Lauren Nathan, MD
ESSENTIALS OF DIAGNOSIS
Natural menopause diagnosed after 12 months of amenorrhea with no obvious pathologic cause
Average age 51 years
Estradiol <20 pg/mL and follicle-stimulation hormone level 21–100 mU/mL helpful in establishing the diagnosis
Induced menopause is defined as permanent cessation of menstruation after bilateral oophorectomy or ablation of ovarian function (ie, by chemotherapy or radiation)
Premature menopause defined as menopause reached at or before age 40 and can be natural or induced
Perimenopause/menopause transition defined by menstrual cycle and hormonal changes that occur a few years before and 12 months after the final menstrual period resulting from natural menopause
May be associated with vasomotor symptoms, sleep disturbance, and vaginal/urinary symptoms
General Considerations
According to the 2010 US census, of the 155 million women in this country, 41 million were 55 years of age or older. Most of these women had or shortly would have their last menstrual period, thus becoming postmenopausal. As a woman at age 55 years can expect to live another 28 years, a large portion of the female population is without ovarian function and lives about one-third of their lives after this function ceases. Consequently, physicians caring for women must understand the hormonal and metabolic changes associated with the menopause, or “change of life,” and the potential benefits and risks of hormone therapy (HT).
According to the Comite des Nomenclatures de la Federation Internationale de Gynecologie et d’Obstetrique, the climacteric is the phase of the aging process during which a woman passes from the reproductive to the nonreproductive stage. The signals that this period of life has been reached are referred to as “climacteric symptoms” or, if more serious, as “climacteric complaints.” Perimenopause, or menopausal transition, refers to the part of the climacteric before the menopause occurs when the menstrual cycle is likely to be irregular and when other climacteric symptoms or complaints may be experienced. The menopause is the final menstruation, which occurs during the climacteric. Postmenopause refers to the phase of life that comes after the menopause.
To develop a more functional staging system of reproductive aging, the Stages of Reproductive Aging Workshop (STRAW) was held in 2001 and again 10 years later in another workshop called “STRAW +10”. The specific goals of the workshop were to (a) develop a useful staging system for reproductive aging, (b) revise nomenclature, and (c) identify knowledge gaps that should be addressed by the research community. STRAW + 10 also added more supportive criteria using endocrinologic parameters (Follicle Stimulation Hormone [FSH], anti-mullerian hormone [AMH], Inhibin B) and Antral Follicle count [AMC]). According to STRAW + 10, reproductive aging is divided into 7 stages (−5 to +2), with −5 beginning with menarche and +2 being defined as the late menopause. This staging system is not applicable to women who have undergone hysterectomy or endometrial ablation, who have chronic menstrual irregularity such as polycystic ovarian syndrome (PCO), or who have chronic illness and undergoing chemotherapy. STRAW +10 may also not be applicable to women with other chronic illnesses such as HIV-AIDs but further research into this population needs to be carried out in order to better characterize ovarian function across time in this group of patients.
The menopausal transition, or perimenopause, is divided into 2 stages—early (−2) and late (−1) and encompasses a wide age range. Both stages vary in length and both are characterized by an elevation in early follicular phase follicle-stimulating hormone (FSH). In stage −2, the menstrual cycles remain regular, but the cycle length changes by 7 days or more (ie, cycle length becomes 24 days instead of 31). FSH may be elevated but levels are variable. AMH, Inhibin B and AMC are all low. Duration is variable. Stage −1 (late menopausal transition) is characterized by an interval of amenorrhea of ≥60 days and is typically characterized by increased variability in cycle length. FSH is usually >25 IU/L during this stage. AMH, Inhibin B and AMC are low. Many women begin to experience symptoms during this time which may include vasomotor symptoms, and sleep disturbance. The duration is typically 1-3 years. The early postmenopausal period (stage +1) is divided into +1a, +1b and +1c and includes the first 6 years following the final menstrual period. +1a begins 12 months following the last menstrual period and marks the end of the menopausal transition or “perimenopause”. During stage +1, FSH remains elevated while AMH, Inhibin B and AMC drop further and become very low. The late postmenopausal period (stage +2) begins 6 years after the final menstrual period and continues until death.
Harlow SD, Gass M, Hall JE, et al. Executive Summary of the Stages of Reproductive Aging Workshop + 10: Addressing the Unfinished Agenda of Staging Reproductive Aging. J Clin Endocrinol Metab, 2012;97:1159–1168. PMID: 22344196.
U.S. Census Bureau. Age and Sex Composition: 2010. www.census.govprod/cen2010
Pathogenesis
A. Perimenopausal State
The decades of mature reproductive life are characterized by generally regular menses and a slow, steady decrease in cycle length. Mean cycle length at age 15 years is 35 days, at age 25 years it is 30 days, and at age 35 years it is 28 days. This decrease is a result of shortening of the follicular phase of the cycle, with the luteal phase length remaining constant. After age 45 years, altered function of the aging ovary is detectable in regularly menstruating women (Fig. 59–1). The mean cycle length is significantly shorter than in younger women and is attributable to a shortened follicular phase. The luteal phase is of similar length, and progesterone levels are no different from those observed in younger women. Estradiol levels are lower during portions of the cycle, including active follicular maturation, the midcycle peak, and the luteal phase. Concentrations of FSH are strikingly elevated during the early follicular phase and fall as estradiol increases during follicular maturation. FSH levels at the midcycle peak and late in the luteal phase are also consistently higher than those found in younger women and decrease during the midluteal phase. Luteinizing hormone (LH) concentrations are indistinguishable from those observed in younger women. The mechanism responsible for this early rise of FSH is probably related to inhibin. Inhibin is a polypeptide hormone that is synthesized and secreted by granulosa cells. It causes negative feedback on FSH release by the pituitary. As the oocyte number decreases, inhibin levels fall, resulting in a rise in FSH levels.
Figure 59–1. Mean and range of LH, FSH, estradiol (E2), and progesterone levels in women over age 45 with regular menstrual cycles. Shaded area represents the mean (±2 SEM) in cycles found in young women. (Reproduced, with permission, from Sherman BM, Korenman SG. Hormonal characteristics of the human menstrual cycle throughout reproductive life. J Clin Invest 1975;55:699.)
The transition from regular cycle intervals to the permanent amenorrhea of menopause is characterized by a phase of marked menstrual irregularity. The duration of this transition varies greatly among women. Those experiencing the menopause at an early age have a relatively short duration of cycle variability before amenorrhea ensues. Those experiencing it at a later age usually have a phase of menstrual irregularity characterized by unusually long and short intermenstrual intervals and an overall increase of mean cycle length and variance.
The hormonal characteristics of this transitional phase are of special interest and importance. The irregular episodes of vaginal bleeding in premenopausal women represent the irregular maturation of ovarian follicles with or without hormonal evidence of ovulation. The potential for hormone secretion by these remaining follicles is diminished and variable. Menses are sometimes preceded by maturation of a follicle with limited secretion of both estradiol and progesterone. Vaginal bleeding also happens after a rise and fall of estradiol without a measurable increase in progesterone, such as is seen during anovulatory menses.
From these findings, it is clear that the transitional phase of menstrual irregularity is not one of marked estrogen deficiency. During the menopausal transition, high levels of FSH appear to stimulate residual follicles to secrete bursts of estradiol. Occasionally, estradiol levels will rise to concentrations 2 or 3 times higher than is normally seen, probably reflecting the recruitment of more than 1 follicle for ovulation. This may be followed by corpus luteum formation, often with limited secretion of progesterone. Because the episodes of follicular maturation and vaginal bleeding are widely spaced, premenopausal women may be exposed to persistent estrogen stimulation of the endometrium in the absence of regular cyclic progesterone secretion.
B. Menopausal State
The 2 types of menopause are classified according to cause.
1. Physiologic menopause—In the human embryo, oogenesis begins in the ovary around the third week of gestation. Primordial germ cells appear in the yolk sac, migrate to the germinal ridge, and undergo cellular divisions. It is estimated that the fetal ovaries contain approximately 7 million oogonia at 20 weeks’ gestation. After 7 months’ gestation, no new oocytes are formed. At birth, there are approximately 1–2 million oocytes, and by puberty this number is reduced to 300,000–500,000. Continued reduction of oocyte numbers occurs during the reproductive years through ovulation and atresia. Nearly all oocytes vanish by atresia, with only 400–500 actually being ovulated. Very little is known about oocyte atresia. Animal studies show that estrogens prevent the atretic process, whereas androgens enhance it.
Menopause apparently occurs in the human female because of 2 processes. First, oocytes responsive to gonadotropins disappear from the ovary, and second, the few remaining oocytes do not respond to gonadotropins. Isolated oocytes can be found in postmenopausal ovaries on very careful histologic inspection. Some of them show a limited degree of development, but most reveal no sign of development in the presence of excess endogenous gonadotropins.
The average age at menopause in the United States is 50–51 years. There does not appear to be any consistent relationship between age at menarche and age at menopause. Marriage, childbearing, height, weight, and prolonged use of oral contraceptives do not appear to influence the age of menopause. Smoking, however, is associated with early menopause.
Spontaneous cessation of menses before age 40 years is called premature menopause, or premature ovarian failure. It appears that approximately 0.9% of women in the United States may experience this early cessation of function. Cessation of menstruation and the development of climacteric symptoms and complaints can occur as early as a few years after menarche. The reasons for premature ovarian failure are unknown.
Disease processes, especially severe infections or tumors of the reproductive tract, can occasionally damage the ovarian follicular structures so severely as to precipitate the menopause. The menopause can also be hastened by excessive exposure to ionizing radiation; chemotherapeutic drugs, particularly alkylating agents; and surgical procedures that impair ovarian blood supply. The possibility of associated endocrine or chromosomal abnormalities should also be considered.
2. Artificial menopause—The permanent cessation of ovarian function brought about by surgical removal of the ovaries or by radiation therapy is called an artificial menopause. Irradiation to ablate ovarian function is rarely used today. Artificial menopause is used as a treatment for endometriosis and rarely may be used to treat estrogen-sensitive neoplasms of the breast and endometrium. More frequently, artificial menopause is a side effect of treatment of intraabdominal disease (eg, ovaries are removed in premenopausal women because the gonads have been damaged by infection or neoplasia). When laparotomy is being performed for intraabdominal or pelvic disease (ie, hysterectomy for leiomyomata), elective bilateral oophorectomy is sometimes used to prevent ovarian cancer. In some women who are genetically predisposed to ovarian cancer, elective laparoscopic oophorectomy is also performed.
C. Changes in Hormone Metabolism Associated with the Menopause
After the menopause, there are major changes in androgen, estrogen, progesterone, and gonadotropin secretion, much of which occurs because of cessation of ovarian follicular activity (Fig. 59–2).
Figure 59–2. Serum androgen and estrogen levels in 16 postmenopausal women with endometrial cancer before and after oophorectomy. (Reproduced, with permission, from Judd HL. Hormonal dynamics associated with the menopause. Clin Obstet Gynecol 1976; 1:775.)
1. Androgens—During reproductive life, the primary ovarian androgen is androstenedione, the major secretory product of developing follicles. In postmenopausal women, there is a reduction of circulating androstenedione to approximately 50% of the concentration found in young women, reflecting the absence of follicular activity. In the year following the last menstrual period, the levels of this hormone are steady. In older women, there is a circadian variation of androstenedione, with peak concentration between 8:00 AM and 12 noon, and the nadir occurring between 3:00 PM and 4:00 AM. This rhythm reflects adrenal activity. The clearance rate of androstenedione is similar in pre- and postmenopausal women; therefore, the change in levels of circulating hormone reflects changes in production. Thus the average production rate of androstenedione is approximately 1.5 mg/24 h in older women, a rate that is 50% of the rate found in premenopausal women. The source of most of this circulating androstenedione appears to be the adrenal glands, but continued secretion by the postmenopausal ovary accounts for approximately 20%.
For testosterone, the level found in postmenopausal women is only minimally lower than that found in premenopausal women before oophorectomy and is distinctly higher than the level observed in ovariectomized young women. There is also a prominent circadian variation of this androgen, with the highest levels occurring at 8:00 AM and the nadir at 4:00 PM. There is no difference in the clearance rate of testosterone before and after the menopause. Thus the production rate in older women is approximately 150 μg/24 h, a rate that is only one-third lower than the rate seen in young women.
The source of circulating testosterone is more complex than that of androstenedione. Oophorectomy after menopause is associated with a nearly 60% decrease in testosterone. There is no change in the metabolic clearance rate of the androgen with oophorectomy; therefore, the fall in the circulating level reflects alterations of its production rate. Approximately 15% of circulating androstenedione is converted to testosterone. The small simultaneous fall of androstenedione after oophorectomy can only account for a small portion of the total decrease of testosterone. The remainder of the loss presumably represents loss from direct ovarian secretion of testosterone. Direct ovarian secretion in the postmenopausal ovary is larger than the amount secreted directly by the premenopausal ovary. Large increments in testosterone have been found in the ovarian compared with the peripheral veins of postmenopausal women. These increments are greater than those observed in premenopausal women, supporting the hypothesis that the postmenopausal ovary secretes more testosterone directly than the premenopausal ovary. Hilar cells and luteinized stromal cells (hyper-thecosis) are present in most postmenopausal ovaries and have been shown to produce testosterone in premenopausal women. Presumably, these cells could do the same in post-menopausal subjects.
A proposed mechanism for increased ovarian testosterone production by postmenopausal ovaries is the stimulation of gonadal cells still capable of androgen production by excess endogenous gonadotropins, which, in turn, are increased because of reduced estrogen production by the ovaries. This increased ovarian testosterone secretion, coupled with a reduction of estrogen production, and decrease in sex hormone-binding globulin (SHBG) may partly explain the development of symptoms of defeminization, hirsutism, and even virilism occasionally seen in older women.
Levels of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are reduced by 60% and 80%, respectively, with age. Whether these reductions are related to the menopause or to aging has not been determined. Again, a marked circadian variation of DHEA has been observed. Whether a similar rhythm is present for DHEAS is unknown. As with younger subjects, the primary source of these 2 androgens is thought to be the adrenal glands, with the ovary contributing <15%. Thus the marked decreases of DHEA and DHEAS reflect altered adrenal androgen secretion, and this phenomenon has been called the adrenopause. The mechanism responsible for it is unknown.
In premenopausal women, plasma androstenedione is approximately 1.5 ng/mL. Plasma testosterone is approximately 0.3 ng/mL. Mean DHEA and DHEAS levels are approximately 4 ng/mL and 1600 ng/mL, respectively, in samples drawn at 8:00 AM.
In postmenopausal women, the mean plasma androstenedione concentration is reduced by at least 50%, to approximately 0.6 ng/mL. Plasma testosterone levels are only slightly reduced (to approximately 0.25 ng/mL). Plasma DHEA and DHEAS levels are decreased to mean levels of 1.8 ng/mL and 300 ng/mL in women in their sixties and seventies.
2. Estrogens—After a woman has passed the menopause, there is good clinical evidence of reduced endogenous estrogen production in most subjects. When circulating levels have been assessed, the greatest decrease is in estradiol. Its concentration is distinctly lower than that found in young women during any phase of their menstrual cycle and is similar to the level seen in premenopausal women after oophorectomy. A decrease of this estrogen occurs up to 1 year after the last menstrual period. There does not appear to be a circadian variation of the circulating concentration of estradiol after the menopause. The metabolic clearance rate of estradiol is reduced by 30%. The average production rate is 12 μg/24 h.
The source of the small amount of estradiol found in older women has been established. Direct ovarian secretion contributes minimally, but the adrenal glands are the major source. Investigators who have examined the concentrations of estradiol in adrenal veins have reported minimal increments, arguing against direct adrenal secretion being a major contributor. Although both estrone and testosterone are converted in peripheral tissues to estradiol, it is conversion from estrone that accounts for most estradiol in older women.
After the menopause, the circulating level of estrone decreases—not as much as that of estradiol—and overlaps with values seen in premenopausal women during the early follicular phase in menstrual cycles. There is a circa-dian variation of circulating estrone, with the peak in the morning and the nadir in late afternoon or early evening. This variation is not as prominent as that observed for the androgens. In postmenopausal women, there is a 20% reduction of estrone clearance, and the average production rate is approximately 55 μg/24 h.
The adrenal gland is the major source of estrone. Direct adrenal or ovarian secretion is minimal. Most estrone results from the peripheral aromatization of androstenedione. The average percent conversion is double that found in ovulatory women and can account for the total daily production of this estrogen. Aromatization of androstenedione occurs in fat, muscle, liver, bone marrow, brain, fibroblasts, and hair roots. Other tissues may also contribute but have not been evaluated. To what extent each cell type contributes to total conversion has not been determined, but fat cells and muscle may be responsible for only 30–40%. This conversion correlates with body size, with heavy women having higher conversion rates and circulating estrogen levels than slender women.
During normal menstrual life, the mean plasma estradiol fluctuates from 50–350 pg/mL and estrone from 30–110 pg/mL. In postmenopausal women, the mean estradiol level is approximately 12 pg/mL, with a range of 5–25 pg/mL. The mean estrone level is approximately 30 pg/mL, with a range of 20–70 pg/mL. Estradiol levels in normal young women do not overlap with those observed in post-menopausal subjects. The finding of estradiol levels below 21 pg/mL can be helpful in establishing the diagnosis of menopause, as the fall of this estrogen is the last hormonal change associated with loss of ovarian function. There is substantial overlap of estrone levels in younger and older women. Measurement of this estrogen is not helpful in determining the ovarian status of a patient.
3. Progesterone—In young women, the major source of progesterone is the ovarian corpus luteum after ovulation. During the follicular phase of the cycle, progesterone levels are low. With ovulation the levels rise greatly, reflecting the secretory activity of the corpus luteum. In postmenopausal women, the levels of progesterone are only 30% of the concentrations seen in young women during the follicular phase. Because postmenopausal ovaries do not contain functional follicles, ovulation does not occur and progesterone levels remain low. The source of the small amount of progesterone present in older women is felt to be caused by adrenal secretion, as dexamethasone suppresses its level, adrenocorticotropic hormone (ACTH) increases its level, and human chorionic gonadotropin (hCG) administration has no effect.
In young menstruating women, the mean progesterone level is approximately 0.4 ng/mL during the follicular phase of the cycle, with a range of 0.2–0.7 ng/mL. During the luteal phase, progesterone levels rise and fall, reflecting corpus luteum function; the mean level is approximately 11 ng/mL, with a range of 3–21 ng/mL. In postmenopausal women, the mean progesterone level is 0.17 ng/mL. To date, no clinical use has been established for the measurement of progesterone in postmenopausal women.
4. Gonadotropins—With the menopause, both LH and FSH levels rise substantially, with FSH usually higher than LH. This is thought to reflect the slower clearance of FSH from the circulation. The reason for the marked increase in circulating gonadotropins is the absence of the negative feedback of ovarian steroids and inhibin on gonadotropin release. As in young women, the levels of both gonadotropins are not steady, but instead show random oscillations. These oscillations are thought to represent pulsatile secretion by the pituitary. In older women, these pulsatile bursts occur every 1–2 hours, a frequency similar to that seen during the follicular phase of premenopausal subjects. Although the frequency is similar, the amplitude is much greater. This increased amplitude is secondary to increased release by the hypothalamic hormone gonadotropin-releasing hormone (GnRH) and enhanced responsiveness of the pituitary to GnRH because of low estrogen levels. Studies with rhesus monkeys suggest that the site governing pulsatile GnRH release is in the arcuate nucleus of the hypothalamus. The large pulses of gonadotropin in the peripheral circulation are believed to maintain the high levels of the hormones found in postmenopausal women.
During reproductive life, the levels of both FSH and LH range from 4–30 mU/mL, except during the preovulatory surge, when they may exceed 50 mU/mL and 100 mU/mL, respectively. After the menopause, both rise to levels above 100 mU/mL, with FSH rising earlier and to higher levels than LH.
When contradictory or uncertain clinical findings make the diagnosis of the postmenopausal state questionable, measurement of plasma FSH, LH, and estradiol levels may be helpful. This situation occurs frequently in women after hysterectomy without oophorectomy. The findings of plasma estradiol below 20 pg/mL and elevated FSH and LH levels are consistent with cessation of ovarian function. In practical terms, it is not necessary to measure LH.
D. Physical Changes Associated with the Menopause
1. Reproductive tract—Because estrogen functions as the major growth factor of the female reproductive tract, there are substantial changes in the appearance of all the reproductive organs. Most postmenopausal women experience varying degrees of atrophic changes of the vaginal epithelium. The vaginal rugae progressively flatten and the epithelium thins. This may lead to symptomatic atrophic vaginitis (see Atrophic Vaginitis).
There are also atrophic changes of the cervix. It usually decreases in size, and the canal may become stenotic. There is a reduction of secretion of cervical mucous. This may contribute to excessive vaginal dryness, which may cause dyspareunia.
Atrophy of the uterus is also seen, with shrinkage of both the endometrium and myometrium. This shrinkage can be beneficial to women who enter the climacteric with uterine myomas. Reduction in size and elimination of symptoms frequently prevent the necessity for surgical treatment. The same applies to adenomyosis and endometriosis, both of which usually become asymptomatic after the menopause. Palpable and symptomatic areas of endometriosis generally become progressively smaller and less troublesome. With cessation of follicular activity, hormonal stimulation of the endometrium usually ceases. Endometrial biopsy may reveal anything from a very scanty, atrophic endometrium to one that is moderately proliferative. Spontaneous postmenopausal bleeding may occur in the presence of any of these patterns. Endometrial tissue revealing glandular hyperplasia (with or without uterine bleeding) is an indication of enhanced estrogenic stimulation from either endogenous estrogen production (eg, increased conversion of androgen) or from exogenous intake of estrogen.
The oviducts and ovaries also decrease in size postmenopausally. Although this produces no symptoms, the small size of the ovaries makes them difficult to palpate during pelvic examination. A palpable ovary in a postmenopausal woman must be viewed with suspicion, and the presence of an ovarian neoplasm must be considered.
The supporting structures of the reproductive organs suffer loss of tone as estrogen levels decline. Postmenopausal estrogen deficiency may be associated with symptomatic progressive pelvic relaxation.
2. Urinary tract—Estrogen plays an important role in maintaining the epithelium of the bladder and urethra. Marked estrogen deficiency may produce atrophic changes in these organs similar to those that occur in the vaginal epithelium. This may give rise to atrophic cystitis, characterized by urinary urgency, frequency, incontinence, and dysuria. Recurrent urinary tract infection may also develop in the setting of estrogen deficiency. Loss of urethral tone, with pouting of the meatus and thinning of the epithelium, favors the formation of a urethral caruncle with resultant dysuria, meatal tenderness, and occasionally hematuria. Treatment of symptomatic women involves topical vaginal estrogen (see Estrogen Therapy).
3. Mammary glands—Regression of breast size during and after menopause is psychologically distressing to some women. For those who have been bothered by cyclic symptoms of breast pain and cyst formation, the disappearance of these symptoms postmenopausally is a great relief.
Erickson GF. Normal ovarian function. Clin Obstet Gynecol 1978;21:31–52. PMID: 343955.
Judd HL. Hormonal dynamics associated with the menopause. Clin Obstet Gynecol 1976;19:775–788. PMID: 791558.
Judd HL, Judd GE, Lucas WE, Yen SS. Endocrine function of the postmenopausal ovary: concentrations of androgens and estrogens in ovarian and peripheral vein blood. J Clin Endocrinol Metab1974;39:1020–1024. PMID: 4430702.
Judd HL, Shamonki IM, Frumar AM, Lagasse LD. Origin of serum estradiol in postmenopausal women. Obstet Gynecol 1982;59:680–686. PMID: 7078905.
Judd HL, Davidson BJ, Frumar AM, Shamonki IM, Lagasse LD, Ballon SC. Serum androgens and estrogens in postmenopausal women with and without endometrial cancer. Am J Obstet Gynecol1980;136:859–871. PMID: 7361834.
Prevention of Menopause
Nothing can prevent the physiologic menopause (ie, ovarian function cannot be prolonged indefinitely), and nothing can be done to postpone its onset or slow its progress. However, artificial menopause can often be prevented. When ionizing radiation is used for the treatment of intraabdominal disease, incidental ablation of ovarian function often cannot be avoided. In such cases, if an operation will serve equally well to treat intraabdominal disease, it should be used in preference to radiation therapy in order to preserve the ovaries.
Elective removal of the ovaries to prevent ovarian cancer is frequently performed at laparotomy or laparoscopy in premenopausal women, with deliberate acceptance of artificial menopause. This form of therapy is increasingly used in women with genetic predisposition to breast and ovarian cancer. However, in low-risk women this remains controversial.
Clinical Conditions Associated with Menopause
A. Atrophic Vaginitis
1. Pathogenesis—As the epithelium thins after menopause, the capillary bed shines through as a diffuse or patchy reddening. Rupture of surface capillaries produces irregularly scattered petechiae, and a brownish discharge may be noted. Further atrophy of the vaginal epithelium renders its capillary bed increasingly sparse, so that the hyperemic appearance gives way to a smooth, shiny, pale epithelial surface. The epithelium lacks glycogen, which leads to a reduction in lactic acid production and an increase in the vaginal pH to 5.0–7.0. This is associated with disappearance of lactobacilli. Early in the process, local bacterial invasion may initiate vaginal pruritus and leukorrhea. Vaginal burning, soreness, dyspareunia, and a thin watery or serosanguineous discharge may also occur. Minimal trauma with examinations or coitus may result in slight vaginal bleeding. Urinary complaints, including urinary frequency, urgency, dysuria, and urge incontinence, have also been described in association with atrophic vaginitis.
2. Diagnosis—There is no specific test that reliably quantifies the degree of atrophy. Clinical decision making is therefore generally based on patient symptomatology and findings on physical examination. However, vaginal cytology has been used to assist in the diagnosis of atrophic vaginitis. The degree of maturation of exfoliated vaginal epithelial cells, as revealed by stained vaginal smears, is an index of estrogenic activity. Among the various methods of assessing the smears, the following are most commonly used: the maturation index consists of a differential count of 3 types of squamous cells—parabasal cells, intermediate cells, and superficial cells, in that order—expressed as percentages (eg, 10/85/5); a greater percentage of parabasal cells reflects a greater degree of atrophy. The cornification count is the percentage of precornified and cornified cells among total squamous cells counted. This is actually a simplified maturation index, because this percentage is essentially the same as that of the superficial cells.
The assessment of exfoliated vaginal epithelial cells is influenced not only by the level of estrogenic activity, but also by other hormones (particularly progesterone and testosterone), local vaginal inflammation, local medication, vaginal bleeding, the presence of genital cancer, the location of the vaginal area sampled, and variations in end-organ (epithelial) responses to estrogenic influence. Thus women with identical levels of circulating estrogens may have quite different cytograms.
The great variation in cytologic findings leads to the following conclusions regarding the use of smears in the clinical management of postmenopausal women: (1) the smear is only a rough measure of estrogenic status, and it may sometimes be grossly misleading. (2) The vaginal cytogram cannot predict whether or not an individual woman is experiencing menopausal signs and symptoms. (3) The smear cannot be used as the sole guide to steroid supplementation therapy; clinical signs and symptoms are more dependable for this purpose.
3. Treatment—Symptomatic atrophic vaginitis may be managed with water-soluble lubricants and/or topical vaginal estrogens, which are available in the form of creams, tablets, or estradiol-releasing rings (see Estrogen Therapy). Systemic estrogens are also effective in the treatment of atrophic vaginitis, but vaginal preparations are preferred when estrogen therapy is being used solely for the treatment of vulvovaginal atrophy.
B. Hot Flushes
1. General considerations—The most common and characteristic symptom of the climacteric is an episodic disturbance consisting of sudden flushing and perspiration, referred to as a hot flash or flush. It is observed in approximately 75% of women who go through the physiologic menopause or have a bilateral ovariectomy. Of those having flushes, 82% experience the disturbance for more than 1 year, and 25–50% complain of the symptom for more than 5 years. Most women indicate that hot flushes begin with a sensation of pressure in the head, much like a headache. This increases in intensity until the physiologic flush occurs. Palpitations may also be experienced. The actual flush is characterized as a feeling of heat or burning in the face, neck, and chest, followed immediately by an outbreak of sweating that affects the entire body but is particularly prominent over the head, neck, upper chest, and back. Less common symptoms include weakness, fatigue, faintness, and vertigo. The duration of the whole episode varies from momentary to as long as 10 minutes; the average length is 4 minutes. The frequency varies from 1–2 per hour to 1–2 per week. In women with severe flushes, the mean frequency is 54 minutes.
Investigators have characterized the physiologic changes associated with hot flushes and have shown that the symptoms result from true alterations in cutaneous vasodilation, perspiration, reductions of core temperature, and elevations of pulse rate. Fluctuations in electrocardiographic data probably reflect changes in skin conductance. Changes in heart rhythm and blood pressure have not been observed.
The patient’s awareness of symptoms does not correspond exactly with physiologic changes. Women become conscious of symptoms approximately 1 minute after the onset of measurable cutaneous vasodilation, and discomfort persists for an average of 4 minutes, whereas physical changes persist for several minutes longer.
2. Pathogenesis—The exact mechanism responsible for hot flushes is unknown, but physiologic and behavioral data indicate that symptoms result from a defect in central thermoregulatory function. Several observations support this conclusion: (1) the 2 major physiologic changes associated with hot flushes—perspiration and cutaneous vasodilation—are the result of different peripheral sympathetic functions. Excitation of sweat glands results from sympathetic cholinergic fibers, and cutaneous vasodilation is under the control of tonic α-adrenergic fibers. It seems unlikely that any peripheral event could cause both cholinergic excitation of sweat glands and α-adrenergic blockade of cutaneous vessels, and it is well recognized that these are the 2 basic functions triggered by central thermo-regulatory mechanisms that lower the central temperature. (2) During a hot flush, the central temperature decreases because of cutaneous vasodilation and perspiration. If hot flushes were the result of some peripheral event, the body’s regulatory mechanisms would be expected to prevent such a decrease. (3) There is also a change in behavior associated with hot flushes. Women feel warm and have a conscious desire to cool themselves by throwing off the bedcovers, standing by open windows or doors, fanning themselves, or by other means. This behavior is observed even in the presence of a steady or decreasing central temperature.
Most investigators believe the core temperature of the body is maintained near a central set point that is controlled by central thermoregulatory centers, particularly those in the rostral hypothalamus. This central set point temperature is analogous to a thermostat setting. Hot flushes appear to result from a narrowing of the thermoregulatory set point such that smaller than normal increases in core body temperature activate heat loss responses. As a consequence, heat loss mechanisms, both physiologic and behavioral, are activated so that the core temperature will be brought in line with the new set point; this results in a fall of central temperature.
Because hot flushes occur after the spontaneous cessation of ovarian function or following oophorectomy, it is presumed that the underlying mechanism is initiated through endocrinologic changes related primarily to ovarian estrogen withdrawal. Low estrogen levels alone do not appear to trigger hot flushes; prepubertal children and patients with gonadal dysgenesis have low estrogen levels but not flushing. Patients with gonadal dysgenesis do experience symptoms if they are given estrogens that are later withdrawn. Thus it appears that estrogen must be present and then withdrawn for hot flushes to be experienced.
Changes in central nervous system (CNS) concentrations of norepinephrine (NE) and serotonin likely play an important role in the development of hot flushes. Animal and human studies indicate that NE plays an important role in the etiology of hot flushes. Increased levels of NE have been correlated with a narrowing of the thermoneutral zone, and it has been demonstrated that plasma levels of metabolites of NE increase after a hot flush. In addition, use of pharmacologic agents that alter central noradrenergic activity (ie, clonidine, serotonin and norepinephrine reuptake inhibitors [SNRIs]) have been shown to lessen the severity and/or frequency of vasomotor symptoms.
Studies also suggest a role for serotonin in the development of vasomotor symptoms. Serotonin is thought to be important in thermoregulation, as studies have shown an increase in stimulation of serotonin receptors after a thermostimulus, which then results in sensation of a hot flush. In addition, an association between serotonin levels and severity of vasomotor symptoms in menopausal women has been demonstrated. Finally, the selective serotonin reuptake inhibitors (SSRI) class of drugs has been shown to be effective in the management of vasomotor symptoms in postmenopausal women.
A close temporal association between the occurrence of flushes and the pulsatile release of LH has been demonstrated. However, the observation that flushes occur after hypophysectomy suggests that they are not directly caused by LH release. The appearance of hot flushes in women with defects in GnRH release or synthesis (Kallmann’s syndrome) also suggests GnRH itself is not involved in the flushing mechanism. The absence of hot flushes in women with hypothalamic amenorrhea and hypoestrogenemia is intriguing. These women have defects in neurotransmitter or neurochemical input to their GnRH neurons. In particular, excessive endogenous opioid and dopamine input to GnRH neurons may account for chronic suppression of GnRH release, leading to hypothalamic amenorrhea. The absence of hot flushes in these women suggests that altered afferent input of neurotransmitters or neurochemicals to the GnRH neuron that is secondary to hypogonadism leads to hot flushes.
Hot flushes are a greater annoyance than most physicians recognize. Patients frequently complain of night sweats and insomnia. There is a close temporal relationship between the occurrence of hot flushes and nighttime awakening. Women with frequent flushes may experience flushes and awakening episodes hourly, which may cause a profound sleep disturbance that may, in turn, cause cognitive (memory) and affective (anxiety) disorders in some women.
3. Treatment—Estrogens are the principal medications used to relieve hot flushes. Estrogens block both the perceived symptoms and the physiologic changes. Their use also relieves some aspects of the sleeping disorder. Estrogen administration has been shown to enhance hypothalamic opioid activity in postmenopausal women. This increase of hypothalamic opiates may be involved in the relief of hot flushes with estrogen administration.
Progestins also block hot flushes and represent a reasonable form of substitutional therapy in women who cannot take estrogens. However, because addition of progestins to hormone therapy has been associated with an increased risk of breast cancer, a progestogen would not be the ideal alternative to estrogen for women who are seeking to avoid effects on breast disease. Clonidine, a centrally acting alpha agonist, is more effective than a placebo but is associated with side effects. More recently, certain SSRIs and SNRIs have been shown to be effective in the treatment of hot flashes. Their side effects may limit their overall benefit, but they are one of the first alternative choices in women who are not taking estrogen. Certain SSRIs may also affect the metabolism of tamoxifen to its active metabolite through the enzyme, CYP2D6, a member of the cytochrome P450 oxidase enzyme system. SSRIs such as paroxetine and fluoxetine have been associated with increased breast cancer recurrence and/or death amongst women using tamoxifen. Therefore, until further studies are available, caution must be used when using SSRIs, particularly paroxetine and fluoxetine, in women receiving tamoxifen. Black cohosh may have modest effects in decreasing hot flashes, but concerns remain regarding its potential to stimulate breast and uterine tissue. Gabapentinalso decreases hot flashes by 50–80% and is therefore comparable to estrogen according to certain studies. However, sedation is a major side effect that limits its acceptability for many women. Small doses at night may be useful for women suffering from night-time awakening due to vasomotor symptoms. Tibolone is a synthetic steroid with estrogenic, progestogenic, and androgenic properties that alleviates menopausal symptoms and has been used in other countries for this purpose, as well as to preserve bone mineral density. However, its long-term safety profile with regard to breast and endometrial cancer remains controversial. Its mechanism of action would suggest that it is unlikely to increase the risk of breast cancer. However, the Million Women Study reported an increased risk of breast cancer among participants using tibolone as compared with controls. In addition, tibolone was associated with an increased risk of breast cancer recurrence in a randomized trial of breast cancer patient using tibolone for relief of vasomotor symptoms. Tibolone’s action on the endometrium also suggests that it is unlikely to cause endometrial proliferation. This is supported by findings from studies demonstrating a low incidence of vaginal bleeding and an absence of endometrial hyperplasia on histology. However, rates of endometrial cancer were also increased in the Million Women Study. Further study is required to ascertain whether tibolone can be used long term without increased risks for breast and endometrial cancer. Tibolone’s potential to modify risk for cardiovascular disease is also unknown. However, a study evaluating the effect of tibolone on myocardial blood flow demonstrated that tibolone improved myocardial blood flow in women with ischemic heart disease. Vitamins E and K, mineral supplements, and phytoestrogens have all been tried to alleviate menopausal symptoms, but have not been proven beneficial. Many women express a preference for bioidentical hormones (BHT), with the expectation that they are safer, with comparable efficacy. The term may be used to describe varying formulations and therefore is not used consistently amongst patients or practitioners. For some, the term refers to hormones that are chemically identical to those produced by humans and includes formulations that are well-tested, US Food and Drug Administration (FDA)– approved brand names. For the majority of others, the term refers to custom-made hormone formulations that provide different doses and routes of administration of estrogens and progestogens. These compounded formulations are not subject to the same regulatory approval process as brand name formulations, and therefore safety, efficacy, and consistency are in no way assured. Cost to the patient can also be greater for these compounded formulations because they are often not covered by third-party payers. The FDA has declared that claims of compounding pharmacies stating that BHT drugs avoid the risks of FDA-approved treatments and these drugs reduce the risk of serious illness such as heart disease, stroke, or breast cancer are not supported by credible scientific evidence. They further state that safety and efficacy of estriol in these formulations has not been proven. Therefore, incorporation of estriol into these formulations may not occur without an investigational new drug authorization. According to the 2010 North American Menopause Society position statement: “Filled prescriptions for BHT should include a patient package insert identical to that required for products that have regulatory-agency approval. In the absence of efficacy and safety data for any specific prescription, the generalized benefit-risk ratio data of commercially available HT products should apply equally to BHT.”
C. Osteoporosis
1. General considerations—Osteoporosis is defined as a systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in fragility of bone and susceptibility to risk of fracture. Although gradual bone loss occurs in all humans with aging, this loss is accelerated in women after cessation of ovarian function. After attainment of peak bone mass by age 25–30 years, bone loss begins, accelerates in women at menopause, and then slows again but continues into advanced years at a rate of 1–2% per year (Fig. 59–3). Women can lose up to 20% of their bone mass in the 5–7 years after menopause.
Figure 59–3. Changes in metacarpal cortical width, as determined by sequential measurements in pre- and postmenopausal women, age range 30–50 years. Note bone loss in postmenopausal women. (Reproduced, with permission, from Nordin BEC, et al. Postmenopausal osteopenia and osteoporosis. Front Horm Res 1975; 3:131.)
Osteoporosis affects an estimated 10 million Americans 50 years of age or older, 80% of whom are women. Of Americans 50 years of age or older, 34 million are estimated to have low bone mass at the hip, placing them at increased risk for osteoporosis. Osteoporosis is most severe in women who have had early oophorectomy or premature ovarian failure, and in those with gonadal dysgenesis. Osteoporosis occurs most often in whites, followed by Asians, Hispanics, and African Americans.
Bone loss produces minimal symptoms, but leads to reduced skeletal strength. Thus osteoporotic bones are more susceptible to fractures. The most common sites of fracture are in the vertebral body, proximal femur, and distal forearm/wrist. Recent figures from the National Osteoporosis Foundation show that osteoporosis is responsible for more than 1.5 million fractures per year. Due to the aging population, the prevalence of osteoporosis is expected to increase such that by 2020, 1 in 2 Americans is expected to have or be at risk for osteoporosis of the hip. Approximately 1 in 2 women older than the age of 50 years will have an osteoporosis-related fracture in her remaining lifetime. The incidence of hip fractures in women is 2–3 times that in men. The mortality rate associated with hip fractures is between 10 and 20% within 12 months after the injury. Of survivors, 15–25% are permanently disabled. The estimated cost for osteoporosis-related fractures in the United States totals more than $17 billion per year. According to the Surgeon General, these costs could double or triple by the year 2040.
Risk factors include certain lifestyle choices (ie, increased caffeine intake, smoking, excessive alcohol intake, lack of exercise, lifetime of low calcium intake), hormonal factors (ie, estrogen deficiency from menopause, eating disorders), genetic factors (ie, family history, cystic fibrosis, Ehlers Danlos), endocrinologic disorders (hyperparathyroidism, adrenal insufficiency, hyperthyroidism), medical disorders (ie, lupus, malabsorption syndromes, lymphoma), medication use (ie, corticosteroids, chemotherapy, excess thyroid supplementation), vitamin D deficiency, slender body size, and advanced age.
2. Pathogenesis—Bone loss occurs because bone resorption is excessive, bone formation is decreased, peak bone mass is low, or a combination of all 3 factors. Bone remodeling is regulated by many factors, including systemic hormones, local cytokines, prostaglandins, and local growth factors. Of the systemic hormones, sex steroids, parathyroid hormones, glucocorticoids, thyroid hormones, and growth hormone/insulinlike growth factors likely play a role.
Ovarian estrogen and estrogen administered postmenopausally are protective against osteoporosis. The exact mechanisms by which estrogen regulates bone remodeling are incompletely understood. Estrogens likely modulate osteoclast and osteoblast function possibly via effects on cytokines and growth factors such as transforming growth factor-β and tumor necrosis factor-α (TNF-α). Estrogens may decrease the depth of erosion of osteoclasts.
Interleukin-1 (IL-1) and TNF-α derived from bone marrow macrophages stimulate bone resorption and may inhibit bone formation. There is evidence to suggest they may be regulated by estrogen, as IL-1 activity in bone increases immediately after the menopause or oophorectomy. Furthermore, it has been shown in animal models that inhibition of IL-1 and TNF-α after ovariectomy attenuates bone loss. IL-6 and prostaglandins, especially prostaglandin E2, are also involved in bone remodeling and are regulated by sex steroids. Other factors, such as insulin-like growth factor and fibroblast growth factor, also likely play a role in the pathogenesis of osteoporosis and may be regulated by sex steroids.
Androgens play a role in bone remodeling as androgen deficiency is associated with increased bone loss. The precise mechanism by which androgens alter bone remodeling is unknown but may involve conversion to estrogen. For example, men with aromatase deficiency have an elevated risk of developing osteoporosis, possibly due to decreased conversion of androgen to estrogen.
Progestogens may affect bone remodeling in a similar way to estrogens and androgens, but the mechanisms underlying these effects are not well understood. It is possible that they work through glucocorticoid receptors.
Parathyroid hormone (PTH) also plays a role in bone remodeling. PTH stimulates bone resorption, and absence of this hormone inhibits development of osteoporosis in animal and human studies. Thus far, it does not appear that PTH is elevated in most women with osteoporosis or that the sensitivity of bone to PTH is enhanced. It is interesting that the amino-terminus of PTH (1-34) inhibits bone resorption.
Thyroid hormones increase bone resorption. The exact mechanism is not fully understood, but possibly involves accelerated osteoclast function and altered calcium metabolism.
Growth hormone stimulates bone remodeling; however, studies evaluating the effect of exogenous growth hormone administration on established osteoporosis are inconclusive. Recently, new factors were discovered that are involved with the regulation of bone remodeling: osteoprotegerin, a naturally occurring protein, and RANKL (receptor activator of nuclear factor kappa beta ligand) both regulate osteoclastogenesis and bone resorption.
Genetic factors may also affect risk for osteoporosis. Variants in the estrogen receptors α and β expressed in bone are associated with altered risk for osteoporosis and fracture. Variants in the vitamin D receptor gene and bone morpho-genetic protein 2 may also play a role in the pathogenesis of osteoporosis.
3. Diagnosis & monitoring—Although much has been done to study urinary and serum factors as predictors of osteoporosis, the most predictive test remains bone densitometry with dual-energy x-ray absorptiometry (DXA). Results are given in grams or g/cm2. In 1994, the World Health Organization created a clinically useful definition of osteoporosis. Bone mineral density (BMD) results are reported using T and Z scores. The T score is the number of standard deviations (SD) above or below the mean bone mineral density for sex-matched young normal controls. The Z score compares the patient with an age- and sex-matched population. Normal bone density is defined as a T score > –1.0 SD at the spine, hip or forearm. Osteopenic patients have T scores between –1.0 and –2.5, whereas osteoporotic patients have T scores below –2.5. In most studies, a decrease by 1 SD in mass increases the risk of fracture 2–3-fold. In postmenopausal women, the WHO T-score criteria should be applied. In premenopausal women, WHO BMD criteria should not be applied and other criteria should be used (ie, ethnic or race adjusted Z-scores, with –2.0 indicating low bone density for chronologic age).
Assessment of risk factors has not been nearly as predictive of fracture risk as density measurement. Similarly, assessment of biochemical markers of bone turnover have not been shown to be useful for diagnosing osteoporosis but may give some indication of future risk for fracture and/or be useful for monitoring response to antiresorptive therapy. Markers of bone formation include serum bone-specific alkaline phosphatase and osteocalcin. Markers of bone resorption include serum C-telopeptide (CTX) and urinary N-telopeptide (NTX).
National Osteoporosis Foundation has created a set of guidelines for the use and interpretation of measurement of bone mineral density. Measurements of bone mineral density are recommended for the following groups: (1) all post-menopausal patients younger than age 65 years who have ≥1 additional risk factors for osteoporosis (other than being white, postmenopausal, and female); (2) all women age 65 years and older regardless of additional risk factors; (3) postmenopausal women who present with fractures; (4) women considering therapy for osteoporosis if testing would facilitate the decision; (5) women who have been on hormone replacement therapy for prolonged periods; (6) women who have been on treatment to monitor the treatment effect; and (7) women considering discontinuation of treatment.
Another tool to assess risk and guide treatment is the Fracture Risk Algorithm (FRAX). This tool incorporates BMD, as well as other factors, to assess 10-year probability of hip fracture and 10-year probability of major osteoporotic fracture. It is most useful in patients with low hip BMD as opposed to low spine BMD. Special consideration needs to be taken into account for patients with normal hip BMD but low spine BMD, as FRAX incorporates hip BMD measurements. It is also intended for postmenopausal women, not for younger women. Therapy can be considered in patients with a 10-year probability of hip fracture of ≥3% and 10-year probability of major osteoporosis-related fracture of ≥20%. The FRAX calculator can be accessed at http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9.
4. Prevention and treatment—All individuals at risk for or who have been diagnosed with osteoporosis should be advised to consume adequate calcium (minimum of 1200 mg elemental calcium per day). The National Osteoporosis Foundation recommends vitamin D (800–1000 IU/d). Smoking cessation, avoidance of excessive alcohol intake, and participation in regular weight-bearing and muscle strengthening exercise should be encouraged. Pharmacologic therapy should be strongly considered in women with a hip or vertebral fracture, in women with BMD scores below –2.5 with no risk factors, and in women with BMD T-scores below –1.0 with a 10-year probability of hip fracture of ≥3% or a 10-year probability of major osteoporotic fracture of ≥20%. Current pharmacologic therapy for osteopenia/osteoporosis, listed in alphabetical order, includes (1) bisphosphonates, (2) calcitonin, (3) estrogens (with or without progestogens), (4) parathyroid hormone, (5) raloxifene, and (6) denosumab.
Bisphosphonates are excellent choices for prevention and treatment of osteoporosis. They are potent antiresorptive agents that bind to hydroxyapatite crystals on the surface of bones, enter osteoclasts, and decrease resorptive actions by reducing the production of hydrogen ions and lysosomal enzymes. In addition, they have indirect effects, causing osteoblasts to produce substances that inhibit osteoclasts. They increase bone mineral density at the spine, wrist, and hip in a dose-dependent manner and decrease the risk of vertebral fractures by 30–50%. In addition, they reduce the risk of subsequent nonvertebral fractures in women with osteoporosis. There are 4 bisphosphonates currently available for oral administration. Alendronate is approved by the FDA for the prevention of osteoporosis (5 mg daily and 35 mg weekly) and for the treatment of established osteoporosis (10 mg daily or 70 mg weekly). Risedronate is approved by the FDA for prevention and treatment of postmenopausal osteoporosis. The recommended daily dose is 5 mg daily or 35 mg weekly. Ibandronate is approved for both prevention and treatment of postmenopausal osteoporosis. It has the advantage of being available in an oral daily (2.5 mg) and oral monthly (150 mg) dosing regimen, as well as an intravenous regimen of 3 mg given every 3 months. The 2.5-mg daily and 150-mg monthly oral doses are approved for prevention and treatment of osteoporosis. The 3-mg intravenous dose is approved for treatment of osteoporosis. Zoledronic acid is approved for prevention and treatment of osteoporosis in postmenopausal women. It is given as 5-mg intravenous infusion over 15 minutes once yearly for treatment or once every 2 years for prevention. Intestinal absorption of bisphosphonates is poor, and therefore these medications should be taken in the morning with 8 ounces of water, before consumption of any food or beverage. Nothing else should be taken by mouth for at least 30–60 minutes after oral dosing. The patient should also remain upright for 30 minutes after administration. The most common side effects of bisphosphonates are gastrointestinal. Pain in the joints, bone, and muscle may also occur. Risks include gastric and esophageal ulceration and, rarely, osteonecrosis of the jaw. Most cases of osteonecrosis of the jaw have been described in cancer patients being treated with intravenous bisphosphonates, but some cases have occurred in patients being managed for postmenopausal osteoporosis. Some studies suggest an increased risk of esophageal cancer following bisphosphonate use, but others do not. Further study is needed to assess whether there is a direct link between use of bisphophonates and esophageal cancer. More recently, an increase in the risk of atypical fracture of the femur has been reported in women using bisphosphonates for >5 years. The risk is probably small, but should be discussed with patients who are considering use of this class of drug, or who have been using these drugs for prolonged periods of time. The FDA has required a labeling change of bisphosphonates to reflect this risk and will continue to monitor these outcomes closely. Clinicians and patients should be aware that diagnosis of these atypical fractures has been preceded by new onset thigh or groin pain.
Calcitonin is a peptide hormone that inhibits osteoclast activity and therefore inhibits bone resorption. It demonstrates positive effects on bone mineral density at the lumbar spine, although less effectively than estrogen or bisphosphonates. Salmon calcitonin is the most potent form and is available for intranasal administration or as a subcutaneous injection. Calcitonin 100 IU is given subcutaneously daily or every other day; the intranasal calcitonin dose is 200 IU daily. The most frequent side effect with the intranasal route is rhinitis. Other antiresorptive therapies, such as bisphosphonates, are preferred over calcitonin, as they produce greater increases in bone mineral density. However, because of calcitonin’s analgesic properties, calcitonin is the preferred therapy in patients with pain from vertebral fracture.
Until recently, estrogen was the mainstay of therapy for prevention and treatment of postmenopausal osteoporosis. However, with the findings from the Women’s Health Initiative (WHI) trial demonstrating overall greater health risks than benefits from hormone therapy, it is no longer first-line therapy for prevention of osteoporosis. Osteoporosis prevention does remain an FDA-approved indication for estrogen therapy, however. It is best used in women who would otherwise use estrogen/hormone therapy for management of menopausal symptoms, or in women who cannot tolerate alternate antiresorptive therapies.
In observational studies, estrogen decreases the risk of hip fractures by 25–50%, of vertebral fractures by approximately 50%, and reduces the risk of other fractures. Daily dosages of 0.3–0.625 mg of conjugated estrogens, 0.5–1 mg of micronized estradiol, 1.25 mg of piperazine estrone sulfate, 0.025–0.05 mg of transdermal estradiol, and a new low dose (0.014 mg) of transdermal estradiol all are appropriate for the prevention of osteoporosis. The lower doses (ie, 0.3 mg of conjugated equine estrogens) are not as effective as higher doses but do prevent bone loss. For best results, therapy should begin soon after the menopause.
Parathyroid hormone, teriparatide (PTH [1-34]) has been approved by the FDA for use in women and men who are at high risk for fracture, including those with previous fracture, multiple risk factors for fracture, and previous failed treatment. Despite its potential deleterious effect on bone, intermittent administration of recombinant PTH stimulates bone formation, and clinical trials support its use in the treatment of osteoporosis. It should only be used in high-risk patients because of its high cost, the need for daily injection, and a possible risk for osteosarcoma.
Selective estrogen receptor modulators (SERMs) are nonhormonal agents that bind to estrogen receptors and may exhibit either estrogen agonist or antagonist activity. Currently, there are 3 SERMs approved for use in humans (tamoxifen, toremifene, and raloxifene); however, raloxifene is the only SERM approved for the prevention and treatment of osteoporosis. It exhibits estrogen agonist properties in the bone (inhibits osteoclast function) and the liver (decreases low-density lipoprotein cholesterol) and acts as an antagonist in the breast and uterus. Raloxifene 60 mg daily for 24 months is associated with a 1–2% increase in lumbar spine and hip bone density.
Combination Therapy has been evaluated in the prevention and/or treatment of osteoporosis. This typically takes the form of a bisphosphonate (ie, alendronate) and systemic estrogen. Small increases in BMD have been seen with combination therapy, but the effect on fracture risk is unknown.
Other therapies have been proposed for osteoporosis treatment and prevention, some without proven benefit. Progestins decrease biochemical markers of bone resorption and preserve bone density. When used as monotherapy for osteoporosis, they may be more effective at preserving bone in the wrist than in the spine.
Fluoride has been used in Europe and the United States and is associated with a marked increase in trabecular bone, but did not improve fracture rates, and in some studies fracture rates were increased. This may be a result of a lack of increase in cortical bone. Sodium fluoride is generally not recommended for the treatment of osteoporosis.
Phytoestrogens are plant-derived compounds that have weak estrogen-like effects. Although some animal studies are promising, no effects on the incidence of fractures in humans have been shown.
Tibolone (see Hot Flushes) also increases lumbar spine and femoral neck bone density. Its effects on bone are comparable to those of estrogens. As discussed previously, however, issues regarding long-term safety are currently being evaluated.
D. Sexual Dysfunction
The determinants of sexual behavior are complex and interrelated. Sexual function is believed to be regulated by 3 general components: the individual’s motivation (also called desire or libido), endocrine competence, and socio-cultural beliefs. Decreased libido is reported with increasing age. However, the relative contributions of the primary decrease in desire, anatomic limitations to sexual function, or beliefs that sexual behavior is inappropriate in older women to this decreased libido are unknown.
The hypoestrogenemic state leads to atrophy of the internal genitalia. Although dyspareunia is the most obvious symptom of vaginal atrophy, suboptimal sexual functioning can occur without frank dyspareunia. Diminished genital sensation (and therefore decreased sensory output in the arousal phase), lessened glandular secretions, less vasocongestion, and decreased vaginal expansion may not be perceived as discrete symptoms by the postmenopausal female, but may influence her perception that she is less responsive.
Genital atrophy, one cause of postmenopausal sexual dysfunction, responds to estrogen therapy. The specific impact of estrogen on libido has been difficult to determine. Improved anatomy may also have a positive psychologic impact and may indirectly encourage sexual motivation.
The role of androgen therapy in female sexual dysfunction is an active area of investigation. Despite the fact that the postmenopausal ovary continues to be a major source of androgens for several years after menopause, androgen levels overall are decreased, and this may contribute to the decrease in libido seen during menopause. Furthermore, the addition of testosterone to hormone therapy has been shown to improve sexual function in women in randomized, placebo controlled trials. However, improvements in sexual function have been modest at best. In addition, long-term safety has not been established. Some studies have suggested an increased risk of breast cancer amongst women using androgens. Therefore, its use remains controversial.
Campisi R, Camilletti J, Mele A, Erriest J, Pedroni P, Guiglioni A. Tibolone improves myocardial perfusion in post-menopausal women with ischemic heart disease: an open-label exploratory pilot study. J Am Coll Cardiol2006;47:559–564. PMID: 16458136.
Dimitrakakis C, Keramopoulos D, Vourli G, Gaki V, Bredakis N, Keramopoulos A. Clinical effects of tibolone in postmenopausal women after five years of tamoxifen therapy for breast cancer. Climacteric2005;8:342–351. PMID: 16390769.
Gambone J, Meldrum DR, Laufer L, Chang RJ, Lu JK, Judd HL. Further delineation of hypothalamic dysfunction responsible for menopausal hot flashes. J Clin Endocrinol Metab 1985;59:1097–1102. PMID: 6436285.
Kenemans P, Bundred NJ, Foidart JM, et al. Safety and efficacy of tibolone in breast cancer patients with vasomotor symptoms: A double blind, randomized, non-inferiority trial. Lancet Oncol 2009; 10:135–146. PMID: 19167925.
Krapf JM, Simon JA. The role of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women. Maturitas 2009; 63:213–219. PMID: 19487090.
National Osteoporosis Foundation. Physician’s Guide To Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2010.
Ness RB, Albano JD, McTiernan A, Cauley JA. Influence of estrogen plus testosterone supplementation on breast cancer. Arch Intern Med 2009;169:41–46. PMID: 19139322.
North American Menopause Society. Estrogen and progestogen use in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause 2010;17: 242–255. PMID: 20154637.
Panay N, Al-Azzawi F, Bouchard C, et al. Testosterone treatment of HSDD in naturally menopausal women with the ADORE study. Climacteric 2010; 13:121–131. PMID: 20166859.
Rapkin AJ. Vasomotor symptoms in menopause: physiologic condition and central nervous system approaches to treatment. Am J Obst Gynecol 2007; 196:97–106. PMID: 17306645.
Schwenkhagen A, Studd J. Role of testosterone in the treatment of hypoactive sexual desire disorder. Maturitas 2009; 63:152–159. PMID: 19359109.
US Food and Drug Administration. Pharmacy Compounding/Compounding of Bio-Identical Hormone Replacement Therapies, 2009. www.fda.gov/News/Events/Testimony/ucm154031.htm
World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser 1994;843:1. PMID: 7941614.
Differential Diagnosis of Common Signs and Symptoms During Menopause
Signs and symptoms similar to those of the climacteric can be caused by a variety of other diseases. In general, seeing the entire clinical picture is helpful in establishing the proper diagnosis. The absence of evidence of other disease points to cessation of ovarian function, whereas the presence of prominent features of other conditions, in the absence of other climacteric symptoms, suggests a nonclimacteric origin.
A. Amenorrhea
By definition, the primary symptom of the menopause is the absence of menstruation for 12 months. Amenorrhea can occur for many reasons, of which physiologic menopause is only one. Cessation of ovarian function is by far the most common reason for amenorrhea to occur in women in their forties or early fifties. Persistent amenorrhea in younger women may be a result of premature cessation of ovarian function, but must be differentiated from other causes. Obvious features of specific disease often suggest the proper diagnosis (ie, extreme weight loss in anorexia nervosa, galactorrhea in hyperprolactinemia, hirsutism and obesity in polycystic ovarian disease).
B. Hot Flashes
Several diseases can produce sensations of flushing that may be misinterpreted as menopausal vasomotor symptoms. Notable are hyperthyroidism, pheochromocytoma, carcinoid syndrome, diabetes mellitus, tuberculosis, and other chronic infections. None of these disorders produces the specific symptoms associated with the climacteric (ie, short duration and specific body distribution). Moreover, the absence of other signs or symptoms of the climacteric suggest some other cause of the flushes should be sought.
C. Abnormal Vaginal Bleeding
Before the menopause, irregular vaginal bleeding is expected and does not necessitate a diagnostic workup in many cases. However, organic disease can occur at this time, and some patients require evaluation. If a woman is in her forties or fifties and experiences an increase in cycle length and a decrease in the quantity of bleeding, menopausal involution can be presumed, and endometrial sampling is usually not necessary. However, if menses become more frequent and heavier, spotting between menses occurs, or any pattern of irregular bleeding persists, assessment of the endometrium should be performed. The usual procedure is an endometrial biopsy or dilatation and curettage (D&C) to rule out endometrial hyperplasia or cancer. The disadvantage of the former is that entry into the endometrial cavity may not be accomplished in the setting of a stenotic os, and the drawbacks of the latter are greater expense, risk and need for anesthesia.
It is most unusual for a woman to experience vaginal bleeding because of ovarian activity by 6 months after the menopause. Thus postmenopausal bleeding is much more ominous and necessitates evaluation each time it occurs. The only exception to this rule is the uterine bleeding associated with estrogen replacement therapy. Other guidelines are recommended for this type of bleeding (see Estrogen Therapy).
Organic disease is commonly associated with postmenopausal bleeding. Endometrial polyps may be found, which can be resected via the hysteroscope. Endometrial hyperplasia may be discovered, frequently in obese women. This can be treated by the periodic administration of progestin or by hysterectomy. If hyperplasia develops in a woman taking estrogens, the addition of progestins should be considered. If hyperplasia develops unrelated to hormone replacement, surgery should be considered if the patient is a good surgical risk or is not reliable in taking progestins. The finding of endometrial cancer necessitates appropriate therapy depending on the stage and grade of the tumor.
D. Vulvovaginitis
Many specific vulvar and vaginal diseases (ie, trichomoniasis and candidiasis) may mimic the atrophic vulvovaginitis of estrogen deficiency. Their special clinical characteristics usually suggest more specific diagnostic testing. When pruritus and thinning of the vaginal epithelium or the vulvar skin are the only manifestations, therapeutic testing with local applications of estrogen may help to establish the diagnosis of vulvovaginitis. When any whitening, thickening, or cracking of vulvar tissues is present, biopsy to rule out carcinoma is mandatory. Raised or erosive lesions should also be sampled. Biopsy to rule out carcinoma is also necessary for suspicious looking vaginal or cervical lesions.
E. Back Pain
Occasionally, the pain of vertebral compression from osteoporosis may mimic that of gastric ulcer, renal colic, pyelonephritis, pancreatitis, spondylolisthesis, acute back strain, or herniated intervertebral disk.
Common Clinical Conditions of the Aged, Postmenopausal Woman: Controversial Role of Estrogens
A. Coronary Heart Disease (CHD)
Heart disease affects approximately 8 million women in the United States. Deaths caused by CHD in women number more than 230,000 per year. The incidence of death from CHD increases with age in all populations and both sexes. Substantially more heart disease is seen in younger men, with the onset of cardiovascular problems occurring an average of 10 years later in women. Before the age of menopause, very few women die of a heart attack. After the menopause, a woman’s risk increases progressively such that CHD rates in women after menopause are 2–3 times those of women of the same age before menopause. Statistics such as these, indicating a role for both sex and menopause on the development of CHD, have led to the suggestion that estrogen deficiency that occurs after menopause is at least partially responsible for the increased risk of CHD in postmenopausal women.
The first attempts at ascertaining whether cessation of ovarian function is associated with an increased incidence of heart disease came from large epidemiologic studies. The Framingham study, in which nearly 3000 women were examined biennially, revealed that after the menopause, there is indeed an increased incidence of heart disease that is not just age-related. In the Nurses’ Health Study cohort of 121,700 women, after controlling for age and cigarette smoking, women who had a natural menopause had no appreciable increase in risk compared with that of premenopausal women. However, women who underwent a bilateral oophorectomy and no estrogen replacement had an increased risk (relative risk = 2.2) compared with that seen in premenopausal women.
Case-control studies were also performed comparing the degree of CHD or the incidence of myocardial infarction in women who had undergone early oophorectomy with age-matched premenopausal controls. Most of these studies revealed an increased risk of cardiovascular disease after ovarian excision. All these reports have been criticized because of patient selection bias, particularly of the controls.
Numerous case-control and large-cohort studies have also since been carried out to assess the role of exogenous estrogens administered during menopause on morbidity and mortality from CHD. Most have shown a beneficial impact of exogenous estrogens on morbidity and mortality from CHD. Although the magnitude of change and the consistency of results appear compelling, it must be recognized that all these studies are observational and that the choice of controls has been questioned. In particular, women who take estrogens are more health conscious and must see a doctor regularly to receive their medication, whereas women who do not take estrogens may or may not receive regular medical checkups. Thus some or all of the apparent benefits of estrogens on heart disease may have been a consequence of these other considerations.
Based on these observational/case-controlled studies suggesting a beneficial effect of estrogens, numerous experimental studies were performed attempting to elucidate the mechanism(s) by which estrogens could prevent CHD. Evidence for both an indirect effect on circulating lipids and a direct action on the vascular system was found. Orally administered estrogens influence hepatic lipid metabolism and raise high-density lipoprotein (HDL) cholesterol and triglycerides and lower low-density lipoprotein (LDL) cholesterol. The impact of nonorally administered estrogens is of lesser magnitude and takes longer to become apparent.
Numerous studies have shown that estrogen and progesterone receptors are present in the heart and aorta. Thus the subcellular components necessary for direct hormonal action exist in these tissues. Endothelial cells of the arteries produce factors in response to estrogen. One of the most potent of these is believed to be nitric oxide (NO). NO exerts several effects on the arterial wall. It increases intracellular cyclic guanosine monophosphate in the arterial smooth muscle, which results in vasodilation. It also inhibits platelet adhesion and aggregation, as well as monocyte adherence to the arterial endothelium. Estrogen appears to increase NO production, and this may be important in preventing coronary vasospasm and thrombus formation. Estrogen has been shown in animals to prevent atherosclerosis. It has also been shown in a rabbit model to prevent 2 of the earliest steps in the atherogenic process—adhesion and migration of monocytes. This likely occurs through an NO-mediated mechanism. Estrogens also likely have adverse effects on the vessel wall. Estrogens lead to a hypercoagulable state which may increase the risk of coronary events. Although these mechanisms are only partially understood, they emphasize the importance of studying the direct effects of estrogen on the vascular system.
Interestingly, use of estrogen had been widespread for many years, yet it was not until recently that large-scale, prospective, randomized, placebo-controlled studies evaluating the effect of hormone therapy on relevant clinical end points in humans were performed. One of the first of these studies was the Heart and Estrogen/Progestin Replacement Study (HERS), which studied the use of estrogen and progestin in the secondary prevention of coronary events in women with known CHD. HERS showed that treatment with oral conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) did not reduce the overall rate of CHD events in postmenopausal women with established heart disease. Furthermore, there was an early increased risk of CHD events within the first year of starting HT. In addition, the ERA (Estrogen Replacement and Atherosclerosis) Trial, which was the first randomized angiographic end point trial to test the effect of HT on the progression of atherosclerosis in postmenopausal women with documented coronary stenosis, showed no benefit of CEE either alone, or in combination with MPA, on angiographic progression of disease. Consequently, it is suggested that physicians not prescribe estrogen therapy (ET)/HT for the sole purpose of secondary prevention of coronary events.
The primary prevention of CHD by HT also had not been evaluated in a prospective, randomized fashion until recently. The WHI, a large, multicenter, prospective, randomized, placebo-controlled trial of primarily healthy post-menopausal women, was initiated to assess the effects of a specific regimen of CEE alone or in combination with MPA on several health-related outcomes, including CHD. The combined estrogen/progestin portion of the study was stopped after 5.2 years as overall health risks exceeded benefits. The increased risks included a greater number of cardiovascular events. The estrogen-only arm of the study was continued for approximately 7 years. This arm of the study was stopped early because of an increased risk of stroke. Overall, there was no reduction in the risk of coronary events. Interestingly, there appeared to be a trend toward a decreased risk of coronary events in the younger subset of postmenopausal women. This finding was confirmed in a subanalysis of the data for the 50–59-year-old age group where the investigators reported a lower relative risk for the combined end points of myocardial infarction, coronary death, coronary revascularization, and confirmed angina among women ages 50–59 years using estrogen alone. In addition, in the subset of women who were 50–59 years of age who were placed on the estrogen-alone arm, lower levels of coronary artery calcium were observed, suggesting that in this group of recently postmenopausal women that estrogen alone slows the development of calcified coronary atherosclerotic plaque.
There were several limitations of the WHI study. It did not assess different dosages, types of estrogens and progestogens, nor different routes of administration (ie, transdermal vs. oral). Finally, many of the subjects had become menopausal several years before entry into the study. Consequently, it was not possible to precisely ascertain whether starting HT with the onset of menopause, when initiation or more rapid acceleration of atherosclerosis may take place, is beneficial. Because estrogen has been shown in experimental models to prevent the very earliest steps in atherogenesis, but to raise cardiovascular risk in the setting of established atherosclerosis (possibly via increases in clotting factors), it is possible that the adverse cardiovascular effects seen in this study may have been because many women started HT following the onset of menopause when subclinical atherosclerotic changes and irreversible endothelial damage may have already set in. In order to evaluate the possible role of age and/or years since menopause in the development of CHD, WHI investigators performed additional analyses in various subgroups of women. These additional analyses suggested no effect of age (i.e. 50-50 vs. 70-79 year of age). However, there were was a suggestion that greater numbers of years since menopause was associated with greater risk. Women starting within 10 years of menopause had fewer CHD events than those starting >20 years since menopause. However, statistical analyses of the combined WHI trials did not demonstrate that time since menopause altered CHD risk overall. This emphasizes the importance of continuing to study the effects of estrogen, particularly in younger, recently postmenopausal women. Additional studies are currently underway to assess whether estrogen administration to younger, healthy, recently post-menopausal women is safe from a cardiovascular standpoint.
The decision to use HT should be based primarily on the proven benefits of ET/HT on other systems, the potential risks of therapy, and patient preference. It should not be prescribed for prevention of CHD. Short-term use of HT for relief of postmenopausal symptoms is still an option for women without contraindications.
B. Diabetes Mellitus
Hormone therapy may decrease the risk of developing diabetes in postmenopausal women. In the HERS trial, the incidence of diabetes was significantly lower in women receiving HT as compared to women receiving placebo. The WHI trial revealed similar results whereby the incidence of diabetes was less in the HT group as compared with the placebo group. The differences between groups in both studies persisted after adjusting for body mass index and waist circumference. These results provide some reassurance regarding the effects of HT on glucose tolerance in women. However, HT should not be prescribed to post-menopausal women for prevention of diabetes.
C. Mood Disorders
Studies assessing the effects of estrogen on depression and other mood disorders are conflicting. Although some studies suggest beneficial effects of estrogen, others, including the recent WHI, do not. Early cross-sectional surveys of community or large, general, medical practice–based populations attempted to measure the temporal association of depression and irritability to the cessation of menses. Some reports indicated an increased incidence of minor symptoms such as irritability, dysphoria, and nervousness early in the menopausal transition.
Reports from community-based cohort studies have refined knowledge in the area of mood, mentation, and menopause. The initial longitudinal report of the US cohort found an increase in overall nonspecific symptom reporting at the menopause. Depression for more than 2 interviews was noted in 26% of the cohort. Perceived health, rather than menopause or coincident life stresses, was most related to depression in this study. These findings are consistent with the concept of variability in a woman’s response to the menopause; individual characteristics and self-perceptions appear to be important determinants of each woman’s experience of the climacteric.
Hypotheses regarding the etiology of the affective complaints at the menopause also include a primary biologic cause (eg, an alteration in brain amines). Studies using the opioid antagonist naloxone have demonstrated that estrogen deficiency is associated with low levels of endogenous opioid activity and that estrogen supplementation increases opioid activity. These findings suggest that central neurotransmitters may contribute to the etiology of affective and cognitive complaints. Sociologic factors postulated to cause psychologic symptoms, such as negative cultural values attached to aging, may also promote a negative climacteric experience.
Double-blind studies have found improvements in self-reported irritability, mild anxiety, and dysphoria in women treated with estrogen alone or when combined with progestin. Improvement of the Beck depression score in women without hot flushes indicates that estrogens likely have direct effects on brain function.
Depression and other quality-of-life outcomes were studied in the WHI trial. Overall, CEE alone, or in combination with medroxyprogesterone acetate, did not improve depressive symptoms among postmenopausal women ages 50–79 years after 1 and 3 years. In a subgroup analysis of 50–54-year-old women experiencing hot flashes, estrogen plus progestin improved hot flashes and sleep disturbance, but no other quality-of-life outcomes. In the estrogen-alone group, there was a slight improvement in sleep disturbance and social functioning, but no other quality-of-life outcomes measured. Therefore, a role for HT/ET in improving depressive symptoms after the menopause remains unproven.
D. Cognitive Decline
As life expectancy in women has risen, there has been more research regarding the effects of estrogen on cognitive functioning in postmenopausal women. Research indicates that estrogen influences areas of the brain known to be important for memory. However, recent data from the WHI suggests that estrogen alone or in combination with progestin does not decrease, and in fact may increase, the risk of cognitive decline in women older than 65 years of age.
E. Skin & Hair Changes
With aging, noticeable changes occur in the skin. There is generalized thinning and an accompanying loss of elasticity, resulting in wrinkling. These changes are particularly prominent in the areas exposed to light (ie, the face, neck, and hands). “Purse-string” wrinkling around the mouth and “crow’s feet” around the eyes are characteristic. Skin changes on the dorsum of the hands are particularly noticeable. In this area, the skin may be so thin as to become almost transparent, with details of the underlying veins easily visible.
Histologically, the epidermis is thinned, and the basal layers become inactive with age. Dehydration is typical. Reduction in the number of blood vessels to the skin is also seen. Degeneration of elastic and collagenous fibers in the dermis also appears to be part of the aging process.
These skin changes are of cosmetic importance and are of great concern to many women. It is unclear whether these changes are primarily caused by the menopause, aging, or a combination of both factors. It is commonly stated that women undergoing estrogen replacement look younger, and the cosmetic industry has been putting estrogens in skin creams for years for precisely this reason.
The possibility that estrogens may have effects on skin was suggested by the demonstration of estrogen receptors in skin. The number of receptors is highest in facial skin, followed by skin of the breasts and thighs. This gives credence to the hypothesis that estrogens affect the skin.
Skin circulation is decreased in women after oophorectomy. Radiolabeled thymidine incorporation (an index of new DNA metabolism) is reported to decrease during the several months after oophorectomy. In some animal studies, estrogens increase the mitotic rate (a reflection of growth) of skin. Estrogens may alter the vascularization of skin. They also change the collagen content of the dermis, as reflected by mucopolysaccharide incorporation, hydroxyproline turnover, and alterations of the ground substance. In addition, dermal synthesis of hyaluronic acid and dermal water content are enhanced.
Skin collagen content and thickness have been studied in postmenopausal women. Decreases of both have been observed at a rate of 1–2% per year. The losses correlated with the number of years since the menopause, but not with chronologic age. Estrogen replacement prevents these losses or restores both parameters to premenopausal values. The greatest recovery is observed in women who began with low values. These data were interpreted to indicate that estrogen can prevent loss in women with high skin collagen levels, whereas it can restore content as well as prevent further loss in women with low collagen levels. Although these results are promising, it remains unclear whether they are clinically relevant. Estrogen should not be prescribed to improve the appearance of skin.
After the menopause, most women note some change in patterns of body hair. Usually there is a variable loss of pubic and axillary hair. Often there is loss of lanugo hair on the upper lip, chin, and cheeks, together with increased growth of coarse terminal hairs; a slight moustache may become noticeable. Hair on the body and extremities may either increase or decrease. Slight balding is seen occasionally. All of these changes may be partly a result of reduced levels of estrogen in the face of fairly well-maintained levels of testosterone.
F. Miscellaneous Symptoms
Many other symptoms are attributed to the endocrine changes of the postmenopausal state, but a direct cause-and-effect relationship has not been established for them. Some of these so-called climacteric symptoms are so common that they deserve brief mention.
Symptoms possibly related to specific autonomic nervous system instability—but equally attributable to anxiety or other emotional disturbances—are paresthesia (pricking, itching, formication), dizziness, tinnitus, fainting, scotomas, and dyspnea. Symptoms clearly not of endocrine origin are weakness, fatigue, nausea, vomiting, flatulence, anorexia, constipation, diarrhea, arthralgia, and myalgia.
Many women erroneously believe that the endocrine changes accompanying menopause will produce a steady weight gain. Women and men do tend to gain weight at this time of life, but the cause is usually a combination of decreased exercise and possibly increased caloric intake. There may be some redistribution of body weight occasioned by the deposition of fat over the hips and abdomen. Perhaps this is partly an endocrine effect, but more likely it is the result of decreased physical activity, reduced muscle tone, and other effects of aging.
Many of the previously mentioned symptoms occasionally respond promptly to administration of estrogen. This should not mislead physicians into assuming a specific endocrine action for what is actually a placebo effect.
Anderson GL, Limacher M, Assaf AR, et al; The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 2004;291:1701. PMID: 15082697.
Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2006;295:1288–1299. PMID: 16537739.
Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: the Women’s Health Initiative Memory Study. JAMA 2004;291:2959–2968. PMID: 15213207.
Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study research group. JAMA 1998;280:605–613. PMID: 9718051.
Kanaya AM, Herrington D, Vittinghoff E, et al. Glylcemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003;138:1–9. PMID: 12513038.
Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523–534. PMID: 12904517.
Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary artery calcium. N Engl J Med 2007;356:2591–2602. PMID: 17582069.
Margolis KL, Bonds ED, Rodabough RJ, et al. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia2004;47:1175–1187. PMID: 15252707.
Nathan L, Stackhouse J, Goulandris N, Snowling MJ. Estradiol inhibits leukocyte adhesion and transendothelial migration in vivo: possible mechanisms for gender differences in atherosclerosis. Circ Res1999; 85:377–385. PMID: 10455066.
Prentice RL, Manson JE, Langer RD, et al. Benefits and Risks of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 2009;170:12–23. PMID: 19468079.
Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women’s Health Initiative Study: a randomized trial. JAMA2003;289:2663–2672. PMID: 12771113.
Estrogen Therapy
Every woman with menopausal symptoms deserves an adequate explanation of the physiologic event she is experiencing to dispel her fears and address symptoms such as hot flashes and sleep disturbance. Reassurance should be emphasized. Specific reassurance about continued sexual activity is important.
As long as ovarian function is sufficient to maintain some uterine bleeding, no treatment is usually required. Occasionally, women complain of hot flushes while menstrual function is still present. Treatment with low-dose oral contraceptive pills, if no contraindications exist, will relieve these symptoms and help to regulate menstrual cycles during the menopausal transition.
A. Indications
Estrogen therapy has been used for many years for a variety of symptoms and conditions seen in the aged female population. However, despite suggestions from observational and experimental studies that estrogens prevent many common conditions of aging, such as Alzheimer’s disease and CHD, estrogen therapy has only been proven to be effective in the prevention of osteoporosis, treatment of vasomotor symptoms, and treatment of vulvovaginal atrophy. Results from the WHI further call into question the degree to which estrogen can act as a “cure-all” for the common conditions of aging, particularly those affecting the brain and heart. Benefits beyond those already established are still possible, but await proof in large-scale studies in humans. Therefore, use of estrogens should be limited to the currently FDA-approved indications: prevention of osteoporosis, treatment of vasomotor symptoms, and treatment of vulvovaginal atrophy (see D. Management Guidelines for Estrogen Therapy).
B. Complications
Before discussing the management of estrogen replacement, it is necessary to review the complications of and contraindications to this type of therapy. These play an important role in the ultimate decision regarding treatment for all patients.
1. Endometrial cancer—The role of estrogen therapy in the development of endometrial cancer is one of the most highly charged issues related to the menopause. Current concerns are based on several lines of investigation. The scope of investigative efforts lead to the conclusion that estrogen stimulation of the endometrium, unopposed by progesterone, causes endometrial proliferation, hyperplasia, and, finally, neoplasia. In most studies, a strong association has been found, with 2- to 8-fold overall risk ratios. High dosage and prolonged treatment increase the risk. Disease is local in most cases, although more widespread invasive tumors have been reported. Consequently, it is recommended that a progestogen be added to ET to reduce the risk of endometrial hyperplasia or carcinoma. Some women may experience adverse side effects from progestogen therapy. In addition, increasing concerns about the role of progestogens in increasing risk of breast carcinoma amongst women using estrogen–progestogen therapy (EPT) have led to further efforts to find alternatives to progestogens to counteract the effects of estrogen on the endometrium. Agents with estrogen agonist/antagonist activity are currently being investigated as such possible alternatives.
2. Breast cancer—Early age at menarche and older age at menopause are known risk factors for breast cancer, and early oophorectomy is known to give protection against this disease. Ovarian activity is an important determinant of risk, thus estrogen may play a role in the development of breast cancer. Studies in rodents support that view. More than 30 epidemio-logic studies have been published since 1974 to determine the possible link between postmenopausal estrogen use and breast cancer. In general, the later studies have had better design, quality, and analytic strategies. The number of subjects in more recent studies has also been larger. These results have not always agreed. The recent prospective, randomized WHI trial also addressed this issue. In this study there was an increased risk of invasive breast cancer in the estrogen/progestin arm. However, in the estrogen-alone arm, the risk of breast cancer was not increased compared with controls.
Despite this inconsistency in studies, some trends have been observed: (1) Long-term use (ie, 4–10 years) has been associated with mild increased risk in some of the meta-analyses and the WHI. (2) The addition of a progestin does not appear to decrease risk and may increase risk. (3) Finally, risk does not vary in strata of family history of breast cancer or with benign breast disease.
It must be remembered that all women are at risk for breast cancer. Thus instructions for breast self-examination, a careful breast assessment, and routine screening mammography should be a part of the medical care of all older women.
3. Thromboembolic disease—Use of oral contraceptives increases the risk of overt venous thromboembolic disease and subclinical disease extensive enough to be detected by laboratory procedures such as 125I fibrinogen uptake and plasma fibrinogen chromatography. The risk of venous thromboembolic disease was also increased among users of ET/EPT in the WHI, as well as among users of HT in the HERS trial.
The effects of estrogen on the clotting mechanism may contribute to or be responsible for a generalized hypercoagulable state. Oral estrogens affect synthesis of coagulation factors through a first-pass effect in the liver, an effect associated with an increased risk of thromboembolic disease. The risk for thromboembolic events with use of ET/EPT is also likely further increased amongst patients with inherited thrombophilias.
Use of transdermal estrogens is probably associated with a lowered risk for thromboembolic events as compared with use of oral estrogens. However, randomized trials are needed to better characterize the effects of transdermal estrogens on risk for clinical thromboembolic events.
4. Stroke—Several recent studies suggest that HT is associated with an increased risk of stroke. In the EPT arm of the WHI, there was an increased risk of ischemic stroke among those using EPT when compared with the placebo. In the estrogen-alone arm of the WHI, there was also a statistically significant increased risk of stroke after approximately 7 years of follow-up, and this outcome led to the trial being terminated.
5. Uterine bleeding—If patients are given sequential estrogen and progestins, the majority will experience some uterine bleeding, particularly soon after initiation of therapy. This bleeding can occur during the treatment-free interval (scheduled bleeding) or while the medications are being administered (unscheduled bleeding). Hyperplastic endometrium can develop with this type of therapy. If the bleeding is heavy or prolonged, a biopsy should be performed. In women using a combined continuous regimen of estrogen and progestin, bleeding is common in the first several months of therapy and usually doesn’t indicate endometrial pathology. However, if bleeding persists in these patients, or is prolonged or heavy at any time, endometrial sampling should be performed. If endometrial hyperplasia is present, the medications can be discontinued, progestin dose can be increased, or a progestin can be given each day of estrogen administration. Whichever approach is adopted, a repeat biopsy should be performed to make certain that the hyperplastic endometrium has resolved. The cost-effectiveness ratio for periodic biopsy in women who do not bleed or bleed only during the medication-free interval is poor and indicates that such biopsy is probably unnecessary.
In women taking estrogen only, the incidence of endometrial hyperplasia can be as high as 25% after only 12 months of therapy. Hyperplasia occurs in women who do not experience vaginal bleeding, bleed only during the medication-free interval, or bleed during drug administration. Thus a pretreatment biopsy and yearly endometrial biopsies are necessary in all women receiving estrogens alone to assess for the presence of hyperplasia. Again, estrogen withdrawal or combined EPT may be used to treat the hyperplasia. The incidence of endometrial cancer will likely be reduced if the programs discussed previously are instituted.
6. Gallbladder disease—An increased incidence of gallbladder disease has been reported after estrogen replacement therapy. Estrogens cause increased amounts of cholesterol to collect in bile. Two primary bile salts, cholate and chenodeoxycholate, are produced by liver cells. In women taking estrogen, decreased levels of chenodeoxycholate and increased levels of cholate are found in bile. Chenodeoxycholate inhibits activity of the enzyme β-hydroxy-β-methylglutaryl-CoA reductase, which regulates cholesterol synthesis, and a decrease in chenodeoxycholate may therefore cause increased activity of β-hydroxy-β-methylglutaryl-CoA reductase, leading to increased synthesis of cholesterol. Bile normally has a 75–90% saturation in cholesterol, and even small increases of this substance can initiate cholesterol precipitation and stone formation. Three-fourths of gallstones are composed predominantly of cholesterol.
7. Lipid metabolism—Estrogen replacement also has an impact on circulating lipids. As discussed earlier, many of these effects are favorable. However, others may pose increased risk. Most lipids are bound to proteins in the blood, and the concentrations of the various types of lipo-proteins are associated with varying risks of heart disease. Lower levels of HDL cholesterol and higher concentrations of total cholesterol, LDL cholesterol, very-low-density lipoprotein cholesterol, and triglycerides are associated with increased risk of atherosclerosis and coronary artery disease. Estrogen replacement decreases LDL cholesterol and increases HDL cholesterol and triglycerides. Use of conjugated estrogens, 0.625 mg/d or less, causes approximately a 10% increase in HDL cholesterol. Much attention has been focused on the impact of estrogens on lipoproteins to explain what appeared to be a beneficial effect of HT on heart disease in earlier observational studies of younger postmenopausal women. The impact of estrogen-induced increases in triglycerides on cardiovascular risk is unclear. In patients with familial defects of lipoprotein metabolism, estrogen replacement therapy is associated with massive elevations of plasma triglycerides, leading to pancreatitis and other complications. However, this is a very unusual complication of estrogen replacement. Transdermal estrogens are probably less likely to raise triglyceride levels and thus are preferred in women with an elevation in triglyceride levels.
8. Miscellaneous—Other side effects of estrogen therapy include uterine bleeding, generalized edema, mastodynia and breast enlargement, abdominal bloating, signs and symptoms resembling those of premenstrual tension, headaches (particularly of a “menstrual migraine” type), and excessive cervical mucous. These side effects may be dose related or idiosyncratic, and are managed by lowering the dosage, by use of another agent, or by discontinuation of the medication.
C. Contraindications to Estrogen Replacement Therapy
Contraindications to ET are as follows: (1) Undiagnosed abnormal vaginal bleeding; (2) known, suspected, or history of cancer of the breast; (3) known or suspected estrogen-dependent neoplasia; (4) active deep vein thrombosis, pulmonary embolism, or a history of these conditions; (5) arterial thromboembolic disease (myocardial infarction, stroke); and (6) liver dysfunction or disease. In general, ET should be avoided in patients with a diagnosis of endometrial cancer. ET may stimulate growth of malignant cells remaining after treatment of breast or endometrial carcinoma and may thus hasten the recurrence of cancer. Therefore, it is prudent to avoid systemic ET in breast cancer patients and most endometrial cancer patients. Recently, it was suggested that women with early (stage 1) and well-differentiated (grade 1) endometrial cancer can be administered estrogens after primary treatment of the cancer. Care must be exercised in following this recommendation until it has been properly studied. Any decision to use ET/EPT after a diagnosis of endometrial cancer should be made in consultation with the patient’s oncologist. Patients who have had estrogen receptor–positive malignant tumors of the breast probably should not receive systemic estrogen supplements. Topical vaginal estrogens to treat symptoms of urogenital atrophy in breast/endometrial cancer patients might be acceptable, but should first be discussed with the patient’s oncologist. A history of treated carcinoma of the cervix or ovary is not a contraindication to ET. Estrogens may have undesirable effects on some patients with preexisting seizures, hypertension, fibrocystic disease of the breast, uterine leiomyoma, collagen disease, familial hyperlipidemia, migraine headaches, chronic thrombophlebitis, and gallbladder disease. At the low dosages recommended for replacement therapy, increased growth of uterine myomas, endometriosis, or chronic cystic mastitis is rarely a concern.
D. Management Guidelines for Estrogen Therapy
1. General—Only general guidelines can be offered, because risks and benefits must be evaluated for each patient. Numerous formulations of estrogen and estrogen plus progestin are available (Table 59–1). Current indications for ET are relief of menopausal symptoms (including hot flushes and vaginal atrophy) and prevention of osteoporosis. Caution should be exercised in providing therapy for other conditions until more definitive studies have been performed. If symptoms of hot flushes and vaginal atrophy are moderate to severe, therapy may be used for the shortest duration possible; minimal or no symptoms may not require hormones.
Table 59–1. Preparations of estrogens and progestogens available in the United States for hormone therapy.
In women who require pharmacologic intervention for prevention of osteoporosis, estrogen may be used. However, ET for osteoporosis prevention is generally reserved for those women who are otherwise using estrogen for menopausal symptoms and/or who cannot tolerate other anti-resorptive therapies. Lower dosages of estrogen are being increasingly used for prevention of osteoporosis to minimize the risks of estrogen therapy. There are several options available for use of estrogen or estrogen plus progestin for prevention of osteoporosis (Table 59–1). In the past, standard doses included 0.625 mg of conjugated equine estrogens, 0.05 mg of transdermal estradiol, and 1 mg of micronized estradiol. However, 0.3 mg of conjugated equine estrogens, 0.5 mg of micronized estradiol, and 0.025-mg transdermal patches also prevent bone loss, although not as well as higher doses. A new low-dose (0.014 mg/d) transdermal formulation of estradiol was recently FDA approved for prevention of osteoporosis. Early commencement of prophylaxis after cessation of ovarian function will maintain the highest bone density. Initiation of HT well after the menopause will stop bone loss, but will not return bone density to that which was present at the time of the menopause.
For women with hot flashes, a standard dosage of estrogen, such as 0.3–0.625 mg of conjugated equine estrogens, 0.025 mg transdermal estradiol, or 0.5 mg oral estradiol should be given daily (Table 59–1). Higher doses may be necessary to relieve hot flashes. Progressive reduction of dosage should be attempted as soon as feasible. Additional formulations containing estradiol, synthetic estrogens, and estrogens plus progestins are also available (Table 59–1).
In women who are suffering from atrophic vaginitis, vaginal preparations can be used and are preferred over systemic estrogens. These preparations are available in the form of creams (ie, CEEs or estradiol 0.25–2 g given nightly for 2 weeks, followed by twice weekly), tablets (10 μg estradiol given nightly for 2 weeks, followed by twice weekly), and rings (estradiol releasing rings, which remain in place for 3 months at a time) (Table 59–1). With the tablets, rings, and lowest dose creams, endometrial proliferation is rare. However, higher doses, presence of vaginal bleeding, or other risk factors may necessitate periodic endometrial biopsy or ultrasound to assess the endometrial thickness. Progestogens may be necessary to prevent endometrial proliferation in some cases.
2. Progestogen–estrogen therapy—One of the most serious concerns about estrogen replacement is the occurrence of endometrial hyperplasia or cancer. Progestogens oppose the action of estrogen on the endometrium. Progestogens reduce the number of estrogen receptors in glandular and stromal cells of the endometrium. These agents also block estrogen-induced synthesis of DNA, and they induce the intracellular enzymes estradiol dehydrogenase and estrogen sulfotransferase. The former reduces estradiol to the much less potent estrone, whereas the latter converts estrogen to estrogen sulfates for rapid elimination from endometrial cells. In addition, full secretory transformation occurs if the progestogen is given at a large enough dosage for a sufficient length of time.
Progestogens reduce the occurrence of endometrial cancer. Epidemiologic studies show significant reduction of the occurrence of endometrial cancer with estrogen plus progestogen compared with estrogen alone. One study indicated use of the progestogen for more than 10 days a month reduced the occurrence more than use for a shorter interval. In treating women with hormones, a more practical concern is the prevention of endometrial hyperplasia. Initially, British investigators showed that high-dose estrogens (1.25 mg or greater of CEEs) resulted in 32% hyperplasia, whereas low doses (0.625 mg or less) stimulated 16% hyperplasias in women followed up for 15 months. In women given estrogen plus progestins, the occurrence of hyperplasia was 6% and 3%, respectively. In comparing length of therapy, 7 days of progestogen reduced the occurrence of hyperplasia to 4%, 10 days reduced it to 2%, and 12 days eliminated hyperplasia. Direct comparisons in drug trials have also shown reductions of hyperplasia in women given estrogens and progestogens compared with those given estrogen alone. It should be pointed out that the majority of endometrial lesions observed in women in these trials were either cystic or simple hyperplasias, which could be reversed by giving a progestogen or discontinuing the estrogen.
One option is to administer a progestogen such as medroxyprogesterone acetate at a dosage of 5–10 mg/d for 12–14 days each month (see Table 59–1). If this is accomplished, 80–90% of women will experience some vaginal bleeding monthly toward the end of or after the progestogen is administered. An alternative is to prescribe a lower dosage, 2.5 mg, continuously. Many newer formulations of hormone therapy contain both estrogen and progestin (Table 59–1). The combined, continuous administration of estrogen plus progestogen is the most common mode of administration today. This regimen promotes endometrial atrophy and results in amenorrhea in 70–90% of women who use continuous therapy for more than 1 year. The remainder will bleed occasionally, with the bleeding usually being less frequent, shorter, and lighter than with sequential therapy.
Administration of progestogens can be associated with other uncomfortable side effects including fatigue, depression, breast tenderness, bloating, menstrual cramps, and headaches. It is also important to keep in mind that it was a progestogen-containing regimen that was used in the WHI trial that was discontinued largely because of a trend toward an increased risk of breast cancer. In the estrogen-only arm, breast cancer rates were not increased over control levels. This raises concerns about the potential role of progestogens in increasing breast cancer risk. This concern combined with potential progestogen side effects may lead to elimination of or nonstandard progestogen administration. If lower dosages or shorter duration of progestogens are used, endometrial sampling to diagnose the development of hyperplasia or cancer should be performed. Use of locally administered progestogens through the use of the levonorgestrel intrauterine device is also being considered as an alternative strategy to minimize systemic side effects and risks while maintaining endometrial protection.
Chlebowski RT, Anderson GL, Gass M, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010; 304:1684–1692. PMID: 20959578.
Beral V, Bull D, Reeves G; Million Women Study Collaborators. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 2005;365:1543–1551. PMID: 15866308.
Prentice RL, Chlebowski RT, Stefanick ML, et al. Conjugated equine estrogens and breast cancer risk in the Women’s Health Initiative clinical trial and observational study. Am J Epidemiol 2008; 167:1407–1415. PMID: 18448442.
Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–333. PMID: 12117397.
Prognosis
The prognosis for the postmenopausal woman who does not develop clinically manifest estrogen deficiency includes only the ordinary hazards of disease and aging. For the woman who does develop signs of estrogen deficiency, hormone therapy can correct physical symptoms and signs and prevent the development of osteoporosis. Correction of minor distressing symptoms and signs can improve the general well-being of the postmenopausal woman and help her to pursue a vigorous life. However, HT for the postmenopausal woman who does not need it serves no purpose and can cause unpleasant side effects and impose unnecessary risks to her health.