Exogenous Hormones and their Effects on the Endometrium

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Exogenous Hormones and their Effects on the Endometrium

Rex C. Bentley

Chapter Outline

Introduction

Exogenous hormonal agents represent one of the most commonly prescribed medications in women. Hormonal therapies are used for a wide range of indications, including birth control, postmenopausal hormone replacement, dysfunctional uterine bleeding, endometriosis, infertility, and the treatment of malignant and premalignant lesions of the endometrium and breast. These drugs can be administered by many methods, including oral, parenteral, transdermal, transvaginal, and subcutaneous, vaginal, or intrauterine implants. Consequently, a significant proportion of endometrial specimens that the surgical pathologist evaluates show the effects of these exogenous hormonal agents. At first glance, the spectrum of changes seen with hormone therapy appears excessively broad, and it is certainly true that nearly any endometrial appearance can be attributed to therapy with hormones. With a basic understanding of the effects of estrogens and progestins on the normal endometrium, however, substantial order emerges from this confusing pathologic array. Essentially, it is possible to predict the common appearances of hormone therapy based on the known effects of the endogenous steroid hormones on normal endometrium.

Estrogens

The basic effect of estrogens on the endometrium is to induce proliferation of the endometrial glands and stroma, including vascular endothelium. The degree of proliferation can vary in proportion to the estrogenic stimulus. Very low levels of estrogen or a very weak estrogen will lead to an inactive or atrophic endometrium. Higher levels lead to proliferation, which when excessive can produce a hyperplastic endometrium (Figure 15.1). The degree of proliferative activity can usually be assessed by the mitotic activity in both the glandular epithelium and the stroma. Women who are many years postmenopausal demonstrate profound endometrial atrophy, secondary to lack of estrogen, but even atrophic endometrium remains estrogen responsive to quite advanced age (Figure 15.2). A number of estrogenic drugs on the market are listed in Table 15.1.¹

Table 15.1 Representative Estrogenic Agents Available in the United States Adapted from Schimmer and Parker (2012).¹

Generic Name	U.S. Brand Name
Estradiol	Estrace
Estradiol valerate	Delestrogen, Gynogen, Valergen
Estradiol (transdermal)	Estraderm, Climara, Fempatch
Diethylstilbestrol
Conjugated equine estrogens	Premarin
Synthetic conjugated estrogens	Cenestin, Enjuvia
Mestranol
Ethinyl estradiol	Estinyl
Estropipate	Ogen, Ortho-Est

Figure 15.1 Normal proliferative endometrium (normal estrogen effect).

Figure 15.2 Atrophic endometrium. The few glands present have minimal cytoplasm and small nuclei. The endometrial stroma is dense.

Persistent exposure to a significant estrogenic stimulus, such as occurs in anovulation, leads to a pattern of continued, unrelieved proliferation. The endometrium cannot support such continued growth. Whether the estrogen source is endogenous or exogenous, the histologic consequence is the same: a combination of proliferative endometrium with episodic coexisting stromal breakdown, or shedding, which accounts for the clinical presentation of irregular bleeding (Figure 15.3 ). This pattern is also called ‘anovulatory bleeding’ or ‘anovulatory shedding.’ Because the endometrial vessels become abnormally large, bleeding can also be quite severe. Some pathologists mistakenly refer to the shedding endometrium as ‘menstrual,’ but it is important to distinguish this appearance from the appearance of menstrual endometrium occurring at the end of a normal cycle. In normal endometrium, the endometrial glands transform soon after ovulation to a secretory pattern and by the time menstrual bleeding begins will still show some residual changes, most commonly secretory exhaustion (see Chapter 14). This change is absent in anovulatory-type bleeding or where the drug administered is progestin poor. Another common difference is the presence of large fibrin thrombi in the vessels of anovulatory shedding endometrium (Figure 15.4). They are absent from menstrual endometrium because of the marked fibrinolytic activity typical of normal menstruation.

Figure 15.3 ‘Persistent’ proliferative endometrium with unopposed estrogen effect and secondary breakdown. Present is proliferative endometrium with scattered cysts and stromal breakdown forming stromal balls and collapsed eosinophilic epithelium. Often associated with fibrin thrombi, this pattern differs from a physiologic late menstrual–early proliferative endometrium in nonuniform distribution of breakdown throughout a thickened, dense, nonspindly stroma.

Figure 15.4 Fibrin thrombi in endometrium with anovulatory bleeding.

With prolonged estrogen exposure, the proliferating glands tend to lose their uniformity of size, shape, and distribution, leading to so-called disordered proliferative endometrium. Cystic dilatation of glands and ‘tubal’ metaplasia are commonly present. With continued, longer term, unopposed estrogen exposure, a high proportion of patients will ultimately develop non-atypical endometrial hyperplasia. A small number will also go on to develop endometrial intraepithelial neoplasia (EIN) (also called ‘atypical hyperplasia’) or even adenocarcinoma (see Chapters 17 and 18).

Progestins

The effect of progestins on the endometrium depends on ‘priming’ by estrogen, which induces progesterone receptors in the endometrial cells. One important feature of progestins is that they act to downregulate estrogen and progesterone receptors; in other words, they reduce the sensitivity of the endometrium to both of these hormones. Prolonged exposure to progestins can thus lead to a histologic picture that is paradoxically similar to the atrophy seen in a postmenopausal or hormone-suppressed patient. Some commonly used progestins are shown in Table 15.2.¹

Table 15.2 Representative Progestational Agents Available in the United States

Adapted from Schimmer and Parker (2012).¹

Generic Name	Brand Name
Progesterone	Prometrium, Crinone
Hydroxyprogesterone	Hylutin, Makena
Medroxyprogesterone	Provera, Prodrox, Cycrin, Amen, Curretab
Megestrol acetate	Megace
Norgestrel	Neogest
Drospirenone
Levonorgestrel	Norplant, Plan B
Norethindrone	Aygestin
Norethynodrel
Desogestrel	Cerazette
Norgestimate

In the short term, however, progestins induce secretory differentiation in endometrial glands and decidual-type change in the stroma, i.e., the classic changes of a normal secretory endometrium. The glands develop large glycogen vacuoles that are then secreted into the increasingly complex gland lumina (Figures 15.5 and 15.6). At the same time, the stromal cells enlarge strikingly, acquire an abundant cytoplasm, and appear relatively cohesive (Figure 15.7). Even when pathology is present, the stroma may demonstrate pseudodecidual changes, but progesterone responsiveness is often diminished in disease states such as endometritis, and in polyps.

Figure 15.5 Secretory endometrium, demonstrating exogenous progesterone effect. The appearance is indistinguishable from a normal cycle. The woman, who was older, had received progesterone for 20 days.

Figure 15.6 Vacuolated secretory glandular changes in response to short-term progestin therapy.

Figure 15.7 Stromal pseudodecidualization, response to progesterone therapy.

With continued exposure or repeated cycles, the receptor downregulation causes the glands to lose their sensitivity to estrogens and progestins, leading to progressively less secretory change (‘secretory exhaustion’), such that they ultimately appear atrophic. At this stage, which only occurs after prolonged exposure or multiple cycles, the appearance is that of decidualized stroma with widely dispersed atrophic glands, often referred to as a ‘pill’ endometrium (Figure 15.8). More slowly, the decidualized stroma also begins to be suppressed by the receptor downregulation, and over months to years will become attenuated and atrophic, ultimately losing most of its decidual features. At this point, the appearance resembles endometrial atrophy due to menopause or hormone suppression.

Figure 15.8 Atrophic gland in decidualized stroma in a woman receiving progesterone.

Exposure to high-dose progestins (often given for dysfunctional uterine bleeding and usually with a good initial response) can, paradoxically, cause secondary necrosis of the superficial endometrium, often in the form of wedge-shaped infarcts, and renewed bleeding. The hysteroscopic appearances are often alarming. Both the continued bleeding and the hysteroscopic findings lead the clinician to perform a dilatation and curettage to exclude hyperplasia or malignancy and yielding abundant, macroscopically suspicious tissue fragments. Occasionally, patients will spontaneously pass large intact sheets of decidualized endometrium (‘decidual casts’).

Oral Contraceptives

Oral contraceptives (OCs) are one of the most widely used medications in the developed world. They are used as treatment for several common medical problems in addition to contraception, including dysfunctional uterine bleeding and endometriosis. A variety of formulations and administration schedules have been developed (Table 15.3).¹ Sequential OCs contain only estrogen during the first half of the cycle, with progestin added during the second half. Because of the increased risk of endometrial cancer with some sequential formulations,² the most commonly used types today are combined estrogen–progestin and progestin-only formulations administered over 21 consecutive days of the cycle, followed by 7 days of placebo tablets yielding a withdrawal week. Combined pills can be monophasic, in which there is a fixed dose of estrogen and a progestin in combination for the 21 days of each cycle, or they can be biphasic or triphasic, depending on whether the progestin dose is altered once or twice during the cycle. In contrast to some sequential OCs and estrogen-only hormone replacement regimens, which increase the risk of endometrial carcinoma, combined OCs are protective, with the degree of protection increasing with the length of therapy. Patients with 10 years of OC use have about a 75% reduction in endometrial carcinoma.^3,4 OC use is also associated with a 30–50% decrease in the risk of ovarian carcinoma; this lowered risk persists for at least 20 years after cessation of their use and is also seen in BRCA1 and BRCA2 mutation carriers.⁵ Recently, a variety of extended cycle (91 day) and even continuous cycle (365 day) OCs have been introduced that appear to have similar effectiveness to traditional OCs.⁶ The histologic effects of these newer formulations have not been well studied.

Table 15.3 Composition of Representative OCs Available in the United States

Adapted from Schimmer and Parker (2012).¹

Combined OCs

The histologic appearance of the endometrium in a patient on combined OCs is extremely variable, but is dominated by the progestin effects. It depends on various factors, some poorly understood, including the type of pill, the duration of therapy, precise dose of the individual pill, levels of compliance with the regimen, and endogenous hormone synthesis and metabolism.7–9 Certain generalizations are possible, however. Within the first several cycles of a combined OC, there is a mixture of proliferative and secretory features seen in the endometrium (‘asynchronous’ or ‘discordant’ endometrium). The glands tend to remain relatively straight and narrow, resembling proliferative endometrial glands but with cuboidal rather than columnar epithelium, and with very minimal mitotic activity. Subnuclear vacuoles may be seen, especially during the first 2 weeks of the cycle. Decidual change can be seen early but is usually more evident after several cycles have been completed (Figures 15.9 and 15.10). Despite the stromal changes, spiral arterioles do not develop normally.¹⁰ With prolonged therapy over many cycles the glands develop secretory exhaustion and become increasingly small, inactive, and ultimately atrophic. As this occurs, the stromal decidual changes become increasingly well developed, until the endometrium is uniformly decidualized, with only rare, atrophic-appearing glands (Figures 15.11 and 15.12). This is the classic appearance of the so-called ‘pill’ endometrium. Prominent ectatic thin-walled veins are also seen, which often contain thromboses in patients having breakthrough bleeding (Figure 15.13). The classic pill endometrium is not seen in all patients, and there is a spectrum from well-developed stromal changes to complete atrophy, with only a very thin endometrium showing little or no identifiable decidual change. The atrophic changes are seen more frequently with some of the lower dose regimens.⁸