UCSF Essentials of Primary Care August 12, 2016 Squaw Creek, CA Disclosure • Understanding Amenorrhea and PCOS None Michael Policar, MD, MPH Professor of Ob, Gyn, and Repro Sciences UCSF School of Medicine [email protected] Amenorrhea: Definitions • Primary Amenorrhea – Absence of menarche by • 16 yo with sexual development – ASRM: 15 yo or > 5 years after breasts develop • 14 yo without sexual development • Secondary Amenorrhea (aka: absent menstrual bleeding) – No vaginal bleeding for at least • Three cycle lengths OR six months – Oligomenorrhea with < 9 menses/ year (ASRM,2008) ASRM Fertil Steril 2008;90:S219–25 ASRM: American Society of Reproductive Medicine 1 Presentation Approach to Amenorrhea Reproductive Hormonal Axis HYPOTHALAMUS Hypothalamic • Most common diagnoses early in workup GnRH Amenorrhea • Minimize potentially unnecessary tests and office visits • Separate evaluation schemes for ANTERIOR PITUITARY Pituitary – Spontaneous secondary amenorrhea FSH Amenorrhea – Post-surgical amenorrhea LH – Primary amenorrhea (not today) OVARY Ovarian – Progestin-induced failure to withdraw Estradiol (E 2 ) Failure Progesterone (P) ENDOMETRIUM Outflow Failure 2o Amenorrhea: Amenorrhea: Causes Hypothalamic Amenorrhea • Hypothalamic amenorrhea • • Pituitary amenorrhea Athlete's amenorrhea – • Ovarian failure Critical ratio of muscle to body fat exceeded – Despite exercise, risk osteoporosis (and fracture) • Outflow tract failure • Female athlete triad : disordered eating, amenorrhea, • Anovulatory amenorrhea and osteoporosis • Pregnancy induced amenorrhea – Preoccupation with food and weight, frequent bathroom use during and after meals, laxative use, brittle hair or nails, dental cavities 2 o The Female Athlete Triad 2 Amenorrhea: 2014 Female Athlete Triad Coalition Consensus Statement Clin J Sport Med 2014; 24(2): 96-119 Hypothalamic Amenorrhea • Medical condition often observed in physically active girls and women, and involves 3 components • Anorexia nervosa – Low energy availability + disordered eating • Chronic stress – Menstrual dysfunction • Post-hormonal suppression – Low bone mineral density – Resolves within 3 months of method discontinuation • Early intervention is essential to prevent progression to serious endpoints that include – Clinical eating disorders – Amenorrhea – Osteoporosis o 2 Amenorrhea: 2o Amenorrhea: Pituitary Amenorrhea Ovarian Failure • Hyperprolactinemia – Prolactinoma (prolactin-secreting adenoma) • > 40 years old: True menopause – Drugs, esp antipsychotics • < 40 years old: Premature menopause – Primary hypothyroidism – Premature ovarian failure • Destructive pituitary lesions •Autoimmune; follicles present – Tumors, tuberculosis – Resistant ovary syndrome – Sheehan's syndrome •Non-autoimmune; follicles sparse • Pituitary atrophy after post-partum hemorrhage – Gonadal dysgenesis (mosaic or Fragile X) • Hypothyroid sxs, difficulty lactating, loss of pubic or underarm hair, low BP, fatigue, weight loss 3 2o Amenorrhea: Outflow Tract Failure Anovulatory Amenorrhea • • Cervical Stenosis Compartments intact, but dyssynchronous • – Normal (or high) E 2 levels Occurs after TAB, cryotherapy, cone, or LEEP • – Will have progestin withdrawal bleeding because of Blockage of internal os with blood accumulation estrogen-induced endometrial priming – Cyclic premenstrual sxs with uterine cramping • Causes • Asherman's Syndrome – Hyperandrogenic anovulation • – Endometrial ablation (TAB or curettage) and uterine PCOS, adult onset CAH infection, leads to intrauterine synechiae – Hypothalamic anovulation : stress, wt. loss – – Cyclic premenstrual symptoms, but no cramps Hyperprolactinemia Secondary Amenorrhea Secondary Amenorrhea: The “Big Four” Conditions ASRM, 2008 Hypothalamic Pituitary Ovarian Outflow Anovulatory Amenorrhea Amenorrhea Failure Failure Amenorrhea Athlete’s am. Prolactinoma Menopause Cervical PCOS 1. PCOS 66% Stress HypoT 4 Premat OF stenosis HyperPRL Anorexia Drugs OIS Asherman’s Stress 2. Hypothalamic amenorrhea nervosa Pit tumors Mosaic syndrome 3. Hyperprolactinemia 13% Sheehans syn E: low E: low E: low E: normal E: normal 4. Ovarian failure 12% FSH: low FSH: low FSH: high FSH:normal LH > FSH Outflow tract 7% Other (CAH, ovarian tumor) 2% 4 Hx, PE, Fritz, Speroff: Spontaneous Hx, PE, ASRM 2008: Spontaneous o o Preg test 2 Amenorrhea Preg test 2 Amenorrhea Preg test NEG Preg test NEG Preg test POS TSH, PRL, FSH,E 2 Preg test POS MPA x10d PRL , TSH, FSH Pregnant Pregnant • Incr TSH •E2, FSH normal • E2 low HyperPRL Incr TSH Incr FSH Normal, low FSH •Location •HyperPRLHyperPRL •Location • W/D Bleed + • NO W/D Bleed Ovarian •GA Dating •GA Dating Evaluate, treat Evaluate, treat Anovulation/ Failure PCOS Incr FSH Low FSH Anovulation/ Hypothal/pit Ovarian Hypothal/pit PCOS Failure Failure Failure If androgen- MRI if unexplained MRI if unexplained ization Amenorrhea: Clinical Symptoms Amenorrhea: Clinical Symptoms Symptom Suggestive of Symptom Suggestive of Pregnancy symptoms • Pregnancy Medications • Anovulation • Missed SAB • Hypothalamic amenorrhea Galactorrhea • Hyperprolactinemia Athletics, weight loss • Hypothalamic amenorrhea Headache • Hypothalamic, pituitary dz Hot flashes • Ovarian, central failure Visual changes • Pituitary tumor Cervical or uterine • Cervical stenosis surgery • Asherman's syndrome Hirsuitism, acne • Chronic anovulation/PCOS Cyclic premenstrual • Cervical stenosis • Psychological stress Anovulation symptoms • Asherman's syndrome • Hypothalamic amenorrhea 5 o Amenorrhea: Physical Examination 2 Amenorrhea: Visit 1 • History, physical exam Organ Signs Cause • Highly sensitive urine pregnancy test Skin • Hirsuitism • PCOS • Findings • Acne – Galactorrhea on hx, PE: galactorrhea W/U Breasts • Galactorrhea • ↑ prolacn – Pregnancy test result: Abdomen • Uterus enlarged • Pregnancy •Positive: DX=PREGNANCY ; locate, date Cervix • Pinpoint os • Cervical stenosis •Neg, unprotected sex: Use BC, repeat 2 wk Uterus • Enlargement • Pregnancy •Neg, protected or no sex: proceed t o lab o Visit 2 2o Amenorrhea: Visit 1 2 Amenorrhea: • • Order lab tests Review lab results – – Prolactin, TSH level; not thyroid function tests PRL elevated: hyperprolactinemia evaluation – o – FSH, Estradiol (E ) level; not LH level TSH elevated: 1 hypothyroidism evaluation 2 – – If signs of virilization: total testosterone, DHEAS Testosterone elevated: evaluate ovarian tumor – • Progestin challenge (if performed) DHEAS elevated: evaluate for adrenal tumor • – MPA 10 mg PO QD x 7days OR Review P challenge outcome and lab test results – – Micronized progesterone 400 mg x10d DX= ANOVULATORY AMENORRHEA if… – • Schedule F/U visit 3 weeks FSH and E 2 levels are normal – Progestin withdrawal bleed occurred 6 Anovulatory Amenorrhea 2o Amenorrhea: Visit 2 • Work up not necessary, unless virilization • – If PCOS, check lipids and fasting +2 o PGL glucose levels FSH >20 IU/L, low E 2: DX = OVARIAN DISORDER – • Management > 40 years old: Menopause – Desire contraception – < 40 years old: Premature menopause • Cycle on OC's • Karyotype: if < 30: gonadectomy if Y ch’some – Desire pregnancy • Autoimmune POF: screen with TSH, anti-thyroid • Induce ovulation: clomiphene or letrazole antibodies, FBG, electrolytes – Neither : cycle bleeding, prevent hyperplasia • Ovarian biopsy not indicated • MPA or microP x 10-14d every 1-2 months – If pregnancy is desired, refer for ART (ovum donation) •LN-IUS (Mirena) Post-surgical o 2 Amenorrhea: Visit 2 Hx, PE, Preg test 2o Amenorrhea Preg test POS Preg test NEG • Low FSH (< 5 IU/L) , low E 2 • Pregnant • DX=HYPOTHALAMIC or PITUITARY DISORDER Molimena • + Molimena Cramps – If explained by athletics, anorexia, poor nutrition, or stress, • • NO cramps Location no further evaluation needed • Dilate cervix MPA x10d •GA Dating – If unexplained, or CNS symptoms, exclude pituitary tumor Bleed NO Bleed Bleed NO Bleed • Anovulation EE x 30d “Pituitary MRI” or head CT with contrast MPA x10d – Provide estrogen replacement: low dose OC Cervical Stenosis Bleed NO Bleed – Pregnancy desired: gain weight or induce ovulation with FSH High Nml, low HMG or pulsatile GnRH Ovarian Hypothal/pit Ashermans Failure Failure Syndrome 7 Which feature is a clinical criteria for the PCOS: Overlaping Syndromes diagnosis of PCOS? 46% PCOS Insulin Hyper- A. Obesity 44% B. Hyperinsulinemia Resistance Androgenism C. Oligo-anovulation PCOS D. Glucose intolerance E. All of the above 6% * Hyperandrogenism 2% 2% Chronic (clinical or biochemical) Anovulation y a e * Chronic oligo-anovulation i t e s i o n n c v e e m i t a o b n r b O u l a a o l e s u l i o v h e i n i n t f t * Exclusion of other disorders e e r o - a n s l l o y p g o A H O l i l u c G [ PAO on ultrasound in Rotterdam criteria set] PCOS Diagnostic Criteria PCOS: Chronic Oligo-Anovulation • Menstrual irregularity Diagnostic NIH Rotterdam AE-PCOS – feature 1990 2002 2006 Amenorrhea, oligomenorrhea Any 2 of 3 – Variable cycle length Androgens Elevated Elevated Elevated – DUB (dysfunctional uterine bleeding) Periods Irregular, fewer Irregular Irregular • Absence of molimenal symptoms than 8 per year OR • Prior need for ovulation induction Ovarian Not included in Polycystic Polycystic • No ovulation can be documented with morphology on NIH criteria morphology morphology – ultrasonography Ovulation prediction kit – Basal body temperature measurement – AE-PCOS: Androgen Excess and PCO Society Luteal phase progesterone level 8 PCOS: Hyperandrogenism Polycystic Appearing Ovaries (PAO) • A functional result of local ovarian hyperandrogenism… • Skin manifestations