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The average age of menopause is 51 years, with a normal range of 43 to 57 years.
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Can also be induced by oophorectomy or iatrogenic ablation of ovarian function.
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In 2001, the Stages of Reproductive Aging Workshop divided normal female reproductive aging into stages, with the goal of clarifying terminology relating to menopause (Fig. 43-1).
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The transition from reproductive to postreproductive life is divided into several stages, with the final menstrual period (FMP) serving as an anchor.
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Five stages (−5 to −1) precede the FMP and two stages follow (+1 and +2).
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Menopausal transition, traditionally termed perimenopause or the climacteric, is the transition period from regular menstruation until menopause.
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May last for 5 years or more, highly variable in duration
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Characterized by menstrual cycle changes that include variable cycle length, with skipped periods and increasingly longer intervals of amenorrhea
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Associated with the cessation of ovulation, a marked decline in estradiol production, and a modest decline in androgen production
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Early menopausal transition (−2) is depicted by variable cycle length (>7 days different from the norm) and increased follicle-stimulating hormone (FSH).
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Late menopausal transition (−1) is characterized by two skipped cycles and an interval of amenorrhea >60 days.
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Diagnosis of menopause is clinical, without reliance on hormonal measurements.
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When any doubt exists about menopause, other causes of secondary amenorrhea must be ruled out. See Chapter 39.
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Oocytes undergo atresia throughout a woman’s life, with follicular quantity and quality undergoing a critical decline approximately 20 to 25 years after menarche. This follicular decline results in loss of ovarian sensitivity to gonadotropin stimulation.
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During perimenopause, follicular dysfunction can lead to variable menstrual cycle length. The follicular phase of the cycle is usually shortened due to the decreased number of functional follicles.
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The early menopause transition is typified by increased levels of FSH leading to overall higher estrogen levels.
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As follicular depletion continues, decreased inhibin produced by follicles leads to continued increased FSH. Follicular depletion also leads to recurrent anovulation and subsequent increase in FSH and luteinizing hormone levels.
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Seventy-five percent of menopausal women experience vasomotor symptoms such as hot flashes and night sweats.
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Symptoms begin an average of 2 years before the FMP.
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Eighty percent of women who have hot flashes endure them for longer than 1 year and 50% for longer than 5 years.
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Pathophysiology: due to vasomotor instability thought to be secondary to dysfunction of the thermoregulatory nucleus which is responsible for maintaining body temperature within a set range known as the thermoregulatory zone
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Characterized by a sudden reddening of the skin over the head, neck, and chest, accompanied by a feeling of intense body heat, palpitations and anxiety, sleep disturbance, and irritability. Concludes with profuse perspiration.
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Risk factors: surgical menopause (up to 90% of women will have vasomotor symptoms), early menopause, low circulating levels of estradiol, smoking, and possibly low body mass index (BMI)
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Treatment: Hormone therapy (HT) is first-line treatment. Current recommendations are that HT use should be limited to the lowest effective dose for the shortest treatment duration and that ongoing use should be reevaluated periodically.
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Estrogen administration: the most effective treatment for hot flashes, given orally, transdermally, or vaginally (Table 43-1)
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Oral dosing: results in plasma level fluctuations and an estradiol to estrone ratio of <1
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Oral estrogen plus androgen combinations are available and may help with decreased postmenopausal libido, but this is somewhat controversial.
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Transdermal estrogen: Delivers estrogen at a relatively constant rate of 50 to 100 µg/dL, comparable to premenopausal endogenous estrogen production. Maintains the 1:1 ratio of estradiol to estrone that approximates the natural, premenopausal ratio.
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Avoids first-pass liver metabolism effect, which prevents an effect on synthesis of clotting factors and decreases the effect on lipid metabolism
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Dosing of HT for vasomotor symptoms is listed in Table 43-1.
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In women with a uterus, progestins must be added to any estrogen regimen to prevent the increased risk of endometrial cancer associated with unopposed estrogen use.
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The progestin is administered either continuously with daily dosing or cyclically with daily dosing only during the last half of each cycle.
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Contraindications for HT: history of venous thromboembolism or stroke or those at high risk for developing these conditions, history of breast cancer, or coronary heart disease (CHD)
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Alternatives to HT for vasomotor symptoms are for patients who feel estrogen produces unacceptable side effects or who have contraindications.
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Selective serotonin and norepinephrine reuptake inhibitors (SSRI, SNRI):
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Venlafaxine 150 mg daily reduces hot flashes by 61% over a 4-week treatment course, and paroxetine at either 12.5 mg or 25 mg/day also reduces hot flashes by approximately 60%.
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Clonidine is a centrally acting alpha-adrenergic agonist. In a meta-analysis of 10 trials, clonidine was effective in less than half of the trials at treating vasomotor symptoms compared to placebo.
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Gabapentin (900 mg/day) is also used to treat side effect symptoms. Clinical trials have shown that gabapentin reduces symptoms by 35% to 38% compared to placebo.
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Progestins:
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Oral and intramuscular progestins have shown good efficacy in randomized trials. There is conflicting evidence regarding the effectiveness of transdermal preparations.
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Medroxyprogesterone acetate, 150 mg intramuscularly per month, has been shown to be 90% effective in the treatment of hot flashes.
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These agents are not recommended for patients with a history of breast cancer.TABLE 43-1 Hormone Replacement Therapies
Drug
Dosage
Oral estrogens
Conjugated equine estrogens (Premarin)
0.3-2.5 mg daily
Synthetic conjugated estrogens (Cenestin, Enjuvia)
0.3-1.25 mg daily
Micronized estradiol (Estrace)
0.5-2 mg daily
Esterified estrogens (Menest)
0.3-2.5 mg daily
Estropipate (Ogen, Ortho-Est)
0.625-2.5 mg daily
Estradiol (Femtrace)
0.45-1.8 mg daily
Oral progestins
Micronized progesterone (Prometrium)
200 mg for 12 d each mo or 100 mg daily
Medroxyprogesterone acetate (Provera)
10 mg daily for 12 d each mo
Norethindrone acetate (Aygestin)
2.5-10 mg for 12 d each mo
Oral estrogen/progestin combinations (continuous)
Conjugated estrogens/medroxyprogesterone acetate (Prempro)
0.3/1.5 mg/daily, 0.45/1.5 mg/daily, 0.625/2.5 mg or 0.625/5 mg/daily
Estradiol/norethindrone acetate (Activella)
1.0/0.5 mg daily
Estinyl estradiol/norethindrone acetate (FemHRT)
5 µg/1 mg daily, 2.5 µg/0.5 g daily
Estradiol + drospirenone (Angeliq)
1 mg/0.5 mg daily
Cyclical oral
Estradiol/norgestimate (Prefest)
1 mg estradiol for 15 d and then 1 mg estradiol/0.09 mg norgestimate for 15 d
Conjugated estrogens/medroxyprogesterone acetate (Premphase)
0.625 mg conjugated estrogens for 14 d, then 0.625 mg conjugated estrogens/5 mg medroxyprogesterone for 14 d
Transdermal estrogen preparations
Transdermal estradiol patch (Alora, Climara, Esclim, Estraderm, Menostar, Vivelle, Vivelle-Dot)
Variable dosing; apply twice weekly or weekly, depending on brand
Topical estradiol gel (Divigel, Elestrin, Estragel)
Variable dosing; apply once daily
Topical estradiol emulsion (Estrasorb)
1.74 g/pouch; two pouches applied daily
Topical estradiol spray (Evamist)
1.53 mg/spray; two or three sprays daily
Vaginal estrogen preparations
Vaginal conjugated estrogens (Premarin)
0.625 mg/g; apply daily
Vaginal estradiol cream (Estrace)
0.01% cream; daily then one to three times/wk
Vaginal estradiol ring (Estring, Femring)
50-100 µg/d (Femring), 7.5 µg/d (Estring); replace every 90 d
Vaginal estradiol tablets (Vagifem)
10 µg daily for 2 wk, then twice weekly
Transdermal estrogen and progestin preparations
Estradiol + levonorgestrel (Climara Pro)
0.45 mg/0.015 mg; apply weekly
Estradiol + norethindrone acetate (Combipatch)
0.05 mg/0.14 mg; 0.05 mg/0.25 mg; apply twice weekly
Oral estrogen and androgen combinations
Esterified estrogens + methyltestosterone (Estratest H.S.)
0.625 mg/1.25 mg daily
Esterified estrogens + methyltestosterone (Estratest)
1.25 mg/2.5 mg daily
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Alternative therapies such as soy, black cohosh, red clover, dong quai, and acupuncture have been used to treat hot flashes. However, the limited trials in this area have not shown a benefit compared to placebo. Further investigation is needed to clarify their role in the alleviation of hot flashes and their side effects.
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Behavior modification:
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The North American Menopause Society recommends maintaining a low core body temperature by using a fan and drinking cool beverages to manage mild hot flashes.
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Relaxation techniques, such as slow breathing and yoga, can reduce the frequency of menopausal symptoms and alleviate hot flashes.
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