Endometrial hyperplasia is abnormal proliferation of the endometrial glands and stroma, defined as diffuse smooth thickening >10 mm One of the main. Endometrial hyperplasia involves the proliferation of endometrial glands that results in a greater than normal gland-to-stroma ratio. This results. What is the optimal dose and schedule for treatment of endometrial hyperplasia using the various progestins?.
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Endometrial hyperplasia EH comprises a spectrum of changes in the endometrium ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma.
Generally, EH is caused by continuous exposure of estrogen unopposed by progesterone, polycystic ovary syndrome, tamoxifen, or hormone replacement therapy.
Since it can progress, or often occur coincidentally with endometrial carcinoma, EH is of clinical importance, and the reversion of hyperplasia to normal endometrium represents the key conservative treatment for prevention of the development of adenocarcinoma. Presently, cyclic progestin or hysterectomy constitutes the major treatment option for EH without or with atypia, respectively.
However, clinical trials of hormonal therapies and definitive endometriuum treatments remain to be established for the management of EH. Moreover, therapeutic options for EH patients who wish to preserve fertility are challenging and require nonsurgical management. Therefore, future studies should focus on evaluation of new treatment strategies and novel compounds that could simultaneously target pathways involved ednometrium the pathogenesis of estradiol-induced EH.
Novel therapeutic agents precisely targeting the inhibition of estrogen receptor, growth factor receptors, and signal transduction pathways are likely to constitute endomtrium optimal approach for treatment of EH. This cyclic phase involves a complex interaction between the two female sex hormones, estradiol, and progesterone Fig.
Estrogen promotes epithelial cell proliferation resulting in thickening of the uterus, while progesterone encourages hiperplasua cell differentiation and the secretory phase of the endometrial cycle [ 23 ]. The fine equilibrium between endometrial proliferation and apoptosis is maintained by an intricate process involving a number of factors including hormonal balance, molecular mechanisms, environment, age, and so forth; accordingly, it is prone to various disturbances leading to several endometrial abnormalities [ 4 ].
Overview of endometrial hyperplasia, risk factors, classification and treatment options. A The cross-sectional view of uterus showing endometrium. Adapted from Horne et al. C Risk factors associated with endometrial hyperplasia.
Adapted from Palmer et al. F Different therapeutic options of endometrial hyperplasia. Endometrial hyperplasia EH is a pre-cancerous, non-physiological, non-invasive proliferation of the endometrium that results in endlmetrium volume of endometrial tissue with alterations of glandular architecture shape and size and endometrial gland to stroma ratio of greater than 1: Currently, the incidence of EH is indistinctly reported to be aroundnew EH cases per year in Western countries [ 7 ].
The majority of cases of EH arise in the presence of chronic exposure to estrogen unopposed by progesterone such as in earlier forms of hormone replacement therapy [ 6 ]. Overproduction of estrogen by fat cells also contributes to the higher risk of EH and endometrial cancer EC in obese women [ 89 ].
In addition to inducing proliferation of the uterus endomefrium 10 ], estrogen induces morphometric alterations in the uterus that include changes in the type of luminal and glandular epithelia, hiperplsia number and shape of glands, the gland to stroma ratio, and hiperolasia morphology of epithelial cells [ 1112 ].
EH also occurs after menopause, when ovulation stops and progesterone is no longer produced, as well as during endometrjum when women experience irregular ovulation. The most common symptom of EH is abnormal endomerium bleeding including, menorrhagia, intermenstrual bleeding, postmenopausal bleeding, and irregular bleeding when on hormone replacement therapy or tamoxifen [ 131415 ]. Currently, the treatment endometriu, for EH are limited, such as hysterectomy or hormone therapy [ 16 ].
EH without atypia is generally treated with progestins [ 171819 ], while hysterectomy is the best treatment option for Endo,etrium with atypia [ 20 ]. Since EH with atypia may progress to or coexist with EC [ 21 ], it is of clinical importance and should not be ignored.
Moreover, conservative treatment with progestins is designed to regress hyperplasia to normal endometrium to prevent subsequent development of adenocarcinoma [ 22 ].
Pathology Outlines – Endometrial hyperplasia – general
However, hormonal management of women with EH has largely been based on case studies, the efficacy of which has hiperplzsia been well assessed. The lack of standard and conservative treatment options emphasizes the need for new therapies. In this review, we discuss the etiology and risk factors for EH and the related advancement or existing therapies.
Two different systems are commonly used to classify EH, the World Health Organization WHO schema [ 13 ] and the endometrial intraepithelial neoplasia EIN Table 1 [ 131523242526272829303132 ]. The WHO classification system, which is the most commonly recognized system, use cellular complexity, crowding of the endometrial gland and the presence of cytological atypia to categorize pathologies as simple or complex hyperplasia, with or without yiperplasia Table 1Fig.
Adapted from Trimble et al. Cases are categorized as EIN based on architectural gland crowding, altered cytology and maximum linear dimension of the lesion exceeding 1 mm, while excluding cancer and mimics [ 353637 ].
This system efficiently classifies samples into high and low cancer risk categories. Various other old classifications are summarized in Table 1. EH represents a continuum of histologically distinct processes, starting from simple EH without atypia and then progress to complex EH with atypia, followed by well-differentiated endometrial carcinoma Fig.
Therapeutic options for management of endometrial hyperplasia
The presence and severity of cytological atypia and architectural crowding are key factors defining the risk for progression to carcinoma. Among patients with atypical hyperplasia, postmenopausal status is associated with the highest risk of progression to adenocarcinoma [ 16 ]. Complex hyperplasia has an intermediate risk of progression, which has been shown to regress in most of cases, while EH with cytological atypia is characterized as direct precancerous lesions and may carry a higher risk of progression to carcinoma [ 40 ].
Postmenopausal, nulliparous, and infertile women are at greater risk of developing EH [ 4243 ]. Diabetes, hypertension, and obesity are also associated with increased EH risk [ 1344 ]. In addition to elevated estrogen levels, obesity causes chronic inflammation that can promote hyperplasia and cancer development [ 8 ].
Postmenopausal women taking estrogen supplements have long been known to be at increased risk of EH if a progestin is not used to oppose estrogen-activity [ 14 ]. The risk of developing EH also increases with increasing dose and length of estrogen treatment [ 464748 ].
Several conditions associated with steroid hormone imbalances cause increased risk of EH and EC. Chronic anovulation, early menarche, late onset of menopause and other conditions associated with increased estrogen levels are also risk factors for EH. Polycystic ovary syndrome PCOS associated with anovulation leads to unopposed estrogenic activity on the endometrium [ 13 ]. Women with hereditary non-polyposis colonic cancer Lynch syndrome may have complex atypical EH at an earlier age [ 50 ] and altered estrogen levels which affects expression of DNA repair genes [ 51 ].
Androgen-secreting tumors of the adrenal cortex may induce the peripheral conversion of androgens to estrogens and is a rare cause of EH [ 14 ].
The endometrium is reported to have a balanced cytokine system with numerous correlations at the proliferative and secretary stages of the menstrual cycle.
Though inflammation is the most important factor in most hyperplasia conditions, only a few studies have focused on the role of various pro- and anti-inflammatory cytokines in EH pathogenesis. Production of IGF-1 is induced by estradiol and implicated in the estrogen effects on uterine growth [ 54 ].
Patients with diagnosed hyperplasia were reported to have significant genome imbalance [ 63 ] and frequent deletions on the short arm of chromosome 8 [ 64 ]. CYP17 polymorphism had correlation with endometrial atypia and cancer. A recent study showed a role of functional single nucleotide polymorphisms SNPs in the catechol-O-methyltransferase, apolipoprotein E, and hemochromatosis genes in EH and EC [ 68 ].
Tamoxifen has been shown to improve the overall survival for both pre- and postmenopausal patients [ 72 ]. The first cases of endometrial carcinoma related to tamoxifen use were reported in [ 73 ]. Since then, many authors have confirmed the association of tamoxifen use with development of endometrial polyps, EH, and abnormal vaginal bleeding [ 74 ]. Multiple studies have evaluated the EH and EC risk in tamoxifen treated breast cancer patients [ 7475 ].
Tamoxifen-treatment may result in endometrial thickness and polyps, leading to irregular endometrial linings that are associated with endometrial neoplasia [ 1477 ].
Endometrial hyperplasia | Radiology Reference Article |
The development of EC due to tamoxifen is a leading cause of concern. One of the molecular theories being investigated is that tamoxifen-induced genotoxicity e. The mechanism of tamoxifen action involves suppression of ER-dependent gene regulation in breast tissue and stimulation of ER-dependent gene regulation in the uterus [ 8081 ]. Although there is no bona fide treatment for EH, most current guidelines recommend hormone therapies including use of progestin, gonadotropin-releasing hormone GnRH or its analogues or their combination or surgical treatment Fig.
The selection criteria for treatment options are based on patient age, health, the presence of cytologic-atypia and fertility status Fig. EH without atypia responds well to progestins. Hormone therapy is also recommended for women whose general health prevents them from tolerating surgery due to coexisting medical conditions. However, women with atypical EH or persistent EH without atypia that are symptomatic abnormal uterine bleeding are treated with hysterectomy. Among women hoping for childbirth, EH treatment is challenging, demanding conservative treatment regardless of whether the hyperplasia is with or without atypia.
The investigations and management schemes for endometrial hyperplasia. CCHRT, continuous-combined hormone replacement therapy. Progestins synthetic progestogens with similar effects as progesterone are most frequently employed to induce EH regression in women with EH without atypia or those who wish to retain fertility. Progestins can provide hormonal contraception either alone or with estrogen, and prevent EH development associated with unopposed estrogen.
In addition, progestins have been found to decrease glandular cellularity by inducing apoptosis [ 85 ] and to inhibit angiogenesis in the myometrium immediately underlying the complex EH [ 86 ].
Progestins can be given to patients via oral, intramuscular, micronized vaginal cream, or intrauterine devices [ 1687 ]. The mode and duration of progestin treatment is essential to its success. EH usually shows a response after week of dosing, but significant responses are commonly observed after 3-months of progestin therapy [ 8990 ], with the median time to resolution being 6 months [ 91 ].
Progestin therapy may be continued or hysterectomy performed in cases of no response. Medroxyprogesterone acetate MPA is a synthetic steroidal progestin synthetic steroid hormone progesterone that is usually used to treat cases with absent or irregular menstrual periods, or abnormal uterine bleeding. MPA prevents overgrowth in the uterine lining in postmenopausal women receiving estrogen hormone and decreases the risk of EH progression. A multicenter trial by Ushijima et al.
Another study reported MPA is commonly administered at 10 mg per day, orally and continuously for 6 weeks, or cyclically for 3 months 2 weeks of each month [ 88 ]. In patients having only partial response, MPA may be continued for another 3 months orally at a dose of 10 mg, four times per day. Megestrol acetate MA is a steroidal progestin specifically, hydroxylated progesterone with predominantly progestational and antigonadotropic effects that has been shown to have the potential to inhibit proliferation in the uterus and treat EH.
Levonorgestrel LNG is a second generation progestin synthetic progestogen commonly used as an active component in some hormonal contraceptives. This device releases a constant amount of LNG inside the uterus and effectively opposes the estrogenic effect [ 97 ].
Norethisterone or norethindrone is a synthetic, orally active steroidal progestin with antiandrogen and antiestrogen effects [ ].
It is commonly used as oral contraceptive pills and to treat premenstrual syndrome, irregular intense bleeding, irregular and painful periods, menopausal syndrome in combination with estrogen, or to postpone a period [ ]. Various studies have validated use of norethisterone as an agent to reduce the incidence of EH in postmenopausal women treated with estradiol [ 74].
A phase-III double-blind, randomized, multi-center study of norethisterone in postmenopausal women was conducted from to However, no final results have been posted to date. Although various studies and randomized trials have shown that progestin is a potent therapeutic option hierplasia EH, there are some common side effects including dizziness, headache, nausea, abdominal pain, uterine pain, delay of menstruation, heavy menstruation, uterine bleeding, fatigue, diarrhea, vomiting, and painful menstruation.
However, these symptoms commonly disappeared within 48 hours. Hence, precautions such as routine checkups and biopsies are recommended for patients while on progestin therapy.
Danazol can induce a hypoestrogenic, as well as, a hypoandrogenic endometriium in the uterus, resulting in atrophy of the endometrium . Various studies have shown the significant effects of danazol against EH hiperp,asia, ].