Ovarian and Uterine Events
The menstrual cycle consists of a coordinated series of ovarian and uterine events. In the ovary, the following sequence occurs: (1) several ovarian follicles ripen; (2) one of the ripe follicles ruptures, causing ovulation; (3) the ruptured follicle evolves into a corpus luteum; and (4) if fertilization does not occur, the corpus luteum atrophies. As these ovarian events are taking place, parallel events take place in the uterus: (1) while ovarian follicles ripen, the endometrium prepares for nidation (implantation of a fertilized ovum) by increasing in thickness and vascularity; (2) after ovulation, the uterus continues its preparation by increasing secretory activity; and (3) if implantation fails to occur, the thickened endometrium breaks down, causing menstruation, and the cycle begins anew.
The Roles of Estrogens and Progesterone
The uterine changes that occur during the cycle are brought about under the influence of estrogens and progesterone produced by the ovaries. During the first half of the cycle, estrogens are secreted by the maturing ovarian follicles. As suggested by Fig. 48.1, these estrogens act on the uterus to cause proliferation of the endometrium. At midcycle, one of the ovarian follicles ruptures and then evolves into a corpus luteum. For most of the second half of the cycle, estrogens and progesterone are produced by the newly formed corpus luteum. These hormones maintain the endometrium in its hypertrophied state. At the end of the cycle, the corpus luteum atrophies, causing production of estrogens and progesterone to decline. In response to the diminished supply of ovarian hormones, the endometrium breaks down.
The Role of Pituitary Hormones
Two anterior pituitary hormones—follicle-stimulating hormone (FSH) and luteinizing hormone (LH)—play central roles in regulating the menstrual cycle. Precisely timed alterations in the secretion of these hormones are responsible for coordinating the structural and secretory changes that occur throughout the menstrual cycle. During the first half of the cycle, FSH acts on the developing ovarian follicles, causing them to mature and secrete estrogens. The resultant rise in estrogen levels exerts a negative feedback influence on the pituitary, thereby suppressing further FSH release. At midcycle, LH levels rise abruptly (see Fig. 48.1). This LH surge causes the dominant follicle to swell rapidly, burst, and release its ovum. After ovulation, the ruptured follicle becomes a corpus luteum and, under the influence of LH, begins to secrete progesterone.
Estrogens
Biosynthesis and Elimination
Females
In premenopausal women, the ovary is the principal source of estrogen. During the follicular phase of the menstrual cycle, estrogens are synthesized by ovarian follicles; during the luteal phase, estrogens are synthesized by the corpus luteum. The major estrogen produced by the ovaries is estradiol. In the periphery, some of the estradiol secreted by the ovaries is converted into estrone and estriol, hormones that are less potent than estradiol itself. Estrogens are eliminated by a combination of hepatic metabolism and urinary excretion.
During pregnancy, large quantities of estrogens are produced by the placenta. Excretion of these hormones results in high levels of estrogens in the urine.
Males
Estrogen production is not limited to females. In the human male, small amounts of testosterone are converted into estradiol and estrone by the testes. Enzymatic conversion of testosterone in peripheral tissues (e.g., liver, fat, skeletal muscle) results in additional estrogen production.
Mechanism of Action
Like other steroidal hormones (e.g., testosterone, cortisol), estrogen acts primarily through receptors in the cell nucleus, not on the cell surface. Hence, to produce its effects, estrogen must diffuse into cells, migrate to the nucleus, and then bind with an estrogen receptor (ER). The estrogen-ER complex then binds with an estrogen response element on a target gene, altering the rate of gene transcription. It is important to note that not all ERs are found in the nucleus: some ERs are found on cell membranes. Activating these surface receptors produces a rapid response—more rapid than can be produced by activating nuclear receptors.
There are two forms of ERs, termed ER alpha and ER beta. ER alpha is highly expressed in the vagina, uterus, ovaries, mammary glands, vascular epithelium, and hypothalamus. ER beta is expressed in the ovary and prostate and to a lesser extent in the lungs, brain, bones, and blood vessels. Some cells have both types of ER receptor.
Physiologic and Pharmacologic Effects
Effects on Primary and Secondary Sex Characteristics of Females
Estrogens support the development and maintenance of the female reproductive tract and secondary sex characteristics. These hormones are required for the growth and maturation of the uterus, vagina, fallopian tubes, and breasts. In addition, estrogens direct pigmentation of the nipples and genitalia.
Estrogens have a profound influence on physiologic processes related to reproduction. During the follicular phase of the menstrual cycle, estrogens promote (1) ductal growth in the breast, (2) thickening and cornification of the vaginal epithelium, (3) proliferation of the uterine epithelium, and (4) copious secretion of thickened mucus from endocervical glands. In addition, estrogens increase vaginal acidity (by promoting local deposition of glycogen, which is then acted on by lactobacilli and corynebacteria to produce lactic acid). At the end of the menstrual cycle, a decline in estrogen levels can bring on menstruation. However, it is the fall in progesterone levels at the end of the cycle that normally causes breakdown of the endometrium and resultant menstrual bleeding. After menstruation, estrogens promote endometrial restoration.
During pregnancy, the placenta produces estrogen in large amounts. This estrogen stimulates uterine blood flow and growth of uterine muscle. In addition, it acts on the breast to continue ductal proliferation. However, final transformation of the breast for milk production requires the combined influence of estrogen, progesterone, and human placental lactogen.
Metabolic Actions
Endogenous estrogens affect various nonreproductive tissues. Important among these are bone, cardiovascular, and central nervous system (CNS). They also have an important roles glucose homeostasis.
Bone
Estrogens have a positive effect on bone mass. Under normal conditions, bone undergoes continuous remodeling, a process in which bone mineral is resorbed and deposited in equal amounts. The principal effect of estrogens on the process is to block bone resorption, although estrogens may also promote mineral deposition.
During puberty, the long bones grow rapidly under the combined influence of growth hormone, adrenal androgens, and low levels of ovarian estrogens. When estrogen levels grow high enough, they promote epiphyseal closure and thereby bring linear growth to a stop.
Cardiovascular Effects
Cardiovascular disease is much less common in premenopausal women. Estrogens have several roles in lowering this risk. For example, estrogen receptors in the vascular smooth muscle respond to activation by decreasing vasoconstriction. Activation of estrogen receptors in vessel endothelium results in the production of nitric oxide, which results in vasodilation and increased perfusion. Estrogens also decrease atherosclerosis through favorable effects on cholesterol levels: levels of low-density lipoprotein (LDL) cholesterol are reduced, whereas levels of high-density lipoprotein (HDL) cholesterol are elevated.
Blood Coagulation
Estrogens both promote and suppress blood coagulation. Estrogens promote coagulation by (1) increasing levels of coagulation factors (e.g., factors II, VII, IX, X, and XII), and (2) decreasing levels of factors that suppress coagulation (e.g., antithrombin). Estrogens suppress coagulation by increasing the activity of factors that promote breakdown of fibrin, a protein that reinforces blood clots. The net effect—increased or decreased coagulation—may be determined by a hereditary defect in one of these targets.
Central Nervous System
In the CNS, estrogens have a neuroprotective effect by defending neurons from the effects of oxidative stress and injury. They also have a role in neuronal growth and repair through stimulation of nerve growth factors. Estrogen-induced synaptic changes, coupled with estrogen-promoted increases in synaptic serotonin, dopamine, and norepinephrine, are thought to preserve cognitive function, enhance short-term memory, and regulate mood. Cerebral perfusion is also enhanced by the release of nitric acid and the resulting vasodilation.
Glucose Homeostasis
Estrogens play an active role in maintaining glucose levels. In conditions that lead to insulin resistance due to impaired transport, estrogen has been shown to increase insulin sensitivity to promote glucose uptake. Estrogens also have a role in insulin secretion and are believed to protect pancreatic islet beta cells from certain types of injury.
Physiologic Alterations Accompanying Menopause
Menopause may occur as the result of surgery (i.e., surgical menopause associated with bilateral oophorectomy) or as the result of declining ovarian function associated with aging. Natural menopause typically begins at about age 51 to 52 years, with 95% of women entering menopause between the ages of 45 and 55 years. During the initial phase, the menstrual cycle becomes irregular, anovulatory cycles may occur, and periods of amenorrhea may alternate with menses. Eventually, ovulation and menstruation cease entirely. Production of ovarian estrogens decreases gradually, coming to a complete stop several years after menstruation has ceased.
Loss of estrogen has multiple effects. Prominent symptoms experienced by the patient include vasomotor symptoms, sleep disturbances, and urogenital atrophy. Additional physiologic changes include bone loss and altered lipid metabolism.
Vasomotor Symptoms
Vasomotor symptoms (hot flashes and night sweats) develop in about 70% of postmenopausal women. Episodes are characterized by sudden skin flushing, sweating, and a sensation of uncomfortable warmth. These episodes can occur at night, resulting in drenching sweats. Severe episodes can cause sleep disturbances, fatigue, and irritability. In most women, hot flashes abate within several months to a few years; in others, they may persist for a decade or more.
Urogenital Atrophy
Of all structures in the body, the urethra and vagina have the highest concentrations of estrogen receptors. Activation of these receptors maintains the functional integrity of the urethra and vaginal epithelium. Hence, when estrogen levels decline during menopause, these structures undergo degenerative change. Atrophy of the urethra causes urge incontinence and urinary frequency. Urethritis and urinary tract infections can also occur. Atrophy of the vaginal epithelium can lead to dryness and pain with intercourse. In addition, alterations in vaginal secretions result in decreased acidity, which can allow the growth of pathogenic bacteria, resulting in vaginal infections.
Mental Changes
Many women report cognitive changes such as difficulty in problem solving and short-term memory loss around the time when menopause begins. Others experience depression or an increase in anxiety. These, also, tended to occur during the time of transition and often compounded sleep disturbances.
Bone Loss
In the absence of estrogen, bone resorption accelerates, leading to a 12% loss of bone density shortly after menopause. Osteoporosis is characterized by bone demineralization, altered bone architecture, and reduced bone strength. Compression fractures of the vertebrae are common and can decrease height and produce a hump. In osteoporotic women, fractures of the hip and wrist can result from minimal trauma.
Altered Lipid Metabolism
Studies have demonstrated slight, but significant, increases in LDL cholesterol with concomitant decreases in HDL cholesterol. These are thought to have a role in the increase in cardiovascular disease that increases after menopause.
Clinical Pharmacology
Now that we have reviewed the effects of endogenous estrogens, let’s examine how estrogen preparations are used clinically. We’ll begin with a discussion of how these drugs are used.
Therapeutic Uses
Estrogens have contraceptive and noncontraceptive applications. In this chapter, discussion is limited to the noncontraceptive applications. Use of estrogens for contraception is discussed in Chapter 49.
Menopausal Hormone Therapy
Hormone therapy in postmenopausal women is the most common noncontraceptive use of estrogens. When estrogen is used for this purpose, it is usually accompanied by the use of progestins. For this reason, we will cover hormone therapy after the discussion of progestins.
Female Hypogonadism
In the absence of ovarian estrogens, pubertal transformation will not take place. Causes of estrogen deficiency include primary ovarian failure, hypopituitarism, bilateral oophorectomy (removal of both ovaries), and Turner syndrome (a genetic disorder that impairs gonadal function). In girls with estrogen insufficiency, puberty can be induced by giving exogenous estrogens. This treatment promotes breast development, maturation of the reproductive organs, and development of pubic and axillary hair. To simulate normal patterns of estrogen secretion, the regimen should consist of continuous low-dose therapy (for about a year) followed by cyclic administration of estrogen in higher doses. Estrogen therapy for these conditions is typically managed by specialists.
Acne
Estrogens, in the form of oral contraceptives, can help control acne. Treatment is limited to patients at least 14 or 15 years old who want contraception. Use of estrogen for acne is discussed in Chapter 85.
Cancer Palliation
Estrogens are sometimes used for palliative therapy in management of advanced prostate cancer in men and in a select type of metastatic breast cancer in both men and women. This use is directed by an oncologist or other specialist in this field.
Adverse Effects
The principal concerns with estrogen therapy are the potential for endometrial hyperplasia, endometrial cancer, breast cancer, and cardiovascular thromboembolic events. Of these, the potential for endometrial hyperplasia and endometrial cancer can be resolved by prescribing a progestin, if indicated.
Estrogens have been associated with gallbladder disease, jaundice, and headache. Use during menopause may produce or uncover gallbladder disease. Jaundice may develop in women with preexisting liver dysfunction, especially those who experienced cholestatic jaundice of pregnancy. Estrogens can increase the risk for headache, especially migraine.
Nausea is the most frequent undesired response to the estrogens. Fortunately, nausea diminishes with continued use and is rarely so severe as to necessitate treatment cessation. Fluid retention with edema commonly occurs. Most other adverse effects are more of a nuisance (e.g., chloasma, a patchy brown facial discoloration) than a concern.
Contraindications
Estrogens should not be taken by patients with a history of deep vein thrombosis (DVT), pulmonary embolus, or conditions such as stroke or myocardial infarction (MI) that occurred secondary to a thromboembolic event. They should not be prescribed to women who are pregnant or who have vaginal bleeding without a known cause. Patients with a history of liver disease, estrogen-dependent tumors, or breast cancer (except when indicated for management) also should not take estrogens.
Interactions
Estrogens are major substrates of CYP1A2 and CYP3A4. Inducers of these isoenzymes may lower estrogen levels, whereas drugs that are inhibitors may raise estrogen levels. Additionally, they may decrease the effectiveness of some antidiabetic drugs and thyroid preparations. Estrogens can also interact with anticoagulants and other drugs that affect clotting.
Preparations and Routes of Administration
Estrogen is available in conjugated and esterified forms. Esterified estrogens are plant based; conjugated estrogens are natural preparations derived from the urine of pregnant horses. Until mid-2016 synthetic conjugated estrogens A [Cenestin] and B [Enjuvia] were available; however, the manufacturer has withdrawn them from the market. At the time of this writing, there is no generic substitution for these synthetic conjugated estrogens.
Oral
Owing to convenience, the oral route is used more than any other. The most active estrogenic compound—estradiol—is available alone and in combination with progestins.
Transdermal
Transdermal estradiol is available in four formulations:
• Gels [EstroGel, Elestrin, Divigel]
• Patches [Alora, Climara, Estraderm, Menostar, Vivelle-Dot, Oesclim 
]
Application is specific to certain body regions. The emulsion is applied once daily to the top of both thighs and the back of both calves. The spray is applied once daily to the forearm. The gel is applied once daily to one arm, from the shoulder to the wrist or to the thigh (Divigel). The patches are applied to the skin of the trunk (but not the breasts). Rates of estrogen absorption with transdermal formulations range from 14 to 60 mcg/24 hr, depending on the product employed.
Compared with oral formulations, the transdermal formulations have four advantages:
Intravaginal
Estrogens for intravaginal administration are available as tablets, creams, and vaginal rings. The tablets [Vagifem], creams [Estrace Vaginal, Premarin Vaginal], and one of the two available vaginal rings [Estring] are used only for local effects, primarily treatment of vulval and vaginal atrophy associated with menopause. The other vaginal ring [Femring] is used for systemic effects (e.g., control of hot flashes and night sweats) as well as local effects (e.g., treatment of vulval and vaginal atrophy).
Selective Estrogen Receptor Modulators
Selective estrogen receptor modulators (SERMs) are drugs that activate estrogen receptors in some tissues and block them in others. These drugs were developed in an effort to provide the benefits of estrogen (e.g., protection against osteoporosis, maintenance of the urogenital tract, reduction of LDL cholesterol) while avoiding its drawbacks (e.g., promotion of breast cancer, uterine cancer, and thromboembolism). Four SERMs are available: tamoxifen [Nolvadex-D], toremifene [Fareston], raloxifene [Evista], and bazedoxifene [Duavee]. None of these offers all of the benefits of estrogen, and none avoids all of the drawbacks.
Tamoxifen was the first SERM to be widely used. By blocking estrogen receptors, tamoxifen (and its active metabolite, endoxifen) can inhibit cell growth in the breast. As a result, the drug is used extensively to prevent and treat breast cancer. Unfortunately, blockade of estrogen receptors also produces hot flashes. By activating estrogen receptors, tamoxifen protects against osteoporosis and has a favorable effect on serum lipids. However, receptor activation also increases the risk for endometrial cancer and thromboembolism. The pharmacology of tamoxifen and toremifene (a close relative of tamoxifen) is discussed in Chapter 82.
Raloxifene is very similar to tamoxifen. The principal difference is that raloxifene does not activate estrogen receptors in the endometrium and hence does not pose a risk for uterine cancer. Like tamoxifen, raloxifene protects against breast cancer and osteoporosis, promotes thromboembolism, and induces hot flashes. Raloxifene is approved only for prevention and treatment of osteoporosis and for prevention of breast cancer in high-risk women. Raloxifene is discussed at length in Chapter 59.
In 2013, the U.S. Food and Drug Administration (FDA) approved Duavee (conjugated estrogens/bazedoxifene) for prevention of vasomotor symptoms and osteoporosis in postmenopausal women with a uterus. Duavee is the first drug to combine estrogen with an estrogen agonist/antagonist (bazedoxifene). The bazedoxifene component of Duavee reduces the risk for excessive growth of the lining of the uterus that can occur with the estrogen component. Contraindications to taking Duavee are the same as for other estrogen-containing products.
