The average age of menopause is 51 years, with a normal range of 43 to 57 years.
Can also be induced by oophorectomy or iatrogenic ablation of ovarian function.
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).
The transition from reproductive to postreproductive life is divided into several stages, with the final menstrual period (FMP) serving as an anchor.
Five stages (−5 to −1) precede the FMP and two stages follow (+1 and +2).
Menopausal transition, traditionally termed perimenopause or the climacteric, is the transition period from regular menstruation until menopause.
May last for 5 years or more, highly variable in duration
Characterized by menstrual cycle changes that include variable cycle length, with skipped periods and increasingly longer intervals of amenorrhea
Figure 43-1. Stages/nomenclature of normal reproductive aging in women. (From Soules MR, Sherman S, Parrott E, et al. Executive summary: stages of reproductive aging workshop [STRAW]. Fertil Steril 2001;76:874, with permission.)
Associated with the cessation of ovulation, a marked decline in estradiol production, and a modest decline in androgen production
Early menopausal transition (−2) is depicted by variable cycle length (>7 days different from the norm) and increased follicle-stimulating hormone (FSH).
Late menopausal transition (−1) is characterized by two skipped cycles and an interval of amenorrhea >60 days.
Diagnosis of menopause is clinical, without reliance on hormonal measurements.
When any doubt exists about menopause, other causes of secondary amenorrhea must be ruled out. See Chapter 39.
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.
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.
The early menopause transition is typified by increased levels of FSH leading to overall higher estrogen levels.
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.
Seventy-five percent of menopausal women experience vasomotor symptoms such as hot flashes and night sweats.
Symptoms begin an average of 2 years before the FMP.
Eighty percent of women who have hot flashes endure them for longer than 1 year and 50% for longer than 5 years.
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
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.
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)
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.
Estrogen administration: the most effective treatment for hot flashes, given orally, transdermally, or vaginally (Table 43-1)
Oral dosing: results in plasma level fluctuations and an estradiol to estrone ratio of <1
Oral estrogen plus androgen combinations are available and may help with decreased postmenopausal libido, but this is somewhat controversial.
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.
Avoids first-pass liver metabolism effect, which prevents an effect on synthesis of clotting factors and decreases the effect on lipid metabolism
Dosing of HT for vasomotor symptoms is listed in Table 43-1.
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.
The progestin is administered either continuously with daily dosing or cyclically with daily dosing only during the last half of each cycle.
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)
Alternatives to HT for vasomotor symptoms are for patients who feel estrogen produces unacceptable side effects or who have contraindications.
Selective serotonin and norepinephrine reuptake inhibitors (SSRI, SNRI):
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%.
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.
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.
Progestins:
Oral and intramuscular progestins have shown good efficacy in randomized trials. There is conflicting evidence regarding the effectiveness of transdermal preparations.
Medroxyprogesterone acetate, 150 mg intramuscularly per month, has been shown to be 90% effective in the treatment of hot flashes.
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
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.
Behavior modification:
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.
Relaxation techniques, such as slow breathing and yoga, can reduce the frequency of menopausal symptoms and alleviate hot flashes.
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