? By Shelley Ferrell Advisor: Eileen VanDyke, PA-C PAS Spring 2006

Behind door #1… 20 yo white female CC: menstrual irregularity over past year, no period in 5 months PE: obesity, acne, hirsutism Labs: (-) HCG, (+) hyperandrogenemia, (+) insulin resistance Diagnosis: ?

Behind door #2 21 yo white female CC: menstrual irregularity over past year, no period in 5 months PE: thin, mild acne, unremarkable Labs: (-) HCG, (+) hyperandrogenemia, (-) insulin resistance Diagnosis: ?

Treatment options Patient #1- Consider Metformin Patient #2- No obesity, no IR… Metformin???

The Use of Metformin in Non-obese Women with Polycystic Ovarian Syndrome By Shelley Ferrell Advisor: Eileen VanDyke, PA-C PAS Spring 2006

Why care about PCOS? Its common It causes other health problems It is emotionally painful for women

Making the diagnosis Two out of three –Oligo and/or an-ovulation –Clinical and/or biochemical hyperandrogenemia –Polycystic ovaries on ultrasound Diagnosis of exculsion

Clinical Presentation Is there a stereotypical PCOS patient? SignPrevalence Polycystic Ovaries80-100% Oligo- or amenorrhea70% Hyperandrogenism20-80% Hirsutism70% Obesity50% Increased LH30-90% Insulin Resistance20-50% Acne33% Other symptoms occur more rarely Obesity makes a difference

Pathophysiology

Three Theories: –Ovarian hypothesis –Central hypothesis –Insulin hypothesis Role of obesity in pathogenesis Obesity status/ IR status makes difference

Treatment Options Obese- weight loss! Non-obese- OCPs, anti-androgens, insulin- sensitizers Drawbacks to each Benefits of metformin Remember the initial question for Patient #2: –Do non-obese pts benefit from metformin? What if they are not insulin resistant?

Lean Women with Polycystic Ovary Syndrome Respond to Insulin Reduction with Decreases in Ovarian P450c17{alpha} Activity and Serum Androgens Nestler et al, normal weight women 1500 mg day metformin vs placebo, 4-6 wks Drop in serum sex steroids –(total T ↓48%, free T ↓70% and androstenedione ↓ 36%) Conclusions: Non-obese PCOS patients benefit from metformin treatment

Non-obese women with polycystic ovary syndrome respond better than obese women to treatment with metformin Maciel et al, women in 2 groups: obese and non-obese Metformin 1500 g/day vs placebo, 6 months Results –Non-obese: ↑menstrual cyclicity, total T↓ 38%, free T ↓58%, androstendione↓30% –Obese: total T ↓48%, otherwise no change Conclusions: Non-obese women experience more benefit than obese women with metformin txt

Effects of metformin and rosiglitazone, alone and in combination, in non-obese women with polycystic ovary syndrome and normal indices of insulin sensitivity Baillargeon et al, non-obese women with normal insulin sens 1700 mg of metformin, 8 mg of rosiglitazone, a combination of both drugs or placebo daily for 6 months Results (met vs placebo): ovulation 6x more common, 100% ovulating monthly by study end- vs 10% placebo, sex steroids ↓67% Conclusions: Metformin benefits non-obese pts without IR

Metformin-diet benefits in women with polycystic ovary syndrome in the bottom and top quintiles for insulin resistance Goldenberg et al, women in top and bottom quintiles for IR out of screening of 898 PCOS pts (all weights!) 2550 mg/day of metformin for 1 year + diet Results: menstruation doubled in non-IR Conclusion: metformin benefits non-IR (many non-obese are also non-IR)

Predictive value of glucose-insulin ratio in PCOS and profile of women who will benefit from metformin therapy: Obese, lean, hyper or normoinsulinemic? Onalan et al, women into 6 groups based on glucose-insulin ratio (normoinsulinemic and hyperinsulinemic) and BMI (lean, overweight and obese) mg/day of metformin (based on BMI) or placebo for 6 months Results: –IR/Lean group: ↑ ovulation, ↓ hirsutism –Both Lean groups, IR/obese group: ↓ Total T –No other significant results Conclusion: Pts who are both lean and IR benefit most from metformin therapy

Inconsistancy? Onalan did not show benefit to overweight women (still considered non-obese) AuthorGroup NameInclusion CriteriaAverage BMI NestlerLean< MacielNon-obese< BaillargeonNon-obese < Onalan Lean < Overweight< No inconsistancy- there may be an inverse relationship between BMI and response to metformin, even within non-obese or normal weight populations

Conclusion OCPs very effective Metformin should be considered also Talk to your patient- see what her goals are

If the intended result…

…isn’t quite achieved, Yikes!

just try something else!  Find a treatment that the patient is satisfied with  Be sensitive to the effects that PCOS can have on self esteem  Let the patient know that there are websites and online groups for “cysters”

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