Ghazeeri, G., Kutteh, W. H., Bryer-Ash, M., Haas, D., & Ke, R. W. (2003). Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. Fertility and Sterility, 79(3), 562-566. https://doi.org/10.1016/s0015-0282(02)04843-4
Ghazeeri G, Kutteh WH, Bryer-Ash M, Haas D, Ke RW. Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. Fertil Steril. 2003;79(3):562-566. doi:10.1016/s0015-0282(02)04843-4
Ghazeeri, Ghina, et al. "Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome." Fertility and Sterility, vol. 79, no. 3, 2003, pp. 562-566.
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Rosiglitazone enhanced ovulation in clomiphene-resistant PCOS
Rosiglitazone plus clomiphene led to ovulation in about 8 out of 10 women with polycystic ovary syndrome (PCOS) who were overweight or obese and had not ovulated on clomiphene alone. Rosiglitazone with placebo did so in about 3 out of 10. The randomized trial included 25 women. PCOS now has a new name, PMOS (polyendocrine metabolic ovarian syndrome).
Key Findings
Across both groups, 14 of 25 women (56%) ovulated. All had previously been resistant to clomiphene.
Ovulation occurred in 4 of 12 women (33%) given rosiglitazone with placebo and in 10 of 13 women (77%) given rosiglitazone with clomiphene (P=.04, Fisher's exact test).
One woman in the rosiglitazone-with-placebo group became pregnant and had a live birth. Two in the clomiphene group conceived: one had a live birth and one had a first-trimester miscarriage.
After rosiglitazone, fasting insulin fell (P=.003), sex hormone-binding globulin rose (P=.001), and luteinizing hormone fell (P=.01). Total testosterone and DHEAS did not decline significantly.
Lipoprotein levels did not change, and hematocrit dropped (P=.008). One woman reported swollen fingers and one reported mild headaches; both completed the study.
Interpretation
The trial was randomized, double-blind and placebo-controlled. It randomized 25 women aged 18 to 40, and 22 completed it. Three women lost to follow-up after the first cycle counted as not ovulating. Both groups took rosiglitazone, so the comparison pits clomiphene against placebo added to it. Ovulation was defined by a luteal progesterone rise, and pregnancy was a secondary outcome with three conceptions. The study lasted two months, and the authors describe their findings as short-term.
RRM Context
The authors state that high insulin levels contribute significantly to the long-term failure to ovulate seen in PMOS / PCOS. Restorative Reproductive Medicine asks a cause-based question: what keeps ovulation from happening? Insulin resistance belongs in that evaluation. The trial judged ovulation by luteal progesterone, a marker of an ovulatory event. Cycle charting tracks that event cycle by cycle.
Our editorial summary of this paper, not the article's abstract.
Abstract
Objective
In women suffering from polycystic ovary syndrome (PCOS), correction of hyperinsulinemia results enhances spontaneous ovulation or alternatively, the responsiveness to ovulation induction agents such as clomiphene citrate (CC). We investigated the effect of rosiglitazone maleate on ovulation induction in overweight and obese, CC-resistant women with PCOS.
Overweight and obese women with clinical and laboratory manifestations of PCOS who desired pregnancy and were resistant to CC.
Interventions
Twenty-five women were randomized into two treatment groups. Subjects in Group I (n = 12) were randomized to receive rosiglitazone 4 mg b.i.d. with a placebo on cycle days 5-9. Group II (n = 13) was randomized to receive rosiglitazone 4 mg b.i.d. with CC on cycle days 5-9. The duration of the study was 2 months.
Main Outcome Measures
The primary outcome was ovulation as defined by luteal serum progesterone greater than 5 ng/dL assessed on days 21, 24, and 28 of the cycle. Secondary outcomes were pregnancy and changes in insulin sensitivity, serum lipoproteins, and androgens.
Results
Overall, 14 of 25 (56%) women, who were previously resistant to CC, successfully ovulated. In subjects taking rosiglitazone alone (Group I), 4 of 12 (33%) subjects ovulated compared with 10 of 13 (77%) women randomized to rosiglitazone with CC (Group II) (P=.04, Fisher's exact). One subject in Group I became pregnant, resulting in one uncomplicated live birth; two subjects in Group II conceived, with one successful live birth and one first trimester, spontaneous abortion. For all subjects, fasting insulin declined from 29.4 +/- 13.8 microU/mL to 17.3 +/- 7.8 microU/mL after rosiglitazone (P=.003, paired t-test). Although mean levels of total testosterone (T) and dehydroepiandrosterone sulfate (DHEAS) did not decline significantly, sex hormone-binding globulin (SHBG) did increase from 0.7 +/- 0.3 microg/dL to 1.0 +/- 0.3 microg/dL after rosiglitazone therapy (P=.001, paired t test). There was also a decrease in luteinizing hormone (LH) from 9.4 +/- 6.3 mU/mL to 7.2 +/- 3.7 mU/mL (P=.01). Lipoproteins including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides did not change.
Conclusions
Short-term rosiglitazone therapy enhances both spontaneous and clomiphene-induced ovulation in overweight and obese women with PCOS. Rosiglitazone therapy improves insulin sensitivity and decreases hyperandrogenemia primarily through increases in SHBG.
