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2. Menopause

3. Thomas A. Klein, MD
Professor, OB-GYN
Has disclosed the following commercial relationships in relation to this content:
Nothing to Disclose
Questions:

4. Objectives
Review the physiologic and clinical events which accompany menopause
Review the long-term health consequences of menopause
Review current research findings regarding the treatment of menopause
Review various hormonal and non-hormonal approaches to the relief of menopausal symptoms

5. Per Cent of Female Population by Age

6. Menopause 2016: State of Affairs
High prevalence: essentially 100 % of women (eventually)
Symptoms often severe and multi-systemic
Major economic impact
Opportunities for prevention: osteoporosis, CHD
Intense pharmaceutical industry research & marketing
Large volume of research
Inherently difficult and complex
Contradictory results
Large number of available therapeutic and preventive interventions
Various drugs, combinations, doses, routes of administration
Most affect more than one organ system: favorable and adverse effects
Rapidly changing landscape

7. Menopause is defined as:
Amenorrhea accompanied by vasomotor symptoms
Infrequent light bleeding after the age of 48
Amenorrhea for more than 3 months in a patient with X-chromosome mosaicism 46XX/45X
Permanent loss of menstruation, caused by cessation of ovarian estrogen secretion
Presence of vasomotor symptoms in a woman over age 51, regardless of bleeding

8. Etiology Normal – Follicle exhaustion Iatrogenic Surgery
Radiation therapy
Chemotherapy
Premature (< age 35)
Genetic
Autoimmune
Idiopathic

9. Follicle Loss

10. Problems Accompanying Menopause
Vasomotor symptoms (“hot flashes”)
Coronary Heart Disease (CHD)
Breast cancer
Osteoporosis
Urogenital atrophic symptoms (urinary symptoms, painful intercourse)
Dementia

11. Osteoporosis: Impact 10 million people with osteoporosis, 80% women
Current estimates (2009), in U.S.:
10 million people with osteoporosis, 80% women
34 million people with osteopenia
547,000 vertebral fractures per year
350,000 hip fractures per year
1,200,000 fractures at other sites per year
24 % mortality in year following hip fracture, in pts > age 50
About 65 % of women sustain permanent losses of function after hip fracture
About $ 19 billion spent annually on osteoporotic fractures
A major public health problem, largely preventable

12. Osteoporosis Risk Factors
Female
Personal or family history of fragility fracture
Caucasian/fair/nordic; asian
Slender: weight < 127 lb
Early menopause
Family history
Alcohol/tobacco/caffiene
Low calcium intake
Sedentary lifestyle
Medications, esp. glucocorticoids, for > 3 months

13. Osteoporosis: Preventive Measures
Lifestyle changes, e.g., weight-bearing exercise, smoking cessation
Nutritional changes: Calcium, Vitamin D
Medications, e.g. bisphosphonates, estrogen

14. 2. African-American ancestry 3. Use of antidepressants 4. BMI = 32
A 45-year-old peri-menopausal patient asks you whether she should take steps to prevent future osteoporosis. Her 77-year-old mother recently broke her hip. Which of the following are risk factors for osteoporosis:
1. Menopausal state
2. African-American ancestry
3. Use of antidepressants
4. BMI = 32
5. Hypertension

15. 1. Calcium/Vitamin D supplements 2. Glucocorticoid therapy
The preceding patient wants to take steps to prevent future osteoporosis. Which of the following would you recommend:
1. Calcium/Vitamin D supplements
2. Glucocorticoid therapy
3. Herbal estrogens
4. Progestin therapy
5. Weight loss regimen

16. Coronary Heart Disease (CHD)
The leading cause of death
Risk for men increases steadily with age
Risk for women much lower until menopause, after which it rapidly approaches that of men
A large body of animal and in vitro evidence shows a beneficial effect of estrogen on cardiovascular health
A large number of carefully-designed retrospective and observational studies show that postmenopausal estrogen therapy results in a 50 % reduction in CHD-related events
Main criticism: Selection bias – Women taking hormones may have a healthier lifestyle than those not on Rx

17. Women's Health Initiative (WHI)
NIH-sponsored long-term multicenter placebo-controlled randomized prospective evaluation of HRT
Designed to determine whether HRT could prevent CHD
Major arms:
0.625 mg CEE/0.25 mg MPA daily vs placebo
0.625 mg CEE only vs placebo (hysterectomy)
>100,000 women, > $1,000,000,000
External Data & Safety Monitoring Board
Study stopped after average 5.2 years because of excessive risk of breast carcinoma

18. WHI: Summary of Results Combination Therapy Arm
Outcome HR C.I Events/yr/10,000 pts.
HRT Placebo
Coronary HD
Stroke
VTE
Breast Ca
Colon Ca
Hip fracture
JAMA 2002;288:321

19. WHI - Criticisms Relatively advanced age of many subjects
Exclusion of women with vasomotor symptoms
Relatively advanced age of many subjects
Average age 63
Average time since menopause 10 years
Internal vs. external validity
Results conflict with biological and in vitro data supporting beneficial effects of estrogens
Nevertheless, WHI indicates that use of HRT in older women, or for long periods of time, increases the risk of breast cancer and CHD.
“Estrogen Forever” no longer recommended

20. She is right; non-hormonal therapy is much safer
A 50-year-old patient has been having severe vasomotor symptoms for several months. She has read about the Women’s Health Initiative (WHI) on the internet and is concerned that estrogen therapy may increase her risk of breast cancer. You tell her that:
She is right; non-hormonal therapy is much safer
The results of the WHI do not apply to her
The WHI is a retrospective study and may not be valid
Her risk of breast cancer will be minimal if she uses non-oral estrogen therapy
Her risk of breast cancer will be lower if she adds a progestin to the estrogen therapy

21. HRT: Contraindications
Absolute:
Current breast or endometrial cancer
Past history of breast or endometrial cancer (??)
Undiagnosed vaginal bleeding
Pregnancy
Acute or chronic liver disease
Active venous thrombosis or thromboembolic disease
Relative:
History of thrombosis or thromboembolism
Strong family history of breast cancer

22. Which of the following is an absolute contraindication to estrogen replacement therapy?
Varicose veins
Positive hepatitis B surface antigen test
Hypertension
Fibrocystic breast change
Undiagnosed vaginal bleeding

23. Oral combined (estrogen + progestin) therapy No hormonal therapy
A 49-year-old patient is requesting estrogen therapy for severe “hot flashes.” Her last menstrual period was 6 months ago. She has a history of chronic hypertension and migraine headaches. What would you recommend?
Oral combined (estrogen + progestin) therapy
No hormonal therapy
Oral progestin therapy only
Oral estrogen therapy only
Vaginal estrogen therapy

24. Non-Hormonal Therapies
Vasomotor Symptoms
Clonidine
SSRI’s
Herbal estrogens, Vitamin E (?)
Osteoporosis
SERM’s
Bisphosphonates
Calcitonin
Calcium, Vitamin D, weight-bearing exercise, smoking cessation
Coronary Heart Disease
Statins
Aspirin
Control hypertension, diabetes
Diet, exercise, smoking cessation

25. Treatment of Menopause: Issues to Consider
Age, menopausal status, potential duration of therapy
Severity and impact of symptoms
Lifestyle and likelihood of change
Smoking, diet, exercise
Other medical problems and medications
Risk factors for coronary heart disease
Diabetes, hypertension, dyslipidemia
Risk factors for breast Ca - ? Gail model
Risk factors for osteoporosis
Risk factors for DVT, VTE
Likelihood of compliance with medication(s)
Patient’s tolerance for risk
Cost of treatment; insurance coverage

26. HRT: Current Situation
ERT is safe and effective in most women for at least 5 years, when begun at time of menopause
HRT should not be given to women at increased risk for CHD, breast cancer or DVT/VTE. This includes age > 60 years
Risk of CHD and breast cancer increases with age and duration of HRT
Use the lowest effective dose of HRT for the shortest necessary time

27. HRT: Current Situation
HRT should not be used without a clear indication and careful consideration of risk/benefit ratio
FDA-approved indications: Relief of vasomotor and vulvovaginal symptoms and prevention of osteoporosis
Non-oral routes of administration may be preferable, to avoid DVT
Benefits of HRT may also be achieved with non- hormonal therapy

28. Prevention of Alzheimer’s disease Prevention of osteoporosis
Which of the following is an FDA-approved indication for postmenopausal hormone replacement therapy (HRT)?
Prevention of Alzheimer’s disease
Prevention of osteoporosis
Prevention of coronary heart disease
Prevention of deep vein thrombosis (DVT)
Prevention of cerebrovascular disease

29. Menopause: Summary
A “normal” hypoestrogenic state with multisystem effects, mostly adverse
Estrogen replacement therapy corrects most of these effects, but with small risk of serious consequences, related to age, dose, duration of use and individual patient risk factors
However, estrogen replacement therapy can relieve suffering and improve quality of life with relatively little risk, when appropriately administered
The concept of “estrogen forever” is discredited
The decision to administer estrogen replacement therapy requires a thorough and detailed evaluation of the patient’s situation, as well as non-estrogenic alternative therapies