Effects of Drugs on the Uterus

Jonathan Emery

Tommaso Falcone

The increasing use of hysteroscopy, both in the office setting and in the operating room, has allowed for greater understanding of the endometrial environment. This environment changes in response to the dynamic forces of a woman’s current hormonal status. This involves changes from prepubescence through puberty and a woman’s reproductive years into menopause. A skilled hysteroscopist needs to recognize the uterine changes that are a response to this endocrine influence. Furthermore, the uterine response to medication can modify these physiologic changes.

Pharmaceutical use in women is continuing to grow with newer treatments for menopause, osteoporosis, and malignancy, as well as new formulations and modifications for contraceptives and reproductive medications. Because of the continued prevalence of medications, it is imperative that the hysteroscopist be aware of the effects of the medications on the uterus and endometrium, specifically. This allows for increased differentiation of visually normal histology from pathologic lesions. Also, use of medications prior to operative hysteroscopy is increasing in order to improve surgical outcomes. The focus of this chapter is to describe the effects of medications on the endometrium and cervix.

Basic Pharmacologic Principles

Prior to a discussion of the effects of medications on the uterus and the subsequent relation to hysteroscopy, it is necessary to review some basic pharmacologic principles. Most medications discussed here are exogenous hormones that may exert effects that are almost identical to natural hormones produced by the body’s own complement of endocrine organs. Still other medications produce effects that are antagonistic to the end-organ being studied.

Although estrogens, such as estradiol and estrone, are the major secretory products of the ovary, they are also the most common hormonal medication taken by women. Various steroidal estrogens are derived from animal sources, and nonsteroidal, synthetic estrogens are produced. These can be administered orally, vaginally, transdermally, and intramuscularly. The influence of these drugs is determined by several factors including route of administration, pharmacokinetics, and pharmacogenetics. It has been clearly demonstrated that a specific response of the individual may vary based on ethnic background as well as individual genetic heterogeneity.

The uterus has estrogen, progesterone, and androgen receptors. Therefore, medication of all three classes will affect the uterus. These receptors belong to the superfamily of nuclear hormone receptors. These receptors will bind to DNA only if bound to the ligand. There are two forms of estrogen receptors, ER α and ER β. ER α is primarily responsible for estrogenic effects in the uterus and ER β in other tissue such as bone. This differential distribution of estrogen receptors will determine the end-organ response to the particular agent. It is often difficult to predict what the response of an estrogenic drug will be without detailed knowledge of this differential effect. For example, a drug such as raloxifene will have an agonist effect on bone but an antagonist effect on the endometrium.

There are two major forms of the progesterone receptor, PR-A and PR-B. These two isoforms are differentially distributed within the cell, but their precise role is unknown. The concentrations of each receptor is different throughout the menstrual cycle. Like the progesterone receptor, the androgen receptor exists in two forms. Progestins will cross-react with androgen receptors, but the response will vary according to the affinity and dose of the drug used.

When taken orally, the estrogen is absorbed and distributed into the enterohepatic vascular supply with resultant first-pass effect taking place in the liver. This effect refers to the rapid metabolism of drugs going through the liver, which may inactivate most of the medication. Transdermal, vaginal, and intramuscular applications avoid this effect. Once into the circulation, estrogen is highly protein bound, mainly by sex hormone binding globulin (SHBG) and, to a lesser extent, by albumin. In the liver, estrogen is broken down into its metabolites. Once past the liver, the protein-bound plasma estrogens dissociate from the carrier protein and enter the cell via the estrogen receptor. The receptor-hormone complex can then exert its effect on the cell. The estrogen receptor is a typical intracellular steroid receptor.

In terms of the uterus, estrogen exerts a proliferative effect on the endometrial cells, predominantly in the functionalis layer, but has effects that also increase stromal edema. Progesterone is the precursor to estrogen in ovarian hormonal biosynthesis. Pharmacologically, multiple formulations of natural and synthetic progestins are available with
an array of differing secondary effects: estrogenic, androgenic, antiestrogenic, and anabolic. The main function at the level of the uterus of all these progestins is to allow for differentiation of the endometrial cells. Progestins are rapidly absorbed when given orally and intramuscularly, but absorption varies with transdermal preparations and metabolism occurs almost solely in the liver.

The uterine and endometrial effects of the many different steroidal and nonsteroidal medications discussed below are dependent on the hormone, its potency and dosage as well as host receptor status. Duration of use is also important as some medications exert short-term effects that will change and evolve with chronic use.

Oral Contraceptive Pills

Combination Oral Contraceptive Pill

The oral contraceptive pill is one of the most widely prescribed medications for women. In 2002, the contraceptive pill was used as contraception by 11.6 million women in the United States. Formulations vary, but the two major classes of contraceptive pills are the combination contraceptive pill and the progestin-only pill. The most commonly prescribed preparations in the United States are combination contraceptive pills, which consist of both estrogen and progestin components. These combination contraceptive pills are being formulated in ever-smaller concentrations of hormonal components (termed second- and third-generation oral contraceptive pills). The combination pill is also prescribed for hormonal manipulation of the menstrual cycle as well as for treatment of other menstrual-related conditions such as dysmenorrhea.

There are several mechanisms by which the combination contraceptive pill renders its effect on the uterus. The estrogen, of which ethinyl estradiol is the most common, exerts its effect mainly at the level of the hypothalamic-pituitary-ovarian axis by inhibiting the midcycle gonado-tropin surge from the pituitary gland, thus inhibiting ovulation. Prior to that, however, there is suppression of gonadotropin secretion during the follicular phase of the cycle, which prevents ovarian follicular maturation and subsequent ovarian steroid production. Typically the three main steroids produced by the ovary—estrogens, progesterone, and androgens—are suppressed. The extent of this suppression is dependent on dose of the steroids in the contraceptive pill. This suppression of endogenous steroids would cause a hypoestrogenic effect on the uterus. However, the pharmacologic effects of the exogenous steroids modify this effect.

The estrogenic component of the pill would have a proliferative effect on the endometrium. However. the progestin portion of the pill alters this. Progestins exert their major effect at the level of the uterus, causing alteration and stabilization of endometrial development and increased cervical mucous consistency.

The effects of the contraceptive pill on the endometrium can be extrapolated from the clinical symptoms. Continuous use of the combination contraceptive pill has been prescribed to induce amenorrhea in women. Kwiecien et al. showed that women who took continuous combined low-dose contraceptive pills (ethinyl estradiol 20 μg and levonorgestrel 100 μg) were more likely to have amenorrhea than women on cyclic combinations.

For the hysteroscopist, use of the typical combination contraceptive pill with 30 μg of estradiol can have a mildly proliferative picture. This can be reduced by scheduling patients on cyclic oral contraceptive agents for hysteroscopic evaluation approximately 1 week after the menses, as there is less endometrial proliferation at that time. Lower doses will have a progestin dominant effect, which would appear as a more atrophic endometrium. Patients on long-term (>6 months) continuous combination OCP will likely have a thinner endometrium than those on cyclic therapies.

Progestins

Many different formulations and uses for progestational agents are currently available. Progestin-only oral contraceptive pills induce amenorrhea in women through their effect of antagonizing the proliferative action of estrogen on the endometrium. Long-term use of these pills can produce a pseudodecidualization pattern within the endometrium. Medroxyprogesterone acetate (MPA) depot is currently used as a long-term contraceptive and has other uses in gynecology as it can be used to treat other menstrual disorders. A low-dose formulation has been approved for use as treatment of endometriosis. The long-term effect of MPA is to induce endometrial thinning, which causes the endometrium to have a pale, flat appearance.

Brooks et al. studied this progestin as a possible preparatory medication before hysteroscopic surgery (MPA depot 200 mg intramuscularly for 6 weeks) and described the endometrium as appearing “fluffy” with no cases of thinning or atrophy seen. It is likely that long-term use does increase endometrial thinning whereas short-term use (<12 months) may have a less uniform effect visually and histologically.

A recent study in women using subdermal levonorgestrel-releasing implants has shown that hysteroscopically there are greater superficial endometrial dilated vessels, which corresponds to the findings of Brooks et al. in patients pretreated with MPA depot injections or norethindrone acetate orally. This increased vascularity and resultant thickness of the endometrium can in theory result in longer operative times if progestins are used as pretreatments before operative hysteroscopic procedures. Multiple studies have reviewed progestins, mainly MPA, as a preoperative endometrial preparation prior to hysteroscopic endometrial resection or ablation.

Hormone Replacement Therapy

Standard Estrogen/Progestin Therapy

Combination hormone replacement therapy (HRT) with estrogen plus progestin has been used for the treatment of menopausal symptom relief since 1975. The initial treatment of estrogen alone in the climacteric was shown to increase the risk of endometrial carcinoma so that since the late 1970s and early 1980s, the addition of progestin in either cyclic or continuous administration has become standard therapy. The addition of progestin, commonly medroxyprogesterone acetate (MPA) in the United States, works to counteract the endometrial stimulatory effect of the exogenous estrogen after menopause. Cyclic use of progestins for 12 days of each cycle induces a menses, whereas daily continuous combined estrogen and progestin therapy causes the endometrium to become suppressed from the effect of daily progestin. However, in the latter case the endometrium may nonetheless bleed.

A common occurrence for women on HRT is irregular or unexpected bleeding during therapy. This may be alarming to the patient and physician because of the possibility of associated adverse pathology with such events. Hysteroscopy can be an invaluable tool in this setting so as to provide an evaluation of the endometrium visually and provide opportunity for directed biopsy.

Hysteroscopic evaluation of the uterine lining of patients on HRT depends on whether therapy is with continuous or cyclic administration of progestin. In women receiving continuous combined therapy, almost all women have shown a homogeneous, thin atrophic endometrium. In women who experience irregular bleeding, two studies have shown that when the ultrasonographic thickness of the endometrium is <4 mm, the endometrium will show atrophy. When irregular bleeding does occur in these patients, hysteroscopy may show increased endometrial stromal blood vessel exposure and rupture; multiple petechial-appearing vessels can be seen within the pale, thin endometrium.

Cyclic HRT patients can have an atrophic endometrium at hysteroscopy, but if the procedure is done during the estrogen-only phase of treatment, a normal proliferative appearance of the endometrium may predominate. Nagele et al. showed that in women on HRT who had abnormal bleeding, functional endometrium was often found at hysteroscopy. deCecco et al. showed that a mixed proliferative and secretory picture was common during hysteroscopic visualization during the cyclic addition of progestin.

Selective Estrogen Receptor Modulators

With a reduction in use of postmenopausal HRT, selective estrogen receptor modulators (SERMs) have gained in use. These compounds bind with high affinity to estrogen receptors, causing estrogen agonistic activity in certain tissues while producing estrogen antagonistic effects in others.

Tamoxifen

Tamoxifen, a nonsteroidal triphenylethylene derivative, is commonly used as adjuvant treatment in patients with breast cancer as it can improve survival in patients with estrogen receptor-positive tumors. The final effect of the drug on the uterus will depend on the estrogenic milieu during the administration of the agent. The final effect on the endometrium of tamoxifen, or any other SERM, will depend on the estrogenic environment. At the level of the endometrium, the drug exerts an estrogen agonistic effect. In premenopausal women, tamoxifen will act somewhat as an antiestrogen. In postmenopausal women, tamoxifen will act more as estrogen. This final effect can vary from patient to patient, with hysteroscopic evaluation revealing a spectrum of appearances from atrophy to hyperplasia.

Hysteroscopic evaluation of the tamoxifen-affected uterus can show endometrial atrophy with a smooth pale-white surface; some authors have described differing levels of vascularity and protuberances. Histologically, however, the cellular layers below the epithelial surface can show dense stroma with edema and cystically dilated endometrial glands; this has been globally termed cystic glandular atrophy.

Tamoxifen-induced endometrial polyps may also be encountered during hysteroscopic visualization. The incidence of finding polyps in women on the drug varies from 32% to just over 56% (Table 8.1). These polyps can vary in size and may be highly vascularized.

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