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Home , Amenorrhea, Anovulation

UCSF Essentials of Primary Care August 12, 2016 Squaw Creek, CA Disclosure • Understanding 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 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 for at least • Three cycle lengths OR six months – 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) Ovarian – Progestin-induced failure to withdraw (E 2 ) Failure Progesterone (P) Outflow Failure

2o Amenorrhea: Amenorrhea: Causes Hypothalamic Amenorrhea • Hypothalamic amenorrhea • • Pituitary amenorrhea Athlete's amenorrhea – • Ovarian failure Critical ratio of muscle to body exceeded – Despite exercise, risk (and fracture) • Outflow tract failure • Female athlete triad : disordered eating, amenorrhea, • Anovulatory amenorrhea and osteoporosis • 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 • – Low energy availability + disordered eating • Chronic – 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 – (-secreting adenoma) • > 40 years old: True – Drugs, esp antipsychotics • < 40 years old: Premature menopause – Primary – 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 – (mosaic or Fragile X) • Hypothyroid sxs, difficulty lactating, loss of pubic or underarm hair, low BP, fatigue,

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 -induced endometrial priming – Cyclic premenstrual sxs with uterine cramping • Causes • Asherman's Syndrome – Hyperandrogenic • – 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 - 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 • enlarged • Pregnancy •Positive: DX=PREGNANCY ; locate, date • 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 function tests PRL elevated: hyperprolactinemia evaluation – o – FSH, Estradiol (E ) level; not LH level TSH elevated: 1 hypothyroidism evaluation 2 – – If signs of : total , 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 : 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 Hyper- A. 44% B. Hyperinsulinemia Resistance Androgenism C. Oligo-anovulation PCOS D. Glucose intolerance E. All of the above 6% * 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 Elevated Elevated Elevated – DUB (dysfunctional uterine bleeding) Periods Irregular, fewer Irregular Irregular • Absence of molimenal symptoms than 8 per year OR • Prior need for Ovarian Not included in Polycystic Polycystic • No ovulation can be documented with morphology on NIH criteria morphology morphology – ultrasonography Ovulation prediction kit – measurement – AE-PCOS: Androgen Excess and PCO Society progesterone level

8 PCOS: Hyperandrogenism Polycystic Appearing (PAO)

• A functional result of local ovarian hyperandrogenism… • Skin manifestations “not a disease” • – Hirsutism (65%); peripubertally Low FSH results in “mid-antral arrest” or adolescence • Polycystic ovaries – – Acne (25%), seborrhea, alopecia 2.8 times normal size (volume > 10 mL) – – Mild to moderate acanthosis Atretic follicles doubled – nigricans Ultrasound: “String of black pearls” (12 follicles/ ovary) • – Obesity (35% to 60%) Prevalence of PAO – 75% with chronic anovulation – 16-23% of normal ovulatory women – 14% of OC users

Not…Criteria for PCOS Diagnosis Causes of Hyperandrogenism

• Ovarian • Obesity is not a diagnostic criterion for PCOS, and  approximately 20% of women with PCOS are not Polycystic ovary syndrome - PCOS  obese Ovarian androgen tumors • • Adrenal  Congenital adrenal hyperplasia • Polycystic appearing ovaries (PAO) on ultrasound  Cushing’s syndrome • Gonadotropin levels or ratios  Adrenal androgen tumors • Exogenous androgens; drug effects • Idiopathic

9 Virilization: Danger Signs Ovarian Tumors

• • Androgen secreting tumors Rapid onset of thick, pigmented hair – • Sertoli-Leydig cell Male pattern baldness – • Hilar cell Clitoral hypertrophy – – Lipoid cell “Cliteromegaly” defined as > 1 cm at base – Adrenal rest cell • Deepening of the voice • Total Testosterone > 200 ng/dL • Androgenic muscle development (in menopause, T > 100 ng/dL is abnormal) • Breast atrophy, masculine habitus • Diagnostic imaging – Pelvic/transvaginal ultrasound – Pelvic CT scan

Late Onset Congenital Adrenal Hyperplasia Cushing’s Syndrome • Overproduction of + adrenal androgens • • Caused by AKA: Non-classical CAH (NCCAH) – o • 1 : Adrenal tumors, hyperplasia Most common form is 21-hydroxylase deficiency – 2o: ACTH secreting adenoma • First seen in childhood or adolescence • Presentation – Late onset type is autosomal recessive – Hypertension – Most commonly seen in E European Jews (1/27), – Moon facies, buffalo hump, easy bruising Hispanics (1/40), Jugoslavs (1/50), Inuits, Italians – Centripetal obesity, striae • Laboratory confirmation – Proximal myopathies, osteoporotic fractures • – Fasting morning follicle phase 17-OHP > 2 ng/ml Laboratory – o – Confirm high level with ACTH stimulation test 24 urinary free cortisol > 100 mcg/24 hours – Confirmed with low dose dexamethasone suppression test

10 Adrenal Tumors Medications • Pathology – Adrenal carcinomas: usually large • Anabolic Steroids (methyl-T or injected) – Adrenal adenomas: small, very uncommon • Phenytoin – Dilantin R • Total Testosterone < 200 ng/dl • R • Cyclosporine – Neoral DHEAS > 700 ug/dl • R R • Confirmation of diagnosis Minoxidil – Loniten , Rogaine • – CT or MRI scan Danazol -Danocrine • Incidentally discovered adrenal • masses require evaluation • DHEA (food supplement)

Case Study Which studies would you offer her?

• 22 year old woman with unpredictable menses every A. 17 alpha hydroxy progesterone (17-OHP) 5-8 weeks, lasting 2-8 days since menarche 33% • Recent immigrant from Mexico B. Total testosterone 24% 24% • Backache and cramps before menses, but no other C. FSH, LH levels molimenal symptoms D. Pelvic ultrasound for PAO 16% • BMI=28, BP 122/78 E. All of the above • PE: mild acne, upper lip has some hair growth, no F. None of the above 1% 1%

e l s n v e v e galactorrhea .. v e o o . r o e r e l b a b s t L H e g e s t e t h e a t h o H, f r S o o f p l t e s t o F e t a A l l x y o rasound for PAO r o T t N o n y d c u l h i a h P e l v l p a 7 1

11 Diagnosis of PCOS Basic Evaluation of PCOS

• PCOS is a clinical diagnosis • Check blood pressure – Chronic oligo-anovulation + hyperandrogenism • Measure BMI + waist circumference ( + hip) • Lab tests may be necessary to… – – Waist circumference >35 inches Differentiate PCOS from other causes of – • Waist/hip ratio > 0.72 Virilization • • In women with “clinical PCOS”, screen for Amenorrhea o – – T2DM: FBS+ 2 post-glucose load test with 75-g glucose Screen (or test) for sequelae of PCOS • •Metabolic syndrome (DM, lipids, HTN) Impaired glucose tolerance (IGT): 140-199 mg/dl • • T2DM: > 200 mg/dl – Choose optimal drug for ovulation induction – Hyperlipidemia: fasting lipid panel – Screen both every 2 years; annually if IGT

Further Evaluation of PCOS Further Evaluation of PCOS

• If cycle irregularity, add • If hirsuitism , add – Prolactin, TSH – • 17a-hydroxy progesterone (17-OHP), if risk factors If amenorrhea ( > 3 missed menses or LMP > 6 months), add for late onset CAH – Prolactin, TSH, pregnancy test – – Normal morning follicle phase level less than 2 Progestin challenge ng/mL or random level less than 4 ng/mL – If no withdrawal bleed, check LH, FSH • If non-hirsuite , add • If dysfunctional uterine bleeding , add – – Total testosterone Pregnancy test, hematocrit – – Some experts recommend free testosterone, but if hyperplasia suspected only from reliable lab

12 Further Evaluation of PCOS PCOS: Goals of Treatment • If virilization (in addition to hirsuitism), add • Support lifestyle changes to achieve normal body wt – DHEAS (for adrenal tumor) and • Treat hirsuitism and acne by reducing androgen – Total testosterone (for ovarian tumor) • Protect the endometrium against unopposed E • If T, pelvic ultrasound for ovarian tumor • Induce ovulation to achieve pregnancy • If stigmata of Cushing’s Disease , add • Minimize insulin resistance to prevent (or delay) type 2 – Urinary 24 hour free cortisol or diabetes – Overnight dexamethasone suppression test • Minimize the impact of metabolic syndrome on the development cardiovascular disease

Treatment of PCOS: Anovulation Treatment of PCOS: Anovulation

• Weight loss (to BMI <27) Cyclic progestins • Combination oral contraceptives • Given first 14 days of each or every other month – Regulates cycles – Regulates cycles – Prevents endometrial hyperplasia – Prevents endometrial hyperplasia – Provides contraception – No contraceptive effect (unless DMPA or POP) – Decreases free T; controls acne and hirsuitism – No studies as treatment for hirsuitism – May prevent atheroma formation and reduce CV risk

13 Treatment of PCOS in Women with PCOS

Improve (reduce) insulin resistance • Restores normal menses and ovulation in 68-95% of • Metformin (Glucophage); insulin-sensitizing agent women with PCOS; uses include – Improves insulin sensitivity – Ovulation induction (with clomiphene) – Decreases LH, decreases free T – Treatment of Type 2 DM – May increase SHBG – Regularize menstrual cyclicity • Metformin use • Unproven uses (and not currently recommended) – 500 mg bid to tid (or 850 mg bid) – Treatment of hirsuitism or obesity – Do not use if creatinine > 1.4 mg/dl or risk of renal – Prevention of diabetes or CVD morbidity dysfunction (risk of lactic acidosis) – Routine treatment of PCOS without glucose intolerance – GI adverse effects

PCOS and Diabetes Risk PCOS and Cardiovascular Risk

• • Exercise with dietary change consistently reduces Women with PCOS should be screened for diabetes risk comparable to or better than meds – CV risk by determination of BMI – • Recent studies have suggested little benefit to the Fasting lipid and lipoprotein levels addition of metformin above lifestyle therapy alone – Metabolic syndrome risk factors • • Data are insufficient to recommend ISAs prophylactically Regular exercise and weight control are proven methods to prevent diabetes in women with PCOS to reduce CV morbidity and mortality – These modalities should be considered before prescription drugs are used

ACOG Practice Bulletin Obstet Gynecol 2009;114:936 ACOG Practice Bulletin Obstet Gynecol 2009;114:936

14 Regional Hair Removal Hair Removal – Permanent

• Hair electrolysis • Bleaching – skin irritation – • Electric current - multiple treatments Depilation (cut to skin surface) – – $60 - $100 per hour, $1,000 to $3,000 per yr Shaving – irritation, acne, hasten growth • – Laser hair removal/ IPL (intense pulsed light) Chemical depilatories – skin irritation – • 20-80% of hair removed in 2-3 treatments Epilation (remove hair to dermal bulb) – – Average 50% less hair at 4 months Plucking – time consuming, scaring – – Waxing – temporary Nd: YAG laser – – Epilatory device Long-pulse ruby or alexandrite – 1 to 3 hours per treatment

Hirsuitism: Oral Contraceptives Hirsuitism: A Multidisciplinary Approach • Mechanism – • Clinician Progestin reduces testosterone secretion • – Estrogen increases SHBG; reduces free T Aestetician – • Drospirenone may block androgen receptor Laser therapist • • Stop further hair growth; will not reverse hirsuitism Electrologist • • Response is slow; > 6 months of treatment required to 3-6 months of treatment required before improvement demonstrate impact for most patients • Choice of progestin – Preferred: drospirenone, , norgestimate – Avoid: l-norgestrel (relatively more androgenic )

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• Inhibits binding of DHT to androgen receptor • Dosage of 75 mg to 200 mg per day – Begin with 50 mg bid, if no response after 3 mo Thanks and safe trip home! increase to 100 mg bid • Adverse effects – Nausea, fatigue, headache – Hyperkalemia (if renal impairment or diabetes) • Change in Ferriman-Gallwey (hirsuitism) score – Spironolactone alone  28% – Spironolactone+OC  41%

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