Natural menopause is traditionally defined as the time period that occurs after 12 consecutive months of amenorrhea. The average age of menopause is about 51 years. The perimenopause or climacteric refers to the time period before the onset of menopause, when changes in a woman's hormonal milieu are associated with irregular menstrual cycles and increased episodes of amenorrhea. The clinical definition of the perimenopause requires: 1) a self-report of 3 to 11 months of amenorrhea and 2) increased menstrual irregularity in women who are not experiencing amenorrhea.¹ This transition lasts about 4 years and usually occurs between ages 45 and 55.^1,2

Smoking is the greatest independent risk factor for earlier menstrual irregularity and earlier menopause. Smoking causes an earlier perimenopause and menopause by about 1 to 2 years.^3,4 Another strong indicator for an earlier age at menopause is a maternal history of early menopause.⁵

Once a woman older than 45 has had 1 year of amenorrhea, she has less than a 10% likelihood of ever menstruating again.⁶ However, there is no clear-cut transition period from the pre- to the postmenopausal state. Cessation of menstrual cyclicity occurs spontaneously at some point during this transition, and it is not necessarily associated with its definition.

Regarding the hormonal milieu of women traversing the menopause, Metcalf and associates⁷ could not distinguish any hormonal changes between those found in the irregular cycles of the perimenopausal woman from those of the immediately postmenopausal woman, except that no progesterone was ever made after menopause. Thus, it was suggested that the point at which menstruation ceases during the menopause transition involves not hormonal changes, but instead endometrial factors. In other words, aging may affect the ability of the endometrium to respond to estrogens. However, the preponderance of evidence now suggests that changes are occurring in a woman's hormonal environment during the perimenopause.

During the perimenopause, there is thought to be an increase in the number of anovulatory cycles. However, the mechanisms responsible for perimenopausal anovulation remain unclear. The anovulatory cycles occurring during the perimenopause appear similar to those occurring in adolescents and may reflect an inability to produce increased gonadotropins after exposure to estrogen.⁸ There may be central changes in the hypothalamic-pituitary axis that affect gonadotropin secretion. This has been suggested by the lack of response to an estradiol challenge with a luteinizing hormone surge in perimenopausal women with dysfunctional uterine bleeding.^8,9,10 However, abnormalities in ovarian steroid or peptide secretion may also play a role.

During the perimenopause, ovarian function appears to be highly variable. Length of menses varies and anovulatory cycles become more common. Hormone levels may fluctuate widely during this time, and as estrogen levels decrease, the inherent protective effects of estrogen may also decrease. Thus, the hormonal changes associated with aging may have detrimental effects that must be recognized, addressed, and ameliorated when possible.

Many of the physiologic changes associated with menopause occur or begin before the last menstrual period¹¹ and may be associated with somatic aging. Somatic aging is reflected by decreases in somatotropic axis function, adrenal androgen production, and continuous loss of bone mineral density after peak bone mass has been attained. Several hormonal systems have age-related changes that may be associated with reproductive aging.⁸

Ovarian function is the most important factor mediating the pace of the menopausal transition. The ultimate causative factor for perimenopause and menopause is depletion of ovarian follicles. However, aging changes in nonreproductive endocrine systems, such as the hypothalamus, pituitary, uterus, and ovary, may also contribute to the perimenopause. As of yet, however, none of these systems has been fully examined in detail in the human. Therefore, their contribution to the perimenopause and menopause remains unclear.

Cycle Length

With increasing age, there is a significant decrease in the length of the follicular phase of the menstrual cycle. Women ages 18 to 24 had an average follicular phase length of 15 ± 2 days, but those ages 40 to 44 had an average length of 10 ± 4 days.¹² Accelerated folliculogenesis during the perimenopause appears to cause this shortening in follicular phase length. This, in turn, causes a decrease of about 3 days in the intermenstrual interval in most women.¹³ This change in follicular phase length is not necessarily continuous. Until the perimenopause, mean menstrual cycle length decreases with increasing age. During the perimenopause, however, mean cycle length becomes highly variable.¹⁴ The irregularity of perimenopausal menstrual cycles is unpredictable, and there is no apparent orderly progression between the extremes of short and long cycles.¹⁵ Although the perimenopausal menstrual cycle is “irregularly irregular,” the average decrease of follicular phase length by 3 to 4 days is clinically useful because it occurs before obvious, clinically detectable endocrine changes.¹⁶

Changes in the Hormonal Milieu

During the perimenopause, midcycle estrogen concentrations have been observed to be normal or increased,^13,17,18,19 and levels of progesterone and androgens have been observed to be normal or decreased, independent of major changes in sex hormone-binding globulin.^20,21

Changes in Gonadotropin Levels

Sherman and associates^17,22 followed six women for several years, including the time of their last menstrual period, and noted: 1) a monotropic rise in follicle-stimulating hormone (FSH) levels occurred even with normal menstrual cycling; 2) occasional anovulatory cycles occurred; and 3) in one woman, the last menstrual period occurred after an ovulatory cycle.

The increase in FSH that occurs during the menopause transition has been attributed to a loss of ovarian inhibin with aging. This relation appears to be supported by available immunoassay data^17,22,23; however, a cause-and-effect relation between the inhibins (A or B) and FSH suppression remains to be established in the human.

Although FSH levels increase progressively with age, there is a great deal of overlap regarding its level and its association with the timing of menopause. Thus, although it may be useful in fertility workups, it is a poor predictor of the time of menopause.^20,21 The age at which the FSH rise first appears may not necessarily correlate with menopause. Longitudinal studies have shown that the increase in FSH occurs as early as the early 40s in normal women.²⁴ Along with the elevation in FSH, there is a lesser, but still significant, rise in perimenstrual levels of luteinizing hormone (LH).²⁴

Changes in gonadotropin receptor levels have also been noted to occur during the perimenopause. A Finnish study²⁵ investigated FSH, LH, and 17-beta-estradiol levels in perimenopausal women before elective abdominal hysterectomy and salpingo-oophorectomy and measured ovarian FSH and LH receptor content. Higher serum gonadotropin levels were found in women with fewer gonadotropin receptors. Postmenopausal women had no detectable FSH or LH receptor levels. Thus, it may be that gonadotropin levels change in the perimenopause in response to low receptor levels. High serum gonadotropin levels in perimenopausal women suggest the presence of low or undetectable ovarian gonadotropin receptors. The authors proposed that measurement of gonadotropin receptors may be a useful indicator of ovarian status during the perimenopause.

However, to date, there exist no absolute markers of ovarian function. The marked variations in FSH and LH excreted during a typical ovulatory menstrual cycle indicate that there is no simple estimate of the effect of age on ovarian function. It is difficult if not impossible to recognize early ovarian failure in the clinical setting.²⁴

Changes in the Estrogenic Environment

Hyperestrogenemia may be a feature of the early perimenopause, but the immediately premenopausal cycles may have reduced estrogen levels.^8,13 An important but often clinically frustrating aspect of the perimenopause is that estradiol levels do not gradually decrease; instead, they fluctuate greatly around the normal range until menopause, when no more responsive follicles are available.²⁶ The anovulatory cycles often seen may be associated with elevated levels of estradiol.^13,19 Thus, as a woman ages, there is not a downward spiral in the estrogenic milieu, but instead a roller coaster in estrogen production.⁸ This fluctuation in estrogen levels, associated with periods of hyperestrogenemia, may predispose a woman to irregular bleeding and endometrial hyperplasia with its potential sequelae. Thus, it is important to take seriously irregular bleeding in the perimenopausal patient and to perform a biopsy when necessary.

The perimenopausal fluctuations in estradiol may result from the aging ovary's being less responsive to FSH. Thus, greater circulating amounts of FSH are needed to initiate folliculogenesis. Once commenced, the FSH may cause an overshoot of estradiol that results in hyperestrogenemia.^8,13

After a woman's final menstrual period, progesterone is no longer produced, but for a brief time, small amounts of estrogen may still be produced. Metcalf and co-workers⁷ observed that although elevations in FSH and LH were common before the final menstrual cycle, episodes of significant estrogen production were not uncommon in the first year after the final menstruation.

Changes in the Progesterone Environment

Both normal^16,17,22,27 and decreased^13,18 levels of progesterone secreted by the corpus luteum have been observed in the perimenopause. Further clarification regarding perimenopausal progesterone levels would be clinically very useful, because if decreased levels of progesterone are associated with increased levels of estradiol, this may also predispose women to dysfunctional uterine bleeding and endometrial hyperplasia.

Changes in Growth Hormone Levels

Growth hormone (GH) is a pulsatile hormone released from the anterior pituitary under hypothalamic regulation by growth hormone-releasing hormone (GHRH). Somatostatin, however, inhibits the secretion of growth hormone. With aging, there is a decrease in GH secretion. It remains to be elucidated whether the decrease in GH is secondary to increased release of somatostatin, decreased levels of GHRH, decreased sensitivity to GHRH, or a combination of these factors.⁸

Estrogen appears to play an important role in GH secretion in women. There is a positive association between estrogen status and GH concentrations. Thus, in a decreased estrogenic environment, such as in menopause, there is decreased GH secretion.²⁸

Age itself may be a more important factor affecting GH concentration than estrogen alone. Recent studies have shown that a decrease in somatotropic axis activity is detectable before any changes occur in menstrual cyclicity or decreased production of estradiol. Older, regularly cycling women (age 42 to 46) have lower daytime GH concentrations than younger, regularly cycling controls (age 19 to 34). This occurred in the older women despite higher estradiol levels on the day of sampling (compared with their younger controls) and overall normal parameters of gonadal hormones. The older reproductive-age women had twice the early follicular phase concentration of estradiol as did their younger controls (mean ± standard error of the mean, 368 ± 51 vs. 167 ± 20 pmol/L).²⁹

INSULIN-LIKE GROWTH FACTOR 1.

Older reproductive-age women with elevated estradiol and decreased GH levels have been observed to demonstrate a trend toward lower levels of insulin-like growth factor 1 (IGF-1).²⁹ How these changes in GH and IGF-1 affect the physiology of a perimenopausal woman is not fully understood. It remains to be shown whether the changes in function of the somatotropic axis and hormonal environment affect sensitivity to insulin. This is an important association to be determined, because during the perimenopause, insulin sensitivity decreases, especially when there is weight gain.^30,31,32 Wing and colleagues³¹ noted a direct correlation with perimenopausal weight gain and insulin resistance. Thus, aging is associated with decreased GH and IGF-1 levels, decreased insulin sensitivity, increased insulin resistance,³³ and weight gain.³⁴

As women age, they gain weight. A prospective study of 485 middle-aged women (42 to 50 years) revealed that after 3 years, the women gained an average of 2.25 ± 4.19 kg. This change is not entirely dependent on menopausal status, as there were no significant differences between the amount of weight gained by women who remained premenopausal versus those who became menopausal (2.07 vs. 1.35 kg).³¹

The possible sequelae of these changes in weight and IGF-1 level may have great clinical impact because they are predictive of cardiovascular disease.^31,32 Thus, the perimenopause is an important time for a woman to mitigate her risk factors for cardiovascular disease (weight control, diet, and exercise).

In vitro, insulin and IGF-1 can both act as stimulants of androgens by the ovarian stroma and theca tissues. Thus, changes in the androgenic environment can be affected by several factors.

Changes in the Androgenic Environment

During a woman's reproductive years, the three major sources for circulating androgens are the ovary, the adrenal cortex, and peripheral conversion of circulating androstenedione and dehydroepiandrosterone (DHEA) to testosterone. The ovary produces 25% of circulating testosterone, 60% of circulating androstenedione, and about 20% of circulating DHEA. The adrenal cortex produces 40% of circulating androstenedione, 25% of testosterone, and almost all DHEA and DHEA sulfate (DHEAS). After menopause, peripheral conversion of androstenedione accounts for about 50% of circulating testosterone levels.³⁵ About 50% of postmenopausal women still have androgens produced by the ovaries. Although the quantities are minimal, their physiologic significance, if any, is unknown.³⁶

The perimenopausal ovary may actually be producing increased levels of estrogen secondary to increased pituitary secretion of FSH, but total androgen (from both adrenal and ovarian sources) levels decrease.²¹ During the perimenopause, androgen levels continue the decline that commenced after age 20. By age 40, serum androgen levels are about half those found at age 20.³⁷

In normally menstruating women, there is a preovulatory increase in intrafollicular and peripheral androgens. At midcycle, peripheral androstenedione and testosterone increase by 15% to 20%.³⁸ There are several speculations regarding the role of the midcycle rise in androgens. It may help accelerate follicular atresia so that at ovulation, there is a single dominant follicle.³⁹ It may be involved in the stimulation of libido: it has been shown that female-initiated sexual activity occurs most often at midcycle.⁴⁰

The increase in midcycle free testosterone and androstenedione seen in younger women has been found to be significantly absent in older women (43 to 47 years) who were cycling regularly and had normal levels of prolactin and thyroid-stimulating hormone. The decreased concentrations of free testosterone and androstenedione, without significant changes in sex hormone-binding globulin, suggest that in older women these hormones are produced in less quantity.

Because the changes were dependent on menstrual cycle stage, it was concluded that an ovarian, not an adrenal, process is involved.³⁹ If androgens are important in the production of a single dominant follicle and in stimulating libido, then the agerelated decrease in androgens may play a role in the increased incidence of multiple pregnancy and speculated decreased libido of older women.

Aromatization of androgens, which occurs mostly in extrasplanchnic tissue, is strongly affected by age. The specific activity of aromatase increases with age,⁴¹ and it has been suggested that age may be a stronger predictor of aromatization than weight or body mass index. It has been observed that as women traverse the menopause, the interconversions of androstenedione to testosterone, estrone, and estradiol change. Thus, in the circulation, there is a greater decrease in the concentration of the products (androstenedione and estradiol) than the precursors (testosterone and estrone).²⁰

Regarding adrenal androgens, DHEAS is the most abundant hormone in the body. Its production peaks in the early 20s, and with increasing age its secretion decreases greatly. Its decrease accelerates after menopause.²⁶ Concentrations of DHEAS in the elderly are only about 10% of those in younger persons.⁴² The age-associated decrease in DHEAS is independent of cortisol.⁴³

DHEAS is not biologically active unless it is converted to testosterone or estradiol. The decrease in adrenal androgen secretion that occurs during the perimenopause appears to be independent of reproductive aging and instead represents a somatic aging event. However, studies to substantiate this belief still need to be performed.⁸ Because the adrenal cortex androgens, DHEA and DHEAS, have such low intrinsic biologic activity unless converted to more active androgens, they have only recently been considered to be potentially important in immunocompetence and general well-being.³⁴ Their role in the perimenopause has yet to be fully established.

Hot Flushes

Before the perimenopause, the incidence of hot flushes is about 10%, but during the perimenopause it greatly increases, reaching a peak at menopause of about 50%. By about 4 years postmenopause, the figure drops to about 20%.² A population-based study of subjective reporting of hot flushes in pre-, peri-, and postmenopausal women found that 13% of premenopausal, 37% of perimenopausal, 62% of postmenopausal women, and 15% of women on hormone replacement therapy (HRT) complained of at least one hot flush in the 2 weeks before the study. FSH levels were higher in the women who had at least one hot flush per day. Estradiol levels were higher in the women who had one or no hot flushes per week. It was concluded that hot flush frequency was associated with increasing FSH and decreasing estradiol levels.⁴⁴

Changes in Bone Mineral Density

Decreasing ovarian function in the perimenopause is associated with reduced trabecular bone mass and altered calcium metabolism.⁴⁵ Although premenopausal bone loss is especially significant in cortical bone such as the hip bone, peri- and postmenopausal bone loss occurs in all skeletal sites, especially trabecular bone. In premenopausal women, bone loss has been significantly associated with lower concentrations of androgens; however, in peri- and postmenopausal women, lower levels of androgens and estrogens have been noted. Thus, sex steroids are important before menopause to maintain integrity of the skeleton and also are important during the peri- and postmenopausal years.⁴⁶

Bone mass measurements may be predictive of perimenopausal traumatic fractures in addition to postmenopausal fractures secondary to osteoporosis. Fractures in perimenopausal women can be weakly but significantly predicted by bone mass quantification (especially of the lumbar spine) using dual-energy x-ray absorptiometry (DEXA) of the hip and spine. One study of screening DEXA involving 1,000 perimenopausal women noted a 2% incidence of stress fractures in women in the 2 years before screening.⁴⁷

A study comparing bone mineral density of pre-, peri-, and postmenopausal women revealed that compared with premenopausal women, bone mineral density was lower only in postmenopausal women not currently using HRT.⁴⁸ However, bone mineral density decreased with age in the perimenopausal group, and bone resorption rates increased in the perimenopausal group. Compared with premenopausal women, perimenopausal women had twice the gonadotropin levels and 20% greater urine N-telopeptide excretion. However, their serum estradiol levels and bone formation markers were no different. In postmenopausal women, bone resorption markers were decreased in women using HRT. The researchers concluded that the overall major independent factors of bone mineral density were age and levels of urine N-telopeptide, serum bone alkaline phosphate, and serum FSH. Urine free deoxypyridoxine was positively associated with bone mineral density in pre- and perimenopausal women. Further studies are necessary to establish the role of urinary bone markers in clinical care of the perimenopausal woman.

Cardiovascular Changes in the Perimenopause

After age 40, cardiovascular disease is the leading cause of death in women in the United States.⁴⁹ After menopause, the incidence of coronary heart disease increases, probably due to multiple mechanisms. Risk factors for cardiovascular disease include high cholesterol and other alterations in the lipid profile, abnormal glucose tolerance, insulin resistance, hypertension, smoking, and obesity. After the menopause, higher triglycerides, cholesterol, total/high-density lipoprotein cholesterol ratio, very low-density and low-density lipoprotein cholesterol, insulin levels, and body weight are present.^31,32,50,51

Hormonal fluctuations that occur during the perimenopause may affect cardiovascular risk factors. Estrogen may have cardioprotective effects independent of its effects on lipids, including vasodilation, improved pulsatility index, improved blood flow, and inhibition of atheromatous plaque formation.^52,53,54,55

Cardiovascular risk factors can be modified by lifestyle changes, including exercise, weight loss, careful diet, blood-pressure monitoring, and stress reduction. The perimenopause presents an ideal time for a woman to modify her risk factors to maximize not only her perimenopausal years but also her menopausal years.

HRT given during the perimenopause may not only alleviate symptoms such as hot flushes and difficulty sleeping, but also may restore hypothalamic-pituitary-ovarian function. In one study, 32 perimenopausal women age 42 to 47 years with irregular anovulatory cycles and menopausal symptoms were given 6 months of treatment with transdermal estradiol patches (0.05 mg/day for 21 days) and oral progestogens (10 mg/day for 10 days).⁵⁶ During therapy, menopausal symptoms were ameliorated and there was an increase in estradiol and a decrease in FSH and LH levels. After 6 months of therapy, FSH and LH concentrations were significantly lower than before HRT.

If a patient has complaints associated with the perimenopause such as hot flushes and difficulty sleeping, it is reasonable to consider starting HRT. It will relieve symptoms such as hot flushes and will also ameliorate the woman's risk factors for cardiovascular disease and osteoporosis, two major causes of morbidity and mortality in the older woman.

However, standard HRT regimens are inadequate for contraception. A sexually active woman who has had less than 1 year of amenorrhea before beginning HRT is at a low but present risk for an unwanted pregnancy. She should be advised and encouraged to consider other forms of contraception. Alternatively, very low-dose (20 μg) ethinyl estradiol oral contraceptives have a high rate of acceptance and an excellent safety profile in the nonsmoking older reproductive-aged woman and may be safely used up to menopause.

The transition from oral contraceptives to hormone replacement therapy is a clinical dilemma. There is no biochemical test that definitively predicts the menopausal state. Without conclusive clinical data, it is our policy to establish prospectively a date at which oral contraceptives will be discontinued and hormone replacement therapy will be commenced. This can be done in partnership with the perimenopausal patient and must take into account the fact that hormone replacement therapy is not an adequate contraceptive. For most women, a comfortable age at which to make this transition is about 51 years, or the average age at natural menopause.

The perimenopause is a poorly defined period in a woman's life. Changes in the hormonal environment may be the cause of many of our patients' clinical signs and symptoms. Women may present with “irregularly irregular” menses, dysfunctional uterine bleeding, hot flushes, difficulty sleeping, and osteoporosis. These and other complaints may result from the periods of hyperestrogenemia, normal or hypoestrogenemia, decreased androgen levels, and decreased levels of GH and IGF-1 seen in the perimenopause. Although the treatment of the perimenopausal woman is sometimes clinically challenging due to the lack of a neatly organized transition period and the variation that exists between women and within each woman, it is important that we become familiar with the perimenopausal woman and her needs. The perimenopause represents an ideal time for amelioration of risk factors that may affect her quality of life, not just during the perimenopause but during menopause as well.

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