On pills, progestins, and sentinels of progress in reproductive health

“Science can give us power over nature, but it cannot give us power over human nature”

Thomas Szasz (https://www.azquotes.com/author/14391)

Call it the P word. And inflate its meaning by taking stock of what the essence of reproductive medicine looked like nearly 75 years ago and how it would change the world we lived in then and now. For many in our specialty, it all started with a somewhat serendipitous dinner meeting held in 1951. The restaurant unknown, the place Manhattan in New York City, and the dinner guests a seemingly unlikely combination of the host, Margaret Sanger a driving force behind the birth control movement at the time, a supportive gynecologist colleague by the name of Abraham Stone, and a basic scientist from Shrewsbury Massachusetts by the name of Gregory Pincus. Asbell’s treatment of how the birth control pill became a reality was launched that evening by this threesome is an engaging and enlightening read for anyone interested in how the melding of reproductive science with philanthropy would have etched its mark for the benefit of society broadly and for access to care when it came to reproductive health [1]. But there is much more to this story and the sequelae having to do with “The Pill,” progestins, and pregnancy control of relevance to this month’s issue of JARG.

Once again, and with a measure of poetic license, experimental advances of yesteryear were poised in the 1950s to add to the growing awareness of ovarian steroid hormones in physiology well beyond their nascent biochemical characterization and concurrently at the dawning of what these newly discovered steroids would have to do with human reproduction. While it took some 10 years for Csapo and colleagues to establish the essential role of progesterone (P4) and the corpus luteum in the establishment and maintenance of pregnancy, coining in the process the term “luteo-placental shift,” it was already within the sights of Csapo’s mentor George Corner that what they happened upon may well serve as a legitimate candidate of and strategy for fertility control [2]. At the core of their prescient insight was the finding demonstrated in animal models that P4 exhibited a remarkable ability to silence contractility in uterine smooth muscle [3]. As one could say, the rest is history as far as oral contraceptive pills and reproductive choice. But it would be shortsighted to fail to recognize the deep science of P4 and progestins and the evolution of reproductive endocrinology into what it is today especially in the context of human ARTs and management of menstrual cycles for purposes of conception of the spontaneous variety [4].

This month, JARG revisits these monumental findings and draws our readership’s attention to a range of studies on estradiol (E2) and P4 in both human and animal models having to do with control of implantation and beyond. From Logsdon and colleagues, estrogen receptor 1 is studied in the context of preimplantation development in mouse and human blastocysts reminding our field that ovarian steroids have direct actions on the conceptus, as proposed years ago, and could be subject to disturbances imposed by exposure to environmental estrogens (Estrogen signaling encourages blastocyst development and implantation potential, 10.1007/s10815-023-02783). Meanwhile, several papers this month bring us back to P4 and ongoing efforts to put the corpus luteum back into perspective for patients seeking treatment for infertility. It is fitting to keep in mind earlier work from the Zelinski laboratory at the Oregon Primate Research Center reporting a clear separation of functions between ovulation itself and oocyte maturation in Rhesus monkeys since P4 alone was unable to induce ovulation in the absence of gonadotropins and yet was sufficient to diminish oocyte atresia and promote nuclear maturation [5]. Not only have P4 and related progestins been known for years to be the physiological trigger for oocyte maturation in lower vertebrates, but key questions remain unanswered as to their potential roles in several periovulatory or postovulatory events germane in current terms to human ART practices and potential uses over and above endometrial preparation in fresh or frozen embryo transfer cycles.

The timing and significance of so-called premature luteinization of follicles destined for OPU remains a subject of attention especially with respect to both short and long term consequences within an ART cycle (Premature progesterone elevation during the early and mid-follicular phases in fresh in vitro fertilization (IVF) cycles is associated with lower live birth, clinical pregnancy, and implantation rates, 10.1007/s10815-023-02786). These concerns in part must reflect at some level the delicate balance of oocyte derived signals serving to prevent luteinization for most of the course of folliculogenesis until at least ovulation. But P4 has emerged over the years as a bit of a renaissance hormone in its own right spanning not only evo-devo and ART landscapes but as is well known, operating at many levels and through a range of receptor-mediated actions throughout the HPA axis.

As far as ovulation induction itself, Villar and colleagues now proffer two case reports using a strategy that reconciles the matter of luteal demise inherent with conventional stimulation protocols while bypassing more traditional means of ovulation triggering (Ovulation and birth after administration of progesterone trigger—two case reports, 10.1007/s10815-023-02750). Ongoing efforts to adjust, validate, and ultimately improve treatment paradigms aimed at achieving high quality oocytes for embryo production are part and parcel of human ARTs service to patients and change built upon sound evidence-based medical research is a cornerstone for any and all progress in the reproductive health arena. With so much of our focus directed towards obtaining “more, stored” materials with which to transfer to hopeful patients, it comes as no surprise that the compilation of methods and approaches currently offered on the ART menu would at some time take a closer look into quality-of-life issues faced during and after pregnancies in embryo recipients. Such is the tenor of the study of Niu and colleagues broaching a subject that will be emphasized in a future issue of JARG (Is artificial endometrial preparation more associated with early-onset or late-onset preeclampsia after frozen embryo transfer? 10.1007/s10815-023-02785) While frozen embryo transfer has assumed prominence in current practice patterns for good reasons, just how the expanded functions of the physiological corpus luteum of pregnancy weighs in as a contributor to pregnancy physiology remains a fascinating and important area to pursue [6].

We close this issue with a sad reminder of how our own professionalism is becoming as vestigial as the corpus luteum has become at least as an academic subject of interest. Dr Jack Resneck Jr., President of the American Medical Association reminds us that court decisions now outweigh the intended purpose of medical science in some societies-

“…the unprecedented judicial ruling issued April 7 by a federal district court judge in Texas to suspend the use of mifepristone—an extremely safe and effective drug backed by hundreds of studies and used by millions of women—favors ideology and pseudoscience over facts, harms patients, interferes with the patient-physician relationship and jeopardizes public health nationwide.”