Understand the mechanisms of action of endogenous estrogens and progesterone.

  Describe the fundamental workings of the menstrual cycle.

  Identify the prototype drug for the estrogens, progestins, and estrogen–progestin combinations.

  Describe the estrogens in terms of their of action, use, contraindications, adverse effects, and nursing implications.

  Describe the progestins in terms of their action, use, contraindications, adverse effects, and nursing implications.

  Describe the estrogen–progestin combinations in terms of their action, use, contraindications, adverse effects, and nursing implications.

  Evaluate the benefits and risks associated with postmenopausal hormone replacement therapy.

  Apply the nursing process to patients taking estrogens, progestins, and estrogen–progestin combinations.

KEY TERMS

Estrogen: hormone produced primarily by the ovaries and secondarily by the adrenal cortex; promotes growth of specific body cells and development of most female secondary sexual characteristics

Menopause: permanent end of menstrual periods, which usually occurs in women 48 to 55 years of age

Progesterone: hormone produced in the ovaries and adrenal cortex; prepares the lining of the uterus for pregnancy

Progestin: synthetic form of progesterone that is similar to the hormone produced naturally by the body; most often used in combination with an estrogen in contraceptive products

Introduction

This chapter focuses on drug therapy in women’s health care. Estrogen and progesterone are female sex hormones produced primarily by the ovaries and secondarily by the adrenal cortex in nonpregnant women. Small amounts of estrogens are also synthesized in the liver, kidney, brain, skeletal muscle, testes, and adipose tissue. In normal premenopausal women, estrogen synthesis in adipose tissue may be a significant source of the hormone. Some evidence indicates that a minimum body weight (about 105 lb) and fat content (16%–24%) are required for initiation and maintenance of the menstrual cycle. The observation that women with anorexia nervosa, chronic disease, or malnutrition, as well as women who engage in long-distance running, usually have amenorrhea supports this view. With anorexia nervosa, regaining weight and body mass usually reestablishes normal menstrual patterns.

As with other steroid hormones, estrogen and progesterone are synthesized from cholesterol. The ovaries and adrenal glands can manufacture cholesterol or extract it from the blood. Through a series of chemical reactions, cholesterol is converted to progesterone and then to androgens, testosterone, and androstenedione. The ovaries use these male sex hormones to produce estrogens. After formation, the hormones are secreted into the bloodstream in response to stimulation by the anterior pituitary gonadotropic hormones, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). In the bloodstream, the hormones combine with serum proteins and are transported to target tissues, where they enter body cells. They cross cell membranes easily because of their steroid structure and lipid solubility. Inside the cells, the hormones bind to estrogen or progesterone receptors and regulate intracellular protein synthesis. Estrogen can enhance target-tissue responses to progesterone by increasing progesterone receptors. Progesterone seems to inhibit tissue responses to estrogen by decreasing estrogen receptors.

Overview of Reproduction in Women

To adequately understand the pharmacologic effects of estrogens and progestins (synthetic progesterone), it is important to understand the physiology of female reproductive hormones and the menstrual cycle.

Physiology

Estrogens

The main function of the estrogens is to promote growth in tissues related to reproduction and sexual characteristics in women. Estrogens also have specific effects on other body tissues (Box 44.1). Three ovarian estrogens (estradiol, estrone, and estriol, known as endogenous estrogens) are secreted in significant amounts. Estradiol is the major estrogen because it exerts more estrogenic activity than the other two estrogens combined.

In nonpregnant women, between puberty and menopause (permanent end of menstrual periods), estrogens are secreted in a monthly cycle called the menstrual cycle. During the first half of the cycle, before ovulation, estrogens are secreted in progressively larger amounts. During the second half of the cycle, estrogens and progesterone are secreted in increasing amounts until 2 to 3 days before the onset of menstruation. At that time, secretion of both hormones decreases abruptly. When the endometrial lining of the uterus loses its hormonal stimulation, it is discharged vaginally as menstrual flow.

During pregnancy, the placenta in conjunction with the fetus produces large amounts of estrogen causing enlargement of the uterus and breasts, growth of glandular tissue in the breasts, and relaxation of ligaments and joints in the pelvis. All these changes are necessary for the growth and birth of the fetus.

Finally, estrogens are deactivated in the liver and readily excreted through the kidneys. Metabolites are also formed in the gastrointestinal (GI) tract, brain, skin, and other steroid target tissues. Most of the conjugates are excreted in urine, and some are excreted in bile and recirculated to the liver or excreted in feces.

Progesterone

In general, progesterone has different effects on lipid metabolism compared with estrogen. That is, progesterones decrease high-density lipoprotein (HDL) cholesterol and increase low-density lipoprotein (LDL) cholesterol, both of which increase the risk of cardiovascular disease. Physiologic progesterone increases insulin levels but does not usually impair glucose tolerance. However, long-term administration of potent synthetic exogenous progestins, such as norgestrel, may decrease glucose tolerance and make diabetes mellitus more difficult to control. Like estrogen, progesterone is metabolized in the liver.

In nonpregnant women, progesterone is secreted by the corpus luteum during the last half of the menstrual cycle, which occurs after ovulation. This hormone continues the changes in the endometrial lining of the uterus begun by estrogens during the first half of the menstrual cycle. These changes provide for implantation and nourishment of a fertilized ovum. When fertilization does not take place, the estrogen and progesterone levels decrease and menstruation occurs.

If the ovum is fertilized, progesterone acts to maintain the pregnancy. The corpus luteum produces progesterone during the first few weeks of gestation. Then, the placenta produces the progesterone needed to maintain the endometrial lining of the uterus. In addition to its effects on the uterus, progesterone prepares the breasts for lactation by promoting development of milk-producing cells. Milk is not secreted, however, until the cells are further stimulated by prolactin from the anterior pituitary gland. Progesterone also may help maintain pregnancy by decreasing uterine contractility. This, in turn, decreases the risk of spontaneous abortion.

Menstrual Cycle

The menstrual cycle consists of the follicular phase (days 1–14) and the luteal phase (days 15–28). Hormones in the hypothalamus, pituitary gland, and ovary regulate this cycle. The usual length of a complete menstrual cycle is 28 days, and the first day of menstrual bleeding is day 1.

Figure 44.1 shows how the hormones interact in this cycle. Initially, the hypothalamus releases gonadotropin-releasing hormone (GnRH), which causes the anterior pituitary gland to produce FSH in the follicular phase of the cycle. FSH results in the maturing of ovarian follicles, which in turn produce estrogens. Increasing estrogen levels result in the continued maturation of the ovarian follicle and increasing growth of the endometrium. A negative feedback system responds to the increasing amounts of estrogen by decreasing the amount FSH. At midcycle (typically day 14 of a 28-day menstrual cycle), the anterior pituitary gland releases LH, resulting in the rupture of the ovarian follicle and the development of the corpus luteum. This process is ovulation. The corpus luteum releases progesterone and estrogen, which causes the endometrial lining to continue to increase in thickness and vascularity. If fertilization of the ovum does not occur, the corpus luteum atrophies, resulting in the reduced production of estrogen and progesterone. As estrogen and progesterone levels continue to decrease, the endometrium begins to regress, causing menstruation, and the beginning of another menstrual cycle.

Drug Therapy

Women may take exogenous estrogens and progestins at various stages in the reproductive cycle. When exogenous estrogens and progestins are administered for therapeutic purposes, they produce the same effects as endogenous hormones. Multiple preparations of estrogens and progestins are available for various purposes and in several forms. Clinical indications, routes of administration, and dosages are presented in the Drugs at a Glance tables.

NCLEX Success

Estrogens

Exogenous estrogens are used to treat women’s health disorders when endogenous estrogen levels are low or absent. Conjugated estrogen (Premarin), the prototype estrogen, is the most commonly used oral estrogen.

Pharmacokinetics

Conjugated estrogen and some synthetic derivatives of natural estrogens (e.g., ethinyl estradiol, the most widely used synthetic steroidal estrogen) are chemically modified to be effective with oral administration. After oral administration, these estrogens are well absorbed and are released slowly over several hours. Degradation occurs very slowly in the liver, allowing for high intrinsic potency. Ethinyl estradiol reaches peak plasma levels within 2 hours. It is 98% bound to plasma proteins, and its half-life varies from 6 to 20 hours. Extensive first-pass metabolism occurs in the liver, where further metabolism and conjugation occur; excretion of the conjugates is in bile and urine.

Transdermal estradiol patches (e.g., Climara, Estraderm, Vivelle) allow for absorption of estrogen through the skin to the bloodstream. The transdermal route bypasses the liver; thus, the amount of estrogen received is less. With this route, patients experience less nausea and vomiting than with the oral route. Serum levels produced through transdermal application more closely mimic premenopausal estrogen levels compared with serum levels with oral estrogens. This form of estrogen reaches peak plasma levels within 4 hours, and its half-life is approximately 4 hours.

Action

Estrogens circulate in the bloodstream to target cells, where they enter cells and combine with receptor proteins in cell cytoplasm. After transport of the estrogen–receptor complex to the cell nucleus, this complex interacts with DNA to produce RNA and new DNA. These substances stimulate cell reproduction and production of various proteins. Estrogen primarily influences the reproductive system, although it also affects the skeletal, metabolic, and coagulation systems, as well as the skin and subcutaneous tissues.

Hormonal contraceptives that include estrogen act by several mechanisms. First, they inhibit hypothalamic secretion of GnRH, which inhibits pituitary secretion of FSH and LH. When these gonadotropic hormones are absent, ovulation and therefore conception cannot occur. Second, the drugs produce cervical mucus that resists penetration of spermatozoa into the upper reproductive tract. Third, the drugs interfere with endometrial maturation and reception of ova that are released and fertilized. These overlapping mechanisms make the drugs highly effective in preventing pregnancy.

Use

Indications for use of exogenous estrogens include the following:

Other uses of estrogens involve the treatment of moderate to severe vasomotor and atrophic symptoms associated with menopause, prevention of postmenopausal osteoporosis, and palliative treatment for metastatic breast carcinoma and advanced androgen-dependent prostatic cancer. Treatment of abnormal uterine bleeding caused by hormonal imbalance, in the absence of organic pathology, requires an intravenous injection. Table 44.1 presents dosage information for the various estrogens.

TABLE 44.1

DRUGS AT A GLANCE: Estrogens

The short-term use (1–2 years) of estrogens (sometimes synthetic) in postmenopausal women may be indicated for management of menopausal symptoms. Note that the long-term use of estrogen-only therapy and estrogen–progestin combinations is no longer recommended for most women because of potentially serious adverse effects.

Use in Children

There is little information about the effects of estrogens in children, and the drugs are not generally indicated for use in the pediatric age group. Because estrogens cause epiphyseal closure, caution is warranted with their use before completion of bone growth and attainment of adult height. When it is necessary to give hormonal contraceptives to adolescent girls, they should receive the smallest effective doses; this is also true in other populations.

Women who take a daily dose of a conjugated estrogen and medroxyprogesterone acetate regimen need education regarding the importance of breast self-examinations and recommendations for clinical breast examinations and mammography screening. It is essential that nurses teach patients to notify their health care providers if a breast lump is detected, because HRT must be discontinued until diagnostic procedures are complete.

Use in Patients With Renal Impairment

Estrogen use has been associated with fluid retention and dilated kidneys, especially when used in higher doses. Therefore, patients with renal impairment require close evaluation and management, and advanced impairment may be a contraindication.

Use in Patients With Hepatic Impairment

Impaired liver function may lead to impaired estrogen metabolism, with resultant accumulation and adverse effects.

Use in Patients With Critical Illness

Patients should avoid taking estrogen during a critical illness that results in limited mobility. There is an increased risk of thromboembolic disorders, such as thrombophlebitis, deep vein thrombosis, and pulmonary embolism.

Use in Patients Receiving Home Care

Patients usually self-administer estrogens. Home care nurses may encounter patients or family members who take an estrogen when visiting the home for another reason. It may be necessary to teach or assist patients to take the drugs as prescribed. In addition, patients may need encouragement to keep appointments for follow-up supervision and blood pressure monitoring. In families that include postmenopausal women, home care nurses may need to teach about nonhormonal strategies for preventing osteoporosis and cardiovascular disease.

Adverse Effects

The most serious adverse effect of estrogen use is the increased risk of thromboembolic conditions such as thrombophlebitis, pulmonary embolism, cerebral thrombosis, and coronary thrombosis. Estrogens promote blood clotting by stimulating hepatic production of four clotting factors (II, VII, IX, X). Thromboembolic disorders are most likely to occur in women older than 35 years of age who take oral contraceptives and smoke cigarettes, postmenopausal women taking long-term estrogen and progestin therapy, and men or women who receive large doses of estrogens for cancer treatment.

Other adverse effects of conjugated estrogens include menstrual disorders, such as breakthrough bleeding, dysmenorrhea, and amenorrhea due to the hormonal imbalance that may occur with estrogen use. GI upset, such as nausea, vomiting, abdominal cramps, and bloating, may occur. Nausea is most commonly associated with early estrogen use (within the first 1–2 weeks) and usually subsides. Sometimes, when high doses of estrogens are used, nausea and vomiting are severe enough to require administration of antiemetic drugs. Gallbladder disease is common with estrogen use. Postmenopausal women who take estrogen are two to four times more likely than those who do not to require surgery for gallbladder disease. Central nervous system adverse reactions such as migraine headache, dizziness, and mental depression may be caused or aggravated in some women. (The mechanism of action is unknown.) Edema and weight gain may occur due to fluid retention.

Cancer may be an effect of estrogen use. When estrogens are used alone in postmenopausal women, they cause endometrial hyperplasia and may cause endometrial cancer. Women with an intact uterus should also be given a progestin, which opposes the effects of estrogen on the endometrium. Opinions differ regarding estrogens as a cause of breast cancer. Most studies indicate little risk; a few indicate some risk, especially with high doses for prolonged periods (i.e., 10 years or longer). However, estrogens do stimulate growth in breast cancers that have estrogen receptors.

The U.S. Food and Drug Administration (FDA) has issued a BLACK BOX WARNING ♦ regarding estrogen use; supervised use at the lowest dose for the shortest duration should be prescribed. Estrogens are associated with the following: