Hormone Therapy in Women
Menopause is the permanent cessation of menses following the loss of ovarian follicular activity. Perimenopause is the transitional period prior to and the first year after menopause, which lasts a total of approximately 5 years.
Approved indications of postmenopausal hormone therapy include the usually short-term treatment of menopausal symptoms (i.e., hot flushes, night sweats, and urogenital atrophy) and long-term treatment for osteoporosis prevention.
The hypothalamic-pituitary-ovarian axis controls reproductive physiology through the reproductive years. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH), produced by the pituitary in response to gonadotropin-releasing hormone (GnRH) from the hypothalamus, regulate ovarian function. Gonadotropins are also influenced by negative feedback from the sex steroids estradiol (produced by the dominant follicle) and progesterone (produced by the corpus luteum). Other sex steroids are androgens, primarily testosterone and androstenedione, secreted by the ovarian stroma and the adrena gland.
Pathophysiologic changes associated with menopause are caused by loss of ovarian follicular activity. The postmenopausal ovary is no longer the primary site of estradiol or progesterone synthesis.
As women age, circulating FSH progressively rises and ovarian inhibin declines. Menopause is characterized by a 10- to 15-fold increase in circulating FSH compared with follicular phase concentrations, a four- to fivefold increase in LH, and 90% decrease in estradiol.
Diagnosis of Menopause :
- Menopause is determined retrospectively after 12 consecutive months of amenorrhea.
- The diagnosis of menopause should include a comprehensive medical history and physical examination, complete blood count, and measurement of serum FSH. When ovarian function has ceased, serum FSH concentrations exceed 40mIU/mL. Altered thyroid function and pregnancy must be excluded.
Treatment of Menopause :
Nonpharmacologic Treatment :
- Mild menopausal symptoms can often be alleviated by lifestyle modification, weight control, smoking cessation, exercise, and a healthy diet.
- Mild vaginal dryness can sometimes be relieved by nonestrogenic vaginal creams, but significant vaginal dryness often requires local or systemic estrogen therapy.
- Current data suggest that phytoestrogens are no more effective than placebo for hot flushes or other symptoms of menopause.
- Phytoestrogens decrease low-density lipoprotein (LDL) and triglyceride concentrations, do not change high-density lipoprotein (HDL) concentrations, and may improve bone density. Adverse effects include constipation, bloating, and nausea.
- The three main classes of phytoestrogens (and common food sources) are isoflavones (soybeans), lignans (cereals and oilseeds such as flaxseed), and coumestans (alfalfa sprouts). The biologic potency of phytoestrogens varies and is less than that of synthetic estrogen.
- Black cohosh has been shown to be effective for vasomotor symptoms in some randomized controlled trials, but it does not appear to have strong intrinsic estrogenic properties and may act through the serotonergic system.
Hormonoal Regimens :
- In women with intact uterus, hormone therapy consists of an estrogen plus a progestogen. In women who have undergone hysterectomy, estrogen therapy is given unopposed by a progestogen.
- The continuous combined oral estrogen-progestogen arm of the Women’s Health Initiative (WHI) study was terminated prematurely after a mean of 5.2-year follow-up because of the occurrence of a prespecified level of invasive breast cancer. The study also found increased coronary disease events, stroke, and pulmonary embolism. Beneficial effects included decreases in hip fracture and colorectral cancer.
- The oral estrogen-alone arm was stopped early after a mean of 7 years of follow-up. Estrogen-only therapy had no effect on coronary heart disease risk and caused no increase in breast cancer risk.
- A subsequent large epidemiologic study found a greater risk for breast cancer with combined estrogen-progestogen use, as well as increased risk for estrogen-only therapy and tibolone.
- The oral and transdermal routes are used most frequently. There is no evidence that one strogen compound is more effective than another in relieving menopausal symptoms or preventing osteoporosis.
- Estradiol is the predominant and most active form of endogenous estrogens. Given orally, it is metabolized, and only 10% reaches the circulation as free estradiol, and estrone concentrations are 3 to 6 times those of estradiol.
- Ethinyl estradiol is a semisynthetic estrogen that has similar activity following administration by the oral and parenteral routes.
- Parenteral estrogens, including transdermal, intranasal, and vaginal, avoid first-pass metabolism and result in a more physiologic estradiol-to-estrone ratio, i.e., estradiol concentrations greater than estrone concentrations. These routes also are less likely to affect sex hormone-binding globulin, circulating lipids, coagulation parameters, or C-reactive protein levels.
- Variability in absorption is common with the percutaneous preparations (gels, creams, and emulsions).
- Estradiol pellets (implants) contain pure crystalline 17 Î²-estradiol and are placed subcutaneously into the anterior abdominal wall or buttock. They are difficult to remove.
- intranasal 17 Î²-estradiol spray is given once or twice daily, and is clinically equivalent to oral or transdermal estradiol, but causes less mastalgia.
- Vaginal creams, tablets, and rings are used for treatment of urogenital atrophy. Systemic estrogen absorption is lower with the vaginal tablets and rings, compared to the vaginal creams.
- Adverse effects of estrogen include nausea, headache, breast tenderness, and heavy bleeding. More serious adverse effects include increased risk for coronary heart disease, stroke, venous thromboembolism, breast cancer, and gallbladder disease. Transdermal estrogen is less likely than oral estrogen to cause nausea, headache, breast tenderness, and deep vein thrombosis.
- In women who have not undergone hysterectomy, progestin should be added because estrogen monotherapy is associated with endometrial hyperplasia and cancer.
- The most commonly used oral progestogens are medroxyprogesterone acetate, micronized progesterone, and norethisterone acetate.
- Several progestogen regimens to prevent endometrial hyperplasia.
- Four combination estrogen and progestogen regimens are currently in use.
- Continuous-cyclic (sequential) results in scheduled vaginal bleeding in 90% of women.
- Continuous-combined prevents monthly bleeding. It may initially cause unpredictable spotting or bleeding; thus, it is best reserved for women who are at least 2 years postmenopause.
- Continuous long-cycle (cyclic withdrawal) reduces monthly bleeding. Estrogen is given daily, and progestogen is given 6 times yearly (every other month) for 12 to 14 days, resulting in 6 periods/year.
- Intermittent-combined (continuous-pulsed)â€”prevents monthly bleeding. It consists of 3 days of estrogen therapy alone, followed by 3 days of combined estrogen and progestogen, which is then repeated without interruption. It may cause fewer side effects than regimens with higher progestogen doses.
- Adverse effects of progestogens are irritability, depression, headache, mood swings, fluid retention, and sleep disturbance.
- The therapeutic use of testosterone in women, although controversial, is becoming more widespread. There is evidence that androgen therapy, usually testosterone, is effective in alleviating some symptoms of androgen insufficiency including loss of sexual desire, diminished well-being, loss of energy, decreased bone mass, and reduced muscle strength.
- Testosterone treatment should not be given to postmenopausal women who are not receiving concurrent estrogen.
- Testosterone is generally accepted for women who have had surgical menopause, but may also be considered for naturally menopausal women and those with premature ovarian failure.
- Estrogen combined with androgen improves sexual activity and satisfaction and increases bone density sooner and to a greater degree than does estrogen monotherapy.
- Testosterone appears safe when given in doses that achieve circulating serum free testosterone concentrations within the physiologic range for young reproductive women. There are no data on the effects of exogenous androgen therapy on the incidence of breast cancer.
- Relative contraindications to testosterone therapy are moderate to severe acne, clinical hirsutism, and androgenic alopecia. Absolute contraindications to androgen replacement include pregnancy or lactation and known or suspected androgen-dependent neoplasia.
- Adverse effects from excessive dosage include virilization, fluid retention, and adverse lipoprotein lipid effects, which are more likely with oral administration.