Polycystic Ovarian Syndrome-implications of new metabolic ...


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  • Making the diagnosis sounds easy but even the experts weren’t in agreement for many yrs in the 90’s. Now I can share with you guidance on making the clinical diagnosis.
  • PCOS shows the following on U/S classically: Multiple, small (8-10) subcapsular cysts reflecting repeated episodes of incomplete follicular growth found adjacent to one another in a “string of Pearls” manner. There is also a dense, hyperplastic stroma reflecting an active thecal component that is over secreting androgens.
  • A ratio of less than 4.5 of fasting glucose to insulin levels correlates significantly with insulin resistance and has been studied for use as a screening test in obese patients with PCOS
  • Testosterone needed if considering treatment with antiandrogen for hisuitism as levels can then be followed. DHEAS not needed. Fasting morning 17-hydroxyprogesterone 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 A ratio of less than 4.5 of fasting glucose to insulin levels correlates significantly with insulin resistance and has been studied for use as a screening test in obese patients with PCOS. Suggested only in selected patients. Information from Legro RS. Polycystic ovary syndrome: current and future treatment paradigms. Am J Obstet Gynecol 1998;179:S101-8.
  • The body recognizes the low levels of cortisol resulting in an up regulation of ACTH in an attempt to stimulate the adrenal cortex. This leads to adrenal stimulation and increased production of androgens.
  • 75% of PCOS women have IR Breast cancer patients found to be hyperinsulinemic and best data to support IR association. Prostate, colon and liver cancers also more common in obese pts with type 2 DM or pts with increased insulin levels. Up to 50% of all pts with essential HTN are IR. Metabolic syndrome is defined to capture subset of people with IR at risk for CVD so as to be a practical dx to address CVD risk but IR syndrome may be better way to describe etiology and more studies are looking at IR. insulin resistance is not a disease but the description of a physiologic state that greatly increases the chances of an individual developing several closely related abnormalities and associated clinical syndromes. PCOS pts may have IR and it is not obesity dependent.
  • 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.
  • 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 .
  • Increased SHBG leads to decreased free testosterone Yasmin (drospirenone/ ethinyl estradiol) contains an anti-androgen roughly equivalent to spironolactone 25mg. Orthotricyclen with norgestimate has FDA approval fot the tx of hirsuitism but most experts believe all the 3 rd generation ocps to be as efficacious for hirsuitism as they all have less androgenic progestins.
  • Per Habif: Excess facial hair may be plucked, shaved, bleached, wax stripped, or removed by chemical depilatories. These treatments only temporarily alleviate the problem because irritation or plucking rapidly induces the anagen stage and hair-follicle growth. Electrolysis and selective photothermolysis with the use of lasers destroy the hair shaft, outer root sheath, bulge, and dermal papilla of the hair follicles. The extent of the destruction determines whether the follicle regenerates. Permanent follicular destruction with an electrical probe that is passed into the follicle is a good option for women with small areas of facial hair. There has been an explosive increase in the use of lasers for hair removal since the first lasers were approved in 1996. Currently most devices target melanin in the hair follicle with millisecond-long pulse durations to produce, to some degree, selective photothermolysis of hair follicles. Multiple treatments are necessary. Hair clearance, after repeated treatments, of 30% to 50% is generally reported 6 months after the last treatment. Temporary adverse effects include erythema and perifollicular edema, which are common. Crusting, vesiculation, hypopigmentation, and hyperpigmentation (depending on skin color and other factors) may also occur. Great article for further info Removal of unwanted facial hair. Shenenberger DW - Am Fam Physician - 15-NOV-2002; 66(10): 1907-11
  • All non-FDA approved indications! These androgen receptor blockers can be used in combination with ocp in cases when ocp alone is not adequate Testosterone levels can be followed to show efficacy with goal < 60. It is postulated that topical eflornithine HCl irreversibly inhibits skin ODC (ornithine decarboxylase) activity which slows the rate of hair growth. Marked improvement was seen consistently at 8 weeks after initiation of treatment and continued throughout the 24 weeks of treatment. Hair growth approached pretreatment levels within 8 weeks of treatment withdrawal. Vaniqa has only been studied on the face and adjacent involved areas under the chin of affected individuals. If skin irritation or intolerance develops, direct the patient to temporarily reduce the frequency of application ( e.g., once a day). If irritation continues, the patient should discontinue use of the product. Apply a thin layer of Vaniqa to affected areas of the face and adjacent involved areas under the chin and rub in thoroughly. Do not wash treated area for at least 4 hours. Use twice daily at least 8 hours apart or as directed by a physician. IV vaniqa is used to treat sleeping sickness caused by Trypanosoma brucei gambiense. Cost $52.90 for 30gm tube. Propecia ( finasteride ), a synthetic 4-azasteroid compound, is a specific inhibitor of steroid Type II 5α-reductase, an intracellular enzyme that converts the androgen testosterone into 5α-dihydrotestosterone (DHT). Cost about $54 for 30d supply. Flutamide warning-Serum transaminase levels should be measured prior to starting treatment with flutamide . Flutamide is not recommended in patients whose ALT values exceed twice the upper limit of normal. Serum transaminase levels should then be measured monthly for the first 4 months of therapy, and periodically thereafter. Liver function tests also should be obtained at the first signs and symptoms suggestive of liver dysfunction, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, hyperbilirubinuria, jaundice or right upper quadrant tenderness. If at any time, a patient has jaundice, or their ALT rises above 2 times the upper limit of normal, flutamide should be immediately discontinued with close follow-up of liver function tests until resolution. Cost $374 for 3 month supply. In animal studies, flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. One metabolite of flutamide is 4-nitro-3-flouro-methylaniline. Several toxicities consistent with aniline exposure, including methemoglobinemia, hemolytic anemia and cholestatic jaundice have been observed in both animals and humans after flutamide administration. In patients susceptible to aniline toxicity ( e.g., persons with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease and smokers), monitoring of methemoglobin levels should be considered. There is a drug interaction with warfarin. Spironolactone- competitively binds androgen receptors as well as inhibits alpha-reductase activity. Concomitant administration of potassium-sparing diuretics and ACE inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., indomethacin, has been associated with severe hyperkalemia. Cost $82 for 100 tablets of 50 mg.
  • There were statistically significant improvements in Ferriman-Galwey scores 12 mos after the end of treatment with spironolactone 100mg/d vs. cyproterone acetate 12.5mg/d first 10 d of cycle and 5mg/d of finasteride as well (Level A) Cyproterone acetate is a 17-hydroxyprogesterone acetate derivative with strong progestagenic properties. Cyproterone acetate acts as an antiandrogen by competing with DHT and testosterone for binding to the androgen receptor. There is also some evidence that cyproterone acetate and ethinyl estradiol in combination can inhibit 5α-reductase activity in skin.[ 355 ] Cyproterone acetate is currently not available in the United States but has been used in other countries. The drug is mostly administered in doses of 50 to 100 mg from days 5 through 15 of the treatment cycle. Because of its slow metabolism, it is administered early in the treatment cycle, whereas ethinyl estradiol, when added, is usually used at 50-µg doses between days 5 and 26. This regimen is needed for menstrual control and is usually referred to as the reverse sequential regimen. Cyproterone acetate in doses of 50 to 100 mg/day, combined with ethinyl estradiol at 30 to 35 µg/day, is as effective as the combination of spironolactone, 100 mg/day, and an oral contraceptive in the treatment of hirsutism.[ 197 ] In smaller doses (2 mg), cyproterone acetate has been administered as an oral contraceptive in daily combination with 50 or 35 µg of ethinyl estradiol Flutamide has risk of hepatic toxicity Finasteride prevents conversion of testosterone to active dihydrotestosterone Doses spironolactone start 25-50mg/d and increase to 100-200mg/d Flutamide start 125mg qd then bid and up to max dose 250mg bid and causes photosensitivity and requires lft monitoring
  • Not FDA approved for this use
  • U/S follow-up is expensive and time consuming but ACOG wants MD’s to not just forget the risk these women have for endometrial CA. A recent study demonstrates the limitations of transvaginal ultrasound for measuring endometrial thickening. In 19% of women with thin endometria on ultrasound, the actual endometrial thickness was >5 mm -- calling into question the common U.S. practice of avoiding further evaluation of bleeding in menopausal women with ultrasonographic endometrial thickness [<=]5 mm. Rigid reliance on ultrasound measurement is inadvisable, especially when clinical symptoms suggest pathology.
  • In a small study, metformin significantly improved the pregnancy rate in clomiphene resistant women with PCOS compared to placebo.
  • Examples of TZD’s are Actos (Pioglitazone Hydrochloride) (cost $109/30d supply) and   or Avandia (Rosiglitazone Maleate) (cost $87 for 30d supply). They work by decreasing insulin resistance and may also benefit TG, HDL profile. And aromatase inhibitors are like Anastrozole or Arimidex which is a potent and selective non-steroidal aromatase inhibitor . It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone. Cost $234 for 1 month. Femara and Teslac are other examples and are used in tx for breast cancer esp in postmenopausal women. Ovarian drilling does not improve cumulative ongoing pregnancy rates compared with gonadotropin ovulation but is assoc with fewer multiple pregnancies Ovarian wedge, drilling or laser vaporization has obvious surgical and anesthesia risk and does not effect IR or obesity but can give long term effect on ovary and androgen production. Serum concentrations of LH and testosterone decrease rapidly after ovarian drilling with a sustained mid- and long-term effect .
  • She has had her lesion since puberty. Per Habif: The interaction between excessive amounts of circulating insulin with insulin-like growth factor receptors on keratinocytes may lead to the development of acanthosis nigricans Drug-induced acanthosis nigricans has occurred with the use of nicotinic acid Lesions are usually asymptomatic and do not require treatment. Reducing thicker lesions in areas of maceration may decrease odor and promote comfort. Lac-Hydrin, a 12% lactic acid cream, applied as needed may soften lesions. Retinoic acid (Retin-A cream or gel) applied each day, or less often if irritation occurs, is effective. Oral isotretinoin (Accutane) is useful, but acanthosis nigricans recurs when the drug is discontinued Acanthosis nigricans can be a paraneoplastic syndrome that occurs in non-obese adults. In 80% to 90% of all instances, the cancer is abdominal ; in 60% of cases, the cancer arises in the stomach. Other associated carcinomas have included those of the uterus, liver, esophagus, pancreas, prostate, ovaries, kidneys, colon, and rectum. Almost all cancers that accompany this dermatosis have been adenocarcinomas . However, there also have been reported instances of anaplastic carcinoma of the lung and stomach, squamous cell carcinoma of the cervix and lung, choriocarcinoma, lymphosarcoma, reticulum cell sarcoma, and Hodgkin's disease associated with acanthosis nigricans .
  • Metformin is Category B in pregnancy
  • Polycystic Ovarian Syndrome-implications of new metabolic ...

    1. 1. Polycystic Ovarian Syndrome-Review of EBM Treatment Recommendations Lisa McGowan CDR, MC, USN US Naval Hospital Naples
    2. 2. Polycystic Ovarian Syndrome (PCOS)- Why is this important? <ul><li>One of the most common endocrine disorders of women </li></ul><ul><li>Most frequent cause of anovulatory infertility </li></ul><ul><li>PCOS strongly associated with Insulin Resistance </li></ul><ul><li>Insulin Resistance puts patients at risk for DM, CVD, HTN, OSA, etc. </li></ul>
    3. 3. Learning Objectives <ul><li>Review diagnostic criteria for PCOS. </li></ul><ul><li>Review evidence supporting metabolic implications such as insulin resistance, dyslipidemia, and hypertension as well as their long term consequences. </li></ul><ul><li>Review EBM treatment options for irregular bleeding, ovulation induction, androgen excess, weight loss, and glucose intolerance. </li></ul>
    4. 4. PCOS Prevalence <ul><li>PCOS is the most common endocrine disorder affecting 5-10% of women of reproductive age. </li></ul>
    5. 5. PCOS Presentation <ul><li>Initial onset in the peri-pubertal years and progressive in nature. </li></ul><ul><li>Sudden onset of these symptoms suggests other differential diagnoses: </li></ul><ul><ul><li>Cushing’s syndrome </li></ul></ul><ul><ul><li>Adrenal or ovarian tumor. </li></ul></ul><ul><li>Women with PCOS may have a wide range of clinical symptoms. </li></ul><ul><ul><li>menstrual irregularities, hirsuitism, acne, or infertility are the most common reasons for seeking medical care. </li></ul></ul>
    6. 6. PCOS Presentation <ul><li>Symptom/Prevalence: </li></ul><ul><ul><li>Infertility 75% </li></ul></ul><ul><ul><li>Hyperandrogenism 70% </li></ul></ul><ul><ul><li>Amenorrhea 50% </li></ul></ul><ul><ul><li>Obesity 60-80% </li></ul></ul><ul><ul><li>Abnormal uterine bleeding 30% </li></ul></ul><ul><ul><li>Normal menstruation 20%  </li></ul></ul>
    7. 7. PCOS Etiology <ul><li>Exact etiology of PCOS is still unknown </li></ul><ul><ul><li>likely due to a steady state of high estrogen, androgens, luteinizing hormone (LH) and insulin levels. </li></ul></ul><ul><li>High estrogen levels can cause suppression of pituitary FSH and relative increase in LH. </li></ul><ul><li>Increased LH stimulates the ovary, which results in anovulation, multiple cysts and theca cell hyperplasia with excess androgen output. </li></ul><ul><li>High insulin levels may also increase the production of testosterone by the ovaries. </li></ul>
    8. 8. PCOS Diagnosis <ul><li>No single confirmatory test for PCOS. </li></ul><ul><li>It is a clinical diagnosis . </li></ul><ul><li>Ovarian cysts are not required for diagnosis. </li></ul><ul><li>Cysts are present on ultrasound in more than 90% of women with PCOS but also present in up to 25% of normal women. </li></ul>
    9. 9. Criteria for Diagnosis of PCOS <ul><li>Task Force for Androgen Excess/PCOS 2006 </li></ul><ul><ul><li>Hyperandrogenism </li></ul></ul><ul><ul><ul><li>Elevated serum androgen levels or </li></ul></ul></ul><ul><ul><ul><li>Biological expression of hyperandrogenism (acne or hirsutism) </li></ul></ul></ul><ul><ul><li>Ovarian Dysfunction </li></ul></ul><ul><ul><ul><li>Anovulation or oligo-ovulation or </li></ul></ul></ul><ul><ul><ul><li>Polycystic ovaries </li></ul></ul></ul><ul><ul><li>Absence of other causes of anovulation </li></ul></ul><ul><ul><ul><li>Thyroid disorders </li></ul></ul></ul><ul><ul><ul><li>Hyperprolactinemia </li></ul></ul></ul><ul><ul><ul><li>Cushing’s syndrome </li></ul></ul></ul><ul><ul><ul><li>Late onset congenital adrenal hyperplasia (CAH) </li></ul></ul></ul><ul><ul><ul><li>Ovarian and adrenal tumors </li></ul></ul></ul>
    10. 10. Hyperandrogenism <ul><li>Non-virilizing signs/sxs include : </li></ul><ul><ul><li>Hirsutism: course hair growth in androgen-dependent body areas such as sideburn area, chin, upper lip, periareolar area, chest, lower abdominal midline and thigh. </li></ul></ul><ul><ul><li>Acne </li></ul></ul><ul><ul><li>Oily skin </li></ul></ul><ul><ul><li>Abnormal menstrual cycles </li></ul></ul><ul><ul><li>Infertility </li></ul></ul>
    11. 11. Hyperandrogenism <ul><li>Virilizing signs/sxs include:* </li></ul><ul><ul><li>Clitorimegaly </li></ul></ul><ul><ul><li>Deepening of the voice </li></ul></ul><ul><ul><li>Male pattern balding </li></ul></ul><ul><ul><li>Masculinization of body habitus </li></ul></ul><ul><ul><li>Increased libido </li></ul></ul><ul><ul><li>*Less commonly seen than non-virilizing symptoms </li></ul></ul>
    12. 12. PCOS Endocrine Abnormalities on Laboratory Tests <ul><ul><li>Elevated androgen (i.e. testosterone > 60 or free testosterone >0.75) levels </li></ul></ul><ul><ul><li>Elevated LH:FSH ratio > 2:1 </li></ul></ul><ul><ul><li>Insulin resistance with hyperinsulinemia </li></ul></ul>
    13. 13. Suggested Laboratory Evaluation of PCOS <ul><li>Prolactin level </li></ul><ul><li>Testosterone level </li></ul><ul><li>LH and FSH </li></ul><ul><li>TSH </li></ul><ul><li>Fasting glucose level or 2 hr OGTT </li></ul><ul><li>Lipid profile, including total, LDL,HDL </li></ul><ul><li>17-hydroxyprogesterone level* </li></ul><ul><li>*--Fasting level to r/o CAH </li></ul>
    14. 14. Screening Tests for PCOS <ul><li>ACOG recommends that all women with a suspected diagnosis of PCOS should be screened with </li></ul><ul><ul><li>17-hydroxyprogesterone level to </li></ul></ul><ul><ul><li>R/O late onset CAH (Level C). </li></ul></ul><ul><li>PCOS and late onset CAH are distinguished from each other only by laboratory testing. </li></ul>
    15. 15. Congenital Adrenal Hyperplasia (CAH) <ul><li>Late-onset presents in early adulthood. </li></ul><ul><li>Autosomal Recessive. </li></ul><ul><li>Presents with oligomenorrhea and/or hirsutism. </li></ul><ul><li>90% due to 21-hydroxylase deficiency. </li></ul><ul><li>Patients with 21-hydroxylase deficiency do not form cortisol in normal amounts. </li></ul><ul><li>Diagnostic test is elevated fasting </li></ul><ul><li>17-hydroxyprogesterone. </li></ul><ul><ul><li>always > 2 ng/mL . </li></ul></ul><ul><ul><li>All abnormal tests should be confirmed with ACTH stimulation test. Consider endocrine referral. </li></ul></ul>
    16. 16. Lab Tests for SUDDEN onset of Hyperandrogenism <ul><li>Test Result </li></ul><ul><li>Total testosterone level Slightly elevated in PCOS </li></ul><ul><li>Total testosterone > 200 ng/dL suspicious for adrenal or ovarian tumor therefore additional evaluation with pelvic US, CT or MRI indicated </li></ul><ul><li>Serum DHEAS level Slightly elevated in PCOS </li></ul><ul><li>DHEAS level > 8 ng/ml suspicious for adrenal tumor therefore additional evaluation should include adrenal gland imaging with CT or MRI </li></ul><ul><li>24 hour urine cortisol or overnight dexamethasone </li></ul><ul><li>Urine free cortisol >20 ug/d is suggestive of Cushing’s Syndrome </li></ul>
    17. 17. Prevalence of Conditions to be Ruled Out <ul><ul><li>Adrenal tumors 2 per million </li></ul></ul><ul><ul><li>Cushing’s Syndrome 2 per million </li></ul></ul><ul><ul><li>Androgen secreting ovarian tumors < 1 per million </li></ul></ul>
    18. 18. Intermediate and Long-Term Consequences Associated with PCOS <ul><li>Infertility </li></ul><ul><li>Recurrent spontaneous abortion </li></ul><ul><li>Depression/anxiety </li></ul><ul><li>Dyslipidemias </li></ul><ul><ul><li>Total cholesterol (elevated) </li></ul></ul><ul><ul><li>LDL cholesterol (elevated) </li></ul></ul><ul><ul><li>HDL cholesterol (decreased) </li></ul></ul><ul><ul><li>Triglycerides (elevated) </li></ul></ul><ul><li>Hypertension </li></ul><ul><li>Type 2 diabetes mellitus </li></ul><ul><li>Coronary atherosclerosis </li></ul><ul><li>Cerebrovascular accidents </li></ul><ul><li>Endometrial carcinoma </li></ul><ul><li>NOTE: Listed in order from most common to least common . </li></ul>
    19. 19. Clinical Syndromes associated with Insulin Resistance <ul><li>Type 2 diabetes    </li></ul><ul><li>Cardiovascular disease    </li></ul><ul><li>Essential hypertension    </li></ul><ul><li>Polycystic ovary syndrome    </li></ul><ul><li>Non-alcoholic fatty liver disease (NASH)    </li></ul><ul><li>Certain forms of cancer -breast,colon,liver,prostate   </li></ul><ul><li>Sleep apnea </li></ul>
    20. 20. PCOS Consequences <ul><li>Insulin Resistance- up to 75% </li></ul><ul><ul><li>Evaluate for HTN, OSA, NASH, Metabolic Syndrome, etc. </li></ul></ul><ul><li>Endometrial Hyperplasia </li></ul><ul><ul><li>Chronic anovulation, obesity and hyperinsulinemia are associated with endometrial hyperplasia and endometrial cancer. </li></ul></ul><ul><ul><li>This is likely due to prolonged exposure to unopposed estrogen. </li></ul></ul><ul><ul><li>Endometrial cancer risk is 3 times that of general population. </li></ul></ul>
    21. 21. PCOS Consequences <ul><li>Dyslipidemias </li></ul><ul><ul><li>70% of women with PCOS will have abnormal lipid panels. </li></ul></ul><ul><ul><li>Elevated triglycerides and LDL and low HDL are the most common abnormalities. </li></ul></ul><ul><ul><li>All women with PCOS should be screened with fasting lipid panel ( Level A). </li></ul></ul><ul><li>Obesity </li></ul><ul><ul><li>60-80% of women with PCOS are obese. </li></ul></ul><ul><ul><li>It is predominantly of the android type with increased hip to waist ratio (>0.8). </li></ul></ul>
    22. 22. PCOS Complications <ul><li>Impaired Glucose Tolerance / </li></ul><ul><li>Type 2 Diabetes </li></ul><ul><ul><li>Up to 40% of women with PCOS have impaired glucose tolerance (IGT). </li></ul></ul><ul><ul><li>Risk of IGT and Type 2 Diabetes Mellitus (DM) is increased in both obese and non-obese women with PCOS. </li></ul></ul><ul><ul><li>Retrospective studies have shown 2 to 5 fold increase of type 2 diabetes in women with PCOS. </li></ul></ul>
    23. 23. Treatment- Acne and Hirsuitism <ul><li>All combination OCPs effective </li></ul><ul><li>OCPs decrease androgen levels by suppressing LH and stimulating sex hormone binding globulin (SHBG). </li></ul><ul><li>OCPs with low androgenic progestins (norgestimate, desogestrel) may be most effective for acne and hirsuitism (Level B) </li></ul>
    24. 24. Treatment of Hirsuitism <ul><li>Mechanical </li></ul><ul><ul><li>Shaving or depilation </li></ul></ul><ul><ul><li>Electrolysis </li></ul></ul><ul><ul><li>Laser epilation (Level A) </li></ul></ul><ul><ul><ul><li>30-50% reduction at 6 mos after multiple txs </li></ul></ul></ul><ul><li>Combination Oral Contraceptive Pills </li></ul><ul><ul><li>OCPs with low androgenic progestins most effective </li></ul></ul>
    25. 25. Hirsuitism Treatment <ul><li>Metformin </li></ul><ul><ul><li>Reduces hirsuitism after 12 mos tx (Level A) </li></ul></ul><ul><li>Androgen Receptor Blockers </li></ul><ul><ul><li>A full clinical effect may take 6 months or more </li></ul></ul><ul><ul><li>Spironolactone 25-100mg bid (Level A) </li></ul></ul><ul><ul><li>Flutamide 250 mg daily x 12 mos ( Level A) </li></ul></ul><ul><ul><li>Cyproterone acetate-ethinylestradiol </li></ul></ul><ul><ul><li>50-100mg daily (Level A) (not avail in US) </li></ul></ul><ul><ul><li>Finasteride 1 mg a day (Level C) </li></ul></ul>
    26. 26. Hirsuitism Treatment <ul><li>Topical </li></ul><ul><ul><li>Ornithine Decarboxylase Inhibitor (Vaniqa) </li></ul></ul><ul><ul><ul><li>13.9% cream BID (Level C) </li></ul></ul></ul><ul><li>Combination therapy </li></ul><ul><ul><li>OCP + antiandrogen may be most effective (Level C) </li></ul></ul>
    27. 27. Oligomenorrhea/Amenorrhea Treatment <ul><li>Weight loss </li></ul><ul><li>OCPs </li></ul><ul><li>Metformin </li></ul><ul><li>Cyclic progesterone </li></ul><ul><li>All treatment options above prevent development of endometrial hyperplasia </li></ul>
    28. 28. Treatment of Oligomenorrhea Prevention of Endometrial Hyperplasia <ul><li>Weight Loss </li></ul><ul><li>Decreases serum testosterone, insulin, and LH levels </li></ul><ul><li>Cyclic menstruation has been reported with weight loss as little as 5% of initial weight </li></ul><ul><li>Oral Contraceptive Pill </li></ul><ul><li>Regulates menstrual cycles </li></ul><ul><li>Associated with a > 50% reduction in endometrial cancer risk in general population, but magnitude of risk reduction in women with PCOS not yet known </li></ul><ul><li>Use 30-35 mcg of ethinyl estradiol and progestin with little androgenic activity </li></ul>
    29. 29. OCP Benefits for PCOS <ul><li>Regular withdrawal bleeding </li></ul><ul><li>Reduction in the risk of endometrial hyperplasia or cancer </li></ul><ul><li>Reduction in LH secretion and consequent reduction of ovarian androgens </li></ul><ul><li>Increased sex hormone binding globulin production and consequent free testosterone reduction </li></ul><ul><li>Improvement in acne and hirsuitism </li></ul>
    30. 30. Treatment of Oligomenorrhea and Prevention of Endometrial Hyperplasia <ul><li>Cyclic Progesterone </li></ul><ul><li>Type of progestin, dose, and frequency to prevent endometrial cancer in women with PCOS is not known. </li></ul><ul><li>Oral provera 10mg daily for ten days either monthly or every three months recommended. </li></ul>
    31. 31. Treatment of Oligomenorrhea and Prevention of Endometrial Hyperplasia <ul><li>Metformin </li></ul><ul><li>500mg PO BID-TID </li></ul><ul><li>Restores menstrual cyclicity in 68-95% of patients treated for as short of a time as 4-6 months </li></ul>
    32. 32. Prevention of Endometrial Cancer <ul><li>PCOS women who do not want to use medications on a regular basis, ACOG recommends transvaginal US every 6-12 mos </li></ul><ul><li>Women with endometrial thickness of > 10mm should undergo an artificially induced bleed. </li></ul><ul><li>If the endometrium is still thickened on follow-up US, endometrial biopsy is recommended. </li></ul>
    33. 33. PCOS Presentation <ul><li>Which of the following is considered first line therapy for infertility associated with PCOS? </li></ul><ul><li>Weight loss </li></ul><ul><li>Clomiphene citrate </li></ul><ul><li>Metformin </li></ul><ul><li>All of the above </li></ul>
    34. 34. Treatment of Infertility in PCOS <ul><li>All of the above. </li></ul><ul><li>Weight loss should be the mainstay of treatment for all women with PCOS (Level A). </li></ul><ul><li>Clomid, metformin and thiazolidinediones (TZDs) can all improve ovulation and pregnancy rates in PCOS women (Level A). </li></ul><ul><li>In a Cochrane review, metformin was found to be an effective first line agent to treat anovulation in PCOS women. </li></ul><ul><ul><li>There was a significant reduction in fasting insulin levels, BP, and LDL (Level A). </li></ul></ul>
    35. 35. Treatment of Infertility in PCOS <ul><li>First Line Therapy is Weight loss </li></ul><ul><li>Changes in body weight have been associated with improved ovulation and pregnancy rates. </li></ul><ul><li>Weight loss as little as 5% of initial weight has shown benefit. </li></ul>
    36. 36. Treatment of Infertility in PCOS <ul><li>Clomiphene Citrate (Clomid) </li></ul><ul><li>Initiates ovulation by anti-estrogenic effect on hypothalamus, results in increased GnRh release; increased FSH drives the development of ovarian follicles. </li></ul><ul><li>Up to 80% of women with PCOS will ovulate in response to clomiphene and 50% of these women will conceive. </li></ul>
    37. 37. Treatment of Infertility in PCOS <ul><li>Metformin </li></ul><ul><li>Randomized trials using metformin have shown improved ovulatory frequency in women with PCOS (Level A). </li></ul><ul><li>Metformin in doses of 500 mg BID/TID restored menstrual cyclicity in 68-95% of patients treated for four to six months. </li></ul><ul><li>Metformin with clomiphene increases ovulation and pregnancy rates compared to clomiphene alone (Level A). </li></ul>
    38. 38. Treatment of Infertility in PCOS <ul><li>Second Line Therapy </li></ul><ul><li>Thiazolidinediones (TZDs) (Level A) </li></ul><ul><li>Gonadotropins </li></ul><ul><ul><li>Use of low-dose (Level B) </li></ul></ul><ul><li>Ovarian drilling </li></ul><ul><ul><li>Does not improve cumulative ongoing pregnancy rates compared with gonadotropins but is associated with fewer multiple pregnancies </li></ul></ul><ul><ul><li>(Level A) </li></ul></ul><ul><li>Miscarriage rates same for gonadotropins and ovarian drilling (Level A) </li></ul>
    39. 39. Prevalence of IGT and DM in PCOS <ul><li>30-40% of women with PCOS have IGT </li></ul><ul><li>8-10% will have undiagnosed Type 2 DM </li></ul>
    40. 40. What is Abnormal Glucose Testing? <ul><li>FPG<100 mg/dl = Normal </li></ul><ul><li>FPG 100 -125 mg/dl = Impaired Fasting Glucose </li></ul><ul><li>FPG 140-199 mg/dl on 2-h OGTT = Impaired Glucose Tolerance </li></ul><ul><li>FPG>126 or >200 mg/dl on 2h OGTT = DM </li></ul><ul><li>FPG- Fasting Plasma Glucose </li></ul>
    41. 41. Insulin Resistance Treatment <ul><li>Lifestyle modification </li></ul><ul><li>Weight loss </li></ul><ul><li>Increased physical activity, exercise </li></ul><ul><li>Insulin sensitizer medication (Metformin,TZD). </li></ul><ul><li>Consider other IR syndromes </li></ul><ul><ul><li>HTN, CVD, Sleep Apnea, NASH, etc. </li></ul></ul>
    42. 42. Condition Associated with Insulin Resistance in PCOS <ul><li>Acanthosis nigricans is a skin condition that causes dark, thickened and velvety skin in body folds and creases. </li></ul><ul><li>It typically affects the armpits, groin and neck </li></ul>
    43. 43. Rule Out Type 2 Diabetes in PCOS <ul><li>The American Diabetes Association recommends screening women with PCOS (high-risk individual) with either a fasting plasma glucose (FPG) or an oral glucose tolerance test (OGTT)by age 30. </li></ul><ul><li>The oral glucose tolerance test (OGTT) is a more sensitive test for diagnosing diabetes in women with PCOS ( Level A). </li></ul><ul><li>A prospective study of 254 women with PCOS demonstrated that only 3.2% were diagnosed with diabetes based on a FPG as compared to 7.5% using an OGTT. </li></ul>
    44. 44. Treatment of Impaired Glucose Tolerance/Type 2 Diabetes <ul><li>Current data is insufficient to support the use of insulin-sensitizing agents prophylactically for the prevention of diabetes in women with PCOS without impaired glucose tolerance (IGT). </li></ul><ul><li>Medications, which improve insulin resistance, are the treatment of choice for women with PCOS and diabetes. These include metformin and TZDs </li></ul><ul><li>( Level A). </li></ul><ul><li>Improvements in insulin sensitivity, by weight loss or by the use of insulin-sensitizing agents, may favorably improve many risk factors for diabetes and cardiovascular disease in women with PCOS (Level B). </li></ul>
    45. 45. Summary of PCOS Management <ul><li>Hirsuitism, Acne </li></ul>Women who desire contraception Combination OCPs Treatment Lifestyle modification Depilatory/electrolysis/laser Glucophage Eflornithine HCl cream Spironolactone Flutamide Finasteride Glucophage,TZDs Insulin Resistance, Oligomenorrhea Obesity
    46. 46. Summary of PCOS Management <ul><li>Hirsuitism, Acne </li></ul>Women who desire pregnancy/ovulation induction Glucophage Clomiphene citrate Gonadotropins Ovarian drilling Treatment Lifestyle modification Depilatory/electrolysis/laser Glucophage Glucophage Insulin Resistance, Oligomenorrhea Obesity
    47. 47. Summary of Evidence -Based Recommendations <ul><li>Level A </li></ul><ul><li>(Good and consistent scientific evidence) </li></ul><ul><ul><li>All women with PCOS should be screened for glucose intolerance with a 2 hr glucose tolerance test with a 75 gram challenge. </li></ul></ul><ul><ul><li>All women with PCOS should be screened for dyslipidemia with a fasting lipid panel. </li></ul></ul><ul><ul><li>Insulin-sentizing drugs are effective in improving clinical and biochemical features of PCOS. </li></ul></ul><ul><ul><li>Laser treatment is effective for facial hisuitism caused by PCOS. </li></ul></ul><ul><ul><li>Spironolactone in combination with OCPs are effective in reducing hirsuitism and/ or acne. </li></ul></ul>
    48. 48. Summary of Evidence -Based Recommendations <ul><li>Level A </li></ul><ul><li>(Good and consistent scientific evidence) </li></ul><ul><ul><li>In non-obese women with PCOS, metformin is more effective than clomid for improving the rate of conception. </li></ul></ul><ul><ul><li>Interventions that improve insulin sensitivity including weight loss, use of metformin, and use of thiazolidinediones, are useful in improving ovulatory frequency in women with PCOS. </li></ul></ul><ul><ul><li>Use of metformin and clomid is appropriate because it effectively results in pregnancy in women with PCOS more than clomid alone. </li></ul></ul>
    49. 49. Summary of Evidence -Based Recommendations <ul><li>Level B </li></ul><ul><li>(Limited or inconsistent scientific evidence) </li></ul><ul><ul><li>OCPs containing desogestrel or norgestrel significantly improve acne and hirsuitism. </li></ul></ul><ul><ul><li>Improvements in insulin sensitivity, by weight loss or by the use of insulin-sensitizing agents, may favorably improve many risk factors for diabetes and cardiovascular disease in women with PCOS. </li></ul></ul><ul><ul><li>When using gonadotropins to induce ovulation, low-dose therapy is recommended because it offers a high rate of monofollicular development and significantly lower risk of ovarian hyperstimulation in women with PCOS. </li></ul></ul><ul><ul><li>The benefit and role of surgical therapy (ovarian drilling) in ovulation induction in women with PCOS is now proven and causes fewer multiple gestations. </li></ul></ul>
    50. 50. Summary of Evidence -Based Recommendations <ul><li>Level C </li></ul><ul><li>(Primarily on consensus/ expert opinion) </li></ul><ul><ul><li>Although vaniqua cream has been effective in treating facial hirsuitism in women, additional benefits or risks for women with PCOS are unknown. </li></ul></ul><ul><ul><li>All women with a suspected diagnosis of PCOS should be screened with a 17-hydroxyprogesterone level for late onset CAH. </li></ul></ul><ul><ul><li>Combining medical interventions may be the most effective way to treat hirsuitism. Combined therapy with an ovarian suppression agent and an antiandrogen appears effective in treating hirsuitism in women with PCOS. The best pill or antiandrogen is unknown. </li></ul></ul><ul><ul><li>The ideal choice of ablative procedures for long term management of hirsuitism in women with PCOS is unknown. </li></ul></ul>
    51. 51. Summary of Evidence -Based Recommendations <ul><li>Level C </li></ul><ul><li>( Primarily on consensus/ expert opinion) </li></ul><ul><ul><li>The optimal progestin, duration, and frequency of treatment to prevent endometrial cancer in women with PCOS is unknown. </li></ul></ul><ul><ul><li>The effects of insulin-sensitizing agents on early pregnancy are unknown; metformin appears safe, but any additional effect at reducing pregnancy loss is uncertain. </li></ul></ul><ul><ul><li>The best or initial treatment for hirsuitism, ovulation induction, or prevention or long-term metabolic sequelae for women with PCOS is unknown. All of these conditions may benefit from lifestyle modification as initial treatment. </li></ul></ul>
    52. 52. References <ul><li>American Academy of Family Physicians: www.aafp.org </li></ul><ul><li>American College of Obstetricians and Gynecologists: www.acog.org Practice Bulletin: Polycystic Ovarian Syndrome. Obstetr and Gyn 2002;100:1389-1402 </li></ul><ul><li>Polycystic Ovarian Syndrome: www.pcosupport.org </li></ul><ul><li>American Infertility Association: www.americaninfertility.org </li></ul><ul><li>American Association of Clinical Endocrinologists (AACE) Guideline for diagnosis and treatment of hyperandrogenic disorders: Endocr Pract 2001;7:120-34 </li></ul>
    53. 53. Questions? U.S. Naval Hospital Naples, Italy