MENOPAUSE A “HOT” TOPIC

1. MENOPAUSEA “HOT” TOPIC Jeffrey Penikas, MD Columbia Women’s Clinic

2. Objectives • Review normal menstrual cycle and hormone production • Review changes that occur with menopause • Review options of treatment of menopausal symptoms • Conventional therapies • Alternative therapies

3. Normal Menstrual Cycle

4. Menopause • Characterized by gradual decrease in ovarian estrogen production. This time is referred to as perimenopause • Decrease gradual and accompanied by irregular periods, hot flashes, night sweats and sleep disturbance • When estrogen levels low enough, periods cease • Average age 51 with 95% of women stopping periods by the age of 55 A year of no bleeding with menopausal symptoms is menopause

6. Symptoms of Menopause • Decrease in estrogen production • Hot flashes • Vaginal dryness • Sleep disturbance • Night Sweats • Mood swings • Depression • Bone loss

7. Hot Flashes • Sudden feeling of heat rushes to upper body and face • May last several seconds to several minutes • Can be as frequent as many times a day to just a few a month • Can be mild to severe depending on the person • May occur for a few months to a few years or not at all for some women • Overweight women may not have as severe symptoms as fat cells produce estrogen and may help keep estrogen levels high enough to minimize symptoms

9. Vaginal Dryness • Decrease in estrogen causes thinning of the vaginal tissue • Causing drying and irritation • Painful intercourse • Increase risk of vaginal infection • Burning and itching • Thinning of urethral tissue • Drying and irritation • Increase in bladder infections possible • Increase in urinary frequency and incontinence

10. Sleep Disturbance • Hot flashes and night sweats • Decrease in REM sleep • REM vital to feeling rested when waking • Without adequate REM, may cause less feeling of restfulness after sleeping • Chronic loss of REM can result in difficulties handling everyday situations • Eventually may lead to mood swings and depressive symptoms • Difficulty getting to sleep

11. Bone Loss • Estrogen important to bone health in women • With menopause, bone loss occurs • Most rapid loss occurs in the years leading up to menopause • Increases the risks of fractures • Bones of the spine, hip and wrist are most affected

12. What can you do to help? • Lifestyle changes • Decrease hot flash “triggers” • Alcohol • Caffeine • Hot drinks • Hot or spicy foods • Stress • Warm environment • Stop smoking • Regular weight bearing exercise • Balanced diet • Adequate rest

13. Hormone Replacement Therapy • The most effective treatment for hot flashes • Originally thought to be protective for heart disease , Alzheimer’s disease and bone loss • First introduced in 1942 • Use dramatically changed after 2000 when results from Women’s Health Initiative (WHI) and Heart and Estrogen/Progestin Replacement Study (HERS) became available • Postmenopausal hormone use decreased 38% in 1 year • Combined therapy dropped 74% • Between 2001 and 2003 use decreased from 42% to 28 %

14. Women’s Health Initiative • Healthy postmenopausal women age 50-79 • 2 treatment regimes studied • Continuous combined estrogen and progesterone therapy vs. placebo • Conjugated equine estrogen 0.625mg with medroxyprogesteone 2.5mg • Continuous unopposed estrogen vs. placebo in women who had had a hysterectomy • 0.625 mg of conjugated equine estrogen • Continuous combined estrogen/progesterone arm included over 16,000 women • Continuous unopposed estrogen included over 11,000 women

15. WHI • Combined estrogen/progesterone arm stopped early • Increased risk of coronary heart disease, breast cancer, stroke and venous thromboembolism (blood clots in veins) • Protection against bone loss and colon cancer • Risks outweighed benefits • Unopposed estrogen arm stopped before end of study • Increased risk of stroke • No overall health benefits noted

16. WHI Limitations • Average age of patient was 62 • Significantly older than when most women start hormone therapy • Patients had to be free of hot flashes • Done to minimize the patient’s ability to tell she was on a placebo • Effects on menopausal symptoms and general sense of overall patient comfort not studied

17. Coronary Heart Disease • Combined therapy found to increase the risk of heart attack • Also seen in HERS trial • Unopposed therapy did not seem to increase risk • If combined therapy started within 10 years of the onset of menopause, risk did not seem to be increased

18. Breast Cancer Risks • Risk increased in the combined hormone therapy group • Tumors found seem to be larger • Tumors more aggressive • Higher rate of positive lymph nodes • Risk does not seem to be increased in the unopposed therapy group

19. Breast Cancer Risk

20. Breast Cancer • After initial results of WHI announced in July of 2002, dramatic drop in usage of hormone therapy occurred • By the end of 2003 a cumulative 15% drop in the diagnosis of breast cancer seen in the US • Similar drop in usage of hormone therapy seen in Canada over same period of time • No similar dramatic drop in breast cancer seen in Canada

21. Stroke • Appeared to increase in both treatment groups • Increased risks seen in all age groups • Did not vary with respect to number of years since onset of menopause • Given low baseline risk of stroke in women 50-59 and modest increase due to hormone therapy, no absolute increase in stroke seen in this age group

22. Venous Thromboembolism • Increased risk seen in both groups • Combined therapy group showed about a 2 fold increase in clotting events in comparison to placebo • Risk highest in the first year of treatment, but persisted at 5 years of treatment • Women with previous clotting history at highest risk • Increased risk also seen in unopposed therapy group but overall less than the combined therapy group • Risks increased by older age, obesity, and Factor V Leiden which is a genetic blood clotting disease • Not influenced by smoking, aspirin use

23. Bone Loss: Osteoporosis • Both combined and estrogen only hormone therapy showed decrease in fractures • In WHI, baseline bone density was not available, so uncertain as to the precise therapeutic advantage • Other studies have shown that the effect is greatest if started soon after menopause and continued indefinitely • Effects do seem to be dose related; low dose estrogen use still is effective, but less so • Benefits do not outweigh the risks to recommend this as a primary treatment for osteoporosis

24. Invasive Colorectal Cancer • Combined hormone therapy appears to reduce the risk of invasive colorectal cancer • Same benefits not seen in the estrogen only treatment group • Like benefits for bone loss, hormone therapy risks outweigh the benefits for protection from invasive colorectal cancer and cannot be advised as a primary use

25. Hormone Replacement • Recommendations include: • Use lowest dose to achieve patient satisfaction • Use for limited time period • Should be used for symptomatic relief of menopausal symptoms only • Consider the use of transdermal therapy which has a lower risk for DVT and stroke • Important to counsel patients on the risks and benefits and work with them to develop plan of care

26. Other Therapies • Selective Estrogen Receptor Modulators (SERM) • Antidepressants • Gabapentin • Blood pressure medications • Low dose vaginal estrogen preparations

27. SERMs • Act on estrogen receptors in the body • Can act like estrogen or an “anti” estrogen depending on the tissue

28. Tamoxifen • Tamoxifen is used in the treatment of hormone sensitive breast cancers • Anti estrogen in breast tissue • Stimulates estrogen effects in the uterus • Hot flashes are a common symptom of use

29. Raloxifene (Evista) • Raloxifene used to treat bone loss in women who cannot take estrogen • Acts like estrogen to protect bone and its effects on cholesterol profile • Acts as an anti estrogen in breast and uterus • Reduces the risk of invasive breast cancer

30. Antidepressants • May help reduce hot flashes • Improve sleep, mood swings and quality of life • Increase circulating levels of the neurotransmitter serotonin in the brain • Neurotransmitters are chemicals that are important to nerve function and brain function • Premenstrual dysphoric disorder (sometimes known as PMS) has been shown by brain scan to involve inadequate regulation of serotonin pathways in the brain

31. Neurontin • Commonly used for treatment of chronic pain disorders • Also used for treatment of fibromyalgia • Has been shown to be as effective as estrogen in the reduction of hot flashes

32. Blood Pressure Medication • Clonidine has been shown to be as effective as antidepressants in treatment of hot flashes • No other benefits seen • May be a consideration for women with blood pressure issues.

33. Vaginal Estrogen • Estrogen absorbed readily though vaginal tissue • Preparations include creams, pills, and silastic rings • Should be used for vaginal dryness symptoms • At low doses, systemic absorption appears to be very minimal and cannot be detected by standard hormonal testing • Very effective for treatment of vaginal symptoms • Typically used if non-hormonal vaginal moisturizes and lubricants have failed

34. Phytoestrogens: Plant estrogens • Soy • Black Cohosh • Dong Quai • St. John’s Wort • Flaxseed • Chasteberry

35. Contain phtyoestrogens which may be able to bind estrogen receptors and act as weak estrogens Interest peaked when it was noted only 10% of Asian women experience hot flashes Diet high in soy in Asian cultures Soy Beans

36. Soy Products • Many different products on the market • Soy tablets have been compared to conventional estrogens with mixed results. • Some studies suggest modest effectiveness • Recent, well designed study showed not as effective as placebo • Women with greater frequency of hot flashes have better results • Not a “magic bullet”

37. Soy and Breast Cancer Soy products can stimulate growth of breast cells in the lab Population studies, mostly in Asian women, show that moderate soy intake may actually decrease the risk of breast cancer Not much evidence in Western women, but some showing it does not help in Western women unless used premenopausally, not postmenopausally Bottom line, women with a history of breast cancer should use phytoestrogens very cautiously if at all

38. Soy Therapy Conclusions • May be effective in some women. • Probably works better in women with more frequent hot flashes • Probably should not be used in women with a history of breast cancer as it has unknown risks for them • Does not seem to be effective in women who have hot flashes due to breast cancer treatment • Women on warfarin (Coumadin) should use caution as it might reduce the effectiveness of the drug

39. Important that this not be confused with blue cohosh or white cohosh which can be toxic BLACK COHOSH

40. Black Cohosh • One of the top-selling herbs in the US primarily for menopausal symptoms • Has estrogen-like effects, but does not bind to estrogen receptors • Remifemin and Estroven are popular commercially available products of black cohosh • Effectiveness is controversial. Some studies do show benefit while others do not • Does not seem to be beneficial in breast cancer patients with hot flashes

41. Black Cohosh: Risks • Some concern with liver toxicity with black cohosh with long term use • Some reports of liver damage up to and including damage severe enough to require liver transplant • Some feel such severe damage due to contamination of uncontrolled products with toxic substances • Consider liver function tests with long term use • If using, would recommend using Remifemin or Estroven as they are commercial products that are closely regulated

42. Traditional Chinese medicine remedy for menopausal symptoms often used in combination with other traditional herbs In US, used alone and has not been proven effective Contains substances considered carcinogenic Unknown if enough of these substances present to cause cancer Not recommended Dong Quai

43. Commonly used for the treatment of depression associated with menopause May be as effective as standard treatment with SSRI antidepressant therapy Much lower side effect profile St. John’s Wort

44. Plant seeds contain a large amount of lignans which are a plant estrogen Inconclusive studies show benefits for slowing growth of certain breast cancers High fiber content Too much can interfere with some medications and can cause bowel obstruction Flaxseed

45. Known as the “women's herb” Might help for symptoms of premenstrual syndrome No reliable evidence for help with menopausal symptoms Don’t use with history of breast cancer as may stimulate growth of breast tissue Chasteberry

46. Phytoestrogen Conclusions • No good evidence to prove safety and consistent effectiveness • Potential interactions with other medications and potential risks of phytoestrogens important. Be sure to discuss use with your health care provider • Given potential estrogenic effects, should not be used by women with a history of breast cancer without close consultation with their breast cancer care team

47. Bioidentical Hormone Replacement • Bioidentical hormone replacement (BHRT) uses hormones identical in structure to those made in the body • Often refers to a combination of diagnostic blood or salivary testing, compounding and prescribing of medication • FDA considers BHRT a marketing term and does not recognize its use

49. Salivary Testing • Commonly used to assess baseline hormone levels and then used to adjust different hormones in the compounded treatment • Adjustment made on hormone levels, not on symptoms • May result in use of unnecessary hormones as levels, not symptoms being addressed

50. Limitations of Salivary testing • Does not take into account the variation of hormone secretion over hours and days • Individual variation in rates of metabolism between patients • Does not measure actual biological activity at tissue levels, only levels in saliva • Poor replication of results and wide variation in results among different assays • Expensive and not covered by most insurances, if any