10 Menopause

MENOPAUSE KEY TERMS AND DEFINITIONS Atrophic Vaginitis

Inflammation of the vaginal epithelium due to atrophy secondary to decreased levels of circulating estrogen.

Bisphosphonates

A new class of compounds characterized by two carbon–phosphorous bonds that inhibit the rate of bone resorption and osteoporotic fractures Bisphosphonates approved for prevention and treatment of osteoporosis include alendronate and risedronate.

Climacteric

The physiologic period in a woman's life during which there is regression of ovarian function.

a bone mineral density T score between -1 and -2.5.

Osteoporosis

A systematic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fractures The bone mineral density T score is less than -2.5.

Perimenopausal Transition

The time between the onset of irregular menses and permanent cessation of menstruation. The average duration is about 4 years.

Premature Failure

Cessation of menstruation due to depletion of ovarian follicles before the age of 40. It is also called premature menopause

Bone in the limbs (axial skeleton). With estrogen deficiency bone density decreases more slowly in cortical than in trabecular bone.

Administration of physiologic doses of estrogen orally Estrogen Replacement or transdermally to postmenopausal women without Therapy (ERT). addition of a progestin (also called unopposed estrogen therapy).

A benzothiophene SERM that has an estrogen agonist effect on bone by suppressing bone resorption and an estrogen antagonist effect on the endometrium and breast tissue.

Raloxifene

Administration of a small dose of progestin every day Continuous Combined together with daily estrogen orally or transdermally to Hormone Replacement postmenopausal women. Cortical Bone

Ovarian

Selective Receptor (SERM)

Agents that bind to estrogen receptors and have Estrogen estrogen agonist effects on certain tissues and Modulator estrogen antagonist effects on other tissues. SERM compounds include raloxifene, clomiphene citrate, and tamoxifen.

Sequential Hormone Replacement (also referred to as cyclic hormone replacement)

Administration of relatively high daily doses of a progestin for 2 weeks or less per month together with daily estrogen for part or all of the remainder of the month.

Tibolone

A synthetic steroid with estrogenic, progestogenic, and androgenic activity. When given orally this agent reduces hot flushes, increases bone density, and does not stimulate endometrial proliferation.

Trabecular Bone

Bone in the spinal column and distal radius. With estrogen deficiency osteoporosis develops more rapidly in trabecular than in cortical bone.

T score

Menopause

Permanent cessation of menstruation caused by failure of ovarian follicular development and estradiol production in the presence of elevated gonadotropin levels.

The difference between bone mineral density of the individual at a specific site and the mean bone density of young adults of the same gender divided by the standard deviation of this mean. The T score is expressed as the difference in standard deviations of the measured bone density from the mean value of young adults.

Osteopenia

Decreased quantity of bone mass of a lesser amount than osteoporosis. An early state of osteoporosis with

Unopposed Therapy.

Hormone Replacement Administration of an estrogen and a progestin to Therapy (HRT). postmenopausal women.

Hot Flush

Pathognomonic symptom of the menopause; an abrupt physiologic phenomenon brought about by changes in hypothalamic thermoregulation to induce loss of body heat. Each episode lasts about 3 to 4 minutes and occurs at unpredictable, irregular intervals. During the symptomatic flush there is increased digital perfusion and increased vascular peripheral skin temperature and sweating.

Estrogen Postmenopausal estrogen therapy given without the addition of a progestin.

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Z Score

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The difference between bone mineral density of the individual at a specific site and the mean normal value of adults of the same age and gender divided by the standard deviation of this mean. The Z score is expressed as the difference in standard deviations of the measured bone density from the mean normal value of age- and gender-matched controls.

MENOPAUSE
Permanent cessation of menstruation caused by failure of ovarian follicular development and estradiol production in the presence of elevated gonadotropin levels
Defined by the last menstrual period
Because cessation of menses is variable and many of the symptoms thought to be related to menopause may occur prior to cessa-tion of menses, there is seldom a precise timing of this event PERIMENOPAUSAL TRANSITION
The time between the onset of irregular menses and permanent cessation of menstruation
The average duration is about 4 years.
Refers to a variable time beginning a few years before and continuing after the event of menopause, and climacteric

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Thai women: age 49.5 Filipina women: ages 47 and 48 Countries at higher altitude (Himalayas or Andes): menopause 1 to 1.5 years earlier Average age of menopause in the United States is 51 to 53 years

PREMATURE OVARIAN FAILURE • Defined as hypergonadotropic ovarian failure occurring prior to age 40 • Occurred in 5% to 10% of women who are evaluated for amenorrhea • Estimates of the overall prevalence of POF in the general population range between 0.3% and 0.9% of women • Ongoing rate of atresia of oocytes, this process is accelerated with various forms of gonadal dysgenesis due to defective X chromosomes, one possible cause of POF is an increased rate of atresia that has yet to be explained • A decreased germ cell endowment or an increased rate of germ cell destruction can also explain POF Possible Causes of Premature Ovarian Failure Genetic Enzymatic

CLIMACTERIC
Refers to the time after the cessation of reproductive function
Time after the cessation of reproductive function

Immune

AGE OF MENOPAUSE
A genetically programmed event, is subject to some variability
By age 58, 97% of women will have gone through menopause
The primary determinate of age of menopause is genetic 1. General health status: (Western Countries) between 51 and 52 years 2. Socioeconomic status: associated with an earlier age of menopause 3. Higher parity: associated with a later menopause 4. Smoking: associated with menopause onset taking place 1 to 2 years earlier 5. Body mass: greater body mass index [BMI] with later menopause 6. Ethnic differences: Black and Hispanic women have been found to have menopause approximately 2 years earlier than white women 7. Geographic Location: age of menopause appears to be somewhat earlier outside the United States • Malay women: age 45

Idiopathic

Gonadotropin defects Ovarian insults

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Type 1 blepharophimosis/ptosis/epicanthus inversus (BPES) syndrome, an autosomal dominant disorder due to mutations in the forkhead transcription factor FOXL2, includes POF Triple X syndrome has also been associated with POF Dystrophic myotonia has also been linked to POF Category of enzymatic defects: o Galactosemia- major cause of POF that is related to the toxic buildup of galactose in women who are unable to metabolize the sugar o 17αhydroxylase deficiency- rare condition, the defect in the production of sex steroids leads to sexual infantilism and hypertension 17.5% of cases, the prevalence of autoimmune disorders in women, the degree to which autoimmunity may be responsible for POF is unclear

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All Autoimmune Disorders have been found to be associated with POF: autoimmune polyendocrinopathies like autoimmune polyendocrinopathy/candidiasis/ectodermal dystrophy (APECED), which is caused by mutations in the autoimmune (AIRE) gene on band 21 q22. The presence of the thymus gland appears to be required for normal ovarian function as PDF has been associated with hypoplasia of the thymus In patients who have undergone ovarian biopsy as part of their evaluation, lymphocytic infiltration surrounding follicles has been described, as well as resumption of menses after immunosuppression Specific enzymes such as 3β-hydroxysteroid dehydrogenase (3βHSD) may also be the target of ovarian autoimmunity Screening for the common autoimmune disorders is appropriate in women found to have POF Abnormalities in the structure of gonadotropins, in their receptors, or in receptor binding could be associated with POF Abnormalities of FSH receptor binding, as mediated by a serum inhibitor, have been described POF may be induced by ionizing radiation, chemotherapy, or overly aggressive ovarian surgery Although not well documented, viral infections have been suggested to play a role, particularly mumps A dose of 400 to 500 rads is known to cause ovarian failure 50% of the time A dose of approximately 800 rads is associated with failure in all women Ovarian failure (transient or permanent) may be induced by chemotherapeutic agents: Alkalizing agents, particularly cyclophosphamide, appear to be most toxic By exclusion, the majority of women are considered to have idiopathic POF

Management of Premature Ovarian Failure Evaluation of POF in women younger than 30 should include: • screening for autoimmune disorders and a karyotype • vaginal ultrasound may be useful for assessing the size of the ovaries and the degree of follicular development Treatment: • Estrogen replacement • If fertility is a concern: the most efficacious treatment is oocyte donation. THE MENOPAUSAL TRANSITION (PERIMENOPAUSE) • The menopausal transition (perimenopause) is divided into early and late phases according to menstrual acy-clicity

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These changes signify a varying period of time (years) during which rapid oocyte depletion occurs, followed by hypoestrogenism The ovary changes markedly from birth to the onset of menopause The greatest number of primordial follicles is present in utero at 20 weeks' gestation and undergoes a regular rate of atresia until around the age of 37 The decline in primordial follicles appears to become more rapid between age 37 and menopause when no more than a thousand follicles remain. These remaining follicles are primarily atretic in nature.

HORMONAL CHANGES DURING THE PERIMENOPAUSE • The basic feature of menopause is depletion of ovarian follicles with degeneration of the granulosa and theca cells while stromal cells continue to produce the androgens androstenedione and testosterone. • A marked diminution of reproductive capacity referred to as gametogenic ovarian failure happens during the LATE REPRODUCTIVE YEARS • As the functional capacity of the follicular units decreases, secretion of substances that suppress FSH also decrease. • Signified by reduced early follicular phase inhibin secretion, rising serum FSH levels, and a marked reduction in fecundity 1. The initial endocrinologic change signaling the onset of menopause is decreased ovarian inhibin production accompanied by an increase in pituitary FSH release. • These changes may occur with normal menstrual function and no obvious endocrine deficiency. • They may occur in some women as early as age 35 (10 or more years before endocrine deficiency ensues). • Inhibin B levels are lower in the early follicular phase in women in their late 30s.

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FSH levels are higher throughout the cycle in older ovulatory women than in younger women. These subtle changes in endocrine and menstrual function can occur for up to 3 years before menopause.

2. There is an increase in ACTIVIN • Although there is a general decline in oocyte number with age, an accelerated atresia occurs around age 37 or 38 • Although the reason for this acceleration is not clear, one possible theory relates to activin secretion. • rise in FSH levels could result in more activin production • more activin stimulates FSH receptor expression • more receptors enhance FSH action: • accelerated growth and differentiation of granulosa cells • increase the size of the pool of preantral follicles • these follicles become more atretic 3. There is a decline in ESTROGEN status • The major reduction in ovarian estrogen production does not occur until approximately 6 months before menopause. 4.There is also a very slow decline in androgen status • Decline in androgen status (i.e., androstenedione and testosterone), which cannot be adequately detected at the time of the perimenopause. • The decline in androgen is largely a phenomenon of aging. Clinical treatment of women in the perimenopause should address three general areas of concern: 1. irregular bleeding 2. symptoms of early menopause, such as hot flushes 3. the inability to conceive • •

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Treatment of irregular bleeding is complicated by the fluctuating hormonal status Estrogen levels may be higher than normal in the early follicular phase and progesterone secretion may be normal, although not all cycles are ovulatory Short-term use of an oral contraceptive (usually 20 µg ethyinl estradiol) may be an option for otherwise healthy women who do not smoke to help them cope with irregular bleeding Early symptoms of menopause, particularly vasomotor changes, may occur as the result of fluctuating hormonal levels. In this setting, an oral contraceptive again may be an option if symptoms warrant therapy. Alternatively, lower doses of estrogen used alone may be another option

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Reproductive concerns often require more aggressive treatment because of decreased cycle fecundity

HORMONAL CHANGES WITH ESTABLISHED MENOPAUSE 1. Marked reductions in E2 and estrone (E1) - most significant findings o Serum E2 is reduced to a greater extent than E1. Serum E1, on the other hand, is produced primarily by peripheral aromatization from androgens, which decline principally as a function of age o Levels of E2 average 15 pg/mL and range from 10 to 25 pg/mL, but are closer to 10 pg/mL in women who have undergone oophorectomy o Serum E1 values average 30 pg/mL but may be higher in obese women because aromatization increases as a function of the mass of adipose tissue o Estrone sulfate (E1 S) is an estrogen conjugate that serves as a stable circulating reservoir of estrogen, and levels of E1 S are the highest among estrogens in postmenopausal women
Premenopausal women: above 1000 pg/mL
Postmenopausal women: average 350 pg/Ml 2. Elevations in FSH and luteinizing hormone (LH)
The rise in FSH, beginning in stage -3 (Late Reproductive Years) as early as age 38, fluctuates considerably until approximately 4 years after menopause (stage +1) when values are consistently greater than 20 mIU/mL
Elevated gonadotropin (FSH/LH) levels arise from reduced secretion of E2 and inhibin 3.

Growth hormone (GH), thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH) levels are normal

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Serum prolactin levels may be very slightly decreased because prolactin levels are influenced by estrogen status

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The ovary continues to produce androstenedione and testosterone but not E2, and this production has been shown to be at least partially dependent on LH
Both the postmenopausal ovary and the adrenal gland continue to produce androgen.
The adrenal gland also continues to produce androstenedione, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S)
Primarily as a function of aging, these values decrease somewhat (adrenopause), although cortisol secretion remains unaffected
Much “ovarian” testosterone production may actually arise from the adrenal

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Most likely, this production is by indirect mechanisms due to the adrenal supplying precursor substrate (DHEA and androstenedione)
Androstenedione and testosterone levels are lower in women who have experienced bilateral oophorectomy, with values averaging 0.8 ng/mL and 0.1 ng/mL, respectively • •

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Testosterone levels also decline as a function of age, which is best demonstrated by the reduction in 24-hour means levels Because of the role of the adrenal in determining levels of testosterone after menopause, adrenalectomy or dexamethasone treatment results in undetectable levels of serum testosterone Compared with total testosterone, the measurement of bioavailable, or “free,” testosterone is more useful in postmenopausal women After menopause, sex hormone-binding globulin (SHBG) levels decrease, resulting in relatively higher levels of bioavailable testosterone or a higher free androgen index In women receiving oral estrogen, bioavailable testosterone levels are extremely low because SHBG levels are increased

EFFECTS OF MENOPAUSE ON VARIOUS ORGAN SYSTEMS Hypoestrogenism

Central nervous system

Hot Flush Disturbed sleep Depressed mood Cognitive decline Dementia (Alzheimer’s Disease)

Collagen

Bone Skin Pelvic structure Urinary system

Genital Atrophy

Vaginal dryness Atrophic vaginitis Dyspareunia

Central Nervous System • The brain is an active site for estrogen action as well as estrogen formation • Estrogen activity in the brain is mediated via estrogen receptor (ER) α and ER β

• The predominance of ER β in the cortex (frontal and parietal) and the cerebellum • 17β E2 is a specific ligand for both receptors • Diethylstilbestrol have greater affinity for ER α • Phytoestrogens have a greater affinity for ER β. 1. HOT FLUSH • The hallmark feature of declining estrogen status in the brain is the hot flush, which is more generically referred to as a vasomotor episode • Refers to the acute sensation of heat, and the flush or vasomotor episode includes changes in the early perception of this event and other skin changes (including diaphoresis) • Hot flushes usually occur for 2 years after the onset of estrogen deficiency, but can persist for 10 or more years • In 10% to 15% of women these symptoms are severe and disabling • May cause a series of “irregular” symptoms, such as irritability, which may affect quality of life • The fall in estrogen levels precipitate the vasomotor symptoms • It has been found that some women who experience hot flushes have a thermoregulatory disruption with a much narrower temperature range between sweating and shivering • Although the proximate cause of the flush remains elusive, the episodes result from a hypothalamic response (probably mediated by catecholamines) to the change in estrogen status • The flush has been well characterized physiologically • It results in heat dissipation as witnessed by an increase in peripheral temperature (fingers, toes); a decrease in skin resistance, associated with diaphoresis; and a reduction in core body temperature • There are hormonal correlates of flush activity, such as an increase in serum LH and in plasma levels of proopiomelanocortin peptides (ACTH, β-endorphin) at the time of the flush, but these occurrences are thought to be epiphenomena that result as a consequence of the flush and are not related to its cause • One of the primary complaints of women with hot flushes is sleep disruption • They may awaken several times during the night and require a change of bedding and clothes because of diaphoresis • Sleep efficiency is lower, and the latency to rapid eye movement (REM) sleep is longer in women with hot flushes compared with asymptomatic women • This disturbed sleep often leads to fatigue and irritability during the day • The frequency of awakenings and of hot flushes are reduced appreciably with estrogen treatment • Estrogen is the best therapy for the hot flush; other effective therapies are progestogens, SSRIs, gabapentin and clonidine

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Pathognomonic sign of the menopause: HOT FLUSHES Description

Sudden, transient sensation of warmth to intense heat over face, chest, neck and head; concluded sometimes by profuse perspiration

Symptoms

Chills, nausea, anxiety, head or chest pressure, feelings of suffocation, inability to concentrate

Duration

Few seconds to several minutes

Frequency

Rare to recurrent every few minutes; more at night or during stress

Effects of Estrogen on Brain Function Organizational Actions Effects on neuronal number, morphology, and connections occurring during critical stages of development Neurotrophic Actions Neuronal differentiation Neurite extension Synapse formation Interactions with neurotrophins Neuroprotective Actions Protection against apoptosis Antioxidant properties Antiinflammatory properties Augmentation of cerebral blood flow Enhancement of glucose transport into the brain Blunting of corticosteroid response to behavioral stress Interactions with neurotrophins Effects on Neurotransmitters Acetylcholine Noradrenaline Serotonin Dopamine Glutamate Gamma aminobutyric acid Neuropeptides

Effects on Glial Cells Effects on Proteins Involved in Alzheimer's Disease Amyloid precursor protein Tau protein Apolipoprotein E 2. DEPRESSED MOOD • Postmenopausal women, estrogen has been found to improve depressed mood regardless of whether or not this is a specific complaint (critics of some of this work point out that mood is affected by the symptomatology and by sleep deprivation) • In an estrogen-deficient state such as occurs after the menopause, a higher incidence of depression (clinical or subclinical) is often manifest • Menopause per se does not cause depression • Estrogen does generally improve depressive mood, it should not be used for psychiatric disorders • Progestogens as a class generally attenuate the beneficial effects of estrogen on mood 3. COGNITIVE DECLINE • Postmenopausal women is related to aging as well as to estrogen deficiency • The literature is some-what mixed about whether there are benefits of estrogen in terms of cognition • Dementia increases as women age, and the most common form of dementia is Alzheimer's disease (AD) • Table 42-3 lists several neurotropic and neuroprotective factors related to how estrogen deficiency may be expected to result in the loss of protection against the development of AD • Estrogen has a positive role in enhancing neurotransmitter function, which is deficient in women with AD • However, once a woman is affected by AD, estrogen is unlikely to provide any benefit • Timing of initiation of hormone therapy is critical • Early treatment in younger women at the onset of menopause may be beneficial, (although not proven yet), but later treatment (e.g., after age 65) has no benefit. Collagen • Important component of bone and skin and serves as a major support tissue for the structures of the pelvis and urinary system • Both estrogen and androgen receptors have been identified in skin fibroblasts • Estrogen has a positive effect on collagen

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Nearly 30% of skin collagen is lost within the first 5 years after menopause, and collagen decreases approximately 2% per year for the first 10 years after menopause Genitourinary problems can occur in 20% to 40% of perimenopausal and postmenopausal women o Urinary incontinence o Irritative bladder symptoms o Pelvic organ prolapse can happen

ESTROGEN THERAPY generally improves collagen content after menopause and improves skin thickness substantially after about 2 years of treatment. • Uterine prolapse and other gynecologic symptoms related to poor collagen support, as well as urinary complaints, may improve with estrogen therapy • Although estrogen generally improves symptoms, urodynamic changes have not been shown to be altered • Estrogen has also been shown to decrease the incidence of recurrence of urinary tract infections • Estrogen may also have an important role in normal wound healing. In this setting, estrogen enhances the effects of growth factors such as transforming growth factor-β (TGF-β) • It appears that oral estrogen does not improve stress urinary incontinence in postmenopausal women and may even cause such symptoms in previously asymptomatic older women • Estrogen may, however, improve urge and other irritative urinary symptoms

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Atrophic Vaginitis: inflammation of the vaginal epithelium due to atrophy secondary to decreased levels of circulating estrogen With this change, an increase in sexual complaints: o Vaginal dryness: Perimenopause 21%; 4 years Postmenopausal 47% o Atrophic changes: Perimenopause 15%; 4 years Postmenopausal 55% o Dyspareunia: 41% in sexually active 60-year-old women

Estrogen treatment: • vaginal cytology changes transforming from a cellular pattern of predominantly parabasal cells to one with an increased number of superficial cells • vaginal pH decreases • vaginal blood flow increases • electropotential difference across the vaginal mucosa increases to that found in premenopausal women EFFECTS OF MENOPAUSE: Long term effects

Bones

Osteopenia Osteoporosis Fracture

Cardiovascular system

Genital Atrophy Vaginal atrophy results in a loss of elasticity and reduced lubrication: Pruritus

Cancer

CVD

Breast Colon

Discharge Post-coital bleeding Dyspareunia Burning on urination Vulvovaginal complaints are often associated with estrogen deficiency • Estrogen deficiency results: o a thin, paler vaginal mucosa o moisture content is low o pH increases (usually greater than 5) o mucosa may exhibit inflammation and small petechiae

BONE LOSS 1.

Attainment of peak bone mass in the late second decade is key to ensuring that the subsequent loss of bone mass with aging and estrogen deficiency does not lead to early osteoporosis o E2, together with GH and insulin-like growth factor-1 act to double bone mass at the time of puberty, beginning the process of attaining peak bone mass o Postpubertal estrogen deficiency (amenorrhea from various causes) substantially jeopardizes peak bone mass o Adequate nutrition and calcium intake are also key determinants

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• THE ROLE OF ESTROGEN: • 2.

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Estrogen is of predominant importance for bone mass in both women and men, testosterone is important in stimulating periosteal apposition; as a result, cortical bone in men is larger and thicker • Estrogen receptors are present in osteoblasts, osteoclasts, and osteocystes • Cortical Bone:
Bone in the limbs (axial skeleton)
Both ER α and ER β are present
With estrogen deficiency bone density decreases more slowly in cortical the trabecular bone • Cancellous or Trabecular Bone:
Bone in the spinal column and distal radius
ER β predominates
With estrogen deficiency osteoporosis develops more rapidly in trabecular than in cortical bone Actions of Estrogen: • Believed to be mediated via ER α • Suppress bone turnover: Estrogen decreases osteoclasts by increasing apoptosis and thus reduces their lifespan • Maintain a certain rate of bone formation E2 antagonizes glucocorticoid-induced osteoblast apoptosis The molecular mechanisms of estrogen action on bone: • involve the inhibition of production of proinflammatory cytokines, including interleukin-1, interleukin-6, tumor necrosis factor-α, colony-stimulating factor-1, macrophage colonystimulating factor, and prostaglandin E2, which lead to increased resorption • Up-regulates TGF-β in bone, which inhibits bone resorption • Receptor activation of nuclear factor kappa (NFκB) ligand (RANKL) is responsible for osteoclast differentiation and action

ESTROGEN DEFICIENCY and BONE LOSS • •

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Estrogen deficiency has been well established as a cause of bone loss This loss can be noted for the first time when menstrual cycles become irregular in the perimenopause from 1.5 years before the menopause to 1.5 years after menopause o spine bone mineral density:
menopausal loss rate: decrease by 2.5% per year
premenopausal loss rate of 0.13% per year. Loss of trabecular bone (spine) is greater with estrogen deficiency than is loss of cortical bone

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Postmenopausal bone loss leading to osteoporosis is a substantial health care problem Bone mass is substantially affected by sex steroids through classic mechanisms In women, bone loss occurs in two phases o Accelerated Phase of bone loss (lost in a span of 4 to 8 years)
cancellous bone loss: predominantly occurs 20% to 30%
cortical bone loss: 5% to 10%
also accentuated by the decreased influence of stretching or mechanical factors, which generally promote bone homeostasis, as a result of estrogen deficiency: Genetic influences on bone mass are more important for attainment of peak bone mass (heritable component, 50% to 70%) than for bone loss o Slower phase of loss (1% to 2%/year)
ensues during which more cortical bone is lost
induced primarily by secondary hyperparathyroidism

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Postmenopausal bone loss leading to osteoporosis is a substantial health care problem o 35% of all white women, have osteoporosis o Lifetime fracture risk for these women is 40%.

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With Estrogen Deficiency: resorption outstrips formation o Increases the activities of remodeling units o Prolongs resorption o Shortens the phase of bone formation o Increase osteoclast recruitment in BMUs

BONE MASS CAN BE DETECTED BY A VARIETY OF WAYS: 1.

Dual-energy X-ray absorptiometry (DEXA) scans have become the standard of care for detection of osteopenia and osteoporosis
T score: reflect the number of standard deviations of bone loss from the peak bone mass of a young adult. The T score is expressed as the difference in standard deviations of the measured bone density from the mean value of young adults.
OSTEOPENIA: Decreased quantity of bone mass of lesser amount than osteoporosis. An early state of osteoporosis with bone density T score between -1 to -2.5 standard deviations
OSTEOPOROSIS: A systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a bone mineral density T score less than -2.5 standard deviations

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incorporation of the bisphosphonate with hydroxyapatite in bone increases bone mass.
These agents reduce both spine and hip fractures
Alendronate: dosage of 5 mg daily (35 mg weekly) prevents bone loss; at 10 mg daily (70 mg weekly), alendronate is an effective treatment for osteoporosis, with evidence available that this treatment reduces vertebral and hip fractures
Risedronate: (35 mg weekly)
Ibandronate: has been approved as a once-a-month treatment (150 mg)

Biochemical assays are also available to assess bone resorption and formation in both blood and urine
At present, serum markers appear to be most useful for assessing changes with antiresorptive therapy

THERAPY FOR OSTEOPOROSIS: 1.

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Estrogen
Use will depend on whether there are other indications for estrogen treatment and any possible contraindications
Shown to reduce the risk of osteoporosis as well as to reduce osteoporotic fractures
Dose
0.625 mg of conjugated equine estrogens (CEE)
0.3 mg of CEE can prevent bone loss although there are no fracture date Progestogens
Can prevent bone loss
Whether the addition of progestogens by stimulating bone formation increases bone mass beyond that produced by estrogen alone is unclear
The androgenic activity of certain progestogens such as norethindrone acetate (NET) also has been suggested to play a role Selective estrogen receptor modulators (SERMs)
Raloxifene, droloxifene, and tamoxifen have all been shown to decrease bone resorption
Raloxifene has been shown to decrease vertebral fractures in a large prospective trial.
SERMs have not been shown to prevent hip fractures

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Tibolone
Has SERM-like properties, but it is not specifically a SERM because it has mixed estrogenic, antiestrogenic, androgenic, and progestogenic properties
The drug does not seem to cause uterine or breast cell proliferation but is beneficial for vasomotor symptoms
It prevents osteoporosis and has been shown to be beneficial in treatment of osteoporosis as well

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Bisphosphonates
Have been shown to have a significant effect on the preven-tion and treatment of osteoporosis
Etidronate, alendronate, risedronate, ibandronate

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Calcitonin
(50 IU subcutaneous injections daily, or 200 IU intranasally)
Has been shown to inhibit bone resorption
Vertebral fractures have been shown to decrease with calcitonin therapy
Long-term effects, however, have not been established

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Fluoride
Has been used for women with osteoporosis because it increases bone density
Currently, a lower dose (50 µg daily) of slow-release sodium fluoride does not seem to cause adverse effects (gastritis) and has efficacy in preventing vertebral fractures

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Intermittent parathyroid hormone (PTH)
Promising as an agent to increase bone mass in women with osteoporosis
Teriparatide 20 µg needs to be injected subcutaneously on a daily basis for no longer than 18 months. It should be reserved for severe osteoporosis.

9. Adjunctive measures for prevention of osteoporosis are calcium, vitamin D, and exercise.
Calcium with vitamin D treatment has been shown to increase bone only in older individuals. It will not prevent bone loss in younger women at the onset of menopause
A woman's total intake of elemental calcium should be 1500 mg daily if no agents are being used to inhibit resorption, and 400 to 800 IU of vitamin D should also be ingested
Exercise has been shown to be beneficial for building muscle and bone mass and for reducing falls. THERAPY FOR OSTEOPENIA:
it is clear that women with established osteoporosis (fractures or a T score of -2.5 or greater) should receive an antiresorptive agent (usually a

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bisphosphonate), there is more controversy with initiating preventative strategies with T scores in the osteopenia range (–1.0 to -2.5)
Many women, may sustain fractures in this range of T scores
Age and risk factors (thinness, immobilization, nutritional deficiencies, family history, etc.) largely help determine the need to treat those with osteopenia
In this setting, depending on the age of the woman and whether she has vasomotor symptoms, she may be offered hormone therapy, a SERM, or a bisphosphonate

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CARDIOVASCULAR BENEFITS OF ESTROGEN THERAPY:
All these parameters (generally) improve
Coronary arterial responses to acetylcholine are dilatory with a commensurate increase in blood flow
Circulating plasma nitrites and nitrates have also been shown to increase
Angiotensin-converting enzyme levels tend to decrease
Estrogen and progesterone receptors have been found in vascular tissues, including coronary arteries (predominantly ER β)
Although replacing estrogen has been thought to be beneficial for the mechanisms pre-viously cited, these beneficial arterial effects may only be seen in younger (stage +1) postmenopausal women
Recent clinical trial data, however, have refuted this notion in women with established disease as noted previously. Results from several randomized trials in women have failed to show a protective effect, including the 3-year extension of the Heart and Estrogen/Progestin Replacement Study (HERS), called HERS-II
Furthermore, a trend toward increased cardiovascular events (early harm) has been observed in this setting in some women within the first 1 to 2 years
The differences in types and regimens of HT in these trials suggest that this lack of benefit in secondary prevention is not dependent on the hormonal preparation. Why aging and progressive atherosclerosis impede the ability of estrogen to be protective is unclear, but it is likely to be due to a variety of mechanisms:

CARDIOVASCULAR EFFECTS
After menopause, the risk of cardiovascular disease in women is increased. Data from the Framingham study: o Incidence is three times lower in women before menopause than in men (3.1 per 1000 per year in women ages 45 to 49) o The incidence is approximately equal in men and women ages 75 to 79 (53 and 50.4 per 1000 per year, respectively) o This trend also pertains to gender differences in mortality due to cardiovascular disease
Coronary artery disease is the leading cause of death in women, and the lifetime risk of death is 31% in postmenopausal women versus a 3% risk of dying of breast cancer
Although cardiovascular disease becomes more prevalent only in the later years following a natural menopause, premature cessation of ovarian function (before the average age of menopause) constitutes a significant risk o Premature menopause, occurring before age 35, has been shown to increase the risk of myocardial infarction two- to threefold, and oophorectomy before age 35 increases the risk sevenfold WHY THERES INCREASE RISK? 1. Accelerated rise in total cholesterol in postmenopausal women is the most prevalent finding. This increase in total cholesterol is explained by :
increases in levels of low-density lipoprotein cholesterol (LDL-C)
oxidation of LDL-C is also enhanced
decrease levels of very low density lipoproteins and lipoprotein (a) lipoprotein
decrease HDL-C levels 2. The changes of weight, blood pressure, and blood glucose with aging, although important, are not thought to be as important as the rate of rise in total cholesterol, which is substantially different in women versus men. 3. Blood flow in all vascular beds decreases after menopause 4. Prostacyclin production decreases 5. Endothelin levels increase

Reduced nitric oxide synthetase activity





•

The inability to alter the endothelium after it is covered substantially by atherosclerotic plaque

•

The inability to improve further on the beneficial effect that occurs with powerful cardiovascular medications

•

Inability of estrogen to work as effectively, due to methylation of the promoter region of ER α

•

The inability to demonstrate any overall benefit when an early detrimental effect is experienced by some women (described below) Two more areas of CVD need to be discussed regarding their interactions with HT, stroke, and venous thrombosis Stroke (ischemic, not hemorrhagic) o Increased in the WHI (both HT and ET) trials o This increase was approximately a 30% increase over the 5 to 6 years of the trial but was con-fined to older women in the trial

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o This was not an early harm phenomenon but tended to occur as the trial progressed. These data are similar to data from the NHS trial when dose is taken into account (women using CEE at 0.625 mg or more) o Lower doses (e.g., CEE 0.3 mg) were not associated with an increased risk of stroke. Venous Thrombosis o There is a two- to threefold increase o The prevalence of this risk is low, particularly in young, healthy women o This two- to threefold risk is similar to that with the use of oral contraceptives Pulmonary Embolism o In women at age 50 to 60 years, the background risk is approximately 10 to 20 events/100,000 women-years o HT, the twofold increase may result in 40 events/100,000 womenyears, which is less than the rate in normal pregnancy (approximately 60/100,000 women).

In summary, there should be no concern regarding increased cardiovascular risk for young, healthy women at the onset of menopause who are contemplating HT/ET for treatment of symptoms. In this setting there is no evidence of increased risk, and, indeed, these women may be found to benefit from a cardiovascular standpoint. CANCER RISKS IN POSTMENOPAUSAL WOMEN
Breast cancer is generally believed to be the leading cause of death in postmenopausal women, in fact it is lung cancer
Woman's risk for endometrial cancer with unopposed estrogen use is twofold to eightfold higher than that for the general population, precursor lesions (primarily endometrial hyperplasia) signal the presence of an abnormality in most patients. Thus, the risk is far less for endometrial cancer than it is for varying degrees of hyperplasia
It is generally thought that HT is linked to breast cancer through a promotional effect; that is, by causing the growth of undetectable preexisting small tumors
Family history and genetic mutations (BRCA 1 and 2, etc.) substantially increases the risk of a woman developing breast cancer Ovarian Cancer
Increased risk of ovarian cancer with long-duration use of ET/HT. However, the data are inconsistent, and the purported risk is in the range of less than a twofold relative risk Colorectal Cancer
Third most frequent cancer in women and is often preventable by the detection and treatment of polyps


Women older than 50 should have a colorectal evaluation by some means (detection of occult blood, sigmoidoscopy, or a colonoscopy) THE DECISION TO USE ESTROGEN
Whether hormonal therapy should be considered is a very individual decision
The woman must take into account symptoms, risk factors, and individual preferences and needs
The predominant indication for estrogen is for symptoms (vasomotor, vulvovaginal, or urinary)
Alternatives should also be considered
If hormonal therapy is chosen, there should be flexibility in prescribing because there is no ideal regimen for every woman, and each woman has individual risks and needs. Risk–Benefit Assessment
The WHI was conceived in an attempt to determine the overall risks and benefits of ET/HT in a prospective randomized trial
Endpoints: ET (CEE 0.625 mg with MPA 2.5 mg) o reduces cardiovascular disease o may increase the risk of breast cancer (primary endpoints) o secondary endpoints were also assessed: venous thromboembolism, stroke, osteoporotic fracture, colon cancer, and mortality BENEFITS:
HT ARM: protection of osteoporotic fracture and colon cancer
ET ARM: protection of osteoporotic CHD, breast cancer RISK:
A tally of the various endpoints pointed to overall risks rather than benefit
“ATTRIBUTABLE” risk: o This is the risk per year for 10,000 women exposed o Thus, an attributable risk of 8/10,000 women/year from cancer with HT is a very small risk and according to WHO terminology has been described as “rare.” o This concept has been lost by the media and others who have misinterpreted both relative risk and attributable risk. Recently there has been a trend to reduce potential risks and adverse effects by using lower doses of ET/HT, which have been shown to be beneficial. Changes in Mortality Rates with Estrogen Use
Overall 40% reduction in all-cause mortality has been observed with longterm estrogen use
Two studies have shown that the benefit in mortality is related to the duration of use; one study has suggested that the effect is decreased

11

beyond 10 years of use because of an increase in breast cancer mortality (only reported in this cohort and not in the others)
Overall reduction was found to be attributable to a reduction in cardiovascular mortality, although there was a small effect in cancer mortality as well. It is important to note that the women in these observational (epidemiologic) trials received therapy at the onset of menopause, and the women observed were healthier
In older women (10 or more years after menopause) who may have silent or established cardiovascular disease, there may not be a protective effect on mortality Other Risks Associated with Estrogen Therapy 1.

Return of menstrual bleeding

2.

Somatic complaints such as breast tenderness and bloating may also occur with ET/HT

3.

Idiosyncratic reactions like hypertension and allergic manifestations have been observed in users of estrogen, particularly oral estrogen
Hypertension with estrogen use, the cause of which is not entirely clear, occurs in about 5% of women using the oral route

4.

Twofold increase in venous thromboembolic phenomena with oral estrogen
Observed events all tend to occur in the first two years of estrogen exposure
This increased risk does not increase mortality, however, and the rate is low
Absolute increased risk for venous thromboembolic events is 15 per 100,000 women per year
Women who have a family history of thrombosis or have had thrombotic events linked to oral contraceptives or any prior estrogen use should be counseled very carefully and monitored closely
A low-dose, nonoral form of estrogen would be a consideration for these patients; again, the need for choosing estrogen as a treatment should be clearly documented

APPROACH TO THERAPY
American women believe that the leading cause of death in women is breast cancer and attribute only a small percentage of deaths to cardiovascular disease. In reality, the opposite is true
Although it has been widely asserted that the incidence of breast cancer in women is approximately one in eight, this is the lifetime risk. The agespecific data is lower: o 1 of 77 in the fourth decade

o o

1 of 32 in the fifth decade 1 of 45 when a woman is in her eighth decade


Misperceptions about the magnitude of cancer risk may lead some women not to consider ET/HT for the prevention of other conditions that actually have greater morbidity and mortality, as well as for the alleviation of menopausal symptoms
Soon after menopause, at age 50 to 54, the death rate for breast cancer decreases, but the death rate for cardiovascular disease rises steadily o Age 55, 20% of all deaths are caused by cardiovascular disease o Overall, 30% to 40% of women eventually will die of cardiovascular disease. IS BREAST CANCER THE LEADING CAUSE OF CANCER DEATH IN WOMEN?
The leading cause of caner death in women is lung cancer
The rationale for choosing estrogen at the onset of menopause for symptom control is expected to have a minimal effect on breast cancer incidence, particularly if the dose of estrogen is lowered
Whether there is also some cardiovascular benefit in this setting cannot be determined at this time. Hormone Regimens
The various hormonal preparations available for treatment are listed in Table
For the clinician and patient, the decision to start estrogen therapy need not involve a long-term commitment. For short-term treatment of symptoms, estrogen should be used at the lowest dose that can control hot flushes or can be administered via the vaginal route for symptoms of dryness or dyspareunia Hormonal Treatment Available for Postmenopausal Women Estrogens Oral Oral CEE, 0.3, 0.45, 0.625, 0.9, 1.25, and 2.5 mg Piperazine estrone sulfate, equivalent of 0.625, 1.25, and 2.5 mg Esterified, 0.3, 0.625, 0.9, 1.25, and 2.5 mg Micronized estradiol, 0.5, 1, and 2 mg Transdermal Estradiol patches, 0.014, 0.025, 0.0375, 0.05, 0.75, and 0.10 mg/d Estradiol gel, 1.5 and 3 mg Vaginal Cream, CEE (0.0625%), estradiol (0.01%) Estradiol ring, 2 mg; vaginal tablets, 25 µg Parenteral

12

o

Intramuscular injections should be avoided Progestins Oral Medroxyprogesterone acetate, 2.5, 5, and 10 mg Norethindrone acetate, 5 mg Micronized progesterone, 100 and 200 mg Vaginal Micronized progesterone, 100 mg Progesterone gel, 4% and 8%

o o

o o

Combinations Oral CEE + MPA (0.625 mg) + MPA (2.5 or 5 mg) CEE + MPA (0.3 mg + MPA, 1.5 mg) Micronized estradiol (1 mg) + norethindrone, acetate (0.5 mg) Micronized estradiol (1 mg) + 0.5 mg drosperinone Ethinyl estradiol 5 µg, norethindrone, 1 mg Transdermal Patch, 0.05 mg estradiol with 140 µg or 250 µg norethindrone acetate Patch, 0.045 mg estradiol with levonorgestrel 0.05 mg







Androgens Oral Esterified estrogen and methyl testosterone (0.625/1/25 mg and 1.25/2.5 mg) Transdermal Patch, 150 µg/300 µg in development Bisphosphonates Alendronate, 5 and 10 mg daily; 35 and 70 mg weekly Risedronate, 5 mg; 35 mg weekly Ibandronate, 150 mg monthly Etidronate, 200 mg (intermittent) Selective estrogen receptor modulators Raloxifene, 60 mg Others for osteoporosis Tibolone, 2.5 mg (not approved in the United States) Human parathyroid hormone 1–34; 20 µg subcutaneously daily CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate. 1. ESTROGEN:
Oral: o ET results in higher levels of estrone (E1) than estradiol (E2)




CEE is a mixture of at least 10 conjugated estrogens derived from equine pregnant urine. Estrone sulfate is the major component, but the biologic activities of equilin, 17αdihydroequilin, and several other B-ring unsaturated estrogens, including D5 dehydroestrone Synthetic estrogens, given orally, are more potent than natural E2 Ethinyl estradiol is used in oral contraceptives, with a dose of 5 µg being equivalent to the standard ET doses used (0.625 mg CEE or 1 mg micronized E2) Standard ET doses are five or six times less than the amount of estrogen used in oral contraceptives Oral estrogens have a potent hepatic “first-pass” effect that results in the loss of approximately 30% of their activity with a single passage after oral administration E2 can be administered in patches, gels, and subcutaneously o These routes of administration are not subject to major hepatic effects as with oral therapy o Whereas levels of E2 with oral therapy may vary widely between women and within the day (peaks and valleys) levels with transdermal therapy are more constant within each woman Vaginal Therapy: Creams, Tablets and an Estrogen Ring o In women with vulvovaginal or urinary complaints, vaginal therapy is most appropriate o With creams, systemic absorption occurs but with levels that are one fourth of that achieved after similar doses administered orally o Absorption decreases as the mucosa becomes more estrogenized Estrogen may be administered continuously (daily) or for 21 to 26 days each month

2. PROGESTOGEN
If the women has uterus, a progestogen should be added.
How? o Sequentially Hormone Replacement (also called Cyclic Hormone Replacement):
10 to 14 days each month
Withdrawal bleeding occurs in about 80% of women o Continuous administration of both estrogen and progestogen (continuous combined therapy):
Developed to achieve amenorrhea
In the first 3 to 6 months, breakthrough bleeding and spotting is common
The most common combinations in the United States are single tablets containing • 0.45 mg CEE with 1.5 mg of MPA • 0.625 mg CEE with 2.5 mg of MPA

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• •





ORAL: o MPA in doses of 2.5 and 5 to 10 mg o NET in doses of 0.3 to 1 mg o Micronized progesterone in doses of 100 to 300 mg VAGINAL (in low doses): o Avoids systemic effects and results in high concentrations of progeste-rone in the uterus o This can be accomplished with capsules, suppositories, or a 4% gel o Intrauterine delivery of progestogens is ideal for targeting the uterus and minimizing systemic effects. However, the only marketed product, the 20-µg Mirena IUS delivers too high a dose of levonorgestrel for lower dose estrogen therapy

MONITORING HORMONE REPLACEMENT THERAPY Pretreatment assessment


At present, androgen therapy should be individualized and considered for those women who have symptoms that are not adequately relieved with traditional hormonal therapies
It is important to note that there are no approved products for androgen therapy in the United States

5 µg of E2 with 1 mg NET 1 mg micronized E2 with 0.5 mg NET

4. SERM
Agents that bind to estrogen receptors and have estrogen agonist effects on certain tissues and estrogen antagonist effects on the other tissues
SERM compounds include Raloxifene, Clomiphene Citrate and Tamoxifen
SERM-like compound: Tibolone (not yet approved in the United States) o This progestogen-like compound exhibits estrogenic, antiestrogenic, and androgenic effects by virtue of its structure and metabolites o At 2.5 mg, tibolone suppresses hot flushes, prevents osteo-porosis, and has a positive effect on mood and sexual function o There is also very limited (or no) uterine stimulation ALTERNATIVE THERAPIES FOR MENOPAUSE

History (potential indications and contraindications for HRT) 1

Phytoestrogens

Physical examination (with measurement of weight and blood pressure)

Red clover 2

Herbalism

Additional Mammography (discontinue HRT for 2-4 weeks before test) investigations if needed Vaginal ultrasound and/or abnormal vaginal bleeding)

Reevaluation

endometrial

biopsy

Soy

(for

Bone mineral density (based on local guidelines)

3

Complimentary interventions

Annual checkups (reconsider indication(s) and risk/benefit equation)

4

Diet and supplements

5

Homeopathy

Black Cohosh

Ginseng

Evening primrose

St John’s Wort

Gong Quai

Agnus Castus

Gingko Biloba

Liquorice & valerian roots

Acupuncture

Reflexology

3.ANDROGEN THERAPY
Proposed to be added androgen to ET or HT for complaints or problems relating to libido and energy, which are not relieved by adequate estrogen

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PHYTOESTROGENS Main classes

1

Isoflavones

Main Sources

soya beans (tofu, soya milk)

Lentils


This popularity is fostered by the notion that plant sterols might provide all the benefits of estrogen replacement therapy without the risks. However, most plant products recommended for menopause have performed poorly in clinical trials
Adulteration, contamination, and poor quality control in their harvesting, manufacture, and formulation yield products of questionable efficacy and safety.

Linseed 2

Lignans

Cereals

Rye

Wheat

Bran

Barely

flaxseeds

GOVERNING PRINCIPLES: • Hormone therapy should be part of an overall strategy including lifestyle, recommendations regarding diet, exercise, smoking and alcohol for maintaining the health of postmenopausal women AHA 2006 DIET AND LIFESTYLE RECOMMENDATIONS: • Balance calorie intake and physical activity to achieve or maintain a healthy body weight.

rice 3

Coumestans

sprouts (alfalfa) bean sprouts


Phytoestrogens are a class of plant-derived estrogen-like compounds conjugated to glycoside moieties
Phytoestrogens are not biologically active in their native forms unless taken orally
After oral ingestion, colonic bacteria cleave the glycosides, producing active compounds that are subject to the enterohepatic circulation
These compounds can produce estrogen-agonistic effects in some tissues, whereas in other tissues they produce antagonistic effects
Few randomized trials have examined the efficacy of phytoestrogens o Hot Flushes: 60 mg isoflavone, limited efficacy o Cholesterol: 30 to 40 mg cholesterol levels may be reduced, but this is not a consistent finding o Bone loss or on vaginal atrophy: Phytoestrogens do not appear to have much of an effect on
Estimates are that between 30% and 60% of women use so-called Alternative Interventions for the symptoms of menopause, including “natural” estrogens, plant estrogens, herbal medicines, and acupuncture
The use of botanicals to alleviate the symp-toms of menopause is extremely popular

EXERCISE IN THE MENOPAUSE • Any physical activity is better than being sedentary. • Regular exercise reduces total and cardiovascular mortality. • Benefits far outweigh possible adverse consequences: the more – the better, but too much may cause harm. • Optimal exercise prescription: o At least 30 minutes of moderate intensity exercise, at least three times weekly o Two additional weekly training sessions of resistance exercise may provide further benefit. o Injury to the musculo-articulo-skeletal system should be avoided KEY POINTS •

The median age of the onset of perimenopause is 47.5 years, and its median length is about 4 years.

•

The initial endocrinologic change signaling the onset of menopause is decreased ovarian inhibin production accompanied by an increase in pituitary FSH release.

•

Ovarian estradiol secretion does not begin to significantly diminish until 6 months to 1 year before the menopause.

•

There is only a slight decrease in circulating testosterone and androstenedione levels immediately postmenopausally, and between 3 and 8 years postmenopausally levels of these two hormones remain relatively constant.

15

•

Measurement of FSH cannot be used to determine the physiologic amount of estrogen replacement needed.

•

Postmenopausally there is an increase in body weight and total body fat that is unaffected by estrogen administration.

•

Postmenopausally there is a distribution of fat from peripheral sites to the abdomen. This change of fat distribution is prevented by exogenous estrogen.

•

About 50% of postmenopausal women experience hot flushes, and the incidence decreases to 20% 4 years after menopause

•

Estrogen is the best therapy for the hot flush; other effective therapies are progestogens, SSRIs, gabapentin, and clonidine.

•

Physiologic replacement doses of estrogen include 0.625 mg of conjugated equine estrogen and estrone sulfate, 1 mg of micronized estradiol, and transdermal administration of 0.05 mg of estradiol daily. Current practice suggests using lower than these doses for initial therapy.

•

According to observational data, exogenous estrogen reduces the overall death rate in postmenopausal women, mainly because of the reduction in risk of death from cardiovascular disease, the major cause of death among women.

•

The mean age of menopause is about 51 years.

•

Age at menopause is genetically predetermined and is not related to the number of ovulations, race, socioeconomic conditions, education, height, weight, age at menarche, or age at last pregnancy.

•

The basic feature of menopause is depletion of ovarian follicles with degeneration of the granulosa and theca cells while stromal cells continue to produce the androgens androstenedione and testosterone.

•

Androstenedione is converted to estrone in the peripheral body fat, and its rate of conversion increases as women age. Obese postmenopausal women have higher levels of estrone than thin women and are less likely to have hot flushes or osteoporosis and more likely to develop endometrial cancer.

•

About 1% to 1.5% of bone mass is lost each year after menopause in nonobese white and Asian women. Fractures begin to occur about age 60 to 65 in trabecular bone, such as the vertebral spine, and by age 60, 25% of these women develop spinal compression fractures. Hip fractures begin to increase after age 70.

•

By age 80, 20% of all white women will develop hip fractures, and 15% of these fractures are fatal within 6 months. In the United States each year osteoporosis causes about 300,000 hip fractures, 100,000 radius fractures, and 400,000 other fractures.

•

Estrogen and estrogen/progestogen therapy has been shown to increase the risk of venous thrombosis.

•

Estrogen plus progestogen may increase the risk of breast cancer.

•

•

Survival rates of breast cancer have been shown in most studies to be greater among women who have this disease diagnosed while taking estrogen therapy than among age-matched controls who are not taking estrogen therapy.

Women with postmenopausal osteoporosis have a higher bone resorption rate than normal, whereas the rate of bone formation with osteoporosis is normal.

•

Estrogen therapy does not further increase the risk of diagnosis of breast cancer in women with a family history of breast cancer compared with that of nonusers.

In terms of equivalent weight, when an increase in liver globulins is used as the parameter of estrogenic activity, ethinyl estradiol is about 90 times as potent as conjugated equine estrogen.

•

Levels of LDL cholesterol have a positive correlation with coronary heart disease, and levels of HDL cholesterol have an inverse relation to coronary heart disease. Postmenopausal estrogen users have decreased levels of LDL cholesterol as well as increased levels of HDL cholesterol compared with postmenopausal nonestrogen users.

•

The risk of developing endometrial cancer is 2 to 10 times greater in postmenopausal women who are ingesting estrogen without progestogens compared with nonestrogen users. The risk is increased with higher dosages and prolonged use of estrogen and can be reduced below the incidence in nonusers by the addition of continuous progestogens.

•

•

Estrogen and estrogen/progestogen therapy appears to reduce the risk of colon cancer and has no effect on the risk of ovarian cancer.

•

If sonographic measurement of the endometrial echo complex (thickness) is 4 mm or less, the chance of endometrial cancer being present is about 0.25%.

•

Contraindications to estrogen include the presence of breast or endometrial cancer, active thrombophlebitis, and undiagnosed abnormal bleeding.

16

•

Estrogen increases the synthesis of both estrogen and progesterone receptors in the endometrium; progesterone and synthetic progestins decrease the synthesis of both these receptors and thus have an antimitotic, antiproliferative action.

usually well differentiated and nearly always cured by hysterectomy. •

Estrogen without a progestogen is recommended for postmenopausal women who have had a hysterectomy.

•

Progestogens can be given cyclically or continuously with estrogen to reduce the risk of endometrial cancer. When given cyclically about 80% of women have regular withdrawal bleeding. When given continuously most women bleed during the first 6 months but become amenorrheic after 1 year.

•

Indications for estrogen therapy in menopause include the presence of vasomotor symptoms as well as prevention of atrophic vaginitis, atrophic urethritis, and osteoporosis.

•

Before estrogen therapy is instituted, a pretreatment mammogram should be performed and repeated annually thereafter.

•

At least 25% of bone needs to be lost before osteoporosis can be diagnosed by routine radiographic examination.

•

Most herbal products have not been shown to decrease menopausal symptoms.

•

Dual-energy X-ray absorptiometry (DEXA) is the most accurate method to measure bone density. The bone mineral density is usually expressed as T scores and Z scores.

•

Soy extracts help prevent hot flushes to a variable degree but have no effect on the vaginal epithelium or bone.

•

Bone mass measurements are indicated only when clinical decisions will be influenced by the information gained.

•

In addition to estrogen, alendronate, risendronate, ibandronate, raloxifene, and calcitonin will reduce postmenopausal bone loss.

•

Postmenopausal oral estrogen use increases the risk of gallbladder disease.

•

Addition of a progestogen to estrogen does not inhibit the beneficial effect of estrogen on reducing the rate of bone reabsorption.

•

Estrogen increases calcium absorption and reduces the rate of bone reabsorption postmenopausally. It does not stimulate bone formation.

•

In young women several small studies have shown that estrogen retards the development of coronary atherosclerosis.

•

The endometrial cancer that develops among estrogen users is

17