Hormone Replacement Therapy

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The beginning of menopause is marked by the last menstrual cycle. This is the result of declining ovarian func tion and reduced synthesis of estrogens and progesterone. Estrogen production in postmenopausal women is usually only about 10% of that in premenopausal women. Almost no progesterone is synthesized in postmenopausal 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 estrogen transdermal patch.

The four most common symptoms associated with menopause are vasomotor disorders, or hot flashes; urogenital atrophy; osteoporosis; and psychological disturbances. 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 develop 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 conjugated 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 acetate are progestins given to postmenopausal women receiving estrogens to control endometrial proliferation.

Alternatives to steroid hormone therapy for osteoporosis 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 administration has been associated with an increased risk of endometrial cancer. Raloxifene has estrogenic activity on bone but antiestrogenic activity in uterus and breast tissue. 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 related deaths in women. The protective effects of estrogens 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 progestin 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 disease is not supported by the most recent clinical studies. The use of estrogen-progestin combinations in post-menopausal women was associated with a slight increase in coronary artery disease and a threefold elevation in thromboembolic episodes.

Conjugated equine estrogens (Premarin) are the most commonly used estrogens in the treatment of menopause-associated vasomotor symptoms and osteoporosis. Premarin is a mixture of estrogen sulfates, including estrone, equilin, and 17-p-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. Premphase 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 estrogens and daily medroxyprogesterone. Esterified estrogens, primarily sodium estrone sulfate (Estratab), and estropipate (Ogen) are also used. Several transdermal patches deliver estradiol continuously. These products 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, affecting 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 effective in suppressing vasomotor symptoms. Short-term estrogen therapy (2 years) for these symptoms is recommended 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 similar 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 improve if untreated. Treatment with a combination of minimally effective dosages of an estrogen and a progestin is recommended. Estrogen can be administered orally or in a topical preparation with equivalent efficacy. Progestins are given orally.

Replacement Therapy in Premenopausal Women

Oophorectomy causes many of the symptoms seen in menopause. The onset and intensity of vasomotor symptoms 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 recommended for postmenopausal women.

Several genetic conditions lead to a failure of ovarian development. These genetic alterations lead to a failure in the synthesis of normal amounts of estrogen or progesterone, so that female secondary sex characteristics do not appear at puberty. Only with estrogen treatment is there stimulation of the growth of the genitalia, breast enlargement, and development of female body contours and distribution of body hair. Some increases 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 correlation 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 evidence 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, including estrogen-progestin replacement, clomiphene citrate, bromocriptine, FSH, LH, human chorionic gonadotropin, 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 result of stimulation of FSH and LH release. The mechanism of this action is probably related to the estrogen antagonist properties of clomiphene citrate. Although estrogens generally exert a negative-feedback inhibition on FSH and LH secretion by means of a suppression of GnRH from the hypothalamus, clomiphene exerts 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 induced; 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 pregnancies occurring during the first three treatment cycles. Clomiphene is also used in conjunction with gonadotropins to induce ovulation for in vitro fertilization.

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  • kye stevenson
    How is clomid and serophene equine estrogen?
    4 years ago

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