Perimenopause: Rocky road to menopause

Symptoms we call “menopausal” often precede menopause by years.

(This article was first printed in the August 2005 issue of the Harvard Women’s Health Watch. For more information or to order, please go to

You’re in your 40s, you wake up in a sweat at night, and your periods are erratic, and often accompanied by heavy bleeding: Chances are, you’re going through perimenopause. Many women experience an array of symptoms as their hormones shift during the months or years leading up to menopause — that is, the natural end of menstruation. Menopause is a point in time, but perimenopause (peri, Greek for “around” or “near,” + menopause) is an extended transitional state. It’s also sometimes referred to as the menopausal transition, although technically, the transition ends 12 months earlier than perimenopause (see “Stages of reproductive aging,” below). Perimenopause has been variously defined, but experts generally agree that it begins with irregular menstrual cycles — courtesy of declining ovarian function — and ends a year after the last menstrual period.

Perimenopause varies greatly from one woman to the next. The average duration is three to four years, although it can last just a few months or extend as long as a decade. Some women feel buffeted by hot flashes and wiped out by heavy periods; many have no bothersome symptoms. Periods may end more or less abruptly for some, while others may menstruate erratically for years. Fortunately, as knowledge about reproductive aging has grown, so have the options for treating some of its more distressing features.

Dance of the hormones

The physical changes of perimenopause are rooted in hormonal alterations, particularly variations in the level of circulating estrogen.

During our peak reproductive years, the amount of estrogen in circulation rises and falls fairly predictably throughout the menstrual cycle. Estrogen levels are largely controlled by two hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH stimulates the follicles — the fluid-filled sacs in the ovaries that contain the eggs — to produce estrogen. When estrogen reaches a certain level, the brain signals the pituitary to turn off the FSH and produce a surge of LH. This in turn stimulates the ovary to release the egg from its follicle (ovulation). The leftover follicle produces progesterone, in addition to estrogen, in preparation for pregnancy. As these hormone levels rise, the levels of FSH and LH drop. If pregnancy doesn’t occur, progesterone falls, menstruation takes place, and the cycle begins again.

Talk about hot … flashes that is

Most women don’t expect to have hot flashes until menopause, so it can be a big surprise when they show up earlier, during perimenopause. Hot flashes — sometimes called hot flushes and given the scientific name of vasomotor symptoms — are the most commonly reported symptom of perimenopause. They’re also a regular feature of sudden menopause due to surgery or treatment with certain medications, such as chemotherapy drugs.

Hot flashes tend to come on rapidly and can last from one to five minutes. They range in severity from a fleeting sense of warmth to a feeling of being consumed by fire “from the inside out.” A major hot flash can induce facial and upper-body flushing, sweating, chills, and sometimes confusion. Having one of these at an inconvenient time (such as during a speech, job interview, or romantic interlude) can be quite disconcerting. Hot flash frequency varies widely. Some women have a few over the course of a week; others may experience 10 or more in the daytime, plus some at night.

Most American women have hot flashes around the time of menopause, but studies of other cultures suggest this experience is not universal. Far fewer Japanese, Korean, and Southeast Asian women report having hot flashes. In Mexico’s Yucatan peninsula, women appear not to have any at all. These differences may reflect cultural variations in perceptions, semantics, and lifestyle factors, such as diet.

Although the physiology of hot flashes has been studied for more than 30 years, no one is certain why or how they occur. Estrogen is involved — if it weren’t, estrogen therapy wouldn’t relieve vasomotor symptoms as well as it does — but it’s not the whole story. For example, researchers have found no differences in estrogen levels in women who have hot flash symptoms and those who don’t. A better understanding of the causes of hot flashes could open the way to new, nonhormonal treatments. Hormone therapy quells hot flashes, but it’s not risk-free.

One line of inquiry has focused on why some women have hot flashes and others don’t. An intriguing explanation has emerged, thanks largely to research led by Wayne State University School of Medicine scientist Robert R. Freedman, who has studied hot flashes for 25 years. He and his colleagues have measured skin temperature, blood flow, and skin conductance (an electrical measure of sweating) in menopausal women before, during, and after hot flashes. They’ve asked subjects to wear monitors to collect hot flash data, swallow radiotelemetry pills to measure core body temperatures, and spend nights in a sleep laboratory to have their hot flashes tracked.

Freedman has found that women who have hot flashes have a lower tolerance for small increases in the body’s core (innermost) temperature than women who don’t have hot flashes. The body tries to maintain its core temperature within a comfortable “thermoneutral zone.” When our core temperature rises above the zone’s upper threshold, we sweat; when it drops below the lower threshold, we shiver. Women who don’t have hot flashes have a thermoneutral zone of several tenths of a degree centigrade. But in women with hot flashes, this thermoneutral zone is so narrow, it’s “virtually nonexistent,” says Freedman (see illustration). As a result, small variations in core body temperature — by as little as one-tenth of a degree centigrade — that don’t trouble some women trigger hot flashes (and chills) in others.

Source: Adapted from Freedman, RR. Seminars in Reproductive Medicine 2005; 23 (2): 117-125.

What causes the thermoneutral zone to narrow? One idea is that elevated levels of the brain chemical norepinephrine are involved. Norepinephrine has been shown to reduce the thermoneutral zone in animals. Conversely, the drug clonidine, which lowers norepinephrine, widens the zone in women with hot flashes. So do estrogen and certain antidepressants, though scientists still don’t understand all the mechanisms.

Because hot flashes are triggered by elevations in core body temperature, the first-line strategy for avoiding them is keeping cool: Drink cold beverages and avoid hot ones, use fans and air conditioners, and dress in layers. Another nondrug technique is paced respiration. In controlled studies, Dr. Freedman has shown that paced respiration can reduce hot flash frequency by about 50%. Women in these studies were trained to take slow, deep, full breaths — expanding and contracting the abdomen gently while inhaling and exhaling — at a rate of about six to eight breaths per minute. One of the best ways to learn paced respiration is by taking a yoga class, then practicing this technique twice a day for 15 minutes. You can also use paced respiration whenever you feel a hot flash coming on.

By our late 30s, we don’t produce as much progesterone. The number and quality of follicles also diminishes, causing a decline in estrogen production and fewer ovulations. As a result, by our 40s, cycle length and menstrual flow may vary and periods may become irregular. Estrogen may drop precipitously or spike higher than normal. Over time, FSH levels rise in a vain attempt to prod the ovaries into producing more estrogen.

Although a high FSH can be a sign that perimenopause has begun, a single FSH reading isn’t a reliable indicator because day-to-day hormone levels can fluctuate dramatically (see middle graphic, below).

By comparison with the regularity of hormone levels before perimenopause (top graph) and their relative quiescence after it (bottom graph), the course of one perimenopausal woman’s hormones over a six-month period (middle graph) looks like Mr. Toad’s Wild Ride. Not all women’s hormones are so adventurous.

Perimenopausal symptoms

It can be difficult to distinguish the hormonally based symptoms of perimenopause from more general changes due to aging or common midlife events — such as children leaving home, changes in relationships or careers, or the death or illness of parents. Given the range of women’s experience of perimenopause, it’s unlikely that symptoms depend on hormonal fluctuations alone.

  • Hot flashes and night sweats. An estimated 35%–50% of perimenopausal women suffer sudden waves of body heat with sweating and flushing that last 5–10 minutes, often at night as well as during the day. They typically begin in the scalp, face, neck, or chest and can differ dramatically among women who have them; some women feel only slightly warm, while others end up wringing wet. Hot flashes often continue for a year or two after menopause. In up to 10% of women, they persist for years beyond that.
    The Study of Women’s Health Across the Nation, which surveyed almost 15,000 women in the United States, found that, on average, African American women had more hot flashes than white women, and Asian women had the fewest of all ethnic groups surveyed. Research has also found that hot flashes are associated with greater body weight, smoking, and stress.
  • Vaginal dryness. During late perimenopause, falling estrogen levels can cause vaginal tissue to become thinner and drier. Vaginal dryness (which usually becomes even worse after menopause) can cause itching and irritation. It may also be a source of pain during intercourse, contributing to a decline in sexual desire at midlife.
  • Uterine bleeding problems. With less progesterone to regulate the growth of the endometrium, the uterine lining may become thicker before it’s shed, resulting in very heavy periods. Also, fibroids (benign tumors of the uterine wall) and endometriosis (the migration of endometrial tissue to other pelvic structures), both of which are fueled by estrogen, may become more troublesome.
  • Sleep disturbances. Data presented at a March 2005 NIH conference on managing menopausal symptoms suggest that about 40% of perimenopausal women have sleep problems. Some studies have shown a relationship between night sweats and disrupted sleep; others have not. The problem is too complex to blame on hormone oscillations alone. Sleep cycles change as we age, and insomnia is a common age-related complaint in both sexes.
  • Mood symptoms. Estimates put the number of women who experience mood symptoms during perimenopause at 10%–20%. Some studies have linked estrogen to depression during the menopausal transition, but there’s no proof that depression in women at midlife reflects declining hormone levels. In fact, women actually have a lower rate of depression after age 45 than before. Menopause-related hormone changes are also unlikely to make women anxious or chronically irritable, although the unpredictability of perimenopause can be stressful and provoke some episodes of irritability. Also, some women may be more vulnerable than others to hormone-related mood changes. The 2005 NIH conference concluded that the best predictors of mood symptoms at midlife are life stress, poor overall health, and a history of depression.
  • Other problems. Many women complain of short-term memory problems and difficulty concentrating during the menopausal transition. Although estrogen and progesterone are players in maintaining brain function, there’s too little information to separate the effects of aging and psychosocial factors from those related to hormone changes.

What to do about symptoms

Several treatments have been studied for managing perimenopausal symptoms. Complementary therapies are also available, but research on them is limited and the results are inconsistent.

  • Vasomotor symptoms. The first rule is to avoid possible triggers of hot flashes, which include warm air temperatures, hot beverages, and spicy foods. You know your triggers best. Dress in layers so you can take off clothes as needed. There’s clear evidence that paced respiration, a deep breathing technique, helps alleviate hot flashes (see sidebar story about hot flashes).The most effective treatment for severe hot flashes and night sweats is estrogen. Unless you’ve had a hysterectomy, you’ll also need to take a progestin to reduce the risk of developing endometrial cancer. Low-dose estrogen by pill or patch — for example, doses that are less than or equal to 0.3 milligrams (mg) conjugated equine estrogen, 0.5 mg oral micronized estradiol, 25 micrograms (mcg) transdermal (patch) estradiol, or 2.5 mcg ethinyl estradiol — works for many women. Other low-dose estradiol-based products include a skin lotion applied to the legs (Estrasorb) and a gel applied to the arms (EstroGel), both available by prescription. The long-term risks of low-dose estrogen aren’t known.
    If you need contraception and don’t smoke, you can take low-dose birth control pills until menopause (see “Irregular periods and heavy bleeding”). Another advantage of these pills is that they regulate your menses and suppress the erratic hormonal ups and downs of perimenopause; some women report feeling more even-tempered while taking them. Progestins taken alone, such as Megace and Depo-Provera, have been shown to reduce hot flashes, but their safety for this purpose has not been tested.Women with severe hot flashes who don’t want or can’t take a hormonal therapy may get some relief from newer antidepressants such as Effexor (venlafaxine) or certain selective serotonin reuptake inhibitors (SSRIs), for example, Prozac (fluoxetine) and Paxil (paroxetine); the epilepsy drug Neurontin (gabapentin); or clonidine, a blood pressure drug. Some of these medications have side effects that may limit their usefulness. Also, some SSRIs can interfere with the metabolism of tamoxifen in certain women.

    Information on the value of nutritional supplements is mixed. Although the NIH is studying black cohosh, results from research on the possible benefits of this herb, isoflavones, and other phytoestrogens have been inconsistent as of summer 2005, in part because of varying doses and preparations. Studies of evening primrose oil, dong quai, ginseng, red clover, acupuncture, and vitamin E have shown little or no benefit in alleviating hot flashes. So-called bioidentical hormones that are compounded individually (sometimes based on blood or salivary tests of hormone levels) may help, just as FDA-approved products do, but their safety and effectiveness haven’t been well-studied.

  • Irregular periods and heavy bleeding. If you have irregular bleeding and don’t want to become pregnant, low-dose birth control pills are a good choice. By suppressing ovulation, they modulate menstrual flow, regulate periods, and stabilize endometriosis. They also protect against endometrial and ovarian cancers, stave off hot flashes, reduce vaginal dryness, and prevent bone loss. If you have abnormal bleeding, such as daily or very heavy bleeding, see your gynecologist.
    Oral contraceptives can be taken until menopause. To help determine whether you’ve reached menopause, your clinician may order a blood test of your FSH level, taken after seven days off the pill. But the only wholly reliable measure is 12 months off hormones without a menstrual period.
  • Vaginal dryness. Low-dose contraceptives or vaginal estrogen (in a cream, ring, tablet, or gel) can help relieve vaginal dryness, but hormonal treatment is not the only approach. Vaginal moisturizers such as Replens, applied twice weekly, increase vaginal moisture, elasticity, and acidity. Continued sexual activity also seems to improve vaginal tone and helps maintain the acidic environment that protects it against infections. Lubricants such as K-Y Jelly, Astroglide, and K-Y Silk-E can make intercourse less painful.

(This article was first printed in the August 2005 issue of the Harvard Women’s Health Watch. For more information or to order, please go to



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