Lecture 18 November 5th -- Hormone Replacement Therapy

1MEN’S AND WOMEN’S HEALTH – NOVEMBER 5TH, 2007 HORMONE REPLACEMENT THERAPY LECTURE 18 Is menopause a deficiency disease? Effects of estrogen on physiology of body: reason why it may be seen as a “disease”: bone density, improvement of cholesterol profiles, Morbidity: is a quality of life issue. Mortality: death Osteoporosis (secondary infections) and CV disease can cause mortality. Estrogen influences biochem of women. Hormone therapy: do we need to replace these hormones? CEE: comes from premarin (“Pregnant mares urine”) Animal rights issue around production of premarin: horses kept pregnant, foals killed Estrogen alone should only be prescribed to women without a uterus (hyperplasia is risk). If she has a uterus, must be on combo form. Premarin tablet: long acting. Oral tablet: body turns it into estrodiol. Also available as vaginal cream. Patch: applied twice per week: gives you more compliance because dosing is easier, fewer side effects. Patch or cream bypasses the liver and intestine. All estrogens in this form are fat soluable (oral form is water soluable). Most women in practice will be on one of these. Premarin is made of many different estrogen compounds, some synthetic. In 1938: already some concerns about carcinogenic property of exogenous estrogen. 1960s-1970s: big push in treatment of menopause, huge rise in prescription of Valium. Women targeted by pharm companies. Book “Feminine Forever”: played upon fears of post-menopausal women: irritability and effect on their partners! Author received a couple of million dollars from the pharma companies. 1975: estrogen linked to uterine cancer: had to be opposed with progesterone in women with intact uterus 1976: estrogen linked to breast cancer 1980’s: used to prevent osteoporosis 1985: more for prevention of CV disease 1992: Premarin was most prescribed drugs in US. Studies came out • HERS: Heart and estrogen replacement study. Funded by drug company. Found that women with pre-existing CV disease had INCREASED incidence of CV events. • Women’s Health Initiative Trial: 161000 participants. Gov’t funded. Looking at best practices re: women’s health in general. Branch looking at Premarin, women without uterus. Estrogen-only branch, AND combined therapy group halted because risk outweighed benefit. • Found overall increase in morbidity (see chart on back of notes) but no increase in deaths. Increased risk of these concerns. Halted study in 2002-2004. • Most women take HRT because of hot flashes, vaginal atrophy, but women don’t report that HRT improves these symptoms. • Good to know about these studies: “increased” was not a huge number of women in the study, but when the number of women on therapy is considered, the numbers are much higher (same percentage) This study had a massive impact on prescribing practices. Recommendation that women only be put on hormone therapy to prevent osteoporosis ONLY if she was at high risk, and only if she couldn’t use non-estrogen therapies. Paradigm shift occurred here: from “hormone replacement therapy” to “hormone therapy”. Not a deficiency disease, just using hormones to treat symptoms. MEN’S AND WOMEN’S HEALTH, NOVEMBER 5th 2007 – PAGE 1

Million Woman study: UK. Confirmed risk of breast cancer and HRT. Benefits of conventional hormone therapy (current indications): Prevention of osteoporosis (sig. Risk), vaginal atrophy, hot flashes. Low dose, short term. Decreased risk of colon cancer. •

Women producing the less potent form of estrogen (2-OH) have more benefit from HRT (re: osteoporosis) than 16-OH metabolizers. 16-OH is a more potent form, also risk for breast cancer. Can look at what kind of metabolizer she is when considering HRT therapy to prevent osteoporosis.

Risks of CHRT, contraindications. Shouldn’t be used in women with the following: • Risk of blood clots -> stroke, MI, DVT. Estrogen decreases LDL, increases HDL, but adding progesterone may contradict this result, offset the benefit. Clotting increased, although lipid panel may be improved. • Liver disease (HRT exacerbates), gall stones • Breast cancer (risk increased with addition of progesterone to therapy) • Hypothyroid exacerbation: Estrogen increases thyroid hormone binding globulin in the blood. Decreases the circulation of thyroid hormone. Normal thyroid will be able to compensate. If patient is hypothyroid, have to do testing to assess if their thyroid dose has to be increased. How does this affect sub-clinical cases of hypothyroidism? • Impaired glucose tolerance: both estrogen and progesterone therapy. Could be problem if patient has difficulty regulating glucose. • • • • • •

In handout, sections that talk about progesterone and estrogen (Premarin) can be combined to see effect of combined therapy. Don’t memorize lists: just look at major risks and indications. Bioidentical HRT: plant-produced. Molecularly identical to what the body produces. Soy is the main source for estrogen, wild yam for progesterone. Estrace: the only one you can buy that is already pre-compounded. Will have binders, adhesives, concerns for health. For compounded ones: use veggie caps, filler is lecithin, rice flour. Not lots of bad ingredients. Creams: have preservatives in them. Patients can give their own bases, can be compounded.

Estriol: emphasized as being the safest form. • This is the form of estrogen that predominates in pregnancy. Study: women with higher levels in pregnancy had reduced breast cancer later in life. Does this justify giving estriol to women post-menopausally? • Although “bioidentical”, still metabolized slightly differently than endogenous estrogen. Metabolites might be different than if endogenous estriol was metabolized. Better idea: stimulate the body to make its own estriol. (don’t know if this can be done). • Particularly effective for vaginal atrophy: see notes. Minimal to no effect on endometrium. Different from estradiol, conjugated estrogens that do this. • Don’t know impact of Estriol on bone mass or heart disease. • •

Benefits and risks: don’t know for sure. Safety: emphasis is on estriol, but is the body using it? What are the long-term effects? Don’t know. Even if it is a safer form of estrogen, there are concerns with Estriol use. Don’t have enough information.

Dosing of bioidentical hormones • Dosed by weight, may be better to dose by how active a compound is. • CEE=Premarin (1 tablet is 0.625mg) • Since estradiol is less active, 1mg = 0.625mg of CEE. • Patch: 0.05 mg to equal 1 dose of CEE. (doesn’t go through liver) • Probably don’t need to know this for exam. • Prometrium is bioidentical hormone. Have to give much larger dose 200mg. • Drug companies are making bioidentical hormones. MEN’S AND WOMEN’S HEALTH, NOVEMBER 5th 2007 – PAGE 2

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Just want to have information so that patients can talk to us about it.

Sequential or cyclic approach Like oral birth control. Causes bleeding. Continuous does not. How does this affect us as NDs? • There may be other ways of dealing with her symptoms. • Can’t stop therapy quickly. Start with alternative treatments before taking her off. Alternative treatments: • Go back to Thursday’s notes. • Estriol/Estradiol cream may be much better than oral therapy, if only symptoms are vaginal dryness. Tests: • Look at salivary levels of hormones, thyroid hormones, estrogen fraction, genetic testing (breast cancer), DEXA scan for bone density. • Cholesterol profile, tendency for clotting, mammogram. Cases: Eleanor is 45-year old peri-menopausal woman considering HRT for osteoporosis. Has had severe hot flashes, nausea, sore back on and off. Smoker 20yr, family history of breast cancer and heart disease. Vows to quit, hasn’t yet. Mother had double mastectomy. Doesn’t drink, walks daily, eats well. Neighbour refused HRT, now walks with cane. Concerned with risks. • •

Benefit to her? Osteoporosis (smoker, walks but not much weight bearing activity), hot flashes Concerns? Family history of breast cancer, heart disease

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Assessment of benefit or risk of HRT to her: 2 vs. 16-OH estrogen (more risk of osteoporosis if she metabolizes to 2oh), DEXA scan: is she osteopenic? Lipid profile, CV function.

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She is peri-menopausal, we could keep working with her for now Is there an estrogen-dependent cancer in her history? She is a smoker: predisposed for CV disease.

Probably too high a risk for conventional HRT. Margaret: 54 year old woman, 3 episodes of brief, substernal pain while carrying groceries. History of mild hypercholesterolemia, smoked until 10 years ago. Has been on HRT for six years for hot flashes. Diagnosed as angina, stent was put in place. Did the HRT contribute to the angina? •

She is on combined HRT.

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Recommendation: come off it, although we aren’t sure the angina was caused by HRT Takes longer than 6 years to develop this condition. (although she might have been developing atherosclerosis, but the HRT might have accelerated the problem?) She is now at risk for CV event as a result if she stays on the HRT as it can cause thromboemboli.

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What would we recommend? Come off HRT, diet and lifestyle suggestions

Donna, 68-year old woman on HRT. Has had unscheduled vaginal bleeding 4 times in 6 months. Mother died of breast cancer. Unsuccessful adjustments to HRT tried. All physical findings are normal, mammograms too. Wants to stop, asks about risks of osteoporosis. • Advice? Hysterectomy and start taking estrogen? Just stop HRT? Stop HRT and start anti-resorptive therapy? Do scan and assess need to intervene?

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55 year old woman. Presents for repeat of HRT meds. Has been on it for 2 years, has managed hot flashes well. Dismissed findings of studies as “fluff”. History of osteoporosis, no history of breast cancer. Maybe she doesn’t need it any more? But no longer at risk for breast cancer, CV disease. Needs to do more weightbearing exercise (walks 3 times a week). Do DEXA scan, is she at that much of a risk?

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