POSTMENOPAUSAL ESTROGEN REPLACEMENT THERAPY

POSTMENOPAUSAL ESTROGEN REPLACEMENT THERAPY

University of Illinois at Chicago

Hormone

Replacement Therapy (HRT) and Estrogen Replacement Therapy (ERT)

Ovarian follicle no longer responds to gonadotropin - thus estrogen not produced Lack of negative feedback results in increased levels of gonadotropins (FSH and LH) Amenorhea lasting 1 year - average age 51.4 years (two years earlier in smokers)

Climacteric - series of physiologic, endocrinologic and psychologic changes that signify the transition from reproductive to nonreproductive life - spans several years - peri-menopausal

Symptoms

1) Genitourinary Atrophy - vaginal epithelium becomes pale, thin, less distensible and secretions reduced, pH becomes more alkaline. Also urethra becomes more inelastic - vaginitis and urethritis

Therapeutics: vaginal estrogen – possibly local – All recommended therapies are changing.

2) Vasomotor Instability - Hot flashes - peripheral blood flow increases causing increased skin temperature, perspiration as a compensatory mechanism, stimulation of sympathetic nervous system in response to increase in skin temperature. Mechanism - estrogen deficiency - surges of GnRH or LH that affects the hypothalmic thermoregulatory center. Other symptoms associated.

Therapeutics: Estrogen 3-5 years then taper. Other: high dose medroxyprogesterone, alpha agonist (clonidine)

3) Osteoporosis - bone loss to the degree that the skeleton is compromised resulting in fractures. 150,000 to 200,000 fractures /yr - 10% die within 6 months from complications - 100,000-150,000 end up in institutionalized rehabilitation .(estrogen deficiency is one factor among many that leads to osteoporosis).

Therapeutics: Estrogen replacement - 10 -15 years post menopause . Other protocols suggested. MOA - not totally clear - stops bone resorption. Other treatments

available. Raloxifene – Evista. Selective estrogen receptor modulators (SERMS); Alendronate (Fosamax)

4) Cardiovascular disease - Estrogen replacement can reduce CV disease and related mortality by at least 50%. Effect of estrogen on blood lipids previously reviewed

Therapeutics - see below and PEPI trial, WHI trial and others

ERT - ESTROGEN REPLACEMENT THERAPY Efficacious for symptoms of menopause

hot flashes, sweating, atrophic vaginitis and prevention of osteoporosis other

Treatment with estrogen preparations 1-Ethinyl estradiol

2-Non Steroidal Estrogens Diethylstibestrol

- orally active

- equal potency with estradiol Chlorotrianisene (TACE)

- very lipid soluble

- converted to estrogen in liver Methallenestril

3-Conjugated Estrogens

- Premarin conjugated with

glucuronide, sulfate etc. (from pregnant mare's urine) -Newer synthetic drug

-Active orally

4-Esters of Estrogen (Carbon #3, first ring) - cypionate, valerate, propionic, etc.

- IM injection, slow absorption, prolonged action Unopposed estrogens - Oral -only post hysterectomy

oral (21-25 d/mo),

0.3 - 1.25 mg/d conjugated - Premarin 0.01- 0.02 mg/d ethinyl estradiol

plus calcium supplements topical

vaginal cream for atrophic vaginitis and urinary problems patch - apply on abdomen, rotate sites

systemically absorbed - but avoids first pass hepatic metabolism and some of the hepatic based side effects (changes in plasma proteins and gall bladder problems)

Transdermal administration of estrogen may have less favorable effects on lipoprotein profiles than oral administration - however more current, longer term studies suggest increased HDL and decreased LDL

Because unopposed estrogens increase the risk of endometrial cancer, it is

recommended that progesterone be added at the end of the cycle of treatment

Other reasons for adding progesterone component - protect against breast carcinoma and

enhance estrogen prophylaxis for osteoporosis

In female with intact uterus - Estrogen and progesterone replacement HRT - HORMONE REPLACEMENT THERAPY

In female with intact uterus - Estrogen and progesterone replacement Current Recommendation

- cyclic administration of estrogen with addition of progestin - Combination of Premarin plus

Progesterone preparation

Medroxy progesterone acetate (MPA) Norethindrone

Micronized progesterone

- Addition of progestin avoids uninterrupted stimulation of endometrium

- Progestin / progesterone decreases estrogen receptor number and enhances conversion of estrogen to estrone - This effect of progesterone actually decreases the risk of

endometrial cancer below that of non users.

- This regimen causes bleeding on "off" days

An alternative is to give estrogen and progesterone every day. This results in breakthrough bleeding.

Protocols

1) Cyclic sequential

Estrogen- day 1-13 // estrogen + MPA - day 14-25 // 5 days without // Repeat Estrogen_____________________ Estrogen_____________________

Progestogen_______ xxss Progestogen_____ xxss

2) Continuous sequential

Estrogen and MPA day 1-12 // estrogen alone day 13-25 // repeat

Estrogen___________________________________________________________ Progestogen__________xxss Progestogen__________ xxss _

3) Continuous combined

Estrogen and MPA continuously

Estrogen ___________________________________________________________ Progestogen_________________________________________________________

sssssssssss sssssssss ssssssssss 4) Cyclic combined

Estrogen and MPA - day 1-25 // 5 days without // repeat

Estrogen______________________ Estrogen__________________________ Progestogen___________________ Progestogen_______________________

Risk-Benefit -

Meta analysis revealed that the decrease in risk of cardiovascular morbidity (30-50% ) and mortality and fractures caused by osteoporosis, outweighs any increased risk of cancer. These studies were observational, epidemiologic and NOT prospective. Prospective studies are

presently being conducted. Goal of Therapy

Primary prevention – especially with regard to cardiovascular health – prevention before any negative cardiovascular events have occurred.

Secondary prevention – protection from further cardiovascular events after already having experienced a negative cardiac event.

- relieve symptoms with lowest effective dose

- gradual reduction and withdrawal ?? Continuous after menopause?? - Individualization of therapy

TRIALS

Prospective clinical trial PEPI - Postmenopausal Estrogen/Progestin Intervention. Estrogen only or Estrogen plus progesterone JAMA, 1995

Examined intermediate outcomes of cardiovascular health - Improves lipoprotein profile

- lowers fibrinogen levels Estrogen alone has the greatest effect

Among the combination therapies, estrogen plus micronized progesterone had the greatest effect Note that this study did not examine cardiovascular events (morbidity) or mortality

WHI – WOMEN’S HEALTH INITIATIVE (Primary Prevention) Prospective Forty Clinical Centers – 184,500 Women – Natl Institute Heart, Lung, Blood Women followed for 9 years

Results in about 2005-2007 Groups:

HRT conjugated estrogens 0.065 mg and medroxyprogesterone acetate 2.5 mg (daily) ERT – conjugated estrogen 0.065 mg/day (women without uterus)

Diet

Calcium and vitamin D Combinations of the above Placebo

Outcomes:

Breast and Colorectal cancer

Coronary Heart Disease

Preliminary Results

Outcomes first 2 years – Women taking HRT and ERT had more cardiovascular events (heart attack, stroke and blood clots). Trial was continued because women were past the 2 year period and the risk did not continue with longer therapy.

May be late benefit

HERS – The Heart and Estrogen Replacement Study (Secondary prevention trial- women with coronary

disease)

Randomized, blinded, placebo controlled – followed for 4-5 years Women with uterus - mean age 66.7 years – 2,763 women

Therapy - Conjugated estrogen 0.625 mg and medroxyprogesterone acetate (MPA) 2.5 mg daily

Or placebo

Measure – occurrence of nonfatal MI or coronary heart disease death Result:

-No overall difference between groups -Beneficial effect on serum lipids

-Increase in negative cardiovascular events in those taking HRT in first year – prothrombotic, proarrhythmic and proischemic more thromboembolism more gall bladder disease

-Fewer cardiac events in women who took HRT for 4-5 years

ERA – Estrogen Replacement and Atherosclerosis Trial (Secondary prevention) Groups:

Unopposed conjugated estrogens

Conjugated estrogens and MPA – as in HERS trial Placebo

Time course – studied for 3-4 years

No difference among groups for fatal and non-fatal MI Decrease in LDL and increase in HDL

WELLHART – Women’s Estrogen/Progestin Lipid Lowering Heart Atherosclerosis Trial (Secondary Prevention)

On-going- Treatment ERT, HRT placebo in combination with lipid lowering therapy (diet, Pravastatin)

EAGAR – Estrogen and Graft Atherosclerosis Research (Secondary Prevention) Treatment groups – HRT and placebo

Determine whether HRT will reduce the occurrence of graft occlusion and delay the development of atherosclerosis in women following coronary artery bypass surgery

WAVE – Women’s Atherosclerosis Vitamin/Estrogen Trial (Secondary Prevention) Treatment groups – HRT and antioxidants, HRT, Antioxidants, placebo

RISKS

Risk of Breast cancer - Research studies are inconsistant. Estrogen is not a carcinogen but it may accelerate the growth of a cancer that is already present. Slightly elevated risk in women taking HRT for more than 5 years (Relative risk 1.35) – Recent results suggest that HRT poses greater risk than ERT. Risk of endometrial cancer is clearly increased with unopposed estrogen therapy

Risk of thrombosis with HRT - less than in women taking combination oral contraceptive – results of trials still conflicting

Appears to be greater in new users HRT – alters hemostasis

Increases prostacyclin production Increases nitric oxide production

Decreases fibrinogen levels

Decreases plasminogen activator inhibitor levels in some women HRT – alters vascular reactivity

Stimulates production of nitric oxide Decreases levels of endothelin Gall Bladder Disease

Some increased risk

Alternative Therapies for management of Menopausal Symptoms Phytoestrogens – isoflavones (genistein, daidzem) Soy

Lignans (seed oils) Coumestins Specific

Licorice Root, Black Cohosh, Red Clover, Casteberry, St. John’s Wort, Dong Quai, Ginseng MANAGEMENT

Assessment:

Discuss Goal – Risks and Benefits Individualization

Proposed Benefits ** = Evidence of Efficacy

Cardiovascular Non Cardiovascular

Improved lipid profiles Prevention of Bone Loss**

Vasodilatory effects Treatment of vasomotor symptoms**

Antiplatelet activity Prevention of colon cancer

Decreased Fibrinogen levels Prevention of Alzheimer’s Disease Direct Myocardial Effects Prevention of Urinary Incontinence Antioxidant activity Alleviation of Sleep Disorders

Before administering - assess for absolute and relative contraindications

For ERT or HRT - R/O estrogen dependent cancers; Get baseline mammogram, breast exam, lipid profile etc

Monitor BP. pulse, weight changes, skin changes

Assess for signs of deep vein thrombosis, pulmonary embolism (leg pain, chest pain, shortness of breath, weakness or numbness of an arm or leg, etc) Look for signs of depression, changes in libido

Monitor liver function tests Monitor electrolytes

Assess for other signs of adverse reactions

Especially signs of thrombotic complications Intervention:

If giving oil-based injection, administer IM into large muscle - slowly

Patch - apply to abdomen or apply to arm , rotate sites, press on for 10 sec and be sure edges are tight, wash hands after application

Choice of protocol Education:

Discuss benefits of therapy, discuss risks (adverse drug reactions/side effects and provide information, discuss patient concerns.

Counsel patient not to smoke, if needed, counsel with regard to weight loss and modification of diet to decrease cholesterol and triglycerides

For replacement:

Counsel and discuss with the patient that if they are taking 1 week off regimen there will be withdrawal bleeding. This does not mean the return of fertility.

Encourage good oral hygiene - gingival hyperplasia may occur during estrogen replacement therapy

Diabetics may need adjustment of diabetic medication – controversy surrounds using HRT in diabetic women

Clients taking estrogen for osteoporosis should take Vit D and Ca2+ supplements