Hormone Therapy Update

From Obstetrics and Gynecology Update: What Does the Evidence Tell Us?
sponsored by the University of California, San Francisco, School of Medicine

Marcelle I. Cedars, MD, Professor, Department of Obstetrics, Gynecology and Reproductive Sciences, and Director,
Division of Reproductive Endocrinology, University of California, San Francisco, School of Medicine

Educational Objectives

The goal of this program is to improve understanding and use of hormone therapy (HT). After hearing and assimilat­ing this program, the clinician will be better able to:

1.   Summarize key findings from primary and secondary prevention trials investigating the effects of HT on car­diovascular disease (CVD).

2.   Describe the mechanisms by which estrogen affects coronary atherosclerosis.

3.   Interpret findings of outcomes in HT-treated women with respect to the timing of treatment initiation.

4.   Discuss the effects of HT on the risk of developing breast cancer.

5.   Distinguish which patients are appropriate candidates for HT.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and plan­ning committee reported nothing to disclose.

Acknowledgments

Dr. Cedars was recorded at Obstetrics and Gynecology Update: What Does The Evidence Tell Us? sponsored by the University of California San Francisco, School of Medicine, held on October 22-24, 2008, in San Francisco, California. The Audio-Digest Foundation thanks Dr. Cedars and UCSF School of Medicine for their cooperaton in the production of this program.

Cardiovascular disease (CVD) and hormone therapy (HT): observational studies suggest estrogen protective in women with CVD; angiographic studies suggest women with most severe CVD derived most benefit; observa­tional studies only source of data before Heart and Estrogen/Progestin Replacement Study (HERS) and Women’s Health Initiative (WHI); HERS secondary prevention trial; concluded HT did not protect women with existing disease and not recommended for further reduction of cardiac risk in these women; additional studies support same conclusion

Estrogen Replacement and Atherosclerosis (ERA) Study: women with documented coronary artery stenosis ran­domized to placebo, estrogen alone, or estrogen plus progestin; concluded neither estrogen alone nor estrogen plus medroxyprogesterone affected progression of coronary atherosclerosis in women with established disease (Herrington DM et al)

WHI: primary prevention trial; participants believed healthy with no underlying CV risks; randomized to estrogen plus medroxyprogesterone or to placebo; absolute excess risk per 10,000 person-yr attributable to estrogen plus progesterone was low (8 additional breast cancers); benefits also low (6 fewer colon cancers per 10,000 person-yr); data showed increased risk for CVD, stroke, and pulmonary embolism (PE); risk for stroke and PE continued to rise over duration of treatment; trial discontinued because risks outweighed benefits (thromboembolic disease greatest risk); no adverse events in >90% of participants; avoid extremes in prescribing (eg, “estrogen for every­one or no estrogen for anyone”); HT should remain option for symptomatic women

WHI Estrogen-Alone Trial: possible reduction in breast cancer risk; however, investigator concluded further re­search required; significant differences only in frequency of strokes (increased) and hip fractures (decreased); lower risk for CVD in younger women

Reconciling observational studies and clinical trials: methodologic issues (eg, intrinsic biases of observational stud­ies, in which women who took estrogen likely younger, healthier, less overweight, and more compliant), attenua­tion of risk (due to changes in regimen over course of study), and biologic explanations

WHI vs observational studies: observational data and level 1 data almost concordant except for CVD; patients in WHI study  —  mean age 63 yr of age (>10 yr postmenopausal); »75% HT-naive; average body mass index (BMI) 28.5; increased risk due to obesity alone greater than risk due to estrogen; speaker recommends discussing with patients issue of risk associated with obesity

Impact of HT on vessel wall

Inflammatory biomarkers: WHI showed median baseline levels of C-reactive protein (CRP) and interleukin-6 (IL-6) significantly higher in women with CV event; HT associated with elevation of CRP; as baseline CRP in­creases, risk for CV event increases (Ridker); comparison of CRP levels with oral vs transdermal estrogen showed elevated CRP at 6 and 12 mo with oral estrogen only; increased understanding of biology of HT begin­ning to evolve

Effect of statin treatment on matrix metalloproteinase-9 (MMP-9) in patients with CVD: MMP-9 in shoulder of ad­vanced atherosclerotic clot; proinflammatory and unstable; statins significantly decrease MMP-9; HERS trial (women with existing CVD) showed no increased risk for CV events in statin users whether in estrogen or nones­trogen group

Estrogen’s effect on prevention of atherosclerosis: in early plaque, estrogen decreases low-density lipoprotein (LDL) oxidation, resulting in decreases in lesion progression, macrophage accumulation, and smooth muscle proliferation, and increased vasodilatation; effects on established plaque  —  increased inflammation; increased plaque instability; elevated MMP-9; increased neovascularization, leading to increased hemorrhage; conclusion  —  coronary vessels respond differently to same dose of estrogen, depending on degree of plaque pro­gression; data support benefit of estrogen in younger women; looking at coronary calcium in youngest group of women in WHI, data show lower scores at end of treatment in youngest group, suggesting estrogen prevented plaque progression (Manson et al); mechanism for prevention of progression  —  27-hydroxycholesterol (27HC; endogenous selective estrogen receptor modulator [SERM]) competes with estrogen at estrogen receptor; levels of 27HC decrease in presence of high estrogen, and increase in presence of low estrogen; plaque formation and proinflammatory process increased when estrogen low; however, when estrogen added via HT as “late interven­tion” (ie, ³10 yr postmenopause), proinflammatory process increases due to effects on advanced plaque

Studies looking at late vs early estrogen therapy: Kronos Early Estrogen Prevention Study (KEEPS)  —hypothesis that estrogen therapy initiated in perimenopause stabilizes plaques and delays progression; Early versus Late In­tervention Trial with Estradiol (ELITE) trial  —compared effect of estrogen therapy in perimenopausal women vs women >6 yr postmenopause; both studies flawed due to lack of outcome data (ie, low numbers of CV events in young women); timing of HT hypothesized as critical for hormone’s effect on CVD

Estrogen and the brain: laboratory studies suggest estrogen has protective effect on brain; indirect effects on vascu­lature and immune system; may be beneficial in young brain, but proinflammatory in older brain; unable to doc­ument decrease in concentration and short-term memory with natural menopause, but shown with surgical menopause (likely because of abrupt drop in estrogen); women with surgically induced menopause often ex­tremely symptomatic; estrogen therapy should remain option for these women

Alzheimer disease (AD): loss of episodic memory (eg, failure to recall appointments and events) characteristic of early disease; estrogen shown to reduce formation of b-amyloid and diminish hyperphosphorylation of tau pro­tein, suggesting protective role against AD; observational studies support protective effect; meta-analysis sug­gested up to one-third reduction; findings from WHI Mental Status (WHIMS) trial  —  increased risk for dementia with HT, but only in oldest participants; impact noted within few years, suggesting effects primarily on vascula­ture (mirrors rapid initial increase in CV events with late HT); initiation in older women with disease not benefi­cial; recent studies show no benefit for women with existing AD; WHI showed history of use of estrogen reduced prevalence of AD, again suggesting importance of timing of initiation of therapy; studies in animals show timing important, particularly for certain skills, probably related to oxidative stress and inflammation; mouse model showed estradiol exerted profound neuroprotective action when administered immediately upon ovariectomy (at­tenuating proinflammatory cytokines), but benefit lost if given later (consistent with WHIMS trial showing nega­tive effect in older women)

Depression: data show depression significantly improved in perimenopausal women randomized to estradiol, com­pared to placebo group; suggests HT in menopausal transition may have beneficial effects on neurologic symp­toms (Soares et al)

Breast cancer: duration of use  —  speaker agrees with recommendation to give lowest dose of estrogen for shortest duration, but believes 5-yr duration arbitrary; no statistically significant increase in risk for all cancers until >20 yr of use; no significant increase in estrogen-receptor (ER)-positive and progesterone-receptor (PR)-positive breast cancer until 15 yr; must individualize treatment, particularly for women with premature ovarian failure; reanalysis of data show increased risk »2.3% per year, 2.8% with delay in menopause; decreased risk in woman undergoing bilateral oophorectomy at 30 yr of age without HT; if given estrogen, risk for breast cancer unchanged or possibly slightly lower than if still menstruating; earlier studies beginning to concur, although more investigation needed; now concluding that no increased risk seen with unopposed estrogen; French study demonstrated increased risk only with synthetic progestin, with increase in risk corresponding to longer duration of use; theory about ER-posi­tive tumors (postulated by Horowitz)  —  cancer stem cells (CK5) up-regulated by progestin only; impact seen mostly in young tumors; progestin causes stem cell reactivation and proliferation; believes estrogen does not cause breast cancer; rather, small nascent preexisting tumor stimulated to grow by HT; laboratory studies suggest proges­tin, not estrogen, responsible for tumor prolilferation; Heiss et al  —  risk for myocardial infarction, deep venous thrombosis, PE, and breast cancer return to normal by 3 yr after discontinuation of estrogen, but beneficial effects also lost

Route of estrogen therapy: thromboembolic event  —  risk primarily with oral, not transdermal, route; blood pressure (BP)  —  small impact with oral route; metabolic syndrome  —  menopause increases metabolic risk; redistribution of fat to midline in menopause; estrogen reduces risk for diabetes and insulin resistance; synthetic progestin can in­crease risk; therefore, natural progesterone or nonandrogenic progestins recommended; CVD  —inflammatory risk associated with oral route only; neuroprotection  —  no difference between oral and transdermal routes; breast cancer  —  no difference between oral and transdermal routes

What we know: public largely unaware that CVD leading cause of mortality in women (weight reduction signifi­cantly important for decreasing risk); women should not take estrogen to prevent CVD and women with known CVD should not start HT to treat CVD; statins remain drug of choice for women with hypercholesterolemia; first-line therapies for women with CVD exactly same as for men; estrogen remains gold standard for treating vasomo­tor symptoms caused by estrogen deficiency; estrogen prevents or improves genital atrophy and slows bone loss; may reduce development of AD and risk for colon cancer; may improve overall quality of life (probably because of lessening of hot flushes and improved sleep and sexual satisfaction)

Alternatives and future directions: progesterone-intrauterine device (IUD) for uterine protection; lower doses of transdermal estrogen; raloxifene (SERM), not associated with change in CRP and lowering of homocystine levels, but increases risk for DVT; tibolone used outside United States, but found to increase risk for stroke; bone-specific SERMs

Indications for menopausal HT: symptomatic women; prevention of osteoporosis in young women at risk for bone loss, and when other drugs contraindicated; speaker cautions against prescribing bisphosphonate for women of childbearing age because of potential for detrimental effects on fetal bone development and on healing after frac­ture; estrogen should remain option for women who report feeling healthier while taking it

Questions and answers: HT for women at genetic risk for breast cancer  —  data show no increased risk for breast cancer over intrinsic family risk; net benefit vs net risk from adding progesterone  —  net benefit of decrease in endo­metrial cancer; increased risk for CVD and breast cancer; options for protection of uterus include giving estrogen alone and performing yearly endometrial biopsies, or supplementing with progesterone-containing intrauterine de­vice (IUD); significant data support progesterone’s role as culprit in increased breast cancer risk with HT; study looking at levonorgestrel-containing device in women on HT showed less hyperplasia than with combined continu­ous HT; systemic absorption during first 6 mo after insertion (unknown whether enough to increase breast cancer risk); estradiol gel or transdermal spray  —  options for patient who does not like or tolerate transdermal patch; dos­ages recommended by manufacturer based on dose needed to protect bone; younger women may need higher dos­ages; at doses >50 pg/mL, most patients get relief from hot flushes; »80 to 110 pg/mL recommended for woman in early to mid 40s; HT for prevention  —  KEEPS and ELITE trials may provide evidence showing no plaque progres­sion in young women; until that time, HT should not be regarded as preventive therapy for CVD; however, clinical data support not withholding estrogen therapy for symptomatic women

Suggested Reading

Chen WY et al: Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med 166:1027, 2006; Herrington DM et al: Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 343:522, 2000; Hulley SB et al: The WHI estrogen-alone trial—do things look any better? JAMA 291:1769, 2004; Manson JE et al: Postmenopausal hormone therapy: new questions and the case for new clinical trials. Meno­pause 13:139, 2006; Manson JE et al: Estrogen therapy and coronary-artery calcification. N Engl J Med 356, 2007; Morrison JH et al: Estrogen, menopause, and the aging brain: how basic neuroscience can inform hormone therapy in women. J Neurosci 26:10332, 2006; Ridker PM et al: Comparison of C-reactive protein and low-density lipopro­tein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 347:1557, 2002; Scarabin PY et al: Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 362:428, 2003; Soares CN et al: Efficacy of estradiol for the treatment of depressive disorders in peri­menopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 58:529, 2001; Umetani M et al: 27-Hydroxycholsterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat Med 13:1185, 2007.