# Presentation: 136991

## Insulin Action on PCO Ovary

- Stimulatory effect on steroidogenesis
- Additive with FSH, GC → estradiol
- Synergistic with FSH, LH, GC → P4
- Mediated by insulin receptor, not IGF-1 R
- Premature follicle arrest
- Amplification of LH-induced A4 production

## Management of PCOS

- Reproductive Issues – Near Term
- Metabolic Issues – Long Term
- Establishing Diagnosis
- Options for Treatment
- Weight Loss
- Insulin-Sensitizing Agents
- Future?

## Management of PCOS

- Reproductive Health
- Anovulation/Oligo-ovulation
- Dysfunctional Uterine Bleeding
- Endometrial Cancer
- Increased Miscarriage Rates
- Increased Risk Gestational Diabets
- Increased Risk Type 2 Diabetes

##  PCOS Diagnosis

- Necessary Lab Tests
- TSH
- PRL
- Consider, if Indicated
- FSH
- Testosterone
- DHEA-S
- 17-OH Progesterone
- Fasting glucose : insulin

## Insulin-Sensitizing Drugs

- Biguanides
- Metformin
- Thiazolidinediones
- Trogliozone
- Pioglitazone
- Rosiglitozone

## Metformin

- Does not stimulate insulin release
- Enhances glucose disposal in peripheral tissues
- Enhances glucose uptake in muscle
- Increases GLUT4 glucose transporters in rat adipocytes
- Increases efficiency of total body glucose uptake in obese but not in lean NIDDM patients
- Decreases basal hepatic glucose release

## Metformin

- Improves glucose tolerance
- Reduces plasma insulin, cholesterol and triglyceride levels
- Inhibits oxidative phosphorylation, risk of increasing plasma lactate levels
- Hepatic and renal disease precautions
- 	*Oral hypoglycemic agents- from A.C.Moses and J.J. Abrahmason, Therapeutic Approaches to Insulin Resistance in *_*Insulin Resistance*_*, DE Moller, ed. 1993*

## Short-Term Management PCOS

- Literature Review 1994 – 2002
- Prospective, clinically relevant endpoints
- Metformin – 23 studies
- Troglitozone – 4 studies

## PCOS ManagementOvulation Induction

- 	Early uncontrolled study of Metformin:
- 		21 of 22 patients ovulated 7 months
- 		Minority became pregnant
- E Velasquez et al  Obstet Gynecol 1997

## Metformin, PCOS, Ovulation

- Nestler, et al. 1998
- First R, P-C trial of metformin in PCOS
- 61obese PCO randomized to met or placebo
- 35 days, add CC 50 mg x 5 days
- First month -  40 % vs 4 % ovulated
- Overall-	89 % vs 12 % ovulated

## PCOS Management

- Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone.
- 										Vandermolen DT, Ratts VS, Evans WS, et al. 	Fertil Steril 2001

## Metformin and Ovulatory Rates

- 56 obese PCOS women refractory to CC
- Metformin 1,700 mg day or placebo x 2 mo
- Add CC 100 mg x 5 d second month
- Met + CC ovulation rate 77.7 %
- Placebo  + CC ovulation rate 14.3 %
- Pregnancy rate 14 % vs 0 %
- Kocak et al, Fertil Steril 77:2002

## PCOSOvulation Management

- Screening for insulin resistance
- Clomiphene resistance
- Role for empiric therapy?
- UNM REI protocol

## UNM REI Protocol

- If warranted- fasting insulin/glucose
- Glucophage 500 mg b.i.d., t.i.d. 8 weeks
- Spontaneous menses, ultrasound, P4
- No menses, ultrasound- hCG or
- Start clomiphene citrate 100 mg x 5 days
- When pregnant, stop glucophage, not FDA-approved

## PCOS, Pregnancy Risk Markers 

- Adverse risks associated with changes in:
- Endothelin-1
- PAI-1
- C reactive protein
- Glycodelin
- IGF BP-1

## PCOS: Extended Management

- Metabolic Syndrome
- Syndrome X
- Insulin resistance syndrome
- ICD-9 (277.7)