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

Formulations that include short estrogen-only periods have been used in an attempt to lower the overall dose of hormones. Mircette, for example, has 21 days of combination treatment followed by a 2 day, hormone-free interval and 5 days of unopposed estrogen. Technically, this is a sequential OC, but to date it has not had the safety issues associated with the older, higher dose sequential therapies. This formulation has a distinctly different histologic pattern than the combined OCs. Biopsies taken during the estrogen-only portion of the cycle show proliferative endometrium while biopsies taken during the combined portion of the cycle show secretory endometrium.¹¹

Pure Progestin OCs (‘Mini-Pill’)

In contrast to the combined OCs, the pure progestin OC (the mini-pill, 300 μg norethisterone) is taken daily without interruption during the cycle. The mechanism of contraception differs from combined OCs in that ovulation is not consistently suppressed. Instead, contraception is due to the production of relatively thick cervical mucus that is impermeable to sperm, and to the atrophic endometrium that will not support implantation. The endometrial changes seen with the mini-pill are not distinctly different from those seen with combined OCs, but marked atrophy is more common and biopsy frequently yields only scanty material. In addition, proliferative endometrium is not infrequently seen, and this correlates with abnormal bleeding.¹²

Long-Term, Progestin-Only OCs

Several systems have been developed for long-term, progestin-only contraception. Medroxyprogesterone acetate microcrystals in an aqueous solution (Depo-Provera) are used as an intramuscular injection. The slow dissolution of the crystals maintains effective progestin levels for several months, allowing for an injection schedule of every 3 months. Levels of progestin are typically higher than with the mini-pill. Early after injection, some women develop exaggerated hypersecretory changes that resemble gestational endometrium, including the presence of Arias-Stella reaction. By 3–6 months these changes have resolved and stromal decidual changes develop, resembling those seen with combined OCs as described earlier. Long-term treatment can result in atrophy or pure decidua-like change (Figure 15.14), just as with combined OCs.^8,13

The Norplant system consists of several Silastic tubes containing levonorgestrel. The tubes are slightly permeable to steroids, and the progestin is slowly released for a period of 3–5 years. As in other progestin-only regimens, ovulation occurs in about one-third of cycles, and contraception is by production of thick cervical mucus and an endometrium inimical to implantation. There are relatively few studies on the histologic findings with Norplant,14,15 but the findings seem to be similar to other progestin-only regimens, with atrophy being the most common finding. Proliferative endometrium can also be seen, and correlates with irregular bleeding patterns.¹⁶

Devices that supply progestins directly to the endometrium are also used. The most common of these uses a slow-release formulation of levonorgestrel in combination with an intrauterine device (Mirena). Although physically located within the endometrium, absorption is systemic and they can be used for treatment of extrauterine disease such as endometriosis as well as abnormal uterine bleeding.17–19 Histologically, the endometrium shows extensive decidualization.²⁰

Unopposed Estrogen HRT

Historically, estrogen alone was given as hormone replacement for postmenopausal women, and the beneficial effects of this therapy in preventing osteoporosis and cardiovascular disease have been well documented. Then a series of case–control studies subsequently demonstrated a markedly increased risk of endometrial adenocarcinoma in women using long-term estrogens unopposed by progestins. Patients receiving unopposed estrogens for 5 years or more have an approximately sixfold increase in endometrial carcinoma. With the addition of progestins, the risk of endometrial carcinoma fell to near control levels.23–25 The risk of endometrial carcinoma is dose related, but low-dose estrogens (0.3 mg conjugated estrogens or equivalent) continue to be associated with a risk of carcinoma if not combined with a progestin.²⁶ Even estrogens applied as vaginal creams have sufficient systemic absorption to increase the risk.²⁷ Although current practice is treatment with combined therapy, occasional patients are still treated with estrogen alone. It should be noted that, although addition of a progestin reduces the risk of endometrial cancer from HRT, combined HRT is associated with a significant increase in the risk of breast cancer.²⁸

The endometrium from a woman being treated with unopposed estrogens will most commonly appear proliferative, and may in fact be indistinguishable from a normal proliferative endometrium in a premenopausal patient. If the estrogen dose is low, there may also be a lesser degree of proliferation that is described as weakly proliferative.²⁹ If the patient is bleeding, the endometrium will often have proliferative glands with associated stromal breakdown deep below the uterine surface lining (Figure 15.3), a feature that specifically suggests unopposed estrogen exposure. Unfortunately, conventional microscopy cannot distinguish these changes due to exogenous estrogens from the effects of endogenous estrogen, as in anovulatory bleeding, or from the effects of other agents that may act as estrogenic agents in the endometrium. These include tamoxifen, various drugs and pharmaceutical agents such as digitalis or phenothiazines, and herbal preparations such as ginseng.

Long-term estrogen exposure can lead to a full spectrum of appearances, ranging from disordered proliferative changes to non-atypical endometrial hyperplasia, EIN, or even adenocarcinoma.⁷ Disordered proliferative endometrium shows a basic pattern of proliferative endometrium, with the addition of irregularly dilated and focally branched glands. This condition is most commonly seen in untreated women during the perimenopause and is not felt to be premalignant (see Chapter 17). Tubal metaplasia is common. The hallmark of non-atypical endometrial hyperplasia is the development of endometrial compartment-wide irregular gland shape and distribution, which in many areas has glandular crowding to more than a 1 : 1 gland to stroma ratio. EIN may emerge from non-atypical endometrial hyperplasia as a localized lesion with discrete cytology.³⁰ Adenocarcinomas are of the endometrioid type, exhibit severe glandular crowding, usually with a cribriform or papillary architecture, and at least mild nuclear atypia (see Chapter 18). Tumors developing from unopposed estrogen exposure, whether endogenous or exogenous, are usually low grade with high long-term survival rates. Patients who develop adenocarcinomas usually have a minimum of 2–3 years of unopposed estrogen use. The risk increases over time, with the highest risk in patients who have taken estrogens for 10 or more years.⁹

Cyclic Estrogen–Progesterone HRT

Because unopposed estrogens elevate the risk of endometrial adenocarcinoma, HRT today nearly always includes a progestin (if the patient has a uterus). The most commonly used agents are conjugated equine estrogen (Premarin) in combination with medroxyprogesterone acetate (Provera). Cyclic or sequential HRT uses daily estrogen for the first 21–25 days of the month with daily progestin added for the last 10–13 days. Consistent reduction of mitotic rates in glandular epithelium is found after generally only 9 or more days of progesterone administration in each cycle.31,32 This regimen mimics to some degree the normal progression of these hormones during a menstrual cycle and typically results in a withdrawal bleed at the end of each cycle. Longer cycle lengths (i.e., 12 instead of 4 weeks) have shown a decrease in the protective effect of the progestin and are not generally recommended.³³

The pathologic findings in the endometrium are somewhat but not entirely predictable based on our understanding of normal endometrial cycles. Not surprisingly, biopsies taken from the estrogen-only portion of the cycle typically have a proliferative appearance, and may be histologically identical to a normal proliferative endometrium (Figures 15.15–15.17). Biopsies taken after the initiation of the progestin are more variable. Most show some degree of secretory change, beginning about 3 days after the beginning of the progestin therapy, but the changes lack the well-ordered daily progression seen in normal secretory endometrium and cannot be ‘dated’ in the same fashion (see Chapter 14).^34–36 Frequently, the glandular component develops no further than an early secretory appearance, with variably developed glycogen vacuoles persisting even late into the artificial cycle. The stroma shows a variable response to the progestin, and may develop a spotty decidual response by day 10 after progestin initiation. This is often described in pathology reports as gland–stromal asynchrony, and can be due to various other factors, including intrauterine devices (IUDs), OCs, underlying mass lesions such as leiomyomas or polyps, chronic endometritis, and other types of hormone such as mifepristone, clomiphene, and gonadotropins. Although this sequence of incomplete cycling is the most common picture with cyclic HRT, other patterns are not infrequent. Some patients will have normal menstrual changes (Figure 15.18) impossible to distinguish from women who have never taken HRT. Up to one-fifth of patients will have an inactive endometrium. This group of patients generally does not experience monthly withdrawal bleeds.

Our understanding of precisely why the endometrium responds so variably to cyclic HRT is poor, but presumably reflects multiple host factors (age, years post menopause, level of endogenous hormones) and medication-specific factors (precise drug, dose, and duration).

Combined Estrogen–Progesterone HRT

Continuous combined estrogen–progestin HRT protects against the carcinogenic effects of unopposed estrogen. These regimens generally have a relatively predictable and uniform effect on the endometrium. As described previously, the continuous long-term use of progesterone leads to downregulation of both estrogen and progesterone receptors, diminishing the responsiveness of the endometrium. This leads to the most common appearance, namely an atrophic or inactive endometrium.8,37 There may be weak, poorly developed decidual change in the stromal cells, and the glandular component may show a few glycogen vacuoles suggesting progestin effect in the glands, but these findings are variable. Least common, there is a well-developed stromal decidual change, similar to that seen with OCs (Figure 15.19). Metaplastic changes such as tubal metaplasia, eosinophilic metaplasia, squamous metaplasia, and papillary syncytial metaplasia are more common with combined continuous HRT.⁷

A clearly proliferative pattern in the endometrium would suggest an inadequate dose of the progestational agent, especially if there is ongoing breakdown (i.e., an anovulatory-like pattern) (Figures 15.20 and 15.21).

Tamoxifen

Tamoxifen has been widely used in the treatment and now the prevention of breast cancer, where it functions as an antiestrogen.³⁸ Toremifene is a closely related agent that is available in several countries; it will be considered together with tamoxifen as they have very similar actions.³⁹ In the endometrium, tamoxifen is a strong competitive inhibitor of circulating estrogens, but also a weak estrogen agonist. In the presence of high estrogen levels, as found in premenopausal women, it competes for receptors, thereby reducing overall estrogen stimulation. In the presence of very low ambient estrogen levels, i.e., in the postmenopausal patient, the agonist activity of tamoxifen can result in mild activation of the endometrial estrogen receptor.⁴⁰ While most postmenopausal women will continue to have atrophic or (regular or cystic) inactive endometrium (Figure 15.22), a few will develop the pathologic changes associated with chronic unopposed estrogen stimulation.⁴¹ As might be expected, women receiving tamoxifen who are symptomatic have far greater frequencies of endometrial pathologies than women who are asymptomatic (93% vs 25%).^42–44

Multiple reports have described unusual-appearing endometrial polyps in tamoxifen-treated patients, with cystically dilated glands sometimes containing luminal secretions, a variety of metaplasias, massive fibrosis and, more rarely, decidualized stroma (Figures 15.23 and 15.24).^44,45 Some of these changes may be dose related.⁴⁶ Many of the polyps are 20 mm or more in size, which is larger than seen with any other form of HRT. No studies have yet to indicate why this drug alone has such a peculiar effect on the endometrial stroma. Malignancies are occasionally found in polyps associated with tamoxifen therapy and at rates much higher than in healthy nonusers (3% vs 0.5%).⁴⁶

Endometrial carcinomas arise at approximately the same rate as with unopposed estrogen and at far greater rates than women not receiving HRT. The risk is related to the duration of therapy, and is increased approximately fourfold in patients exposed to tamoxifen for more than 5 years.⁴⁷ Some initial anecdotal reports and small series suggested that tamoxifen-induced carcinomas might be more frequently high grade,⁴⁸ but larger subsequent series including results from the NSABP B-14 study have shown a similar proportion of high-grade tumors to those arising sporadically.^49,50 Most cancers are low-grade, low-stage endometrioid adenocarcinomas. Uterine sarcomas also occur rarely in association with tamoxifen therapy,⁵¹ but most of these examples are carcinosarcomas that the current body of opinion places into the category of ‘metaplastic carcinomas’ (see Chapter 18).

Other Selective Estrogen Receptor Modulators

There are at least two types of estrogen receptors that are differentially active between reproductive and somatic target organs. This has led to the development of selective estrogen receptor modulators (SERMs), designed for relatively tissue-specific effects.³⁹ Clinically beneficial compounds would minimize the stimulatory effect in endometrial tissue while retaining the beneficial effects in bone and the cardiovascular system. The first of these to come into wide use was tamoxifen, but in recent years a number of additional SERMs have become available.

Raloxifene, an antiestrogen designed initially for breast cancer treatment, has selective beneficial effects on bone and cardiovascular systems, while lacking any evident estrogenic activity within the endometrium itself. Endometrial biopsies from postmenopausal women taking raloxifene show atrophy or inactive endometrium,⁵² and treated patients show no increase in endometrial thickness as measured by ultrasound.⁵³ Long-term follow-up studies now confirm that patients receiving raloxifene have neither increased endometrial hyperplasia nor carcinoma when compared with control groups,^54–56 although there has been an increase in endometrial polyps.

A number of other SERMS are entering clinical use or have shown promise in clinical trials, including lasofoxifene, arzoxifene, bazedoxifene, ospemifene and fulvestrant. None of these have had detailed, long-term evaluations of their endometrial effects, but at least one (lasofoxifene) has been shown to be associated with increased endometrial thickness and polyps.⁵⁵ It appears that each of these agents has a unique combination of activities and their effects on the endometrium will need to be documented individually rather than as a single class of drugs.

Aromatase Inhibitors

Aromatase inhibitors are a class of endocrine agents that block the peripheral conversion of steroids into estradiol by inhibiting the aromatase enzyme. Letrozole, anastrozole, and exemestane are the three mostly thoroughly studied members of this drug class. These drugs are used primarily to treat estrogen receptor-positive breast cancers in postmenopausal women (in this situation they are highly effective)57,58 and, more recently, endometriosis⁵⁹ and ovulation induction for in vitro fertilization.^60,61 Because they reduce circulating estrogen levels to near zero, the primary effect on the endometrium is atrophy, and the rate of endometrial carcinoma is lower than in tamoxifen-treated patients.⁶² As measured by transvaginal ultrasound, aromatase inhibitors do not increase endometrial thickness. Some preliminary evidence suggests that aromatase inhibitors could even help treat pre-existing endometrial hyperplasias.⁶³ Although aromatase inhibitors effectively shut down endometrial proliferation, endometrial polyps continue to develop, an observation that contradicts current dogma that endometrial polyps are estrogen induced.

Phytoestrogens and Other Dietary Agents

Dietary and herbal remedies are widely used worldwide for relief of menopausal symptoms. Commonly used herbs include black cohosh (Cimicifuga racemosa), chaste tree berry (Vitex agnus-castus), dong quai (Angelica sinensis), ginseng (Panax ginseng and other Panax species), evening primrose oil (Oenothera biennis), motherwort (Leonurus cardiaca), red clover (Trifolium pratense), and licorice (Glycyrrhiza glabra). In many cases the active ingredients of these herbal preparations have not been clearly identified.⁶⁴

Phytoestrogens, new forms of SERM still being evaluated, are plant estrogens that occur naturally as constituents of many plants, most notably beans and a variety of grains and seeds. Soybeans and flaxseed are commonly cited in the lay literature as sources of phytoestrogens,65,66 which have a weak estrogen-like effect in the body. One tantalizing observation is that Asian women, who are known to have a much lower incidence of endometrial carcinoma than Western women, consume much higher amounts of phytoestrogen-rich foods, such as soy and tofu. Human studies suggest that a diet high in phytoestrogens may protect against endometrial adenocarcinoma and provide benefits in bone density.⁶⁷ Nationwide population-based studies, while not specifically evaluating phytoestrogens, suggest that a diet with a low fruit and vegetable intake is associated with higher rates of endometrial cancer.⁶⁸

The most common types of phytoestrogen in plants and foods are the isoflavones. The richest sources in nature are the leaves of the subterranean red clover with levels of up to 5 g/100 g dry weight, and soybeans with levels up to 300 mg/100 g dry weight. The most commonly studied phytoestrogens within this group are genistein and daidzein.

The initial data available on the effects on the endometrium itself suggest that phytoestrogens likely function as weak estrogen agonists. Long-term exposure to high doses may increase the risk of endometrial hyperplasia in postmenopausal women, but most evidence suggests that short-term exposure to lower doses has no discernible histologic effect on endometrium.69,70 In premenopausal women, the endometrium appears to cycle normally (Figure 15.25).

Wild yam preparations contain diosgenin, which can be converted to progesterone in a laboratory but not in the human body. Whether dietary supplementation with wild yams has any histologic effects on the endometrium is unknown.⁶⁶

Clomiphene/Ovulation Induction Therapy

Clomiphene citrate (Clomid) is an agent with strong affinity for the estrogen receptor. It binds essentially irreversibly to the receptor, reducing turnover. Its clinical usefulness stems from its effects on the hypothalamus, which interprets this activity as a low level of estrogen, causing increased gonadotropin-releasing hormone (GnRH) stimulation of the pituitary, and hence increased follicle-stimulating hormone (FSH) production. This increases ovarian estrogen production, which then feeds back to the pituitary and causes a luteinizing hormone (LH) surge, followed by ovulation.⁸ This drug, used to induce ovulation, is usually given on cycle days 5–10, with ovulation occurring 5–10 days after its administration. The increased stimulation of the dominant follicle results in higher serum estrogen and progesterone levels during the resulting secretory phase.

The effects of clomiphene on the endometrium are relatively subtle.71,72 Some, but not all, studies suggest that, in a clomiphene-induced secretory phase, the glandular development is delayed relative to the time of ovulation (Figure 15.26). Although delayed, the early secretory changes are unusually well developed, with large, uniform subnuclear glycogen vacuoles that persist longer than in a normal cycle. Later in the cycle, decidual changes in the stroma are less prominent, and a coiled glandular architecture persists. These findings probably represent the antiestrogenic effects of clomiphene in combination with the high circulating levels of estrogen and progesterone.⁷³

In more recent years, ovulation induction has involved more complex regimens, generally involving administration of GnRH agonists and antagonists, FSH, human chorionic gonadotropin, and aromatase inhibitors. There are few treatment-specific studies on endometrial morphology, and it is difficult to extrapolate results between regimens. At least some studies suggest a relative delay in secretory phase maturation, similar to that seen with clomiphene. Other studies show in-phase or even advanced date endometrium.74,75 The alterations in endometrial function may be responsible for the reduced rate of successful implantation seen in some patients.

Progesterone Receptor Modulators

This class of agents modulates the activity of the progesterone receptor. Although developed originally as progesterone receptor antagonists, their actions in vivo appear to be more complex, varying by agent and modified by the hormonal environment of the individual patient. The most widely known agent in the United States is mifepristone, which is primarily used as an agent of very early abortion (‘morning after pill’), but these agents are also effective in the treatment of a variety of common conditions such as endometriosis and leiomyomata.⁷⁶ Other drugs in this category include asoprisnil, and Proellex (CDB-4124). Several studies have shown unique histologic changes in the endometrium in patients receiving progesterone receptor modulators (PRMs), and a National Institutes of Health-sponsored workshop has suggested the term ‘progesterone receptor modular associated endometrial changes’ (PAEC) as a name for this constellation of findings.^77–79 Common findings include the development of multiple cysts, and glandular epithelium with nonphysiologic combinations of estrogen and progesterone effects: mitoses with apoptosis, or secretory vacuoles with proliferative activity (Figures 15.27 and 15.28). Stromal predecidual change is rare, and they differ from unopposed estrogens in lacking fibrin thrombi. PAEC changes are not seen in every treated patient, some of whom have proliferative or atrophic endometria that lack any distinctive features that would suggest exposure to a PRM. Long-term clinical outcomes are generally unknown or poorly understood, as the majority are newly introduced agents. However, as PRMs become more widely used, it will be important for pathologists to be aware of these changes so they are not confused with polyps or unopposed estrogen effects.

GnRH Agonists and Antagonists

Pulsatile release of GnRH from the hypothalamus is the normal stimulus to the pituitary to secrete FSH and LH. Paradoxically, chronic nonpulsatile treatment has the opposite effect and results in the inhibition of FSH and LH secretion (after an initial surge), apparently via downregulation of the GnRH receptors in the pituitary. Several GnRH agonists make use of this pathway to suppress pituitary gonadotropin secretion, including leuprolide acetate, buserelin acetate, triptorelin, nafarelin, and goserelin acetate. More recently, direct GnRH antagonists have been developed (cetrorelix, ganirelix) that have similar suppressive effects but without the initial surge in FSH and LH secretion. Administering these agents blocks ovarian follicle development and induces a marked reduction in estrogen and progesterone levels, comparable to a postmenopausal state. Indeed, long-term treatment with these agents is limited due to the side effects of marked hypoestrogenemia, including profound bone density loss.

Currently, GnRH agonists and antagonists are used to reduce the size of uterine leiomyomas and endometrial stromal sarcomas.⁸⁰ They are also used in the diagnosis and treatment of endometriosis, and in the suppression of ovulation during oocyte harvest for in vitro fertilization. Histologically, it is not surprising that the endometrium from patients treated chronically with GnRH shows profound atrophy.⁸¹

Gonadotropins

Gonadotropins are used primarily to treat infertility. Human menopausal gonadotropins, LH and FSH, are extracted from the urine of postmenopausal women. Human chorionic gonadotropin is closely related to LH, and can be used to simulate the mid-cycle LH surge in ovulation induction. The effects of these agents on the endometrium are not clear. Various conflicting findings report delayed, normal, or advanced histologic maturation relative to the clinical dates, as well as hypersecretory changes similar to Arias-Stella reactions.8,9,82

Corticosteroids

High doses of corticosteroids can have a progestational effect on the endometrium. Presumably, this is due to a weak affinity for the progesterone receptor. The histologic appearance is similar to other progestational agents. Chronic lower dose therapy will eventually result in endometrial atrophy.

Danazol

Danazol is a weak androgen that is structurally related to testosterone and is used to treat endometriosis and endometrial hyperplasia. The endometrial changes resemble those seen with progestational agents. As with progestins, long-term therapy usually leads to atrophy83,84 or a reduction in the severity of hyperplasia.⁸⁵

Progestin Therapy of Persistent Estrogen States (Hyperplasia)

Non-atypical endometrial hyperplasia, or benign endometrial hyperplasias, can be viewed as a primary endocrine abnormality of unopposed estrogens. In this circumstance even a functionally ‘normal’ endometrium responds by hyperplastic growth, and, eventually, development of symptoms of irregular menses and bleeding. Clinical management incorporates several elements, including establishing an underlying endocrine mechanism (anovulation, polycystic ovary syndrome, for example), assessment of intrinsic endometrial risk for neoplasia (to be ruled out on pathologic sampling), and symptomatic relief. Although symptomatic relief is often achieved through short- or medium-term progestin therapy and synchronized shedding of affected tissues, the condition may recur if the causal estrogen excess persists.

Short-term therapy with oral progestins leads to the formation of secretory vacuoles within the maintained architectural structure of the pre-existing lesion (Figure 15.29). Stromal decidualization and secretory exhaustion follows, but initially with the cysts and irregular glands of the underlying lesion (Figure 15.30). Eventually, and especially if a withdrawal shedding is allowed to occur, the hyperplastic architecture is lost (Figure 15.31). Incomplete responses are common, and may be caused by patient noncompliance, inadequate dose or duration, or lack of endometrial responsiveness. Adequacy of treatment can be assessed by repeat endometrial sampling, in conjunction with clinical symptoms.

If the underlying production of persistent estrogens is not remedied, the endometrium will revert to an anovulatory, or hyperplastic, appearance upon cessation of progestin therapy. Direct intrauterine delivery of progestins by placement of a hormonally impregnated IUD can provide long-term (years) endometrial treatment with the additional advantage of reducing the level of systemic exposure (Figure 15.32).

Progestin Therapy of Neoplastic Lesions: EIN and Carcinoma

The histologic response of neoplastic (EIN and endometrioid type adenocarcinoma) endometrial tissues to progestin therapy is discussed in Chapters 17 and 18, respectively. Generally, the therapeutic goal is to stabilize or ablate lesional tissues, and when successful the histologic appearance is dominated by hormonally altered background endometrium, which may revert to normal after cessation of therapy. Presently there are no clinically useful parameters to predict which lesions will, or will not, respond to therapy. A decision to treat medically is thus made on a clinical basis once a specific qualifying diagnosis is rendered.

Progestin-altered glands of persistent premalignant EIN lesions and adenocarcinoma may become widely separated by an expanded decidualized stroma, and acquire a bland nuclear cytology. This can make persistent disease difficult to recognize in biopsies taken while the patient is still receiving hormonal therapy. Close follow-up is always warranted even when there has been an apparently complete histologic response.⁸⁷

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