Identify common causes of secondary amenorrhea, and conduct an appropriate work-up in such patients.

Recognize patients whose amenorrhea may be due to weight fluctuations, eating disorders, or the athletic triad, and work with psychiatric colleagues and coaches to protect patients’ bone health.

Utilize one’s knowledge of normal menstrual regulation (eg, role of prostaglandins in the control of menstrual flow) to better understand abnormal/irregular menstrual patterns.

Choose the appropriate medical therapy to control heavy menstrual bleeding, based on the patient’s specific situation (eg, combined hormonal or progestin-only oral contaceptive for woman who prefers monthly period).

Debate the differences between traditional hormone replacement therapy (HRT) and bioidentical HRT, especially use of estradiol vs estriol.

Abnormal Vaginal Bleeding
Anita L. Nelson, MD, Professor of Obstetrics and Gynecology, the David Geffen School of Medicine at the University of California, Los Angeles; Director, Women’s Health Care Clinic, and Staff Physician, Divisions of General Gynecology and Women’s Health, Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center

Background: menstrual cycle—normal, 24 to 28 days; frequent cycle, <24 days; infrequent cycle, >38 days; normal cycle varies by ±20 days; irregular, >20-day variation; menstrual flow (duration)—normal, 4.5 to 8 days; prolonged, >8 days; shortened, <4.5 days; menstrual flow (volume)—normal (if patient on oral contraceptives [OCs], 5-80 mL); long- term heavy flow (>80 mL) causes anemia

Secondary amenorrhea: absence of menses for 3 mo (if previous menstrual cycles normal), or 9 missed cycles (if previously irregular); delayed menses—one cycle missed and now 2 mo without menses

Causes of secondary amenorrhea: surgical—eg, cervical stenosis from loop electrocautery excision procedure (LEEP), dilation and curettage (D and C), especially if infection present or septic abortion (Asherman’s syndrome); fluctuations in body weight; medications; concomitant health issues; irradiation; chemotherapy; autosomal disorders associated with early ovarian failure; family history of endocrinopathies

Physical examination: look for spontaneous (not subtle expressible) galactorrhea on breast examination; cervical obstruction; hirsutism; virilization; acromegaly; profound endocrinopathies; pregnancy evaluation; follicle-stimulating hormone (FSH); other tests as needed

Chronic conditions causing amenorrhea: uncontrolled juvenile diabetes (patients do not metabolize estrogen well; high risk for endometrial cancer); end-stage renal disease (ESRD; patients have heavy prolonged bleeding and no erythropoietin [EPO]; start dialysis and protect endometrium with medroxyprogesterone acetate [eg, Depo-Provera]); HIV and AIDS; malabsorption; malignancies; hepatic failure

Medications causing amenorrhea: cocaine; selective serotonin receptor inhibitors (SSRIs); centrally acting drugs; reserpine; dopamine receptor agonists; antiemetics; protease inhibitors; cimetidine

Progesterone challenge: progesterone 10 mg once daily for 10 days; if withdrawal bleeding occurs, indication that endometrium exposed to estrogen and therefore no obstruction; important therapeutic intervention, especially during work- up of anovulatory cycles to avoid unopposed estrogen stimulation

Limitations of progesterone challenge test: false positives (no withdrawal bleeding)—20% of patients with adequate estrogen have excess androgen levels that block estrogen action on endometrial proliferation; false negatives (withdrawal bleeding)—patients may be obese or postmenopausal; occurs in ≤40% of cases due to stress, weight loss, exercise, or hyperprolactinemia; seen in ≤50% of women with ovarian failure

Evaluation of ovarian failure: thyrotropin (TSH) useful screening test; if TSH abnormal, protect endometrium and normalize TSH, then continue work-up if no menses; prolactin elevation; FSH (if elevated, recheck in 14 days to rule out ovulation), luteinizing hormone, estradiol; treat underlying condition before further work-up

Genetic causes of premature ovarian failure: possible sex chromosome translocations and presence of occult Y chromosome (karyotype patients 25 to 30 yr of age who may be at risk for ovarian cancer and need ovaries removed); other autosomal dominant diseases

Androgen evaluation: measure testosterone level in woman with long-term anovulation; total testosterone less sensitive as marker but more reliable than free testosterone; if elevated, look for androgen-producing tumor; medications; consider adrenal tumor if dehydroepiandrosterone sulfate (DHEA-S) levels elevated

Hyperprolactinemia: if no hypothyroidism, and patient not on medication that elevates prolactin, obtain magnetic resonance imaging (MRI) of head; ≥50% of these patients have pituitary tumor

Stress: common, but rule out other serious causes; hypothalamic amenorrhea—diagnosis of exclusion; low normal gonadotropins, normal prolactin, normal pituitary MRI, and no withdrawal bleeding on progesterone challenge; typically due to stress eating disorders; bulimic women at normal body weight can present with amenorrhea; these patients difficult to diagnose, but estrogen levels low enough to affect bone health; 72% of women with long-term stressors resume menses in ≤6 yr (however, too long to wait because of deleterious effects on bone health); cannot give antiresorptive agents to young patients; work with patient’s psychiatrist to protect bone health

Athletic triad: eating disorder not otherwise specified (EDNOS); self-induced vomiting, laxative and diuretic abuse, and excessive exercise; low body weight plus strenuous exercise causes hypoestrogenemia and oligo-amenorrhea; coaches may encourage amenorrhea; treat with estrogen using cyclic or extended-cycle OCs

Role of progestin: if patient unable to take estrogen, protect endometrium with progestin-only methods (progestin-only OC or medroxyprogesterone acetate) to decrease risk for amenorrhea; not appropriate for women with eating disorders, but good choice in women with secondary causes of amenorrhea and unopposed estrogen

Heavy bleeding: patient complains of blood clots; determine normal and heavy flow for that woman and whether her quality of life affected; recent study showed only 50% of those with >80 mL blood loss characterized flow as heavy; 10% thought it was light; possible that blood dyscrasias may present only during menses

Etiologies of heavy bleeding: organic gynecologic conditions, systemic diseases, blood dyscrasias, medications, trauma, and foreign bodies (eg, intrauterine device [IUD], retained tampon); anovulatory bleeding (replaces term “dysfunctional uterine bleeding”) diagnosis of exclusion; consider all women pregnant; consider all pregnancies ectopic; postcoital bleeding usually cervical (possibly polyp, infection, or cancer); bleeding between menses typically uterine; hyperthyroidism typically associated with excessive or prolonged bleeding (hypermenorrhea), and hypothyroidism typically associated with hypomenorrhea (but crossover possible); liver cirrhosis (via vitamin K metabolism); active hepatitis; adrenal hyperplasia; renal failure; hypersplenism (via platelet activity); von Willebrand’s disease; platelet disorders

Bleeding disorders: in study of patients with physician-diagnosed excessive menstrual bleeding, 47% had underlying hemostatic abnormality, with no previous history of easy bruising or other symptoms; in speaker’s study of women with excessive bleeding during normal ovulatory cycles and with no other pathology, 30% had bleeding disorder; always check for bleeding disorder before surgery in any woman nonresponsive to medical therapy; review genetic issues and cofactor antigen studies; check platelet count, prothrombin time (PT), and partial thromboplastin time (PTT); hemostatic and coagulation factor defects seen in every age group; platelet aggregation defects more common in adolescents; ristocetin- and epinephrine-related defects more common in older women

Medications that increase blood loss: anticoagulants; phenytoin and phenobarbital (disrupt vitamin K synthesis); ask patient whether medications affecting menses; patients on these medications should not ovulate (high risk for internal bleeding when ovarian follicle ruptures)

Normal menstrual regulation: prostaglandin E2 (PGE2 ) induces vasodilation and increases bleeding; prostaglandin F2α (PGF2α ) causes spiral arteries to vasoconstrict, and reduces blood flow; thromboxane assists platelet aggregation, prostacyclin inhibits platelet aggregation; in women with normal cycles, PGE2 and PGF2α increase near time of menses; however PGF2α /PGE2 ratio increases, so vasoconstriction more likely

Anovulatory bleeding: dyssynchronous bleeding; need to resynchronize shedding and balance prostaglandins; matrix metalloproteinases responsible for synchronous sloughing affect unscheduled spotting associated with progestin-only methods; incidence—occurs at extremes of reproductive life; no moliminal signs; patients typically awaken with unexpected bleeding; no progestin withdrawal

Treating heavy bleeding: cause organic and treatable? ovulatory or anovulatory? cyclic medroxyprogesterone acetate (Provera) synchronizes bleeding in anovulatory cycles by mimicking ovulation (however, increases blood loss in ovulatory cycles); assess burden of symptoms and patient’s expectations for therapy; pretreatment preparation—obtain menstrual, medication, and sexual histories; pregnancy test; complete blood cell count (CBC) or hemoglobin; check for blood dyscrasias in pubertal women and those with family history; consider patient age, symptom severity, associated pelvic pathology, and future fertility plans; treatment choices—most current regimens off-label; cyclic Provera only Food and Drug Administration (FDA)-approved therapy

Endometrial biopsy (EMB): consider history and context; appropriate candidates—younger women with unopposed estrogen stimulation; overweight women (3-fold higher risk for endometrial cancer if 21-50 lb overweight, 10-fold higher risk if ≥50 lb overweight); patients with diabetes; hereditary nonpolyposis colorectal carcinoma (HNPCC) hereditary carriers; for effective EMB, spiral catheter while sampling endometrium

Further diagnostic evaluation: D and C for unresponsive bleeding; consider ultrasonography in postmenopausal patient (preferable to hysteroscopy)

Medical therapies for heavy bleeding: coordinate endometrial sloughing—appropriate for woman who prefers monthly period; combined hormonal OC or progestin-only OC (eg, Provera, norethindrone [Aygestin]); suppress endometrium—prevents bleeding; less worry about endometrial cancer in future; progestin-only method or extending cycle with vaginal estrogen ring or OC; levonorgestrel-releasing intrauterine system (Mirena); normalize prostaglandins— nonsteroidal anti-inflammatory drugs (NSAIDs; eg, ibuprofen 800 mg tid) from first day of bleeding through heaviest day; use prophylactically as endometrium sloughs off and releases prostaglandins; cannot be used once clots start to form; NSAIDs can reduce blood loss by 20% to 30%; prevent endometrial thickening and uncoordinated sloughing— conventional 21/7 OC cycling, or 24/4; other alternatives include extended cycling with transdermal system, and vaginal contraceptive rings; give progestins (eg, medroxyprogesterone acetate 5 mg daily, norethindrone 5 mg daily) for cycling, or suppress completely with progestin-only product (Ortho-Micronor); consider surgery only if hormone therapy fails or if excessive acute bleeding cannot be stopped; effects of D and C temporary

Bioidentical Hormone Therapy
Julia A. Files, MD, Assistant Professor of Medicine, Mayo Clinic College of Medicine, and Chair, Division of Women’s Health, Department of Internal Medicine, Mayo Clinic Thunderbird Family Medicine, Scottsdale, AZ

Women’s Health Initiative (WHI): study halted in 2002 due to safety concerns; estrogen plus progesterone treatment associated with 24% relative risk (RR) increase in breast cancer; estrogen-only arm of trial (ie, women with hysterectomies) continued for 7.1 yr; RR for breast cancer decreased, but not statistically significant; as result, precipitous decrease in number of women prescribed hormone replacement therapy (HRT); patients looking for alternatives

Bioidentical HRT: marketing (ie, not medical) term; no standardized definition; can mean natural, not artificial, or compounded; implied advantage over manufactured or pharmacologic or FDA-approved options; claims made—safer alternative to conventional therapy; mimics body’s hormone production with customized estrogen mixtures; uses estrogens found in ovary; therapeutic option for women with symptoms not controlled by commercial products; variety of vehicles (lozenges, gels, pellets, creams); individualized testing available with salivary testing of hormone levels

Custom compounds available: triestrogen (Triest)—10% estrone, 10% estradiol, 80% estriol; biestrogen (Biest)— estradiol plus estriol (no estrone); available in oral, transdermal, sublingual, and vaginal forms; progesterone and testosterone also available

Estradiol: gold standard; 100% binding affinity for α- and β;-estrogen receptors; rapidly converts to estrone; significant first-pass effect when given orally; good transdermal absorption; estradiol 80 times more potent than estriol; many FDA- approved estradiol products derived from plant sources

Estriol: 1966 rodent data (studies not well-constructed) showed estriol protective against breast cancer, but subsequent studies do not support claim; safety now questioned; trial (Padwick, 1986) demonstrated dose-dependent histologic, proliferative, and hyperplastic effects on endometrium and endometrial hyperplasia; population-based case-control study (Rosenberg, 2006) showed increased sustained risk for lobular breast cancer with short-term (<5 yr) estriol use

Progesterone: delivered in micronized form (1995, Prometrium); previously used progestins (rapidly metabolized in stomach acid and have poor bioavailability); progesterone micronized in peanut oil (contraindicated in patients with peanut allergy); topical progesterone effective for hot flushes, but inadequate to protect endometrium of intact uterus

Testosterone: indications limited; in 2005, North American Menopause Society (NAMS) endorsed testosterone use for postmenopausal women with symptoms of decreased sexual desire associated with personal distress and who have no other identifiable cause of their sexual concerns; however, concomitant estrogen required (no studies on testosterone use in women not taking estrogen therapy); final recommendation that testosterone should be used at lowest dose, for shortest time that meets treatment goals (speaker considers too vague for clinical relevance)

Pellet therapy: contains estrogen (with or without progesterone) plus testosterone; nonremovable subcutaneous pellets placed by practitioner; unpredictable serum levels; significant androgenic side effects; overdosing testosterone associated with hair loss and balding, hirsuitism, hyperglycemia, hypertension, and elevated low-density lipoproteins

Summary: bioidentical HRT not regulated; no rigorous testing for safety and efficacy; salivary hormone level testing may not correlate with serum levels; do not dose HRT to laboratory value, but treat to clinical end point of symptom relief; absence of evidence of harm not same as proven safety; customized dosing practices not evidence-based