LAUSR

One of the marvels of the reproductive process of viviparous organisms like ourselves is the extraordinary synchronization of events driving everything from ovulation to implantation. There is no better case to make than the remarkable off-on switch triggered by the LH surge, the raison d’être for the resumption ofmeiosis, andmaturation of the oocyte in parallel with an instantaneous transformation of granulosa cells into the progesterone secreting cells of the corpus luteum (CL). Simply put, the Graafian follicle is a time bomb holding in abeyance both the oocyte cell cycle and luteinization of the follicle. While there is little doubt that mammals have together propelled this paradigm of synchronicity into an essential and well-tuned survival strategy, recapitulating such a strategy in the clinical setting, where controlled ovarian stimulation (COS) is deployed to obtain as many eggs as possible, continues to be an obstacle in the alleviation of infertility. Default systems are off for a reason. And the factors that actively prevent luteinization of granulosa cells have been resistant to explanation since the pioneering work of Channing, Tsafriri, and others suggesting there was an intrafollicular force inhibiting this capability until ovulation. In a sense, letting go of de facto constraints (otherwise known to the masses as ACTIVATION) has been receiving the welldeserved attention it is getting in other spheres of reproductive medicine such as awakening follicles, or hyper-motivating sperm, or delimiting the embryo’s potentially harmful metabolism (Bkeeping quiet^) until implantation is well on its way under the guidance of a CL of pregnancy! When such constraints breakdown in the ovarian follicle, particularly in the presence of exogenous gonadotropins as during COS, the result is the all too familiar case of premature luteinization (PL). As Kaponis and colleagues share with us this month in our lead article (BThe curious case of premature luteinization,^ https://doi.org/10.1007/s10815-018-1264), this troublesome condition often determines the course of treatment for many patients. And despite attempts for many years by practitioners to come to grips with the predispositions, causes, and remedies for delimiting the occurrence and extent of PL, management strategies remain inadequate in some circumstances. Given the timely and broad-spectrum view they provide on PL in leading off this issue of JARG, tracing the history of this seemingly turnkey mechanism at the heart of fecundity for all mammals is deserving of a retrospective treatment. Well before there were human ARTs, the importance of the CL in determining menstrual cycle length—and as a crucial determinant in the establishment of pregnancy—was appreciated by the classical work of Csapo and his collaborators [1]. It was a decade later, shortly after the birth of Louise Brown, that the consequences of disrupting follicle fate for the expressed purpose of laparoscopically removing an oocyte (referred to by some at the time as ovectomy) were noticed by Steptoe and Edwards as a rate-limiting factor in the early days of ARTs. Trepidation was evident at the time given questions about the activity of available progestins, the timing and route of administration if any hope of iatrogenically creating an operational luteal phase and beyond was to be achieved following embryo transfer [2]. With the adoption of more aggressive ovarian stimulation protocols and improvements in egg retrieval technology, the name of the game became one of obtaining as many oocytes as possible and in so doing, evacuate (sic eradicate) follicles of luteinizing potential—of course to various extents. Somewhere along the way to establishing this standard of care, reproductive biologists were coming to grips with the enormous powers that oocytes seemed to exert on their surrounding companion granulosa cells. The tools of mouse genetics were brought to bear on genes essential for various aspects of reproduction, and one of the first stars of the show to emerge was a gene known as GDF9 [3]. This oocytespecific gene yielded products that appeared to regulate the earliest stages of follicle development and would come to be the first of many factors to be identified in oocytes that would * David F. Albertini [email protected]