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Chapter: Modern Pharmacology with Clinical Applications: Estrogens, Progestins, and Specific Estrogen Receptor Modulators (SERMs)

Selective Estrogen Receptor Modulators (SERMs): Clinical Uses

The chief therapeutic uses of estrogens and progestins are as oral contraceptives and hormone replacement therapy. Progestins and SERMs are also important agents in the treatment of osteoporosis, breast cancer, endometrial cancer, and infertility.



The chief therapeutic uses of estrogens and progestins are as oral contraceptives and hormone replacement therapy. Progestins and SERMs are also important agents in the treatment of osteoporosis, breast cancer, endometrial cancer, and infertility.

Oral Contraception


Oral contraceptives are among the most effective forms of birth control (Table 61.1). The most widely used type of oral contraceptive in the United States today is the combination preparation, that is, a combination of es-trogen and progestin (Table 61.2). Users take a tablet daily that contains both an estrogen and a progestin for 20 to 21 days of the menstrual cycle and then nothing or a placebo for the remainder of the cycle or the next 7 to 8 days. Withdrawal bleeding occurs 2 to 3 days after dis-continuation of this regimen. Combination preparations vary in the dose of synthetic estrogen and progestin they contain. The use of sequential and triphasic oral contraceptives minimizes the overall dose of hormone delivered. 


These preparations are designed to more closely simulate estrogen-to-progestin ratios that occur physiologically during the menstrual cycle. Ethinyl estradiol and mestranol are the only two estrogen con-stituents used for oral contraception in the United States. The use of ethinyl estradiol is favored. Mestranol is in-active until it is metabolized to ethinyl estradiol.


Several progestins are used in combination prod-ucts. Norgestrel (Ovrette) is a mixture of active and in-active enantiomers; levonorgestrel (Norplant) is the ac-tive enantiomer. Levonorgestrel and norethindrone are the most potent synthetic progestins in oral contracep-tive preparations.


Inhibition of ovulation is the primary mechanism of the contraceptive action of sequential and combination birth control preparations. Ovulation is prevented by the suppression of the midcycle surge of FSH and LH. Estrogens are most active in inhibiting FSH release, but at high enough doses, they also inhibit LH release. In low-dose combination products, the progestin causes LH suppression. The progestin component is also important in causing withdrawal bleeding at the end of the cycle.


Combination oral contraceptive drugs having the lowest effective concentration of both estrogen and progestin should be prescribed. These preparations are known as low-dose oral contraceptive agents. Adverse effects of both estrogen and progestin are minimized with the use of these agents.


Clinical experience with the low-dose combination drugs indicates that the estrogen-to-progestin ratio is critical in achieving maximum contraceptive activity. In certain combinations (Ortho-Novum 7/7/7, Tri-Norinyl, Tri-Levlen, Triphasil), the estrogen-to-progestin ratio is varied in three phases over the initial 21 days by chang-ing the progestin content of the tablets. An example of the estrogen and progestin doses found in this type of oral contraceptive is shown in Table 61.3.


Progestin-only oral contraceptive formulations consist of a low dose of either norethindrone or norgestrel (Table 61.2). 

Because of an increased incidence of cer-tain side effects and slightly decreased contraceptive ac-tivity, progestin-only oral contraceptives are not exten-sively used. The undesirable side effects associated with progestin-only contraceptives are irregular bleeding episodes, headache, weight gain, and mood changes. Progestin-only contraceptive devices are used. The Norplant System for contraception consists of a series of levonorgestrel-filled pliable plastic tubes that are im-planted subcutaneously on the inside of the upper arm by a physician. While one set of six tubes can remain ef-fective for up to 5 years, the contraceptive effects are readily reversible with removal of the implant. Adverse effects are similar to those seen with other progestin-only contraceptives; however, accidental pregnancy is less frequent.


Mirena is a relatively new intrauterine contraceptive device that releases levonorgestrel into the uterine cav-ity for 5 years. Use of this contraceptive device is asso-ciated with fewer systemic progestin side effects and is at least as effective as Norplant.


Abortifacients and Emergency Contraceptives


Progesterone is a hormone required for the mainte-nance of pregnancy. Termination of early pregnancy is effected using the steroidal antiprogestin drug, mifepri-stone (RU486), which acts by blocking progestin bind-ing to the progesterone receptor. A single oral dose of RU486 followed by a single dose of a prostaglandin (Misoprostol) 48 hours later is 90 to 95% effective in terminating pregnancy. The side effects are generally mild except for heavy bleeding. Severe cardiovascular complications have occurred and may be due to the prostaglandin component of this treatment. The use of RU486 is therefore contraindicated in women at risk for cardiovascular disease, including smokers and women over 35 years of age.


High-dose estrogen and high-dose progestin are ef-fective in emergency contraception when given immedi-ately following unprotected coitus. Plan B is an emer-gency contraceptive kit consisting of two tablets of the progestin levonorgestrel (0.75 mg). The first tablet must be taken as soon as possible but no later than 3 days af-ter coitus, and the second tablet is taken 72 hours later. This regimen is more effective and better tolerated than the Preven emergency contraceptive kit, an estrogen– progestin combination (two tablets of 50 g ethinyl estradiol and two tablets of 0.25 mg of levonorgestrel). The high doses of estrogen in the Preven regimen are as-sociated with severe nausea and vomiting.


Hormone Replacement Therapy


The beginning of menopause is marked by the last men-strual cycle. This is the result of declining ovarian func-tion and reduced synthesis of estrogens and proges-terone. Estrogen production in postmenopausal women is usually only about 10% of that in premenopausal women. Almost no progesterone is synthesized in post-menopausal women. Hormone replacement therapy (HRT) generally refers to the administration of estrogen– progestin combinations. Estrogen replacement therapy (ERT) consists of the use of an estrogen alone, usually in the form of conjugated equine estrogens or an estro-gen transdermal patch.


The four most common symptoms associated with menopause are vasomotor disorders, or hot flashes; uro-genital atrophy; osteoporosis; and psychological distur-bances. A varying proportion of women may have one or more of these symptoms.




One in four postmenopausal women have osteoporosis. Osteoporosis, a decrease in bone mass, constitutes the most serious effect of menopause. It has been estimated that following cessation of ovarian function, the loss of bone mass proceeds at a rate of 2 to 5% per year. As a result of osteoporosis, as many as 50% of women de-velop spinal compression fractures by age 75, and 20% will have hip fractures by age 90.


Estrogen replacement therapy can prevent bone loss and actually increase bone density in postmenopausal women. Estrogen treatment is the most effective therapy for osteoporosis and significantly reduces the incidence of bone fractures in postmenopausal women. The usual dose of estrogen prescribed is 0.625 mg/day of conju-gated equine estrogens (Premarin). Alternatively, a transdermal estrogen patch can be used.


Endometrial cancer is not a concern in women who have undergone hysterectomy. However, in women with an intact uterus, there is a risk of endometrial cancer with ERT. A preliminary endometrial biopsy should be performed before instituting therapy to rule out en-dometrial hyperplasia or cancer, and biopsies should be repeated at 6- to 12-month intervals in women receiving ERT. When endometrial cancer is a concern, patients should consider HRT. Estrogens should be given in an intermittent fashion followed by at least 7 to 10 days of treatment with a progestin alone. Oral norgestimate, norethindrone acetate, and medroxyprogesterone ac-etate are progestins given to postmenopausal women re-ceiving estrogens to control endometrial proliferation.


Alternatives to steroid hormone therapy for osteo-porosis include raloxifene, bisphosphonates, sodium fluoride, vitamin D and calcium supplementation, calci-tonin, and parathyroid hormone. Tamoxifen has estro-genic effects on bone and delays bone loss in post-menopausal women. However as a result of estrogenic activity in the uterus, long-term tamoxifen adminis-tration has been associated with an increased risk of endometrial cancer. Raloxifene has estrogenic activity on bone but antiestrogenic activity in uterus and breast tis-sue. Raloxifene is a SERM that was specifically approved for the prevention and treatment of osteoporosis.


Cardiovascular Actions


Declining estrogen levels associated with menopause are correlated with an increased risk of cardiovascular re-lated deaths in women. The protective effects of estro-gens on the lipid profile are well recognized. There is a relationship between elevated levels of cholesterol, triglycerides, very low density lipoproteins, low-density lipoproteins, and coronary artery disease; in contrast, the elevation of high-density lipoproteins appears to be related to a reduced incidence of cardiovascular effects. The hormonal effects produced by estrogen and pro-gestin therapy vary with the dosage, duration, route of administration, and particular preparation. In general, estrogenic compounds lower levels of “bad cholesterol” (low-density lipoproteins), while progestins raise low-density lipoproteins and triglycerides.


The use of HRT for mitigation of cardiovascular dis-ease is not supported by the most recent clinical studies. The use of estrogen–progestin combinations in post-menopausal women was associated with a slight in-crease in coronary artery disease and a threefold eleva-tion in thromboembolic episodes.


Conjugated equine estrogens (Premarin) are the most commonly used estrogens in the treatment of menopause-associated vasomotor symptoms and os-teoporosis. Premarin is a mixture of estrogen sulfates, including estrone, equilin, and 17- -dihydroequilin. The sulfate derivatives are orally active and are cleaved within the body to yield the active, unconju-gated estrogen.


Premphase is an estrogen–progestin combination that introduces a cyclic progestin component. Prem-phase packets consist of a 2-week regimen of daily 0.625-mg conjugated equine estrogens followed by a 2-week period of a combination of conjugated equine es-trogens and daily medroxyprogesterone. Esterified es-trogens, primarily sodium estrone sulfate (Estratab), and estropipate (Ogen) are also used. Several transder-mal patches deliver estradiol continuously. These prod-ucts differ in their dose of estradiol: Climara, 0.025 mg/day; Estraderm, 0.05 mg/day; and Vivelle, 0.0375 mg/day.



Vasomotor Symptoms


Vasomotor disorders (hot flashes) are common, affect-ing 70 to 80% of postmenopausal women. The cause of the vasomotor changes appears to be associated with the release of LH after normal female estrogen levels have fallen. These symptoms occur with variable frequency but generally disappear without treatment within 2 to 3 years of onset. Estrogen or progestin therapy is often ef-fective in suppressing vasomotor symptoms. Short-term estrogen therapy (2 years) for these symptoms is recom-mended and is not associated with increased cancer risk. Continuous therapy is usually not required.


Urogenital Atrophy


The tissues of the distal vagina and urethra are of simi-lar embryonic origin, and both are sensitive to the trophic action of estrogens. Postmenopausal atrophy of these tissues may result in painful sexual intercourse, dysuria, and frequent genitourinary infections. Unlike the vasomotor complaints, these symptoms seldom im-prove if untreated. Treatment with a combination of minimally effective dosages of an estrogen and a prog-estin is recommended. Estrogen can be administered orally or in a topical preparation with equivalent effi-cacy. Progestins are given orally.


Replacement Therapy in Premenopausal Women


Oophorectomy causes many of the symptoms seen in menopause. The onset and intensity of vasomotor symp-toms and osteoporosis, however, may be more severe than in women proceeding into the more gradual age-associated process of menopause. The regimens for estrogen–progestin replacement therapy in oophorec-tomized patients are comparable to those recom-mended for postmenopausal women.


Several genetic conditions lead to a failure of ovar-ian development. These genetic alterations lead to a failure in the synthesis of normal amounts of estrogen or progesterone, so that female secondary sex charac-teristics do not appear at puberty. Only with estrogen treatment is there stimulation of the growth of the gen-italia, breast enlargement, and development of female body contours and distribution of body hair. Some in-creases in body height also occur with estrogen therapy, but this is more marked after androgen treatment. Replacement estrogens can be administered using a transdermal patch formulation or micronized estradiol (Estrace, Gynodiol).



Central Nervous System Effects


Insomnia and fatigue in many postmenopausal women may be related to reduced estrogen levels; there is a cor-relation between the incidence of waking episodes and low levels of estrogen. Estrogen replacement therapy may be used to treat severe cases.


There is considerable interest in the role of estrogen hormone replacement therapy as a cognitive enhancer in postmenopausal women. Although there is some evi-dence for improved cognitive abilities in postmeno-pausal women receiving estrogen replacement therapy, the effects reported thus far are modest.



Anovulation, often related to altered ratios of estrogen to progestin, can be treated with a variety of agents, in-cluding estrogen–progestin replacement, clomiphene citrate, bromocriptine, FSH, LH, human chorionic go-nadotropin, and GnRH. Clomiphene citrate (Clomid, Serophene) and bromocriptine (Parlodel) are the two most widely used agents.


Induction of Ovulation


Anovulation can be due to an insufficient release of LH and FSH during the mid phase of the menstrual cycle. Induction of ovulation by clomiphene citrate is the re-sult of stimulation of FSH and LH release. The mecha-nism of this action is probably related to the estrogen antagonist properties of clomiphene citrate. Although estrogens generally exert a negative-feedback inhibi-tion on FSH and LH secretion by means of a suppres-sion of GnRH from the hypothalamus, clomiphene ex-erts its action by stimulating secretion of these hormones. Antagonism of this feedback system results in a surge of FSH and LH secretion, hence ovulation.


Patients with normal or elevated estrogen levels and normal pituitary and hypothalamic function respond most frequently to treatment with clomiphene citrate. In this group, the ovulation rate following clomiphene citrate may be 80%. Clomiphene citrate is administered on a cyclic schedule. First, menstrual bleeding is in-duced; next drug is given orally for 5 days at 50 mg/day. Ovulation is expected 5 to 11 days after the dose of clomiphene citrate. Pregnancy rates approach 50 to 80% after six such treatment cycles, with most pregnan-cies occurring during the first three treatment cycles. Clomiphene is also used in conjunction with go-nadotropins to induce ovulation for in vitro fertiliza-tion.


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