THE 1999 LONG COURSE ON PATHOLOGY OF THE UTERINE CORPUS AND CERVIX Hormonal Pathology of the Endometrium Liane Deligdisch, M.D. Departments of Pathology and Obstetrics-Gynecology and Reproductive Science, The Mount Sinai–NYU Medical Center, New York, New York plastic changes may persist and coexist with secre- The endometrial tissue is a sensitive target for ste- tory changes. roid sex hormones and is able to modify its struc- Lupron therapy produces a shrinking of uterine tural characteristics with promptness and versatil- leiomyomas by accelerating their hyaline degener- ity. This article discusses briefly endogenous ation, similar to that in postmenopausal involution. hormonal effects (cyclic changes, luteal phase de- It generally produces endometrial atrophy. fect, unopposed estrogen effect) and describes the Tamoxifen for breast carcinoma has an estrogen- histologic patterns encountered in the most com- agonist effect on the uterus in approximately 20% of monly used hormone therapies: oral contracep- patients, who develop endometrial polyps, glandu- tives, ovulation stimulation, hormone replacement lar hyperplasia, adenomyosis, and/or leiomyomata. therapy, and antitumoral hormone therapy. Both endometrioid and nonendometrioid carcino- Oral contraceptives exert a predominant proges- mas are seen, often in polyps. Their causal relation- tational effect on the endometriun, inducing an ar- ship to tamoxifen therapy is debatable. rest of glandular proliferation, pseudosecretion, and stromal edema followed by decidualized Mod Pathol 2000;13(3):285–294 stroma with granulocytes and thin sinusoidal blood vessels. Prolonged use results in progressive endo- Hormone therapy is widely used throughout the metrial atrophy. world by women of all ages for a variety of reasons, Ovulation induction therapy accelerates the mat- ranging from oral contraception and ovulation uration of the stroma and is often associated with a stimulation for family planning to hormone re- discrepancy between early secretory glands and an placement therapy in menopause, to adjuvant ther- edematous or decidualized stroma with spiral arte- apy of tumors of the breast and uterus. The his- rioles. topathologic changes of the uterus, and particularly Hormone replacement therapy with estrogen of the endometrium, associated with these thera- alone may result in continuous endometrial prolif- pies encompass a variety of morphologic features eration, hyperplasia, and neoplasia. The use of both that are often difficult to interpret. The endome- estrogen and progesterone elicits a wide range of trium is a sensitive target tissue for steroid sex histologic patterns, seen in various combinations: hormones and is able to modify its structural char- proliferative and secretory changes, often mixed in acteristics with promptness and versatility. The the same tissue sample; glandular hyperplasia (in physiologic changes of the endometrium during polyps or diffuse) ranging from simple to complex reproductive life and after menopause reflect the atypical; stromal hyperplasia and/or decidual trans- influence of ovarian-secreted steroid sex hormones formation; epithelial metaplasia (eosinophilic, cili- and of their withdrawal. Hormone manipulation in ated, mucinous); and inactive and atrophic endo- fertility problems and hormonal substitution ther- metrium. apy result in histologic patterns that do not fit the Progesterone therapy for endometrial hyperpla- classical descriptions of the cyclic and involutional sia and neoplasia induces glandular secretory changes of the endometrium. Various combina- changes, decidual reaction, and spiral arterioles. tions of hyperplastic, proliferative, secretory, and atrophic changes of endometrial glands, stroma, Glandular proliferation is usually arrested, but neo- and blood vessels may result in confusing histologic patterns. As hormone therapy changes over time, with new regimens continuously being imple- Copyright © 2000 by The United States and Canadian Academy of Pathology, Inc. mented, the effect on the endometrium can result VOL. 13, NO. 3, P. 285, 2000 Printed in the U.S.A. in unpredictable structural changes. Date of acceptance: November 8, 1999. Address reprint requests to: Liane Deligdisch, M.D., Mount Sinai Medical The histologic patterns of the endometrium as- Center, Department of Pathology, One Gustave Levy Place, New York, NY sociated with hormone therapy vary with the dos- 10029. age, duration of therapy, and individual hormone receptor activity. The same endometrium may dis- 285 play a number of changes under different condi- The secretory activity in the second half of the tions, resulting in a diversity of histologic patterns menstrual cycle is characterized by a diversity of that may render some endometrial biopsies diffi- structural changes that are apparent on routine cult to interpret. Although the endometrial re- examination of endometrial biopsies, showing a sponse may vary from patient to patient, certain different pattern on every day of the cycle. “Dating” general histologic patterns for specific hormone the endometrium is identifying morphologic therapies can be recognized. To comprehend the changes characteristic for early, middle, and late iatrogenic effect of exogenous hormone therapy, a proliferative endometrium and for each of the 14 review of the normal and abnormal endogenous days of secretory endometrium (1, 2). hormone-related endometrial changes is appropri- Perhaps the most significant change in terms of ate. adequacy of the luteal phase is that involving the blood vessels. The thin endometrial arterioles un- ENDOMETRIAL MORPHOLOGY AND dergo a process of endothelial proliferation, thick- PATHOPHYSIOLOGY ening of the wall, and coiling forming the spiral arterioles on the ninth postovulatory day. These Before puberty, the endometrial tissue is inactive; arterioles have a critical role in the process of im- it is composed of tubular glands, a dense fibroblas- plantation because of the tropism for arterial blood tic stroma, and thin blood vessels. The advent of that characterizes trophoblastic tissue. Their coiling cyclic pituitary and ovarian hormonal activity re- increases the surface to be “tapped” by the im- sults in endometrial cyclic morphologic changes planting trophoblast; therefore, the chances for a involving glands, stroma, and blood vessels that can normal implantation are reduced if the spiral arte- be identified as characteristic for each day of the rioles are not well developed. The evaluation of cycle. endometrial biopsies properly performed a few In normal cycles, the menstrual shedding is fol- days before the onset of menstrual shedding is one lowed by endometrial proliferation under estro- of the most important diagnostic tools in the genic stimulation. The endometrial thickness in- work-up of infertility: It offers an insight into the creases more than 10-fold as a result of active tissue that will play host to the implanting concep- growth of glands, stroma, and blood vessels. The tus, assessing its adequacy. proliferative phase has a variable length from 10 to Pathologists are often asked to evaluate luteal 20 days, with an ideal duration of 14 days. During phase defects (LPD) in their reports on endometrial this phase, the endometrial glands grow and be- biopsies. LPD considered to be due to an inade- come tortuous because of the active proliferation of quate progesterone production is clinically some- epithelial cells. These estrogen-induced changes times associated with infertility and with spontane- occur as a response to the binding of the hormone ous abortions. Histologically, the maturation of the to nuclear receptors. The presence of estrogen re- endometrium is most commonly associated with a ceptors in the nuclei of endometrial cells is respon- lag of more than 2 days of the histologic date from sible for the prompt translation of hormonal im- the actual postovulatory date, possibly the result of pulses into structural changes, including, at an delayed ovulation (3). In insufficient follicle matu- ultrastructural level, protein synthesis by free ribo- ration, the endometrium appears immature; in per- somes and by the rough endoplasmic reticulum sistent graafian follicle, proliferative changes persist and accumulation of intermediate filaments, mito- throughout the secretory phase. A dissociation be- chondria, Golgi apparatus, and lysosomes. The nu- tween glandular and stromal maturation can also clei increase in size, nucleoli become prominent, be seen in LPD (see Table 1). The pathogenesis of and chromatin is coarse. The individual cell mass LPD is not completely understood. It may occur increases as does the nuclear-cytoplasmic ratio. when the corpus luteum fails to develop adequately Numerous mitoses are seen throughout the glands or as a result of deficient progesterone receptors. To and stroma. be diagnostically significant, LPD has to be found in After ovulation, the secretion of progesterone in- at least two consecutive cycles (3). hibits the proliferative activity of the endometrium and induces a complex secretory activity starting with the polarization of glycogen at a subnuclear TABLE 1. Luteal Phase Defect location followed by its transport via microfila- Ovarian Changes Endometrial Changes ments to the apical region of the cell. The Golgi Delayed ovulation Ͼ2-day delay in maturation apparatus “packages” the glycogen and various Insufficient follicle maturation Thin endometrium, low glycogen, thin arterioles, tubular glands other substances, which become secretory