The Menopause

The menopause is defined by the World Health Organization as the point in time of permanent cessation of menstruation due to loss of ovarian function. Clinically, the menopause is characterized by persistent amenorrhea for a period of twelve months. Laboratory findings in the menopause generally reveal low serum estradiol levels with elevated follicle stimulating hormone (FSH) levels. The specific levels may vary depending on the assay used. The perimenopause, or climacteric, is defined as the period of diminishing ovarian function preceding the menopause to one year following the final menses, generally lasting between 2 and 8 years. Currently, the average age of menopause in the United States is approximately 51 years and the average life expectancy is approximately 80 years. Consistent with this, almost one half of the average woman’s life is spent in the post-menopausal period.

The Transition

The reproductive life span can be divided into three phases: the reproductive years, the perimenopause, and the postmenopause. The perimenopause can be further subdivided into early and late stages. The greatest stability and efficiency of ovarian function is between the ages of 25 and 34. Ovulatory variability is greatest before the age of 20 and after the age of 40 years, resulting in an increased frequency of anovulatory cycles, erratic cycle length, and abnormal uterine bleeding.

The early perimenopause is characterized by slowly declining ovarian function, increasing frequency of anovulatory cycles, irregular cycle lengths, fluctuating gonadotropin levels, and an overall increase in follicle stimulating hormone and luteinizing hormone (LH) levels. follicle stimulating hormone levels, in particular, may fluctuate widely, changing with each cycle, largely due to a decrease in the number of ovarian follicles. With loss of ovarian follicles as well as granulosa cells, inhibin levels, which normally provide negative feedback on the pituitary follicle stimulating hormone secretion, decrease. This results in the loss of the negative feedback loop between inhibin and follicle stimulating hormone, leading to an elevation of follicle stimulating hormone levels. follicle stimulating hormone levels trend upward starting in the late reproductive years, even before changes in the menstrual cycle, once inhibin levels fall low enough to allow a rise in follicle stimulating hormone levels. Thus, the routine measurement of serum follicle stimulating hormone to determine if a woman is perimenopausal can be misleading. Therefore, clinical evaluation becomes important in making the diagnosis of perimenopause. Symptoms of early perimenopause are variable but include: hot flashes, premenstrual dysphoria, breast tenderness, insomnia and the menstrual cycle changes described above.

As the transition proceeds to the late perimenopause phase, continued alterations in the production and subsequent levels of sex steroid hormones occur. Ovulation eventually ceases and the supply of ovarian follicles is eventually exhausted, resulting in permanent loss of fertility. However, the ovarian stroma continues to produce androstenedione and testosterone in significant amounts. As estrogen levels decline into the postmenopausal range, estradiol is no longer made by the follicle, but by peripheral conversion of estrone, testosterone, and, most importantly, androstenedione. The major estrogen sources throughout this period are the adrenal glands via the conversion of androstenedione to estrone in adipose tissue. In addition, the adrenals continue to secrete testosterone and small amounts of estrogen, as well as dihydroepiandrostenedione (DHEA) and dihydroepiandrostenedione-sulfate (DHEAS). However, with increasing age, the adrenals produce smaller amounts of androgen, which also results in diminished peripheral estrogen production over time. With the menopause, significant reductions in estrogen levels are noted with a less significant decrease in androgen levels. follicle stimulating hormone and luteinizing hormone levels increase markedly without change in other pituitary hormones. Finally, at the completion of the late perimenopause, now 12 months after the last menses and beginning the menopausal phase, gonadotropin levels have reached their final menopausal levels (usually >40 mill/ml).

Symptoms of Menopause

Common early symptoms of menopause include hot flashes, insomnia, irritability, and mood disorders, which can occur secondary to vasomotor instability. Physical changes include vaginal atrophy, urinary stress incontinence and skin atrophy. Long term health risks that have been attributed to the hormonal changes from menopause, include: osteoporosis, cardiovascular disease, and in some studies Alzheimer’s disease, macular degeneration, and stroke.

Vasomotor Symptoms

Vasomotor instability or the “hot flash” is a common complaint of the perimenopausal and menopausal woman, affecting 60 to 85% of all women. Hot flashes usually occur suddenly, though some women may experience an aura or premonition of the impending hot flash, and generally begin with an intense feeling of heat in the face and thorax. Visible flushing or reddening of the face and neck often follows, with a rise in heart rate and skin blood flow. Skin resistance drops rapidly, resulting in increased skin conductance of heat and a sensation of skin warmth. An increase in peripheral blood flow, heart rate, and finger temperature can result in palpitations and profuse sweating.

Although hot flashes occur for 0.5 to 5-0 years on average after last menses, they may persist beyond five years, and up to 10% of women experience hot flashes for greater than 15 years. Their frequency ranges from 5 to 50 per day, with an average duration of 4 minutes. Women who have undergone surgical menopause are more likely to experience hot flashes than naturally menopausal women, often reaching an incidence of 100% in the first year postoperatively and most commonly described as severe. Although hot flashes often occur spontaneously, they may also be provoked by stress, emotional situations, external heat or warm weather, confining spaces, alcohol use, or caffeine use. Therefore, avoidance/modification of these factors can improve symptoms in some patients.

The cause of hot flashes remains unclear, but they are thought to occur secondary to sudden changes in hypothalamic control of temperature regulation. Estrogen is believed to reduce hot flashes by modulating the firing rate of thermosensitive neurons in the preoptic area of the hypothalamus. Hot flashes are worse at night for many women, resulting in night sweats, multiple episodes of awakening, and overall nonrestful sleep. The resulting decreased sleep efficiency caused by hot flashes may explain the associated chronic fatigue and irritability from which many menopausal women suffer. The most effective treatment for hot flushes is estrogen, which can be given through a variety of regimens, that are described below and listed in Tables Currently available and combined oral hormone replacement therapy preparations in the US, Currently available transdermal/topical estrogen replacement therapy preparation in the US, Currently available single intravaginal estrogen replacement therapy preparations in the US.

Table Currently available and combined oral hormone replacement therapy preparations in the US

Medication Brand Name Available Doses
Single Agent
Conjugated equine estrogens Cenestin 0.3, 0.625, 0.9, 1.25 (mg)
Menest 0.3,0.625, 1.25,2.5 (mg)
Premarin 0.3, 0.45, 0.625, 0.9, 1.25 (mg)
Estradiol Estrace 0.5, 1,2 (mg)
Estropipate (piperazine estrone sulfate) Ogen 0.75, 1.5, 3, 6 (mg)
Ortho-Est 0.75, 1.5 (mg)
Combined Agents
Conjugated equine estrogen / medroxyprogesterone acetate Prempro 0.3/1.5; 0.45/1.5; 0.625/2.5; 0.625/5 (mg/mg)
Premphase 0.625/0x21 days, then
  0.625/5 x 7 days (mg/mg)
Conjugated equine

estrogens / methyltestosterone

Estratest 1.25/2.5 (mg/mg)
Estradiol/norgestimate Prefest 1/0x21 days, then
  1/0.09×7 days (mg/mg)
Estradiol/norethindrone Activella 1/0.5 (mg/mg)
Ethinyl estradiol/ norethindrone FemHRT 5/1 (mg/mg)

Table Currently available transdermal/topical estrogen replacement therapy preparation in the US

Medication Brand Name Available Doses
Single Agent
Estradiol Alora 0.05, 0.075, 0.1 (mg) 2 x per wk
  Climara 0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 (mg) 1 x per wk
  Estraderm 0.05,0.01 (mg) 2 x per wk
  Vivelle 0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 (mg) 1 x per wk
  EstroGel 1.25g 1 x per day
Combined Agents
Estradiol/norethindrone Combipatch 0.05/0.14; 0.05/0.25 (mg/mg) 2 x per wk
Estradiol/levonorgestrel ClimaraPro 0.045/0.015 (mg/mg) 1 x per wk

Table Currently available single intravaginal estrogen replacement therapy preparations in the US

Medication Brand Name Available Doses
Conjugated equine Estrogen cream Premarin cream 0.625 mg/g; 1-2 g daily x 2 wk, then 1 g daily 1-3 x wk
Estradiol cream Estrace cream 0.1 mg/g; 2-4 g daily x 2 wk, then 1 g daily 1-3 x wk
Dienestrol cream Orthodienestrol 0.01 mg/g; 1-2 app qd x 2 wk, then taper to 1 -2 x wk
Estradiol tablets Vagifem tablets 0.025 mg daily x 2 weeks, attempt to discontinue over 3 to 6 mos
Estradiol ring Estring 0.075 mg/d ring; insert ring vaginally every 90 days
  Femring 0.05 mg, 0.1 mg/d ring; insert vaginally every 90 days

Regimens for Hormone Replacement

Genitourinary

With declining estrogen levels, vaginal pH rises from acidic to basic levels, resulting in the decline of the previously predominant lactobacilli and a newly hospitable environment to previously atypical bacteria colonizing the vagina, most significantly enterobacteria. This is thought to result in an increased risk of urinary tract infections. There are also marked atrophic changes of the urethra, resulting in dysuria and frequency. Atrophy of the vulva and vagina can also be seen in the menopause. Genital symptoms include: decreased lubrication, burning, itching, discharge, dyspareunia, and sexual dysfunction. Urinary symptoms include frequency, dysuria, hematuria, and incontinence. Numerous studies have demonstrated the effectiveness of local, oral, or transdermal estrogen for treating symptoms of vulvar and vaginal atrophy. A review of the literature shows conflicting results regarding the role of estrogen therapy in treating urinary incontinence, including a meta-analysis that concluded that estrogen has only a small effect, if any, on urinary incontinence.

Local Therapy (Vaginal or Topical Administration)

Estrogen creams, estrogen tablets and the estrogen ring are options for localized hormonal therapy, which can allow administration of a lower dose of estrogen, avoiding systemic effects. The low dose estradiol vaginal ring (Estring) is placed in the vagina delivering estrogen associated with no detectable changes in blood estradiol or estrone levels. These alternative methods of localized estrogen therapy offer important alternatives for those women who cannot or choose not to receive oral or transdermal therapy. Localized estrogen therapy primarily addresses symptoms related to vaginal atrophy.

Treatment of Menopause: Osteoporosis

Treatment of Menopause: Prevention / Treatment of Osteoporosis

Treatment of Menopause: Cardiovascular Disease

Alzheimer’s Disease

Alzheimer’s disease (AD) is a significant health problem for aging men and women in the United States. After age 65 the prevalence of Alzheimer’s disease exponentially increases with age, with the number of affected persons doubling every five years and commonly affects women far more often than men. Multiple epidemio-logical studies have suggested a beneficial effect of estrogen on AD, while others have shown no benefit. In the WHI memory study (WHIMS), investigators found an increase in all-cause dementia in the hormone replacement therapy arm although this was not seen in the estrogen replacement therapy arm. AD was not addressed separately in this study, and the results are further limited by small numbers of cases. The women in this study were 65 years or older. Based on the current literature, estrogen probably does not slow or improve AD progression, and when hormone replacement therapy is given to older women it may increase the risk of dementia.

Risks of Hormone Replacement

Other Risks of Hormone Replacement Therapy

Observational studies of the risk of stroke among users of hormone replacement therapy have yielded inconsistent results. The WHI study demonstrated an increased risk among combination hormone replacement therapy users as well as users of estrogen alone compared to placebo. A meta-analysis of randomized clinical trial found that oral estrogen use was primarily associated with increased risk of ischemic stroke rather than hemorrhagic stroke or transient ischemic attacks.

HRT appears to increase the risk of gallbladder disease in observational studies as well as randomized clinical trials. Estimates from the WHI suggests that the magnitude of the absolute risk translates into about 3 additional cases per 1000 women. Previous cholecystectomy is not a contraindication to hormone replacement therapy.

Benefits

Colon Cancer

Colon cancer is the third leading cancer and cause of cancer death in women. Multiple studies (retrospective as well as observational cohort studies like the Nurses Health Study) have suggested an association between hormone replacement therapy and a decreased incidence of colon cancer and were confirmed by recent findings from the WHI. In the WHI trial, patients receiving hormone replacement therapy had a significantly lower incidence of colon cancer compared to placebo. However, there was no such reduction in the estrogen replacement therapy arm.

Macular Degeneration

Macular degeneration (MD) is the leading cause of legal blindness in the United States, accounting for 25 to 60% of all new cases. The pathogenesis of MD is unknown and currently there is no effective medical therapy, with surgical photoco-agulation being useful in only a limited number of patients. Multiple retrospective studies as well as data from the WHI has suggested that hormone replacement therapy may decrease the incidence of MD.

Skin

As postmenopausal women age, there is a linear decrease in skin collagen content of 2.1 % and skin thickness of 1.13% per year from premenopausal levels during the initial 15 to 18 postmenopausal years. hormone replacement therapy prevents some of this collagen loss but is not currently an indication for long term estrogen use.

Benefits of Hormone Replacement

There is an increased prevalence of sexual dysfunction following the menopause. Causes include psychogenic, endocrinologic, vascular, neurogenic, muscular, medication-related and infection. Endocrinologic changes associated with loss of estrogen at the menopause include vulvo-vaginal atrophy and possibly decreased desire or arousal. The use of estrogen replacement therapy or hormone replacement therapy can improve symptoms of sexual dysfunction by improving genital sensation, as well as decreasing pain and burning during intercourse. Some studies suggest that a combination of estrogen and testosterone may improve libido.

Key Points on hormone replacement therapy Use

In the past, hormone replacement therapy was prescribed for women for a multitude of potential health benefits. It was previously thought that hormone replacement therapy, in addition to its beneficial role in osteoporosis, could protect against cardiac disease, stroke, and Alzheimer’s disease. The recent prospective, randomized, and blinded studies have challenged the validity of this. Based on current literature, hormone replacement therapy is indicated today only for the treatment of vasomotor symptoms and vaginal atrophy, and prevention/treatment of osteoporosis. hormone replacement therapy should be prescribed in the lowest effective dose for the shortest period of time. Therefore, bone-specific agents would likely be more appropriate in patients requiring long-term osteoporosis prevention/treatment. Ultimately, the decision regarding whether or not to take hormone replacement therapy is a personal one, to be decided by the patient herself with guidance from her physician.

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