What term describes the ending of a womans menstrual cycle at around age 50 which does not create psychological problems?

Biologic Consequences of Menopause and the Menopause Transition

The brain is enriched with estrogen receptors, and estrogen receptor signaling is hypothesized to mediate multiple key processes in the central nervous system (CNS), including but not limited to neurotrophic effects and neuroprotection.3 Menopause and advancing age both impose adverse effects on CNS function.

Human as well as nonhuman studies demonstrate sex differences in the structure and function of the hippocampus and the temporal lobe that are thought to be related to differences in the activational and organizational effects of estradiol on memory performance. Estrogen-mediated structural differences in the hypothalamus are hypothesized to translate into higher executive functioning in women. Consequently, anxiety and mood changes are more common in perimenopausal and recently menopausal women, especially in women who have a history of mood dysfunction.4,5 The hypogonadism of menopause may provide a reason for why perimenopausal and early postmenopausal women frequently complain of memory loss and the inability to focus. However, studies in menopausal women report conflicting results regarding the benefit of hormone therapy on attention and executive functions such as nonspatial and spatial working memory, as well as verbal memory.6 Moreover, many of these executive functions spontaneously recover within a few years of the menopause. Last, age-related changes in brain-derived steroids are hypothesized to account for the increased incidence of dementia.

Bone health is significantly affected by gonadal steroids.7 Over the menopausal transition, serum estradiol and estrone concentrations decrease by as much as 90%. This decline closely parallels a period of accelerated and progressive bone loss. Reduced estrogen signaling in the menopause disrupts the balance of receptor activator nuclear factor-κβ ligand (increased) and osteoprotegerin (decreased) concentrations, with the end effect being increased osteoclast activity, accelerated bone reabsorption, and attenuated rates of bone remodeling. Consequently, markers of bone reabsorption and formation are significantly increased in the serum and urine of menopausal women. Bone mineral density changes begin slowly during the early perimenopause. With the advent of the early postmenopause bone mineral density loss accelerates, with annual rates of loss approximately 1.8 to 2.3% in the spine and 1.0 to 1.4% in the hip and as much as 30% loss of trabecular and 10% loss of cortical bone over the 6 to 10 years spanning the perimenopausal and early menopausal period. Altered bone physiology results in increased risk for osteoporosis and anywhere from 50 to 100% higher fracture rates. Estrogen attenuates bone loss in a dose-dependent manner.

Increased weight gain and altered fat distribution is a common complaint in perimenopausal and menopausal women that transcends race and socioeconomic status. Midlife women tend to gain approximately 1.5 pounds. Of particular note, adipose tissue, an endocrine organ, expresses estrogen receptors and estrogen is hypothesized to increase adipocyte lipolysis. Thus it is reasonable to hypothesize that menopause may drive adipose tissue pathophysiology.

Therapeutic Approach

Menopause is a normal and natural part of aging, and each woman experiences it in her own way. However, premature, surgical, or medication-induced menopause is not normal and should be addressed with individual consideration as to the benefits and risks of each therapy. Using natural therapies, HT, other pharmaceuticals, or some combination of each is a personal decision for each woman. Our views of menopause and aging and our concerns about long-term health problems evolve over time. Balance is necessary, and the overmedicalization of menopause is inappropriate. The integrative provider can remind women that menopause can be a time of positive, life-changing insights, empowerment, and personal growth.

Many natural measures can help alleviate the most common symptoms of menopause. In most cases, HT either is not necessary or is needed for only 1 to 4 years. However, in women at high risk for osteoporosis and those who have already experienced significant bone loss and also have menopausal symptoms or do not tolerate osteoporosis medications, HT may be indicated. For women who have menopausal symptoms that they are not tolerating well, bHT, cbHT, or cHT can be used, with periodic attempts at reducing or discontinuing the hormones.

Therapy

Estrogen represents the most effective therapy for VMS and related symptoms. Higher doses are more effective; oral and transdermal formulations have comparable efficacy. Many estrogen formulations/doses are also approved for the prevention of osteoporosis. Because estrogen-only therapy (ET) in women with an intact uterus increases the risk of endometrial neoplasia, EPT is appropriate when treating VMS in women with a uterus. In the United States, the most commonly used oral estrogens for systemic treatment of VMS are estradiol (E2, Estrace) and conjugated equine estrogens (CEE, Premarin). Standard doses of these estrogens are 1.0 mg and 0.625 mg, respectively; lower and higher doses are available. Weekly and twice-weekly skin patches and other transdermal E2 formulations are available; estradiol patches releasing 0.05 mg and 0.0375 mg daily are considered standard dose; and lower- and higher-dose patches are available. A 3-month vaginal systemic E2 ring (Femring) for treatment of VMS is also available; the ring releasing 0.05 mg E2 daily is considered the standard dose.

In the United States, the progestational agents most commonly prescribed to accompany systemic ET in women with an intact uterus are medroxyprogesterone acetate (MPA [Provera], available in 2.5-mg, 5-mg, and 10-mg doses) and micronized progesterone (Prometrium) in 100-mg and 200-mg capsules. Micronized progesterone is formulated with peanut oil. With standard-dose estrogen, an appropriate daily dose of MPA or micronized progesterone used continuously is 2.5 mg and 100 mg, respectively. Because micronized progesterone has a hypnotic effect, it should be taken at night. A variety of oral estrogen–progestin formulations, all of which have demonstrated endometrial safety, are available in different doses and combine CEE with MPA (Prempro); E2 or ethinyl E2 with norethindrone acetate (Activella, Femhrt); or E2 with drospirenone (Angeliq) or norgestimate (Prefest). Transdermal estrogen–progestin combination formulations combine E2 with norethindrone acetate (CombiPatch) or levonorgestrel (Climara Pro). The North American Menopause Society regularly updates and posts tables listing all formulations approved in the United States or Canada for treating menopausal symptoms (http://www.menopause.org/docs/default-source/professional/nams-ht-tables.pdf?sfvrsn=18.pdf). Although off-label use of testosterone can increase sexual desire in menopausal women, efficacy is achieved only with supraphysiologic doses, which may cause hyperandrogenic adverse effects.

CE 0.45 mg combined with the selective estrogen receptor modulator bazedoxifene 20 mg (Duavee; without the concomitant use of a progestational agent) is approved to treat VMS and prevent osteoporosis in women with an intact uterus and does not increase the incidence of uterine bleeding or endometrial hyperplasia. This novel combination formulation may be useful for women with an intact uterus who choose not to use progestin, including those intolerant of progestin side effects.

PHASES OF THE MENOPAUSAL TRANSITION

Menopause is the anchor point of a woman's transition to midlife and, because menstrual cycles can be irregular for many reasons, menopause can be declared only after 12 months of amenorrhea. Menopause occurs at a mean of 51.4 years of age for Western women, but the range can be as wide as 40 to 58 years of age. For many years, menopause was considered to be simply a consequence of the depletion of ovarian follicles (the primary source of estrogen and progesterone). However, it is now clear that transitional processes and events begin several years before menopause itself, and continue for several years after menopause. This perimenopausal developmental transition in a woman's life is a dynamic process that consists of a series of complex and interactive changes in the endocrine system and central nervous system.12

A menopause terminology and staging system has been developed to provide a consistent way of describing this transition in midlife women3(Fig. 110-1). The early menopausal transition stage is characterized by elevated follicle-stimulating hormone (FSH) and a variable cycle length (more than 7 days deviation from normal). FSH levels increase in response to the absence of estrogen and progesterone that would normally provide negative feedback to the hypothalamus to inhibit FSH secretion. The late menopausal transition stage is characterized by two or more skipped menstrual cycles and an interval of amenorrhea (at least 60 days) as well as elevated FSH levels. The postmenopausal period is also divided into stages. The early postmenopause stage is defined as 5 years since the final menstrual period, and is subdivided into two segments: (1) the first 12 months after the final menstrual period, and (2) the next 4 years. The late menopause stage begins with year 6 after the final menstrual period and continues through the remaining life span.

Menopause is a universal phenomenon, but the timing of these stages and associated signs and symptoms vary considerably from woman to woman. The age at which menopause occurs is strongly influenced by several factors: smoking, adiposity, race/ethnicity, and reproductive variables such as age at menarche, duration of breastfeeding, and oral contraceptive use. The vasomotor signs and symptoms associated with menopause, such as hot flashes and night sweats, also vary to such a great extent that they are not specified as one of the staging criteria3 for ascertaining phases of menopause (see Fig. 110-1). The perimenopausal transition and postmenopausal experience for an individual woman arise from a complex interaction of biologic, cultural, psychological, and environmental factors. The timing and duration of this midlife transition cannot be easily predicted.

Acute General Rx

Vasomotor symptoms are best managed with systemic hormone therapy given in the lowest dose and for the shortest period possible. Estrogen replacement in symptomatic patientscan be administered in a variety of forms, including oral estrogen and transdermal estrogen patch. The lowest effective dose should be prescribed.

Examples of oral estrogen include:

Conjugated estrogens: Start with 0.3 mg daily and increase to 1.25 mg daily depending on symptoms.

Estradiol: Start with 0.5 mg daily and increase up to 2 mg daily.

Esterified estrogens: Start with 0.3 to 1.25 mg daily.

Estropipate: Start with 0.75 to 3.0 mg daily.

Esterified estrogen/testosterone combination: Give 1.25 mg and methyltestosterone 2.5 mg (Estratest) and esterified estrogen 0.625 mg and methyltestosterone 1.25 mg (Estratest HS [half-strength]). May improve sexual enjoyment and libido.

If the patient has had a hysterectomy for benign disease, estrogen alone is sufficient. In patients who have an intact uterus, progestin is critical to prevent endometrial hyperplasia associated with unopposed estrogen, which is protective against endometrial cancer. Progestins can be prescribed as continual daily dose or cyclic fashion. Most commonly prescribed progestins include medroxyprogesterone acetate 2.5 mg, 5 mg, and 10 mg; Prometrium 100 mg, 200 mg, and 400 mg; and Aygestin 5 mg. Continuous hormone replacement therapy is preferred because after time the patient should be amenorrhoeic. Patients should be counseled that they may experience some irregular spotting for the first 6 to 9 mo after starting hormone replacement therapy. Cyclic therapy will cause withdrawal bleeding.

Combination oral preparations Femhrt, Prefest, Prempro, Activella, Premphase are commonly used. However, the U.S. Preventive Services Task Force recommends against the use of combined estrogen and progestin for the prevention of chronic conditions such as cardiovascular disease in postmenopausal women.

The combination of conjugated estrogen and bazedoxifene is approved for the treatment of moderate to severe vasomotor symptoms associated with menopause and also for prevention of postmenopausal osteoporosis in women with an intact uterus.

Transdermal patches can be either estradiol (Estraderm, Vivelle, FemPatch) 0.025 to 0.1 mg applied twice weekly or Climara 0.025 to 0.1 mg used once a wk. With these preparations, progesterone should be used in a similar fashion. Apply CombiPatch twice weekly (combination estrogen and progesterone) or Climara Pro once per wk (one patch).

Vaginal estrogen creams can be used; these should be reserved for local therapy of atrophic vaginitis. Minimal systemic absorption does occur; however, blood levels are unpredictable. Usual dose 0.5 to 2 g intravaginally daily, cyclically 3 wk on 1 wk off. When symptoms improve, once to twice weekly is adequate maintenance.

Vagifem estradiol vaginal tablets. Initial dosage: One Vagifem tablet, inserted vaginally, daily for 2 wk. Maintenance dose: One Vagifem tablet, inserted vaginally, twice weekly.

Femring vaginal ring delivering the equivalent of 0.5 mg/day inserted every 3 mo or Estring 0.0075 mg/day.

EstroGel 0.06% (estradiol gel). One pump (1.25 g/day) applied to one arm from wrist to shoulder.

The FDA contraindications to menopause hormone therapy include the following diseases and disorders: Active liver disease; current, past, or suspected breast cancer; active or recent anterior thromboembolic disease; cardiac disease (angina, myocardial infarction); known or suspected estrogen-sensitive malignant conditions; known hypersensitivity to the active substance of the therapy or to any of the excipients; porphyria cutanea tarda; previous idiopathic or current venous thromboembolism; undiagnosed genital bleeding; untreated hypertension; untreated endometrial hyperplasia.

For women in whom estrogen is contraindicated or for those who do not wish to take estrogen, the following regimens can be used:

Serotonin reuptake inhibitors, especially in women with menopausal mood disorders

Depo-Provera 150 mg IM every mo (may be helpful in alleviating hot flashes)

Clonidine 0.05 to 0.15 mg PO daily (questionable efficacy) or transdermal clonidine patch

Bellergal-S (questionable efficacy)

Tibolone significantly improves vasomotor symptoms, libido, and vaginal lubrication. Not available in the U.S.

Introduction

Menopause is a natural part of the reproductive life cycle that portends significant meaning in many women’s lives. The menopausal experience is greatly influenced by varied cultural and psychosocial backgrounds which affect each individual woman’s understanding of these hormonal changes and her choice of acceptable management strategies. Women experiencing the menopausal transition will typically seek treatment for symptoms associated with the transition and/or preventative health care. Adverse changes in function and number of germ cells as well as hormone milieu underlie this pivotal event in reproductive aging. Menopause is a uniquely female experience; although men undergo gonadal and hormonal changes in reproductive functioning as they age, there is no male equivalent to menopause.

Menopause, clinically interpreted as the permanent cessation of menstruation in age-appropriate women, is caused by a decline in ovarian follicular activity. It is useful to categorize types of menopause based on the cause and the timing of the final menstrual period. Natural menopause is a retrospective diagnosis made after 12 months of amenorrhea with no apparent pathologic cause. Induced menopause is the permanent cessation of menstruation after surgery, chemotherapy, or radiation treatment caused by the iatrogenic destruction of germ cells. Early menopause can be either a natural or induced final menstrual period that occurs before age 45. Premature menopause is diagnosed when a woman has a final menstrual period before age 40 and can be natural or induced. This is in contrast to premature ovarian failure, which is ovarian insufficiency that occurs before age 40 that results in permanent or transient amenorrhea.1,2

In retrospect, the final menstrual period is an easily identifiable sign of menopause, but this is of limited use to women and clinicians who are often concerned with wanting to determine where the patient is in her natural transition to menopause. In an attempt to address this clinical question, the Stages of Reproductive Aging Workshop (STRAW) developed a staging system based on menstrual cycle features to better characterize the typical woman’s late reproductive function as she transitions to natural menopause. A woman traverses from the reproductive stage of her life cycle to the menopausal transition at a point when her regular menstrual cycles remain regular but they vary more than seven days in length from previous cycle lengths; this is the early menopausal transition. Usually the variation is shorter cycles than the previous menstrual cycle lengths that the woman recorded in her earlier reproductive years. The late menopausal transition occurs when there are two or more skipped cycles with at least one intermenstrual interval of 60 days or greater. The menopausal transition ends with the final menstrual period, which marks the onset of menopause. Early postmenopause is the first 5 years after the final menstrual period. The life cycle years after this point denote the late postmenopause years, which categorize that reproductive period of a woman’s life cycle until that woman’s death.3

Many studies have investigated the age of menopause and factors associated with late or early menopause. A large multi-ethnic, cross-sectional study found that the median age of natural menopause is 51.4 years of age in the United States. In this study, current smoking, being single, and lower educational attainment were all independently associated with earlier age at menopause. This study also found that a history of oral contraceptive use, increasing parity, and Japanese-American ethnicity were associated with later age at menopause. In these data, the average age of menopause in Japanese women was 51.8 years, while there was no significant difference in the age of menopause in White, Hispanic, black, or Chinese women in the US.4

Data are also being reported that the US population is an aging one. By the year 2020 45% of the female population in the US will be over the age of 45.5 Healthy women live over one-third of their life as post-menopausal, so the study of this time frame in women’s lives is taking on greater significance for clinicians. Current and future physicians who care for older women will require the skill-set to deal with the issues unique not only to aging, but also to the adverse changes that occur in women with significantly diminished gonadal function.

Introduction

Menopause generally occurs in midlife while most women are still healthy and vigorous. The word ménespausie, meaning the cessation of menstrual flow, was coined in eighteenth century France; later it was shortened to ménopause and became adopted by the English language. Menopause is defined retrospectively after 12 months of amenorrhea as the last day of menses, although there is still a 5% probability of more cycles. The associated terms perimenopause and climacteric apply to the variable phase before and shortly after the last flow when estrogen deficiency symptoms are showing. Although menopause normally marks the final and irreversible termination of the female reproductive life span, fertility is not coextensive with menstrual cyclicity: there is relative subfertility in both the early and late years of the menstrual life span.

Menopause is a transitory biological phenomenon, but it also marks a social passage, the significance of which varies in different cultures. It has often been regarded as a negative reinforcement of the aging process and loss of sexual attractiveness. Yet, in some societies, past and present, it is considered a welcome relief from the burden of continuously bearing children and of menstruation. While biologists attempt to find ways of slowing the process of reproductive aging, many women are glad to embrace the change and regard it as an exciting new phase of life. This positive attitude surely bodes well for health care and enjoyment of the remaining decades of life.

Definition/Terminology/Physiology

Menopause is the gradual progression to a permanent loss of ovarian follicular function and is retrospectively diagnosed 12 months after the cessation of menses. The average age of menopause onset is 51 years, with approximately 1% of women transitioning before the age of 40 years and 5% after the age of 55 years. Menopause is considered premature when it occurs before the age of 40 years.

With women's life expectancy approaching 80 years, two thirds of the total U.S. population will survive to beyond the age of 85 years. At the end of the millennium, 42 million U.S. women were postmenopausal. The majority of women will spend more than 30% of their lives in the postmenopause years. Despite this increase in life expectancy, the average age of menopause has not changed in centuries.

Most believe that all mammalian females are born with a finite number of ovarian follicles as the primordial follicle oocyte is arrested in the prophase of the first meiotic division. Through the reproductive life span, germ cells are depleted by mostly atresia and, to a lesser degree, ovulation, leading to eventual ovarian failure at menopause. This theory has recently been questioned based on results of mouse studies suggesting that adult ovaries may contain oocytes with the capacity for mitotic division.

During menstrual life, the ovaries make estrogens, androgens, progesterone, and inhibin. The ovarian dominant follicle and corpus luteum produce the most potent of the three human estrogens, 17 β‐estradiol (E2). The peripheral aromatization of androstenedione in adipose and muscle and the metabolism of E2 produce most of the second most abundant estrogen, estrone (E1). Small amounts of estrone are also produced by the ovary and adrenal glands. The premenopausal ratio of circulating estradiol to estrone of greater than 1 reverses after menopause, with estrone becoming the dominant circulating estrogen. Estriol (E3) is the weakest of the three human estrogens. During the childbearing years, the ovary makes inhibin, which inhibits the release of follicle‐stimulating hormone (FSH). Inhibin is no longer made in the postmenopausal years, thus allowing for the rises in FSH seen with menopause. Progesterone is produced primarily by the corpus luteum and is the only naturally occurring progestogen. Progesterone opposes estrogen's actions and converts proliferative endometrium into a secretory endometrium in preparation for implantation and pregnancy, with levels decreasing during the menopause transition. Chemically altered, predominantly plant‐based progestins are synthetically manufactured to oppose the effects of estrogen in pharmacologic hormone therapy (HT).

Menopause is a defined point in time, with the years preceding the actual onset called the menopause transition (or perimenopause). Ovarian function usually begins to decline during the mid‐30s, accounting for the beginning of menstrual irregularity and decreased fertility. This is due to a decreasing number of ovarian follicles, with the remaining ones likely less sensitive to the stimulatory effects of FSH and luteinizing hormone (LH). Thus, anovulatory cycles occur with increased frequency, causing cycle irregularity. Alternatively, some cycles are associated with the release of several follicles (perhaps accounting for an increased incidence in twins in women in the later reproductive years). During this time of significant hormonal fluctuation, however, pregnancy remains a possibility and should always be considered in the differential diagnoses of secondary amenorrhea.

Although most factors influencing the age of menopause are poorly understood, inherited variations in the estrogen receptor and a dose‐dependent association between the quantity and duration of active smoking have been linked to an earlier age of menopause.

Effects of Menopause

Menopause has different implications for women depending on their culture and tradition. In societies in which menstruating women are considered to be unclean and may thus be excluded from praying in public, the release from such inferior status allows them to assume an important and rewarding role in the family and society (in most Indian languages there is no word for menopause). In contrast, the modern, Western societal values and attitudes are more likely to emphasize the negative aspects, such as loss of femininity and sexual attractiveness. This time of life may also coincide with domestic changes such as children leaving home (empty nest syndrome), parents becoming aged and infirm, husband and wife at a stressful time in their careers, all of which may influence how a woman adjusts to the climacteric and menopause. It is therefore not without good reason that the phrase ‘change of life’ has often been applied to this time.

Bone Density and Calcium Mobilization

Menopause represents a vulnerable time for a woman’s skeletal health. Estrogen declines associated with menopause increase bone remodeling, leading to an imbalance between bone formation and bone resorption.153,154 This increase in bone remodeling persists over several years and becomes associated with an increased rate of bone loss.155,156 Early cross-sectional studies compared bone mineral density (BMD) in pre-, peri-, and postmenopausal women and generally reported lower BMD in the peri- and post- menopausal periods.157–159 However, these cross-sectional studies could not determine when bone loss began or the rates of bone loss during various phases of the transition.160

To our knowledge, the first longitudinal study of bone loss during the menopausal transition was published by Riggs et al. in 1987.161 A total of 139 women were followed for a median of 2 years and were classified as post-menopausal if they had no menstrual periods for 6 or more months and estradiol levels were lower than 50 pg/ml. All other women were classified as premenopausal. BMD was measured by older methods, e.g., single and dual photon absorptiometry techniques which have lower precision than the methods in use today. BMD at the mid-radius did not change before menopause, but decreased by about 1% per year after menopause. For lumbar spine, there was significant bone loss both before (−1.32 %/yr) and after (−0.97 %/yr) menopause. These results suggested that bone loss at primarily trabecular bone sites such as the vertebrae decrease substantially before menopause.

Other earlier studies showed bone loss in the perimenopausal period, but not in the premenopausal period.162 The first longitudinal study using state-of-the-art dual energy x-ray absorptiometry (DXA) demonstrated significant change in femoral neck BMD, but not lumbar spine BMD among perimenopausal women.163 Finally, a longitudinal study of 75 women with a mean age of 46 years at baseline, who were followed for 9.5 years, showed that bone loss began about 2–3 years before menopause and ended 3–4 years after the last menses.164 The total loss in the spine and femoral neck was 10.5% and 5.3%, respectively, over the menopausal period. Results suggested that menopausal bone loss is a composite of loss caused by estrogen deprivation and age for the hip, but estrogen deprivation alone for the spine.164

In SWAN, BMD was measured annually in 1,902 African American, Caucasian, Chinese, or Japanese women.165 Little change occurred in lumbar spine or total hip BMD during the pre- or early perimenopause. Bone loss accelerated markedly in the late perimenopause, with an average loss of 0.018 g/cm2yr (1.6%) and 0.010 g/cm2yr (1.0%) from the spine and hip, respectively (P<0.001 for both). In postmenopausal women, rates of spine and hip bone loss were 0.022 g/cm2yr (2.0%) and 0.013 g/cm2yr (1.4%) respectively (P<0.001 for both).

Bone loss during the late peri- and postmenopause was approximately 35–55% slower in women in the top (kg>77.3) versus lowest tertiles (kg<60.7) of body weight. Apparent ethnic differences in rates of spine bone loss were largely explained by differences in body weight.

Although BMD is a major determinant of bone strength, it does not capture important aspects of bone quality, including the microarchitecture and geometry of bone. Transmenopausal changes in trabecular bone structure were described in 28 women who underwent paired transilial biopsies pre- and 12 months after the FMP.166 Bone volume/total volume declined, trabecular number decreased by almost 13%, while trabecular spacing increased by 7% with an overall 10% decrease in apparent density.166

Bone strength is also a function of bone size, with larger bones conferring greater strength. Changes in bone size were described in 108 women followed from the time of menopause for a mean period of 15 years.167 The medullary bone diameter and periosteal diameter increased while BMD decreased, all of which were correlated with serum estradiol levels. These results suggest that periosteal apposition may compensate in part for the decreased bone strength. Thus, focusing solely on bone density across the menopause may miss important changes in bone strength that are reflected in the trabecular architecture and bone size.

Several mechanisms likely underlie bone loss at menopause. Estrogen deficiency leads to T-cell activation, and studies in mice have shown that ovariectomy does not induce bone loss in mice depleted of T-cells with T-cell antibodies.168 Activation of T-cells by ovariectomy increases T-cell production of TNF, a cytokine that stimulates osteoclast formation by potentiating the activity of RANKL, and by promoting production of RANKL by osteoblast cells.169 Gene expression also differs in pre- and postmenopausal women.170

In SWAN, FSH level and increases in FSH were found to correlate strongly with changes in BMD.171 Estradiol levels were not significant, but this may be due to assay variability rather than biology. Estradiol was shown to correlate with changes in BMD, with higher levels being associated with slower rates of bone loss and inversely associated with changes in periosteal diameter.167

Bone loss in women with oophorectomy has not been sufficiently studied.172 Studies of women with early natural menopause (before 45 years of age) differ greatly regarding the subsequent impact on osteoporosis and fractures.60,173–177 A number of studies relate menopause to biochemical markers of bone turnover.178 One study of 178 women aged 29–78 found that the estrogen decline after menopause occurred simultaneously with changes in biochemical indices of bone turnover.179 Many researchers have observed a rise in serum osteocalcin levels, which has been positively correlated with bone loss of menopause,157,179–184 although studies have reported different menopause phase-specific patterns.180,182 Urinary calcium has been found to increase at the menopause179,180,182,183,185 and after the menopause.179,185 This increased calcium excretion has been shown to be negatively associated with bone density and bone mineral content.176,185

The responsiveness of the vitamin D system to estrogen may also contribute to the bone loss observed with menopause. 1,25-dihydroxyvitamin D is an integral part of the hormonal environment that maintains calcium balance by regulating calcium absorption from the intestine, calcium resorption from the skeleton, and calcium retention in the kidney. Sowers186 has shown that there is a significantly greater 1,25-dihydroxyvitamin D level in premenopausal women versus postmenopausal women.