Issues in Women’s Health

Educational Objectives

The goal of this program is to improve women’s health through prevention of cardiovascular disease, promotion of appropriate use of screening for breast cancer and human papillomavirus vaccine, and improvement of management of abnormal uterine bleeding and chronic pelvic pain. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe and discuss risks and benefits of aspirin as primary prevention of cardiovascular disease in women.

2.   Utilize the United States Preventive Services Task Force risk calculator to calculate risks and benefits of aspirin as prophylaxis for a specific patient.

3.   Describe implications of breast cancer screening, and incorporate these into clinical practice.

4.   Determine causes of abnormal uterine bleeding.

5.   Diagnose causes for and treat chronic pelvic pain.

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. Wathen spoke in Seattle, WA, at 2009 Scientific Meeting of the Washington Chapter of the American College of Physi­cians, presented November 5-7, 2009, by the American College of Physicians. Dr. Paik spoke in Monterey, CA, at Women's Health Conference, presented June 15-19, 2008, by the University of California, Davis, Health System. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Aspirin and Cardiovascular Disease, Breast Cancer Screening, and Human Papillomavirus Vaccine

Patricia Wathen, MD, FACP, Professor of Medicine, Department of General Medicine, University of Texas Health Science Center, San Antonio

Low-dose aspirin (acetylsalicylic acid [ASA]): reduces risk for recurrent myocardial infarction (MI) and ischemic stroke in men and women (secondary prevention); increases risk for extracranial bleeding in primary and secondary prevention; controversial for primary prevention of cardiovascular disease (CVD) in women, due to lower baseline CVD risk; ASA may have different effects on CVD events in women, compared to men

ASA in primary and secondary prevention (meta-analysis): data from 6 primary- and 16 secondary-prevention trials show risk for gastrointestinal (GI) bleeding in control group 0.3% per year; in men  —  for primary prevention, baseline CV event risk 3.9% per year; 50 to 100 mg/day of ASA reduces CV risk by »0.5% per year, but reduction in fatal and, particularly, nonfatal CV events partially offset by increased risk for bleeding; for secondary prevention, clear benefit in prevention of fatal and nonfatal CV events in ASA group, compared to control group; in women  —  at 50 to 59 yr of age, lower baseline risk for extracranial bleeding than in men; risk for extracranial bleeding increased by 50% with ASA, compared to control group; baseline CV risk 1.1% per year; in primary prevention, absolute benefit from ASA »0.2% per year; ASA as primary prevention may cause harm in women with higher risk for GI bleeding and lower CV risk; for sec­ondary prevention, ASA has clear benefit; at 65 to 74 yr of age, baseline risk for GI bleeding higher and increased by low-dose ASA; baseline risk for CV events higher in these women (therefore, benefits of ASA higher); risks and benefits of ASA close to equal for primary prevention in women (especially younger women)

Women’s Health Study: large primary prevention study of coronary heart disease (CHD); 39,976 healthy women >45 yr of age randomized to 100 mg ASA every other day or placebo; outcomes measured  —  CHD events; strokes; GI bleeding; death; subjects  —  mean age 55 yr; 10-yr follow-up; results  —no significant reduction in any major CV event; no significant effect on mortality or CHD events; significant reduction in ischemic stroke; no increase in hemorrhagic stroke; results  —51 nonfatal isch­emic strokes prevented in ASA group, but with 36 episodes of GI bleeding requiring transfusion; women aged ³  65 yr  —  44 fewer CV events, but 16 more GI bleeding episodes; only group that had reduction in CHD events; also had significant reduc­tion in ischemic strokes; conclusion of study  —  decisions about use of ASA as primary prevention among women should be made only after woman consults physician to ascertain net absolute benefits and risks; United States Preventive Services Task Force (USPSTF) recommendations  —start ASA for women 55 to 79 yr of age when potential benefit of reduction in risk for ischemic stroke outweighs potential harm of risk for increase in GI hemorrhage

Risk-benefit calculator (USPSTF): online 10-yr cumulative stroke risk calculator incorporates various risk factors (eg, sex, age, blood pressure, diabetes); chart from USPSTF gives 10-yr CHD risk at which benefits of ASA probably out­weigh risk; USPSTF recommends calculation of 10-yr risk for CHD for men and 10-yr risk for stroke for women; be­cause risk for GI bleeding increases with age, higher risk for CHD needed to offset increased risk for GI bleeding in older patients; women  —  in younger women, 10-yr risk for stroke of 3% warrants ASA, due to lower risk for bleeding; in older women, higher 10-yr risk for stroke needed to justify ASA due to higher risk for bleeding; American Heart Association (AHA) recommendations  —  in women ³65 yr of age, consider ASA (81 mg daily or 100 mg every other day) if blood pressure controlled and benefits for ischemic stroke and myocardial infarction (MI) prevention outweigh risk for GI bleeding and hemorrhagic stroke; in women <65 yr of age, prevention of ischemic stroke probably major benefit of ASA; reduction in CHD events not as well established in women as in men; nonsteroidal anti-inflammatory drugs (NSAIDs)  —  increase risk for GI bleeding 4-fold in patients on low-dose ASA and 2-fold in patients with history of bleeding; consider adding proton pump inhibitor in patients with previous GI bleeding and compelling reason for ASA prophylaxis

Women’s Health Initiative (WHI): results of trial of combination estrogen and progestin (2002)  —  increased risk for CHD, stroke, venous thromboembolism (VTE) invasive breast cancer, and increased global risk for adverse effects; rec­ommended use of combination for symptom relief only, for short duration, and at lowest effective dose; results of estro­gen-only arm (2004)  —  no significant effect on CHD or VTE; increased risk for stroke; no effect on global risk; timing hypothesis  —average age of WHI participants 63 yr; <50% of participants previously used hormone replacement therapy (HRT); HRT may prevent atherosclerosis if started soon after menopause; HRT may promote thrombosis and prove harm­ful in women with existing atherosclerosis who started HRT later; subgroup analysis  —  nonsignificant reduction in CHD events and total mortality in women <10 yr post-menopause; higher CV risk in women who started HRT later; used to support timing hypothesis; limitations of subgroup analysis  —  only 10% of women in estrogen-only trial and 17% of women in combination trial £5 yr past menopause at randomization; combined data from WHI randomized trial and ob­servational study  —  increased number of women (93,000) who started HRT early after menopause; compared “early” and “late” HRT starters; early starters  —  significant increase in risk for stroke, no cardioprotective effect, and no effects on breast cancer or global risk in estrogen-only arm; in combination arm, increase in risk for invasive breast cancer and global risk, with no cardioprotective effect; conclusion  —  effects of estrogen and combination estrogen and progestin did not depend on gap time from menopause to first use of HRT, except higher risk of invasive breast cancer in “early start­ers” of combination; WHI data provide little support for timing hypothesis

Breast cancer screening: perfect screening test should not result in significant increase in total number of individuals diag­nosed with disease; if screening results in diagnosis of more cases of early-stage breast cancer, overdiagnosis and over­treatment likely; since initiation of screening (mammography), 23% decrease in breast cancer mortality (8/100,000 absolute decline; half due to treatment, half to screening); 700% increase in diagnosis of ductal carcinoma in situ (DCIS) (26/100,000 absolute increase); DCIS aggressively treated with surgery and chemotherapy or irradiation, with or without metastasis; mortality reduction comes with high cost for diagnosis and treatment of early disease; recommendations  —searching for increasingly sensitive tests not best strategy; need markers to discriminate significant from minimal-risk cancers; reduce DCIS treatment; focus on high-risk patients

Human papillomavirus (HPV) vaccine: randomized trial of vaccine against strains 18,16, 6, and 11 in women aged 15 to 26 yr found 40% reduction in cancer precursor lesions, 76% reduction in genital warts, and 50% to 70% reduction in vul­vovaginal premalignant lesions; not effective in women HPV-positive at baseline; 95% effective for preventing premalig­nant lesions in HPV-negative women; HPV quadrivalent (Types 6, 11, 16, and 18) vaccine, recombinant (Gardasil)  —  approved for girls and women aged 9 to 26 yr; United States Vaccine Adverse Event Reporting System  —  voluntary re­porting by patients, parents, health care workers, and manufacturer; 12,000 reports; 54 adverse effects following immuni­zation (AEFIs) per 100,000 doses; most common AEFIs  —  syncope; injection site reaction; dizziness; urticaria; hypersensitivity; nausea; 772 serious events and 32 deaths reported; AEFI rates compared to other vaccines  —  no differ­ence in Guillain-Barré syndrome or death; increased rates of syncope and VTE, perhaps due to characteristics of target population

Gynecology for the Primary Care Physician

Clara K. Paik, MD, Assistant Professor, Department of Obstetrics and Gynecology, University of California Davis Health System, Sacramento

Hormonal causes of dysfunctional uterine bleeding (DUB): diagnosis of exclusion; most frequently due to anovulation; estrogen  —  predominant in anovulation; causes abnormal, irregular, heavy bleeding; common cause of abnormal uterine bleeding in any age group, particularly perimenopausal women; progesterone withdrawal bleeding  —  administration and discontinuation of oral contraceptives (OC) or progesterone can result in spotting and bleeding; estrogen withdrawal bleeding  —  abrupt estrogen decrease causes midcycle spotting for 24 to 48 hr; progesterone breakthrough bleeding  —  occurs after long-term use of OC, levonorgestrel intrauterine device (Mirena), or depot medroxyprogesterone acetate (MPA; eg, Depo Provera); thin lining leads to spotting and bleeding; estrogen breakthrough bleeding  —  in anovulation, lining builds up and does not shed properly without progesterone withdrawal; cycles of lining build-up and shedding cause unpredictable bleeding

Causes of anovulation: obesity; polycystic ovary syndrome (PCOS); perimenopause; adolescence

Causes of abnormal uterine bleeding by age group: adolescence  —  anovulation; immature hypothalamic-pituitary-ovar­ian axis; underlying coagulopathy (prevalence 5%-20%); sexually transmitted infections (STIs); pregnancy-related com­plications; reproductive age  —  pregnancy-related complications; PCOS; STIs; polyps; fibroids; endometrial cancer; perimenopause  —  anovulation; fibroids; polyps; hypothyroidism; endometrial hyperplasia; endometrial cancer; fibroids  —  cause heavy prolonged menses without anovulatory-type bleeding; operative intervention not necessary; postmenopause  —  atrophy; en­dometrial cancer

Evaluation by history: questions  —  is bleeding predictable? how much bleeding? does patient use both maxi pads and tam­pons? does she soil clothes or sheets? does she pass large clots? is patient on hormone therapy? if on hormone therapy, is she taking it regularly? take gynecologic history; screen for underlying coagulopathy in adolescents with heavy pro­longed bleeding

Physical examination: vital signs; screen for PCOS; pelvic examination  —  look for active bleeding from cervical os

Further evaluation: test for pregnancy and anemia; laboratory studies  —  thyrotropin (TSH); von Willebrand disease, if sus­pected; imaging  —  transvaginal ultrasonography (US) for determining endometrial thickness postmenopause; saline infu­sion US for enhanced view of uterine cavity; invasive studies  —endometrial biopsy; dilation and curettage; hysteroscopy

Management of abnormal uterine bleeding: NSAIDS  —effective for idiopathic menorrhagia; ibuprofen for first 3 days of menses or throughout bleeding episode; not effective for women with irregular cycles; estrogen  —  oral or intravenous (IV) for acute bleeding; causes rapid regeneration of endometrial lining; 25 mg IV every 4 hr for 24 hr »85% effective; oral estro­gen used for outpatient treatment; after bleeding subsides, start progesterone (withdrawal bleeding needed); progestins  —provide medical curettage; stop endometrial growth; not as effective for acute bleeding; MPA 10 mg/day for 10 to 14 days every month induces withdrawal bleeding; thickened endometrial lining must be shed £3 times per year; levonorgestrel IUD also effective (»30% of women become amenorrheic); used also in women with high estrogen and anovulatory-type bleed­ing; MPA also thins lining over time, but seldom used because of side effect (6-9 mo of abnormal bleeding); progesterone-dominant OCs  —  treatment of choice if not contraindicated; cause lining to thin; less abnormal bleeding than with progester­one–only methods; treat with monophasic OC bid for 7 days; counsel patient to expect heavy bleeding after stopping, then to start new pack in usual fashion; after lining thins out, patient can continue OC without withdrawal bleeding; 2 to 3 mo of medical therapy recommended before stopping; gonadotropin-releasing hormone (GnRH) agonists  —  for poor surgical can­didates or medical therapy failures

Causes of chronic pelvic pain (CPP): irritable bowel syndrome  —  diagnosis of exclusion; interstitial cystitis (IC)  —  indicated by score >8 on pelvic pain and urinary/frequency (PUF) symptom scale; depression  —  lowers pain threshold; other psychiatric disorders  —  history of abuse; somatization; sleep disturbances; drug-seeking behavior; factitious dis­order; myofascial pain syndrome  —  trigger points provide focus of hyperirritability; fibromyalgia  —abnormal pain pro­cessing

Gynecologic causes: endometriosis  —  major gynecologic cause of CPP; adenomyosis  —  in multiparous women aged 40 to 49 yr with history of cesarean delivery or dilation and curettage with menorrhagia and dysmenorrhea; pelvic inflammatory dis­ease (PID)  —  persistent infection; scarring; tissue damage; one-third of women with PID have CPP; adhesions  —  little evi­dence to support adhesiolysis unless extensive, dense, vascularized adhesions cause internal organ fixation; lysis often results in more adhesions; pelvic congestion  —  controversial diagnosis

Other causes: neuropathic pain syndrome

Evaluation of CPP: take history; abdominal examination  — look for trigger points; palpate abdomen with muscles contracted; examine previous surgical sites, particularly cesarean scars (nerve entrapment can cause pain); pelvic examination  —perform pain mapping with cotton-tipped swab to look for vulvodynia; palpate levator ani muscles for spasm or tenderness; palpate anterior vagina for tenderness due to IC; assess for cervical motion tenderness (may indicate untreated PID); perform biman­ual and rectovaginal examinations (look for adnexal mass or endometriosis); imaging  —pelvic US; magnetic resonance im­aging, if concerned about endometriosis or adenomyosis; laparoscopy  —  does not rule out microscopic endometriosis; visual inspection requires experienced surgeon; 25% of random biopsies of normal-appearing peritoneum contain endometriosis implants; diagnosis of endometriosis does not ensure correct diagnosis of CPP; endometriosis-related pain does not correlate with disease stage

Treatment algorithm for CPP: depends on suspected cause; endometriosis  —  stepwise approach; start with least resource-intensive medications; discontinue if pain does not improve after 2 to 3 mo; GnRH agonists  —  leuprolide (Lupron) 3.75 mg intramuscular injection every 4 wk or 11.25 mg every 3 mo; prescribe add-back hormone therapy for menopause-type symptoms; 85% to 90% of patients with endometriosis-related CPP have significant pain relief with GnRH agonists; American College of Obstetricians and Gynecologists opinion  —  GnRH agonists effective in relief of endometriosis-re­lated CPP and acceptable as empiric treatment without surgical confirmation of endometriosis if detailed initial evalua­tion fails to show other cause

Suggested Reading

Al-Azemi M et al: Immediate and delayed add-back hormonal replacement therapy during ultra long GnRH agonist treatment of chronic cyclical pelvic pain. BJOG 12:116, 2009; Anderson GL et al: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 14:291, 2004; Antithrombotic Trial­ists' (ATT) Collaboration et al: Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373:9678, 2009; Benjamins LJ: Practice guideline: evaluation and man­agement of abnormal vaginal bleeding in adolescents. J Pediatr Health Care 3:23, 2009; Berger JS et al: Aspirin for the primary pre­vention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 3:295, 2006; Ely JW, et al: Abnormal uterine bleeding: a management algorithm. J Am Board Fam Med 6:19, 2006; Esserman L et al : Rethink­ing screening for breast cancer and prostate cancer. JAMA 15:302, 2009; Hurskainen R et al: Clinical outcomes and costs of the le­vonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up. JAMA 12:291, 2004; Parsons CL et al: Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity. Urology 4:60, 2002; Prentice RL et al: Benefits and risk of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 1:170, 2009; Ridker PM et al: A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 13:352, 2005; Rossouw JE et al: Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 13:297, 2007; 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 3:288, 2002; Vercellini P et al: Chronic pelvic pain in women: etiology, pathogenesis and diagnostic approach. Gynecol Endocrinol 3:25, 2009; Vercellini P et al: Medical, surgical and alternative treatments for chronic pelvic pain in women: a descriptive review. Gynecol Endocrinol 4:25, 2009; Yildizhan B et al: Transvaginal ultrasonography and saline infusion sonohysterography for the detection of intra-uterine lesions in pre- and post-menopausal women with abnormal uterine bleeding. J Int Med Res 6:36, 2008.