Gynecology: Menopause

Guest · **posting in usmle forum about Obstetrics & Gynecology**

Menopause is the physiologic cessation of menses due to diminished ovarian function. By definition, the diagnosis is made after 6 months of amenorrhea. Hormone replacement may abolish many of the symptoms and may prevent further health risks including osteoporosis and possibly cardiovascular disease.

1. Clinical Features:
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Average age 51 years: Symptoms begin in premenopausal years and progress as estrogen and progesterone levels decrease. Vasomotor symptoms: Hot flashes, night sweats. Atrophic symptoms: Vaginal dryness, pruritus, irritation, and dyspareunia; urinary frequency, dysuria, incontinence and increased incidence of cystitis. Emotional symptoms: Lability, irritability, depression, and insomnia. Increased risk of coronary artery disease. Osteoporosis: 50% of postmenopausal bone loss occurs in the first 7 years; resultant fractures (hip, vertebral) are a major cause of increased morbidity and mortality.

2. Hormone Replacement Therapy (HRT):
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1. Estrogen:
1. Benefits:
1. Short-term (months): estrogen effectively controls perimenopausal vasomotor and psychologic symptoms. There are few risks for short-term use beyond venous thromboembolism and endometrial stimulation.

2. Long-term (years): estrogen prevents osteoporosis, decreases osteoporotic fractures, controls atrophic symptoms.

3. Cardiac effects: The overall effect of estrogen/progesterone replacement on the development of cardiac disease is unclear. The HERS trial (a large randomized controlled trial of estrogen/progesterone HRT versus placebo in women with established coronary artery disease) showed that estrogen is ineffective in secondary prevention. In fact, there was an increase in cardiac events in the first year on hormones but a decrease in cardiac events in years 4 and 5 yielding no overall benefit. Patients already on estrogen for cardiac protection may elect to continue it, but new patients should not be counseled to start estrogen specifically for cardioprotection pending further data.

2. Risks:
1. Endometrial hyperplasia or neoplasia risk doubles if estrogen is used alone; however, when progestin is added, there is less risk of these cancers than in non-hormonally treated patients.

2. Breast cancer: Most recent data indicate that relative risk of invasive breast cancer is about 1.46 in those taking estrogen and progesterone for 5 years or greater, but the excess cancers tend to be less aggressive and are caught earlier, so mortality appears unchanged or decreased. Adding progesterone does not reduce the risk of breast cancer and may increase it.

3. Thromboembolic disease: relative risk is about 2.9 in the first year of therapy.

4. Gallbladder disease risk may be doubled with estrogen.

5. Contraindications include unexplained vaginal bleeding, active liver disease or chronically impaired liver function, carcinoma of the breast, endometrial carcinoma, recent vascular thrombosis, or past history of thromboembolic disease with previous hormone therapy.

6. Relative contraindications include hypertension, uterine leiomyomas, migraine headaches, familial hyperlipidemia, hypertriglyceridemia, endometriosis, and gallbladder disease, close family history of venous thromboembolism (consider work-up before starting estrogen).

3. Initial assessment:
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1. History including family history, focusing on areas of risk and benefit from HRT.

2. Physical exam highlighting breast and pelvic exam.

3. Pap smear at baseline and annually thereafter.

4. Mammogram at baseline and annually.

5. FSH measurement: if the patient is clearly menopausal, with amenorrhea x 6 months and/or compatible vasomotor symptoms, confirmation with serum FSH is not necessary. If the clinical picture is unclear, check FSH and start HRT if FSH >30. For women on oral contraceptives, look for hot flashes during the placebo week or check FSH on the 6th or 7th placebo day.

6. Endometrial biopsy is not necessary prior to initiation of HRT unless there are risk factors such as abnormal vaginal bleeding, history of prolonged anovulation, history of unopposed estrogen use, obesity, diabetes.

4. Regimens:
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1. Continuous combined estrogen/progesterone. Prempro provides continuous combined therapy in one tablet daily. Available with differing pro-gestin dosages.

1. Estrogen component: Premarin 0.625 mg PO QD or estradiol 1 mg PO QD or estradiol patch 0.05 mg/day or estropipate 1.25 mg PO QD. Dose may be increased to up to double the initial dose if vasomotor symptoms persist. If hot flashes do not resolve on the higher dose, obtain an estradiol level and consider psychological causes such as stress.

2. Progestin component: medroxyprogesterone acetate 2.5 mg PO QD or micronized progesterone 100 mg PO QD or norethindrone 0.35 mg PO QD. Micronized progesterone and norethindrone may have fewer side effects.

2. Cyclic combined. Premphase comes in a monthly package similar to OCPs to help improve compliance.

1. Estrogen component: Daily dose same as above (A1). Older cyclic regimens using only 25 days of estrogen each month produced vasomotor symptoms.

2. Progestin component: medroxyprogesterone acetate 5 mg PO QD or micronized progesterone 200 mg PO QD or norethindrone 0.7 mg (2 tabs of 0.35) PO QD for 10-14 days each month. Micronized progesterone and norethindrone may have fewer side effects.

3. Unopposed estrogen. Primarily for hysterectomized patients. Daily estrogen dose same as above (section A 1). Very occasionally a patient with a uterus will elect unopposed estrogen due to intolerance of pro-gesterone: if so, annual endometrial sampling is imperative and periodic withdrawal/progestin use to induce menses every 3-6 months is recommended.

4. SERMs (Selective Estrogen Receptor Modulators)
1. Raloxifene is indicated for the prevention and treatment of osteoporosis but not vasomotor symptoms. Use Raloxifene: 60 mg PO QD. Added progestin is not needed.

1. Effects: estrogenic in bone and lipid metabolism, and anti- estrogenic in endometrial and breast tissue. Raloxifene preserves bone density and decreases osteoporotic fractures without increasing the risk of endometrial or breast cancer. Raloxifene’s effect on lipids and the cardiovascular system is still under investigation, as is the possibility that Raloxifene decreases breast cancer risk (similar to tamoxifen).

2. Side effects include increased hot flashes, leg cramps and increased risk of venous thromboembolism (consider work-up before starting raloxifene if there is a close family history of venous thromboembolism).

2. Additional SERMs, such as idoxifene are under clinical development.

5. Managing vaginal bleeding on combined estrogen-progesterone HRT

1. Breakthrough bleeding occurs in 10%-20% of patients on cyclic HRT and 40%-60% on continuous HRT during the first 6 months. Breakthrough bleeding is more common in women who recently had periods.

2. Evaluation. Endometrial biopsy if irregular bleeding continues longer than 6 months. Scant tissue will be recovered if the endometrium is atrophic. Another option is transvaginal ultrasound: endometrial stripe >5 mm requires endometrial sampling (but this occurs in more than half of patients on HRT). With either test, continued abnormal bleeding will warrant further evaluation such as hysteroscopy.

3. Treatment options. In a continuous regimen, double the baseline daily progestin dose (i.e., from 2.5 to 5 mg of medroxyprogesterone) or consider changing to a cyclic regimen. Consider endometrial ablation, pro-gestin IUD, or hysterectomy.

4. Special considerations

1. Elderly women who have never taken HRT may still benefit from fracture prevention. Consider risks and benefits for each patient individually. Start with lower than usual doses and increase after 6 months to minimize side effects.

2. Libido. Women with persistently decreased libido despite HRT may benefit from addition of methyltestosterone (e.g., Estratest)

3. Endometriosis: women with a history of endometriosis who have had a hysterectomy should probably be given progestin in addition to estrogen, to avoid adenocarcinoma developing from residual pelvic and intra-abdominal endometrial implants.

4. Bisphosphonates and HRT have an additive effect in treating established osteoporosis, and can be used together.

5. Duration of treatment: long-term HRT should be continued as long as the benefits are desired. Rapid bone loss ensues after discontinuation

6. Other treatments are available for most HRT indications. Osteoporosis can be treated with bisphosphonates; cardiovascular risk can be modified with lipid-lowering agents and aspirin; hot flashes can be treated with progesterone, venlafaxine, clonidine, naloxone, or methyldopa; vaginal atrophy can be treated with topical estrogen cream (although high doses may have systemic effects) or hydrating agents (e.g., Replens).

7. Other notes.

1. Lower than usual doses (i.e., 0.3 mg of Premarin) of estrogen probably will prevent bone loss if adequate calcium (1500 mg daily) and Vitamin D intake (400-800 IU daily) are ensured through diet or supplements.
2. Phytoestrogens such as those in soy have been popularized for herbal treatment of menopausal symptoms, but have not been extensively studied. Doses large enough to effect symptomatic relief are likely to also produce estrogen-related side effects such as endometrial stimulation.