Chu, Adrienne2; Zhu, Lei2; Blum, Ian D2; Mai, Oliver2; Leliavski, Alexei2; Fahrenkrug, Jan4; Oster, Henrik2; Boehm, Ulrich2; Storch, Kai-Florian2
1 Section of Diagnostic Sciences, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 unknown3 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet4 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
While there is evidence for a circadian regulation of the preovulatory luteinizing hormone (LH) surge, the contributions of individual tissue clocks to this process remain unclear. We studied female mice deficient in the Bmal1 gene (Bmal1(-/-)), which is essential for circadian clock function, and found that they lack the proestrus luteinizing hormone (LH) surge. However, spontaneous ovulation on estrus day was unaffected in these animals. Bmal1(-/-) females were also deficient in the proestrus follicle stimulating hormone (FSH) surge, which -as the LH surge- is GnRH-dependent. In the absence of circadian or external timing cues, Bmal1(-/-) females continued to cycle in constant darkness albeit with increased cycle length and time spent in estrus. Because pituitary gonadotropes are the source of circulating LH and FSH, we assessed hypophyseal circadian clock function and found that female pituitaries rhythmically express clock components throughout all cycle-stages. To determine the role of the gonadotrope clock in the preovulatory LH and FSH surge process, we generated mice that specifically lack BMAL1 in gonadotropes (GBmal1KO). GBmal1KO females exhibited a modest elevation in both proestrus and baseline LH levels across all estrous stages. BMAL1 elimination from gonadotropes also led to increased variability in estrous cycle length, yet GBmal1KO animals were otherwise reproductively normal. Together our data suggest that the intrinsic clock in gonadotropes is dispensable for LH surge regulation, but contributes to estrous cycle robustness. Thus clocks in the suprachiasmatic nucleus or elsewhere must be involved in the generation of the LH surge, which, surprisingly, is not required for spontaneous ovulation.
Endokrinologiya, 2013, Vol 154, Issue 8, p. 2924-2935