Table 2.
Summary of reports published within the past 2 years on the use of PPARG activating agents for reproductive symptoms. Abbreviations used: AUC, area under the curve; BMI body mass index; CC clomiphene citrate; DHEA-S dehydroepiandrosterone sulfate; E2, estradiol; FAI, free androgen index; FSH, follicle-stimulating hormone; GnRH, gonadotropin releasing hormone; HbA(1C), haemoglobin A1C; HDL-C, high density lipoprotein-cholesterol; HOMA, homeostasis model of assessment for insulin sensitivity; IGF1 insulin-like growth factor 1; IGFBP-1/3, insulin-like growth factor binding protein 1 or 3; LDL-C, low density lipoprotein-cholesterol; LH, luteinizing hormone; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; QUICKI, quantitative insulin-sensitivity check index; SHBG, sex hormone binding globulin; T, testosterone; WHR, waist to hip ratio.
| Reference: | Rautio et al. [75] and Rautio et al. [76] |
| Patient profile: | Overweight but not obese PCOS (n = 30) |
| PPAR agonist: | Rosiglitazone (4 mg once daily for 2 weeks then 4 mg twice daily for 16 weeks) |
| Metabolic outcomes: | Serum C-reactive protein levels, leukocyte count, and alanine aminotransferase enzyme activity decreased, but lipid and blood pressure did not change. Glucose tolerance and peripheral insulin response normalized in the rosiglitazone group. |
| Reproductive outcomes: | Rosiglitazone improved menstrual cyclicity, SHBG levels; and decreased serum levels of androstenedione, 17-hydroxyprogesterone (17-OHP), DHEA and DHEA-S. |
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| Reference: | Rouzi and Ardawi [77] |
| Patient profile: | Obese PCOS (n = 12) |
| PPAR agonist: | Rosiglitazone (4 mg twice daily for 3 cycles, CC administered for 5 days starting 3 days after rosiglitazone initiated) |
| Metabolic outcomes: | No changes in fasting plasma glucose or HbA(1C) or IGFBP-3 values. Fasting serum insulin, DHEA-S, androstenedione, and IGF-1 levels decreased significantly and IGFBP-1 exhibited significant increases. |
| Reproductive outcomes: | Total-T, free-T, LH, and SHBG decreased. Follicular development and ovulation rate increased, trend for increased pregnancy rate in group receiving short-term administration of rosiglitazone compared to matched control receiving metformin. |
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| Reference: | Mitkov et al. [78] |
| Patient profile: | Obese, insulin resistant PCOS (n = 15) |
| PPAR agonist: | Rosiglitazone (4 mg/day for 12 weeks) |
| Metabolic outcomes: | Hyperinsulinemia and insulin resistance normalized. |
| Reproductive outcomes: | Total-T and FAI profile tended to normalise. Number of women with oligomenorrhea was reduced by 67% |
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| Reference: | Cataldo et al. [79] |
| Patient profile: | Insulin resistant PCOS (n = 11–16/group) |
| PPAR agonist: | Rosiglitazone (2, 4 or 8 mg/day for 12 weeks) |
| Metabolic outcomes: | Steady state plasma glucose declined and hyperinsulinemia fell in a dose-dependent manner. |
| Reproductive outcomes: | Serum LH, total-T, and free-T were unchanged; SHBG increased. Ovulation occurred in 55%, without significant dose dependence. Before and during treatment, ovulators on rosiglitazone had lower circulating insulin and free-T and higher SHBG than nonovulators. |
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| Reference: | Lemay et al. [80] |
| Patient profile: | Overweight, insulin resistant PCOS (n = 15) |
| PPAR agonist: | Rosiglitazone (4 mg/day for 6 months) |
| Metabolic outcomes: | Plasma insulin, insulin resistance indices and insulin AUC in response to OGTT all decreased compared to controls receiving antiandrogenic estrogen-progestin. Effect on lipids was limited. |
| Reproductive outcomes: | No significant effect on androgens or hirsutism. |
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| Reference: | Garmes et al. [81] |
| Patient profile: | Obese insulin resistant PCOS (n = 15) |
| PPAR agonist: | Pioglitazone (30 mg/day for 8 weeks) |
| Metabolic outcomes: | Insulin response to OGTT significantly decreased. |
| Reproductive outcomes: | Total-T and free-T levels decreased, SHBG increased, and LH response to GnRH stimulation decreased. |
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| Reference: | Yilmaz et al. [82–84] |
| Patient profile: | Obese or lean PCOS (n = 20 obese, n = 20 lean) |
| PPAR agonist: | Rosiglitazone (4 mg/day for 12 weeks) |
| Metabolic outcomes: | Indices of oxidative stress improved. HOMA, insulin AUC, fasting insulin and C-peptide levels decreased significantly. Glucose/insulin ratio and BMI increased |
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| Reference: | Rautio et al. [75] and Rautio et al. [76] |
| Patient profile: | Overweight but not obese PCOS (n = 30) |
| PPAR agonist: | Rosiglitazone (4mg once daily for 2 weeks then 4 mg twice daily for 16 weeks) |
| Metabolic outcomes: | Serum C-reactive protein levels, leukocyte count, and alanine aminotransferase enzyme activity decreased, but lipid and blood pressure did not change. Glucose tolerance and peripheral insulin response normalized in the rosiglitazone group. |
| Reproductive outcomes: | Rosiglitazone improved menstrual cyclicity, SHBG levels; and decreased serum levels of androstenedione, 17-hydroxyprogesterone (17-OHP), DHEA and DHEA-S. |
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| Reproductive outcomes: | Seurm levels of free-T, androstenedione, and DHEA-S decreased significantly. Menstrual disturbances improved in 61.5% of lean and 53.8% of obese patients. In a second cohort of patients, menstrual cycles became regular in 87.8%. |
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| Reference: | Tarkun et al. [85] |
| Patient profile: | Young, lean PCOS (n = 31) |
| PPAR agonist: | Rosiglitazone (4 mg/day for 12 months) |
| Metabolic outcomes: | Fasting insulin and insulin resistance indices significantly improved. No changes in BMI, waist circumference, serum total cholesterol, or LDL-C. Serum C-reactive protein levels decreased; and endothelium-dependent vascular responses improved. |
| Reproductive outcomes: | Significant decreases in serum T, although no change in FSH and LH levels. Hirsutism score decreased significantly after treatment. 77.4% of women reverted to regular menstrual cycles. Levels of SHBG increased significantly after treatment. |
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| Reference: | Dereli et al. [86] |
| Patient profile: | Nonobese PCOS (n = 20/group) |
| PPAR agonist: | Rosiglitazone (2 mg/day or 4 mg/day for 8 months) |
| Metabolic outcomes: | 75% of women in the 2 mg group and 95% in the 4 mg group achieved normal glucose tolerance. Improved insulin resistance in a dose-related fashion, without adverse events or liver enzyme elevations. |
| Reproductive outcomes: | Decreased free-T levels were better in the 4 mg group than the 2 mg group, and 70% of women in the 2 mg group and 85% of women in the 4 mg group achieved ovulatory menses. |
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| Reference: | Mehta et al. [87] |
| Patient profile: | Obese PCOS (n = 9) |
| PPAR agonist: | Pioglitazone (45 mg/day for 20 weeks) |
| Metabolic outcomes: | Significant improvement in insulin sensitivity |
| Reproductive outcomes: | LH levels, LH pulse frequency and amplitude, as well as gonadotropin responses to GnRH were not influenced. |
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| Reference: | Ortega-González et al. [88] |
| Patient profile: | Obese, insulin resistant PCOS (n = 25) |
| PPAR agonist: | Pioglitazone (30 mg/day for 6 months) |
| Metabolic outcomes: | Body weight, BMI, and WHR increased significantly. Fasting insulin and insulin AUC during a 2-h OGTT decreased. Insulin resistance decreased and insulin sensitivity increased after treatment with either pioglitazone or metformin received by control group. |
| Reproductive outcomes: | Hirsutism, free-T and androstenedione declined to a similar extent after treatment with either drug. Treatment with both drugs was associated with the occurrence of pregnancy |
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| Reference: | Sepilian and Nagamani [89] |
| Patient profile: | Obese insulin resistant PCOS (n = 12) |
| PPAR agonist: | Rosiglitazone (4 mg/day for 6 months) |
| Metabolic outcomes: | Fasting insulin, insulin AUC, fasting glucose, and glucose AUC significantly decreased. No significant change in BMI |
| Reproductive outcomes: | Both total-T, free-T and DHEA-S levels decreased significantly. No significant change in LH levels. Levels of SHBG increased significantly after treatment, 91.7% of women reverted to regular ovulatory cycles during the treatment period |