Dihydrotestosterone treatment in mice induces a persistent polycystic ovary syndrome phenotype
E. van Houten, P. Kramer, B. Karels, A. McLuskey, A. Themmen & J. Visser
Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women in their reproductive years, is defined by two out of the following three criteria: hyperandrogenism, oligo/anovulation, and polycystic ovaries. Affected women are often obese and insulin-resistant. Recently, we developed a mouse PCOS-model through chronic exposure to dihydrotestosterone (DHT). Here, we studied whether the PCOS-phenotype remains after withdrawal of DHT treatment, which would more closely resemble PCOS in women.
Prepubertal mice were treated with a 90-days continuous release DHT or placebo pellet. After treatment (90 days) mice were sacrificed (chronic group, n=17) or allowed a 30-day wash-out period before sacrifice (sustained group, n=17). Before sacrifice mice vaginal smears were taken and an Intraperitoneal Glucose Tolerance Test (IPGTT) (n=89 per group) or an Insulin Tolerance Test (ITT) (n=89 per group) was performed.
After 90 days, DHT-treated mice were acyclic, their ovaries contained antral follicles with a cyst-like structure and an increased number of atretic follicles, bodyweights were higher, and chronically DHT-treated mice were glucose intolerant.
Mice of the sustained group remained anovulatory, their ovaries still contained cyst-like follicles and an increased number of atretic follicles. In contrast to the chronically DHT-treated mice, DHT-treated mice of the sustained group had an increased number of healthy follicles compared to placebo-treated mice. Bodyweight and weights of fat depots remained significantly increased in the sustained group and mice remained glucose intolerant. Insulin sensitivity did not appear to be affected in the DHT-treated mice, although the counter regulatory mechanisms after insulin administration were impaired in both the chronically and sustained DHT-treated mice.
We confirmed that chronic DHT-treatment induces a PCOS-like phenotype in mice. A 30-day wash-out period did not improve the ovarian and metabolic phenotypes. This suggests that in mice after a 90-day DHT treatment period, a sustained PCOS phenotype is induced.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.