MENOPAUSE & HORMONE REPLACEMENT THERAPY (HRT)

Attitudes towards post-menopausal HRT continue to change.  Oral HRT enjoyed widespread use through the 1990s, when it was thought to reduce cardiovascular disease.  Then came the Women’s Health Initiative (WHI), a prospective study of HRT that eventually enrolled 160,000 women.  In 2002, the WHI stopped the combined oral HRT arm of the study (daily oral conjugated equine estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg), finding of an increased risk of breast cancer, coronary heart disease, pulmonary embolism, and stroke.  In 2004, the WHI stopped the oral estrogen-only HRT arm of the study (daily oral conjugated equine estrogen 0.625 mg), finding a reduced risk of breast cancer but an increased risk of stroke.  With such risks of oral HRT established, the use of postmenopausal estrogen replacement dropped dramatically.  But things have changed.

Since the WHI, there has been a monumental advance in HRT; namely, transdermal estradiol preparations have been developed that do not increase the risk of coronary heart disease, pulmonary embolism, or stroke; in fact, use of transdermal estradiol in the first 15 years after menopause reduces the risk of cardiovascular disease and improves overall survival.  Transdermal estradiol can also dramatically improve many other symptoms that are described below. Additionally, breast cancer risk is not increased with low-dose estrogen replacement, using a progestin just intermittently or not at all.  The decision about using HRT must be individualized.  Each woman and her health care provider should be well-informed about HRT’s potential benefits vs risks and the variety of preparations available.

In this section, I will discuss Menopause & HRT:  1) Menopausal Symptoms; 2) Menopause Laboratory Diagnosis;  3) HRT Benefits vs Risks;  4) HRT Medications (comprehensive list);  5) Menopause: references from peer-reviewed journals (searchable). This information in also found in my chapter entitled  “Endocrine Disorders”in the medical textbook Current Medical Diagnosis & Treatment, published internationally by McGraw Hill.

Menopause – Symptoms and Signs:

• Vasomotor symptoms (hot flushes) are experienced by 60-80% of women at menopause. Hot flushes can begin during the climacteric, years before menstrual periods cease; they can continue for decades after the menopause transition. The duration of hot flushes can vary from seconds to many minutes.  Women experience heat, particularly around the upper body, including the head, neck, chest, and back.  The severity can vary from mild to debilitating and many women experience drenching nocturnal sweats. Hot flushes peak in early menopause and then usually decline gradually over a median of 10 years, but some women continue to experience uncomfortable hot flushes after age 65. African-American women tend to experience more severe hot flushes. Asian women are less affected.   Obese women tend to have more severe hot flushes than do women at ideal body weight.  Lower socio-economic status also predisposes women to more severe hot flushes, for unknown reasons.   Smokers tend to experience worse symptoms.
• Mild cognitive impairment commonly occurs at menopause.
• Depression & irritability are common during menopause.  The relationship between menopause and emotional lability is often not recognized, such that many women are prescribed antidepressants when the real problem is estrogen deficiency.
• Sleep disturbances are very common and lack of sleep may cause daytime fatigue and predispose to the cognitive impairment noted above.
• Fatigue is common during menopause, and may be aggravated by sleep disturbances noted above.
• Joint pains (arthralgias) are sometimes so severe in menopause that some women often seek help from rheumatologists who usually prescribe NSAIDS and may not recognize that the arthralgias are caused by estrogen deficiency.
• Diminished libido is commonly experienced at menopause.
• Headaches may become more frequent after menopause.
• Postmenopausal osteoporosis with fractures is caused in large part by estradiol deficiency.
• The skin becomes more wrinkled. 
• Atherosclerosis risk is increased. Estradiol deficiency typically increases LDL (bad) cholesterol and reduces HDL (good) cholesterol.
• Vulvovaginal atrophy is common after menopause, with symptoms of vaginal dryness, painful intercourse, and irritation.

A careful pelvic examination is useful to check for uterine or adnexal enlargement and to obtain a Papanicolaou smear and a vaginal smear for assessment of estrogen effect.  Vulvovaginal complaints are not always due to estrogen deficiency and direct inspection of the vulva is necessary to detect other conditions, such as lichen sclerosis, contact dermatitis, squamous hyperplasia, or malignancy.

Menopause – Laboratory Findings:

Early Menopause (< age 45): Elevated serum or urine hCG overwhelmingly indicates pregnancy.  Further laboratory evaluation for women who are not pregnant includes serum estradiol PRL, FSH, LH, and TSH. Hyperprolactinemia or hypopituitarism (without obvious cause) should prompt an MRI study of the pituitary and hypothalamus. Routine testing of kidney and liver function (BUN, serum creatinine, bilirubin, alkaline phosphatase, and alanine aminotransferase) is also performed. A serum testosterone level is obtained in hirsute or virilized women. Patients with manifestations of hypercortisolism (Cushing syndrome) receive a 1-mg overnight dexamethasone suppression test for initial screening.  Nonpregnant women without any laboratory abnormality may receive a 10-day course of a progestin; absence of withdrawal menses typically indicates a lack of estrogen or a uterine abnormality.

Normal Menopause:  No laboratory testing is required to diagnose menopause, when amenorrhea occurs at the expected age. The expected age of menopause correlates with a woman’s mother’s age at menopause and varies among different kindreds and ethnic groups. An elevated serum FSH with a low or low-normal serum estradiol helps confirm the diagnosis.

Menopause Treatment:

Nonhormonal Medical Therapy

Hot flushes may be reduced with low room temperatures, dressing coolly, and consuming cold beverages. Night sweats may be reduced by sleeping in a cool room and by avoiding the use of excessively warm blankets or down comforters. Slow, deep breathing can ameliorate hot flushes. Women may try avoiding known triggers for hot flushes, such as smoking, alcohol, caffeine, and hot spicy foods. Idiosyncratic triggers for hot flushes may be discerned and avoided. Aerobic training for 50 minutes four times weekly reduced all menopausal symptoms except vaginal dryness in a randomized controlled trial. Clinical hypnosis reduced hot flushes over 12 weeks in one study. Acupuncture may help alleviate symptoms in some women.

For women with severe hot flushes who cannot take estrogen, SSRIs may offer modest relief effective within a week; escitalopram (10-20 mg/day) can reduce hot flushes significantly, but must not be used by women taking tamoxifen for breast cancer, since it inhibits tamoxifen’s metabolism to its active metabolite. Venlafaxine extended release (75 mg/day) may also be effective and does not have a drug interaction with tamoxifen. Sexual dysfunction has not been less of a problem with the latter drugs when used for vasomotor symptoms, compared to their use for depression. Gabapentin is also quite effective in oral doses titrated up to 200-800 mg every 8 hours. Side effects such as drowsiness, fatigue, dizziness, and headache, which are most pronounced during the first 2 weeks of therapy, often improve within 4 weeks. An herb, black cohosh, may possibly relieve hot flushes. Replens is a vaginal lubricant that can be used daily or 2 hours prior to intercourse. It improves vaginal moisture and elasticity and reduces vaginal irritation and dyspareunia.

Hormone Replacement Therapy (HRT)

Estrogen replacement is most commonly prescribed for women in early menopause, when symptoms are worst and the benefits are greatest. Transdermal estrogen is favored over oral therapy to reduce the risk of thromboembolism. In women with an intact uterus, estrogen replacement without a progestin risks endometrial hypertrophy and dysfunctional uterine bleeding. The addition of an oral progestin, however, increases the risk of breast cancer. Therefore, only the smallest effective dose of estrogen should be used in order to reduce the need for progestins in such women. Progestin can be delivered directly to the uterus with progesterone-eluting intrauterine devices (Mirena IUD). The decision to take menopausal hormonal therapy and its type and duration are dictated by individual symptoms, risk profile, and personal preferences, while considering potential benefits and risks.

A. Benefits of Hormone Replacement Therapy (HRT)

• Overall survival is improved among women who begin HRT before age 60 or within 10 years of menopause.  Women aged 50-59 years in the WHI who received estrogen alone developed significantly lower CT coronary calcium scores (a marker for coronary atherosclerosis) than women receiving placebo. In the California Teachers Study, HRT in women under age 60 was associated with a dramatic 46% reduction in all-cause mortality, particularly cardiovascular disease.  Another 20-year study of 8801 women living in a retirement community found that estrogen use was associated with improved survival. Age-adjusted mortality rates were 56.4 (per 1000 person-years) among nonusers and 50.4 among women who had used estrogen for 15 years or longer.  Although the association of HRT and lower mortality may suffer from self-selection bias, there appears to be a survival advantage of HRT that requires longer-term administration (more than 5 years) to become apparent. The survival advantage is particularly strong for women under age 60 and diminishes with age; no reduction in mortality was noted in the group of women aged 85-94 years. The reduction in cardiovascular disease among younger postmenopausal women taking HRT may be explained by the reduction in serum levels of atherogenic lipoprotein(a) with HRT, with or without a progestin. Improvement in serum HDL cholesterol is greatest with unopposed estrogen but is also seen with the addition of a progestin.  However, no survival advantage was found in much older women, according to a meta-analysis of 43 randomized controlled trials.
• Breast cancer risk is reduced in women taking replacement estrogen alone, according to the Women’s Health Initiative Study.  However, breast cancer risk is increased among women taking combined daily estrogen and progestin (see below).
• Hot flushes and sweats are reduced by more than 70% by HRT, usually within a month. Vaginal moisture is improved and libido is enhanced in some women.
• Sleep disturbances are common in menopause and can be reversed with HRT.
• Overactive bladder and vaginal dryness can be improved by HRT and by estradiol vaginal rings.
• Mild memory impairment is often improved with HRT.  Although HRT does not prevent Alzheimer disease, short-term transdermal estradiol has been demonstrated to slightly improve memory in women with existent mild to moderate Alzheimer disease.
• Joint pains (arthralgias), generalized body pain, and reduced physical function may be caused or aggravated by estrogen deficiency.  Some women have evaluations for arthritis by rheumatologists.  HRT often improve such symptoms.
• Perimenopausal depression can be significantly improved with estrogen replacement.  Many women feel an overall improved sense of well-being when taking HRT.
• Skin dryness, atrophy, seborrhea may be improved with estrogen replacement.  However, HRT does not prevent facial skin wrinkling.
• Postmenopausal osteoporosis is prevented by HRT. The WHI study found that women who received estrogen therapy experienced a reduced number of hip fractures (six fewer fractures/year per 10,000 women) compared with placebo. Even microdose transdermal estradiol (0.014 mg/day) helps preserve bone density.

Estrogen replacement without progestin (unopposed HRT)  Interestingly and counterintuitively, the WHI study found that postmenopausal women taking unopposed estrogen had a 23% reduction in breast cancer risk. Unopposed estrogen replacement improves glycemic control in women with type 2 diabetes mellitus. Perimenopause-related depression is improved by unopposed estrogen replacement; the addition of a progestin may negate this effect.

B. Hormone Replacement Therapy (HRT): Risks

• Breast cancer risk is slightly increased among women taking combined daily estrogen and progestin HRT, whereas breast cancer risk is slightly reduced in women taking estrogen alone.
• Oral estrogen increases the risk of arterial and venous thrombotic events in a dose-dependent manner, although the absolute risk is small. The WHI study found that women who received long-term conventional oral combined HRT had an increased risk of deep venous thrombosis (3.5 per 1000 person-years) compared with women receiving placebo (1.7 per 1000 person-years); however, transdermal estradiol does not increase vascular thrombosis.  Oral estrogen also increases the risk of ischemic stroke by about 30%. Oral estrogen causes a particularly increased risk for thromboembolic disease among older women and those with increased stroke proclivity (current smokers and those with hypertension, atrial fibrillation, prior thromboembolic event). Long-term use of oral conjugated estrogens in women over age 65 has been associated with poorer cognitive performance, perhaps due to small strokes. Transdermal or vaginal estrogen administration avoids this risk.
• Urinary stress incontinence appears to be increased by conventional-dose oral estrogen replacement, whereas topical vaginal estrogen may have a beneficial effect.
• Mastalgia (breast discomfort) may occur with estrogen replacement, but typically responds to dose reduction.
• The risk of seizures in women with epilepsy may be increased with estrogen replacement.
• Large pituitary prolactinoma tumors may grow in response to estrogen.  However, estrogen may be taken safely by women with pituitary prolactinomas that are controlled with cabergoline.
• Gastroesophageal reflux disease (GERD) may be increased by oral estrogen and selective estrogen receptor modulators (SERMs).
• Hepatic hemangiomas can grow in response to oral estrogen, but significant enlargement is uncommon. Transdermal estradiol at low doses minimizes this risk.

The risks for HRT also depend on whether estrogen is administered alone (unopposed HRT) or with a progestin (combined HRT).

Estrogen replacement without progestin (unopposed HRT)  Surprisingly, the WHI study found that postmenopausal women who received conventional-dose estrogen-only therapy had a reduced risk of breast cancer (7 fewer cases/year per 10,000 women) compared with a placebo group. However, the California Teachers Study monitored women for a longer period; a group of 37,000 women who had been taking conventional-dose estrogen-only therapy for 20 years or longer did have a slightly increased risk of breast cancer. Women taking lower-dose unopposed estrogen therapy would be expected to have lower long-term risk of breast cancer.

Conventional-dose unopposed conjugated estrogen replacement (0.625 or 1.25 mg daily) increases the risk of endometrial hyperplasia and dysfunctional uterine bleeding, which often prompts patients to stop the estrogen. However, lower-dose unopposed estrogen confers a much lower risk of dysfunctional uterine bleeding. Recurrent dysfunctional bleeding necessitates a pelvic examination and possibly an endometrial biopsy. There has been considerable concern that unopposed estrogen replacement might increase the risk for endometrial carcinoma. However, a Cochrane Database Review found no increased risk of endometrial carcinoma in a review of 30 randomized controlled trials. Therefore, lower-dose unopposed estrogen replacement does not appear to confer any significant increased risk for endometrial cancer.

Long-term conventional-dose unopposed estrogen increases the mortality risk from ovarian cancer, although the absolute risk is small. The annual age-adjusted ovarian cancer death rates for women taking estrogen replacement for 10 years or longer are 64:100,000 for current users, 38:100,000 for former users, and 26:100,000 for women who had never taken estrogen. Lower-dose estrogen replacement is believed to confer a negligible increased risk for ovarian cancer.

The WHI trial was stopped in 2002 because of an increased risk of stroke among women taking conjugated oral estrogens in doses of 0.625 mg daily; the risk was about 44 strokes per 10,000 person-years versus about 32 per 10,000 person-years in women taking placebo. However, transdermal or transvaginal estrogen does not increase the risk of stroke.

Oral estrogens can cause hypertriglyceridemia, particularly in women with preexistent hyperlipidemia, rarely resulting in pancreatitis. Postmenopausal estrogen therapy also slightly increases the risk of gallstones and cholecystitis. These side effects may be reduced or avoided by using transdermal or vaginal estrogen replacement.

Estrogen replacement with a progestin (combined HRT)  Long-term conventional-dose oral combined HRT increases breast density and the risk for abnormal mammograms (9.4% versus 5.4% for placebo). There is also a higher risk of breast cancer (8 cases per 10,000 women/year versus 6.5 cases per 10,000 women/year for placebo); the increased risk of breast cancer is highest shortly after menopause (about 2 cases per 1000 women annually). This increased risk for breast cancer appears to mostly affect relatively thin women with a BMI less than 24.4. The Iowa Women’s Health Study reported an increase in breast cancer with HRT only in women consuming more than 1 oz of alcohol weekly. No accelerated risk of breast cancer has been seen in users of HRT who have benign breast disease or a family history of breast cancer. Women in whom new-onset breast tenderness develops with combined HRT have an increased risk of breast cancer, compared with women without breast tenderness.

The Women’s Health Initiative Mental Study (WHIMS) followed the effect of combined conventional-dose oral HRT on cognitive function in women 65 – 79 years old.  HRT did not protect these older women from cognitive decline. In fact, they experienced an increased risk for severe dementia at a rate of 23 more cases/year for every 10,000 women over age 65 years. It is unknown whether this finding applies to younger postmenopausal women.

In the WHI study, women receiving conventional-dose combined oral HRT experienced an increased risk of stroke (31 strokes per 10,000 women/year versus 26 strokes per 10,000 women/year for placebo). Stroke risk was also increased by hypertension, diabetes, and smoking.

Women taking combined oral estrogen–progestin replacement do not experience an increased risk of ovarian cancer. They do experience a slightly increased risk of developing asthma.

Progestins may cause moodiness, particularly in women with a history of premenstrual dysphoric disorder. Cycled progestins may trigger migraines in certain women. Many other adverse reactions have been reported, including breast tenderness, alopecia, and fluid retention. Contraindications to the use of progestins include thromboembolic disorders, liver disease, breast cancer, and pregnancy.

Hormone Replacement Therapy (HRT): Agents

Hormone replacement needs to be individualized. Ideally, in women with an intact uterus, very low-dose transdermal estradiol may be used alone or with intermittent progestin or a progesterone-eluting intrauterine device, in order to reduce the risk of endometrial hyperplasia, while avoiding the need for daily oral progestin. Vaginal estrogen can be added if low-dose systemic estradiol replacement is insufficient to relieve symptoms of vulvovaginal atrophy. Women who have had a hysterectomy may receive transdermal estrogen at whatever is the lowest dose that adequately relieves symptoms. However, some women cannot find sufficient relief with transdermal estradiol and must use an oral preparation.

Transdermal estradiol –

Estradiol can be delivered systemically with different systems of skin patches, mists, or gels.  Transdermal estradiol works for most women, but some women have poor transdermal absorption. If a woman has a skin reaction to an estradiol patch, then a gel or mist may be tried at different doses until the ideal formulation is found.

A. Estradiol patches mixed with adhesive: These systems tend to cause minimal skin irritation. Generic estradiol transdermal is available as a patch that is replaced biweekly (0.025, 0.0375, 0.05, 0.075, 0.1 mg/d) or weekly (0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 mg/day). Brand products include: Vivelle-Dot (0.025) or Minivivelle (0.0375, 0.05, 0.075, or 0.1 mg/day) or Alora (0.025, 0.05, 0.075, or 0.1 mg/day), replaced twice weekly; Climara (0.025, 0.0375, 0.05, 0.06, 0.075, or 0.1 mg/day), replaced weekly; and Menostar (0.014 mg/day), replaced weekly. This type of estradiol skin patch can be cut in half and applied to the skin without proportionately greater loss of potency. Minivivelle patches are the smallest.

B. Estradiol gels, lotions, and mists:   EstroGel 0.06% is available in a metered-dose pump that dispenses 1.25 g gel per actuation (dose: half to 2 actuations/day). Elestrin 0.06% is available in a metered-dose pump that dispenses 0.87 g gel per activation (dose: half to 2 actuations/day). These gels are applied daily to one arm from the wrist to the shoulder after bathing. Divigel 0.1% gel (0.25, 0.5, 1 g/packet) is applied to the upper thigh daily.  Estrasorb 2.5% is available in 1.74 g pouches (4.35 mg estradiol); 1 – 2 pouches of lotion are applied to the thigh/calf daily.  Evamist is available as a topical mist dispenser that dispenses 1.53 mg estradiol/spray; sprays are applied to the inner forearm daily; a single daily spray may provide sufficiently low-dose estradiol to possibly obviate the need for daily progestin in women with an intact uterus. To avoid spreading topical estradiol to others, the hands should be washed and precautions taken to avoid prolonged skin contact with children. Application of sunscreen prior to estradiol gel has been reported to increase the transdermal absorption of estradiol.

C. Patches with both estradiol and progestin mixed with adhesive:  These preparations mix estradiol with either norethindrone acetate or levonorgestrel. Combipatch (0.05 mg E with 0.14 mg norethindrone acetate daily or 0.05 mg E with 0.25 mg norethindrone acetate daily) is replaced twice weekly. Climara Pro (0.045 mg E with 0.015 mg levonorgestrel daily) is replaced once weekly. The addition of a progestin reduces the risk of endometrial hyperplasia, but breakthrough bleeding occurs commonly. The combined patch increases the risk of breast cancer. Scalp hair loss, acne, weight gain, skin reactions, and poor skin adherence have been reported with these patches.

Oral estrogen –

A. Oral estrogen-only preparations:  These preparations include conjugated equine estrogens that are available as Premarin (0.3, 0.45, 0.625, 0.9, and 1.25 mg), conjugated plant-derived estrogens (eg, Menest, 0.3, 0.625, and 2.5 mg), and conjugated synthetic estrogens that are available as Cenestin (0.3, 0.45, 0.625, 0.9, and 1.25 mg) and Enjuvia (0.3, 0.45, 0.625, 0.9, and 1.25 mg). Other preparations include estradiol (0.5, 1, and 2 mg), and estropipate (0.75, 1.5, and 3 mg).

B. Oral estrogen plus progestin preparations:  Conjugated equine estrogens with medroxyprogesterone acetate is available as Prempro (0.3/1.5, 0.45/1.5, 0.625/2.5, and 0.625 mg/5 mg); conjugated equine estrogens for 14 days cycled with conjugated equine estrogens plus medroxyprogesterone acetate for 14 days is available as Premphase (0.625/0, then 0.625 mg/5 mg); estradiol with norethindrone acetate (0.5/0.1 and 1 mg/0.5 mg); ethinyl estradiol with norethindrone acetate is available as Femhrt (2.5/0.5 and 5 mcg/1 mg) and Jinteli (5 mcg/1 mg); estradiol with drospirenone is available as Angeliq (0.5 mg/0.25 mg, and 1.0 mg/0.5 mg); estradiol with norgestimate is available as Prefest (estradiol 1 mg/day for 3 days, alternating with 1 mg estradiol/0.09 mg norgestimate daily for 3 days). Oral contraceptives can also be used for combined HRT.

Vaginal estrogen –

Urogenital atrophy commonly develops in postmenopausal women and can cause dryness of the vagina, genital itching, burning, dyspareunia, and recurrent urinary tract infections. Urinary symptoms can include urgency and dysuria. Vaginal estrogen is intended to deliver estrogen directly to local tissues and is moderately effective in reducing these symptoms, while minimizing systemic estrogen exposure. Some estrogen is absorbed systemically and can relieve menopausal symptoms. Manufacturers recommend that these preparations be used for only 3–6 months in women with an intact uterus, since vaginal estrogen can cause endometrial proliferation. However, most clinicians use them for longer periods. Vaginal estrogen can be administered in three different ways: creams, tablets, and rings.

A. Estrogen vaginal creams:  These creams are administered intravaginally with a measured-dose applicator daily for weeks for atrophic vaginitis, then administered one to three times weekly. Available preparations include conjugated equine estrogens, which is available as Premarin Vaginal (0.625 mg/g cream), dosed as 0.25–2 g cream administered vaginally one to three times weekly. Estradiol is available as Estrace Vaginal (0.1 mg/g cream), 1 g cream administered vaginally one to two times weekly.

B. Estradiol vaginal tablets: These tablets are sold prepackaged in a disposable applicator and can be administered deep intravaginally daily for 2 weeks for atrophic vaginitis, then twice weekly. The tablets dissolve into a gel that gradually releases estradiol. This preparation is available as Vagifem (10 mcg/tablet), administered vaginally two times weekly.

C. Estradiol vaginal rings: These rings are inserted manually into the upper third of the vagina, worn continuously, and replaced every 3 months. Variable amounts of the released estradiol enters the systemic circulation. Vaginal rings do not usually interfere with sexual intercourse. If a ring is removed or descends into the introitus, it may be washed in warm water and reinserted. Estring (2 mg estradiol/ring) releases estradiol 7.5 mcg/day with only 8% entering the systemic circulation, resulting in mean serum estradiol concentrations of only about 10 pg/mL; it is most effective for local vaginal symptoms.  Femring releases estradiol acetate that is quickly hydrolyzed to estradiol and is available in two strengths: 12.4 mg/ring releases estradiol acetate 0.05 mg/day or 24.8 mg/ring releases estradiol acetate 0.1 mg/d, resulting in mean serum estradiol concentrations of about 40 pg/mL and 80 pg/mL, respectively; it is effective for both systemic and local vaginal symptoms.  Both rings are replaced every 90 days. For women with postmenopausal urinary urgency and frequency, even the low-dose Estring can successfully reduce urinary symptoms.

D. Estradiol with progestin vaginal rings:  The available preparation in NuvaRing that releases a mixture of ethinyl estradiol 0.015 mg/day and etonogestrel 0.12 mg/day. It is a contraceptive vaginal ring that is placed in the vagina on or before day 5 of the menstrual cycle, left for 3 weeks, removed for 1 week, and then replaced.

Estradiol injections –

Parenteral estradiol should be used only for particularly severe menopausal symptoms when other measures have failed or are contraindicated. Estradiol cypionate (Depo-Estradiol 5 mg/mL) may be administered intramuscularly in doses of 1–5 mg every 3–4 weeks. Estradiol valerate (20 or 40 mg/mL) may be administered intramuscularly in doses of 10–20 mg every 4 weeks. Women with an intact uterus should receive a progestin for the last 10 days of each cycle.

Oral progestins –

For a woman with an intact uterus, long-term conventional-dose unopposed systemic estrogen therapy can cause endometrial hyperplasia, which typically results in dysfunctional uterine bleeding and might rarely lead to endometrial cancer. Progestin therapy transforms proliferative into secretory endometrium, causing a possible menses when given intermittently or no bleeding when given continuously.

The type of progestin preparation, its dosage, and the timing of administration may be tailored to the given situation. Progestins may be given daily, monthly, or at longer intervals. When given episodically, progestins are usually administered for 7–14 day periods. Bedtime administration may improve sleep. Some women find that progestins produce adverse effects, such as irritability, nausea, fatigue, or headache; long-term progestins given with estrogen replacement increase the risk for breast cancer.

Oral progestins are available in different formulations: Micronized progesterone (100 mg and 200 mg/capsule), medroxyprogesterone (2.5, 5.0, and 10 mg/tablet), norethindrone acetate (5 mg/tablet), and norethindrone (0.35 mg/tablet). Topical progesterone (20–50 mg/day) may reduce hot flushes in women who are intolerant to oral HRT. It may be applied to the upper arms, thighs, or inner wrists daily. It may be compounded as micronized progesterone 250 mg/mL in a transdermal gel. Its effects upon the breast and endometrium are unknown. Progesterone is also available as vaginal gels (eg, Prochieve, 4% = 45 mg/applicatorful, and 8% = 90 mg/applicatorful) that are typically given for secondary amenorrhea and administered vaginally every other day for six doses.

Progestin-releasing intrauterine devices –

Intrauterine devices that release progestins can be useful for women receiving ERT, since they can reduce the incidence of dysfunctional uterine bleeding and endometrial carcinoma without exposing women to the significant risks of systemic progestins. The Mirena intrauterine device releases levonorgestrel and is inserted into the uterus by a clinician within 7 days of the onset of menses. It is equally effective at reducing endometrial hyperplasia as cycled medroxyprogesterone acetate and is associated with less hirsutism. It remains effective for up to 5 years. Parous women are generally better able to tolerate the Mirena intrauterine device than nulliparous women.

Selective estrogen receptor modulators (SERMs) –

SERMs (eg, raloxifene, ospemifene, tamoxifen) are an alternative to estrogen replacement for hypogonadal women at risk for osteoporosis who prefer not to take estrogens because of their contraindications (eg, breast or uterine cancer) or side effects.  Raloxifene (Evista) does not reduce hot flushes, vaginal dryness, skin wrinkling, or breast atrophy; it does not improve cognition. However, in doses of 60 mg/day orally, raloxifene inhibits bone loss without stimulating effects upon the breasts or endometrium. Raloxifene does not stimulate the endometrium and actually reduces the risk of endometrial carcinoma, so concomitant progesterone therapy is not required. Another advantage to raloxifene is that it reduces the risk of invasive breast cancer by about 50%. Raloxifene slightly increases the risk of venous thromboembolism (though less so than tamoxifen), so it should not be used by women at prolonged bed rest or otherwise prone to thrombosis. Ospemifene (Osphena) is a SERM that has unique estrogen-like effects on the vaginal epithelium and is indicated for the treatment of postmenopausal dyspareunia when other therapies are ineffective. Given orally in doses of 60 mg/day, it commonly aggravates hot flushes, increases the risks of thromboembolism, and increases endometrial hyperplasia. Ospemifene has unknown long-term effects upon bone and breast.  Therefore, I have never seen a reason to prescribe it.

Tibolone (Livial) is an SERM whose metabolites have mixed estrogenic, progestogenic, and weak androgenic activity. It is comparable to HRT for the treatment of climacteric-related complaints. It does not appear to significantly stimulate proliferation of breast or endometrial tissue. It depresses both serum triglycerides and HDL cholesterol. Long-term studies are lacking. It is not available in the United States.

Testosterone replacement for women –

In premenopausal women, serum testosterone levels decline with age. Between 25 and 45 years of age, women’s testosterone levels fall 50%. After natural menopause, the ovaries remain a significant source for testosterone and serum testosterone levels do not fall abruptly. In contrast, very low serum testosterone levels are found in women after bilateral oophorectomy, autoimmune ovarian failure, or adrenalectomy, and in hypopituitarism. Testosterone deficiency contributes to hot flushes, loss of sexual hair, muscle atrophy, osteoporosis, and diminished libido, also known as hypoactive sexual desire disorder. Flibanserin (Addyi) is a centrally acting drug that stimulates serotonin 5-HT1A receptors and blocks other brain receptors.  Flibanserin is modestly effective for treating premenopausal women with acquired hypoactive sexual desire disorder. It is administered orally 100 mg at bedtime; side effects may include hypotension, appendicitis, nausea, xerostomia, sleep disorders, and fatigue.  If there is no improvement within 8 weeks, it is discontinued.

In women, diminished libido is common and multifactorial. Although low serum testosterone levels may contribute to hypoactive sexual desire disorder, hysterectomy and sexual isolation are major causes. Low serum testosterone levels may also cause fatigue, a diminished sense of well-being, and a dulled enthusiasm for life. Androgen replacement may improve these problems.

Selected women may be treated with low-dose testosterone. Oral methyltestosterone can be compounded into capsules and taken orally in doses of 1.25 – 2.5 mg daily. Methyltestosterone also is available combined with esterified estrogens: 1.25 mg methyltestosterone/0.626 mg esterified estrogens or 2.5 mg methyltestosterone/1.25 mg esterified estrogens. The latter formulations are convenient but carry the same disadvantages as oral estrogen—particularly an increased risk of thromboembolism.  Topical testosterone can also be compounded as a cream containing 1 mg/mL, with 1 mL applied to the abdomen daily.

Women receiving testosterone therapy must be monitored for the appearance of any acne or hirsutism, and serum testosterone levels are determined periodically if women feel that they are benefitting and long-term testosterone therapy is instituted. Side effects of low-dose testosterone therapy are usually minimal but may include erythrocytosis, emotional changes, hirsutism, acne, an adverse effect on lipids, and potentiation of warfarin anticoagulation therapy. Testosterone therapy tends to reduce both triglyceride and HDL cholesterol levels. Hepatocellular neoplasms and peliosis hepatis, rare complications of oral androgens at higher doses, have not been reported with oral methyltestosterone doses of 2.5 mg or less daily.

Vaginal testosterone is an option for postmenopausal women who cannot use systemic or vaginal estrogen due to breast cancer. Testosterone 150 – 300 mcg/day vaginally appears to reduce vaginal dryness and dyspareunia without increasing systemic estrogen levels.

Caution: Androgens should not be given to women with liver disease or during pregnancy or breastfeeding. Testosterone replacement therapy for women should be used judiciously, since long-term prospective clinical trials are lacking. An analysis of the Nurses’ Health Study found that women who had been taking conjugated equine estrogens plus methyltestosterone experienced an increased risk of breast cancer, so breast cancer screening is recommended.

REFERENCES:  (To view an abstract, go to https://www.ncbi.nlm.nih.gov/pubmed/  and plug in the PMID number.)

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