title: The effects of metformin and rosiglitazone, alone and in combination, on the ovary and endometrium in polycystic ovary syndrome.
abstract: OBJECTIVE
  To examine the effects of metformin and rosiglitazone, alone and in combination, on endometrial histology and ovarian steroid production.
  
  
  METHODS
  Randomized open-label study of metformin and rosiglitazone in 16 women with polycystic ovary syndrome (PCOS) performed at a single academic health center. The study consisted of a 6-week baseline observation period, a 3-month treatment period of single-agent therapy (rosiglitazone or metformin), and then a 3-month period of combined therapy.
  
  
  RESULTS
  Abnormal endometrial histology was found in 3 subjects at baseline, including 1 case of adenocarcinoma of the endometrium in an asymptomatic subject, who was excluded from further study. The 2 other abnormal cases (simple hyperplasia) resolved with treatment. Three months of single-agent therapy showed a benefit of rosiglitazone (n = 9) over metformin (n = 6) in terms of reducing circulating unbound testosterone levels (-11.8; 95% CI: -21.7 to -2.0 ng/dL) and 2-hour glucose (-42.0; 95% CI: -76.2 to -7.8 mg/dL), 2-hour insulin (-150.4; 95% CI: -272.7 to -28.1 microU/mL) as well as a significant decrease in integrated levels of glucose and insulin by area under the curve analysis, all obtained from oral glucose tolerance testing. Daily urinary progestin-to-estrogen ratios improved on rosiglitazone compared to metformin therapy (0.08; 95% CI: 0.02 to 0.14). Ovulatory rates tended to improve on both single-agent and combined treatments (30/90 cycles, 33%), compared to baseline ovulatory rate (2/15, 13%). Despite 6 months of therapy alone or in combination, 5 women displayed no evidence of biochemical ovulation by urinary or serum progestin measurements.
  
  
  CONCLUSIONS
  This study provides preliminary evidence that insulin-sensitizing drugs may have beneficial effects on the endometrium, although the exact mechanism beyond improving ovulatory function is still unknown. In addition, we suggest that rosiglitazone may be more beneficial than metformin therapy on raised insulin and androgen levels in an obese PCOS population. Combined therapy did not demonstrate significant benefit above and beyond single-agent therapy.
authors.affiliation: Department of Obstetrics and Gynecology, The Pennsylvania State University College of Medicine, Hershey, PA, USA. RSL1@psu.edu
authors.forename: Richard S
authors.initials: RS
authors.lastname: Legro
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Zaino
authors.forename: Laurence M
authors.initials: LM
authors.lastname: Demers
authors.forename: Allen R
authors.initials: AR
authors.lastname: Kunselman
authors.forename: Carol L
authors.initials: CL
authors.lastname: Gnatuk
authors.forename: Nancy I
authors.initials: NI
authors.lastname: Williams
authors.forename: William C
authors.initials: WC
authors.lastname: Dodson
mesh_terms: D000328:Adult; D001707:Biopsy, Needle; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004717:Endometrium / Q000187:drug effects / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D016014:Linear Models; D008687:Metformin / Q000627:therapeutic use*; D010053:Ovary / Q000187:drug effects / Q000473:pathology*; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy* / Q000473:pathology; D011336:Probability; D011446:Prospective Studies; D000077154:Rosiglitazone; D016037:Single-Blind Method; D045162:Thiazolidinediones / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D045162:Thiazolidinediones; D000077154:Rosiglitazone; D008687:Metformin