WOMEN S HEALTH: A REVIEW OF THIS YEAR S MOST IMPORTANT PAPERS OVERVIEW BUT NOT. TOPICS 8/14/2009. Judith Walsh, MD, MPH Professor of Medicine UCSF

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1 WOMEN S HEALTH: A REVIEW OF THIS YEAR S MOST IMPORTANT PAPERS Judith Walsh, MD, MPH Professor of Medicine UCSF OVERVIEW Update in Women s Health for SGIM Drs. Mary Beattie and Pam Charney Review of literature from March, 2008 through February, 2009 Updated Journals, Cochrane, Medline search using medical subject heading sex factors Criteria Scientific rigor Potential to impact clinical practice Osteoporosis Menopause BUT NOT. Colorectal, breast, cervical or lung cancer screening Other topics covered at this course TOPICS Cardiovascular disease Ovarian Cancer Screening Vitamin D Urinary Incontinence Sexual Health 1

2 In whom would you consider ordering a hscrp? CARDIOVASCULAR DISEASE IN WOMEN year old diabetic woman with a glycohemoglobin of 9.5 and an LDL of 175 mg/dl year old healthy woman with an LDL of 190 mg/dl year old healthy woman with an LDL of 130 mg/dl 4. All of these individuals 5. 2 and 3 only 37% 24% 15% 22% 2% hscrp: Background CRP is an inflammatory biomarker that has been shown to predict cardiovascular events CRP is elevated in many inflammatory conditions hscrp can detect levels down to 0.3 mg/dl Clinical Questions Does hscrp add prognostic value to traditionally measured cardiovascular risk factors? Does treating an elevated hscrp affect clinical outcomes? 2

3 hscrp and CHD outcomes Ridker PM et al for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. NEJM 2008: 359: Aim: To determine whether treating individuals with elevated CRP but normal LDL-cholesterol with statins can reduce the rate of first cardiovascular events C reactive protein Randomized controlled trial with 17,802 individuals (6,801 women) who received rosuvastatin 20 mg or placebo LDL <130 mg/dl and hscrp 2.0 mg/dl Composite outcome: MI, stroke, revascularization, unstable angina, CV death Results Trial stopped early after 1.9 years LDL cholesterol lowered by 50% and hscrp by 37% Rosuvastatin treated individuals had a lower rate of the primary endpoint RH 0.56 (0.46, 0.69) 1.8% of placebo participants vs 0.9% of rosuvastatin treated had an MI, stroke or death RH 0.53 (0.40, 0.69) NNT 120 for 1.9 years Results in Women Similar effects when women analyzed separately High rate of physician reported diabetes in rosuvastatin treated group 3

4 Impact for Practice Impact for Practice JUPITER was a study of statin therapy, not of hscrp testing Highly select group of participants 89,000 screened; 80% excluded Consider measurement of hscrp in individuals with an intermediate level of risk, if the decision about drug therapy would change CDC and AHA, 2003 How many individuals would qualify for statin treatment using JUPITER criteria? Using NHANES data from , an additional 6.5 milliion adults would qualify for statin treatment Key Articles Rosuvastatin therapy is also associated with a lower risk of VTE Ridker, NEJM 2009 Adherence to DASH diet associated with lower CHD risk in women after 24 year follow-up Fung, Arch Intern Med, 2008 Which of the following women would you consider treating with aspirin to reduce CHD risk? year old woman with hypertension year old woman with hypertension and diabetes year old woman with no cardiac risk factors 4. All of these women 5. 2 and 3 only 0% 38% 0% 56% 7%

5 Aspirin use in women U.S. Preventive Services Task force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force Recommendation Statement. Annals Intern Med 2009: 150: AIM: To update recommendations about the use of aspirin for the prevention of cardiovascular disease. Aspirin in Women New evidence since prior USPSTF recommendations ASA reduces risk of CHD in men and stroke in women Risk assessment in men CHD and GI bleeding Risk assessment in women Stroke and GI bleeding Aspirin in Women Women s Health Study 39,876 women ASA 100 mg qod vs placebo 10 year follow-up Reduction in ischemic stroke RR , 0.93) No reduction in MI, CV death, all cause mortality or combined CV outcome Ridker NEJM 2005 Aspirin in Women Meta-analysis of 6 primary prevention trials Reduced ischemic stroke Reduced CV events (ischemic stroke, MI or CV death) No reduction in MI or CV death No increased risk of hemorrhagic stroke Vs men» Berger, JAMA

6 Assessment of Stroke Risk Risk Assessment for GI Bleeding Age Blood Pressure Diabetes Smoking Hx CVD Atrial fibrillation LVH Risk1.xls Age and sex are the most important risk factors Men at higher risk Upper GI tract pain, GI ulcers, NSAID use Uncontrolled HTN and anti-coagulation increase the risk of serious bleeding USPSTF Recommendations Women aged should use ASA when potential benefit of a reduction in ischemic strokes outweighs the potential harms of a gastrointestinal hemorrhage USPSTF 2008 USPSTF Recommendations Evidence is insufficient to assess the balance or risks and harms of ASA for CVD prevention in women aged 80 and over ASA is not recommended for stroke prevention in women younger than 55 years old USPSTF

7 Question OVARIAN CANCER Ms. O. is a 52 year old woman whose best friend was recently diagnosed with ovarian cancer. She is concerned about ovarian cancer and wants whatever test you can give her for it. What do you recommend? Ovarian Cancer: What Test? OVARIAN CANCER: SHOULD WE SCREEN? 1. Bimanual pelvic examination 2. CA Transvaginal ultrasound 4. Bimanual examination and CA Bimanual examination, CA-125 and transvaginal ultrasound 62% Lifetime risk of ovarian cancer No affected relatives 1.2% One affected relative 5% 2 affected relatives 7% Hereditary syndrome 40% Ovarian cancer limited to the ovaries is associated with a much higher survival rate 6. None of these tests 11% 7% 11% 9% 0%

8 OVARIAN CANCER RISK FACTORS Advancing age Nulliparity North American or Northern European Personal history of endometrial, colon or breast cancer Family history of ovarian cancer Fertility drugs? PROTECTIVE FACTORS More than one full term pregnancy Breast feeding Oral contraceptive use OVARIAN CANCER: SCREENING TECHNIQUES Serum CA-125 assay Trans-vaginal ultrasound Serum CA-125 plus ultrasound PLCO TRIAL Partridge E et al. Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol 2009:113: AIM: To determine whether annual screening with CA-125 and transvaginal sonography can reduce ovarian cancer mortality PLCO 34,261 women aged randomized to screening vs usual care Annual CA 125 plus ultrasound CA 125 >35 or abnormal sono was positive Follow-up of positive screens by patients physicians Four annual screens so far 8

9 Results 89 invasive ovarian or peritoneal cancers diagnosed 60 screen detected Ca-125 positive % per round Ultrasound positive % per round PLCO Results PPV for combination of tests % Cancer yield per 10,000 women screened surgeries for each screen detected cancer Most screen detected cancers were late stage OVARIAN CANCER SCREENING: CONCLUSIONS Many women must be screened to detect a few cases PPV 1-1.3% To detect one cancer, many surgeries have to be done Effect on mortality is not known OVARIAN CANCER: SCREENING NIH Consensus Conference: There is no evidence available yet that the current screening modalities of CA-125 and transvaginal ultrasound can be effectively used for widespread screening to reduce mortality from ovarian cancer nor that their use will result in decreased rather than increased morbidity and mortality Many organizations recommend annual pelvic examination No evidence 9

10 OVARIAN CANCER: SCREENING A woman with two or more relatives should be referred to a gynecologic oncologist for counseling Although there are no data regarding screening in high risk women, annual screening with rectovaginal pelvic examination, CA-125 and transvaginal ultrasound are recommended PRIMARY PREVENTION Oral contraceptives 37% risk reduction Pregnancy Breast feeding QUESTION QUESTION Ms. O. is also having significant hot flashes and is not sleeping well. She is considering taking estrogen but is worried about her risk for ovarian cancer on estrogen. What do you tell her? 1. Her risk for ovarian cancer is not affected 2. Her ovarian cancer risk is increased while she takes hormone therapy and remains elevated when she stops 3. Her risk of ovarian cancer is increased on hormone therapy but decreases when she 55% stops 40% 5%

11 Hormone Therapy and Ovarian Cancer Morch LS et al. Hormone therapy and ovarian cancer. JAMA 2009: 302: AIM: To assess the risk of ovarian cancer in perimenopausal and postmenopausal women receiving different hormone therapies. Hormone Therapy and Ovarian Cancer Prospective cohort study Over 900,000 Danish women 8 year follow-up Prescription data 3068 incident cancers Results Increased risk of ovarian cancer in current users RR 1.38 ( ) Risk declined with years since past use Risk did not differ by type of hormone therapy or duration of use 1 ovarian cancer per 8,300 women taking hormone therapy each year Impact for practice Hormone therapy is associated with a small increase in ovarian cancer risk and the risk declines after HT is discontinued No effect of type or dose of estrogen or progestin or route of administration Additional factor to consider in decision making about hormone therapy 11

12 VITAMIN D VITAMIN D Violet D. is a 69 year old woman who comes in for a health care maintenance exam. You order a bone mineral density. She tells you she also wants a Vitamin D level checked. What do you do? Question: Vitamin D BACKGROUND 1. Order a Vitamin D level 2. Don t order a Vitamin D level because you are not sure to do with the results 3. Don t order it but start her on a 55% calcium/vitamin D supplement 45% Vitamin D deficiency is common in older adults, homebound individuals and women admitted with hip fracture Association between Vitamin D level and fracture risk is inconsistent Association could be influenced by renal function, muscle strength and estrogen receptors 0%

13 DEFINITONS Vitamin D optimum minimal level 25(OH)D concentration >30 ng/ml Vitamin D insufficiency 25(OH)D concentration ng/ml Vitamin D deficiency 25(OH)D concentration <20 ng/ml CLINICAL QUESTIONS What is the association between Vitamin D level and fracture? When should Vitamin D levels be checked? When and how should Vitamin D supplementation be given? VITAMIN D AND FRACTURE RISK Cauley JA et al. Serum 25(OH) vitamin D concentrations and risk for hip fractures. Ann Intern Med 2008:149: AIM: To determine whether serum 25 (OH) D concentration is associated with hip fracture in community dwelling older women METHODS Nested case-control study within the Women s Health Initiative Observational Study 400 cases and 400 controls followed for a median of 7.1 years Women had no prior history of hip fracture, were not on estrogen or other bone active therapies 13

14 RESULTS: HIP FRACTURE RISK Odds Ratios of Risk for Hip Fracture* 25-Hydroxyvitamin D Level Unadjusted Odds Ratio (95% CI) Adjusted Odds Ratio (95% CI) Per 2.5-nmol/L decrease 1.03 ( ) 1.03 ( ) Per 25-nmol/L decrease 1.30 ( ) 1.33 ( ) Quartile (according to control group) First ( nmol/l) 1.73 ( ) 1.71 ( ) Second ( nmol/l) 1.08 ( ) 1.09 ( ) Third ( nmol/l) 0.78 ( ) 0.82 ( ) Fourth ( nmol/l) 1.00 (reference) 1.00 (reference) HIP FRACTURE RISK Association was linear Dose response effect No difference by age Independent of geographic location P for trend for unadjusted and for adjusted models IMPACT FOR PRACTICE Low serum 25 (OH) vitamin D concentrations can help identify women at high risk for hip fracture Perhaps we should consider Vitamin D level in decision making about anti-resorptive therapies Vitamin D Evidence AHRQ Systematic Review of the efficacy and safety of Vitamin D in relation to bone health BMD-fair Fractures- inconsistent Performance measures (body sway, gait speed)- inconsistent Falls- fair, but few studies Harms- check levels 14

15 TRENDS OF VITAMIN D INSUFFICIENCY Comparison of NHANES III ( ) to NHANES Mean serum 25(OH)D level is decreasing 30 vs 24 ng/ml Prevalence of Vitamin D deficiency is increasing Ethnic differences persist Majority of non-hispanic Blacks and most Mexican Americans have vitamin D insufficiency Ginde Arch Intern Med 2009 Measuring 25(OH)D Should we measure it or encourage adequate intake/exposure? For those without regular sun exposure, consumption of 800 IU per day necessary to keep 25 (OH) D levels >30 ng/ml Measure in homebound, malabsorption, individuals with osteoporosis TREATMENT Nutritional Deficiency 50,000 IU of Vitamin D2 or D3 per week for 6-8 weeks and then IU per day Nutritional Insufficiency IU per day Goal will be reached in 3 months TREATMENT Monitor at 3 months Safe upper limit for Vitamin D 2000 units per day National Academy of Sciences Higher doses appear to be safe for several months 15

16 Urinary Incontinence: Treatment URINARY INCONTINENCE Mrs. Ima Leeker is a 72 year old woman who comes to see you. She admits to increasing episodes of urinary incontinence when she rushes to get to the bathroom and just before she gets there she loses urine. What do you recommend for Mrs. Ima Leeker? URINARY INCONTINENCE 1. Behavioral therapy -Bladder training and Kegels exercises 2. Drug therapy 3. Weight loss 4. All of the above 28% 68% Urinary incontinence (UI) affects more than 13 million U.S. women and significant impacts quality of life Stress vs urge incontinence Behavioral treatments and drug therapy are useful for urge incontinence but compliance is a problem 4% 0%

17 Clinical Questions Does weight loss result in improvement in incontinence? Can combining drug and behavioral treatment improve symptoms of incontinence and can these improvements be sustained after stopping drug therapy? Weight loss and incontinence Subak et al for the PRIDE investigators. Weight loss to treat urinary incontinence in overweight and obese women. NEJM 2009:360: AIM: Can weight loss reduce incontinence episodes? KEY RESULTS Women in the intervention group lost an average of 7.8 kg Vs 1.5 kg in the control group At 6 month follow-up, intervention group had a 70% reduction in all incontinence episodes Stress and urge Behavioral therapy Burgio KL et al for the Urinary Incontinence Treatment Network. Ann Intern Med 2008: 149: AIM: To determine whether supervised behavioral training added to drug therapy improves incontinence and to determine whether the improvement can be sustained after stopping drug therapy 17

18 KEY RESULTS Combined therapy resulted in a greater reduction in incontinence at 10 weeks Vs Drug therapy alone 69% vs 58% achieved a 70% reduction in incontinence episodes At 8 month follow up, the effect was not sustained after stopping drug therapy IMPACT FOR PRACTICE One of the many benefits of weight loss is an improvement in urinary incontinence Although adding behavioral therapy to drug treatment may improve symptoms, it does not improve the ability to discontinue drug therapy SEXUAL HEALTH Question Desiree O is a 48 year old married peri-menopausal woman who notes decreased sexual desire, arousal and orgasm for the past two years. She is not depressed and both she and her husband are dissatisfied with their sex life. Are there any medical interventions that might help her? 18

19 Options for Desiree O 1. Estrogen/progestin 2. Estrogen/testosterone combination 3. Testosterone gel 4. Testosterone spray 51% 23% 23% Female Sexual Dysfunction Decrease in sex drive, aversion to sexual activity, difficulty with arousal, inability to achieve orgasm, dyspareunia that causes distress Most common in women aged % Percent of women 90% 80% 70% 60% 50% 40% 30% 20% 10% BACKGROUND: Self-reported sexual desire in US women 0% 22% 39% 74% Low sexual desire 18 to 44 y.o. 45 to 64 y.o. 65 y.o. or older 9% 12% 7% Distressing low desire Adapted from Shiftren JL et al, Obstet & Gynecol, TREATMENT Non-pharmacologic Communication Lifestyle changes Vaginal weights Vaginal lubricants Tactile Stimulation Sexual Frequency Pharmacologic Estrogen Progestin added to estrogen Testosterone 19

20 Testosterone Most studies in women with surgical menopause Gels, creams and tablets Compounding Not FDA approved Transdermal testosterone Transdermal spray Testosterone: 2 Trials Hypoactive Sexual Desire Disorder Outcome was satisfactory sexual events Transdermal spray in 261 premenopausal women, 16 weeks* Patch in 814 postmenopausal women not on estrogen, 52 weeks** *Davis S, Annals 08 **Davis S, NEJM 08 Testosterone Spray: RESULTS Testosterone Patch: RESULTS 20

21 Testosterone Trials: IMPACT Adverse events in pre-menopausal women included hypertrichosis, headache, nausea, acne, dysmenorrhea Adverse events in post-menopausal women included excess hair growth 4 women on active patch diagnosed with breast cancer (vs. 0 in placebo) Long-term safety follow-up is key CONCLUSIONS Consider measuring hscrp in intermediate risk women in whom management might change Consider the risk of stroke and GI bleeding when considering aspirin prophylaxis There is no evidence that screening for ovarian cancer reduces mortality Low vitamin D levels can help identify women at high risk for hip fracture CONCLUSIONS Prevalence of Vitamin D insufficiency is increasing Weight loss leads to an improvement in urinary incontinence Behavioral therapy is helpful for urge incontinence but does not improve the ability to discontinue drug therapy Testosterone may lead to improved sexual function but long term side effects are not known 21