8th Edition APGO Objectives for Medical Students Climacteric

8th Edition APGO Objectives for Medical Students

Climacteric

Rationale

Women spend as much as one-third of their lives in the postmenopausal years. Understanding the physical and emotional changes caused by estrogen depletion is important for all physicians who provide health care for women.

Objectives

The student will be able to describe: Physiologic changes in the hypothalamic-pituitary-

ovarian axis Symptoms and physical findings associated with

hypoestrogenism Long-term changes associated with hypoestrogenism Management, including:

Hormone therapy Nutrition and exercise Non-hormonal therapeutic options

Risks and benefits of hormone replacement therapy

Population demographics

Older population aging - today, life expectancy for a woman = age 80 yr.

Older population growing - in 1990 >30M menopausal women

Menopause

Definition - cessation of spontaneous menses due to loss of ovarian function

Endocrinology Ovarian deficit poor response to

gonadotropins cease ovulation decreased ovarian steroid production

Epidemiology

MenopauseClinical concerns Symptoms (early)

Hot flushes Insomnia Irritability Mood disturbances

Physical changes (intermediate) Vaginal atrophy Urinary incontinence Skin atrophy

Diseases (late) Osteoporosis Cardiovascular disease Alzheimer’s disease

Hormone replacement therapy (HRT) -

What is it?

Estrogens (E) Affects many target organs - bone, brain, eyes,

teeth, coronary vascular system, colon, urogenital tract, breast

Two (2) receptors identified, alpha and beta Similar amino acid homology Identical DNA binding domains Tissue selectivity of different ligands Different estrogens acting through the same receptor

can induce different biological activity

Hormone replacement therapy (HRT) -

What is it?

Progesterone (P) Reduces numbers of cellular receptors for E Induces target cell enzymes that convert estradiol

to estrone Reduces overall intracellular availability of potent E Suppress E mediated transcription of oncogenes Operate via mechanism that requires time to take

effect, duration exposure critical Minimal requirement of exposure at least 10 days

(Varma, 1985)

Counseling - Benefits (indications)

Vasomotor symptoms/cognitive processes Hot flushes, mood swings, depression,

sleep disturbances, poor memory E most effective treatment hot flashes


Alzheimer’s disease (AD)Neurodegenerative process causing slow

progressive loss of mental function 40% persons age > 80 yr., women earlier

onset Some studies indicate reduction in

relative risk AD with ERT (unopposed)


Sexual function No clear evidence of reduced drive after

menopause - studies confounded by body image, health of partner, urogenital changes

E or E/A can induce positive effect on sense of well-being


Genitourinary symptoms Reduced E reduced mitosis reduced

exfoliation surface cells reduced tissue vascularity thinning of mucosal layer

Vaginal dryness, dyspareunia, urethritis E can reverse atrophic changes E decreases incidence of urinary tract

infections in postmenopausal women


Coronary vascular disease Leading cause of death in women Epidemiologic data found decreased relative risk

with E E - many side effects on coronary vascular

system 50% lipid-dependent Reduced LDL (4%), increase HDL

(9%) P can blunt these effects short-term 50% lipid-independent Direct antiatherosclerotic effect,

augmentation of antiplatelet aggregation factors, direct inotropic actions on heart, improved glucose metabolism, inhibition of lipoprotein oxidation


Coronary vascular disease (con’t)No longer considered an indication because of

recent data from randomized controlled trials: HERS (1998) - E/HRT did not show reduction in overall

rate of CHD events (i.e. not effective for secondary prevention.)

WHI (2002) HRT arm of trial stopped prematurely because of increased risk of breast cancer and lack of cardiovascular benefit in this primary prevention trial (as well as small increase in risk of CVD.)


Osteoporosis Gradual loss bone mineral density Accelerated after menopause E reduces osteoclast activity E - FDA approval for prevention of

osteoporosis Overall reduction fracture rate 20-60%

with ERT


Colon cancer Third leading cause of cancer death in women E may affect bile acid metabolism or promote tumor

suppressor activity in colon E reduces incidence of colon CA by up to 50% in

postmenopausal women (20 epidemiological studies) E reduced incidence of colon CA by 30% in 2002 WHI

(randomized placebo controlled blinded trial) E reduces incidence adenomatous polyps in

postmenopausal women


Age-related macular degeneration (AMD) Leading cause of blindness in U.S. 17% population age 43-86 HRT may reduce risk of AMD

Safety issues

Venous thromboembolic disease (VTE)Studies show (2x) increased risk DVT

with current use NHS (1996) - increased risk PE with

current users

Safety issues

Stroke NHANES (1993) - in postmenopausal

women, HRT 31% reduction stroke incidence, 63% reduction in stroke mortality

Majority of studies show HRT does not increase stroke risk

Safety issues

Endometrial cancer Unopposed ERT increases risk of endometrial

cancer 2 to 10- fold PEPI (1996) unopposed ERT increased risk of:

Simple hyperplasia 27% Complex hyperplasia 22%

Risk increased with duration of exposure and lasts up to 10 yr. After E is discontinued

Safety issuesBreast cancer Since 1940s, increased incidence of breast cancer,

mortality unchanged 50 epidemiological studies show no clear trend with

E use Meta-analysis (1991-93) - possible increased risk

with current use and long duration of use WHI (2002) 26% increase in risk after 4 years of use Studies inconclusive - may be increased risk, likely

small

Safety IssuesHypertension - no relationship between BP and HRT use

Diabetes - no contraindication

Liver disease - increased circulating E levels

Familial hyperlipidemias - E will increase triglycerides

Migraines - may worsen with cyclic therapy

Cholecystitis - E may carry 1.5 to 5-fold increased risk of gall bladder disease

Leiomyomas - usually not stimulated by HRT

Endometriosis - increased doses E may induce recurrence

Office evaluation History, physical exam Family history Lifestyle evaluation Height, weight, blood pressure Labs/studies

FSH-determine change OCPs HRT if > 30IU/L during pill- free week

Fasting lipid profile; consider fasting glucose, TSH Bone densitometry Mammogram Colon cancer screening

Verify absence of contraindications

Side effects

Irregular bleeding Breakthrough bleeding originates from

endometrium dominated by P 40-50% patients with breakthrough

bleeding in first 6 mo. (20% after 1 yr.) Increased likelihood with

perimenopause

Side effects

Irregular bleeding - When to evaluate Pretreatment if high-risk (obesity,

dysfunctional bleeding, high alcohol intake, liver disease, hypothyroidism)

With irregular bleeding first 6 mo. Prior h/o unopposed ERT Prior hyperestrogenic environment Women on sequential therapy with bleeding before

day 10 With irregular bleeding after 6 mo. - all

patients

Side effectsIrregular bleeding - How to evaluate

Endometrial biopsy (EMB) - 3mm plastic suction device, office biopsy

Transvaginal ultrasound Endometrial thickness positively correlates with

presence or absence of pathology in women not receiving HRT

Thickness <5mm in postmenopausal women reassuring

Thickness >5mm (15%) require further evaluation

Side effectsIrregular bleeding - How to evaluate Progesterone challenge test Withdrawal bleed to progesterone to detect presence

of E-dependent endometrium in postmenopausal women

Validity not established Dilation and curettage - if unable to perform office EMB Hysteroscopy Visual inspection of uterine cavity with hysteroscope If bleeding persists, to determine presence of

endometrial polyps or submucous myomas

Side effects

Breast tenderness

Bloating

Depression Progesterone dependent May respond to changing type/route

administration

Therapeutic options

Estrogens Specific E not as important as duration, dose

and presence/absence of progestin Relative estrogen potencies Route of administration

Oral - first pass through liver predominately estrone Others - no first pass, predominately estradiol

• Vaginal • Injectable • Percutaneous ointment

Progesterone’s

Compounds Medroxyprogesterone acetate-21 carbon

compound Micronized progesterone Norethindrone-19 carbon compound

Progesterone’s

Routes of administration Oral IUD Vaginal

Sequence of administration

Continuous

Sequential/cyclic

Unopposed

Other hormones

Selective estrogen receptor modulators (SERMs) Tamoxifen

Adjuvant chemotherapy for breast cancer Prophylaxis for patients at high risk for breast cancer Improved lipids, increased BMD Agonist at uterus, increased risk of endometrial

abnormalities Vasomotor symptoms may be worsened Increased risk of VTE, similar to E

Other hormones

Selective estrogen receptor modulators (SERMs) Raloxifene

Approved for prevention and treatment of osteoporosis

No endometrial/vasomotor effects HDL/TG unchanged, same VTE risks

Other hormones

Androgens (A) Decreased production with menopause; may

improve vasomotor symptoms, enhance libido and improve fatigue; concentration

No endometrial protection Side effects

Adverse effect on lipid profile Masculinization rare

Alternative therapies

Hot flushes/vasomotor symptoms Soy phyto-estrogens (legumes)

Mixed agonist/antagonists Can decrease hot flashes >placebo

Clonidine - transdermal 0.1-0.3mg patch, twice as effective as placebo

Venlafazine - 100 mg/d, effective at inhibiting flushes Mergestrol

Alternative therapies - homeopathy, acupuncture

Alternative therapies Osteoporosis Biphosphonates

Inhibit bone resorption (Hasking, 1998) -

alendronate increases BMD > placebo < HRT

Raloxifene SERM, FDA approved to

prevent and treat osteoporosis

Calcitonin - may prevent bone loss at spine in late menopause

Calcium RDA/NIH

• Premenopausal - 800-1000 mg elemental

• Postmenopausal - 1200-1500 mg elemental

Modest beneficial effect on osteoporosis

With Vitamin D for best effect


Cardiovascular disease Statins Antioxidants Aspirin Reduction risk factors


Urogenital atrophy vaginal estrogen ring

Sexual function/libido Androgen supplementation Continued sexual activity


Alzheimer’s disease Tacrine/danozepil (Schneider, 1996)

(cholinesterase inhibitors) affect symptoms, not disease process

NSAIDs (Rogers, 1993) - delay expression AD

Vitamin E (Sano, 1997) - slows progression

Complimentary lifestyle interventions

Normalization of weight Dietary intervention Smoking cessation Regular exercise Control of other medical conditions

ReferencesWriting Group for the Women’s Health Initiative Investigators. Risks and

benefits of estrogen plus progestin in healthy menopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321-33.

Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995; 273:199-208.

Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA 1998; 280:605-13.

ReferencesGrady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, et al.

Cardiovascular outcomes during 6.8 years of hormone therapy; Heart and Estrogen/Progestin Replacement Study follow-up (HERS II) JAMA 2002; 288:449-57.

Nelson HD, Humphrey LL, Nygran P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy: Scientific Review. JAMA 2002; 288: 872-81.

Nelson HD, Assessing benefits and harms of hormone replacement therapy: Clinical applications. JAMA 2002; 288:882-4.

Varma TR. Effect of long-term therapy with estrogen and progesterone on the endometrium of postmenopausal women. Acta Obstet Gynecol Scand 1985. 64:41.

Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. NHS (1996); Lancet 1996; 348:983-7.

Finucane FF, Madans JH, Bush TL, Wolf PH, Kleinman JC. Decreased risk of stroke among postmenopausal hormone users. Results from a national cohort. NHANES (1993); Arch Intern Med 1993; 153:73-9.

ReferencesHeinemann DF. Osteoporosis. An overview of the National Osteoporosis Foundation

clinical practice guide. Geriatrics 2000; 55:31-6, 39. \U.S. Preventive Services Task Force. Guide to Clinical Preventive Services, 2nd ed.,

Williams and Wilkins, Baltimore, MD, 1996. Speroff L, Glass RH, Kase NG. Clinical Gynecologic Endocrinology and Infertility, 6th

ed. Williams and Wilkins, Baltimore, MD; 1999. Beckmann CRB, Ling FW, et al. Obstetrics and Gynecology, 4th ed. Lippincott Williams

and Wilkins, Philadelphia, PA; pp.568-76 ACOG Educational and Technical Bulletin #210, Health Maintenance for

Perimenopausal Women. Washington, DC. ACOG Educational and Technical Bulletin #247. Hormone Replacement Therapy.

Washington, DC. ACOG Practice Bulletin #28. Use of Botanicals for Management of Menopausal

Symptoms. Washington, DC.

Adapted from Association of Professors of Gynecology and Obstetrics Medical Student

Educational Objectives, 7th edition, copyright 1997

Clinical Case

Climacteric

Patient Presentation

A 48-year-old female G3P3 whose last menstrual period was 6 months ago presents to your office complaining of hot flushes, emotional liability and insomnia. She has tried to use an over-the-counter soy supplement, but her symptoms are unchanged.

She began her menses at age 14. Her periods have been regular until 2 years ago. At that time, they began to space out to every 2-3 months. She denies intermenstrual bleeding.

Patient PresentationShe had a negative Pap test one year ago and has never

had an abnormal Pap. She is sexually active and recently has noted some dyspareunia. Her husband had a vasectomy 15 years ago.

Her past medical and surgical history is significant only for an appendectomy at age 18. She has smoked one pack of cigarettes per day for 30 years. Her family history is significant for a mother that fractured her hip at age 83. She takes no medications or supplements on a regular basis.

Patient Presentation

Physical exam

Slightly obese white female. Weight 180 lbs., 5’6” BP 126/76. General physical exam, including breast exam within normal limits. Pelvic exam shows normal external genitalia. Her vagina is slightly atrophic with decreased rugae. Her cervix is normal in appearance; uterus is small and antiverted. Neither ovary is palpated on bimanual or rectal exam. Her stool is guiac negative

Patient PresentationLaboratory

Pap smear – normal squamous epithelial and endocervical cells present.Cholesterol 195 TSH 2.0FSH 80 MIU/mlMammogram – negative

Differential DiagnosisMenopausal vasomotor symptoms

Management plan

Encourage patient to stop smoking. Initiate incorporation of approximately 1200 mg calcium and 400 units of vitamin D in her diet. After lengthy discussion of risks and benefits of hormone therapy (HT), the patient decided to proceed with treatment, and was given estrogen and progesterone in a continuous daily fashion.

Management plan1. Cigarette smoking is the largest preventable

cause of death and disability among women in the United States. Among women of reproductive age, 29% smoke. Several studies have shown that smokers cease menstruating 1-2 years earlier than non-smokers. This effect is dose dependent and the difference persists after controlling for the subject’s weight. Moreover, female smokers 60 years of age and older have significantly reduced bone mineral density of the hip compared with nonsmokers.

Management plan

2. With the onset of menopause, ovarian production of estrogen is significantly reduced, lending to physiologic changes including hot flushes, mood disturbances, sleep difficulty, thinning of genitourinary tissues, dyspareunia, metabolic shift to a more atherogenic lipoprotein profile and accelerated loss of bone mass. This transition in a woman’s life often is a good time to assess current health risks and plan risk reduction strategies.

Management plan

3. Estrogen/progestin hormone therapy is approved by the FDA for the treatment of menopausal hot flushes, prevention of osteoporosis and treatment of urogenital atrophy. Hormone therapy is the most effective agent known for the treatment of hot flushes. Studies have also shown it to be significantly more effective than placebo in reducing insomnia, irritability and poor short-term memory during the menopausal transition.

Management plan

4. Risks associated with hormone therapy include increased thromboembolic events, increased triglyceride levels, breast cancer, gall bladder disease and other possible conditions. It is reasonable to continue hormone therapy for the shortest amount of time to address current vasomotor symptoms in an attempt to decrease overall risk

Management plan

5. This patient’s risk for osteoporosis is increased by her mother’s history of hip fracture. In addition to the protection provided by her HT, she should be encouraged to maintain an appropriate daily intake of calcium and vitamin D. Weight training exercise will also decrease her risk of fracture.

Management plan

6. The patient should be encouraged to use a water-based lubricant to decrease discomfort during sexual intercourse. The hormone therapy she has initiated should improve the quality of her urogenital tissues over the next few months. If these changes are not sufficient, the addition of a vaginal estrogen product may be helpful.

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8th Edition APGO Objectives for Medical Students Climacteric