1. Robina Rana PGY- 4 Endocrinology February 1st , 2012
Endocrine perspective of PCOS & Ground breaking studies in reproduction
Robina Rana
PGY- 4 Endocrinology
February 1st , 2012

2. OBJECTIVE: PCOS :Metabolic disease/ reproduction condition
Discuss the background, pathophysiology of PCOS and its impact on Reproductive Endocrinology.
To Review Journal Articles of particular importance to Reproductive Endocrine Practice

3. PCOS – Historical perspective:
ACHARD and THIERS reported the first observation of co-existing hirsutism and diabetes, and related this syndrome to hyperplasia of the adrenal cortex, detected at autopsy and was given the name,
“Diabetes in Bearded Women”
(ACHARD – THIERS –SYNDROME)

4. PCOS – Historical perspective:
In 1935, Stein and Leventhal published a paper on their findings in seven women with
amenorrhea
hirsutism
obesity
a characteristic polycystic appearance to their ovaries
— one of the first descriptions of a complex phenotype today known as the
“polycystic ovary syndrome.”

5. Polycystic ovarian syndrome:
The condition is now well recognized as having a major effect throughout life on the
reproductive,
metabolic, and
cardiovascular health of affected women.

7. PCOS: clinical features
ACNE
HIRSUTISM
ACANTHOSIS
NIGRICANS

8. pcos: Sonographic and histologic features

9. Factors contributing to difficulties in diagnosis of and treatment of PCOS:
Lack of precise and uniform definition of PCOS
Presenting signs and symptoms are;
Heterogeneous
Vary over time
No Definite treatment is available.

12. Conditions for Exclusion in the Diagnosis of the Polycystic Ovary Syndrome.
Ehrmann DA. N Engl J Med 2005;352:

15. Estrogen biosynthesis in women
The biologically active estrogen estradiol (E2) is produced in at least three major sites:
(1) by direct secretion from the ovary in reproductive-age women;
(2) by conversion of circulating androstenedione (A) of adrenal or ovarian origins, or both, to estrone (E1) in peripheral tissues; and
(3) by conversion of A to E1 in estrogen target tissues.
In the latter two instances, estrogenically weak E1 is further converted to E2 within the same tissue by
aromatase
17β-hydroxysteroid dehydrogenase (17β-HSD)
E2 formation by peripheral and local conversion is particularly important in postmenopausal women and in estrogen-dependent diseases such as breast cancer, endometriosis, and endometrial cancer.

16. Androgen biosynthesis in women:
DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; HSD, hydroxysteroid dehydrogenase
There are two biologically active androgens,
testosterone (T) and
dihydrotestosterone (DHT).
Depending on the menstrual cycle phase or postmenopausal status,
20% to 30% of T is secreted by the ovary.
Rest of T production is accounted for by the conversion of circulating androstenedione (A) T in peripheral tissues
Both the adrenal and ovary contribute to circulating A directly or indirectly.
Finally, T is converted to the more potent androgen DHT within the target tissues and cells.
For example, local conversion of T to DHT in sex skin fibroblasts and hair follicles amplifies androgenic action for clitoral enlargement and hirsutism.

17. Extraovarian conversion of androstenedione to androgen and estrogen:
Biologically active amounts of estradiol in serum are measured in pg/mL (pmol/L), whereas biologically active levels of testosterone in serum are measured in ng/mL (nmol/L).
Androstenedione of adrenal or ovarian origin, or both, acts as a dual precursor for androgen and estrogen.
Five percent of circulating androstenedione is converted to circulating testosterone, whereas 1.3% of circulating androstenedione is converted to circulating estrone in peripheral tissues.
Testosterone and estrone are further converted to biologically potent steroids, dihydrotestosterone and estradiol, in peripheral and target tissues.
Thus, 1.3% conversion of normal quantities of androstenedione to estrone may have a critical biologic impact in settings such as postmenopausal endometrial or breast cancer.
Furthermore, significant androgen excess is observed in conditions with abnormally increased androstenedione formation (e.g., polycystic ovary syndrome).

18. Regulation of (GnRH), (LH), and (FSH) secretion:
Regulation of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) secretion.
CRH, Corticotropin-releasing hormone; E2, estradiol; P, progesterone.
Locally synthesized and systemic hormones regulate the pulsatile secretion of GnRH from the hypothalamus into the portal circulation.
In turn, GnRH together with a number of steroid and peptide hormones regulate the synthesis of α and β gonadotropin subunits and the formation and secretion of FSH and LH.

19. The Hypothalamic–Pituitary–Ovarian Axis and the Role of Insulin.
Figure 2. The Hypothalamic–Pituitary–Ovarian Axis and the Role of Insulin. Increased ovarian androgen biosynthesis in the polycystic ovary syndrome results from abnormalities at all levels of the hypothalamic–pituitary–ovarian axis. The increased frequency of luteinizing hormone (LH) pulses in the polycystic ovary syndrome appears to result from an increased frequency of hypothalamic gonadotropin-releasing hormone (GnRH) pulses. The latter can result from an intrinsic abnormality in the hypothalamic GnRH pulse generator, favoring the production of luteinizing hormone over follicle-stimulating hormone (FSH) in patients with the polycystic ovary syndrome, in whom the administration of progesterone can restrain the rapid pulse frequency. By whatever mechanism, the relative increase in pituitary secretion of luteinizing hormone leads to an increase in androgen production by ovarian theca cells. Increased efficiency in the conversion of androgenic precursors in theca cells leads to enhanced production of androstenedione, which is then converted by 17β-hydroxysteroid dehydrogenase (17β) to form testosterone or aromatized by the aromatase enzyme to form estrone. Within the granulosa cell, estrone is then converted into estradiol by 17β. Numerous autocrine, paracrine, and endocrine factors modulate the effects of both luteinizing hormone and insulin on the androgen production of theca cells; insulin acts synergistically with luteinizing hormone to enhance androgen production. Insulin also inhibits hepatic synthesis of sex hormone–binding globulin, the key circulating protein that binds to testosterone and thus increases the proportion of testosterone that circulates in the unbound, biologically available, or “free,” state. Testosterone inhibits and estrogen stimulates hepatic synthesis of sex hormone–binding globulin. The abbreviation scc denotes side-chain cleavage enzyme, StAR steroidogenic acute regulatory protein, and 3β-HSD 3β-hydroxysteroid dehydrogenase. Solid arrows denote a higher degree of stimulation than dashed arrows.
Ehrmann DA. N Engl J Med 2005;352:

20. Pathologic mechanisms in polycystic ovary syndrome :
17b-HSD, 17β-hydroxysteroid dehydrogenase; 5a-red, 5α-reductase. A deficient in vivo response of the ovarian follicle to physiologic quantities of follicle-stimulating hormone (FSH), possibly because of an impaired interaction between signaling pathways associated with FSH and insulin-like growth factors (IGFs) or insulin, may be an important defect responsible for anovulation in PCOS.
Insulin resistance associated with increased circulating and tissue levels of insulin and bioavailable estradiol (E2), testosterone (T), and IGF-I gives rise to abnormal hormone production in a number of tissues.
Over secretion of luteinizing hormone (LH) and decreased output of FSH by the pituitary, decreased production of sex hormone-binding globulin (SHBG) and IGF-binding protein 1 (IGFBP-1) in the liver, increased adrenal secretion of dehydroepiandrosterone sulfate (DHEAS), and increased ovarian secretion of androstenedione (A) all contribute to the vicious circle that maintains anovulation and androgen excess in PCOS.
Excessive amounts of E2 and T arise primarily from the conversion of A in peripheral and target tissues.

21. Hypothesis for Prenatal Androgen Programming of Females for PCOS

22. PCOS health consequences
Cardiometabolic:
Increased risk of type 2 Diabetes
Hypertension
Dyslipidemia
Increased inflammation
Increased cardiovascular disease risk
Non-alcoholic steatohepatitis (NASH)
Sleep apnea
Reproductive
Infertility
Increased risk of miscarriage
Increased risk of gestational diabetes/ preeclampsia
Increased risk of endometrial cancer(RR 3.1)
Psychosocial
Depression & anxiety
Cosmetic concerns
(hyperandrogenic symptoms)

23. Figure 2. Pathophysiology of Polycystic Ovary Syndrome.
Legro, R. S. JAMA 2007;297:

24. Management Goal: Overall goals of treatment are to:
Restore appropriate Gonadotropin secretion
Decrease androgen levels to prevent long-term deleterious effects of PCOS
Restore menstrual cyclicity
Manage the cosmetic symptoms and signs
Restore fertility if desired
Long-term health - Chronic disease prevention
Diabetes prevention
Cardiovascular disease risk reduction
Cancer prevention

25. Management : Lifestyle management is the foundation of treatment.
1.Metabolic Management:
Lifestyle management is the foundation of treatment.
Weight Reduction.
Insulin Sensitizing agents.
Up to half of women with PCOS are overweight or obese
Abdominal obesity is typical
Even lean women with PCOS tend to have increased omental and visceral fat
Modest weight loss of 5 – 10% can restore menstrual cyclicity
Healthy eating and exercise essential for management of both hormonal and metabolic aspects of PCOS.
Multidisciplinary approach to weight management.

26. Management: 2. Symptomatic Management: Oral Contraceptives
Choose progestin with low androgenic
potential
Increases SHBG levels
Suppresses androgen production
Effective in reducing acne & hirsutism
Cycle regulation and thus reducing risk of endometrial hyperplasia/cancer
Antiandrogens
Spironolactone

28. PCOS – Other Potential Drug Treatments
Exenatide(Byetta):
GLP-1 Analogue
Exenatide restores first- and secondphase
insulin secretion which
is attenuated in
women with PCOS,
as well as promote weight loss, thereby potentially further improving insulin sensitivity

29. 1. Metformin in polycystic ovary syndrome:

31. Metformin in PCOS: systematic review and meta-analysis
Objective To assess the effectiveness of metformin in improving clinical and biochemical features of polycystic ovary syndrome.
Data sources Randomized controlled trials that investigated the effect of metformin compared with either placebo or no treatment, or compared with an ovulation induction agent.

32. Metformin in PCOS: Selection of studies
13 trials were included for analysis, including 543 women with polycystic ovary syndrome that was defined by using biochemical or ultrasound evidence.
Main outcome measure
Pregnancy and ovulation rates.
Secondary outcomes of
clinical and biochemical features of polycystic ovary syndrome.

33. Metformin compared with placebo or no treatment:
significant effect of metformin compared with placebo on ovulation
Metformin compared with placebo or no treatment–ovulation rate
a significant effect of metformin compared with placebo on ovulation became obvious (3.88, 2.25 to 6.69, P < ). We detected no significant heterogeneity. The funnel plot was limited as only seven trials were included, but no bias was evident. The two trials with the lowest weight (total weight 11.8%) are the two that did not show a significant effect.
Lord J M et al. BMJ 2003;327:951
©2003 by British Medical Journal Publishing Group

34. Metformin combined with clomifene compared with clomifene alone–ovulation rate.effect for metformin and clomifene compared with clomifene alone was significant
Metformin combined with clomifene compared with clomifene alone–ov
ulation rate
shows that the effect for metformin and clomifene compared with clomifene alone was also significant (4.41, 2.37 to 8.22, P < ) based on the results of three trials. However, we detected significant heterogeneity. Two of the trials used participants who were known to have been resistant to clomifene previously, and consequently the ovulation rate in their placebo and clomifene arms was relatively low (17.5%) These two trials showed a significant effect for metformin and clomifene compared with clomifene and placebo (9.34, 3.97 to 21.97, P < ), without any heterogeneity. In contrast the third trial, where participants were not selected on the basis of being resistant to clomifene, had a high ovulation rate in their placebo and clomifene arm (64%).24 This trial did not show evidence of benefit for metformin compared with clomifene in our analysis when odds ratios were used, although it did in the original report.
©2003 by British Medical Journal Publishing Group
Lord J M et al. BMJ 2003;327:951

35. Metformin compared with placebo or no treatment–side effects.
Adverse events
Only one trial reported miscarriage rates and multiple pregnancy rates.20 Neither reached significance.
Metformin caused a significantly higher incidence of nausea or vomiting (odds ratio 3.84, 95% confidence interval 1.07 to 13.81, P = 0.05,) and other gastrointestinal disturbance (4.40, 1.82 to 10.66, P = 0.003).
Lord J M et al. BMJ 2003;327:951
©2003 by British Medical Journal Publishing Group

36. Metformin compared with placebo or no treatment–fasting insulin:
Metformin had a significant effect in reducing fasting insulin concentrations
Metformin compared with placebo or no treatment–fasting insulin
Metformin had a significant effect in reducing fasting insulin concentrations with a weighted mean difference of (-8.11 to -2.63, P = ) (fig 4). Overall nine trials were included in the analysis, and all had wide confidence intervals Significant heterogeneity was attributable to the large treatment effect seen in two trials When these trials were excluded, the significance remained without significant heterogeneity, which implies a genuine effect of treatment. The funnel plot implies publication bias, although the symmetry is improved when the two trials are excluded from the analysis.
Lord J M et al. BMJ 2003;327:951
©2003 by British Medical Journal Publishing Group

37. Results: Characteristics Metformin vs. placebo
Clomiphene + Metformin vs. Clomiphene alone
Ovulation
Effective with OR 3.88
Effective with OR 4.41
Pregnancy Rate
Significant with combined Rx
Fasting Insulin Level
Reduced level
reduced
Blood pressure
Reduced
LDL-C level
BMI / Waist hip ratio
No effect
------
Adverse effects
Nause/vomiting/GI
Higher incidence
high
Metformin is effective in achieving ovulation in women with PCOS with odds ratios of
3.88 (95% CI 2.25 to 6.69) for metformin compared with placebo
4.41 (2.37 to 8.22) for metformin and clomifene compared with clomifene alone.
An analysis of pregnancy rates shows a significant treatment effect for metformin and clomifene(odds ratio 4.40, 1.96 to 9.85).
Metformin has an effect in reducing fasting insulin concentrations, blood pressure, and low density lipoprotein cholesterol.
Metformin has no evidence of any effect on body mass index or waist:hip ratio.
Metformin was associated with a higher incidence of nausea, vomiting, and other gastrointestinal disturbance

38. Conclusions:
Metformin is an effective treatment for anovulation in women with PCOS
Can be used as first line agent There is some evidence of benefit on variables of the metabolic syndrome.
It should be used as an adjuvant to general lifestyle improvements and not as a replacement for increased exercise and improved diet.
Safety of Metformin
No data for long term use in young women
only limited data on in early pregnancy.

39. 2. Metformin Versus Oral Contraceptive Pill in Polycystic Ovary Syndrome: A Cochrane Review Human Reproduction. 2007;22(5):  © 2007 

40. Oral Contraceptives in Polycystic Ovary Syndrome:
The OCPs are a key component of the chronic treatment of PCOS addressing many of the goals of the reproductive-aged PCOS women not seeking pregnancy.
Earlier epidemiologic studies of OCPs in healthy women have raised concern regarding
potential adverse cardiometabolic effects
increase the risk of diabetes particularly in obese patients with severe insulin resistance.

41. OCPs vs Insulin Sensitizing Drugs in PCOS
ORAL CONTRACEPTIVES
INSULIN SENSITIZING DRUGS
Insulin Resistance
May Worsen
Improves Insulin Sensitivity
Glucose Intolerance
May induce
Improves Glucose tolerance
Serum TG
May Increase
May Reduce
Risk for Type 2 DM
Decrease
Risk for CVD
Redcue
dec. level of CRP,
Edothelin levels

42. Metformin vs. OCP in PCOS: (A Cochrane Review)
Background: The objective of this review was to compare metformin versus oral contraceptive pill (OCP) treatment in polycystic ovary syndrome.
Methods: A systematic review and meta-analysis employing the principles of the Cochrane Menstrual Disorders and Subfertility Group was undertaken.
Conclusions: Limited RCT evidence to date does not show adverse metabolic risk with the use of the OCP compared with metformin. Further long- term RCTs are required.
Michael F. Costello; Bhushan Shrestha; John Eden; Neil P. Johnson; Peter Sjoblom
Human Reproduction. 2007;22(5):  © 2007 Oxford University Press

43. Study
Allocation concealment
Blinding
Number randomized
Number analysed (type of analysis)
Mean age (years)
Mean BMI (kg m-2)
Duration of treatment (months)
Total daily metformin dose (mg)
Type of oral contraceptive pill
Notes
Harborne et al. (2003b), Scotland A No 52
34 (ACA) 31 32 12
1500
Diane 35
Recruited polycystic ovary syndrome (PCOS) women whose primary complaint was hirsutism
Morin-Papunen et al. (2000), Finland
18 (ACA) 30 35 6
1000 increasing to 2000 after 3 months
Recruited obese women with PCOS
Morin-Papunen et al. (2003), Finland 20
17 (ACA) 28 22
Recruited non-obese women with PCOS
Rautio et al. (2005), Finland
35 (ACA) 29
Assessed lipid levels only. The patients included the combined patients of Morin-Papunen et al. (2000; 2003)
ACA = available case analysis; Allocation concealment: A = clear; BMI = body mass index; Diane 35 = 35 µg ethinyl estradiol plus 2 mg cyproterone acetate.

44. Primary Outcome Measures Comparison of metformin vs
Primary Outcome Measures Comparison of metformin vs. oCP outcome of hirsutism:
69 participants analyzed reported on hirsutism using either Ferriman-Gallway (FG) scoring system or a subjective (patient self-assessed) visual analogue scale from 0 to 10
Meta-analysis demonstrated no difference in effect on hirsutism between metformin and OCP
Hirsutism. Three trials comparing metformin versus OCP with a combined total of 69 participants analysed (104 particpants randomized)
(Morin-Papunen et al., 2000, 2003)
Harborne et al., 2003b).

45. Primary Outcome Measures Comparison of metformin versus ocp with outcome of acne.
There was a single trial comparing metformin versus OCP
with 34 participants analyzed (52 participants randomized)
reporting acne subjectively (patient self-assessed) using a
visual analogue scale ranging from 0 to 10 (Harborne et al., 2003b).
This trial demonstrated no significant difference in acne
scores between metformin and the OCP
Acne.

46. Primary Outcome Measures Comparison of metformin versus OCP with outcome of type 2 diabetes mellitus
One trial comparing metformin versus OCP with 18 participants analysed (32 participants randomized) reported diagnosis of T2DM (Morin-Papunen et al., 2000).
No significant difference was seen in the development of T2DM between the metformin and OCP groups (Peto OR 0.17, P = 0.37, 95% CI 0.00 to 8.54)
Type 2 Diabetes Mellitus.

47. Primary Outcome Measures
Cardiovascular Disease There were no trials comparing metformin versus OCP reporting the outcome measure of CVD (stroke or myocardial infarction).
Endometrial Cancer There were no trials comparing metformin versus OCP reporting endometrial cancer as an outcome.

48. Secondary Outcomes Measures Improved Menstrual Pattern.
There were two trials comparing metformin versus OCP with a total of 35 participants analysed (52 participants randomized) reporting on improvement in menstrual cyclicity (Morin-Papunen et al., 2000, 2003).
Eighteen of 21 participants on metformin and 20 of 24 participants on the OCP had either oligomenorrhoea or amenorrhoea at baseline.
Both trials reported menstrual pattern in terms of days between menses and metformin was significantly less effective in improving menstrual pattern Peto OR 0.08, P = 0.004, 95% CI )

49. Secondary Outcomes Measures Hormonal: Serum Total Testosterone (nmol l-1).
There were three trials comparing metformin versus OCP with a total of 69 participants analysed (104 participants randomized) reporting on total serum testosterone (Morin- Papunen et al., 2000, 2003; Harborne et al., 2003b).
Meta-analysis demonstrated a significantly higher serum total testosterone with metformin compared with the OCP

50. Secondary Outcomes Measures Metabolic: Fasting Glucose (mmol l-1).
Three trials comparing metformin versus OCP with a total of 69 participants analysed (104 participants randomized) reported on fasting glucose levels(Morin-Papunen et al., 2000, 2003; Harborne et al., 2003b).
There was no significant difference in fasting glucose levels between the two interventions (WMD 0.13, P = 0.25, 95% CI to 0.35)

51. Secondary Outcomes Measures Metabolic: Fasting Total Cholesterol (mmol l-1).
There were two trials comparing metformin versus OCP with a total of 69 participants analysed (104 participants randomized) reporting on total cholesterol levels (Harborne et al., 2003b; Rautio et al., 2005).
Meta-analysis demonstrated no significant difference in total cholesterol levels between metformin and the OCP

52. Secondary Outcomes Measures Metabolic: Fasting Triglycerides (mmol l-1).
Two trials comparing metformin versus OCP with a total of 69 participants analysed (104 participants randomized) reported on triglyceride levels (Harborne et al., 2003b; Rautio et al., 2005).
Metformin resulted in a significantly lower triglyceride level than the OCP (WMD -0.48, P = 0.01, 95% CI to -0.09

53. Results: mETFormin vs. OCP in PCOS:
CHARACTERISTIC
METFORMIN
OCP
HIRSUTISM
No Difference
ACNE
TYPE 2 DM
FASTING GLUCOE
TOTAL CHOLESTEROL
SEVERE ADVERSE EFFECTS
CVS DISEASE
ENDOMET. CA
IMPROVED MENSTRUAL PATTERN
Less effective
More effective
S. TESTOSTERONE LEVEL
Less effective in decreasing levels
More effective in decreasing levels
FASTING S. INSULN LEVEL
FASTING TRIGLYCERIDE LEVEL
More effective not increasing level
Four randomized controlled trials (RCTs) (104 subjects) were included
No evidence of a difference in effect between metformin and the OCP on hirsutism, acne or development of type 2 diabetes mellitus.
There were no trials assessing diagnosis of cardiovascular disease or endometrial cancer.
Metformin, was less effective in
improving menstrual pattern [Peto odds ratio (OR) 0.08, 95% confidence interval (CI) )
in reducing the serum total testosterone level (WMD) 0.54, 95% CI ]
Metformin was more effective in
reducing fasting insulin (WMD -3.46, 95% CI to -1.52)
not increasing fasting triglyceride (WMD -0.48, 95% CI to -0.09) levels.
No evidence of a difference in effect between the two therapies on reducing fasting glucose or total cholesterol levels and severe adverse events.

54. 3. Troglitazone in Women with PCOS: Improves Defects in Insulin Action, Insulin Secretion, Ovarian Steroidogenesis, and Fibrinolysis

55. Troglitazone: PPAR gamma activator

56. Troglitazone in PCOS:
Insulin-sensitizing agent troglitazone was administered to 13 obese women with PCOS and impaired glucose tolerance to determine whether attenuation of hyperinsulinemia ameliorates ovarian steroidogenesis, and fibrinolysis.
All subjects had oligomenorrhea, hirsutism, polycystic ovaries, and hyperandrogenemia.
The Journal of Clinical Endocrinology & Metabolism July 1, 1997 vol. 82 no

57. Before and after treatment with troglitazone (400 mg daily for 12 weeks), all had
a GnRH agonist (leuprolide) test,
a 75-g oral glucose tolerance test,
a frequently sampled iv glucose tolerance test to determine the insulin sensitivity index and the acute insulin response to glucose,
an oscillatory glucose infusion to assess the ability of the β-cell to entrain to glucose as quantitated by the normalized spectral power for the insulin secretion rate, and
measures of fibrinolytic capacity
[ plasminogen activator inhibitor type 1 (PAI-1)
and tissue plasminogen activator].

58. Glucose (top panel) and insulin (bottom panel) responses during the OGTT before (closed symbols) and after (open symbols) treatment with troglitazone.
Glucose (top panel) and insulin (bottom panel) responses during the OGTT before (closed symbols) and after (open symbols) treatment with troglitazone. Glucose and insulin levels decreased significantly (P < 0.05) throughout the 180-min period. Data are the mean ± sem.
Ehrmann D A et al. JCEM 1997;82:
©1997 by Endocrine Society

59. Measures derived from the rapidly sampled iv glucose tolerance test before (solid) and after (hatched) treatment with troglitazone. (improved b-cell fucntion)
Measures derived from the rapidly sampled iv glucose tolerance test before (solid) and after (hatched) treatment with troglitazone. There was a significant increase in Si after treatment. Improved β-cell function is evidenced by the significant increase in disposition index (product of Si and AIRg) after treatment with troglitazone (see text for details). Data are the mean ± sem.
AIRg – Acute insulin response
Ehrmann D A et al. JCEM 1997;82:
©1997 by Endocrine Society

60. Profiles of the glucose concentrations and ISR in response to an oscillatory glucose infusion in one representative subject before (upper panel) and after (lower panel) treatment with troglitazone.
Profiles of the glucose concentrations and ISR in response to an oscillatory glucose infusion in one representative subject before (upper panel) and after (lower panel) treatment with troglitazone. Note that the glucose levels and ISRs are lower after treatment. The ISR oscillations are more regular and more closely parallel the oscillations in glucose after troglitazone treatment, as reflected in a normalized spectral power value of 13.1 compared to a pretreatment value of 5.4.
Ehrmann D A et al. JCEM 1997;82:
©1997 by Endocrine Society

61. PAI-1 antigen and activity levels before (solid) and after (hatched) treatment with troglitazone.
PAI-1 antigen and activity levels before (solid) and after (hatched) treatment with troglitazone. A concordant decline in both PAI-1 antigen and activity levels was observed in response to treatment. Data are the mean ± sem.
©1997 by Endocrine Society
Ehrmann D A et al. JCEM 1997;82:

62. Results of Troglitazone Therapy in PCOS :
Characteristic
Post Treatment with Troglitazone
BMI
No Change
Body Fat Distribution
Glycated Heamoglobin
Concordant Reduction
6.1 ± 0.1% 5.7 ± 0.1 (P < 0.03).
Total & Free Testosterone level
Significant Reduction
Luprolide Stimulation
17-Hydoxy progesterone level
Andreostenddione level
Total Testosterone level
Total Cholesterol
No Significant change
LDL – C
Triglyceride levels
Declined ( not statically significant.)
No change in body mass index (39.9 ± 1.4 vs ± 1.4 kg/m2) or body fat distribution after treatment
There was a concordant reduction in glycosylated hemoglobin to 5.7 ± 0.1 from a pretreatment level of 6.1 ± 0.1% (P < 0.03).
Basal levels of total testosterone (109.3 ± 15.2 vs ± 9.8 ng/dL; P < 0.05) and free testosterone (33.3 ± 4.0 vs ± 2.6 pg/mL; P < 0.01) declined significantly after troglitazone treatment.
Leuprolide-stimulated levels of 17-hydroxyprogesterone, androstenedione, and total testosterone were significantly lower posttreatment compared to pretreatment. The reduction in androgen levels occurred independently of any changes in gonadotropin levels.
There was no significant change in levels of total cholesterol, HDL cholesterol, or LDL cholesterol after troglitazone treatment. Although triglyceride levels declined from 164 \ 33 to 115 \ 15 mg/dL, this did not achieve statistical significance

63. Conclusion:
Administration of troglitazone to women with PCOS and IGT ameliorates each of the metabolic and hormonal derangements that characterize these women.
Troglitazone was removed from the market because it caused liver dysfunction and, in some patients, liver failure.
Thiazolidinedione therapy has been investigated for induction of ovulation, but routine use of these drugs has not been suggested secondary to side effect profile.

64. 4. Comparison of Single and Combined Treatment with Exenatide vs
4.Comparison of Single and Combined Treatment with Exenatide vs.Metformin on Menstrual Cyclicity in Overweight Women with Pcos:

65. Metformin vs. exanetide IN polycystic ovarian syndrome:
Objective:
Evaluate effect of exenatide (EX) and metformin (MET), alone and in combination (COM) on ;
menstrual cyclicity,
hormonal parameters
metabolic profiles
inflammatory markers
in overweight, insulin-resistant women with PCOS.

66. Design, Setting, and Participants:
Sixty overweight oligo ovulatory women with PCOS (body mass index 27; 18–40 yr)were randomized to one of three treatment groups:
MET[1000mgtwice daily (BID)]
EX (10 mcg BID) or
COM (MET 1000 mg BID, EX 10 g BID) for 24 wk.
The primary outcome was menstrual frequency;
Secondary outcome measures included changes in ovulation rate, insulin action, anthropometric measures, androgen levels, and inflammatory markers.

67. Menstrual cycle frequency index at baseline and after 24 wk of
(only patients who completed the study are included).
Data shown are the mean SEM. *, P , pre- vs.
posttreatment; †, P , between-treatment effect (COM vs. MET).
J Clin Endocrinol Metab, July 2008, 93(7):2670–2678
Menstrual cycle frequency index at baseline and after 24 wk of
treatment with EX, MET, or COM

68. Data are presented as mean SEM. *, P 0.001, baseline vs.
posttreatment for all groups; #, P , COM, EX vs. MET, P 0.05, COM vs. EX at 24 wk. B, AG (centimeters) of women with PCOS at baseline and after 12 and 24 wk of treatment with EX, MET, or COM.
Data are presented as mean SEM. *, P , baseline vs. post treatment groups and #, P , COM vs. MET, P 0.05, EX vs. MET and EX vs. COM at 24 wk.
Absolute body weight (kg) of women with PCOS at baseline and after 12 and 24 wk of treatment with EX, MET, or COM.

69. Results: Forty-two (70%) patients completed the study.
COM therapy was superior to EX or MET monotherapy in
improving
menstrual cyclicity
ovulation rate
free androgen index
insulin sensitivity measures
reducing
weight
abdominal fat.
Both EX arms were more effective in promoting weight loss than MET (P ).

70. Conclusions:
COM appears better than either EX or MET alone on menstrual cycle frequency and hormonal and metabolic derangements.
A marked decrease in central adiposity could partly explain the improvements in
reproductive function,
insulin-glucose parameters, and
adiponectin observed in these overweight women with PCOS treated with COM therapy.
Larger trials of longer duration are warranted to assess the long-term efficacy and safety of combined EX-MET therapy in overweight women with PCOS.
(J Clin Endocrinol Metab 93: 2670–2678, 2008)

71. Table 2. Selected Randomized Trials of Common Medical Therapies in Women With Polycystic Ovary Syndrome With at Least 100 Participants According to Outcomes Assessed.
Table 2. Selected Randomized Trials of Common Medical Therapies in Women With Polycystic Ovary Syndrome With at Least 100 Participants According to Outcomes Assessed
Legro, R. S. JAMA 2007;297:

72. Polycystic Ovary Syndrome Associated with Morbid Obesity Resolves after Weight Loss ??

73. PCOS associated with morbid obesity may resolve after weight loss Induced by Bariatric Surgery
Objective:
The objective of this study was to evaluate the response of PCOS to the sustained and marked weight loss achieved by bariatric surgery in morbidly obese women.

74. Design: Patients:
This was a longitudinal prospective nonrandomized evaluation.
36 consecutive premenopausal women submitted to bariatric surgery were screened for PCOS, which was present in 17
Main Outcome Measures:
Hyperandrogenism,
menstrual function, and
insulin resistance
were estimated before and at least 6 months after bariatric surgery in 12 patients with PCOS

75. Clinical and biochemical characteristics of the morbidly obese PCOS patients submitted to bariatric surgery, before and after weight loss. ○, Individual values; ▪, mean ± sd.
Clinical and biochemical characteristics of the morbidly obese PCOS patients submitted to bariatric surgery, before and after weight loss. ○, Individual values; ▪, mean ± sd. The shaded areas represent the reference range for each variable. All paired comparisons are statistically significant (P ≤ 0.02). To convert to Systeme International units, multiply androstenedione by 3.19 (results in nmol/liter), dehydroepiandrosterone sulfate by (results in μmol/liter), insulin by (results in pmol/liter), SHBG by (results in nmol/liter), free testosterone by (results in pmol/liter), and total testosterone by (results in nmol/liter).
©2005 by Endocrine Society
Escobar-Morreale H F et al. JCEM 2005;90:

76. Results: Weight loss (41 ± 9 kg after 12 ± 5 months)
Decreases in the hirsutism score
(from 9.5 ± 6.8 to 4.9 ± 4.2; P = 0.001),
Decrease in Total Testosterone
(69 ± 32 to 42 ± 19 ng/dl; P < 0.02)
Decrease in Free testosterone
from 1.6 ± 0.7 to 0.6 ± 0.3 ng/dl; P < 0.005),
Androstenedione level decrease
(from 4.1 ± 1.5 to 3.0 ± 0.9 ng/ml; P < 0.02),
Dehydroepiandrosterone sulfate level
(from 2000 ± 1125 to 1353 ± 759 ng/ml; P < 0.005);
Amelioration of insulin resistance
(from 6.0 ± 3.0 to 1.6 ± 1.0; P < 0.001);
Restoration of regular menstrual cycles and/or ovulation in all patients

77. Results:
Regular menstrual cycles were restored in the 12 PCOS patients after weight loss and 10 of these patients have confirmed ovulation.
Diabetes and dyslipidemia resolved in the PCOS patient presenting with both disorders.
In another patient, diabetes returned to glucose intolerance, whereas hypertension persisted.
In one of the two PCOS patients presenting with hypertension but no other metabolic complication, blood pressure returned to normal after weight loss.
Regular menstrual cycles were restored in the 12 PCOS patients after weight loss. Furthermore, in 10 of these patients who were available for determination of luteal phase serum progesterone concentrations, values above 4 ng/ml (10 ± 4 ng/ml; range, 5–16 ng/ml) confirmed ovulation in all of them, suggesting that the restoration of menstrual cycle regularity was also accompanied by restoration of ovulation in these hyperandrogenic patients. Therefore, in none of the 12 PCOS patients could this diagnosis be sustained after the marked weight loss achieved after bariatric surgery.
Finally, diabetes and dyslipidemia resolved in the PCOS patient presenting with both disorders; in another patient, diabetes returned to glucose intolerance, whereas hypertension persisted, and in one of the two PCOS patients presenting with hypertension but no other metabolic complication, blood pressure returned to normal after weight loss.

78. Conclusions:
The PCOS is a frequent finding in women with morbid obesity and may resolve after weight loss induced by bariatric surgery.

79. Effective treatment of polycystic ovarian syndrome with Roux-en-Y gastric bypass
Surgery for Obesity and Related Diseases 1 (2005) 77–80

80. Purpose:
This study investigated the impact of weight loss surgery on the clinical manifestations of PCOS in morbidly obese women with PCOS —a major risk factor for the development of heart disease, stroke, and type II diabetes.

81. Methods: Reviewed the outcomes of women diagnosed with PCOS
who had undergone weight loss surgery at the University of Pittsburgh between July and November 2001.
Evaluated the changes in
menstrual cycles,
hirsutism,
infertility, and
type II diabetes.

82. Patient characteristics pre- and post-gastric bypass
Pre-Operative
Post- Operative
% change
AGE( yr)
34+/- 9.7
N/A
WEIGHT( LB)
306 =/- 44
201 +/- 30
12-93%
BMI (Kg/m2)
50 +/- 7.5
30 +/- 4.5
25-38%
HTN 9 2 77 DM 11
100
HB A1C(%) only 5 pts who have preop HBA1C
8.2
5.14 62
GERD 12
DYSLIPIDEMIA 1 92
HIRSUTISM 23 5 79
DEPRESSION 10
MENSTRUAL DYSFUNCTION 24
MEDS PER HYPERTENSIVE
1.3 (9 pt on 12 M)
0.67 (2 pt on 3 M)
DIABETIC MEDICATION
1.1( 11 pt on 12 M)

83. Conclusion:
Results suggest that obese patients with PCOS who undergo gastric bypass will experience a significant improvement in multiple clinical problems related to the disorder.
Larger prospective studies are needed to confirm further the benefit of surgically induced weight loss in the treatment of women with PCOS.

84. The Impact of Bariatric Surgery on Menstrual Patterns

85. Background:
Weight loss of at least 5% has been shown to reverse obesity-related anovulation.
The aim of this study was to assess the impact of bariatric surgery on infertility in morbidly obese women and to identify factors associated with return of normal menses following bariatric surgery.

86. Methods: A survey of patients was collected from
the bariatric surgery data-base at the Hospital of the University of Pennsylvania.
410 women under the age of 40 were sent questionnaires.
195 patients completed the questionnaire, resulting in a 51.2% response rate.
Patients who reported menstrual cycle lengths >35 days were considered abnormal.
92 of the 195 responders were considered anovulatory preoperatively, based on menstrual history.

87. Results: Both groups had a decrease in BMI of >18 kg/m2.
The mean menstrual cycle length preoperatively among those categorized as ovulatory and anovulatory was 27.3 and days, respectively.
Of the 98 patients who were anovulatory preoperatively, 70 patients (71.4%)
regained normal menstrual cycles after
surgery.
Those patients who regained ovulation had greater weight loss than those who remained anovulatory (61.4 kg vs 49.9 kg, P=0.02).

88. Conclusions:
Anovulation resulting in abnormal menses is a common problem in morbidly obese premenopausal women.
The menstrual cycle disorders may completely resolve after bariatric surgery.
Thus, infertility due to anovulation among morbidly obese women could potentially be viewed as an additional indication for bariatric surgery.

89. Conception rate after bariatric surgery

90. Pregnancy and Fertility Following Bariatric Surgery:
Large numbers of women in their childbearing years may undergo bariatric surgery, which may
change fertility following weight loss,
alter nutritional requirements during pregnancy,
or impact contraception to prevent pregnancy.

91. Objectives & Evidence Acquisition
To estimate bariatric surgery rates among women aged 18 to 45 years and to assess the published literature on pregnancy outcomes and fertility after surgery.
Search of the Nationwide Inpatient Sample ( ) and multiple electronic databases (Medline, EMBASE, Controlled Clinical Trials Register Database, and the Cochrane Database of Reviews of Effectiveness) to identify articles published between 1985 and February 2008 on bariatric surgery among women of reproductive age.

92. Bariatric Surgery and Fertility.
6 studies that addressed fertility outcomes in patients after bariatric surgery and most of these compared pregnancy rates before and after surgery .
Three small studies reported improvements in fertility and 1 study noted no change.
Six studies found evidence of normalization of hormones and menstrual cycles and lessening of polycystic ovarian syndrome following bariatric surgery.

93. Conclusion:
Most observations on fertility following bariatric surgery lack complete data on the total number of women attempting to get pregnant and pregnancy rates.
Most studies present convenience samples of women who were able to get pregnant, in whom pre surgery fertility histories were available.
With these significant limitations in mind, data suggest that surgery may have a beneficial influence on fertility, which is supported by the normalization of hormones in polycystic ovarian syndrome and correction of abnormal menstrual cycles.

94. PCOS: Clinical Pearls
Most common endocrinopathy in reproductive age women(need early recognition of syndrome).
Clinical diagnosis: (irregular menses and hyperandrogenism)
Not only reproductive disorder! Need to address
metabolic defect and cardiometabolic risks.
Evaluation:– hormonal parameters, fasting glucose & OGTT (with insulin levels), lipids with other atherogenic markers; appropriate eval for sleep apnea and cardiovascular disease

95. PCOS: Clinical Pearls
Management approach - aggressive reduction of CV risk factors
Multidisciplinary team approach with support / resources for patients
Lifestyle management
Diet, exercise, sleep, minimize exposure to
environmental toxins.
Pharmacologic treatment
First line medication - Metformin
Use of OCPs with low androgenic progestin for cycle regulation and symptomatic treatment of skin manifestations (acne, hirsutism, alopecia)
Clomiphene Citrate for ovulation Induction.

96. Thank YOU