Polycystic Ovary Syndrome & Metformin November 19, 2008.

Polycystic Ovary Polycystic Ovary Syndrome & MetforminSyndrome & Metformin

November 19, 2008November 19, 2008

Polycystic Ovary SyndromePolycystic Ovary Syndrome

EpidemiologyEpidemiology

Clinical manifestationsClinical manifestations

Diagnostic criteriaDiagnostic criteria

Metformin and other medical treatmentsMetformin and other medical treatments

EPIDEMIOLOGYEPIDEMIOLOGY

Very prevalent disease affecting between 6.5 Very prevalent disease affecting between 6.5 and 8 percent of women overall.and 8 percent of women overall.

Prevalence much higher in obese women (28% Prevalence much higher in obese women (28% versus 5.5%)versus 5.5%)

Prevalence between racial groups in Prevalence between racial groups in Southeastern US not significantly differentSoutheastern US not significantly different

Genetic factors – genes involved in insulin Genetic factors – genes involved in insulin secretion and action, gonadotropin secretion secretion and action, gonadotropin secretion and action, and androgen biosynthesis, and action, and androgen biosynthesis, secretion, transport, and metabolismsecretion, transport, and metabolism

CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS

ObesityObesity

Up to one half of women Up to one half of women with PCOS are obese, with PCOS are obese, with an increased with an increased prevalence of abdominal prevalence of abdominal or central obesityor central obesity

Most women with PCOS Most women with PCOS are hyperinsulinemic and are hyperinsulinemic and insulin resistantinsulin resistant

OligomenorrheaOligomenorrhea

Classically have a peripubertal onsetClassically have a peripubertal onset May have apparently regular cycles at first, May have apparently regular cycles at first,

followed by irregularity and weight gainfollowed by irregularity and weight gain

Normal PCOS

Hirsutism and VirilizationHirsutism and Virilization

Excess body hair in a male distributionExcess body hair in a male distribution Male pattern baldingMale pattern balding Deeper voice, muscle mass, clitoromegalyDeeper voice, muscle mass, clitoromegaly

InfertilityInfertility

Female infertility occurs when the woman Female infertility occurs when the woman does not conceive after one year of does not conceive after one year of attempting to become pregnant attempting to become pregnant

DIAGNOSTIC CRITERIADIAGNOSTIC CRITERIA

vs.vs.

RotterdamRotterdam

NIH CriteriaNIH Criteria

1990 Consensus1990 Consensus Menstrual irregularity due to oligo/anovulationMenstrual irregularity due to oligo/anovulation Evidence of hyperandrogenismEvidence of hyperandrogenism Exclusion of other causes of the above twoExclusion of other causes of the above two

Rotterdam CriteriaRotterdam Criteria

Oligo- and/or Oligo- and/or anovulationanovulation

Clinical and/or Clinical and/or biochemical signs of biochemical signs of hyperandrogenismhyperandrogenism

POLYCYSTIC POLYCYSTIC OVARIES by OVARIES by ultrasound!!!ultrasound!!!

Transvaginal UltrasoundTransvaginal Ultrasound

12 or more follicles in each ovary12 or more follicles in each ovary Each follicle measuring 2-9 mm diameterEach follicle measuring 2-9 mm diameter Increased ovarian volume (>10 mL)Increased ovarian volume (>10 mL)

MEDICAL TREATMENTMEDICAL TREATMENT

Weight lossWeight loss HyperandrogenismHyperandrogenism Endometrial protectionEndometrial protection Insulin resistanceInsulin resistance Ovulation inductionOvulation induction

Weight LossWeight Loss

Weight loss alone is Weight loss alone is associated with a associated with a reduction in reduction in testosterone, leading testosterone, leading to resumption of to resumption of ovulation and often ovulation and often pregnancy.pregnancy.

HyperandrogensimHyperandrogensim

Many women shave, wax, use Nair or get Many women shave, wax, use Nair or get electrolysiselectrolysis

Combination oral contraceptivesCombination oral contraceptives Spirinolactone – antiandrogen propertiesSpirinolactone – antiandrogen properties

Endometrial ProtectionEndometrial Protection

Risk of unopposed estrogen Risk of unopposed estrogen endometrial hyperplasia endometrial hyperplasia

Combination OCPs vs. Intermittent Combination OCPs vs. Intermittent progestin therapyprogestin therapy

MetforminMetformin

MetforminMetformin

A biguanide – most widely used drug A biguanide – most widely used drug worldwide for the treatment of type 2 worldwide for the treatment of type 2 diabetes.diabetes.

Primary action – inhibits hepatic glucose Primary action – inhibits hepatic glucose productionproduction

Secondarily increases peripheral Secondarily increases peripheral sensitivity to insulinsensitivity to insulin

Clinical Evidence for PCOSClinical Evidence for PCOS

1996 study by Nestler demonstrated 1996 study by Nestler demonstrated reduced circulating insulin levels and reduced circulating insulin levels and decreased ovarian secretion of androgens decreased ovarian secretion of androgens Studies demonstrating decreased clinical Studies demonstrating decreased clinical signs of androgen excess are limitedsigns of androgen excess are limited

2003 Meta-analysis showed PCOS 2003 Meta-analysis showed PCOS women on Metformin 3.88 times more women on Metformin 3.88 times more likely to ovulatelikely to ovulate

Clinical Evidence cont’dClinical Evidence cont’d

Indian Diabetes Prevention Programme Indian Diabetes Prevention Programme and U.S. Diabetes Prevention Program and U.S. Diabetes Prevention Program have shown that metformin decreases the have shown that metformin decreases the relative risk of progression to type 2 relative risk of progression to type 2 diabetes by 26% and 31% respectivelydiabetes by 26% and 31% respectively

Limited evidence suggests that OCPs Limited evidence suggests that OCPs alone can aggravate insulin resistance and alone can aggravate insulin resistance and glucose intolerance.glucose intolerance.

RecommendationsRecommendations

Androgen Excess Society recommends Androgen Excess Society recommends that all women with PCOS be screened for that all women with PCOS be screened for glucose intolerance at initial presentation glucose intolerance at initial presentation and every 2 years thereafter.and every 2 years thereafter.

AES does not mandate use of metformin AES does not mandate use of metformin until more studies can demonstrate until more studies can demonstrate efficacy. efficacy.

Metformin use should be considered in all Metformin use should be considered in all patients with PCOS and glucose patients with PCOS and glucose intolerance.intolerance.

Recommendations cont’dRecommendations cont’d

American Association of Clinical American Association of Clinical Endocrinologists recommends that Endocrinologists recommends that metformin be considered the initial metformin be considered the initial intervention in most women with PCOS, intervention in most women with PCOS, particularly those who are overweight or particularly those who are overweight or obese.obese.

Adverse EffectsAdverse Effects

Lactic acidosis – rare complication (0.3 Lactic acidosis – rare complication (0.3 episode per 10,000 patient-years).episode per 10,000 patient-years).

GI distress – nausea and diarrhea in 10-GI distress – nausea and diarrhea in 10-25% of patients25% of patients

B12 Malabsorption.B12 Malabsorption. Category B drug – no teratogenic effects Category B drug – no teratogenic effects

in animal models and limited human in animal models and limited human anecdotal evidenceanecdotal evidence

Thank you!Thank you!

Taquito, 4 years old

Tyler Hansborough and Barack Obama

RESOURCESRESOURCES Alvarez-Blasco, F., et al. “Prevalence and characteristics of the polycystic ovary syndrome in Alvarez-Blasco, F., et al. “Prevalence and characteristics of the polycystic ovary syndrome in

overweight and obese women.” overweight and obese women.” Arch Intern MedArch Intern Med. 2006 October.. 2006 October. ““Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic

ovary syndrome (PCOS).” Human Reproduction 2004; 19:41. ovary syndrome (PCOS).” Human Reproduction 2004; 19:41. Adams, J, Polson, DW, Franks, S. “Prevalence of polycystic ovaries in women with anovulation Adams, J, Polson, DW, Franks, S. “Prevalence of polycystic ovaries in women with anovulation

and idiopathic hirsutism.” BMJ 1996; 293:355. and idiopathic hirsutism.” BMJ 1996; 293:355. Legro, RS, Barnhart, HX, Schlaff, WD, et al. “Clomiphene, metformin, or both for infertility in the Legro, RS, Barnhart, HX, Schlaff, WD, et al. “Clomiphene, metformin, or both for infertility in the

polycystic ovary syndrome.” N Engl J Med 2007; 356:551. polycystic ovary syndrome.” N Engl J Med 2007; 356:551. Harborne L, Fleming R, Lyall H, Sattar N, Norman J. Metformin or antiandrogen in the treatment Harborne L, Fleming R, Lyall H, Sattar N, Norman J. Metformin or antiandrogen in the treatment

of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:4116-23of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:4116-23 Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17alpha activity and serum Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17alpha activity and serum

free testosterone after reduction in insulin secretion in polycystic ovary syndrome. N Engl J Med free testosterone after reduction in insulin secretion in polycystic ovary syndrome. N Engl J Med 1996;335:617-23.1996;335:617-23.

Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003;327:951-3.meta-analysis. BMJ 2003;327:951-3.

Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V. The Indian Diabetes Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian and Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 2006;49:289-Asian and Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 2006;49:289-97.97.

Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.

Salley KES, Wickham EP, Cheang KI, Essah PA, Karjane NW, Nestler JE. Glucose intolerance Salley KES, Wickham EP, Cheang KI, Essah PA, Karjane NW, Nestler JE. Glucose intolerance in polycystic ovary syndrome: a position statement of the Androgen Excess Society. J Clin in polycystic ovary syndrome: a position statement of the Androgen Excess Society. J Clin Endocrinol Metab 2007;92:4546-56.Endocrinol Metab 2007;92:4546-56.

Polycystic Ovary Syndrome Writing Committee. American Association of Clinical Polycystic Ovary Syndrome Writing Committee. American Association of Clinical Endocrinologists positiion statement on metabolic and cardiovascular consequences of polycystic Endocrinologists positiion statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Endocr Pract 2005;11:126-134.ovary syndrome. Endocr Pract 2005;11:126-134.