Effects of Hormone Therapy on the Uterus: A Review

Numerous health issues of women are related to hormonal anomalies including sexual development, fertility, menopause and gynecologic tumors (benign and malignant). Endometrial cancer is now the most common gynecologic cancer in the USA, with 67.880 new cases and over 13.000 deaths due to the disease, estimated for 2024. Worldwide, mostly in the industrialized countries, the incidence of this cancer has risen by about 20% over the two last decades, while other gynecologic malignancies, such as uterine cervical cancer have decreased in spectacular proportions. 

Hormone therapy is used to change some physiological effects and to counteract abnormal and deleterious effects of natural hormonal activity. Millions of women all over the world receive hormone therapy at some point of their life: young women receive oral contraceptives; hormonal components are used in the treatment of infertility, such as ovulation stimulation and IVF; peri - and postmenopausal women receive hormone therapy for menopausal symptoms. Hormone adjuvant therapy for benign and malignant gynecologic tumors is often prescribed to peri and postmenopausal patients. Patients with congenital sexual abnormalities as well as persons with gender dysphoria are also receiving hormone therapy, most often at young age. 

The structural and physiological effects of natural hormones include a large spectrum of changes in the uterus, especially in the endometrium, the inner layer of the uterine wall, endowed with a rich amount of hormone receptors, capable to transform the structure and function of the tissue. The effect of hormone therapy depends on the dosage and duration of therapy, which is permanently changing due to new pharmaceutical products, new technologies as well as changing scientific conceptions. Endometrial cancers are often causally related to abnormal hormonal stimulation. The carcinogenic potential of estrogenic stimulation and its mitogenic effect were extensively studied but are still incompletely understood. The diagnostic interpretation of the commonly taken endometrial biopsies is often difficult, and some therapeutic regimens are controversial. This article includes the description of contemporary relevant aspects of endometrial physiopathology, the effects of the most commonly used hormonal therapy and an overview of endometrial carcinogenesis, its diagnosis and therapy.

The uterine tissue is exquisitely sensitive to hormonal influences, capable to translate them into functional and structural changes with promptitude and versatility. The complex interplay between pituitary and gonadal functions is mediated by a finely tuned feedback mechanism between pituitary and ovarian hormonal activities, functionally related to the central nervous system. It reaches its target in the uterine tissue. The ultimate biological goal is to secure the reproductive role of the uterus. Normal reproduction is based on the cyclic changes taking place in the entire genital system of women during the reproductive years, most importantly in the endometrial inner layer of the uterus, a highly differentiated and diversified tissue composed chiefly of glands, stroma and blood vessels. The programming of events in the endometrium is regulated by the presence of receptors, essential to the transfers and translocation of hormones secreted into the blood stream, and their translation into structural changes at the target tissue level. 

The menstrual cycle is composed of a preovulatory phase with proliferative endometrium and a post ovulatory phase with secretory glands and predecidual stroma, serving as a potential host for an implanting conceptus. If no fertilized ovum is implanted, the endometrium is shedding and a new cycle starts. The most commonly involved gonad-secreted hormones are estrogens and progesterone, which are bound to receptors, forming hormone-receptor complexes. The activated steroid-receptor functions as a transcription factor modulating the specific synthesis of a specific mRNA, are responsible for the cellular action of the hormone. The receptor-bound hormone is transported into the cellular compartments during normal menstrual cycles, eliciting proliferation and secretion, followed by menstrual shedding in normal menstrual cycles without fertilization [1]. 

The biologic activity of the steroid hormones is maintained only while the nuclear site is occupied by the hormone- receptor complex, thus duration of exposure and concentration are related to effect. The decrease or absence of estrogenic hormones eventually results in atrophy of the target endometrial tissue, while the excess of the same may produce irregular patterns of proliferation, hyperplasia and neoplasia. Clinically, abnormal hormonal stimulation may be associated with infertility, abnormal vaginal bleeding (prolonged, reduced or irregular), as well as with abnormal benign tissue growth such as endometrial polyps or myometrial leiomyomas and adenomyosis. Peri- and postmenopausal systemic disorders (hot flashes, osteoporosis and insomnia) are frequently related to decrease of steroid hormone secretion. Endometrial precancerous lesions such as atypical hyperplasia and endometrial cancer are most often causally associated with hyperestrogenic stimulation.

Hormonal therapy is used to counteract the deleterious effects of “natural”, non-iatrogenic hormonal effects. Hormone therapy is now widely prescribed being used by millions of women all over the world. It actually seems that most women use some hormone therapy at least at some point of their life. Adolescents and young women use oral contraceptives containing predominantly Progesterone, sometime also prescribed for irregular vaginal bleeding. Hormonal suppression of ovulation is based on negative feedback of Estrogen and Progesterone on the Gonadotropin-Releasing Hormone (GnRH). The endometrial tissue undergoes “pseudogestational” changes, with weakly secretory and atrophic glands and decidualized stroma [Figure 1]. Steroid ovarian and pituitary hormones are also used to treat infertility associated with hormonal inadequacy, including inducing ovulation with Follicle Stimulation Hormone (FSH) which recruits as many oocytes as possible and produces normal ovulatory endometrial menstrual cycles, with well-developed proliferative and secretory endometrium [2]. Also, recent studies using computerized virtual histological images for endometrial dating correlated with measurements of serum hormone levels the same day permit maximum accuracy in the process of artificial insemination [3].

 Figure 1: Oral contraceptive effect on the endometrium: pseudo-gestational decidual changes.

Postmenopausal symptoms are frequently treated with Hormone Replacement Therapy (HRT), despite controversial data on their safety and efficiency. Regimens consist presently of the administration of Estrogens and Progesterone combined, in variable dosages; the regimens are permanently shifting due to changing concepts and new pharmaceutical products The current consensus for treating symptomatic women without contraindications should be individualized to identify the most appropriate hormone therapy type, dose, timing and duration of use, to maximize benefits and minimize risk [4]. The endometrial tissue responds most often by developing simultaneous proliferative and secretory changes, occasionally hyperplasia and in relatively rare cases endometrial neoplasia. Interpretation of endometrial biopsies may be sometime difficult, as neoplastic changes may masquerade into decidual pseudogestational changes due to Progesterone effect on endometrial glands and stroma. Endometrial hyperplasia and carcinoma may occasionally develop, especially in HRT without Progesterone, Estrogen Replacement Therapy (ERT), as some patients do not tolerate Progesterone side effects.

Common benign uterine tumors such as myometrial leiomyomas, adenomyoma, and endometrial hyperplastic polyps benefit from hormone therapy with Progesterone, in addition to surgical resection, by inhibiting and possibly reverting the proliferative myometrial changes. Leiomyomas (fibroids) are caused by the estrogenic effect on the uterine smooth muscle tissue, growing during the reproductive period and shrinking with menopause. Shrinking of leiomyomas is also obtained using hormone therapy consisting of Gonadotropin-Releasing (GnRH) analogues (Lupron), reducing considerably, but reversibly, the size of the leiomyomas by inducing an iatrogenic reversible temporary menopause [5]. The management of congenital abnormal sexual development and gender dysphoria (transgender situations) includes hormone therapy aimed at target organ tissue modifications [6].

Endometrial Carcinoma (EC) is now the most common gynecological malignancy in the USA and in most industrialized countries. It is known to be strongly associated with excessive Estrogen (E) secretion. The presence of Estradiol in the serum and its receptor in the nuclear DNA of the endometrial cells stimulates their growth by mitotic division. The mitogenic function of estradiol is essential for the reproductive function of the endometrium. Around or after menopause this function decreases progressively as does the inhibitory function of Progesterone due to failing ovulation [1]. In ovarian Polycystic Disease (PCOD) or ovarian gonadal hormonally active tumors (granulosa or granulosa-theca cell tumors), Estrogen is secreted excessively, without Progesterone counteraction resulting in abnormal endometrial growth stimulation in premenopausal women. After menopause, with the progressive diminution and eventual cessation of ovarian E secretion, due to failure to respond to gonadotropin hormone, FSH and LH continue to rise, but in the absence of E the endometrium becomes gradually atrophic. Extragonadal Estrogen in postmenopausal women is derived from androgen conversion mostly by adipose tissue [3]. Available Estrogen varies with the substrate: as the level of fat and the aromatase capacity of fat tissue increase, circulating levels of estrone and estradiol increase. With obesity, sex hormone-binding globulin levels decrease, providing greater androgen substrate availability and higher concentration of free biologically active Estrogen. 

Obesity (BMI over 30), nulliparity, late menopause and exogenous estrogen intake without adequate Progestin opposition are the most common risk factors for EC. Polycystic ovarian disease with anovulatory menstrual cycles may as well generate a continuous and unopposed Estrogen production which results in endometrial hyperstimulation with possible hyperplastic and neoplastic endometrial changes. It should be mentioned that in younger, premenopausal women obesity is recently becoming considerably more frequent, contributing to the total increase of EC and its precursors overall [7].

Endometrial Hyperplasia (EH) is most common in early post menopause, often manifested by postmenopausal vaginal bleeding, on endometrial biopsy displaying irregular glandular proliferation, glandular crowding and outpouching, epithelial cell piling up with or without atypical nuclear changes. EH without atypia is usually reversible with Progesterone therapy (84%) and spontaneously (60%). EH with atypia is often diagnosed in older women and is characterized by an atypical glandular pattern with piled up epithelial cells, lost cell polarity and atypical nuclei varying in size, shape and texture. Molecular histologic analysis reveals the presence of strong Estrogen Receptors. Mitotic activity resulting from estrogenic stimulation may be present in both hyperplastic lesions, typical and atypical, as it is seen also in normally cycling proliferative endometrium. Atypical Endometrial Hyperplasia [Figure 2] is a precancerous condition. It is also classified into intraepithelial glandular neoplasia and intraepithelial carcinoma, both representing an early noninvasive stage of EC, the first being possibly reversible with Progesterone therapy [8]. The differential diagnosis is subtle and therapeutic decisions should be made in consultation with Gynecologic Pathologists. Atypical hyperplasia has a 36% progression rate to malignancy, even with Progestins in 27% of cases [9].

 Figure 2: Atypical hyperplasia and positive IHC staining for the Estrogen Receptors (ER) in obese 39-years old patient. 

The management of EH depends on the histopathologic diagnosis especially the evaluation of the malignant potential, fertility requirements and patient preferences, as well as medical comorbidities. All therapeutic strategies should include removal of intrinsic or extrinsic sources of Estrogen. Hormone replacement therapy (including oral, patch, vaginal ring with systemic dose) with Estrogen without an opposing Progestin in a woman with a uterus may result in a markedly increased risk of EH or EC. For EH without atypia the diagnostic D&C can also be therapeutic; Progestin or oral Contraceptives are usually effective. Gonadotropin Releasing Hormone (GnRH) agonists, ovulation induction with aromatase inhibitors may be used as alternatives to Progestins. For EH with atypia diagnosed on biopsy there is a risk of finding an EC in the subsequent hysterectomy specimen of 14% to 57% [7], therefore hysterectomy is indicated to be performed as soon as possible after the diagnosis is established. Progestin therapy is an option for women who wish to preserve fertility or do not tolerate surgery. Megestrol 160mg per day in divided doses is the drug of choice [7].

As mentioned before, Endometrial Carcinoma (EC) is presently the most common malignant gynecological tumor in the industrialized world having increased considerably in frequency over the past two decades, while most other gynecological malignant tumors have decreased due to diagnosis of precursor, precancerous stages and preventive measures related to lifestyle, nutrition and genetic counseling. In the case of endometrial neoplastic proliferation, demographic and economic factors seem to play an important role as prolonged longevity and obesity represent the major risk factors of this cancer more frequently occurring in elderly, African American and overweight patients. The ethiopathogenic factors include hyperestrogenism associated with abnormal metabolic diseases (obesity, diabetes), which elicits endometrial proliferation due to the mitogenic effect of estrogens in postmenopausal women, whose lifespan is prolonged in most industrialized countries. The other potential ethiopathogenic factor of EC in postmenopausal women is the iatrogenic intake of estrogens, as demonstrated by the WHI (Women’s Health Initiative) published study of 27,000 postmenopausal women followed over 10 years, that yielded surprising results on the deleterious effects of HRT [8]. More recent studies reassessed the evaluation of HRT, concluding that prescribed early after menopause inception, in lower doses and associated with Progesterone, HRT is basically safe [4]. 

Endometrial carcinoma is classified in two major types [Figure 3]. The majority of EC, about 80%, are Type I and represent EC associated with hyperestrogenism, mostly diagnosed in earlier postmenopausal stages, with histologically well differentiated endometrioid carcinoma, rarely mucinous, and often associated changes suggestive of cancer precursors (endometrial hyperplasia) resulting from hyperestrogenic stimulation [10]. This type of EC is also characterized by an abundance of Estrogen Receptors (ER) in the tumor cell nuclei. Type I EC is most often diagnosed in early stages, therefore amenable to treatment and resulting in low mortality. Type II EC is less often diagnosed early, affecting more elderly post menopausal women. It is frequently diagnosed in late stages of the disease, histologically predominantly non-endometrioid, poorly differentiated to undifferentiated, clear cell, serous cell and papillary carcinoma, histologically sometime resembling ovarian serous carcinoma. Endometrial hyperplasia, as often seen associated with Type I EC, is usually absent. Non-tumoral endometrium, if present, is often atrophic. The prognosis of type II EC is generally poor; most tumors are invasive to the myometrium and sometime metastatic at the time of diagnosis.

 Figure 3: Pathogenetic and clinical classification of endometrial carcinoma. 

The clinical background of the patients is generally different in the two groups: the known risk factors for EC commonly present in Type I are rarely present in Type II. Patients diagnosed with Type I are on average, younger, peri- or recently post-menopausal, have few or no children, sometime a history of infertility, are often overweight. They present with a history of irregular vaginal bleeding and sometime a history of prior diagnosed endometrial biopsies with glandular hyperplasia. There also may be a history of Estrogen intake in this group of patients. Patients with Type II EC are often first seen in emergency rooms with severe vaginal bleeding, are most commonly elderly late postmenopausal women, some multiparous, usually not overweight. Lab tests confirm the hyperestrogenic profile of Type I EC patients: high serum estradiol and strong Estrogen Receptors in the examined endometrial biopsied tissue, as compared to Type II EC biopsies revealing positivity of cancer markers such as tp53 and mostly absent Estrogen and Progesterone Receptors. The carcinogenic factors of EC Type II are still poorly understood: they are histologically similar to ovarian serous carcinoma with yet unknown etiology, may include hereditary, genetic factors as in Lynch syndrome, or viral cofactors [11] as Human Mammary Tumor Virus (HMTV) demonstrated in Type II but not in type I EC [12] [Figure 4].

 Figure 4: Electron microscopy of human mammary tumor virus envelope particles. 

The profound differences between the two types of EC require different management. The diagnosis and prognosis however may be difficult in some cases [13]. In a subgroup of EC, the previously diagnosed low-grade Type I tumor may recur after surgery as high grade Type II EC. The recurrence of aggressive tumors occurring occasionally after a primary low grade malignant EC may result from epigenetic loss of original tumor identity with altered DNA methylation that changes the biological progression to a more aggressive tumor phenotype (the follow-up tumor behavior is not consistent with the one predicted by the initial diagnosis. The FIGO (International Federation of Gynecology-Obstetrics) adopted a surgical-pathological classification into prognostic groups based on the extent of disease and tumor grades (degree of differentiation) [14]. Older patients and African American patients are generally diagnosed in higher stages and higher grades. An important prognostic factor is the presence of extrauterine tumor invasion and lymph node metastases. 

Endometrial Carcinoma type I with a history of prolonged estrogen exposure is most often diagnosed in earlier stages, with tumor confined to the inner layer of the uterus, the endometrium, or invading less than the inner half of the myometrial wall. Histologically, it is the endometrioid type with well to moderately well glandular differentiation. Squamoid cell differentiation and secretory features are seen occasionally. Type I EC is fortunately the statistically most common uterine neoplasm (80%), with a relatively good prognosis after surgical resection in early stages (95% five-year survival). While surgery is the therapy of choice, the patients who are younger, desire pregnancy or have medical conditions incompatible with surgery, have the option of adjuvant therapies such as radiotherapy and hormone therapy, the latter if the diagnosed tumor was Estrogen-Progesterone Receptor positive. Medroxy Progesterone Acetate (MPA) and Megace are currently used in these cases [15]. Despite the risk of prolonged and unopposed Estrogen intake, the hormonally treated patients usually appear to have a better prognosis as stage and histologic grade are lower in Estrogen users and their survival rates are higher [7]. The effects of hormone therapy on atypical glandular hyperplasia and EC are dose- and duration dependent and include a wide variety of histologic changes of the endometrium. The diagnosis of residual malignant changes on biopsies performed after hormone therapy, mostly in younger women desiring pregnancy or in patients unfit to have surgery, is critical and often difficult. Molecular biology tests proved recently to be relevant [16]. 

Type II Endometrial Carcinoma, high grade and histologically non-endometrioid, is less common (about 20%), and is usually diagnosed in Stage III-IV, having a worse prognosis and a higher mortality rate than Type I EC. Histologically, it presents as a poorly differentiated, non- endometrioid, clear cell, serous, sometime mixed epithelial-stromal (carcinosarcoma) or undifferentiated carcinoma. Estrogen effect features such as positive Estrogen Receptors in the tumor cells and benign endometrial glandular hyperplasia are absent, the uninvolved endometrium being often atrophic. Surgical staging is usually high, with deep myometrial, extrauterine invasion and lymph node involvement. Estrogen Receptors are mostly absent in the tumor cells which are positive for a number of tumor markers, most often tp53. In addition to surgical resection consisting of radical hysterectomy, adjuvant therapy, radiation, chemotherapy and more recently immune therapy are used. Hormone therapy appears to be effective when combined with targeted therapeutic agents known to disrupt Estrogen Receptor pathway (Combination of hormonal based therapy). Advanced studies in molecular biology paved the way for targeted chemotherapy. Therapeutic decisions for treatment options are basically surgery for most cases of EC, and adjuvant therapy for most Type II EC. Chemotherapeutic strategies are evolving with the progress of molecular biology [7]. Therefore, the classification into Type I and II may not apply in cases in which Type I EC was diagnosed first and recurred exhibiting histological and molecular features associated with a worse prognosis. Presently, EC 5-year survival is estimated for Type I as 95% and for Type II as 17%. 

Recent progress of molecular biology studies added significant information to the knowledge of the submicroscopic mechanisms of malignant endometrial tissue proliferation. A better risk stratification of both EC and Ovarian Carcinoma can be obtained by adding molecular studies such as mismatch DNA repair, p53 abnormalities, microsatellite instability. It seems that EC NSMP is the most common molecular subtype, having a low number of somatic copy number alterations, a low number of mutational burden, high levels of Estrogen and Progesterone Receptors, and no p53 abnormalities [16]. Immunotherapy, the study of immune checkpoint blockade and lymphoid cell infiltrates may be relevant as well. Recently, substantial and unexpected favorable results were obtained with Immunotherapy in cases of advanced EC with genetic changes such a mismatched repair deficiency or microsatellite instability [17]. It may be therefore recommended to integrate molecular parameters to standard pathologic reports using the 2020 ESTRO/SGO/ESP for risk stratification and treatment algorithm.

Tamoxifen is a non-steroidal synthetic methylene estrogen derivative used successfully in the treatment and prevention of breast cancer. It binds to estrogen receptors in a manner similar to that of estradiol, decreasing the unbound tamoxifen- receptor complex binding to nuclear DNA. This results in an antiestrogenic effect which can also be obtained by Aromatase Inhibitors, without the side effect produced by Tamoxifen on the Endometrium. While acting as an Estrogen antagonist on the breast, in some cases, the uterus responds to Tamoxifen therapy as an Estrogen agonist developing leiomyomas, adenomyosis and more often, endometrial polypous hyperplasia [18] [Figure 5]. Occasionally, in older patients who received Tamoxifen therapy for over 5 years, Endometrial Carcinoma was found in the endometrial polyps. So while Tamoxifen acts as an estrogen antagonist on breast tissue, it is an antagonist-agonist of Estrogen in the endometrium. The largest study of endometrial tissue changes in patients treated with Tamoxifen for Breast Cancer (700 cases) reported 24% endometrial polyps and 4,7% (33 cases) of EC of which 22 were Type II EC [19]. Multiple other reports of EC in patients treated with Tamoxifen for breast cancer mentioned high grade uterine neoplasms, including mixed mullerian tumors [20-22]. It has been suggested that adding intrauterine levonorgestrel may prevent the estrogen-agonist effects of Tamoxifen on the uterus [23]. Also used are Aromatase Inhibitors for the prevention [24] and treatment of Breast Cancer [25].

Figure 5: Uterine leiomyomata, adenomyosis and endometrial polyps in patients treated with Tamoxifen for breast cancer.

The hormonal effects on the uterus are a fascinating example of the unique biological organization of reproduction. Progress in the knowledge of the finely tuned mechanisms of stimulation, inhibition and feedback between hormones along with advanced technology reached spectacular achievements in human reproduction and opened new horizons in the prevention and cure of neoplasms of the reproductive organs.

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