A case of PCOS: A 30-year-old woman comes to clinic to discuss abnormal menstrual periods. Menarche was at age 14. Her periods were never entirely predictable but over the past year they have been occurring less often, about every two or three months. Her last menstrual period was two months ago. She has not been sexually active for over a year. She has no chronic medical problems. She takes ibuprofen occasionally for headaches and menstrual cramps but otherwise is on no other medications. Hypothalamic dysfunction is the most common cause of secondary amennorrhea (excluding pregnancy). Hypothalamic dysfunction due to emotional and/or physical stress is one of the most common causes of oligomenorrhea/secondary amenorrhea. Emotional stress, strict dieting, vigorous exercise, organic illness or anorexia nervosa may lead to menstrual irregularities. These symptoms should not be assumed to cause menstrual irregularities without a thorough physical and endocrine evaluation She complains of feeling “fat” and states she can’t lose weight even though she walks to work three times per week. She went for a facial last week and the beautician recommended that she start waxing her chin. She has been frustrated lately because she has been spending a lot of time plucking her chin hairs. Signs/symptoms of hyperandrogenism include: Non-virilizing Hirsutism: course hair growth in androgen-dependent body regions such as sideburn area, chin, upper lip, periareolar area, chest, lower abdominal midline and thigh. Acne Oily skin Abnormal menstrual cycles Infertility Virilizing* Clitorimegaly Deepening of the voice Male pattern balding Masculinization of body habitus Increased libido *Less commonly seen than non-virilizing symptoms The syndrome has an initial onset in peri-pubertal years and is progressive. Sudden onset of these symptoms suggests a different disorder such as Cushing’s syndrome or a hormone producing adrenal or ovarian tumor. Women with PCOS can display a wide range of clinical symptoms. Concerns about menstrual irregularities, hirsuitism, acne, or infertility are the most common reasons for seeking medical care. Presenting symptoms of PCOS: Symptom Prevalence Infertility 75% Hyperandrogenism 70% Amenorrhea 50% Obesity 60-80% Abnormal uterine bleeding 30% Normal menstruation 20% The etiology of PCOS is unknown but it is due to a steady state of high estrogen, androgens, luteinizing hormone (LH) and insulin levels. High estrogen causes cause suppression of pituitary follicle stimulating hormone (FSH) and a relative increase in LH. The increased LH stimulates the ovary, which results in anovulation, multiple cysts and theca cell hyperplasia with excess androgen output. High insulin levels may also increase the production of testosterone by the ovaries. PCOS is a common endocrine disorder affecting 4-7% of women of reproductive age. She read an article in her woman’s magazine about PCOS. She thinks she fits the bill. She wants you to test her for PCOS. There is not a confirmatory test for PCOS. It is a clinical diagnosis based on certain criteria as shown below. Ovarian cysts are not required for diagnosis. Cysts are present on ultrasound in more than 90% of women with PCOS but also present in up to 25% of normal women. Criteria for diagnosis of PCOS (4,5) Hyperandrogenism Sufficient to have elevated serum androgen levels or a biological expression of hyperandrogenism (acne or hirsutism) Irregular menses Anovulation or oligo-ovulation Absence of other causes of anovulation Thyroid disorders Hyperprolactinemia Cushing’s syndrome Late onset congenital adrenal hyperplasia (CAH) Ovarian and adrenal tumors Her exam is significant for oily skin, mild acne, coarse hair on her chin, and obesity (BMI 31). You tell her that you will check laboratory tests to screen for other conditions that could be causing her menstrual irregularities and excess hair growth. Initial work up in a patient with oligomenorrhea/secondary amenorrhea without signs of hyperandrogenism Test Indication Urine or serum B-HCG To exclude pregnancy TSH To exclude hypo or hyperthyroidism Serum prolactin level Prolactin > 250ng/ml virtually diagnostic of prolactin secreting pituitary adenoma Fasting morning 17hydroxyprogesterone Levels > 800 ng/dL (8ng/ml) highly suspicious for late-onset congenital adrenal hyperplasia (CAH) Levels between 200-800 ng/dL (2-8ng/ml) unclear Levels < 200 ng/dL (2ng/ml) usually no CAH Additional tests indicated in a patient with signs of hyperandrogenism Test Indication Total testosterone level Serum DHEAS level 24 hour urine cortisol orovernight dexamethasone Slightly elevated in PCOS Total testosterone > 200 ng/dL suspicious for adrenal or ovarian tumor Additional evaluation with pelvic US, CT or MRI indicated Slightly elevated in PCOS DHEAS level > 8 ng/ml suspicious for adrenal tumor Additional evaluation should include adrenal gland imaging with CT or MRI Urine free cortisol >20 ug/d is suggestive of Cushing’s Syndrome The rapid development (< 6 months) of symptoms of androgen excess such as menstrual irregularities, hirsutism, and weight gain are concerning for adrenal tumors, ovarian tumors or Cushing’s syndrome.* Although these are rare diseases, they must be screened for in women presenting with these symptoms. Prevalence per million population Adrenal tumors 2 Cushing’s Syndrome 2 Androgen secreting ovarian tumors less than 1 *Cushing’s Syndrome This term refers to the manifestations of excessive corticosteroids due to any number of underlying causes. Signs of corticosteroid excess include: Central obesity Violaceous abdominal striae Buffalo hump Moon facies Hypertension PCOS and late onset CAH are distinguished from each other only by laboratory testing. Congenital Adrenal Hyperplasia (CAH) Late-onset CAH (or non-classical), an autosomal recessive disease, presents in early adulthood with symptoms of oligomenorrhea and/or hirsutism. 90% of CAH is due to 21-hydroxylase deficiency. Patients with 21-hydroxylase deficiency do not form cortisol in normal amounts. The body recognizes the low levels of cortisol resulting in an upregulation of ACTH in an attempt to stimulate the adrenal cortex. This leads to adrenal stimulation and increased production of androgens. The diagnostic test for CAH is an elevated fasting level of 17hydroxyprogesterone. These levels are always greater than 200 ng/dL (6 nmol/L) in CAH. All abnormal tests should be confirmed with an ACTH stimulation test. Adrenal Gland Steroid Production Pathway You check lab tests and she has normal levels of TSH, 17-hydroxyprogesterone, prolactin, and DHEAS. She has a mildly elevated total testosterone level. You decide she most likely has PCOS. You counsel her on the complications of PCOS. Ovarian cancer Women with PCOS are not at increased risk for developing ovarian cancer. They are at increased risk for the following: Endometrial hyperplasia Chronic anovulation, obesity and hyperinsulinemia are associated with endometrial hyperplasia and endometrial cancer. This is likely due to prolonged exposure to unopposed estrogen. The risk of endometrial cancer in this population is hard to determine because there are so few cases of endometrial cancer in women under 40 (<4% of all cases) and few studies of endometrial cancer in women with PCOS. One retrospective study of 1270 anovulatory women found the RR of endometrial cancer to be 3.1 compared to the general population. Dyslipidemias 70% of women with PCOS will have abnormal lipid panels. Elevated triglycerides and LDL and low HDL are the most common abnormalities. Obesity 60-80% of women with PCOS are obese. It is predominantly of the android type with increased hip to waist ratio (>0.8). Impaired glucose tolerance and Type 2 diabetes Up to 40% of women with PCOS have impaired glucose tolerance (IGT) due to decreased insulin mediated glucose uptake by skeletal muscle. Risk of IGT and type 2 Diabetes Mellitus (DM) is increased in both obese and non-obese women with PCOS. Retrospective studies have shown two to five fold increase of type 2 diabetes in women with PCOS. A Prospective study of 254 women with PCOS without known diabetes was compared to a control group without PCOS or diabetes. In the PCOS group (obese and non-obese), the overall prevalence of IGT and type 2 diabetes was 31.1% and 7.5%, respectively. In the control group, the prevalence of IGT and type 2 diabetes was 14% and 0%, respectively. She is very concerned about her hirsutism and wants to know what her treatment options are. All combination oral contraceptive pills (OCPs) are effective in treating hirsutism, even those containing the more androgenic progestins (14). They decrease androgen levels by suppressing LH and stimulating serum hormone binding globulin (SHBG). OCPs with low androgenic progestins (norgestimate, desogestrel) may be the most effective. Treatment of Hirsutism Mechanical Shaving or depilation Electrolysis Laser epilation Combination Oral Contraceptive Pills OCPS with low androgenic progestins may be the most effective Androgen Receptor Blockers A full clinical effect may take 6 months or more Spironolactone 25-100mg bid. Flutamide 250 mg once a day Finasteride 1 mg a day Ornithine Decarboxylase Inhibitor (Vaniqa) A full clinical effect may take 6 months or more 13.9% cream BID Weight loss, OCPs, metformin and cyclic progesterone are all treatment options for oligomenorrhea/secondary amenorrhea and for preventing the development of endometrial hyperplasia. Treatment of Oligomenorrhea/Secondary Amenorrhea and Prevention of Endometrial Hyperplasia Weight Loss Decreases serum androgen, insulin, and LH levels Cyclic menstruation has been reported with weight loss as little as 5% of initial weight Oral Contraceptive Pill Regulates menstrual cycles Associated with a > 50% reduction in endometrial cancer risk in general population , but magnitude of risk reduction in women with PCOS not yet known Use 30-35 mcg of ethinyl estradiol and progestin with little androgenic activity (avoid norgestrel and levonorgestrel) Cyclic Progesterone Type of progestin, dose, and frequency to prevent endometrial cancer in women with PCOS is not known. Oral medroxyprogesterone 10mg daily for ten days either monthly or every three months Metformin 500mg bid-tid Restores menstrual cyclicity in 68-95% of patients treated for as short of a time as four to six months NOTE. For oligo/amenorrheic women who do not want to use medications on a regular basis, a transvaginal ultrasound every 6-12 months should be obtained. Women who are found to have an endometrial thickness of > 10mm should undergo an artificially induced bleed. If the endometrium is still thickened on follow-up ultrasound, an endometrial biopsy is recommended.