Ovary Hyperstimulation 1


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Ovary Hyperstimulation 1

  1. 1. Polycystic Ovary (Ovarian) Syndrome
  2. 2. Polycystic Ovary Syndrome <ul><li>PCOS is the most common form of chronic anovulation associated with androgen excess , perhaps occurring in 5~10% of reproductive-age women. </li></ul><ul><li>PCOS risk is increased with positive family history , and PCOS may be inherited in a polygenic fashion. </li></ul>
  3. 3. Associated morbidity of PCOS <ul><li>Increased reproductive morbidities: </li></ul><ul><ul><li>Infertility </li></ul></ul><ul><ul><li>Irregular uterine bleeding </li></ul></ul><ul><ul><li>Increased pregnancy loss </li></ul></ul><ul><li>Increased risk for endometrial cancer </li></ul><ul><li>Increased risk for insulin resistance (both obese and non-obese women) and metabolic syndrome </li></ul><ul><li>Increased risk for cardiovascular disease </li></ul>
  4. 4. Stein-Leventhal Syndrome <ul><li>Stein I, Leventhal M. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935 ; 29:181. </li></ul><ul><ul><li>Association between bilateral polycystic ovaries and signs of amenorrhea, oligomenorrhea, hirsutism, and obesity. </li></ul></ul><ul><ul><li>Most patients resumed menses and achieved pregnancy after ovarian wedge resection (at least one half of each ovary). </li></ul></ul>
  5. 5. Correlation of Hyperandrogenism with Hyperinsulinism in Polycystic Ovarian Disease <ul><li>Burghen GA, Givens JR, Kitabchi AE. </li></ul><ul><li>J Clin Endocrinol Metab 1980 ; 50:113-6. ( AN : 80072366 ) </li></ul><ul><li>We evaluated basal plasma total immunoreactive insulin ( insulin ), androstenedione , and testosterone in 14 obese women: 8 with polycystic ovarian disease (PCOD) and 6 obese controls. All 3 hormones were significantly elevated (P < 0.02 to P < 0.001) in PCOD patients. A significant correlation among basal levels of plasma insulin, androstenedione, and testosterone was demonstrated. The PCOD group had significantly higher levels of glucose at 1, 2, and 3 h, with similar significant increases in plasma insulin levels at 0, 2, and 3 h. A significant correlation was found between plasma insulin response areas and plasma testosterone (P < 0.001) in the control and PCOD patients. These studies demonstrate that hyperandrogenism correlates with hyperinsulinism. </li></ul>
  6. 6. Insulin resistance and polycystic ovary syndrome: mechanism and implication for pathogenesis <ul><li>Dunaif A. </li></ul><ul><li>Endocr Rev 1997 ; 18:774-800. ( AN : 98073041 ) </li></ul><ul><li>It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women. The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women. Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this. </li></ul>
  7. 7. Polycystic Ovaries <ul><li>Polycystic ovaries alone were found in 20%–25% of women in surveys in the United Kingdom and New Zealand. </li></ul><ul><li>While women with polycystic ovaries and no evidence of menstrual dysfunction or hyperandrogenism appear normal, they do have an overexaggerated response to stimulation with gonadotrophins such as follicle-stimulating hormone (FSH) in cycles of assisted reproduction. </li></ul>
  8. 8. Polycystic Ovaries <ul><li>The presence of polycystic ovaries on ultrasound examination is particularly controversial as a criterion. </li></ul><ul><li>Polycystic ovaries are characterised by peripheral cysts (10 or more) < 10 mm in size in an enlarged ovary with significant increase in the central stroma. However, the ultrasound characteristics are subjective. </li></ul><ul><li>Polycystic ovaries are also found in women with no evidence of menstrual dysfunction or hyperandrogenism . </li></ul>
  9. 9. Polycystic Ovaries <ul><li>As polycystic ovaries arise through incomplete follicular development or failure of ovulation, they may also occur in: </li></ul><ul><ul><li>Early to mid-adolescence </li></ul></ul><ul><ul><li>Women with bulimia </li></ul></ul><ul><ul><li>When recovery from anorexia nervosa </li></ul></ul><ul><ul><li>Conditions of increased adrenal androgen production </li></ul></ul><ul><ul><li>Hyperprolactinaemia </li></ul></ul><ul><ul><li>Women taking oral contraceptives ( 14% ) </li></ul></ul><ul><li>Most publications on PCOS do not include the presence of polycystic ovaries as a diagnostic criterion. </li></ul>
  10. 10. Polycystic Ovaries
  11. 11. * Sonography of polycystic ovary.
  12. 12. A: Polycystic ovaries, showing increased size and a smooth white surface reflecting thickening of the capsule. B: Section through polycystic ovary, showing multiple cysts with diameter < 10 mm arranged around the periphery of the ovary. The stroma is increased, and the ovary enlarged. ©The Medical Journal of Australia 2004 www.mja.com.au ISSN: 0025-729X
  13. 13. Diagnosis of PCOS
  14. 14. Opinion of Ricardo Azziz… <ul><li>Emerging data indicate that patients with hyperandrogenism and polycystic ovaries , but apparently normal ovulation , demonstrate in vivo abnormalities of insulin action , albeit milder than those patients originally defined by the NIH 1990 criteria. These data suggest that this group of individuals may be at greater risk for the metabolic consequences, including type 2 DM, compared with healthy controls, although this remains to be confirmed. As such, and based on current evidence, it may be possible to expand the phenotypic limits of PCOS to include this group of women. </li></ul>From “Controversy in Clinical Endocrinology, Diagnosis of PCOS: Premature Rotterdam Criteria Are Premature; J of Clinical Endo & Meta, 2006
  15. 15. Diagnosis of PCOS
  16. 16. Diagnosis of PCOS
  17. 17. Diagnosis of PCOS
  18. 18. Clinical Features of PCOS <ul><li>Ovulatory dysfunction </li></ul><ul><ul><li>Amenorrhea </li></ul></ul><ul><ul><li>Oligomenorrhea </li></ul></ul><ul><ul><li>Irregular uterine bleeding </li></ul></ul><ul><ul><li>Infertility </li></ul></ul><ul><li>Androgen excess </li></ul><ul><ul><li>Hirsutism </li></ul></ul><ul><ul><li>Seborrhea </li></ul></ul><ul><ul><li>Acne </li></ul></ul><ul><ul><li>Alopecia </li></ul></ul><ul><ul><li>Virilization </li></ul></ul><ul><li>Insulin resistance </li></ul><ul><ul><li>Acanthosis nigricans </li></ul></ul>
  19. 19. Young woman with PCOS showing facial hirsutism (A) and axillary acanthosis nigricans (B). The latter is associated with severe insulin resistance and hyperinsulinaemia and is an occasional finding in PCOS (photographs courtesy Dr John Casey, St Vincent’s Clinic, Sydney, NSW). ©The Medical Journal of Australia 2004 www.mja.com.au ISSN: 0025-729X
  20. 20. Clinical Features of PCOS <ul><li>Some women with PCOS may never have signs of androgen excess because of genetic differences in target tissue sensitivity to androgens. Infertility may be the only presenting symptom. </li></ul><ul><li>Acquired insulin resistance after weight gain of unknown cause may occasionally induce the clinical pictures of PCOS in a woman with previous normal ovulatory function. </li></ul>
  21. 21. * Manifestations of polycystic ovary syndrome at different ages ©The Medical Journal of Australia 2004 www.mja.com.au ISSN: 0025-729X
  22. 22. Differential Diagnosis of PCOS <ul><li>Idiopathic hirsutism </li></ul><ul><li>Hyperprolactinemia </li></ul><ul><li>Hypothyroidism </li></ul><ul><li>21-hydroxylase-deficient non-classical adrenal hyperplasia ( late-onset congenital adrenal hyperplasia ) </li></ul><ul><li>Ovarian tumors </li></ul><ul><li>Adrenal tumors </li></ul><ul><li>Cushing’s syndrome </li></ul><ul><li>Glucocorticoid resistance </li></ul><ul><li>Other rare causes of androgen excess </li></ul>
  23. 23. Laboratory Tests for the differential Diagnosis of Androgen Excess <ul><li>Initial testing </li></ul><ul><ul><li>Total testosterone </li></ul></ul><ul><ul><li>Prolactin </li></ul></ul><ul><ul><li>TSH </li></ul></ul><ul><li>Further testing based on clinical presentations </li></ul><ul><ul><li>17-OH-progesterone (8:00 AM) – CAH : >2 ng/mL </li></ul></ul><ul><ul><li>17-OH-progesterone 60 min after iv. ACTH – CAH : > 10 ng/mL </li></ul></ul><ul><ul><li>Cortisol (8:00 AM) after 1 mg dexamethasone at midnight – Cushing’s : > 5 ug/dL or > 2 ug/dL </li></ul></ul><ul><ul><li>DHEAS – Adrenlal tumors : > 8 ug/mL (but also in 50% of PCOS) </li></ul></ul><ul><ul><li>Androstenedione </li></ul></ul><ul><ul><li>Imaging of ovaries (transvaginal ultrasonography) </li></ul></ul><ul><ul><li>Imaging of adrenals (ABD echo, adrenal CT scan, adrenal MRI) </li></ul></ul><ul><ul><li>Nuclear imaging after iv. radiolabeled cholesterol </li></ul></ul>
  24. 25. Flow diagram for the laboratory evaluation of amenorrhea. Such a scheme must be considered as an adjunct to the clinical evaluation of the patient. CAH -= congenital adrenal hyperplasia; DHEAS = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; HCA = hypothalamic chronic anovulation; PCO = polycystic ovary syndrome; PRL = prolactin; T = testosterone; TSH = thyroid-stimulating hormone. Originally from Rebar RW, The ovaries. In: Smith LH Jr, ed. Cecil textbook of medicine, ed. 18. Philadelphia. WB Saunders, 1992:1367)
  25. 26. Laboratory Tests for PCOS <ul><li>LH/FSH ratios </li></ul><ul><ul><li>Elevated LH level and/or increased LH/FSH ratio are not required for diagnosis of PCOS. </li></ul></ul><ul><ul><li>Pulsatile nature of LH secretion give heterogeneity of LH values in PCOS. </li></ul></ul><ul><ul><li>LH levels are not increased in obese women with PCOS (LH pulse amplitude is normal in overweight, increased in nonobese women with PCOS; LH pulse frequency is increased with anovulation regardless of body fat content.)  Low LH level dose not rule out PCOS !! </li></ul></ul><ul><ul><li>High LH/FSH ratio is supportive of PCOS, esp. in differentiating mild cases of non-obese women without prominent androgen excess from hypothalamic anovulation. </li></ul></ul>
  26. 27. Laboratory Tests for PCOS <ul><li>Urine pregnancy test </li></ul><ul><li>Progestin challenge test after negative urine pregnancy test </li></ul><ul><li>Hysteroscopy for anatomic defect of uterine (ex. Intrauterine adhesions) </li></ul><ul><li>Endometrial biopsy if chronic anovulation persists (for fear of endometrial cancer) </li></ul>
  27. 28. Laboratory Tests for PCOS <ul><li>Glucose testing </li></ul><ul><ul><li>Fasting glucose </li></ul></ul><ul><ul><li>75 g-OGTT </li></ul></ul><ul><ul><li>Homeostasis model assessment [HOMA] or quantitative insulin sensitivity check index [QUICKI] </li></ul></ul><ul><li>Lipid profiles </li></ul><ul><ul><li>Total cholesterol </li></ul></ul><ul><ul><li>Triglyceride </li></ul></ul><ul><ul><li>HDL </li></ul></ul><ul><ul><li>LDL </li></ul></ul>
  28. 29. Management of PCOS <ul><li>Lifestyle changes: diet, exercise, weight reduction </li></ul><ul><li>Insulin sensitizers </li></ul><ul><ul><li>Metformin </li></ul></ul><ul><ul><li>Thiazolidinediones (TZD) </li></ul></ul><ul><li>Oral contraceptives </li></ul>
  29. 30. Management of PCOS <ul><li>Lifestyle modification </li></ul><ul><ul><li>Several studies have shown that weight loss can lead to resumption of ovulation within weeks . </li></ul></ul><ul><ul><li>Clark and colleagues demonstrated that even a 5% reduction in body mass restores ovulation and fertility. </li></ul></ul><ul><ul><li>High-protein diets seem to be as effective as high-carbohydrate diets, provided that fat and total calories are comparable. </li></ul></ul><ul><ul><li>While lifestyle changes are difficult to maintain, women seeking pregnancy are highly motivated, making this a first-line intervention in overweight women with PCOS. </li></ul></ul><ul><ul><li>Longer-term changes in weight are more difficult to maintain. </li></ul></ul>
  30. 31. Management of PCOS <ul><li>Metformin </li></ul><ul><ul><li>Reduce hyperinsulinemia </li></ul></ul><ul><ul><li>Reduce basal and stimulated LH levels </li></ul></ul><ul><ul><li>Reduce free testosterone concentrations </li></ul></ul><ul><ul><li>Increasing menstrual cyclicity </li></ul></ul><ul><ul><li>Induce ovulation and pregnancy </li></ul></ul><ul><ul><li>GI side effects to cause weight reudction </li></ul></ul>
  31. 32. Management of PCOS <ul><li>Metformin </li></ul><ul><ul><li>Use at doses of 500–2500 mg daily is controversial. (mostly, 500 mg Tid) </li></ul></ul><ul><ul><li>Recent systematic reviews suggest that the drug has efficacy for ovulation induction, either as a sole agent or in combination with clomiphene citrate. </li></ul></ul>
  32. 33. Randomized, Double-Blind, Placebo-Controlled Trials of Metformin in PCOS
  33. 34. Management of PCOS <ul><li>Thiazolidinediones </li></ul><ul><ul><li>Pharmacologic ligands for nuclear receptor-PPARr. </li></ul></ul><ul><ul><li>Troglitazone (400 mg/day) decreased insulin, LH, and testosterone levels, and resumed ovulation in obese women with PCOS. [This drug had been withdrawn from market due to hepatotoxicity.] </li></ul></ul><ul><ul><li>Newer drug needs further testing: Pioglitazone , Rosiglitazone </li></ul></ul><ul><ul><li>Contraindications for pregnancy: teratogenesis </li></ul></ul>
  34. 35. <ul><li>Authors: Baillargeon JP . Jakubowicz DJ . Iuorno MJ . Jakubowicz S . Nestler JE . </li></ul><ul><li>Source: Fertility & Sterility. 82(4):893-902, 2004 Oct. </li></ul><ul><li>Abstract: </li></ul><ul><li>OBJECTIVE: To determine whether insulin-sensitizing drugs would improve ovulation and T levels in women with polycystic ovary syndrome (PCOS), without clinical or biochemical criteria indicating insulin resistance and whether the combination of two distinct insulin-sensitizing drugs would be of any benefit over either drug alone. DESIGN: Randomized controlled double-blind trial. SETTING: A referral center in Caracas, Venezuela. PATIENT(S): 128 nonobese PCOS women with normal indices of insulin sensitivity-that is, normal glucose tolerance , fasting insulin, peak insulin during an oral glucose tolerance test (OGTT), and fasting glucose-to-insulin ratio. </li></ul>Effects of Metformin and Rosiglitazone , Alone and in Combination, in Nonobese Women with Polycystic Ovary Syndrome and Normal Indices of Insulin Sensitivity.
  35. 36. Effects of Metformin and Rosiglitazone , Alone and in Combination, in Nonobese Women with Polycystic Ovary Syndrome and Normal Indices of Insulin Sensitivity. <ul><li>Abstract: (continued) </li></ul><ul><li>28 women were lost to follow-up initially and did not receive any intervention. INTERVENTION(S): 100 women received twice daily one of the following for 6 months : metformin (850 mg) , rosiglitazone (4 mg) , combination of both drugs, or at least one placebo. MAIN OUTCOME MEASURE(S): Frequencies of ovulation and serum free T after 6 months. RESULT(S): Frequencies of ovulation were higher after treatment with an insulin-sensitizing drug (ovulations per subject in 6 months: metformin, 3.3 ; rosiglitazone, 2.4 ; and combination, 3.4 ) than with placebo ( 0.4 ). Ovulatory frequencies increased significantly more with metformin than rosiglitazone, and the combination was not more potent. </li></ul>
  36. 37. Effects of Metformin and Rosiglitazone , Alone and in Combination, in Nonobese Women with Polycystic Ovary Syndrome and Normal Indices of Insulin Sensitivity. <ul><li>Abstract: (continued) </li></ul><ul><li>After treatment, serum free-T levels were comparable among all active treatment groups (metformin: 2.34 pg/mL, rosiglitazone: 3.06 pg/mL, and combination: 2.39 pg/mL) and were significantly lower than in the placebo group ( 7.26 pg/mL). Compared with placebo, fasting insulin levels , area under the insulin curve during OGTT, the homeostatic model assessment of insulin sensitivity, and OGTT-derived insulin sensitivity index improved significantly after metformin or combination therapies but not after rosiglitazone. CONCLUSION(S): These findings suggest that insulin-sensitizing drugs increase ovulatory frequency and ameliorate hyperandrogenemia, even in nonobese women with PCOS who appear to have normal insulin sensitivity. </li></ul>
  37. 38. Management for Hirsutism <ul><li>Oral contraceptive pill (ex, ethinyloestradiol 35 ug + cyproterone acetate 2 mg daily for 21 of 28 days) </li></ul><ul><li>Cosmetic measures (ex, laser electrolysis, bleaching, waxing or shaving) </li></ul><ul><li>Oral estrogen + cyproterone acetate (estradiol valerate 2 mg daily and cyproterone acetate 50 mg for 14 days a month) </li></ul><ul><li>Spironolactone (75–200 mg daily) </li></ul><ul><li>Other drugs, such as the anti-androgen flutamide (treatment of prostate cancer) or the antifungal agent ketoconazole. These drugs either reduce androgen production or inhibit androgen-binding to the receptor. They are not in general use for this purpose. </li></ul><ul><li>Response times for drugs can be up to 3 months </li></ul>
  38. 39. Cyproterone Acetate <ul><li>17-OH-progesterone acetate derivatives with strong progestagenic properties. </li></ul><ul><li>Acts as an anti-androgen by competing with DHT and testosterone for binding to the androgen receptor. </li></ul><ul><li>Cyproterone acetate + ethinyl estradiol in combination can inhibit 5 α -reductase activity in skin . </li></ul><ul><li>Mostly administered in doses of 50~100 mg/day from day 5 through day 15 of the treatment cycle. Combined with ethinyl estradiol (50 ug/day) between day 5~day 26 for menstrual control. </li></ul>
  39. 41. <ul><li>泌尿生殖系統用藥/避孕劑 藥名(學名): DIANE-35    商品名(廠商): DIANE-35( 德‧ Schering) 劑型: 糖衣錠   成份: 每錠含有 Cyproterone Acetate 2 , Ethinylestradiol 0.035 ㎎ 。   藥物作用: 本藥中所含的 Cyproterone Acetate 成分,會抑制女性體內雄性激素的產生,所以服藥期間體內 並不排卵 ,所以可達到避孕的功效;也會降低皮脂線的功能,因而抑制粉刺和皮脂溢出。因為單獨服用 Cyproterone Acetate 會影響月經週期的規律性,所以本藥中含有可避免月經週期紊亂的動情素 Ethinylestradiol 。   治療項目: 痤瘡 、 皮脂溢出 、 多毛症 、 避孕 。   用法用量: 開始服用本品之前需做徹底的全身體檢及婦科檢查(乳房在內)而且不得懷孕。長期用藥治療,每六個月需做檢查。由月經出血的第一天開始服藥, 每天服一錠連續 21 天, 21 錠藥全部服用後,接著是 7 天停藥期。 7 天停藥期之後,繼續服用下一包, 服藥三星期,停藥一星期 ,用藥治療期間通常應該治療數月時間,在症狀消失後最少還要服用本品 3~4 個週期。而服藥期間不會排卵,可避孕。   副作用: 頭痛、胃不適、噁心、胸部緊張、體重和性慾改變、情緒低潮、臉上出現黃斑,應避免在太陽下太久。   注意事項: 男性不得使用。   懷孕及授乳注意事項: 懷孕及授乳皆禁止使用。   使用禁忌: 懷孕、哺乳、嚴重肝功能障礙、黃疸、肝臟腫瘤、血栓性栓塞病症(包含中風,心肌梗塞)、鏈狀血球性貧血 、現有或曾有乳癌或子宮內膜癌、糖尿病、脂質代謝障 礙、曾患庖疹。   </li></ul>
  40. 42. Management for Infertility <ul><li>Lifestyle changes and weight reduction </li></ul><ul><li>Metformin </li></ul><ul><li>Clomiphene citrate </li></ul><ul><ul><li>An oral estrogen antagonist that raises circulating concentrations of FSH and induces follicular growth in most women with PCOS and anovulation. </li></ul></ul><ul><ul><li>The initial regimen is 25–50 mg per day for 5 days . Therapy can be monitored by estrogen levels, follicular ultrasound examination and luteal progesterone level (> 20 nmol/L). </li></ul></ul><ul><ul><li>Failure of response is associated with high body mass index and high androgen levels. Doses up to 200 mg per day can be used before failure of response is established. </li></ul></ul><ul><ul><li>In the rare situation in which side effects limit treatment, tamoxifen can be used. Both treatments increase the risk of multiple pregnancy. </li></ul></ul>
  41. 43. Management for Infertility <ul><li>Gonadotropin therapy </li></ul><ul><ul><li>Need skill and experience to avoid multiple pregnancies and ovarian hyperstimulation syndrome (esp. on conventional-dose gonadotropin therapy – 150 IU FSH, +75 IU every 3~7 days). </li></ul></ul><ul><ul><li>Low-dose recombinant FSH (75 IU for 14 days) administered subcutaneously. </li></ul></ul><ul><ul><li>Monitoring of ovarian response involves ultrasound examination, often with estradiol measurement. Human chorionic gonadotrophin (HCG) is given when one follicle reaches 16–20 mm in size. Any more than two follicles of an appropriate size gives the risk of multiple pregnancies. Multiple gonadotropin cycles may be required to achieve pregnancy, but this approach is preferable before more invasive procedures, such as in-vitro fertilisation </li></ul></ul>
  42. 44. Management for Infertility <ul><li>In-vitro fertilisation (IVF) </li></ul><ul><ul><li>Provided there is no problem other than anovulation, this has little place in the management of infertility resulting from PCOS. </li></ul></ul><ul><ul><li>Ovulation induction by a skilled reproductive endocrinologist is preferable to in-vitro fertilisation because of the risks of hyperstimulation and multiple pregnancy with the latter procedure. </li></ul></ul>
  43. 45. Oral Contraceptives and Glucose Tolerance/Insulin Sensitivity in Women With PCOS: Clinical Trials
  44. 46. FIG. 1. Case-control studies on myocardial infarctions associated with current use of low-dose oral contraceptives versus no current use. Odds ratios (ORs) are expressed with their 95% confidence interval. OR were adjusted for multiple confounding factors, depending on the study. The combined OR was weighted based on the variance of the ORs in each study.
  45. 47. FIG. 2. Case-control studies on ischemic strokes associated with current use of low-dose oral contraceptives versus no current use. Odds ratios (ORs) are expressed with their 95% confidence interval. OR were adjusted for multiple confounding factors, depending on the study. The combined OR was weighted based on the variance of the ORs in each study.
  46. 48. The cardinal feature is functional ovarian hyperandrogenism. ©The Medical Journal of Australia 2004 www.mja.com.au ISSN: 0025-729X