Hormone Therapy Use in Menopause

Advisor : dr Edihan, SpOG

Presenter : Winda JL 2010-061-017 Michael 2011-061-001 Rani Puspitasari 2011-061-059

Introduction
Hormone replacement therapy can improve the quality of life for women with hypo-estrogenic symptoms Many women are still prescribed estrogen therapy to treat postmenopausal symptoms despite recent data showing that risks.

Hormone replacement therapy effective preventing osteoporotic fractures among current users.

In contrast, harmful effects of hormone replacement therapy include breast cancer,venous thromboembolism, coronary heart disease and stroke.

Coronary Heart Disease

Estrogen and progestin increase the risk of CHD among generally healthy postmenopausal women, especially during the first year.
Women with an elevated LDL/HDL ratio > 2.5 had an increased risk of CHD

Manson JE et al. Womens Health Initiative (WHI) RCT 16.608 women, 50-79 yo

Coronary Heart Disease

Randomized controlled trials of hormon therapy in which 10.739 postmenopausal women who had undergone a hysterectomy were randomized to conjugated equine estrogens (CEE) and 16.608 postmenopausal women who had not had a hysterectomy were randomized to CEE. For Women with less than 10 years since menopause began, the Hazard Ratio (HR) for CHD was 0.76; 10 to 19 years, 1.1.; 20 or more years, 1.28

Rossouw JE et al.

Womens Health Initiative (WHI)

Meta-Analisys, 50-79 yo

RESULT

Thromboembolism
Oral estrogen increases the risk of venous thromboembolism, especially during the first year of treatment
Canonico M,
et al. systematic review and meta-analysis

The risk of venous thromboembolism in women using oral estrogen was higher in the first year of treatment (4.0, 2.9 to 5.7) compared with treatment for more than one year (2.1, 1.3 to 3.8) Past users of oral estrogen had a similar risk of venous thromboembolism to never users.

Thromboembolism
Transdermal estrogen may be safer with respect to thrombotic risk. Ratio of first time venous thromboembolism in current users of oral estrogen was 2.5 (interval 1.9 to 3.4) and in current users of transdermal estrogen was 1.2 (0.9 to 1.7)

Canonico M,
et al. systematic review and meta-analysis

Breast Cancer
The use of combination MHT have not increase the risk of breast cancer
Prentice RL, et al

WHI clinical trial and observational study

Study medication with conjugated equine estrogen (CEE) lowering the invasive breast cancer significantly The effect (gap time) occurring between the onset of menopause and the start of therapy

Breast Cancer
53,310 postmenopausal women (8.1 year Follow Up) 1,726 invasive identified varied according to the timing of treatment initiated 2 year onset , HR 1.54 3 year onset , HR 1.00

Observational study of risk of breast cancer varied by gap time (1992-2005)

Breast Cancer
The gap time hyphothesis support by studies using estrogen to treat breast cancer In postmenopausal woman breast tumor express estrogen receptor respond to treatment with high dose estrogen therapy (>MHT) In premenopausal women dont respond estrogen

In summary, rapid and dramatic change in estrogen exposure appear to alter breast cancer growth

Endometrial Cancer
Endometrial cancer is common diagnosed in 40.000 women annualy (age>50) Endometroid (type1) endometrial cancer is the most common variant and usually well differentiated and hormonally responsive Contrary to the papilary serous and clear cell endometrial cancers

Endometrial Cancer
Jaakkola S, et al
Endometrial Cancer in Postmenopa usal Women Using Estradiol Progestin Therapy

Use of a continuous rather than a sequential estradiolprogestin regimen decreases the risk of endometrial cancer, whereas the route of administration or type of progestin does not differ in terms of endometrial cancer risk.

Ovarian Cancer
WHI population based study Cohort (age 5079) Nearly 1 million women

MHT increased relative risk for all ovarian cancer and epithelial ovarian cancer The risk decline after cessation of therapy

The effect seen regardless of duration or formulation of hormone administration

Colon Cancer
Chlebowski RT, et al
Estrogen plus Progestin and Colorectal Cancer in Postmenopausal Women

Relatively short-term use of estrogen plus progestin was associated with a decreased risk of colorectal cancer. Colorectal cancers in women who took estrogen plus progestin were diagnosed at a more advanced stage than those in women who took placebo.

Ritenbaugh C, et al
Conjugated Equine Estrogens and Colorectal Cancer Incidence and Survival

conjugated equine estrogens in a randomized clinical trial did not reduce colorectal cancer incidence nor improve survival after diagnosis.

WHI RCT
10,739 women

Lung Cancer
Chlebowski RT, et all
WHI posthoc analysis of RCT 16,608 women (age 50 79)

Treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer. These findings should be incorporated into risk benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer.

Stroke
Grodstein F
et al. Nurses Health Study.

Prospective observational study.

121.700 women, yr 1976-2004

MHT increased risk of stroke Women initiating hormone therapy at a young age (near menopausal transition) & at > 10 yr from menopause Women within 4 yr of menopause onset taking lower than traditional dose of MHT did not have an elevation in stroke risk.

Cognitive Function
WHI Memory Study Trial RCT 1403 women

MHT Increased risk of dementia in women (>65 yr).

Speculated: TIMING HYPOTHESIS

WHI Study of Cognitive Aging RCT 2303 women, yr 1999-2008 Ryan J, et al: Study in French Prospective study 3130 women, > 65 y.o.

MHT beneficial on cognitive ability in women remote from menopause.

3000 postmenopausal women current hormone therapy users (longer durations) performs cognitive test better than never users.

Not supporting TIMING HYPOTHESIS

Cognitive Function
900 postmenopausal women prior hysterectomy, mean age of 64, free of dementia CEE use lower spational rotational ability 2,7 yr after stopping hormone therapy no enduring effect on cognitive function

WHI & WHIMS CEE trial

RCT 900 women, > 64 y.o

Menopausal Symptoms

Welton et al.
Randomized placebo controlled double trial

3721 women, 50-69 y.o, postmenopause.

Assesed health related quality of life after MHT in 3721 women. Combined MHT or placebo Combined MHT decreased severity of vasomotor symptoms, improved sexual functioning, diminished sleep problems.

Menopausal Symptoms
Stopping MHT therapy
Benefits of MHT dissipate. Decreased risk: thromboembolism, CVD, colorectal cancer. Increased risk: cancer.

MHT appropriate for symptom management. Not appropriate for primary & secondary prevention of chronic disease.

Alternate MHT Regimens

KEEPS Trial Randomized placebo controlled double blinded study 729 women, 4 yr evaluation Karim et al. RCT 180 women, postmenopause.

Ongoing trial Transdermal vs oral regimen effect on the progression of atherosclerosis

Appropriate dose of estradiol BMI Increased BMI Higher serum estradiol levels Lower estrogen doses is effective

Weaver et al.
RCT. 11 women, postmenopause.

Alternative therapies: phytoestrogen suppelments & isoflavones against osteoporosis Little benefits.

Alternate MHT Regimens

No evidence support any benefit combining estradiol + estrone/estriol. Oral vs transdermal route outcome? Progestin should be administered prevent endometrial cancer. Dosing estrogen starting with low dose

Future Development in MHT

Alternative therapy for menopausal symptoms that would not increase the risk of cancer. Combination of low dose CEE + selective estrogen receptor modulator tissueselective estrogen complex (TSEC)

Conclusions
Hormone therapy:
Appropriate relief of vasomotor symptoms Should not be used for chronic disease prevention Used in limited duration

Transition to a selective estrogen rx modulator / biphosphonate continued benefit of MHT after the cessation.

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