Physiology--Perimenopause---short-cutres

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Menopause BasicsPhysiology, Perimenopause and Menopause : 

Menopause BasicsPhysiology, Perimenopause and Menopause 2007 JoAnn V. Pinkerton, MD Director, Midlife Health Center Professor of Ob/Gyn University of Virginia

Menopause BasicsLearning Objectives: : 

Menopause BasicsLearning Objectives: Describe the hypothalamic-pituitary-ovarian axis Differentiate between Perimenopause and Menopause Learn physiologic and anatomic changes at menopause Describe typical menopausal symptoms Perform focused history +physical for menopausal woman Interpret selected laboratory tests to evaluate menopause. Counsel patients regarding female sexuality and aging physical, emotional, and relationship-based issues

What does menopause mean to women? : 

What does menopause mean to women? Cessation of menstrual periods End of reproductive capacity Hormonal changes Change of life, a life stage End of prior symptoms Beginning of new symptoms Changing emotions Changing body Aging process Disease risks Medical care needs Woods et al. Menopause 1999.

Menopause: The Reality : 

Menopause: The Reality Clinical diagnosis Permanent cessation of menses following the loss of ovarian activity Lack of menses for 12 months Mean age in US is 51 (45-55 years) Women will spend one-third to one-half of their lives postmenopausally Katz VL, Lentz GM, Lobo RA, Gershenson DM. Comprehensive Gynecology. 5th ed. Philadelphia, PA: Mosby; 2007

? : 

? “The anchor point that is defined after 12 months of amenorrhea following the final menstrual period (FMP), which reflects a near complete but natural diminution of ovarian hormone secretion.” Soules et al. Menopause 2001. STRAW Menopause

Natural (spontaneous) menopause : 

“Occurs after 12 consecutive months of amenorrhea, for which there is no other obvious pathologic or physiologic cause.” (Average age in Western world is 51 years) Natural (spontaneous) menopause ? CA MS Utian. Climacteric 1999.

Premature menopause : 

Premature menopause “Menopause that occurs in women at or under 40 years old.” Utian. Climacteric 1999. ? CA MS

Premature ovarian failure : 

Premature ovarian failure Hypergonadotropic amenorrhea = 40 years old Associated with many other health conditions (eg, autoimmune, toxic, genetic) May not be permanent Is not the same as premature menopause

Premature ovarian failure (continued) : 

Premature ovarian failure (continued) Ovarian insufficiency leading to amenorrhea that occurs in women = 40 Can be transient (eg, from over-exercising, eating disorders, high stress levels Can be permanent (eg, from autoimmune disease or genetic abnormalities) and equivalent to premature menopause

Slide 10: 

STRAW reproductive aging system Length decreases -2 days Stages of Reproductive Aging Workshop. Menopause 2001.

“Symptoms” of perimenopause : 

“Symptoms” of perimenopause Natural, normal changes, not a disease Subtle hormonal changes during the 30s Symptoms noticeable during the 40s Disturbances may be acute or gradual Not all midlife symptoms are attributable to menopause

Induced menopause : 

Induced menopause “Cessation of menstruation that follows bilateral oophorectomy (surgical menopause), iatrogenic ablation of ovarian function by chemotherapy or pelvic radiation therapy.” (No perimenopause transition for these women) Utian. Climacteric 1999. ? CA MS

Premature or induced menopause: complicating factors : 

Premature or induced menopause: complicating factors Early loss of fertility More severe symptoms Greater risk of osteoporosis and CVD Possibly complicated by sequelae of underlying disease Little research regarding benefits/risks of treatment

Hypothalamic-pituitary-ovarian axis : 

Hypothalamic-pituitary-ovarian axis Pituitary Hypothalamus GnRH (+) Estradiol Progesterone LH FSH Inhibins Ovary

Reproductive aging : 

Reproductive aging 1-2 million follicles at birth, only approximately 1,000 by menopause Most follicular loss due to atresia, not ovulation Atresia accelerates at around age 37 Age-related uterine changes also contribute to decreased fertility

Ovarian function in perimenopause : 

Ovarian function in perimenopause Ovaries begin decreasing in size Estradiol still dominant estrogen Number of follicles decreases substantially Production of inhibin decreases Remaining follicles respond poorly to elevated FSH and LH Erratic ovulation results in menstrual cycle irregularity

Decline in fertility : 

Decline in fertility Fertility wanes starting at about age 37, before perimenopause signs occur By age 45, risk of spontaneous miscarriage increases to 50% Fertility-enhancing techniques available Natural pregnancy still possible until menopause is reached

Physiology: perimenopause : 

Physiology: perimenopause Estrogen and progesterone levels fluctuate erratically Very high serum estrogen levels may result Gradual decline in testosterone with age beginning mid-30s Zumoff et al. J Clin Endocrinol Metab 1995. Burger et al. J Clin Endocrinol Metab 2000.

Serum hormone levels at menopause : 

Serum hormone levels at menopause Circulating estrogens Ratio of estrogen to androgen Sex hormone-binding globulin secretion Peripheral aromatization of DHEA to estrone Reversal of E2 to E1 ratio No significant change in testosterone levels •

Slide 20: 

Burger et al. J Clin Endocrinol Metab 1999. E, FSH, and inihibins prior and following FMP

Health evaluation at perimenopause : 

Health evaluation at perimenopause Determine the primary complaint(s) Medical, psychological, and social history Family history Complete physical examination Determine quality of life Laboratory tests For differential diagnosis of problems Screening tests for specific chronic conditions

Routine screens : 

Routine screens Standard blood screens Periodic serum cholesterol (total, HDL, LDL, TG) Fasting glucose Thyroid screen Annual Pap test Periodic stool guaiac test, sigmoidoscopy, colonoscopy Annual mammogram Urine screen, when indicated Sexually transmitted infections, when indicated Bone density, when needed

Evaluate need for contraception : 

Evaluate need for contraception Proportion of all US unintended pregnancies by age: 1994 Unintended pregnancies Unintended pregnancies ending in abortion Henshaw. Fam Plann Perspect 1998.

Confirming menopause : 

Confirming menopause Age, medical/menstrual history, and symptoms usually sufficient Rule out other causes of symptoms (eg, thyroid disorder) Consistently elevated FSH (> 30 mIU/mL) diagnostic, but rarely necessary except with nonsurgically induced menopause Serum estradiol testing may be of value; value of salivary levels unproven

Evaluate risk for specific conditions and diseases : 

Evaluate risk for specific conditions and diseases Vasomotor symptoms/sleep disturbance Vulvovaginal health Psychological health Cardiovascular disease Diabetes Osteoporosis Cancer Sexual function Sexually transmitted infections Urinary incontinence Alcohol/drug use/abuse Domestic abuse/violence risk

Assess all women for alterable risk factors : 

Assess all women for alterable risk factors Smoking Poor diet Obesity Lack of exercise Stress Habit-forming drugs Unsafe sex Excess alcohol No seat belts

Therapeutic options : 

Therapeutic options No intervention/treatment Lifestyle modification Nonprescription remedies Complementary and alternative medicine (CAM) approaches Prescription drugs Surgical procedures

Write a lifestyle Rx : 

Write a lifestyle Rx Stop smoking Have a nutritionally sound diet Achieve and maintain healthy weight Reduce stress Avoid excess alcohol Say no to drugs and unsafe sex Wear seat belts Exercise regularly

Benefits of regular exercise : 

Benefits of regular exercise Decreases hot flashes Improves mood and sleep Decreases/maintains weight Supports joint/muscle flexibility Prevents bone loss Decreases risk of many other diseases

Slide 30: 

“Improved control of behavioral risk factors, such as use of tobacco, alcohol, and other drugs, lack of exercise, and poor nutrition, could prevent half of premature deaths, one-third of all cases of acute disability, and all cases of chronic disability.” US Preventive Services Task Force. Guide to Clinical Preventive Service 1989.

Vasomotor symptoms : 

Vasomotor symptoms One of the hallmarks of perimenopause Includes hot flashes and night sweats Recurrent, transient episodes of flushing, perspiration, and intense warmth on upper body and face Skin temperature increases 1-7 ºC, returns to normal gradually Chill often follows

Causes of hot flashes : 

Causes of hot flashes Precise cause is unknown Estrogen levels alone not predictive of hot flash frequency or severity Other conditions: thyroid disease, epilepsy, infection, insulinoma, carcinoid syndromes, leukemia, pancreatic tumors, autoimmune disorders, mast-cell disorders

Hot Flushes May Continue Years After Menopause : 

33 Number of years women report having hot flushes as estimated by a survey of 501 untreated women who experienced hot flushes Hot Flushes May Continue Years After Menopause Ages 29 to 82 Years Mean age of natural menopause was 49.5 years; mean age of surgical menopause was 43.7 years. Kronenberg F. Ann NY Acad Sci. 1990;592:52-86. Used with permission.

Causes of hot flashes(continued) : 

Causes of hot flashes(continued) Drugs: tamoxifen, raloxifene Lifestyle factors: warm ambient air temperature, higher BMI, cigarette smoking, less physical activity

Hot Flashes: Demographics, Lifestyle, Health : 

Hot Flashes: Demographics, Lifestyle, Health Symptoms vary by race/ethnicity More African Americans and Hispanics than Caucasians affected Fewer Chinese than Caucasian affected Significant association with BMI Passive smoke exposure History of premenstrual symptoms Use of OTC pain medication History of comorbidities Perceived stress Age Gold EB et al. Am J Epidemiol. 2004;159(12):1189-1199

Alternative Approaches for Vasomotor Symptoms: Lifestyle AdaptationsGuidelines from NAMS : 

Alternative Approaches for Vasomotor Symptoms: Lifestyle AdaptationsGuidelines from NAMS Limited effectiveness Cooling body core temperature Exercise Paced respirations (catecholamine control) Relaxing activities yoga, massage, meditation, paced respiration, leisurely bath Avoid Triggers spicy food, hot drinks, caffeine, alcohol NAMS Position Statement (Treatment of menopause-associated vasomotor symptoms) Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:805-813 Huntley AL, Ernst E. Menopause. 2003;10:465-76.

Non-Prescription RemediesSide effects and drug interactions clearly occurLack long-term safety and efficacy data : 

Non-Prescription RemediesSide effects and drug interactions clearly occurLack long-term safety and efficacy data Phytoestrogens/isoflavones Dietary or supplements (soy-derived) Red clover Black cohosh Vitamin E - not clinically significant Studies show no effect compared with placebo Dong quai Ginseng Evening primrose oil NAMS Position Statement (Treatment of menopause-associated vasomotor symptoms). Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:805-813; Huntley AL, Ernst E. Menopause. 2003;10:465-76.

Clinical Management Mild Vasomotor Symptoms : 

Clinical Management Mild Vasomotor Symptoms For mild vasomotor symptoms Encourage lifestyle changes Non-prescription remedies- tested short term with little efficacy over placebo but no evidence of harm Dietary isoflavones Black cohosh Vitamin E

Clinical Management Mod-Severe Vasomotor Symptoms : 

Clinical Management Mod-Severe Vasomotor Symptoms Hormone therapy is only FDA approved treatment “gold standard” SSRI’s and gabapentin have efficacy in early studies Progestogens effective however large doses required Clonidine (oral or transdermal)

Lifestyle Issues in Menopause : 

Lifestyle Issues in Menopause Vasomotor (hot flushes and night sweats) Low libido/painful intercourse Weight gain Memory problems, difficulty concentrating Mood swings Insomnia, fatigue Dizziness, rapid irregular heartbeat Atrophic vaginitis, bladder irritability Headaches Rapkin AJ. Am J Obstet Gynecol. 2007;196(2):97-106.

OCs: noncontraceptive benefits : 

OCs: noncontraceptive benefits Suppress vasomotor symptoms Restore predictable menses Decrease dysmenorrhea Enhance BMD Prevent endometrial and ovarian malignancies

OCs: when to stop : 

OCs: when to stop FSH testing not reliable in perimenopausal women or in those using OCs If contraception needed, continuation to mid-50s reasonable Otherwise, consider stopping early 50s Low-dose OC has more hormone than EPT

Depression or Menopause? : 

Depression or Menopause? Depressed1,2 Weight change1 Energy2 Sleep2 Libido1 Thoughts of death1,2 Worthlessness1,2 Concentration2 Anhedonia1,2 Hot flushes1 Perspiration1 Vaginal dryness1 1. Soares CN, Cohen LS. CNS Spectrums. 2001;6:167-174. 2. Joffe H et al. Psychiatr Clin North Am. 2003;26:563-580. Irritable1,2 Depression Menopause

Sleep disturbances : 

Sleep disturbances 1/3 - 1/2 of US women aged 40-54 report sleep problems Occur mainly in women with nighttime hot flashes Most adults require 6-9 hr sleep nightly Potential causes: ovarian hormone changes, advancing age, onset of sleep disorders (eg, apnea), stress, painful chronic illnesses (eg, arthritis), other conditions (eg, CVD, allergies), drugs (eg, thyroid medication) Insomnia produces fatigue, irritability, chronic illness (eg, CVD), mood disorders (eg, depression)

Improve sleep hygiene : 

Improve sleep hygiene Lower light and noise Adjust temperature (cool preferred) Avoid heavy evening meals Avoid alcohol, caffeine, nicotine throughout the entire day Exercise daily, but not close to bedtime Use bedroom only for sleep and sexual activities Have a regular sleep schedule, even on weekends Use relaxation techniques

ET effects on sleep : 

3Erlik et al. JAMA 1981.4Polo-Kantola et al. Am J Obstet Gynecol 1998. 5Antonijevic et al. Am J Obstet Gynecol 2000. ET effects on sleep Decreases frequency of Night sweats1-4 Periods of wakefulness during the night 3,4 Reduces sleep latency 1,2 Improves sleep in menopausal women with insomnia, even in the absence of vasomotor symptoms4 Increases the percentage of REM sleep 2,5 For EPT, use bedtime dosage of progesterone, a mild soporific, to improve sleep 1Scharf et al. Clin Ther 1997. 2Schiff et al. Maturitas 1980.

Uterine bleeding changes during perimenopause : 

Uterine bleeding changes during perimenopause Strong predictor of perimenopause About 90% of women have 4-8 years of cycle changes before reaching menopause No universal definition of “irregular” but unique to each woman Possible changes: lighter bleeding (avg blood loss, < 20ml) heavier bleeding (avg blood loss, > 40ml) bleeding lasting for < 2 days or > 4 days cycle length < 7 days or > 28 days skipped periods

Bleeding during postmenopause : 

Bleeding during postmenopause Must be assessed Vaginal causes Uterine fibroids Endometrial or endocervical polyps Uterine or cervical malignancy EPT

Diagnostic workup for AUB : 

Diagnostic workup for AUB Comprehensive history and pelvic exam Blood tests Endometrial biopsy Vaginal ultrasound Additional tests, such as sonohysterogram or hysteroscopy

Presenting genital symptoms and physical signs of vaginal atrophy : 

Dryness Itching Burning Dyspareunia Symptoms Presenting genital symptoms and physical signs of vaginal atrophy Bachmann et al. Am Fam Physician 2000. Pale, smooth, or shiny vaginal epithelium Loss of elasticity or turgor of skin Sparsity of pubic hair Dryness of labia Fusion of labia minora Introital stenosis Friable, unrugated epithelium Signs on physical exam Pelvic organ prolapse Rectocele Vulvar dermatoses Vulvar lesions Vulvar patch erythema Petechiae of epithelium Burning leukorrhea Vulvar pruritus Feeling of pressure Yellow malodorous discharge

Physiology of Vulvovaginal Changes: Structure and Histology : 

1Oriba HA, Maibach HI. Acta Derm Venereol. 1989;69:461-5. 2Bachmann GA, et al. In: Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. 2nd ed. 1999:195-201. Physiology of Vulvovaginal Changes: Structure and Histology Loss of collagen and adiposity in vulva1 Clitoral glans loses protective covering2 Vaginal surface thinner, less elastic; more friable2

Non-Rx therapies for vaginal dryness : 

Non-Rx therapies for vaginal dryness Vaginal moisturizers effective; also produce low pH to guard against infection Vaginal lubricants ease penetration Avoid use of petroleum-based products Douches may worsen condition; antihistamines may have drying effect Continued sexual activity and/or stimulation may benefit vaginal health

ET and vulvovaginal atrophy : 

ET and vulvovaginal atrophy Local estrogen appears at least as effective as systemic ET If genital atrophy present without vasomotor symptoms, nonsystemic therapy preferred Stimulation of endometrium observed with high doses, some advise adding progestogen1 1NAMS Position Statement. Menopause 2004.

Improvement in vaginal cytology with local CEE : 

Improvement in vaginal cytology with local CEE Baseline Cycle 1 Raymundo et al. International Federation of Gynecology and Obstetrics 2000. Open-label, single-treatment group, outpatient study N = 105 women with data valid for efficacy analysis Treatment significantly increased superficial and intermediary cells and decreased parabasal cells (P < .05)

Traditional sex response cycle : 

Sexual excitement and tension Desire Time Reduction Arousal Plateau Orgasm Traditional sex response cycle Kaplan. The New Sex Therapy: Active Treatment of Sexual Dysfunctions 1974.

Slide 56: 

Sexual Response: Male vs Female

Female sexual dysfunction:definition and classification : 

Female sexual dysfunction:definition and classification International Consensus Development Conference on Female Sexual Dysfunction Basson et al. J Urol 2000. Sexual desire disorders – hypoactive sexual desire disorder – sexual aversion disorder Sexual arousal disorder Orgasmic disorder Sexual pain disorders – dyspareunia – vaginismus – noncoital sexual pain disorder

Female sexual dysfunction : 

Female sexual dysfunction Affects 20% to 50% of women1 Multidimensional and multicausal combining biological, psychological, and interpersonal factors1 Physically and emotionally distressing, and socially disruptive1 Increases with age2 Must cause distress to be a dysfunction 1Basson et al. J Urol 2000. 2Goldstein. Int J Impot Res 2000.

Effect of perimenopause on parameters of sexual functioning : 

Effect of perimenopause on parameters of sexual functioning Cross-sectional data reported from longitudinal, population-based Australian cohort, 45-55 yrs ? Sexual responsivity ? Sexual frequency ? Libido ? Vaginal dyspareunia ? Partner problems Dennerstein et al. Obstet Gynecol 2000.

Physician-Patient Communications Concerning Sexual Problems May Not Be Optimal : 

*Numbers do not add up because of rounding; n = 500. Bennett, Petts & Blumenthal. National Survey of American Adults 25 and Older. Washington, DC: March 1999. Marwick C. JAMA. 1999:281:2173-4. Used with permission. If You Wanted to Talk to Your Doctor About a Sexual Problem, How Concerned Would You Be About the Following? 76 71 68* Physician-Patient Communications Concerning Sexual Problems May Not Be Optimal There Would Be No Medical Treatment for Your Problem Your Doctor Would Dismiss Your Concerns and Say It Was All Just in Your Head Your Doctor Would Be Uncomfortable Talking About the Problem Because It WasSexual in Nature Percentage

Sexual history sample questions : 

Sexual history sample questions “Are you sexually active?” “Are you having any sexual difficulties or problems at this time?” “Have you noted any change in your sexual interest?” “Are you having any difficulty with vaginal lubrication?” “Do you have any concerns about your sexual health?” Bachmann et al. Obstet Gynecol 1989.

Model of complete clinical care : 

63 Model of complete clinical care Opening Closing Communication Tasks Biomedical Tasks

Criteria for Informed Decision Making : 

Criteria for Informed Decision Making Discussion of patient’s role in decision making Discussion of clinical issue or nature of decision Discussion of alternatives Discussion of the pros and cons of alternatives Discussion of uncertainties of decision Assessment of patient understanding Exploration of patient preference Source: Braddock CH et al. J Gen Intern Med. 1997;12(6):339-345

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