endometrial polyps. Historically polyps have been known to have ERs, though current literature suggests the presence of both ERs and PRs. It is suggested that both estrogen and progesterone contribute to the elongation of endometrial glands, stroma, and blood vessels to give them a characteristic appearance. Progestins also have an antiproliferative function on polyps, as do androgens; however, data suggest that testosterone does not substitute for progestational activity for endometrial polyps.


The estimated prevalence of polyps varies widely from 7.8% to 34.9% depending on the definition and diagnostic modality used. The reported prevalence of polyps is as low as 0.9% in women less than 30 years of age and increases with age. Risk factors for development of endometrial polyps include obesity, hypertension, diabetes, and advancing age, especially postmenopausal status. At least one paper has challenged these classical risk factors and has shown only age to be a statistically significant risk factor. Women with Lynch and Cowden syndromes may also have an increased incidence of endometrial polyps compared with the general population, possibly accompanied by an increased risk of associated endometrial cancer.


Tamoxifen use in postmenopausal women can lead to the development of polyps in around 2% to 36% of women. Tamoxifen-induced polyps may be large in number and size and also show unique molecular alterations. The levonorgestrel-loaded IUD has been shown to reduce tamoxifen-induced polyp development in patients being treated for breast cancer who were followed for a year. Data regarding a relationship between endometrial polyps and postmenopausal hormone therapy are contradictory.


The most frequent symptom in women with endometrial polyps is AUB, or AUB-P in the updated FIGO classification, and is reported in 50% of symptomatic cases. Conversely, of women who have abnormal bleeding, approximately 30% have evidence of endometrial polyps. Although abnormal bleeding is the most common clinical representation, most polyps tend to remain symptom free and are an incidental finding on imaging. The size, number, and location of polyps do not correlate with clinical symptomatology.


Most polyps are benign and malignant transformation can occur in 0% to 12.9%. Microsatellite instability has been noted in patients with multiple polyps or polyps with hyperplasia. A meta-analysis revealed that the prevalence of malignant polyps was higher in postmenopausal women compared with women in their reproductive years (5.42% vs. 1.7%) and that malignant polyps were more likely to bleed than nonmalignant ones. Risk factors associated with malignant endometrial polyps include age greater than 60 years, polyp size greater than 1.5 cm in length, menopausal status, having polycystic ovarian syndrome, and abnormal bleeding.


Endometrial polyps are still diagnosed following dilation and curettage (D&C) or hysterectomy, although new methods of diagnosis and treatment are being used more frequently. Increasingly, saline-infusion sonography (SIS), (also termed sonohysterography or, less commonly, office hysteroscopy ) is used to diagnose polyps ( Fig. 26.4A to C ). A pipelle biopsy has a positive predictive value of 56.3% for polyps and is more useful in postmenopausal women compared with premenopausal women. Polyps can also be diagnosed by hysterosalpingography if the uterine cavity is also visualized. Newer 3D ultrasound probes provide more accurate visualization between the endometrium and myometrium at the fundus and the cornual angles, hence improving the diagnostic accuracy compared with standard ultrasound. Another review reported a similar performance of TVS, saline infusion sonography, and hysteroscopy for the detection of endometrial polyps. Both hysteroscopy and SIS give a better sense of the endometrial cavity than TVS; however, SIS has the added advantage of providing the examiner with information regarding the adnexa and myometrium. Newer reports demonstrate the usefulness of 3D-SIS in the identification of endometrial polyps.




FIGURE 26.4


Comparison of imaging modalities for the diagnosis of endometrial polyps.

(A) A sagittal view of a retroverted uterus obtained by transvaginal ultrasound. A thickened endometrial stripe is appreciated, although the thickness is not well defined. (B) A saline-infusion sonogram of the same patient. After infusion of saline into the endometrial cavity, the endometrial polyp is visualized protruding into the endometrial cavity and a thin endometrium is seen. (C) A photograph taken during hysteroscopy reveals a well-defined polyp in the endometrial cavity. Polyps tend to have blood vessels that are not as coarse as seen in submucosal fibroids, and they have softer edges.

(Images courtesy Dr. Mary Frates, Department of Radiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.)


Medical management of polyps has a limited role. There are data regarding the use of a levonorgestrel-releasing intrauterine system (LNG-IUS) for the prevention of polyp formation in women being treated for breast cancer with tamoxifen. Observing asymptomatic polyps can be an option in low-risk individuals. When left untreated, asymptomatic polyps can regress spontaneously. In one trial, 27% of lesions resolved within 1 year of follow-up in premenopausal patients. Polyps with a mean length of 1.5 cm or more were less likely to resolve. Other studies have shown complete resolution of polyps less than 1 cm. The majority of cases of endometrial polyps are, however, treated with hysteroscopic resection or hysteroscopically guided D&C rather than the traditional D&C. Visualization and direct removal with this technique is reported to be more effective in reducing recurrence rates. Lower recurrence rates after hysteroscopic polypectomy are seen in women with fewer polyps at the time of initial surgery if the initial surgery is combined with an endometrial ablation procedure or LNG-IUS placement, if intrauterine morcellation rather than hysteroscopic resection is used, and if such women have a shorter duration of follow-up. It has been reported that the volume of menstrual loss in women who underwent polypectomy did not differ from that of women who did not undergo polypectomy, but intermenstrual bleeding was significantly improved by polypectomy.


There are few data regarding the effects of polyps on infertility. There are many theories of how polyps can affect implantation. These include mechanical obstruction hindering ostium function and affecting sperm migration, as well as decreased endometrial receptivity due to cytokines and cellular adhesion molecules. The only randomized trial showed an improvement in pregnancy rates after polypectomy in women undergoing intrauterine insemination (IUI). Other retrospective data have shown no difference in pregnancy rates, especially if the polyp was less than 1.5 cm in length. In light of conflicting data, expert opinion recommends removal of polyps when diagnosed prior to in vitro fertilization (IVF) treatment. When lesions are seen during stimulation, the treatment decision is best made on an individual basis.




Abnormal Uterine Bleeding




  • ◆

    AUB can affect up to one third of women of reproductive age and accounts for a third of all outpatient gynecologic visits.


  • ◆

    The Federation Internationale de Gynecologie et d’Obstetrique (FIGO) has created a universal classification of causes of AUB, which has helped in organizing the approach totreatment.


  • ◆

    The pathophysiology of abnormal uterine disease depends on the cause of the bleeding, and this also dictates treatment options.



AUB affects up to one third of reproductive-age women and can occur in conjunction with the pathologic processes we have already discussed or in their absence. AUB also accounts for around one third of all outpatient gynecologic visits. In the United States, AUB (previously called dysfunctional uterine bleeding ) is commonly equated with anovulatory bleeding, whereas in Europe it is a diagnosis of exclusion of excessive bleeding not due to demonstrable pelvic disease, complications of pregnancy, or systemic disease. HMB may occur in 10% to 30% of women and in up to 50% of perimenopausal women. However, the self-reporting of menstrual pattern and flow is highly variable. Change in pattern of flow is probably the most important sign of pathology. HMB is the type of abnormal bleeding frequently associated with benign uterine pathology, including leiomyomata and adenomyosis. Fragile, large, thin-walled vessels and an aglandular endometrium appear to underlie the menorrhagia associated with some submucous myomas. These vessels may arise from abnormalities in angiogenesis associated with growth factors released by myomata (e.g., bFGF, VEGF).


There has been a push toward changing and standardizing the terminology for AUB, as confused terminology has made research collaborations and the interpretation of clinical trials difficult. Terms like menorrhagia, metrorrhagia , and dysfunctional uterine bleeding should be abolished. To standardize communication, FIGO created a universal classification of causes of AUB for women in their reproductive years. The PALM-COEIN nomenclature has four categories that are defined by structural criteria. These are, first, PALM : bleeding due to polyps, adenomyosis, leiomyomas and malignancy or hyperplasia. The other four are unrelated to structural abnormalities and include COEIN : bleeding due to coagulopathy, ovulatory disorders, endometrial causes, iatrogenic and (pathologies) not classified. It is hoped that this classification system will facilitate collaborations to study AUB; however, their ease of use has to be demonstrated. The four structural causes of AUB, excluding bleeding due to malignancy, have already been discussed in this chapter. Previously classified true dysfunctional uterine bleeding equates to the four nonstructural causes of bleeding in the FIGO classification.


Around 13% of women with HMB have some form of coagulopathic disorder. Systemic disease as a cause of HMB should be suspected in adolescents where coagulopathies including thrombocytopenia, von Willebrand disease, or others may be the underlying cause.


Ovulatory disorders include both ovulatory and anovulatory dysfunction leading to AUB. Anovulatory dysfunctional uterine bleeding is characterized by irregular and prolonged bleeding secondary to disturbances in the hypothalamic-pituitary-ovarian axis. It is most common at the extremes of reproductive life and in association with polycystic ovary syndrome. The unopposed action of estrogen on the uterus, resulting in dilated veins and the lack of suppression of spiral arteriole development, may represent the underlying pathophysiology. Large, thin-walled, tortuous vessels can be demonstrated on the surface of the hyperplastic endometrium. Unopposed estrogen reduces vascular tone either through direct effects of estrogen on vascular smooth muscle cells or increased production of nitric oxide (NO), leading to vasodilatation. The endometrium often breaks down unevenly in these circumstances. Scattered patches of thrombotic foci and necrotic degeneration are found adjacent to abnormally proliferated endometrium.


Ovulatory dysfunctional uterine bleeding is characterized by regular episodes of heavy menstrual flow, usually with the heaviest loss during the first 3 days of menstruation. Although many ovulatory disorders can be traced back to endocrinopathies, the underlying abnormalities appear to be defects in processes that regulate the loss of blood during menstruation, primarily angiogenesis, vasoconstriction, and hemostasis. In contrast to anovulatory dysfunctional uterine bleeding, the surface vessels of the endometrium appear to be grossly normal, and only minor abnormalities, such as venular ectasia, have been described in endometrial and myometrial veins.


Endometrial causes of AUB are similar in pathogenesis to those of ovulatory disorders. Hypoxia, inflammation, hemostasis, and angiogenesis all play critical roles in the shedding and subsequent scarless repair of the functional upper layer of the endometrium. Perturbation of local glucocorticoid metabolism, aberrant prostaglandin synthesis, and excessive plasminogen have all been implicated in AUB-E. The disruption of local endometrial hemostatic processes can be due to deficient production of vasoconstrictors such as endothelin-1 and prostaglandin F2α, increased production of vasodilators such as prostaglandin E2 and prostacyclin, and excessive breakdown of clot in the endometrium by abnormal production of plasminogen activator. In addition, vascular smooth muscle cell proliferation is reduced in the spiral arterioles in the mid- and late secretory stages in women with menorrhagia, possibly contributing to vessel instability. Endometrial bleeding-associated factor (EBAF) (also known as TGF-β4), a member of the TGF-β family of growth factors, suppresses production of collagen and promotes expression of collagenolytic and elastinolytic enzymes by antagonizing the normal signaling pathway activated by TGF-β growth factors. Abnormal expression of EBAF, which in a normal cycle occurs only in the late secretory and menstrual phases, has been reported in the endometrium of women with HMB. Angiopoietin 1 and 2 (Ang-1 and Ang-2) may also be involved in the pathogenesis of HMB. Ang-1 promotes vascular maturation, while Ang-2 destabilizes vessels and initiates neovascularization. An altered ratio of Ang-1 to Ang-2 in the endometrium due to the down-regulation of Ang-1 expression is also associated with HMB.


AUB due to iatrogenic causes (AUB-I) usually includes the use of exogenous steroid therapy in the form of a combined estrogen and progestin pill, patch, or ring and levonorgestrel-releasing IUD. The “not classified” category (AUB-N) includes a number of entities that do not fall into any group—for example, AUB due to a uterine arteriovenous malformation. Furthermore, this category has been left open for new entities that may cause AUB and have not yet been discovered. It is important to note that a woman can have AUB due to more than one cause; for example, a woman with HMB due to a submucosal fibroid (AUB-L) can also have concomitant anovulation if she has polycystic ovarian syndrome (PCOS), and she would have AUB-O type of bleeding as well.


These pathophysiologic mechanisms proposed to underlie dysfunctional uterine bleeding are targets for novel therapeutic interventions ( Fig. 26.5 ). Use of the nonhormonal oral antifibrinolytic medication called tranexamic acid has shown a 66% response rate for HMB and appears to be extremely helpful in patients with AUB. Although tranexamic acid has been widely used internationally for many years, its recent FDA approval is leading to increasing use in the United States. Other options would include the use of antiprogestins or selective PR modulators to suppress endometrial growth and stabilize the endometrial vasculature; MMP inhibitors to prevent ECM catabolism, including the matrix of the vessel walls; and NSAIDs or selective cyclooxygenase 2 (COX-2) inhibitors to suppress prostanoid synthesis. Even though their use is not novel, combined estrogen and progestin formulation in the form of a patch, ring, or pill; cyclical oral progestins; and progestin-releasing IUDs are still unfortunately being used as the primary therapy for such patients. Surgical destruction or removal of endometrium via endometrial ablation with newer nonresectoscopic, operator-friendly devices has shown impressive success rates and has also shown to be safe. Hysterectomy is a definitive but less desirable option for AUB patients who are not concerned about fertility preservation.




FIGURE 26.5


Ovarian and uterine mechanisms underlying breakthrough bleeding.

A schematic drawing detailing the interaction between ovarian steroids and local endometrial factors leading to abnormal uterine bleeding. MMPs , Matrix metalloproteinases.




Intrauterine Adhesions




  • ◆

    The formation of intracavitary adhesions in an organ that routinely undergoes sloughing and regrowth every month is not well understood.


  • ◆

    In the developed world any form of uterine instrumentation, especially after childbirth or in the setting of an infection, is the most common cause for adhesion formation. In the developing world the most common cause is intrauterine infection, particularly Mycobacterium tuberculosis.


  • ◆

    Women with intrauterine adhesions may have no symptoms or may experience hypo- or amenorrhea.


  • ◆

    Treatment includes restoration of the normal cavity by a skilled hysteroscopic surgeon.



The formation of intracavitary synechiae in an organ that routinely undergoes sloughing and regrowth without scarring is not well understood. The true prevalence of intrauterine adhesions is difficult to establish, as it is a rare and often asymptomatic condition. Prevalence ranges from 1.5% as incidental finding on hysterosalpingography to 21.5% in women with a history of postpartum curettage. The clinical literature consistently reports that pregnancy frequently precedes the formation of intrauterine adhesions. The relationship between intrauterine adhesions and pregnancy is thought to be the result of defects in the regeneration of the endometrium after delivery, especially the area underlying the placenta. The placental site takes up to 6 weeks to repair, with the thrombosed vessels and superficial necrotic tissue exfoliated as growing endometrium undermines the area. Trauma to the regenerating endometrium involved in restoring stroma and epithelium at this site (e.g., as a consequence of curettage performed 1 to 4 weeks after delivery) may result in a permanent scar with adhesions. This is considered the primary reason for intrauterine adhesions in the industrialized world. In a meta-analysis that included over 900 women evaluated with hysteroscopy within 12 months following a spontaneous abortion (86% underwent curettage), the prevalence of intrauterine adhesions was 19.1%. In another study, women were either randomized to nonsurgical treatment or D&C after incomplete abortion. Of the women that underwent D&C, 7.7% had some form of intrauterine adhesions compared with no adhesions in the nonsurgical group. Curettage in the first 48 hours postpartum seems to cause fewer adhesions than when the procedure occurs later than that. Uterine compression sutures used to treat severe postpartum hemorrhage have been associated with the development of intrauterine adhesions. In four retrospective reviews, adhesions were diagnosed in 19% to 27% of women who received uterine compression sutures to treat postpartum hemorrhage. Not only D&C but any sort of intrauterine instrumentation can lead to the development of intrauterine synechiae. The average incidence of adhesion formation after hysteroscopic myomectomy, for example, has been reported around 10% at second-look hysteroscopy after surgery. In another study, the rate of adhesion formation was noted at 6.7% after uterine septum takedown, 31.3% after myoma resection, and as high as 45.5% after multiple myoma resection. The role of infection after abortion or delivery in the formation of uterine synechiae is controversial. A comparison of uterine cavities in women who delivered via cesarean section with and without endometritis at the time did not show any differences when it came to intrauterine adhesions.


In the developing world, infection of the endometrium, particularly with M. tuberculosis , is an important cause of uterine synechiae. With the human immunodeficiency virus–acquired immune deficiency syndrome (HIV-AIDS) epidemic and ease of air travel, genital tuberculosis should not be considered a threat to the developing world only. It is also important to note that most African studies have still attributed the major cause of intrauterine adhesions to be previous cavitary instrumentation. The estimated prevalence of genital tuberculosis varies widely between 2% and 25% in infertile women, depending on the diagnostic criteria used and the geographic location. Tuberculous adhesions can be present in as many as 35% of women with the infection and have a poor prognosis for future fertility. A characteristic “pipe stem” or “beaded” appearance on hysterosalpingography and culture with acid-fast stains on endometrial biopsy is helpful, but both tests have poor sensitivity. Newer tests such as interferon gamma release assays are more useful currently.


Women with intrauterine adhesions may have no symptoms or a variety of menstrual disorders including hypomenorrhea, oligomenorrhea, amenorrhea, dysmenorrhea, and very rarely HMB. Infertility, amenorrhea, and hypomenorrhea are the most common presenting complaints, with infertility rates reported as high as 43%. A number of classification systems have been proposed for women with intrauterine adhesions. All systems require a thorough evaluation of the endometrial cavity to note the consistency, extent, and location of the adhesions. There is paucity of data from comparison of these classification systems.


Hysterosalpingography performed to view the cavity, along with hysteroscopy, reveals the intrauterine lesions. Ultrasonography, sonohysterography, and MRI can also be valuable in certain cases ( Fig. 26.6 ). One group compared hysterosalpingography, sonohysterography, and TVS in patients with infertility and found both hysterosalpingography and sonohysterography imaging to have similar sensitivities of around 75% in detecting intrauterine adhesions. There was very limited use of TVS in detecting synechiae in this study. The “gold standard” for the diagnosis of intrauterine adhesions is the use of diagnostic hysteroscopy.




FIGURE 26.6


A sagittal view of an anteverted uterus obtained during saline-infusion sonography.

An adhesion can be appreciated in this patient with a history of dilation and curettage to treat a first-trimester pregnancy loss.


Since asymptomatic adhesions do not interfere with a woman’s general well-being, expectant management in such women has led to a resumption of regular menses in 1 to 7 years in up to 78% of women in one report. There is no role for medical therapy in the treatment of intrauterine adhesions. Before widespread use of the hysteroscope, blind D&C was used. Schenker and colleagues have reported an 84% rate of resumption of normal menses in women after D&C. Of these women, 51% conceived and 55% had term deliveries. Surgical removal of adhesions hysteroscopically (see ) with blunt dissection, scissors, electrocautery, or laser ablation is now recommended. Return of normal menses after hysteroscopic resection varies between 92% and 96%. The primary goal of surgery is to restore the normal volume and shape of the uterine cavity. In the nonindustrialized world, where hysteroscopic resection may not be feasible, there have been reports showing D&C to be equivalent to hysteroscopic resection, which is reassuring.


Postoperative management is focused on reducing the risk of the reformation of adhesions, the rate of which can be as high as one in three women with mild to moderate and two in three women with severe adhesions. Even though there is a need for larger randomized trials, there is some evidence that highlights the use of adhesion barriers after hysteroscopic procedures. There is, however, no consensus regarding the optimal methods for treating and preventing intrauterine adhesions. Insertion of an IUD or balloon catheter after lysis of adhesions is commonly employed to prevent recurrence. Stimulation of endometrial proliferation with exogenous estrogens alone or in combination with a progestin has been advocated by some. There is, however, a lack of high-quality evidence to assess the effectiveness of all the various antiadhesion therapies. Most recently the use of autologous peripheral blood bone marrow–derived stem cells as a treatment for patients with intrauterine adhesions has shown promising results.


Successful pregnancy rates after hysteroscopic resection of adhesions can be up to 40% to 80% and a live birth rate of 30% to 70%, with issues of placentation being most the serious complication of pregnancy. Of 696 births reported in a review, 17 pregnancies had placenta accreta. The preterm delivery rate was 40% to 50% in this group of patients.




Dysmenorrhea




  • ◆

    Primary dysmenorrhea is menstrual pain not associated with recognizable pelvic disease and is thought to be due to an intrinsic uterine dysfunction.


  • ◆

    Uterotonic agents like prostaglandins are thought to be key players in the pathophysiology of the disease.


  • ◆

    Treatment for dysmenorrhea is individualized, with the goal of providing pain relief.



Primary dysmenorrhea, or menstrual pain not associated with recognizable pelvic disease, is due to intrinsic uterine dysfunction. Occurring only in ovulatory cycles, the symptoms of dysmenorrhea usually commence a few hours before the onset of the menstrual flow. Pain is greatest when the endometrium is shedding rapidly, approximately 12 hours after flow begins. The diagnosis of primary dysmenorrhea is established when secondary causes of dysmenorrhea are ruled out and based on medical history and normal findings on pelvic and rectovaginal examination and imaging.


The prevalence of dysmenorrhea in women varies between 50% and 90% in most studies. Under 30 years old, smoking, irregular or heavy menstrual flow, BMI less than 20 kg/m 2 , menarche before age 12 years, history of sexual assault, and a strong family history of dysmenorrhea are a few of the many risk factors known for primary dysmenorrhea. There also appears to be a familial predisposition to primary dysmenorrhea. Women with dysmenorrhea, when compared with women without dysmenorrhea, have a greater sensitivity to experimental pain. This may increase their susceptibility to other chronic pain conditions and fibromyalgia later in life.


The painful cramps of dysmenorrhea are associated with uterine contractions; in women with dysmenorrhea, uterine contractile activity is heightened during menses, and the basal myometrial tone and amplitude of contractions are increased. These contractions are nonrhythmic, occur at high frequency (more than 4 to 5 times per minute), begin at an elevated basal tone (more than 10 mm Hg), and result in high intrauterine pressures, frequently more than 150 to 180 mm Hg. During intense contractions, there is a reduction in blood flow to the endometrium, suggesting that ischemia and the buildup of anaerobic metabolites stimulates type C neurons, which causes the pain of dysmenorrhea. There is also evidence from Doppler studies to show higher resistance in uterine vessels in women with primary dysmenorrhea, which can reduce blood flow to the endometrium. The uterine contractions are prompted by prostaglandins, which are potent uterotonic agents both in vitro and in vivo, acting through cell-surface prostaglandin receptors. Prostanoids may also directly sensitize uterine pain fibers. The notion that prostanoids are central to the pathogenesis of dysmenorrhea is supported by the observation that eicosanoids, most prominently prostaglandin F2-α (PGF 2α ), are found in high concentrations in menstrual fluid and that PGF 2α levels are higher in the endometrium and menstrual fluid of women complaining of dysmenorrhea than in those with pain-free menses. This high concentration of prostaglandins has been shown not only in the endometrium but also in the saliva of women during attacks of menstrual migraine associated with dysmenorrhea. More recently, patients with primary dysmenorrhea have also been hypothesized to have endothelial dysfunction.


Treatment of primary dysmenorrhea is individualized to each patient’s severity of symptoms. The goal of the treatment is to provide adequate relief of pain. At a minimum, pain relief should be sufficient to allow the woman to perform most or all of her usual activities. All drugs effective in inhibiting prostaglandin synthesis, including the potent NSAIDs (ibuprofen, naproxen, and mefenamic acid), alleviate symptoms of dysmenorrhea. A Cochrane database review included 80 randomized trials comparing NSAID therapy with placebo and paracetamol. NSAIDs were significantly more effective in reducing pain symptoms compared with placebo or acetaminophen. A combination of NSAID and paracetamol may also be helpful in relieving the pain of primary dysmenorrhea. Choosing an appropriate NSAID may be difficult, as it is not clear whether some NSAIDs work better than others. Some studies suggest that fenamates (a class that includes mefenamic acid, flufenamic acid, tolfenamic acid, and others) may have better pain-relieving propensities than phenylpropionic acid derivatives (a class that includes ibuprofen and naproxen). Although there may not be sufficient data to prove the superiority of medications from the fenamates class, a reasonable option would be to start with NSAIDs from the group of phenylpropionic acid derivatives and move onto the fenamate class of medications if insufficient relief is noted.


Combined OCPs are second-line medications after NSAIDs for the relief of pain from primary dysmenorrhea. No randomized trials have compared the efficacy of NSAIDs with OCPs. A systematic review compared OCPs with placebo and evaluated 10 randomized trials. A treatment benefit with OCPs was noted (pooled odds ratio [OR], 2.99, 95% confidence interval [CI], 1.76 to 5.07). Continuous rather than cyclic administration of OCPs has shown more success in treating patients with primary dysmenorrhea, although this difference is lost after 6 months of therapy. Contraceptive ring users have similar results to OCP users for dysmenorrhea, whereas contraceptive patches have not shown comparable results to OCPs. The use of a levonorgestrel-releasing IUD has been tried for primary dysmenorrhea with success in limited studies. Commonly, if treatment with NSAIDs is not successful after 3 months, OCPs are tried for another 3 months. If no relief is then noted, the reasons for secondary dysmenorrhea should be explored.


A long list of complementary and alternative medicines has been used in the treatment of primary dysmenorrhea. Most of them have shown similar efficacy to the conventional NSAIDs. Heat applied to the lower abdomen, aerobic exercise, yoga, acupuncture, massage with aromatic essential oils, and the use of far infrared emitting belts are among the few nonpharmacologic agents that have been tested for the treatment of dysmenorrhea in randomized clinical trials with promising results. Data on dietary supplements lack high-quality evidence to support the effectiveness of any particular supplement, and evidence of safety is lacking. A low-fat vegetarian diet, a diet rich in dairy foods, a diet rich in omega-3 fatty acids, and vitamin E supplementation have been effective in pain management from primary dysmenorrhea according to some reports.


Newer medications that include calcium antagonists like nifedipine are also effective because they prevent uterine contraction. Magnesium and glyceryl trinitrate have also been used to treat primary dysmenorrhea. Reductions in NO, which relaxes uterine smooth muscle, may also contribute to the intensified contractions associated with dysmenorrhea. Sildenafil citrate, a type 5 specific phosphodiesterase inhibitor, prevents the degradation of cyclic guanosine monophosphate (cGMP); thus it augments the local action of NO and has been shown to be an effective agent for the treatment of primary dysmenorrhea.


In addition to prostanoids, other uterotonic substances including lipoxygenase products, vasopressin, and oxytocin may have a role in dysmenorrhea. Thus, antagonists of the V 1 receptor and oxytocin receptor have a therapeutic effect in dysmenorrheic subjects.


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May 12, 2019 | Posted by in ENDOCRINOLOGY | Comments Off on Benign Uterine Diseases

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