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Program Written Summary
Audio-Digest Obstetrics/Gynecology
Volume 60, Issue 22
November 21, 2013

Hormone Replacement Therapy and the Heart: The Timing Hypothesis – Chrisandra Shufelt, MD, MS
Polycystic Ovary Syndrome – Vidya Palta, MD

Digital Media $24.99
Audio CD $27.99

The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program.

Obstetrics/Gynecology Program Info  Accreditation InfoCultural & Linguistic Competency Resources

Hormone Replacement/Polycystic Ovary Syndrome

Educational Objectives

The goals of this program are to encourage appropriate use of hormone replacement therapy and to improve management of polycystic ovary syndrome (PCOS). After hearing and assimilating this program, the clinician will be better able to:

1. Summarize the objectives and findings of major studies assessing cardiovascular effects of hormone replacement therapy.

2. Describe the physiologic rationale supporting the timing hypothesis.

3. Use accepted criteria for diagnosis of PCOS.

4. Interpret clinical laboratory and ultrasonographic findings in a patient with suspected PCOS.

5. Manage symptoms and sequelae of PCOS.

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, Drs. Shufelt and Palta and the planning committee reported nothing to disclose. In her lecture, Dr. Palta presents information that is related to the off-label or investigational use of a therapy, product, or device.

Hormone Replacement Therapy and the Heart:
The Timing Hypothesis

Chrisandra Shufelt, MD, MS, Assistant Professor, Cedars-Sinai Medical Center, and Assistant Director, Women’s Heart Center and Preventive Rehabilitative Cardiac Center, Cedars-Sinai Heart Institute, Los Angeles, CA

Hot flashes: affect 75% of women; symptoms typically last 6 mo to 5 yr, but 20% of women have symptoms for decades; pathophysiology unknown; 0.625 mg conjugated equine estrogen (CEE) 90% to 95% effective

Women’s Health Initiative (WHI): in early studies, hormone replacement therapy (HRT) appeared cardioprotective; WHI first randomized controlled trial (RCT) to study HRT as primary prevention for cardiovascular disease (CVD); women with uteri received 0.625 mg CEE plus medroxyprogesterone; women without uteri treated with CEE alone; doses used in study produce serum estradiol (E2) 50% higher than physiologic level; CEE plus progesterone (P) trial stopped 3 yr early due to association with increased coronary heart disease (CHD), stroke, pulmonary embolus, and breast cancer; treatment protective against colon cancer and hip fractures; CEE-alone trial stopped 1 yr early due to 40% increase in strokes

Analysis of data: CEE-alone trial — showed that starting HRT unwise in women 70 yr of age and questionable in women 60 yr of age; 50- to 59-yr-olds had lower absolute risk than those on placebo; CEE plus P trial — showed similar trends; suggests using time since menopause and CV risk factors to determine whether HRT appropriate; relative risk (RR) <1 if time from menopause <10 yr, but RR 1.71 in women >20 yr past menopause; timing hypothesis — HRT possibly beneficial if initiated early and CVD not already present; if carotid intima media thickness (IMT) present, necrotic core can erupt and rupture; presence of plaque buries endothelial receptors in vessel wall, which results in decreased expression of E receptors; vessel cannot bind E, produce nitric oxide, and vasodilate; increased platelet activation and instability and rupture of plaque can occur due to upregulation of matrix metalloproteinase-9 (MMP-9)

Coronary Artery Calcium (CAC) Study: evaluated 1000 50- to 59-yr-olds in CEE-alone study; mean duration of treatment 7.5 yr; women had stopped HRT 1 yr previously; mean age 55 yr; patients treated with CEE had lower posttreatment CAC scores, especially those adherent to treatment

Women’s Ischemia Syndrome Evaluation: in 654 postmenopausal women undergoing coronary angiography, risk for obstructive coronary artery disease (CAD) 60% lower only in women who started HRT at <55 yr of age

Current practice: lower doses and different regimens available, for which safety not known; transdermal E2 bypasses metabolism by liver and results in higher ratio of E2 to estrone (E1); with oral use, higher concentration in liver sinusoids associated with increases in MMP-9, high-sensitivity C-reactive protein (CRP), and prothrombin

Observational studies: French registry data show 80,000 users of oral E had 2.5-fold higher risk for VTE than users of transdermal E, but finding not statistically significant; Danish registry shows lower risk for myocardial infarction (MI) with transdermal than oral E; in United Kingdom database, no increased risk for stroke at transdermal doses <50 μg; 12-yr data from 100,000 women in WHI showed 70% lower risk for CHD and VTE with CEE <0.625 mg; in Nurses’ Health Study, women on 0.3 mg CEE had no increased risk for stroke; Danish registry showed no association of E with MI

Danish Osteoporosis Prevention Trial: study of 1000 healthy, recently menopausal women who received HRT vs no treatment for 11 yr; women on HRT had 50% decrease in composite end point of death, admission to hospital for heart failure, or MI; women receiving early HRT had reduced mortality, heart failure, and MI, without increases in cancer, VTE, or stroke; trial not designed to assess CV end points; trial open-label and analysis post hoc; although study supports timing hypothesis, more data needed

Kronos Early Estrogen Prevention Study: multicenter double-blinded study designed to evaluate timing hypothesis; 727 women within 3 yr of final menses received oral or transdermal E or placebo; study assessed annual carotid IMT and CAC at baseline and study exit; systolic blood pressure (SBP) — decreased at 1 yr with both oral and transdermal E, but not at 3 to 4 yr (while WHI showed increased SBP in women receiving HRT); lipids — low-density lipoprotein (LDL) decreased at 3 yr, but triglycerides (TG) increased in those receiving oral E, as expected with first-pass effect (suggests transdermal better for women with dyslipidemia); high-density lipoprotein (HDL) increased in women on oral E and decreased after 1 yr in those on transdermal E; fasting blood glucose (FBG) — significantly lower in women on transdermal E; FBG rose by 36 mo, then leveled out; markers — no difference seen among groups in interleukin (IL)-6; CRP increased by oral E; no effect seen on IMT; in women with baseline CAC, progression of disease greater in placebo arm, but finding not statistically significant; conclusions — oral and transdermal E had neutral effects on lipids and BP, and no adverse effect on protection from atherosclerosis; study used lower doses of E and shorter follow-up than WHI; HRT acceptable option for women 59 yr of age or within 10 yr of menopause for symptomatic control; other findings — both E-only and E plus P increase risk for VTE and stroke, but stroke rare in 50- to 59-yr olds; >5 yr of continuous use of HRT associated with increased risk for breast cancer

Conclusions: benefits of HRT outweigh risks in women <60 yr of age or <10 yr after menopause; E alone may decrease risks for CHD and mortality; risk for VTE and stroke rare and lower with transdermal E

Polycystic Ovary Syndrome

Vidya Palta, MD, Director, New York Fertility, Forest Hills, NY

Diagnosis: definition of polycystic ovary syndrome (PCOS) per 2003 Rotterdam criteria — requires presence of 2 of 3 criteria (oligo-amenorrhea or anovulation, clinical or biochemical hyperandrogenism, and polycystic ovaries on ultrasonography); hyperprolactinemia, nonclassical congenital adrenal hyperplasia (CAH), Cushing syndrome, and androgen-secreting neoplasms must be excluded

Definitions: definition of PCOS proposed by National Institutes of Health (NIH) requires oligomenorrhea (8 menses per year or cycles lasting >35 days) and clinical or biochemical hyperandrogenism; Rotterdam criteria include women who have oligo-anovulation and PCOS on ultrasonography, even if hyperandrogenism absent (most East Asian women with PCOS fit this phenotype); Rotterdam definition — includes women with oligo-anovulation plus polycystic ovaries, or hyperandrogenism plus polycystic ovaries, or all 3, or oligomenorrhea plus hyperandrogenism; Androgen Excess and PCOS Society (AEPCOS) — requires hyperandrogenism for definition; biochemical hyperandrogenism may not correlate with clinical findings; best to overscreen using Rotterdam criteria, then obtain additional evidence by testing levels of testosterone (T)

Polycystic ovaries: defined as 1 ovary with 12 follicles having mean diameter 2 to 9 mm, irrespective of location, and ovarian volume >10 mL on transvaginal imaging; transitory appearance of multicystic ovaries complicates diagnosis in adolescents; with classic appearance, follicles seen at periphery; when ovary multicystic but follicles not peripheral, ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH) should be tested; definition does not apply to women taking oral contraceptives (OCs); if dominant follicle >10 mm or corpus luteum present, repeat scan in later cycle

Etiology: PCOS multigenic; genetic predisposition, aging, pregnancy, lifestyle, drugs, and obesity contribute to hyperinsulinemia, which alters ovarian metabolism and causes hyperandrogenic state with dysfunctional theca and granulosa cells; acne, hirsutism, and infertility may result; hyperinsulinemia leads to increases in weight, abnormal lipids, android obesity, and insulin resistance; prevalence — 6% to 10% by NIH criteria, but 1.5-fold higher by Rotterdam criteria; 13% of Mexican-Americans, 8% of blacks, and 4.8% of whites have PCOS

Differential diagnosis: PCOS diagnosis of exclusion; rule out hypothyroidism, pregnancy, and 21-hydroxylase deficient nonclassical CAH; normal fasting 17-hydroxyprogesterone (17-OHP) <200 ng/dL; if 17-OHP inconclusive (200-600 ng/dL), perform adrenocorticotropic hormone (ACTH) stimulation test; values >1000 ng/dL considered conclusive; rule out elevated prolactin (PRL) and use of antipsychotics; T >2 ng/mL suggests androgen-secreting neoplasm; dehydroepiandrosterone sulfate (DHEAS) >700 μg/dL suggests adrenal tumor; Cushing syndrome suggested by moon facies, buffalo hump, abdominal striae, centripetal fat, and hypertension (HTN); assess use of androgens and acromegaly

Adolescence: acne and hirsutism may be intermittent; 1 to 2 yr of oligo-ovulation suggests PCOS; in adolescents, diagnose PCOS when all 3 criteria met; if transvaginal sonography not feasible, obtain other evidence, such as ratio of LH to FSH, insulin, T, androstenedione, or DHEAS; expectant management controversial in adolescents; intervention may prevent metabolic syndrome (MetS); if diagnosis cannot be confirmed, continue close observation

Evaluation: morning PRL level >250 ng/mL in fasting patient suggests tumor, but lower levels possible with microadenomas; assess 2 PRL levels and obtain magnetic resonance imaging if elevated; consider T and DHEAS, especially if patient hirsute; obtain 17-OHP because 1 in 100 patients has nonclassical CAH; do ACTH stimulation test for values 200 to 800 ng/dL; 1 in 27 Ashkenazi Jews, 1 in 40 Hispanics, 1 in 50 Slavs and 1 in 300 Italians have CAH; PCOS associated with elevated T, androstenedione, and DHEAS; neither radioimmunoassay nor liquid chromatography/mass spectrometry completely reliable; preferred test free androgen index (FAI; equivalent to total T divided by sex hormone-binding globulin [SHBG], and multiplied by 100); however, when T levels significantly elevated, diagnosis likely accurate; hyperandrogenism and insulin resistance alter gonadotropins; LH rises and loses its pulsatility; chronic anovulation occurs, with impaired folliculogenesis and unopposed E; endometrial proliferation and hyperplasia can result, but some patients have thin endometrium and inactive ovaries; ensure patient has 4 bleeding episodes per year; hyperandrogenemia causes hirsutism; insulin resistance associated with type 2 diabetes (T2DM), dyslipidemia, chronic subclinical inflammation, and MetS

Phenotypes: obesity more common in blacks and Hispanics than whites and Asians; after adjusting for body mass index (BMI), Hispanic women more likely to have T2DM and black women more likely to have HTN; obese and overweight women with PCOS have decreased SHBG, increased total T and FAI, hirsutism, increased FBG and fasting insulin, and abnormal lipid profile; central obesity increases insulin resistance, even in lean people; odds ratio for endometrial carcinoma 2.7; data on association of PCOS with ovarian and breast cancers inconclusive; acne and alopecia associated with PCOS, especially in adults; risk for sleep apnea increased when obesity and PCOS coexist; anxiety and depression possible; menstrual dysfunction typically has peripubertal onset

Hirsutism: excess terminal thick pigmented body hair in male distribution; commonly found on upper lip, chin, around nipples, and along lower linea alba; indicated by Ferriman-Gallwey score (FG) 6 to 8, but evaluate any woman reporting hirsutism; hirsute women may have normal T but increased peripheral conversion; 50% to 90% of women with PCOS have elevated serum androgens; other causes of hirsutism — nonclassical CAH (<5%); androgen-secreting tumor (0.2%); androgenic agents and anabolic steroids; drug-related (<1%; eg, hydrocortisone, minoxidil [Rogaine]); skin irritants; Cushing syndrome; idiopathic (5%); treatment — OCs and antiandrogens not approved by Food and Drug Administration (FDA); eflornithine (Vaniqa) FDA-approved; only electrolysis or laser removes hair permanently; other treatments include cyproterone, antifungals, glucocorticoids, and metformin; while treating, observe patients closely and give OCs due to teratogenicity; flutamide associated with hepatitis, dry skin, and teratogenicity; finasteride associated with minimal risks of hepatic and renal toxicity (teratogenic in male fetuses); side effects of eflornithine rare and localized

Diet: 50% of patients with PCOS obese; obesity contributes to elevated TG and LDL, decreased HDL, and IGT; manage with tight control of BP, weight loss, diet, and (possibly) lipid-lowering agents

Metabolic syndrome: requires presence of 3 features (ie, abdominal obesity, serum TG 150 mg/dL or treatment for TG, HDL <40 mg/dL in men or <50 mg/dL in women, or treatment for low HDL; BP 130/85 mm Hg or treatment for HTN, FBG 100 mg/dL or treatment for same); in women with PCOS, abnormal glucose tolerance likely to worsen; screen women with PCOS with FBG and 2-hr glucose after 75-g load; although earlier studies reported elevated TG and low HDL, apolipoprotein ratios and particle size of LDL most important lipid parameters; lipid abnormalities lead to endothelial dysfunction, carotid stenosis, and IMT; however, no data show increased risk for CV events; check BMI and fasting lipoproteins; Coronary Artery Risk Development in Young Adults found increasing BMI in 5115 adults associated with progression of components of MetS

Treatment: includes diet, exercise, and pharmacologic therapy; if sibutramine and metformin ineffective, bariatric surgery decreases levels of androgens and lipoproteins

Studies: Diabetes Prevention Program — found that metformin and intensive lifestyle changes reduced risk of developing MetS; Cochrane review — found lifestyle changes affected waist circumference (WC) or waist-to-hip ratio (but not BMI), and improved FG, fasting insulin, and T (but not IGT)

Evaluation and treatment: measure WC, BP, fasting lipids, oral glucose tolerance, and insulin; treatment must include lifestyle modification; add other therapies based on symptoms; use OCs to protect endometrium (may increase TG and HDL); alternatively, use intermittent P; if no menses for 6 wk, induce withdrawal bleed before initiating OCs, or check endometrial thickness; first rule out pregnancy

Infertility: evaluate other possible causes; review found lifestyle intervention and weight loss did not improve ovulation, menstrual changes, or infertility, but some studies refute this

Treatment: clomiphene (Clomid, Serophene) first-line agent; gonadotropins associated with multiple gestation and difficult to administer, but safer than diathermy, which can produce adhesions; use diathermy if patient cannot afford gonadotropins and does not respond to clomiphene; next step in vitro fertilization; unknown whether letrozole superior to clomiphene; unclear whether letrozole teratogenic, but effective for PCOS; use metformin only for IGT; RCT in 626 patients with PCOS found clomiphene superior to metformin for infertility; obese patients had higher birth rate with metformin, but finding not statistically significant


Dr. Shufelt was recorded at the 7th Annual Women and Ischemic Heart Disease Symposium, presented by Cedars-Sinai Heart Institute, and held on April 19, 2013, in Los Angeles, CA. Dr. Palta spoke at the 15th Annual Comprehensive Obstetrics & Gynecology Review Course, sponsored by State University of New York Downstate Medical Center, and held May 17-19, 2013 in Brooklyn, NY. To learn about the next Women and Ischemic Heart Disease Symposium, please go to, click on the Education tab at the top of the page, and then on the Continuing Medical Education tab on the left-hand side. Information about the annual Comprehensive Obstetrics & Gynecology Review Course sponsored by the State University of New York Downstate Medical Center is available at The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Suggested Reading

Anderson GL et al: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291(14):1701-12; Carnethon MR et al: Coronary Artery Risk Development in Young Adults study. Risk factors for the metabolic syndrome: the Coronary Artery Risk Development in Young Adults (CARDIA) study, 1985-2001. Diabetes Care 2004;27(11):2707-15; Ehrmann DA et al: Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999;22(1):141-6; Goldberg R et al: Lifestyle and metformin treatment favorably influence lipoprotein subfraction distribution in the Diabetes Prevention Program. J Clin Endocrinol Metab 2013 Aug 26 [Epub ahead of print]; Legro RS et al: Total testosterone assays in women with polycystic ovary syndrome: precision and correlation with hirsutism. J Clin Endocrinol Metab 2010;95(12):5305-13; Manson JE et al: Estrogen therapy and coronary-artery calcification. N Engl J Med 2007;356(25):2591-602; Moran LJ et al: Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2011;(2):CD007506.pub2; update in: Cochrane Database Syst Rev 2011;(7):CD007506; Rossouw JE et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288(3):321-33; Rossouw JE et al: Lessons learned from the Women’s Health Initiative trials of menopausal hormone therapy. Obstet Gynecol 2013;121(1):172-6; Shufelt CL et al: Timing of hormone therapy, type of menopause, and coronary disease in women: data from the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation. Menopause 2011;18(9):943-50; Stuenkel CA et al: A decade after the Women’s Health Initiative — the experts do agree. Menopause 2012;19(8):846-7; Tang JW et al: Health-care access and weight change among young adults: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Public Health Nutr 2013;16(10):1796-800; Wei J et al: Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women’s Ischemia Syndrome Evaluation) study. JACC Cardiovasc Interv 2012;5(6):646-53; Wolff EF et al: Self-reported menopausal symptoms, coronary artery calcification, and carotid intima-media thickness in recently menopausal women screened for the Kronos early estrogen prevention study (KEEPS). Fertil Steril 2013;99(5):1385-91.

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