1. JANET P. PREGLER, MD; CAROLYN J. CRANDALL, MD, MS. ANNALS OF INTERNAL MEDICINE. 2011; 155:52-57. JULIANNA L. MURPHY PHARM.D. CANDIDATE PRECEPTOR: ALI RAHIMI, MD AUGUST 26, 2011 Update in Women’s Health: Evidence Published in 2010

2. Issues in Women’s Health Osteoporosis Menopause Hereditary breast and ovarian cancer Cervical cancer and HPV testing Emergency contraception

3. Osteoporosis: Bisphosphonate Therapy Generally considered first-line therapy  Reduces risk of vertebral, nonvertebral, and hip fractures  Good safety profile Increased rates of subtrochanteric and diaphyseal femur fractures? 3 large randomized trials  FIT  FLEX  HORIZON-PFT Not associated with higher risk for femur fractures  HR for alendronate vs. placebo (FIT) 1.03 (CI: 0.06 to 16.46)  Continued alendronate vs. placebo (FLEX) 1.33 (CI: 0.12 to 14.67)  Zoledronic acid vs. placebo (HORIZON-PFT) 1.50 (CI: 0.25 to 9.00)

4. Limitations and Implications Limitations  Wide confidence intervals due to rare occurrence of femur fractures  Secondary analysis only reviewed studies on alendronate and zoledronic acid  Influence of duration of treatment not discernible Implications  Causal relationship not established  Risk for atypical fracture does not outweigh benefits of bisphosphonate therapy  Femur fracture should be considered in women presenting with signs and symptoms, regardless of bisphosphonate therapy status

5. Calcium and Vitamin D Calcium and Vitamin D commonly used as dietary supplements Potential increased cardiovascular risk Possible beneficial effect of vitamin D on diabetes and hypertension risk

6. Calcium, Vitamin D, and Cardiovascular Risk Secondary analysis of 8 randomized trials to assess effect on cardiovascular risk  No effect with calcium, vitamin D, or combination supplementation  Possible reduction in CVD mortality with vitamin D Limitations  Few eligible studies available  Not designed to assess effect on cardiovascular risk  No analysis based on race, gender, or ethnicity Recommendations about supplementation based on cardiovascular risk are not supported by good evidence

7. Effects of Vitamin D on Diabetes, Hypertension Systematic review examining 13 observational studies and 18 randomized trials  3 of 6 analyses based on 4 different cohorts showed lower risk for diabetes in higher vitamin D groups  8 randomized trials showed no effect of supplementation on diabetes  Meta-analysis of 3 cohorts found lower 25-hydroxyvitamin D concentrations were associated with hypertension Not recommended to supplement vitamin D for prevention of diabetes or hypertension

8. Menopause: Hormonal Therapy Women’s Health Initiative (WHI) study on conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) 16,608 women randomly assigned to CEE (0.625 mg/day) plus MPA (2.5 mg/day) therapy or placebo  12,788 of these women consented to follow-up Risk for invasive cancer was 25% higher in treatment group vs. placebo (HR, 1.78: CI, 1.07 to 1.46) More deaths attributed to breast cancer in treatment group (HR, 1.57: CI, 1.01 to 2.48) Women should consider increased cancer risk when weighing risks and benefits of HRT

9. Menopause: Hormonal Therapy CEE plus MPA increases risk for CHD in postmenopausal women  Limited to women who start therapy late in menopause? Adherence-adjusted analysis of the WHI data of 16,608 postmenopausal women Women within 10 years of menopause, HR for CHD events was 1.29: CI, 0.52 to 3.18 for first 2 years after randomization and 0.64: CI, 0.21 to 1.99 for the first 8 years after randomization Results not statistically significant Women who begin CEE plus MPA therapy at menopause should NOT expect a reduction in CHD risk

10. Menopause: Weight Loss and Hot Flushes Multiple cohort studies have shown more that women with higher BMI report more hot flushes Randomized, controlled trial comparing an intensive behavioral weight loss intervention to a structured educational program to promote weight loss 338 overweight or obese women enrolled At start of study, 154 women reported bothersome hot flushes

11. Menopause: Weight Loss and Hot Flushes Reductions in weight, BMI, and abdominal circumference associated with reduced hot flushes  Weight (OR: 1.32, CI: 1.08 to 1.61) per 5-kg decrease  BMI (OR: 1.17, CI: 1.05 to 1.30) per 1-kg/m 2 decrease  Abdominal circumference (OR: 1.32, CI: 1.07 to 1.64) per 5-cm decrease More women lost to follow-up in control group (educational program) than in the intervention group Overweight/obese women may reduce hot flushes by losing weight

12. Hereditary Breast and Ovarian Cancer BRCA mutations  BRCA1 and BRCA2: tumor suppression genes  Associated with breast-ovarian cancer syndrome  Account for 5 to 10 % of all breast cancer cases in women  Harmless to high-risk variations Women with harmful mutation have ~5 times the normal risk of breast cancer, ~10 to 30 times the risk for ovarian cancer

13. BRCA Mutations and Risk-Reducing Surgery Multicenter, prospective cohort 2482 carriers of BRCA1 or BRCA2 mutations Prophylactic mastectomy  247 recipients, 0 breast cancer diagnoses  1372 women without prophylactic mastectomy, 98 breast cancer diagnoses Prophylactic salpingo-oophorectomy  Recipients had lower all-cause mortality, 10% vs. 3% (HR, 0.44: CI, 0.26 to 0.61)  Recipients had lower ovarian cancer-specific mortality, 3% vs. 0.4% (HR, 0.21: CI, 0.06 to 0.80) Counseling regarding risks and benefits of surgery should be given to all women with BRCA mutations

14. Cervical Cancer and HPV Testing Testing for high-risk HPV DNA in women who have atypical cells is standard practice U.S. Preventative Services Task Force found insufficient evidence to recommend HPV testing to screen for cervical cancer in 2003 Compared cervical cytology screening with those of high-risk HPV screening with or without cytology screening  Italian women  Aged 25 to 60 years

15. Cervical Cancer and HPV Testing 33,851 women received cervical cytology screening alone 32,998 women received HPV screening followed by a second round of cytology screening alone 9 cases of cervical cancer in the group that had initially had cytology screening alone 0 cases of cervical cancer were found in the second round of screening in the HPV screening group Among women aged 35 to 60 years  Relative detection rate at the first round was 2.08 (CI: 1.47 to 2.95) for HPV testing vs. cytology screening  Relative detection rate at the second round was 0.48 (CI: 0.21 to 1.11)

16. Emergency Contraception Levonorgestrel 1.5 mg is the most widely used emergency contraceptive in the United States  Not completely efficacious  Must be taken soon after intercourse Ulipristal, a selective progesterone-receptor modulator, seems to be more efficacious in preventing ovulation than levonorgestrel

17. Emergency Contraception 2,221 women randomly assigned to receive ulipristal (30 mg) or levonorgestrel (1.5 mg) Follow-up conducted 5 to 7 days after next expected menses Rates of pregnancy did not significantly differ if treatment was begun within 72 hours of intercourse 203 women received treatment between 72 and 120 hours after intercourse  3 pregnancies occurred in levonorgestrel group  0 pregnancies in ulipristal group

18. Emergency Contraception Meta-analysis of this and a previous trial  24 pregnancies in 1617 women randomly assigned to ulipristal  35 pregnancies in 1625 women randomly assigned to levonorgestrel  OR: 0.58, CI:0.33 to 0.99 Limitations  Women receiving hormonal contraceptives were excluded  Women were advised to abstain from sexual intercourse or to use barrier methods for remainder of cycle Ulipristal 30 mg approved by FDA for the prevention of pregnancy up to 120 hours after unprotected sex