Rethinking progesterone regulation of female reproductive cyclicity

Kubota et. al. 2016

Proceedings of the National Academy of Sciences, USA

                Control of the female reproductive cycle by the hypothalamic-pituitary-ovarian axis has been known for a long time. Hormones secreted by the hypothalamus cause the pituitary to produce hormones and release them into the bloodstream to affect the ovaries to release their hormones – progesterone and estrogen which in turn provide negative and positive feedback to the axis. This feedback is at the center of the regulation of female sex hormones. The current paper aimed to assess the role that progesterone has via the progesterone receptor on the cyclicity of the rat female reproductive cycle.

                Sprague-Dawley female rats were used in this experiment and maintained on a 14:10d light dark cycle. CRISPR/Cas-9 genome editing was used to create progesterone receptor mutations that rendered the receptors nonfunctional. This was confirmed with multiple measurements including ovulation, fertility of the rat, uterine responses to progesterone, mammary gland branching morphogenesis and others. All these measurements failed in the null progesterone receptor animals as expected from other studies. Vaginal lavages and cytology were performed to determine the stage and regularity of the reproductive cycle as well as analysis of blood samples that were taken during each of the stages. Rats were also allowed to run voluntarily on a wheel and this was recorded to determine daily running activity during the cycle.  

                It was found that despite the absence of a functional progesterone receptor, the progesterone receptor null rats demonstrated a highly regular estrous cycle. The paper states that this is in contrast to a similarly genetically modified mouse. Cyclic changes were observed in both groups of rats, progesterone null and wild type, in multiple measurements including morphology of the vaginal cell types, wheel running activity, hormone levels and uterine weights. However, it was found that there were some differences in the cyclicity and length of the estrous cycle between wild type and progesterone receptor null rats. Specifically, the estrous cycle was significantly longer in the wild type rats compared to the progesterone receptor null rats. It was also found that progesterone treatment abolished the estrous cycle in wild type rats but did not have an effect in the progesterone receptor null rats.

                Consistent with other papers the current study showed that progesterone is necessary for many aspects of female fertility, however, this paper provides evidence that while progesterone may be important for regulating the female reproductive cycle, it is not necessary for a rat to keep cycling. Progesterone does seem to be important for the feedback loops of the hypothalamus-pituitary-ovarian axis but is not necessary for the regular cycling of the estrous cycle. These findings were unexpected in the paper as previous studies have shown that in a progesterone receptor null mouse the cyclicity of the reproductive cycle is abolished. It seems that estrogen is the driving factor for the cycling of the cycle in rats, although, progesterone is important for many secondary sex characteristics and sexual behaviors.

Ben R