1. DEFINITIONS

   Menopause

   1. Permanent cessation of menstruation due to failure of follicle development in the presence of adequate gonadotropin stimulation
   2. Perimenopause - the period immediately before menopause
   3. Climacteric - is a more encompassing term as it refers to the period in a woman's life during which there is a regression of ovarian function (menopause and perimenopause)

2. GENERAL INFORMATION
   • Mean age for menopause 51.3 years. The median onset of perimenopause was 47.5 years. Only 10% of women ceased menstruating abruptly. The perimenopause transition was approximately 4 years
   • Loss of ovarian function prior to age 40 is premature ovarian failure. This needs a full endocrinologic workup.
   • Race, parity and height have no influence on the age of menopause.
   • Cigarette smokers experience earlier menopause; a shift of approximately 1.5 years earlier.

3. REPRODUCTIVE ENDOCRINOLOGY OF PERIMENOPAUSE AND MENOPAUSE
   • At the onset of the climacteric, there is an elevation in FSH and a decrease in the inhibin, but normal levels of estradiol and LH.
   • FSH production increases in an attempt to stimulate the ovary due to a decline in inhibin. This decline in inhibin begins around age 35.
   • As the climacteric continues and as menopause starts, there is decreased estradiol due to depletion of ovarian follicles. Estradiol levels do not gradually wane but remain within normal range until follicular growth and development ceases.
   • Perimenopause is a time period during which FSH increases, while LH remains within the normal range. At menopause, there is an increase in LH.
   • Women are not safe from an unplanned pregnancy until both FSH and LH increase.
   • FSH levels are higher than LH levels at menopause because LH is cleared more rapidly from the blood (4 hours vs. 30 minutes).
   • The inability to suppress FSH with postmenopausal hormone therapy is a consequence of the loss of inhibin and this is why FSH levels cannot be used to clinically titrate estrogen dose.

4. THE CLIMACTERIC OVARY

   When women are in their 40's, anovulation becomes more prevalent. At the same time, fewer follicles grow during each cycle until the supply of follicles is depleted. The hormonal contribution of the ovary changes with both functional state and age. Below is a summary of the changes in the ovary that occur at the climacteric.

   1. Ultrasonography
      Ovarian volume has been evaluated by pelvic ultrasonography on 2246 healthy postmenopausal women. The average volume was found to be 3.6 cm². With significant predictors for volume being years since menopause, weight, parity, age at menopause, h/o HRT and h/o breast cancer.

   2. Microscopically
      The cortex is thin and devoid of follicles. Residual degenerating follicles may be noted. There is a state of granulose cell failure, however, the theca interstitial cell component is spared to a large degree.

   3. Hormonally
      Marked changes occur in the production and circulating levels of all three sex hormones during menopause.
      1. Estrogens. As ovarian follicles are depleted, estrogen levels fall: Estrone by 60% and estradiol by over 90%. This leads to a dramatic decrease in the daily production rate of estradiol and estrone. Therefore, estrogen production in the postmenopausal woman is almost exclusively due to extra glandular aromatization of adrenal androstenedione. Thus, estrone is the major estrogen in the blood of postmenopausal women. Castration does not change these circulating levels. Glucocorticoids, however, substantially reduce the circulating levels of estrogen in the postmenopausal woman. Moreover, adrenalectomy after castration virtually eliminates measurable amount of estrogen. In vitro studies have suggested in the past that the climacteric ovarian stroma is unable to engage in the aromatization of androgens to estrogens (Mattingly and Huang, 1969). However, Judd and coworkers have suggested that the climacteric ovary may synthesize limited amounts of estrogen based on the observation that the concentrations of estradiol and estrone are two times higher in ovarian venous blood than the peripheral blood in postmenopausal women. This is supported by the finding of aromatase in individual cells and in clusters of cells in the stromal compartment of postmenopausal ovaries.
      2. Androgens. The view that the climacteric ovary is an androgen-producing organ is supported by in vitro isotopic labeling studies. Injected titrated pregnenolone yield labeled progesterone, dehydroepiandrosterone and testosterone in the ovarian stroma of postmenopausal women. Additionally, treatment of postmenopausal women with GnRH-a decreases circulating levels of testosterone. The postmenopausal ovary secretes more testosterone than the premenopausal ovary but it is equally recognized that menopause is associated with a decrease in overall testosterone production (28% decrease). The decrease in testosterone is mostly accounted for by a decrease in the contribution of nonovarian sources. In relative terms, a 75% extra ovarian contribution to the circulating testosterone pool is reduced to 60%. At the same time, the ovarian relative contribution to the pool increases from 25% to 40%. Further support for this reveals that serum testosterone levels decline 50% after oophorectomy.
      3. Progesterone. Level drops at menopause by approximately 60%.
      4. Role of Gonadotropins. It has been suggested that ovarian androgen production in the climacteric woman is gonadotropin dependent. This theory is supported by Vermeulen (1976) and Poliak (1968) who gave hCG injections to postmenopausal women and noted increases in circulating testosterone levels and histochemical evidence of steroidogenesis. Also, GnRH agonists decrease T production in menopause.

5. PHYSIOLOGIC CHANGES
   1. Urogenital Tract Changes
      • Atrophy of vagina causing vaginitis symptoms of itching, burning, dyspareunia, and vaginal bleeding.
      • Atrophy of urinary tract tissues producing urinary urgency, incontinence, dysuria, and urinary frequency.
      • Decreased support of urethra due to atrophy of elastic vaginal tissue producing cystocele, rectocele, and stress incontinence.
      • Treatment of choice is estrogen.

   2. Integument
      • Decreased collagen content
      • Increased body fat

   3. Vasomotor Symptoms
      • For most women, the onset of hot flashes will occur before the final period.
      • A hot flash is a sudden onset of reddening over the face and chest with a feeling of intense body heat lasting from seconds to minutes.
      • Occurs in 75% of postmenopausal women within 3 months of natural or surgical menopause. (Obese women less likely to have flushes.)
      • Resolves spontaneously in 1-5 years in 65% of women who suffer from hot flushes. Only 35% of women will have hot flushes longer than 5 years.
      • Prevalence of hot flushes is greater in smokers.
      • Hot flashes occur more frequently at night and may awaken patients from sleep.
      • Hot flushes are related to a decrease in estrogen levels and are more likely to occur with abrupt fall in estrogen levels (i.e., surgical menopause). Hot flushes are thought to be more severe in surgical menopause although this has not been shown in studies.
      • Vasomotor flushes appear to result from a sudden lowering of the thermoregulatory set point leading to vasodilation and heat loss. A rise in plasma LH occurs about 12 minutes after a flush. A rise in epinephrine is noted 3 minutes after a flush.
      • The physiology of the hot flush is not well understood. It was initially thought to be due to changes in LH. However, this is now known not to be true because if was found that the 23% rise in LH occurs 12 minutes after a flush. Moreover, flushes do not require an intact pituitary gland. Total hypophysectomy does not prevent hot flushes. It is now thought that hot flushes are due to a reduced a² adrenergic activity which leads to thermoregulatory instability.
      • Treatment of choice is estrogen. In a study by Haas et. al. (1988), hot flush frequency was not reduced until 2 weeks of treatment and was not maximal until 4 weeks of therapy. Hot flushes remained suppressed for about 2 weeks after discontinuing therapy.
      • Alternative treatments
        • Oral medroxyprogesterone acetate 20 mg qd (Provera, Cycrin)
        • Clonidine po 0.05-0.10 mg BID or transdermally delivery of 0.2 mg/day changed weekly
        • Bellergal - ergotamine and Phenobarbital (1 tablet BID)

   4. CNS Symptoms
      • Anxiety, depression, irritability, and fatigue
      • The view that menopause has a deleterious effect on mental health is not supported.
      • Attempts to study estrogen therapy benefits with regard to CNS effects is hampered by high placebo responses, and a "domino" effect of the reduction in hot flushes improving sleep which, in turn, improves mental health.
      • Estrogen improves the quality of sleep decreasing the time of onset to sleep and increasing REM sleep time.
      • In the Rancho Bernardo study (n=800), no benefit could be detected in the measures of depression in current users of HRT compared to untreated women.
      • Leisure World cohort indicates that Alzheimer's disease and related dementia occurs less frequently in estrogen users. Furthermore, the administration of estrogen to patients with Alzheimer's improved cognitive function in some studies.
      • Alzheimer's new area of research.

   5. Bone (see attached osteoporosis handout)
      • The precise mechanism of action of sex steroids protection of bones remain unknown. Estrogen modulates the production of bone resorbing cytokines (interleukin 1 and 6), bone stimulating factors (IGF I and II), and transforming growth factor β. Estrogen promotes the synthesis of calcitonin and increases vitamin D receptors in osteoblasts.
      • Loss of estrogen affects trabecular bone more rapidly than cortical bone.
      • Dual energy x-ray absorptiometry is currently the method of choice for measuring bone density (see attached osteoporosis handout for details).
      • By age 60, 25% of white and oriental women will develop spinal compression fractures. 30,000 women die each year due to osteoporosis and its complications.
      • Postmenopausal women on estrogen should receive 1000 mg/day of calcium, however, the recommended calcium intake is 1500 mg/day for those postmenopausal women not receiving estrogen or low-dose estrogen therapy. Calcium alone does not prevent bone loss.

   6. Cardiovascular Disease
      • Number one cause of mortality in the U.S. for postmenopausal women.
      • Estrogen decreases LDL and increases HDL and triglycerides.
      • Throughout adulthood and even into menopause, HDL levels are about 10 mg/dL higher than men of the same age.
      • More than 30 published studies have addressed postmenopausal estrogen use and CVD. Only a handful of studies have failed to find a protective effect of estrogen; in women who do not have cardiovascular disease. Most noteworthy are the 1978 and 1985 Framingham studies which failed to show an effect. Problem felt to be due to study design flaws.
      • The HERS trial has shown that women with established cardiovascular disease, have an increase risk of CV events in the first year of HRT. Therefore HRT is not advised in women with established cardiovascular disease.
      • It may be best to initiate hormone therapy at a young age to prevent cardiovascular disease. Be cautious of starting HRT in women 10 years post menopause because they may have unrecognized cardiovascular disease (WHI).

6. NEOPLASTIC EFFECTS
   1. Endometrial
      • Increased risk of endometrial cancer or hyperplasia with unopposed estrogen. Only 1 year of 0.625 mg conjugated estrogens will produce a 20% incidence of endometrial hyperplasia.
      • Estrogen users have better survival rates with endometrial cancer than nonusers.
      • Addition of a progestin to replacement therapy decreases the endometrial cancer risk below that of nonusers.
      • Duration of the progestin more important than the dose (minimum duration 12 days).
      • Endometrial hyperplasia was noted in 4%, 2%, and 0% of women after 7, 10, and 12 days of progestin therapy.

   2. Breast
      • Most evidence shows no increased risk of breast cancer in postmenopausal estrogen users using estrogen for less than 10 years. Women using estrogen for more than 10 years may have a slight 2-3% increase in the disease.
      • The CASH study (Cancer and Sex Hormone) by the CDC has not detected an overall increased risk of breast cancer in postmenopausal estrogen users with a duration of use up to 20 years.
      • The Nurses Health Study revealed that women who had used estrogen in the past, even for greater than 10 years, were not at increased risk for breast cancer. However, this study revealed a RR of 1.33 (CI 1.22-1.57) for current users.
      • An Australian study (3033 women) followed for a mean duration of 17 years found that women with benign breast disease had a reduced risk of breast cancer with ERT.
      • Because of the concern raised by some studies, this issue requires discussion prior to starting HRT.
      • Clinical observation of relevance
        • Breast cancer in pregnant women. Subsequent pregnancy after diagnosis and treatment has no negative impact on prognosis.
        • OCP's and breast cancer. No definitive evidence.

7. TREATMENT REGIMENS
   • Estrogen should be given in the lowest possible dose to relieve vasomotor symptoms, prevents vaginal urethral mucosa atrophy, protects bones and cardiovascular system. 0.625 mg/day conjugated estrogens, or 1.0 mg micronized estradiol, or 0.5 mg micronized estradiol plus Ca++. New lower doses have been introduced with 0.3 mg and 0.45mg of conjugated estrogens per day.
   • Select a hormone regimen that produces the least amount of vaginal bleeding. This will improve compliance.
   • 12 days of Progestin each month offers greater endometrial protection than a shorter interval.
   • Unopposed estrogen recommended for those postmenopausal women without a uterus except for the consideration of combination HRT in hysterectomized women with a history of Stage I adenocarcinoma of the uterus, endometrioid tumors of the ovary, endometriosis, severe osteoporosis, and elevated triglyceride levels.
   • Estrogen only treatment in those women with a uterus must be in conjugation with annual endometrial biopsy. Encourage combination HRT to decrease risk of endometrial cancer.
   • Dosing
     • Daily dose estrogen days 1-25 with progestin the last 12 days. Women with cyclic treatment have withdrawal bleeding. Usually stops within 2-3 years.
     • Continuous daily estrogen and progestin, 38% uterine bleeding first 3 months, 60% by 6 months, and 14% after 6 months. Virtually no endometrial bleeding after 2 years.
     Routine pretreatment endometrial biopsy unnecessary in completely amenorrheic prior to starting therapy
   • Contraindications include: recent endometrial cancer and active liver disease

8. BLEEDING ON HRT
   1. Continuous Daily Treatment -E+P
      • 38% of bleeding in first 3 months; 40-60% by 6 months.
      • 14% of continuous HRT users have bleeding after 6 months of therapy; bleeding after 6 months requires an endometrial biopsy and sonohysterogram. (An impressive (38%) number of polyps and fibroids will be found if sonohysterogram added to the evaluation.)
      • 4% - by 1 year will have bleeding.
      • 0% - by 2 years will have bleeding.
      • The breakthrough bleeding is similar to that seen with OCP's, originating from an endometrium with progestational influence.

   2. Cyclic E+P
      • 63% withdrawal bleeding for up to 2 years.

   3. Measurement of Endometrial Thickness by Ultrasound
      1. Measurements under 5 mm is reassuring. Measurements = 5 mm require an endometrial biopsy.
      2. Measurements > 8 mm are associated with an increased risk of endometrial cancer.
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