Pioglitazone improves insulin action and normalizes menstrual cycles in a majority of prenatally androgenized female rhesus monkeys.
OBJECTIVE
To determine whether pioglitazone will improve menstrual cyclicity in a fetal programming model for polycystic ovary syndrome.


METHODS
Eight prenatally androgenized (PA) and 5 control female rhesus monkeys of similar age, body weight and body mass index received an oral placebo daily for 6-7 months followed, after at least 90 days, by daily oral dosing with pioglitazone (3mg/kg) for an additional 6-7 months. Blood was sampled thrice weekly to monitor ovulatory function, and a variety of endocrine challenges were performed to quantify changes in ovarian, gonadotropin and glucoregulatory function.


RESULTS
Pioglitazone normalized menstrual cycles in 5 out of 8 (62%) PA females (pioglitazone responsive; Pio(RESP)). Pioglitazone increased serum 17alpha-hydroxyprogesterone responses to an hCG injection in Pio(RESP) PA females, while diminishing serum progesterone, and increasing DHEA and estradiol responses to hCG in Pio(RESP) PA and all normal females.


CONCLUSIONS
Insulin resistance plays a mechanistic role in maintaining anovulation in a majority of PA female monkeys.
Zhou
Rao
R
National Primate Research Center, University of Wisconsin, Madison, WI 53715, United States.
Bruns
Cristin M
CM
Bird
Ian M
IM
Kemnitz
Joseph W
JW
Goodfriend
Theodore L
TL
Dumesic
Daniel A
DA
Abbott
David H
DH
D000735:Androstenedione / Q000097:blood; D000818:Animals; D019540:Area Under Curve; D001835:Body Weight / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000097:blood; D004958:Estradiol / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000502:physiology*; D007986:Luteinizing Hormone / Q000097:blood / Q000187:drug effects; D008253:Macaca mulatta; D008597:Menstrual Cycle / Q000187:drug effects* / Q000502:physiology; D010060:Ovulation / Q000187:drug effects; D000077205:Pioglitazone; D011085:Polycystic Ovary Syndrome / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control; D011374:Progesterone / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000097:blood; D043343:Testosterone Propionate / Q000097:blood; D045162:Thiazolidinediones / Q000493:pharmacokinetics / Q000494:pharmacology*
D000735:Androstenedione; D006063:Chorionic Gonadotropin; D003687:Dehydroepiandrosterone; D004958:Estradiol; D005230:Fatty Acids, Nonesterified; D005640:Follicle Stimulating Hormone; D006442:Glycated Hemoglobin; D007987:Gonadotropin-Releasing Hormone; D007004:Hypoglycemic Agents; D007328:Insulin; D007986:Luteinizing Hormone; D000077205:Pioglitazone; D011374:Progesterone; D043343:Testosterone Propionate; D045162:Thiazolidinediones; C002175:progesterone 17 alpha-hydroperoxide