Repro 13 - Female Reproductive Aging
Clinical manifestations of menopause: Bone Changes
*At the menopausal transition, bone resorption exceeds formation* - bone mass may be lost at annual rate of 3-5% in the first few postmenopausal years - Eventually, rate of loss slows to 1-2%/yr - Trabecular bone (predominant bone in spine, hip, and distal radius) is affected first and to a greater degree than cortical bone, located predominantly in the shaft of the long bones
Clinical manifestations of menopause: CNS Changes
*CNS changes, esp mood and cognition* are most likely related to alterations in Dopamine, Norepi, and Serotonin pathways associated w/ systemic reproductive hormonal fluctuations - risk for new onset depression is increased in late menopause transition when hormonal fluctuations are greatest - Rates of depression decrease in postmenopausal period as hormonal fluctuations stabiliz - Forgetfulness and difficulty concentrating have been associated w/ changes in reproductive hormone levels during menopausal transition, but this finding has not been consistently demonstrated - Migraine headaches may worsen - Dementia and Parkinsonism become more common w/ age, but recent evidence suggests these neurodegenerative conditions may also be influenced by chronic hypoestrogenism as observed in women w/ bilateral oophorectomy at <35y/o
Clinical manifestations of menopause: CV and Respiratory Changes
*CV risks and events increase after menopause* - Levels of LDL and ApoB, are higher after menopause *promoting atherosclerotic changes* - Estrogen receptors have been found in the muscularis of CV arteries; estrogen has a direct vasodilatory effect - *Coag factors*, specifically factors VII and VIII, plasminogen activator inhibitor-1 (PAI-1), and fibrinogen increase at menopause - these changes can lead to *hypercoagulable states* - Conversely, menopause is associated w/ increased levels of anti-thrombin III and activated protein C - these factors may diminish coagulation. Overall however, an unfavorable balance of coagulation factors increases VTE risk at menopause - *Respiratory symptoms increase* and lung volumes (FEV1 and FVC) decline w/ menopause transition and w/ menopause, esp in slender women
Clinical manifestations of menopause: Changes in Bleeding Patterns
*Changes in bleeding patterns* in menopausal transition include heavier flow (menorrhagia), and irregular cycle length (metrorrhagia) - Inter-menstrual bleeding may also occur, and warrants specific attention bc of its association w/ endometrial neoplasia in women >35yrs - woman w/ vasomotor symptoms who has completely missed a menses is likely to experience her final menstrual period w/in next 1-2yrs - Menopause usually occurs several yrs after the onset of menstrual changes; however, ~10% of women experience abrupt onset of amenorrhea - *Any postmenopausal bleeding or perimenopausal bleeding at intervals <21 days is abnormal and warrants evaluation for neoplasm*
Clinical Diagnosis of Menopause
*Clinical diagnosis of natural menopause is made if a woman is >40yrs and has had 12mo of amenorrhea accompanied by symptoms suggestive of ovarian failure* - *lab tests typically not indicated if hx and PE rule out other potential causes of amenorrhea*
Treatment of sexual dysfunction
*Depends on underlying etiology* - If cause of decreased libido is not psychosocial, testosterone therapies may improve sexual function, interest, frequency of desire, and psychological well-being - No FDA-approved products for diminished libido in women - Esterified estrogen combined w/ methyl-testosterone is approved for vasomotor symptoms and has been used for diminished libido *Local vaginal estrogen therapy for diminished sexual function in women w/ pain and genitourinary atrophy* that typically becomes more troublesome over time - Tx options include local very low dose vaginal estrogen creams, tablets or rings that have *minimal or no systemic absorption* - GU symptoms usually improve w/in 2-4wks after initiation - Cessation of estrogen therapy results in the return of GU atrophy symptoms - Nonhormonal alternatives may include lubricants for use during intercourse, and vaginal moisturizers
Hormone Therapy (HT)
*Effective in controlling menopausal symptoms, but may carry risks* - *FDA has recommended HT be used only for women w/ severe symptoms, at the lowest possible dose and for the shortest duration required to ease symptoms* - Tissue-targeted therapies should be used whenever possible to decrease overall systemic dose and transdermal products that bypass first pass effect of the liver may carry lower risks by providing same effect at lower doses - recommended that all women taking HT be re-evaluated on an annual basis - Pt should stop taking HT one week before an annual visit to allow assessment of current symptom severity - Women who choose to permanently stop HT may prefer a slow taper, ranging from 3-6mo, but taper has not been shown to increase successful cessation
Estrogen Therapy
*Estrogen is highly effective for the treatment of vasomotor symptoms* - *Estrogen therapy can be classified by doses*: - *Standard Dose: reduces vasomotor symptoms by 80% w/in 2wks* - *Low Dose*: vasomotor sxs reduction *65% w/in 3-4wks* - *Ultra-Low Dose*: vasomotor sxs reduction *60% by 4-5wks* - Risks and side effects of estrogen appear to be dose-dependent - "Low dose" transdermal postmenopausal hormone therapy contains estradiol 0.025mg and is estimated to be 1/8 as potent as "low-dose" oral contraceptives containing ethinyl estradiol 0.020mg and is a reasonable starting dose for women with moderate, but not severe hot flashes
Treating Vasomotor Symptomsin Menopause
*Estrogen is highly effective for the treatment of vasomotor symptoms*; Progestin alone is also effective and used for hot flashes in men but has theoretical risk of breast cancer - Systemic administration of estrogen can be achieved orally, transdermally (gel, mist, patch or vaginal ring) - Some formulations include progestins that may augment estrogen effect on VMS - Cyclical HT is preferable for women in menopausal transition who are predominantly anovulatory and do not need contraception, bc it provides lower doses of hormones than OCPs - Continuous HT is commonly used in women who are >12mo from the final menstrual period but can be associated w/ postmenopausal bleeding (requires evaluation) - Bioidentical hormones have not been proven to provide lower risks; production in compounding pharmacies may in fact increase risks
Treatment of Menopause-Related Depression
*Estrogen may be beneficial to help address Mild depression in menopausal transition* - estrogen alone, w/out an antidepressant, does not appear to be sufficient to treat significant clinical depression in postmenopausal women - Antidepressants should be used for tx in women during and after menopause transition if clinically indicated
Hallmark of Menopausal Hormonal Changes
*Hallmark of menopausal hormonal changes is a rise in concentration of day 3 FSH*: earliest and most consistent measurable hormonal change - *As ovarian steroid secretion falls, GnRH rises* - Early selective increase in FSH appears to be caused by *decreased secretion of inhibin B and anti-muellerian hormone (AMH)* by ovarian granulosa cells - *As anovulation predominates, FSH and LH remain chronically and tonically elevated* (10-20X increase in FSH and 3-5X increase in LH ) and *Estradiol (E2) levels fall* <50pg/ml - Despite diminished fertility and ongoing follicular atresia, *ovulatory cycles of women in menopausal transition have normal to high concentrations of circulating estradiol (E2) and estrone (E1). In fact, during menopausal transition, preovulatory estradiol levels can be higher than those seen in younger women.*
Clinical manifestations of menopause: Cancer
*Hormonally sensitive neoplasms* include breast, colon, lung, skin, ovary, endometrium, and myometrium (leiomyoma) - risks of growth may increase during menopausal transition - *Leiomyomas commonly increase in size during menopausal transition (increased estrogen and low progesterone) but diminish in postmenopausal period*, presumably as a result of low steroid hormone levels
Pelvic Ultrasound
*May be indicated in women w/ abnormal vaginal bleeding before or after menopause* - can help detect leiomyomas, endometrial polyps and adenomyosis - can screen for endometrial neoplasia in postmenopausal women who experience bleeding or spotting spontaneously or in conjunction w/ hormone therapy (HT) - *In a postmenopausal woman, a homogeneous endometrial thickness of <5mm confers assurance that endometrial neoplasia is not present in >96% of cases*
Testosterone in Menopause
*Mean plasma testosterone levels in postmenopausal women are slightly reduced* (from 0.3 to 0.25 ng/mL) - DHEA reduced by 60% - DHEAS reduced by 80% - Mean plasma androstenedione concentration is reduced by at least 50%
Peri- Pre- and Post- Menopause [KNOW]
*Perimenopause*: the time between onset of symptoms and 12mo after final menstrual period - *Menopause Transition* is the symptomatic time of physiologic change around the cessation of ovarian function but prior to final menstrual period *Premenopause*: the entire reproductive span before onset of menopausal transition *Postmenopause*: the span of life after menopause
Premature Ovarian Insufficiency (POI) (previously called Premature Ovarian Failure (POF)): Etiologies
*Prevalence of POI, menopause <age 40, is ~1%* - Ethnicity, BMI and smoking influence POI risk. - Rare genetic and chromosomal causes of POI include familial predisposition, FSH receptor mutations, galactosemia, 17a-hydroxylase deficiency, alterations in gonadotropin structure or function, and X chromosome alterations (e.g. Turner syndrome mosaicism) - Most common genetic cause of POI is the* fragile X premutation*; up to 3% to 5% of women with POI are premutation carriers of fragile X, the most common cause of mental retardation in males - ~16% of women who are fragile X premutation heterozygotes have POI - Premature menopause may be immune-mediated in 30-50% of women w/ POI and other autoimmune diseases may be observed - chance of spontaneous pregnancy in POI is est <10%
Clinical manifestations of menopause: Skin and Musculoskeletal Changes
*Skin changes* associated w/ hypoestrogenism - decrease in dermal collagen production and subsequent reduction in dermal thickness - increase in wrinkles and dryness *Increase in generalized muscle and joint aches and pains and possibly osteoarthritis (OA)* observed w/ reproductive aging - Synovial membranes contain ER beta, and estrogen may play a role in synovial function, as well as mediate inflammation in the muscles and joints
Clinical manifestations of menopause: Sleep Disruption
*Sleep disruption* associated w/ vasomotor symptoms - Decreases in estrogen and allopregnanolone, a potent endogenous steroid that modulates GABA-A receptor activity may be responsible for changes in sleep - Sleep disruption may contribute to mood and neuropsychiatric changes - Prevalence of sleep-disordered breathing, including snoring and obstructive sleep apnea, increase after menopause, likely due to hormonal changes in upper airway musculature as the increase in prevalence is greater than can be explained by aging or weight gain alone
Physical Exam Changes in Menopause [KNOW ALL]
*There are NO pathognomonic physical findings in the menopausal transition* BUT might see.... - w/in *first 5yrs* after menopause, *vulvovaginal tissue becomes pale, thin, or erythematous and friable w/ loss of rugae and possible fissuring* - *Uterus becomes smaller, measuring 5-6cm long, and ovaries usually non-palpable* - *Cervix atrophies and os may become stenotic* - *Urethral caruncle may be present immediately posterior to the external urethral meatus; this is a benign erythematous nodule which occurs due to extrusion of uroepithelial tissue*
Physical Exam for Reproductive Aging
*There are NO pathognomonic physical findings in the menopausal transition* but PE important to rule out other causes for sxs: - Elevated BP w/ facial flushing may be a sign of carcinoid - Fevers may indicate infectious or malignant etiology for flushing - Palpation of thyroid gland and exam for physical signs of hypo- or hyperthyroidism warranted - Speculum examination should be performed to look for cervical or vaginal lesions, e.g. endocervical polyps if there is abnormal bleeding - Bimanual pelvic exam indicated when bleeding is heavy or frequent, to rule out presence of hormone secreting adnexal masses, pregnancy, or uterine fibroids - Clinical presentation of oligomenorrhea or amenorrhea in a younger woman = prolactinoma may be suspected --> visual-field testing and breast exam - Inspection of skin for needle tracks from possible heroin injection and eval for low body weight or significant weight loss may suggest a hypothalamic cause for oligomenorrhea or amenorrhea
Clinical manifestations of menopause: Vasomotor Symptoms
*Vasomotor symptoms (hot flushes, sweats, shivering) are caused by thermoregulatory dysfunction* - *most likely initiated by hypothalamus in response to hormonal fluctuations, in which the "thermoregulatory null zone" is decreased, meaning that threshold in core temperature for cooling (flushes, sweats) is lowered and threshold for warming (shivering) is raised* - Women typically describe hot flushes or night sweats as a strong sensation of warmth accompanied by flushing, a prickling sensation of the skin; and at times, a sensation of anxiety w/ occasional heart palpitations - Perspiration seems to move from trunk toward the head before it dissipates - Flushes are spontaneous, uncomfortable, and unpredictable - Each episode is self-limited and typically lasts several min - Hot flushes/night sweats may also be symptoms of a number of disease processes, including hyperthyroidism, pheochromocytoma, carcinoid, and occult infection or neoplasm (e.g. TB, HIV and lymphoma). - Non-volitional weight loss or documented fevers w/ vasomotor symptoms require further evaluation for significant underlying disease
*Menopause Epidemiology*
*Women experience symptoms for ave duration of 10yrs, w/ most bothersome symptoms in the 2yrs before and 2yrs after the final menstrual period* - *51ys = Mean age at which menopause occurs in developed countries* ~*90% of women experience menopause between 45-55yrs* - *Hot flushes are experienced by 80% of white women; 10% of women report symptoms into old age* - *Menopause occurs at least 1yr earlier in smokers, and in women who have had hysterectomies or are nulliparous and may occur earlier in women who have had ovarian cystectomies or unilateral oophorectomies*
Menopause Labs: β-hCG, TSH, and CBC
*β-hCG* should be tested if a woman has potential for pregnancy and presents w/ a *missed period or irregular vaginal bleeding* - Although chance of pregnancy is low (< 1% after age 50), pregnancy may occur during menopausal transition *TSH* level should be considered when *menorrhagia, excessive diaphoresis, or neurocognitive changes* are present *CBC*: should be performed if symptoms are associated w/ *fever* or suggest *neoplastic etiology (e.g. B symptoms)*
Clinical manifestations of menopause: Matabolic Changes
- *Increase in visceral and central adiposity* - *Increase in total body fat,* - *Decrease in muscle mass* - *Increase in insulin resistance*, independent of aging - On average, there is a 2lb weight gain - Most changes are likely due to alterations in hormones produced by the GI tract from fat (adipocytokines), such as ghrelin, leptin and resistin
Menopause Labs: Vaginal Labs
- *Vaginal pH elevated after menopause* - vaginal *cytology* shows a *decreased maturation index (increase in parabasal cells)* - w/ genitourinary atrophy, the shift toward a more basic pH can precipitate bacterial overgrowth and infection - *Pap smears are commonly unsatisfactory* and do not warrant repeat in women w/ normal screening history and no increased risks for cervical neoplasm
Clinical manifestations of menopause: Sexual and Genitourinary Changes
- Decreased testosterone (esp in women who undergo bilateral oophorectomy), and decreased estrogen leading to urogenital atrophy and dyspareunia, may contribute to *diminished libido* - Mood disorders, sleep disturbances, fatigue or stress, sexual inactivity or dysfunction in a partner, social instability, and a hx of sexual abuse may all contribute to sexual dysfunction in midlife - *Genitourinary atrophy* typically mild and asymptomatic during menopausal transition, but is progressive and can become severe in postmenopausal years --> presents as dryness, pruritus, dyspareunia, or post-coital spotting - Atrophic urethritis and recurrent cystitis can manifest as dysuria, frequency, and incontinence
*Menopause* [KNOW]
- Defined as the day of permanent cessation of menses; Dx is not made until a woman has had 12mo of amenorrhea - it is the hormonal changes, rather than cessation of menstruation itself, which results in clinical manifestations associated w/ menopause - Natural menopause occurs at or >40 yrs of age and has no underlying pathologic cause - Induced menopause may occur after chemotherapy, pelvic radiation, or, most commonly, bilateral oophorectomy
Progesterone in Reproductive Years and Menopause
- During *reproductive years, the principal source of progesterone is the corpus luteum* - *small concentrations of progesterone continue to be produced by adrenal gland after menopause*
Estrogens in Reproductive Years
- During reproductive years Estradiol (E2) is the principal estrogen in quantity and in potency - Estrone (E1) is present in a significant amount but is less potent than estradiol - Estriol (E3), a weak estrogen highest during pregnancy, is present as a metabolite of estrone and estradiol.
Study Questions
1. Define female reproductive stages (page 1). 2. What are the major changes in gonadotropin and reproductive steroid production that occur during the menopausal transition (specifically changes in serum concentrations of FSH, LH, estradiol, estrone, and total testosterone)? (page 2, Figure 2) 3. How do hormone levels in the postmenopause vary from those in the premenopause? (page 2) 4. What are the clinical manifestations of menopause? (pages 3-4) 5. Define abnormal bleeding in the menopausal transition and postmenopause and discuss appropriate evaluation. (page 3 and page 5 "Imaging studies" and "Endometrial biopsy") 6. Why does irregular bleeding occur during the menopausal transition? (pages 2 and 4) 7. What treatment options are available for abnormal bleeding in the menopausal transition? (page 6)) 8. What is the physiologic basis for vasomotor symptoms and when and how should they be treated? (pages 3, 6 and 8). 9. Describe risks and benefits of hormone therapy as found in WHI and the differences observed between estrogen plus progestin therapy vs estrogen alone (page 7, table 1). 10. Define premature ovarian insufficiency (POI) and describe presentation, laboratory evaluation, management and long term risks/concerns. (page 8).
In summary, when treating menopausal symptoms it is recommended to: [KNOW ALL]
1.) Use *lowest doses of hormones possible* to achieve an effect 2.) Use *transdermal products that provide same effect w/ lower dose* 3.)* Tx for <5yrs in women <60y/o* 4.) *Avoid systemic progestogens (lower breast cancer and CHD risks)* 5.) *Target therapy to specific bothersome symptom* 6.) *Consider weaning* therapy in all women *>60y/o* as these women have a *higher baseline risk of CHD, VTE, CVA, and dementia and any small increase in RR has greater effect on overall risk*
Case Study examples CASE 3.) Q2: Do you do any lab tests or imaging studies and if so, describe your anticipated findings. A. Transvaginal ultrasound with thickened endometrium B. Estradiol 200 pg/ml (Menopause < 50 pg/mL) C. FSH 5 (Menopause > 25 IU/mL) D. ANA 1:20 (Normal < 1:80) E. DEXA: T score - 3.5 spine and -2.5 hip (Osteoporosis < -2.5)
ANSWER DEXA: E. T score - 3.5 spine and -2.5 hip
Case Study examples CASE 3.) Q1: CASE 3. Sarah is a 59 yo G0 female with Stage 1 breast cancer diagnosed 4 years ago. She has the following symptoms: • Persistent moderate hot flashes • Dyspareunia and diminished libido • Low mood, depression She is taking an aromatase inhibitor to treat her breast cancer. She does not exercise regularly and feels stressed. She has a family history of ovarian cancer. What do you anticipate finding on physical examination? A. Atrophic vulva & vagina B. Small thyroid gland C. Bright cheerful affect D. Enlarged thyroid gland E. Swollen joints
ANSWER: A. Atrophic vulva & vagina
Case Study examples CASE 1.) Q6: What hormonal treatment do you recommend? A. Mirena IUD and low dose transdermal estrogen 25 mcg transdermal B. Ortho Novum 1/35 combined oral contraceptive C. Medroxyprogesterone acetate 10 mg for 10 d each month D. GnRH analog E. Unopposed estrogen 25 mcg transdermal
ANSWER: A. Mirena IUD and low dose transdermal estrogen 25 mcg transdermal
Case Study examples CASE 1.) Q2: She asks you, on average, how long bothersome symptoms will last and what is the median age of menopause? A. On average, bothersome symptoms last 4 years and median age of menopause is 51. B. On average, bothersome symptoms last 6 years and median age of menopause is 53. C. On average, bothersome symptoms last 2 years and median age of menopause is 48. D. On average, bothersome symptoms last 10 years and median age of menopause is 50. E. On average, bothersome symptoms are life long and median age of menopause is 55.
ANSWER: A. On average, bothersome symptoms last 4 years and median age of menopause is 51.
Case Study examples CASE 2.) Q1: Yvette is a 33 yo G0 female with amenorrhea for 12 months with the following symptoms: • Moderate hot flashes • Recent weight gain of 4 lb • No galactorrhea or headaches She is otherwise healthy and takes no medications, BMI 25 kg/m2. She has a family history of heart disease, diabetes, hypertension, lipid disorders and obesity. What is the most likely diagnosis? A. Premature ovarian insufficiency (POI) B. Polycystic Ovarian Syndrome (PCOS) C. Prolactinoma D. Hypothalamic amenorrhea E. Hyperthyroidism
ANSWER: A. Premature ovarian insufficiency (POI)
Case Study examples CASE 3.) Q3: What nonhormonal RX do you recommend (may select more than one)? A. SSRI/SNRI B. Calcium and vitamin D C. Weight bearing exercise D. Behavioral modification E. Fosamax
ANSWER: All of the above
Case Study examples CASE 2.) Q2: Normal ranges for a 33 y/o woman: - FSH (Day 3) <20Miu/dL - Estradiol (Day 3) 25-75pg/mL - Prolactin <20ng/mL - TSH 0.3-5.0U/mL - AMH 1-3ng/mL Do you do any tests to confirm your diagnosis? If so, describe possible findings: A. I would not do any tests B. FSH 80 mIU/dL, estradiol 20 pcg/mL, fasting prolactin 8 ng/mL C. FSH 8 mIU/dL, estradiol 40 pcg/mL, fasting prolactin 135 ng/mL D. TSH 0.2 U/mL E. AMH 3.2 ng/mL
ANSWER: B. FSH 80 mIU/dL, estradiol 20 pcg/mL, fasting prolactin 8 ng/mL
Case Study examples CASE 1.) Q1: Nancy is a 48 yo G3P3 female, not using contraception, who is worried about pregnancy. She has skipped 2 menses and has the following symptoms: • Irregular, heavy menses (q 18-61 d), fatigue, Hct 31 • Moderate hot flashes • Severe sleep disturbance She is otherwise healthy with the exception of stress headaches for which she takes ibuprofen. What is her reproductive stage? A. Postmenopause B. Early transition C. Late transition D. Premenopause E. Premature ovarian insufficiency (POI)
ANSWER: C. Late transition
Case Study examples CASE 3.) Q4: What hormonal RX do you recommend? A. I would not recommend hormonal therapy B. Ultra-low dose transdermal estrogen without progesterone C. Mirena IUD D. Nonsystemic vaginal estrogen ring (Estring) E. Estrogen vaginal cream
ANSWER: C. Nonsystemic vaginal estrogen ring (Estring)
Case Study examples CASE 1.) Q3: Do you do any lab tests or imaging studies and if so, describe your anticipated findings. A. Testosterone (Elevated) B. Estradiol (Elevated) C. Urine pregnancy test (negative) D. FSH (Decreased) E. AMH (increased)
ANSWER: C. Urine pregnancy test (negative)
Case Study examples CASE 1.) Q5: What nonhormonal treatment do you recommend? A. Iron sulfate B. Fans and layered clothing C. SSRI D. Behavioral modification E. All of the above
ANSWER: E. All of the above
Case Study examples CASE 2.) Q3: If your diagnosis is POI, how do you treat Yvette and at what age do you stop treatment? A. I would not treat her B. Low dose oral contraceptives until age 50 C. Transdermal low dose estrogen without progestin until age 45 D. Mirena IUD until age 50 E. SSRI
ANSWER: Low dose oral contraceptives until age 50
Case Study examples CASE 1.) Q4: Does she need an endometrial biopsy? Yes/No
ANSWER: Yes
Treating Abnormal Bleeding in Menopause
After appropriate evaluation for neoplasia, *vaginal bleeding during menopausal transition can be managed with*: - *low-dose, combination OCPs (containing 10 μg ethinyl estradiol)* - *progestin only OCPs* - Or a *Progestin IUD* All protect against pregnancy and reduce menstrual blood loss
Physiology of Menopause
As early as *10-15yrs before menopause, length of menstrual cycle progressively shortens, due to shortening of Follicular Phase* - *Insufficient follicular development results in lower estrogen production --> w/ progressively diminishing estrogen to stimulate endometrium, amenorrhea eventually results* - Some poorly responsive follicles persist for a few yrs after menopause and may on occasion result in estrogen stimulation and spotting - Evidence that timing of natural menopause is genetically programmed but specific genes not well defined - Common allelic variants of estrogen receptor gene (estrogen receptor-alpha [ER-α] and estrogen receptor-beta [ER-β]) and co-activators and co repressor proteins contribute to the variability in physiologic estrogen effects
WHI Memory Study (WHIMS)
Asub-study of the EPT and ET trials; *evaluated* effects of EPT and ET on *memory and cognition in women aged 65-79 (average age 73)* - Primary outcomes were dementia and cognition
Endometrial Biopsy
Indicated in postmenopausal women at increased risk for endometrial neoplasia or in women w/ an abnormal ultrasound - *Because ultrasound does not screen for neoplasm in menopausal transition, endometrial biopsy should be performed if there is bleeding at intervals of <21 days, esp if the woman is obese* - Office endometrial biopsies have a false negative rate of up to 10% - women w/ ongoing abnormal bleeding should have repeat biopsy or D&C
Menopausal Transition and Postmenopausal Symptom Management
Management of women experiencing menopausal symptoms is best approached by 1.) defining her reproductive phase 2.) identifying the menopausal symptoms for which treatment is desired 3.) identifying medical conditions that might influence management options Many women find menopausal symptoms do not significantly impact their quality of life. However, women who experience bothersome symptoms may consider treatment.
*Reproductive Hormone Changes in the Menopausal Transition* [KNOW]
Overall changes in reproductive steroids following menopause are: - *Negligible ovarian estradiol (E2) production* - *shift from ovary to adrenal gland as primary source of estrogen precursors* - *Estrone (E1) becomes dominant estrogen, aromatized from androstendione in peripheral tissues (e.g. adipose tissue, brain)* - *Decrease in progesterone levels due to anovulation* - *Continued testosterone production by ovarian stroma and adrenal gland* - *Increase in the ratio of androgens to estrogens*
*Stages of Female Reproductive Aging (STRAW)* [KNOW]
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*Non-Hormonal Alternatives for Vasomotor Symtpoms*
Several *non-hormonal alternatives for treatment of vasomotor symptoms have some efficacy*; include: - *SSRIs* - *SNRIs* - *Gabapentin* - *Possibly Clonidine* - Results from controlled clinical trials evaluating effectiveness of black cohosh for vasomotor symptoms vary, but most studies show no significant improvement over placebo in reducing frequency of hot flushes - Herbal therapies and botanicals have not been found to be effective or have not been adequately studied - *Behavioral modification and soy products may diminish bother from hot flushes*
*Premature ovarian insufficiency (POI)* [KNOW]
Term used for *menopause that occurs <40yrs of age but is otherwise "natural"*
Women's Health Initiative Estrogen plus Progestin Therapy (EPT) Trial
The WHI EPT trial *randomized >16,000 women, ages 50-79 (mean age 63) to take 0.625mg conjugated equine estrogen (Premarin) w/ 2.5mg medroxyprogesterone acetate (Provera) or placebo* - EPT trial stopped prematurely (July 2002), after a mean of 5.2yrs of follow up, because overall therapy risks outweighed benefits
Treatment of Sleep Disruption and Cognition in Menopause
Vasomotor instability may contribute to *sleep disruption; estrogen is effective* for some women who begin to experience insomnia during menopausal transition - Alternative therapies w/ demonstrated benefit include short-term zolpidem, some SSRIs and low-dose trazodone - Micronized progesterone may also have a sedating effect by increasing levels of allopregnanolone *Minor improvement in cognition w/ HT*, among recently menopausal women has been observed - HT is not beneficial for cognition among women >65
Women's Health Initiative Estrogen Therapy (ET) Trial
WHI ET trial *randomized >10,000 women, aged 50-79 (mean age 64), to take 0.625mg conjugated equine estrogen or placebo* - Intended follow up was 8yrs, but trial was stopped 1yr early (March 2003), because stroke risk was found to be elevated
Premature Ovarian Insufficiency (POI) (previously called Premature Ovarian Failure (POF)): Risks and Treatments
Women w/ POI may be at higher risk for younger onset of CV disease - *Epidemiologic studies suggest earlier age at menopause is associated w/ substantially increased mortality, possibly due to osteoporosis and CV disease* - Est women w/ POI who do not take estrogen have a lower background risk of breast cancer and thromboembolism than general pop. - oophorectomy before menopause is associated w/ increased risk of dementia and of Parkinsonism - NOT known whether women w/ POI are at higher risk of neurodegenerative conditions *Treatment w/ low dose OCs or postmenopausal hormone therapy until age 50 may decrease risk of these outcomes*
Risks and Benefits of Hormone Therapy - Women's Health Initiative (WHI) Studies
Women's Health Initiative (WHI) enrolled >160,000 women in an observational study or 1 of 4 randomized controlled clinical trials from 1993-1998 at 40 U.S. clinical sites and was the largest funded NIH study for women ever performed: 1.) *Estrogen plus Progestin Therapy (EPT)* 2.) *Estrogen Therapy (ET)* 3.) low fat diet 4.) Ca and VitD - Use of HT has declined since publication of WHI major findings, although experts agree use of HT in healthy women <59 is relatively safe - *HT is no longer indicated for primary prevention of osteoporosis or CV disease*, unless a woman at high risk for osteoporosis chooses HT over other options after careful risk/benefit counseling
Menopause Labs: FSH [KNOW ALL]
w/ normal reproductive aging, there are wide variations in production of FSH, estradiol, and LH in late menopause transition - Because of wide variations, *measurement of FSH and estradiol is generally not useful or indicated in a woman w/ irregular menses and vasomotor symptoms* *Some notable exceptions...FSH and estradiol may be useful in women*: 1.) who have had a hysterectomy w/out oophorectomy 2.) are <40 3.) are on OCPs which tx menopausal symptoms, suppress FSH and elevate estradiol 4.) who continue to have menses after age 55 (rule-out postmenopausal w/ occult endometrial neoplasm) *Menopause is confirmed if FSH is >25 IU/L, and estradiol <50pg/ml* - *Labs should be drawn on the 7th day of placebo pills if a woman is taking OCPs or on day 3 of spontaneous menses*