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  • One study by Norman, et al followed PCOS pts over mean 6 yrs— of those w/ initially nml glu tolerance, 17% developed glucose intolerance, 54% w/ initial impaired glucose tolerance developed type II DM
  • Insulin Effects . Looking at the effects of insulin in a larger scheme, this table adapted from Cristello and colleagues portrays the cascading consequence of life choices, aging and genetics leading to insulin resistance which progresses into other complications including PCOS. For examples, intrauterine environment may influence expression of PCOS resulting in prenatal exposure to androgens in offspring of PCOS mothers causing a stimulus for low birth weight (LBW) and development of PCOS.
  • Total testosterone may be normal, OCPs may lower total testosterone.
  • Polycystic ovaries not required for Dx. Only need 2 of these 3 criteria so far.
  • Not an official diagnosis
  • Medical: target testosterone: either decrease production or prevent action.
  • Moran LJ, Pasquali R, Teede HJ, Hoeger KM, Norman RJ. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society.  Fertil Steril . Dec 3 2008; [Medline] .
  • a) Leeman L, Acharya U. The use of metformin in the management of polycystic ovary syndrome and associated anovulatory infertility: the current evidence.  J Obstet Gynaecol . Aug 2009;29(6):467-72.  [Medline] . b) Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome.  N Engl J Med . Jun 25 1998;338(26):1876-80.  [Medline] . c) Sinawat S, Buppasiri P, Lumbiganon P, Pattanittum P. Long versus short course treatment with Metformin and Clomiphene Citrate for ovulation induction in women with PCOS.  Cochrane Database Syst Rev . Jan 23 2008;CD006226.  [Medline] . d) Badawy A, State O, Abdelgawad S. N-Acetyl cysteine and clomiphene citrate for induction of ovulation in polycystic ovary syndrome: a cross-over trial.  Acta Obstet Gynecol Scand . 2007;86(2):218-22.  [Medline] .
  • Polycystic Ovary Syndrome Writing Committee. American Association of Clinical Endocrinologists position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Endocr Pract 2005 Mar-Apr;11(2):125-34. [64 references]
  • Medical: target testosterone: either decrease production or prevent action.
  • Spironolactone: unknown safety during pregnancy. Yasmin: combined with ethinyl estradiol Problem with finasteride: not specifically target the isoenzyme of 5a-reductace in the pilosebaceous unit. !Notice metformin and weight loss again.
  • g) Cumming DC, Yang JC, Rebar RW, Yen SS. Treatment of hirsutism with spironolactone.  JAMA . Mar 5 1982;247(9):1295-8.
  • Need 4 menses annually to minimize risk endometrial CA. Metformin: addressing insulin resistance will decrease the effects of elevated insulin levels on SHBG, gonadotropins, and ovarian cells.
  • 28 Farquhar C, Lilford RJ, Marjoribanks J, Vandekerckhove P. Laparoscopic 'drilling' by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome.  Cochrane Database Syst Rev . Jul 18 2007;CD001122.  [Medline] .
  • Outcomes: extrapolated from general population: no specific study of TZDs on insulin resistance in PCOS women. Improves fertility/ovuluation, known to improve insulin resistance in rest of population, so it MUST work by extrapolation.
  • Outcomes: extrapolated from general population: no specific study of TZDs on insulin resistance in PCOS women. Improves fertility/ovuluation, known to improve insulin resistance in rest of population, so it MUST work by extrapolation.
  • ASA, statins, ACE-I/BB for HTN; manage like DM (already a CAD equivalent)!
  • Polycystic Ovary Syndrome Writing Committee. American Association of Clinical Endocrinologists position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Endocr Pract 2005 Mar-Apr;11(2):125-34. [64 references]
  • Polycystic Ovary Syndrome Writing Committee. American Association of Clinical Endocrinologists position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Endocr Pract 2005 Mar-Apr;11(2):125-34. [64 references]
  • Polycystic Ovary Syndrome Writing Committee. American Association of Clinical Endocrinologists position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Endocr Pract 2005 Mar-Apr;11(2):125-34. [64 references]
  • Polycystic Ovary Syndrome Writing Committee. American Association of Clinical Endocrinologists position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Endocr Pract 2005 Mar-Apr;11(2):125-34. [64 references]
  • Polycystic Ovary Syndrome Writing Committee. American Association of Clinical Endocrinologists position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Endocr Pract 2005 Mar-Apr;11(2):125-34. [64 references]
  • Polycystic Ovary Syndrome Writing Committee. American Association of Clinical Endocrinologists position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Endocr Pract 2005 Mar-Apr;11(2):125-34. [64 references]
  • American College of Obstetricians and Gynecologists (ACOG). Polycystic ovary syndrome. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); 2009 Oct. 14 p. (ACOG practice bulletin; no. 108). [85 references]
  • PCOS

    1. 1. Polycystic Ovarian Syndrome Prof. M.C. Banal. Founder Principal & Controller; Jhalawar Medical College and Hospital , Jhalawar. Ex Principal& Controller ; Mahatma Gandhi Medical College And Hospital, Sitapura, Jaipur. Dr, Khusboo Saxena. PG (st) NIMS Medical College Jaipur.
    2. 2. INTRODUCTION • Most common cause of infertility in women • Classic syndrome originally described by Stein and Levanthal • Hyperandrogenism • Menstrual irregularity • Polycystic ovaries • Central adiposity • Syndrome, not a disease—multiple potential etiologies with variable clinical expression
    3. 3. History • Originally described by Stein and Leventhal in 1935, first known as the “Stein-Leventhal syndrome” • 7 women with amenorrhea, hirsutism, and obesity, found to have a polycystic appearance to their ovaries.
    4. 4. PCOS Syndrome characterized by • Oligoammenorhoea / amenorrhoea Laboratory criteria of • Hyperandrogenemia • Hyperinsulinemia
    5. 5. Diagnostic criteria based on the modified consensus of National Institutes of Health and Child Health and Human Development. • Major – Chronic anovulation – Hyperandrogenemia – Clinical signs of hyperandrogenism – Other etiologies excluded • Minor – Insulin resistance – Perimenarchal onset of hirsutism and obesity – Elevated LH : FSH ratio – Intermittent anovulation associated with hyperandrogenemia (free testosterone, DHEAS).
    6. 6. Rotterdam criteria •2 of 3 •Polycystic ovaries (>12 peripheral follicles or increased ovarian volume >10cm3 ) •Oligo- or anovulation •Clinical and/or biochemical signs of hyperandrogenism •And exclusion of other etiologies such as hypothyroidism, hyperprolactinemia, congenital adrenal hyperplasia, cushing syndrome, androgen secreting tumors
    7. 7. AE-PCOS SOCIETY 2006 • Hyperandrogenism-hirsutism and/ or hyperandrogenemia • And • Ovarian dysfunction-oligo-anovulation and/ or polycystic ovaries • Exclusion of other androgen excess or related disorders
    8. 8. Pituitary –ovarian –Adrenal Inter action
    10. 10. Abnormal Pituitary Function— Altered Negative Feedback Loop • Increased GnRH from hypothalamus • Excessive LH secretion relative to FSH by pituitary gland • LH stimulates ovarian thecal cells-- androgen production • Ineffective suppression of the LH pulse frequency by estradiol and progesterone • Androgen excess increases LH by blocking the hypothalamic inhibitory feedback of progesterone
    11. 11. Abnormal steroidogenenesis • Intraovarian androgen excess results in excessive growth of small ovarian follicles • Follicular maturation is inhibited • Excess androgen causes thecal and stromal hyperplasia
    12. 12. HYPERANDROGENISM • Hirsutism, acne, male pattern balding, alopecia • 50-90% patients have elevated serum androgen levels • Free testosterone levels most sensitive • Rare: increased muscle mass, deepening voice, clitormegaly (should prompt search for underlying neoplasm)
    13. 13. Pathogenesis: Hyperandrogenism • Symptoms of androgen excess • Reduced sex-hormone-binding globulin (SHBG)  more free testosterone • Insulin insensitivity • Lipid abnormalities • Abdominal obesity
    14. 14. Origin and sequelae of abnormal neuroendocrine function in PCOS PCOS Women Persistent rapid LH dysfunction (1LH pulse/hour)Persistent rapid LH dysfunction (1LH pulse/hour) ↑↑ LH & LH : FSH ratioLH & LH : FSH ratio ↓↓ FSHFSH ↑↑ ovarian androgensovarian androgens Impaired follicular developmentImpaired follicular development Impaired hypothalamicImpaired hypothalamic Progesterone sensitivityProgesterone sensitivity Impaired ProgesteroneImpaired Progesterone productionproduction Source : Blank SK et al Hum Reprod updare 2006 Jul - AugSource : Blank SK et al Hum Reprod updare 2006 Jul - Aug
    15. 15. Insulin resistance in PCOS: • Insulin resistance in PCOS is independent of obesity – Obese women with PCOS tend to be more insulin resistant than normal-weight counterparts. – Obesity is an independent risk factor for glucose intolerance or DM in PCOS • 3-fold increased incidence of metabolic syndrome in PCOS, vs general population, independent of obesity. • Insulin resistance ≠ glucose intolerance – Many insulin resistant PCOS pts have normal glucose tolerance – 30-40% prevalence of glucose intolerance in PCOS women – 7-10% prevalence of type 2 DM in PCOS women – Insulin resistance worsens over time – Increased risk for impaired glucose tolerance and type 2 DM
    16. 16. ETIOLOGY OF INSULIN RESISTTANCE • Unknown largely. • Mutation of the insulin receptor gene in the peripheral target tissues • Reduced tyrosine auto phosphorylation of the insulin receptor.
    17. 17. Pathogenesis: Insulin resistance • Favors anovulation, androgen excess, reduced SHBG • Metabolic syndrome • Abdominal obesity
    18. 18. HYPERINSULINEMIA • Excess insulin production and insulin resistance • Genetic link
    19. 19. Genetic Predisposition Aging Pregnancy Drugs Lifestyle Insulin ResistanceInsulin Resistance HyperinsulinemiaHyperinsulinemia Altered Fat MetabolismAltered Fat Metabolism Altered Steroid Hormone MetabolismAltered Steroid Hormone Metabolism PCOS: Acne, hirsutism, hyperandrogenism infertility PCOS: Acne, hirsutism, hyperandrogenism infertility Adapted from Cristello F et al, Gynecological Endocrinology, 2005. Android Obesity Android Obesity ↑ Lipid Storage↑ Lipid Storage
    20. 20. Insulin Resistance: Associated Conditions Insulin ResistanceInsulin Resistance Type 2 diabetesType 2 diabetes HypertensionHypertension Impaired GlucoseImpaired Glucose tolerancetolerance Obesity (central)Obesity (central) Polycystic ovaryPolycystic ovary diseasediseaseHyperuricemiaHyperuricemia AcanthosisAcanthosis NigricansNigricans DecreasedDecreased FibrinolyticFibrinolytic ActivityActivity DyslipidemiaDyslipidemia AtherosclerosisAtherosclerosis
    21. 21. Elevated AndrogensElevated Androgens PancreasPancreasPancreasPancreas Insulin Receptor Dysfunction Hyperinsulinaemia LiverLiverLiverLiver LHRH HypothalamusHypothalamusHypothalamusHypothalamus PituitaryPituitaryPituitaryPituitary AdrenalAdrenalAdrenalAdrenal StromaStromaStromaStroma FollicleFollicleFollicleFollicle ↑ LH FSH Elevated DHEASElevated DHEASReduced SHBGReduced SHBG  Free androgens Free androgens Hyperinsulinaemia & Hyperandrogenaemia
    22. 22. Clinical Presentation of Women with PCOS Adolescent Period Reproductive Period Menopausal  Menstrual Irregularity Cosmetic concerns  Acne  Hirsutism  Hair Loss  Infertility  Early Pregnancy loss  During pregnancy  PIH  GDM  Metabolic Syndrome  Ca Endometrium ObesityObesity
    23. 23. MENSTRUAL DYSFUNCTION • Oligo or amenorrhea – Menstrual irregularity typically begins in the peripubertal period – Delayed menarche • Reduction in ovulatory events leads to deficient progesterone secretion • Chronic estrogen stimulation of the endometrium with no progesterone for differentiation—intermittent breakthrough bleeding or dysfunctional uterine bleeding • Increased risk for endometrial hyperplasia and/or endometrial CA
    24. 24. OBESITY • Prevalence of obesity varies from 30- 75% • 2/3 of patients with PCOS who are not obese have excessive body fat and central adiposity • Obese patients can be hirsute and/or have menstrual irregularities without having PCOS
    25. 25. Apple Shape Pear Shape
    26. 26. OBESITY AND INSULIN RESISTANCE • ½ patients with PCOS are obese • > 80% are hyperinsulinemic and have insulin resistance (independent of obesity) • Hyperinsulinemia contributes to hyperandrogenism through production in the theca cell and through its suppressive effects on sex hormone binding globulin production by the liver
    27. 27. ASSOCIATED MEDICAL CONDITIONS • Increased risk of developing Type 2 Diabetes and Gestational diabetes • Low HDL and high triglycerides • Sleep apnea • Nonalcoholic steatohepatitis • Metabolic syndrome—43% of PCOS patients (2 fold higher than age-matched population) • Elevated CRP and heart disease • Advanced atherosclerosis
    28. 28. Hair & sebaceous Follicle Response to Hyperandrogenism
    29. 29. HIRSUTISM
    30. 30. Hirshutism
    31. 31. Male Type Hair Growth on Abdomen- PCOS
    32. 32. Ferriman Gallwey score Extent of terminal (coarse pigmented) hair growth at each of the following 11 hormonally sensitive sites Upper lip Sideburn area Chin Jaw & Neck Upper back Lower back Upper arms Thighs Chest Upper abdomen Lower abdomen Score of 6 or above used to define clinical hyperandrogenemia
    33. 33. Modified Ferriman Gallwey score 9 areas • Score 1-4 • 0-absence of terminal hair • 4-extensive terminal hair growth >8 - hirsutism
    34. 34. Modified Ferriman Gallwey score
    35. 35. Ref : Hum Reprod 2004: 19 Ovulation Fertilization Implantation Fetal Viability Healthy Live born Poor Oocyte Quality ?Effects gestational Diabetes and hypertension Endometrial Abnormality Effects Hyperinsulinemia PCOS and infertility
    36. 36. PCOS & Metabolic Syndrome Metabolic Syndrome: • Cluster of Cardiovascular risk factors related to Insulin Resistance: - Obesity - Hyperinsulinemia - Hypertension - Atherogenic Dyslipidemia - Atherosclerosis - Hyperglycemia • Major Risk Factors: - Physical inactivity - Atherogenic diet - Adiposity / abdominal obesity
    37. 37. ATP III Clinical Identification of the Metabolic Syndrome • Waist circumference: – Women>88 cm (>35 in) • Triglycerides >150 mg/dL • HDL cholesterol: – Women<50 mg/dL • Blood pressure 130/ 85 mm Hg • Fasting glucose >110 mg/dL* •New ADA guidelines suggest >100mg/dl increases risk for Metabolic Syndrome •Presence of any 2 of 5 criterias required
    38. 38. Gross Appearance of Ovaries • Polycystic ovaries are enlarged and have a smooth thickened capsule that is avascular • On cut section, subcapsular follicles in various stages of atresia are seen in the peripheral part of the ovary • The most striking ovarian features of PCOS is hyperplasia of the theca stromal cells surrounding arrested follicles • Microscopically luteinizing theca cells are seen
    40. 40. Diagnosis 1. Hyperandrogenism  Laboratory features  Elevated total testosterone  Most values in PCOS <150 ng/dl (if >200 ng/dl, consider ovarian or adrenal tumor)  Free testosterone assays not reliable yet  DHEA-S  Most normal or slightly high in PCOS  If >800 mcg/dl, consider adrenal tumor  LH/FSH ratio  Levels vary over menstrual cycle, released in pulsatile fashion, affected by OCPs  LH/FSH ratio >2 has little diagnostic sensitivity and need not be documented
    41. 41. Diagnosis 2. Oligoovulation or anovulation  Oligomenorrhea or amenorrhea  Dysfunctional uterine bleeding  Infertility  30-50% 1st trimester miscarriage rate  3-fold increased risk endometrial carcinoma
    42. 42. Diagnosis 3. Polycystic Ovaries  Criteria by ultrasound  Increased ovarian area (>5.5 cm2) or volume (>11 ml) w/ presence of >12 follicles measuring 2-9 mm in diameter  Polycystic ovaries not specific for PCOS  > 20% normal women have incidental polycystic ovaries
    43. 43. Ultrasonic Criteria of PCOUltrasonic Criteria of PCO • At least one of the following – 12 or more follicles measuring 2–9 mm in diameter – increased ovarian volume (>10 cm3 ). • If there is a follicle >10 mm in diameter, the scan should be repeated at a time of ovarian quiescence in order to calculate volume • The presence of a single PCO is sufficient for diagnosis • The distribution of follicles and a description of the stroma (volume & echogenicity) are not required for diagnosis
    44. 44. USG IMAGE OF PCOS
    45. 45. Polycystic VS. Multicystic Ovaries • Polycystic ovaries – Bilateral – At least 12 follicles – Follicular diameter 2 - 9 mm – Stroma increased • Multicystic ovaries – Bilateral – Multiple cysts – Cyst diameter usually > 10 mm – Stroma not increased
    46. 46. OVARIAN ABNORMALITIES • Thickened sclerotic cortex • Multiple follicles in peripheral location • 80% of women with PCOS have classic cysts
    48. 48. INFERTILITY • Intermittent ovulation or anovulation • Inherent ovarian disorder—studies show reduced rated of conception despite therapy with clomiphene citrate
    49. 49. Diagnosis 4. Absence of other disorders to account for these symptoms.  Pregnancy  pregnancy test  Hypothyroidism  TSH  Hyperprolactinemia  prolactin  Late onset congenital adrenal hyperplasia  17- hydroxyprogesterone (r/o if <200 ng/dl)  Ovarian tumor  total testosterone (esp if >200 ng/dl) – Adrenal tumor  DHEA-S (esp if > 800 mcg/dl) – Cushing’s syndrome  salivary cortisol, 24 hr urine cortisol
    50. 50. Diagnosis 5. Supportive of insulin resistance  “Syndrome XX”: 3 or more of the following criteria: • Waist circumference > 88 cm • Triglycerides > 150 mg/dl • HDL <50 mg/dl • BP > 130/85 • Fasting glucose >110 mg/dl  ACOG and ADA suggest screening all women w/ PCOS for glucose intolerance, type 2 DM.  Oral glucose tolerance test more sensitive than fasting glucose.  Personal or family history of DM  Acanthosis nigricans
    51. 51. Acanthosis Nigrans
    52. 52. Acne & Hirsutism
    53. 53. DIFFERENTIAL DIAGNOSIS 1. Hyperprolactinemia – Prominent menstrual dysfunction – Little hyperandrogenism 2. Congenital Adrenal Hyperplasia – morning serum 17-hydroxyprogesterone concentration greater than 200 ng/dL in the early follicular phase strongly suggests the diagnosis – confirmed by a high dose (250 mcg) ACTH stimulation test: post-ACTH serum 17- hydroxyprogesterone value less than 1000 ng/dL
    54. 54. Androgens Level--- 3. Ovarian and adrenal tumors – serum testosterone concentrations are always higher than 150 ng/dL – adrenal tumors: serum DHEA-S concentrations higher than 800 mcg/dL – LOW serum LH concentrations 4. Cushing’s syndrome 5. Drugs: danazol; OCPs with high androgenicity
    55. 55. TESTING • Serum HCG • Serum prolactin • Thyroid panel • FSH: r/o ovarian failure • Serum luteinizing hormone (LH)— elevated • Serum estradiol—normal • Serum estrone—elevated
    56. 56. TESTING • Fasting glucose: elevated -->110mg / dl • 2 hour OGTT: elevated ---140-199mg/dl • Ratio of fasting glucose(mmol/L) To fasting insulin (mu/ L ) -- < 4.5 . • Fasting insulin: elevated • Free testosterone: elevated • DHEA-S: normal • 17-hydroxyprogesterone: normal • Pelvic US • Lipids
    57. 57. TREATMENT
    58. 58. Women with PCOD (adolescent / unmarried) 1.The Report with--- • Menstrual problem. • Acne . • Obesity. • Hersutism. 2. Their treatment— *Modification in life style . * Weight Reduction. * Diet management. * Hormone therapy
    59. 59. Management – Immediate/Acute issues – Hirsutism – Regulation of menses – Fertility issues – Long-term issues – Insulin resistance – Cardiovascular risk – Obstructive sleep apnea – Malignancy risk
    60. 60. Diet and Exercise • In patients with PCOS who are obese, endocrine-metabolic parameters markedly improve after 4-12 weeks of dietary restriction. • Their SHBG levels rise and free testosterone levels fall by 2-fold. • Serum insulin and IGF-1 levels also decrease. • Weight loss in patients with PCOS who are obese is associated with a reduction of hirsutism and a return of ovulatory cycles in 30% of women. Moran LJ, Pasquali R, et all Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril. Dec 3 2008;
    61. 61. Diet and Exercise • A moderate amount of daily exercise increases of levels of IGF-1 binding protein and decreases IGF-1 levels by 20%. • Modest weight loss of 2-5% of total body weight can help restore ovulatory menstrual periods in obese patients with PCOS. • A daily 500-1000 calorie deficit with 150 minutes of exercise per week can cause ovulation. • The Androgen Excess and Polycystic Ovary Syndrome Society recommends lifestyle management as the primary therapy in overweight and obese women with PCOS for the treatment of metabolic complications. Moran LJ, Pasquali R, et all Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril. Dec 3 2008;
    62. 62. Metformin • This anti-diabetic drug improves insulin resistance and decreases hyperinsulinemia in patients with PCOS. • Metformin also has a small but beneficial effect on metabolic syndrome. Ascertain that kidney and liver function are normal and that the patient does not have advanced congestive heart failure before starting metformin. • The usual starting dose is 500 mg given orally twice a day. • Inform patients that they have a high likelihood of having ovulatory cycles while taking metformin. • The US Food and Drug Administration has not approved metformin for this indication; therefore, this use is off label Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta- analysis. BMJ. Oct 25 2003;327(7421):951-3. [Medline].
    63. 63. • Metformin – will restore ovulation and menses in > 50% of patients – Treat with cyclic progestin to reduce endometrial hyperplasia if regular menses not attained • 10 mg for 7 to 10 days every two to four months
    64. 64. METFORMIN • Decreases hepatic glucose production • Reduces need for insulin secretion • Improves insulin sensitivity (increases peripheral glucose uptake and utilization) • Antilipolytic effect—reduces fatty acid concentrations and reduces gluconeogenesis
    65. 65. Metformin and Anovulation • Evidence suggests that metformin frequently—but not universally—improves ovulation rates in women with PCOS. • In addition, pretreatment with metformin has been shown to enhance the efficacy of clomiphene for inducing ovulation. • Whether short-course metformin pretreatment (less than 4 weeks) is as effective as conventional long- course metformin remains uncertain. • N-acetylcysteine may also enhance the effect of
    66. 66. METFORMIN DOSING • Target—1500-2550 mg per day • Clinically significant responses not regularly observed at doses less than 1000 mg per day • Extended release formulations—fewer side-effects. Entire dose should be given with dinner
    67. 67. Guidelines: Metformin • Consideration of metformin therapy as the initial intervention in most women with PCOS, particularly in those who are overweight or obese. • Metformin improves many metabolic abnormalities in PCOS and may improve menstrual cyclicity and the potential for pregnancy. • Of note, metformin has not been approved by the US Food and Drug Administration for use in PCOS, although abundant medical literature supports its efficacy.
    68. 68. SIDE EFFECTS • Diarrhea, nausea, vomiting, flatulence, indigestion, abdominal discomfort – Caused by lactic acid in the bowel wall – Minimized by slow increase in dosage • Lactic acidosis—rare – Avoid in CHF, renal insufficiency, sepsis – Discontinue for procedures using contrast (withhold X 48 hours) – Temporarily suspend for all surgical procedures that involve fluid restriction – Cimetidine causes increased metformin levels
    69. 69. Hormone therapy for Adolescent Patients • Combined OCPs containing ---estrogen and Progesterone given cyclically help in controlling menstrual problem , hirsutism, acne, and extra weight. • Estrogen salt used is- --- Ethinylestradiol in the dose 0f 20/ 30 ug / day. • Progeserones used are of many types and they have variable effect on Acne, weight , hirsutism, and menstrual with drawl bleeding also and have variable adverse side effect; to be considered when prescribing OCPs.
    70. 70. Pharmacological Profile of natural progesterone and other synthetic progestrogens Drug Progestrongic activity Anti androgenic activity Antimenraocorti coid activity Glucocorticoid activity Progestrone( Nat Ural + ( + ) + - Drosperinone + + + - Cyproteron Acetate + + - ( + ) Desogestrel + - - - Dienogest + + - - Gestodene + - ( + ) - Levonorgestrel + - - - Norgestimate + - - - + Effct (+) negligible - No effct
    71. 71. Advantages of Drospirenone over other Progesterogens 1. Counter acts water retension due to its anti mineralocorticoid activity. 2. 78% patient loose weight or remained same ( 105 lost >1kg , 24% lost < 1kg , 44% wt did not change. 3. Nearly half of Patients having skin Problem as acne / Hirsuitism or both report improvement ( 74%). It is due to its antiandrogenic activity. 4. women having Premenstrual symptoms also have significant relief. Source—Gynaecology -2002 Vol 7 No 1: 23-26
    72. 72. Management:  Control of hirsutism  Medical (need a trial of 6-12 months before deemed ineffective) – Decrease testosterone production (predominantly from ovary) » OCPs (improvement scores 33%) -Increase SHBG » Lifestyle modification/weight loss » Metformin (improvement scores 10-13%) » Glucocorticoids? -Theory: ACTH stimulates adrenal androgen synthesis. So, suppress ACTH via glucocorticoids. -Study by Vanky, et al- dexamethasone 0.25 mg/day vs placebo —reduction in testosterone, androstenedione, DHEA-S by 25- 50%. No significant change in BMI, glucose, insulin, lipids -problematic
    73. 73. Management:  Control of hirsutism (cont’d) • Decrease testosterone action – Antiandrogens » Spironolactone (start 50 mg bid  100 mg bid) -Reduction in hirsutism 45% -Preferred use w/ OCPs, 75% response » Drospirenone (analogue of spironolactone, approved in Yasmin) » 5α-reductase inhibitors (ex. Finasteride) – Lifestyle modification/weight loss – Metformin
    74. 74. Management:  Control of hirsutism • Mechanical – Plucking/shaving/electrolysis/laser – Vaniqa cream (eflornithine hydrochloride 13.9%) » Mechanism: slows growth of hair by inhibiting L- ornithine decarboxylase (enzyme involved in hair growth) » 58% demonstrated some improvement in hair growth vs 32% with placebo » Hair growth rates return to normal 8 wks off therapy » Not covered by most insurance policies
    75. 75. Hirsutism • Mechanical hair removal • Vaniqa (eflornithine hydrochloride) • OCPs with minimal androgenicity • OCP plus antiandrogen (spironolactone) • Spironolactone, 50-200 mg per day • Flutamide – Potential hepatic dysfunction
    76. 76. Hirsutism • Spironolactone: – Antiandrogens, such as spironolactone, are effective for hirsutism. – Spironolactone 50-100 mg twice daily is an effective primary therapy for hirsutism. – Because of the potential teratogenic effects of spironolactone, patients require an effective form of contraception (eg, an oral contraceptive). – Adverse effects of spironolactone include GI discomfort, and irregular menstrual bleeding (which can be managed by adding an oral contraceptive).
    77. 77. Management: • Regulation of menses • Oral contraceptives • Periodic progesterone withdrawal – Medroxyprogesterone 10 mg/day x 7-10 days, every 3 months (approx 4 menses annually) • Lifestyle modification/weight loss • Metformin- ie., hitting the “root cause” – 500-1000 mg bid, 6 month trial reasonable for improvement of menses
    78. 78. Oligomenorrhea • Combination estrogen-progestin pill first line when fertility is not desired – Decrease in LH secretion and decrease in androgen production – Increase in hepatic production of sex- hormone binding globulin – Decreased bioavailablity of testosterone – Decreased adrenal androgen secretion – Regular withdrawal bleeds – Prevention of endometrial hyperplasia
    79. 79. Management: • Fertility issues – Lifestyle modification/weight loss • Loss of >5% body wt, calorie-restricted diet, and exercise associated with improvement in spontaneous pregnancy rates (7.5-15% improvement) – Clomiphene citrate – Most women with PCOS do not respond to normal dose— 20% ovulation rate!
    80. 80. Management • Fertility issues (cont’d) – Metformin – OR 3.88 in achieving fertility (compared to placebo), 4.4 (for metformin+clomiphene compared to clomiphene alone) – Improved outcomes with in vitro fertilization (reduced risk of ovarian hyperstimulation when treated with FSH) – Reduction in 1st trimester spontaneous abortions – Thiazolidinediones • Early studies w/ rosiglitazone prior to conception  30% improvement in fertility rates.
    81. 81. TREATMENT—no fertility desired • Monophasic antiandrogenic OCP – ON 1/35 (norethindrone) – Orthocyclen (norgestimate) – Desogen or Orthocept (desogestrel) – Yasmin
    82. 82. INFERTILITY TREATMENT • Metformin – 500 mg daily – Increase by 500 mg each week until: • Normal menses • Reached max dose • Side-effects • Clomid – 50 mg days 3-7 for 3 months – 100 mg days 3-7 for 3 months
    83. 83. Infertility • Weight loss—reduction in serum testosterone concentration and resumption of ovulation • Clomid: 80% will ovulate, 50% will conceive • Metformin: when added to clomid, improves ovulatory rates • FSH injections • Laparoscopic surgery: wedge resections, laparoscopic ovarian laser electrocautery • IVF
    84. 84. Clomid Challenge Test • Day 3 FSH and estradiol levels • 100 mg of Clomid on cycle days 5-9 • Day 10 FSH levels • The test is abnormal if either the day 3 or day 10 FSH values are elevated (greater than 10) or if the day 3 estradiol is greater than 80
    85. 85. Surgical Management • Aimed mainly at restoring ovulation. • Ovarian wedge resection: This procedure has fallen out of favor because of postoperative adhesion formation and the introduction of ovulation-inducing medications. • Laparoscopic surgery: Various laparoscopic methods, including electrocautery, laser drilling, and multiple biopsy, have been used with the goal of creating focal areas of damage in the ovarian cortex and stroma. – Potential complications include formation of adhesions and ovarian atrophy. – Multiple pregnancy rates are lower with ovarian drilling than with gonadotrophin treatment (1% versus 16%), but there are ongoing concerns about the long-term effects on ovarian function.28
    87. 87. Management: Long-Term Issues • Insulin resistance – Metformin • Function – Lowers hepatic glucose production by reducing gluconeogenesis – Increases peripheral glucose uptake by skeletal muscle and adipose tissue – Reduces intestinal glucose absorption • Outcomes – Estimated 31% reduction in development of type II DM over mean period 3 years – Taken during pregnancy, reduction in gestational diabetes and major fetal complications
    88. 88. Management: Long-Term Issues • Insulin resistance – Thiazolidinediones • Function – Selective ligands of the nuclear transcription PPARγ, expressed in adipose tissue, pancreatic beta cells, vascular endothelium, macrophages, HPO axis. – “fatty acid steal” hypothesis » Promote fatty acid uptake and storage in adipose tissue, sparing other tissues (muscle, liver) from harmful metabolic effects of free fatty acids (high levels in PCOS) – Increased expression of adiponectin (adipocytokine with an insulin sensitivity effect) – Decreased expression of 11β-hydroxysteroid dehydrogenase type 1 (enzyme converts inactive cortisone to active cortisol) • Outcomes
    89. 89. Management: Long-Term Issues • Cardiovascular Risk – Increased prevalence of HTN – Dyslipidemia (↑ TG, ↓ HDL, ↑ LDL) – Predisposition to macrovascular disease and thrombosis
    90. 90. Management: Long-Term Issues • Obstructive Sleep Apnea – 30-fold increased risk of OSA, not explained by obesity alone. – Insulin resistance strongest predictor of OSA (not BMI, age, testosterone) – Consider polysomnography if at risk
    91. 91. Management: Long-Term Issues • Risk for malignancy – 3 fold increased risk endometrial carcinoma in PCOS – Increased risk of ovarian and breast cancer – Warrants regular screening, low threshold for endometrial biopsy
    92. 92. Other issues Role of epilepsy? – Increased incidence of reproductive disorders in patients with epilepsy – Pts on valproic acid may have higher levels of insulin, testosterone, and TG
    93. 93. New things on the horizon… • Somatostatin analogs – Function • Blunts LH response to GnRH • Decreases GH secretion by pituitary • Inhibits pancreatic insulin release – Outcomes: limited studies • 7 d administration octreotide in PCOS women  decreased fasting and glucose-stimulated insulin levels • Reduced LH, androgen, IGF-1 levels • Short half-life (80-110 min) requiring multiple injections • Extended release octreotide (octreotide-LAR)- inject IM Q28 days- results in improvement in GH, insulin, IGF-1, hirsutism • Not approved yet
    94. 94. RCOG Guidelines (May 2003) Evidence based guidelines for reduction of long-term PCOS consequences
    95. 95. Guidelines (RCOG, May 2003) • Patients presenting with PCOS particularly if they are obese, should be offered measurement of fasting blood glucose and urine analysis for glycosuria. Abnormal results should be investigated by a glucose tolerance test. • Such patients are at increased risk of developing type II diabetes • Women who have been diagnosed as having PCOS before pregnancy (eg those requiring ovulation induction for conception) should be screened for gestational diabetes in early pregnancy, with referral to a specialized obstetric diabetic service if abnormalities are detected
    96. 96. Guidelines (RCOG, May 2003) • Measurement of fasting cholesterol, lipids and triglycerides should be offered to patients with PCOS, since early detection of abnormal levels might encourage improvement in diet and exercise. • Olig- and amenorrhoeic women with PCOS may develop endometrial hyperplasia and later carcinoma. It is good practice to recommend treatment with progestogens to induce withdrawal bleed at least every 3-4 months. • 4-
    97. 97. Guidelines (RCOG, May 2003) • A body of evidence has accumulated demonstrating safety and in some studies efficacy of insulin- sensitizing agents in the management of short-term complications of PCOS, particularly anovulation. • Long-term use of these agents for avoidance of metabolic complications of PCOS can not as yet be recommended . • No clear consensus has yet emerged concerned regular screening of women with PCOS for later development of diabetes and dyslipidemia but obese women with a strong family history of cardiac disease or diabetes should be assessed regularly.
    98. 98. Guidelines (RCOG, May 2003) • Young women diagnosed with PCOS should be informed of the possible long- term risks to health that are associated with their condition. • They should be advised regarding weight and exercise.
    100. 100. Guidelines-2005 • Well-defined published data indicate a high risk for development of T2DM and CVD in women with PCOS. • In view of the lack of protective effect of female sex on CVD risk in patients with diabetes, the associated risks of CVD are magnified in women with diabetes who have PCOS. • Clearly, this situation means that PCOS is a general health disorder of young women, with potential for reversal of some of the associated risk with early diagnosis and treatment.
    101. 101. Guidelines-2005 • Lifestyle modification with weight loss and exercise, avoidance of tobacco, correction of lipid abnormalities, and use of metformin may be of value. • Metformin therapy not only reduces hyperinsulinism and improves steroidogenic dysfunction but also is helpful in achieving better regularity of menses and fertility potential. • Thiazolidinediones have also been shown to decrease androgen levels, improve ovulation, and reduce progression to overt T2DM in patients with PCOS and IGT.
    102. 102. Guidelines-2005 • Early recognition of the syndrome. • Lifestyle modification, with emphasis on the need for controlled eating patterns and regular aerobic exercise. • Encouragement should be offered by an empathic physician, who will monitor the patient carefully during the course of treatment. • Measurement of glucose (and possibly insulin levels). An oral glucose challenge may be considered, particularly in obese women with PCOS and those with a family history of T2DM.
    103. 103. Guidelines: Lipids and BP • Detection and treatment of lipid abnormalities, with dietary measures first and then use of appropriate medications, such as a statin, fibrate, niacin, or ezetimibe (or some combination of these agents), as necessary. • Careful attention to and treatment of blood pressure abnormalities. • Measurement of atherogenic markers (C-reactive protein [CRP], fibrinogen, and possibly homocysteine).
    104. 104. Guidelines: OC and Anti-Androgen • The use of a nonandrogenic oral contraceptive agent and an antiandrogen such as spironolactone for the skin manifestations of PCOS. • The presence of hair thinning requires the maximal dose of spironolactone in conjunction with an oral contraceptive agent. • Ancillary use of electrolysis and laser therapy may also be helpful.
    105. 105. Guidelines: TZD • The use of these agents to improve hyperandrogenism and ovulation is considered only investigational at this time. • Thiazolidinediones are category C drugs; their use is contraindicated during pregnancy.
    106. 106. RECOMMENDATIONS ACOG 2009
    107. 107. Grades of Recommendations • A- Requires at least one randomized controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation. (Evidence levels Ia, Ib) • B- Requires the availability of well controlled clinical studies but no randomized clinical trials on the topic of recommendations (Evidence levels IIa, IIb, III) • C- Requires evidence obtained from expert committee reports or opinions and/ or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality. (Evidence level IV)
    108. 108. The following recommendations and conclusions are based on good and consistent scientific evidence (Level A): • An increase in exercise combined with dietary change has consistently been shown to reduce diabetes risk comparable to or better than medication. • Improving insulin sensitivity with insulin-sensitizing agents is associated with a decrease in circulating androgen levels, improved ovulation rate, and improved glucose tolerance. • The recommended first-line treatment for ovulation induction remains the antiestrogen clomiphene citrate. • The addition of eflornithine to laser treatment is superior in the treatment of hirsutism than laser alone.
    109. 109. The following recommendations and conclusions are based on limited and inconsistent scientific evidence (Level B): • Women with a diagnosis of polycystic ovary syndrome (PCOS) should be screened for type 2 diabetes and impaired glucose tolerance with a fasting glucose level followed by a 2-hour glucose level after a 75-g glucose load. • Women with PCOS should be screened for cardiovascular risk by determination of body mass index (BMI), fasting lipid and lipoprotein levels, and metabolic syndrome risk factors. • Reduction in body weight has been associated with improved pregnancy rates and decreased hirsutism, as well as improvements in glucose tolerance and lipid levels. • There may be an increase in pregnancy rates by adding clomiphene to metformin, particularly in obese women with PCOS. • If clomiphene citrate use fails to result in pregnancy, the recommended second-line intervention is either exogenous gonadotropins or laparoscopic ovarian surgery.
    110. 110. The following recommendations and conclusions are based primarily on consensus and expert opinion (Level C): • Combination low-dose hormonal contraceptives are most frequently used for long-term management and are recommended as the primary treatment of menstrual disorders. • Women in groups at higher risk for nonclassical congenital adrenal hyperplasia and a suspected diagnosis of PCOS should be screened to assess the 17- hydroxyprogesterone value. • A low-dose regimen is recommended when using gonadotropins in women with PCOS. • There is no clear primary treatment for hirsutism in PCOS.
    111. 111. Doctor’s MESSAGE TO THE YOUNG GIRLS During early school age , at the time of health education girls should be advised to adopt healthy life style in the form of balanced diet having locally available food articles like all cereals, pulses, beans, green leafy vegetables, seasonal fruits , jaggery and dairy products in appropriate amount. Monotonous diet should be avoided as it will cause nutritional deficiencies. Under the effect of advertisement in TV and print media , they should avoid to become crazy to soft cold drinks, chocolates and junk food. They should be advised to play out door games and regular physical exercise like cycling, skipping, jogging and running / swimming etc. This will go long way to prepare a girl to let her develop in a perfect adolescent with minimal menstrual dysfunction..