Perimenopause & Menopause

Menopause Facts:

* #1 killer of women is heart disease * heart disease risk incr after menopause * women more likely to develop osteoporotic fx's than men (1 in 2 women will fx after menopause) * osteoporosis risk incr after menopause * bone loss is accelerated during first 4 years after menopause

Manifestations of Menopause

* bone loss (5-6 years accelerated bone loss after menopause starts; why women reach menopause earlier than men) * impaired balance & forearm fx * hyperlipidemia * incr risk CHD (esp after menopause) * depression * cognitive decline (after hormones decr) * decr cutaneous collagen * incr fat deposition & decr lean muscle mass (more issues w/ weight gain/obesity; exercise critical at this stage to help with lean body mass)

Women's Health Initiative: Estrogen-only arm

- 10739 women with hysterectomy - conjugated equine estrogens or placebo: * CHD-no change *breast cancer-no change *incr stroke *decr hip fx

Women's Health Initiative (study done by NIH)

- 16608 postmenopausal women aged 50-79 with intact uterus were included - mean age 63 yrs - active group received prempro-conjugated equine estrogens: 0.625 mg/d & medroxyprogesterone acetate 2.5 mg/d - study terminated early due to breast cancer risk

If 10,000 more women took estrogen & progesterone for a year, there would be:

- 7 more CHD events - 8 more breast cancers when used more than 5 years - 8 more PE, ischemic strokes - 6 fewer colorectal cancers - 5 fewer hip fx's

Menopause: definition

- abscence of periods for 12 months - mean age ~ 51 yrs - women live avg 30 yrs beyond - occurs 2 years earlier in smokers *always ask about sx: night sweats, hot flashes, sleep disturbances

Thromboembolic Disease and estrogen:

- absolute risk in nonusers: 1:10,000 - estrogen + progestin have 2-fold incr in risk (should screen for clotting factors/hx) - highest risk in first year of use - lower doses of estrogen have a lower risk - transdermal delivery decr the risk - should be screening routinely for clottign factors (don't-not cost effective)

Hot flashes treatment:

- associated with thermoregulatory dysfunction - initiated at level of hypothalamus by low estrogen levels - treat: * mild: non-pharmacologic * mod-severe: hormonal therapy or non hormonal therapies (gabapentin, SSRIs, SNRIs)

Take home points

- do not use for prevention - if urogenital sx's, use topical - if mod-severe vasomotor sx's, use oral/transdermal - always use lowest dose possible for shortest amt time possible (less than 5 years) - evaluate annually - consider tapering therapy to avoid hot flashes (instead of abruptly stopping)

Role of progestins in therapy:

- endometrial protection in woman with intact uterus - must be taken 12-14 days each month (not needed for the entire month)

Combination regimens:

- estrogen given each day - progestin is added for 12-14 days: * can be combine therapy (estro+progest): more BTB assoc early on b/c giving her back her hormones - if bleeding very heavy like a period-send to PCP (possibility endometrial cancer) * can be sequential (when giving progest, there is no estrogen)

CVD and Estrogen:

- estrogen has positive effects on lipid panel - early observational studies demonstrated a decr risk of MI in patients receiving estrogen - RCTs showed incr risk in MI in patients taking estrogen+progesterone - women who initiate therapy 10 yrs after menopause may be at higher risk of CHD - estrogen therapy should not be initiated or continued for prevention of cardiac disease

Breast Cancer and estrogen therapy:

- estrogen+progesterone incr risk invasive breast cancer - risk incr with 5 or more years of use (hard to pick up breast cancer in mammogram when estrogen levels higher - cancers were more advanced and harder to diagnose - risk breast cancer returns to baseline after d/c

Staying healthy after menopause:

- evaluate risks for CHD & treat - choose healthy lifestyle-nutrition&exercise - maintain healthy weight - get mammogram - annually - get colonoscopy - at age 50 then Q 5yrs - get DEXA - ensure adequate calcium & vit D intake

Hot flashes

- hot flashes or vasomotor sx's occur in 80% women - at night, can result in night sweats - involves feeling of heat around chest & face, becoming generalized --> usually lasts a few minutes --> may be followed by chills, shivering, anxiety-->may have many episodes per day - can last 4-5 years post-menopause; 9% will have them past age 70 (variable across cultures)

History of HRT:

- in 1980s/90s: women took HRT for years (Ca and estrogen) - goal was to prevent osteoporosis & CHD - observational studies had shown a decr risk of fx & improved lipid panels with estrogen after menopause - thought that estrogen deficiency might incr risk for dementia

Vaginal Estrogens:

- indicated for tx atrophic vaginitis - available in creams, tablets, rings - low systemic absorption - progestin NOT NEEDED in pt with intact uterus - however Femring does achieve systemic concentrations of progestin & is indicated for mod-severe vasomotor sx's

What are side effects of progestin?

- irritability - depression - headache - premenstrual sx's - mood swings, bloating, fluid retention, sleep disturbance

Vaginal Symptoms

- lining of vagina and urethra is estrogen-dependent (has estrogen receptors) - changes when estrogen levels change - epithelium thins, leading to dryness, itching, dyspareunia, urinary infections, incontinence (overactive & stress incontinence) - 47% women 3 yrs past menopause will experience dryness - treatment options: vaginal lubricants, vaginal estrogen, oral estrogen

Cause of Menopause:

- loss of ovarian function & subsequent hormonal deficiency - causes: * normal process of aging * surgery (total abdominal hysterectomy, bilateral oophorectomy-pushes into early menopause-no more estradiol) * chemotherapy * pelvic irradiation - postmenopausal ovary no longer produces estradiol or progesterone

What are side effects of estrogen?

- nausea - headache - breast tenderness - vaginal bleeding - gall bladder disease - ACHES applies to HRT and OCPs

Perimenopause: when does it start and what are the manifestations

- occurs after primary reproductive years but before menopause (~45) - begins about 4 yrs before final menstrual period - manifestations: irreg periods, hormonal fluctuations (don't measure hormones this time), hot flashes, sleep disturbances, vaginal dryness * if taking OCP, may not notices some of these changes

What are some things to think about regarding dosage forms of estrogen?

- oral estrogen undergoes first pass-need higher dose to have intended effect (can incr HLD & TG's) - transdermal doses lower than oral & avoid first pass - transdermal estrogen does NOT impact TG or HDL and may have less risk DVT/PE

What to think about when giving estrogen to a woman?

- pts with intact uterus must ALSO take progesterone pdt to prevent uterine hyperplasia and cancer** - estrogen is given continuously to avoid hot flashes - HRT most effective for tx vasomotor and vaginal sx's **do not use HRT for prevention**

CVD and menopause

- risk of CHD incr after menopause - LDL incr after menopause by a mean of 6% - NCEP recognizes menopause as a risk factor for CHD - women tend to gain fat mass and lose muscle mass - treatment of estrogen does NOT decr risk

Estrogen therapy is individualized, what should be assessed before starting?

- severity of menopausal sx's - CHD risk - DVT/PE risk - breast cancer risk * choose lowest effective dose for shortest duration needed for effective sx control (women with hysterectomy need highest dose)

New drug approved for hot flashes: Duavee

CEE 0.45mg and bazedoxifene 20mg (estrogen agonist/antagonist) - approved to treat mod-severe hot flashes & prevent osteoporosis - used in women with intact uterus - bazedoxifene decr risk uterine hyperplasia

Examples of vaginal estrogens: Premarin

CEE Cream twice weekly (initially, two weeks straight to build lining, then drop to twice weekly) * should not have intercourse after application of the cream-avoid for that day

What are the two main types of estrogen used in drugs?

Conjugated estrogens: - from urine of pregnant mares (Premarin) - synthetic form available as well (cenestin-plant based) Estradiol: - active form of endogenous estrogen - micronized oral form (Estrace) - transdermal form (Vivelle)

Examples of vaginal estrogens: Femring

Estradiol acetate vaginal ring (higher conc of progestins for systemic effects) replace every 90 days

Examples of vaginal estrogens: Estrace

Estradiol cream twice weekly (initially, two weeks straight to build lining, then drop to twice weekly) * should not have intercourse after application of the cream-avoid for that day

Examples of vaginal estrogens: Estring

Estradiol vaginal ring (lower conc for local effects) replace every 90 days

Observational Studies and Estrogen

Estrogen users experience: - 50% reduction in CHD - 50% reduction in vertebral fractures - 25% reduction in hip fractures

What herbal & OTC therapies are there for hot flashes?

Evening primrose oil: considered ineffect. Phytoestrogens: considered ineffect. - act as SERM & may incr risk breast cancer & decr efficacy of tamoxifen Black Cohosh: considered ineffect. - may have SERM effects - may cause liver dysfunction

What progestin products are used?

Norethindrone: first generation Medroxyprogesterone; less androgenic (WHI) Dropsirenone: antiandrogenic & antialdosterone (incr K+, monitor K if on ACEI/ARB, incr risk hyperkalemia) Micronized progesterone

Converting from Premarin dosing to Vivelle or Estrace:

Premarin 0.625mg:Vivelle 50 mcg/day Premarin 0.625 mg: Estrace 1 mg

Outcomes of WHI and Quality of life and Dementia

QOL: - estrogen+progestin improved vasomotor sx's; did NOT improve QOL-related health measures Dementia: - estrogen+progestin did NOT improve cognition in women over 65; INCR risk of dementia in women over 65

What non-hormonal options are there for hot flashes?

SSRIs and SNRIs: relieve sx's of vasomotor instability - AVOID with breast cancer pts on tamoxifen (may decr formation of tamoxifen's active metabolite) Gabapentin: mech unknown Clonidine: considered less effective

Dosing for Combipatch

apply twice weekly Estradiol 0.05mg/day Norethindrone 0.14mg and 0.25mg/day

Which estrogen circulates before then after menopause?

before menopause: - estradiol after menopause: - estrone

Dosing for Premarin:

conjugated estrogens 0.3, 0.45, 0.625, 0.9, 1.25 mg * start low (0.3/0.45mg) then titrate up if no relief from sx's

Dosing for Estrace:

estradiol (micronized) 0.5, 1, 1.5, 2 mg

Lifestyle changes that can be made for hot flashes:

keep room cool dress in layers avoid hot/spicy foods take cool bath/shower exercise/lose weight decr caffeine/stop smoking

New example of vaginal estrogen: Osphena

ospemifeme: SERM specific for vagina, approved for dyspareunia due to vulvar and vaginal atrophy - not to be used with breast cancer or osteoporosis - can incr hot flashes

Angelique

tablets-take daily Estradiol 0.5mg or 1mg Drosperinone 0.25mg or 0.5mg

Dosing for Prempro

take daily CEE 0.3 mg, 0.45mg, 0.625mg Medroxyprogesterone 1.5mg, 2.5mg, 5mg

Dosing for Premphase

take daily CEE 0.625 mg days 1-28 medroxyprogesterone 5mg days 15-28

Dosing for Vivelle:

transdermal estradiol 14, 25, 37.5, 50, 60, 75 & 100 mcg/day