title: Excess androgen during puberty disrupts circadian organization in female rats.
abstract: Circadian clocks have been described in each tissue of the hypothalamo-pituitary-ovarian axis. Although a role for the clock in the timing of ovulation is indicated, the impact of diseases that disrupt fertility on clock function or the clocks' role in the etiology of these pathologies has yet to be fully appreciated. Polycystic ovary syndrome (PCOS) is a particularly devastating endocrinopathy, affecting approximately 10% of women at childbearing age. Common features of PCOS are a polycystic ovary, amenorrhea, and excess serum androgen. Approximately 40% of these women have metabolic syndrome, including hyperinsulinemia, dyslipidemia, and hyperleptinemia. It has been suggested that excess androgen is a critical factor in the etiology of PCOS. We have examined the effects of androgen excess during puberty on the phase of circadian clocks in tissues of the metabolic and hypothalamo-pituitary-ovarian axes. Female period1-luciferase (per1-luc) rats were exposed to androgen (5α-dihydrotestosterone [DHT]) or placebo for 4-6 weeks (short term) or 9-15 weeks (long term). As expected, DHT-treated animals gained more weight than controls and had disrupted estrous cycles. At the end of treatment, tissues, including the liver, lung, kidney, white adipose, cornea, pituitary, oviduct, and ovarian follicles, were cultured, and per1-luc expression in each was recorded. Analysis of per1-luc expression revealed that DHT exposure increased phase distribution of multiple oscillators, including ovarian follicles, liver, and adipose, and altered phase synchrony between animals. These data suggest that excess androgen during puberty, a common feature of PCOS, negatively affects internal circadian organization in both the reproductive and metabolic axes.
authors: Department of Medicine, Division of Endocrinology and Metabolism, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 693, Rochester, New York 14642, USA. michael_sellix@urmc.rochester.edu
authors: Michael T
authors: MT
authors: Sellix
authors: Zachary C
authors: ZC
authors: Murphy
authors: Michael
authors: M
authors: Menaker
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D057906:Circadian Clocks / Q000187:drug effects* / Q000502:physiology; D003315:Cornea / Q000187:drug effects / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004195:Disease Models, Animal; D030762:Estrous Cycle / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D006080:Ovarian Follicle / Q000187:drug effects / Q000378:metabolism; D056950:Period Circadian Proteins / Q000187:drug effects* / Q000378:metabolism; D011085:Polycystic Ovary Syndrome / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D012741:Sexual Maturation / Q000187:drug effects
chemical_list: D000728:Androgens; C539024:Per1 protein, rat; D056950:Period Circadian Proteins; D013196:Dihydrotestosterone