Lect 2-polycystic ovarian syndrome
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  • ACCESS Medical Group D220/PCOS CME Slide Kit November 22 2002 References 1. Bauer J, et al. Epilepsy Res . 2000;41:163-167. 2. Dunaif A, et al. Annu Rev Med . 2001;52:401-419. 3. Franks S. N Engl J Med . 1995;333:853-861.
  • ACCESS Medical Group D220/PCOS CME Slide Kit November 22 2002 Clinical Features of PCOS. Menstrual Irregularity. PCOS is a disorder characterized by menstrual irregularity and hyperandrogenemia. Menstrual irregularity: This problem may manifest itself at puberty with a delayed menarche followed by the onset of irregular periods or as the breakdown of a previously regular cycle within a few years and is often associated with weight gain. 1 Anovulation in PCOS is usually chronic and presents as oligomenorrhea or amenorrhea around the time of the onset of menstruation. 2 It has been reported that 50% of women with PCOS are obese, and 20% of these obese women will have either impaired glucose tolerance or type 2 diabetes by the age of 40 years. 1 Other conditions associated with PCOS include infertility, endometrial hyperplasia or malignancy, hypertension, coronary artery disease, and adverse lipid profiles. 3 References 1. Duncan S. Epilepsia . 2001;42(suppl 3):60-65. 2. Lobo RA, et al. Ann Int Med . 2000;132:989-993. 3. Ernst CL, et al. J Clin Psychiatry . 2002;63(suppl 4):42-55.
  • ACCESS Medical Group D220/PCOS CME Slide Kit November 22 2002 Clinical Features of PCOS. Hyperandrogenism. Hyperandrogenemia is a key feature of PCOS, and it may appear as hirsutism, acne, male pattern balding, and/or male distribution of body hair. 1 Reference 1. Lobo RA, et al. Ann Intern Med . 2000;132:989-993.
  • ACCESS Medical Group D220/PCOS CME Slide Kit November 22 2002
  • ACCESS Medical Group D220/PCOS CME Slide Kit November 22 2002
  • ACCESS Medical Group D220/PCOS CME Slide Kit November 22 2002
  • 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
  • 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.
  • 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)!

Transcript

  • 1. Polycystic Ovarian Syndrome
  • 2. Polycystic Ovarian Syndrome (PCOS) Overview
    • Polycystic ovarian syndrome (Stein-Leventhal syndrome) is a complex endocrine disorder affecting women in their reproductive years.
    • It is characterized by increased androgen production and disordered gonadotropin secretion, which results in chronic anovulation.
    • It is the leading cause of anovulatory infertility and hirsutism.
    • PCOS is also associated with disorders of reproduction, metabolism, and general health, including increased risk of miscarriage, insulin resistance, hyperlipidemia, cardiovascular disease, and endometrial cancer.
    • Obesity is common but not universal in women with PCOS.
    • Women with PCOS have high rate of type 2 diabetes; these women have hyperlipidemia and a greatly increased risk of cardiovascular disease.
  • 3. 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
  • 4. Why is PCOS important?
    • Affects 4-12% of women of reproductive age
    • Significant association between obesity, insulin resistance, and PCOS.
    • Huge impact on the reproductive, metabolic, and cardiovascular health of affected women.
  • 5. Clinical Features of PCOS Menstrual Irregularity
      • May appear at puberty with a delayed menarche followed by the onset of irregular periods or as the breakdown of a previously regular cycle
      • Anovulation is usually chronic and presents as oligomenorrhea or amenorrhea
  • 6. Clinical Features of PCOS Hyperandrogenism
    • Symptoms may include hirsutism, acne, male pattern balding, and/or male distribution of body hair
    Hirsutism Acne
  • 7. Pathogenesis
    • 1. Hyperandrogenism
    • 2. Insulin resistance
  • 8. Common Endocrine Abnormalities in PCOS
      • Elevated luteinizing hormone (LH)
      • Increased LH/follicle-stimulating hormone (FSH) ratio
      • Elevated androgen levels
      • Decreased sex hormone binding globulin levels
  • 9.  
  • 10.
    • In PCOS, discovered increased pulse frequency of GnRH (2/2 abnml pulse generator), resulting in relatively increased pulse frequency of LH, over FSH.
    • Increased frequency of LH pulses in PCOS. Progesterone administration can restrain rapid pulse frequency. Increased LH results in increased production of androgens by ovarian theca cells.
    • INSULIN acts synergistically with LH to enhance androgen production. INSULIN suppresses SHBG (the key protein that binds testosterone), resulting in increased free testosterone.
    • TESTOSTERONE inhibits and estrogen stimulates hepatic synthesis of Sex hormone-binding globulin (SHBG).
  • 11. Pathogenesis: Hyperandrogenism
    • Symptoms of androgen excess
    • Reduced sex-hormone-binding globulin (SHBG)  more free testosterone  conversion of androstenedione in adipose tissue
    • Insulin insensitivity
    • Lipid abnormalities
    • Abdominal obesity
  • 12. Metabolic Abnormalities in PCOS
      • Hyperinsulinemia and insulin resistance
      • Insulin resistance may be independent of the effect of obesity
      • Decreased peripheral insulin sensitivity and consequent hyperinsulinemia may play an important role in the pathogenesis of PCOS
  • 13. Lipid and Lipoprotein Abnormalities in PCOS
      • Elevated LDL cholesterol
      • Elevated triglycerides
      • Decreased HDL cholesterol
      • Decreased apolipoprotein A-I
      • Impaired fibrinolytic activity
  • 14. Pathogenesis: Insulin resistance
    • Favors anovulation, androgen excess, reduced SHBG
    • Metabolic syndrome
    • Abdominal obesity
  • 15.  
  • 16. 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(such as testosterone or androsterone) excess increases LH by blocking the hypothalamic inhibitory feedback of progesterone
  • 17. hypothalamus pituitary ovary GnRH LH androgens Androgens block inhibitory effect of progesterone X
  • 18. Abnormal steroidogenenesis
    • Intraovarian androgen excess results in excessive growth of small ovarian follicles
    • Follicular maturation is inhibited
    • Excess androgen causes thecal and stromal hyperplasia
  • 19. HYPERINSULINEMIA
    • Excess insulin production and insulin resistance
    • Genetic link
    • Hyperandrogenism vs. hyperinsulinemia
      • Which came first?
  • 20. DIAGNOSTIC CRITERIA AND CLINICAL MANIFESTATIONS
  • 21.
      • Menstrual irregularity due to anovulation or oligo-ovulation
      • Evidence of clinical or biochemical hyperandrogenism
        • Hirsutism, acne, male pattern baldness
        • High serum androgen levels
      • Exclusion of other causes (CAH, tumors, hyperprolactinemia)
    DIAGNOSTIC CRITERIA
  • 22. 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
  • 23.  
  • 24. 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)
  • 25. Diagnosis
    • Hyperandrogenism (cont’d)
      • 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 ( contraceptives)
          • LH/FSH ratio >2 has little diagnostic sensitivity
  • 26. Diagnosis
    • 2. Oligoovulation or anovulation
        • Oligomenorrhea or amenorrhea
        • Dysfunctional uterine bleeding
        • Infertility
          • 30-50% 1 st trimester miscarriage rate
        • 3-fold increased risk endometrial carcinoma
  • 27. Diagnosis
    • 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
  • 28. OVARIAN ABNORMALITIES
    • Thickened sclerotic cortex
    • Multiple follicles in peripheral location
    • 80% of women with PCOS have classic cysts
  • 29.  
  • 30.  
  • 31.  
  • 32. INFERTILITY
    • Intermittent ovulation or anovulation
    • Inherent ovarian disorder—studies show reduced rated of conception despite therapy with clomid
  • 33. 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
  • 34. 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
  • 35. 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
  • 36. 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
  • 37. DIFFERENTIAL DIAGNOSIS
    • 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
  • 38.
    • 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
  • 39. TESTING
    • Serum HCG
    • Serum prolactin
    • Thyroid panel
    • FSH: r/o ovarian failure
    • Serum luteinizing hormone (LH)—elevated
    • Serum estradiol—normal
    • Serum estrone—elevated
  • 40. TESTING
    • Fasting glucose: elevated
    • 2 hour OGTT: elevated
    • Fasting insulin: elevated
    • Free testosterone: elevated
    • DHEA-S: normal
    • 17-hydroxyprogesterone: normal
    • Pelvic US
    • Lipids
  • 41. TREATMENT Management
      • Immediate/Acute issues
          • Hirsutism
          • Regulation of menses
          • Fertility issues
      • Long-term issues
          • Insulin resistance
          • Cardiovascular risk
          • Malignancy risk
  • 42. WEIGHT LOSS
    • Weight loss
    • Weight loss
    • Weight loss
  • 43. Management: Immediate/Acute Issues
    • 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
  • 44. 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
  • 45. Management: Immediate/Acute Issues
      • no fertility desired
    • Monophasic antiandrogenic OCP
      • ON 1/35 (norethindrone)
      • Orthocyclen (norgestimate)
      • Desogen or Orthocept (desogestrel)
      • Yasmin
    • Fertility issues
      • Metformin
      • Thiazolidinediones
  • 46. INFERTILITY TREATMEN T
    • 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
  • 47. 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
  • 48. 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= Vitro Fertilization
  • 49. 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
  • 50. 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)
  • 51. Management: Long-Term Issues
    • Cardiovascular Risk
      • Increased prevalence of HTN
      • Dyslipidemia (↑ TG, ↓ HDL, ↑ LDL)
      • Predisposition to macrovascular disease and thrombosis
      • Aggressive management…”CHAMP”?
  • 52. Management: Long-Term Issues
    • Risk for malignancy
      • 3X increased risk endometrial carcinoma in PCOS
      • Increased risk of ovarian and breast cancer
      • Warrants regular screening, low threshold for endometrial biopsy
  • 53.  
  • 54. 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.
  • 55. 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.
  • 56.