On the perils of prematurity-deconvolving luteinization from physiology to cycle management

In a long-ago decade, and on a long-ago experimentalists’ list of questions to ask, reproductive biologists el-Fouly and colleagues posed a simple but provocative query: what would happen to the Graffian follicle if the oocyte were to be removed? No LH surge was to be found in the mammalian species chosen to address this question because of its reproductive strategy being that of a reflex ovulator, nor was there any hint of a coital stimulation that would have so triggered and endogenous LH surge. But the answer was clear: removing the oocyte led to the formation of a corpus luteum, functional in every sense according to the techniques available in the day [1]. Not soon thereafter would arrive a series of publications touting in one mammalian species after another the remarkable and striking tendency of mural granulosa cells to “spontaneously” luteinize upon their removal from the ovarian follicle. Moreover, leaders of the field were quick to realize and propose that a two-way line of communication and influence was at play upon the realization that granulosa cells were somehow repressing the re-initiation of meiosis of the oocyte [2]. To suggest that the rest is “history” would be short-sighted as these core findings, deeply entrenched in the annals of reproductive biology, are as relevant today to reproductive medicine as one could ever have imagined.

Medically assisted reproduction (MAR) entices patients to begin a journey that is based on sound and complex matters having to do with manipulation of a sophisticated HPG axis operating within time constraints and biological redundancies that have escaped comprehension by our hominin brain, but then again, AI is on the doorstep! With this issue of JARG we deliver to our readership a long overdue and critical look at how contemporary practices have evolved into biologically defiant clinical constructions (sic COS) that have yet to incorporate the nuanced transformation of the Graafian follicle into a corpus luteum. The nuanced relationship between the oocyte meiotic status and the ability of granulosa cells to luteinize was presciently forecast by a series of papers led by the late Ken McNatty and colleagues, should any of our followers care to revitalize the foundation of human follicle physiology [3, 4].

Our journey starts with the matter of premature luteinization, that turning point in the execution of COS whereby factors like AMH, follicle size and growth, and E2/P output all conspire to put control of the resumption of meiosis into the hands of designers of the ovulation “trigger.”

The Graafian follicle is a remarkable and poised entity delimited in its ability to transform into the corpus luteum by reciprocal forces from within (oocyte secreted factors, OSFs) and without (pituitary-derived LH). In anticipation of an LH surge, endogenous and physiological (or iatrogenically induced), the follicle sometimes takes matters into its own hands as though “its’ time has yet to come” eliciting what clinically is referred to as premature luteinization (PL). With advancing maternal age, and whatever attendant alterations in ovarian function might have been set into play, adjustments to the timing of egg retrieval have in some instances been shown to improve clinical outcomes in an effort to preclude PL [5]. Fast forward to what artificial intelligence can bring to the table, and again that subtleties in follicle size emerge as determinants of egg quality and clinical outcomes [6]. But why? Is it a matter of too little too late? Or is something going on within the confines of the follicle in its developmental history that we have yet to massage into a productive clinical outcome?

The developmental trajectory of ovarian follicles is one of temporal and spatial complexity, owing in part to what has become recognized as an elaborate network of signaling cascades executed at various, and possibly overlapping, milestones along the journey ending with ovulation. The so-called gonadotropin-independent and -dependent phases are no longer as discretely separated in time and space as previously thought, with basal follicular growth, while clinically intractable and the subject of much speculation, assuming the character of a “point of no return” for the ultimate fate of follicles being directed by the “conventional wisdom” of COS [7]. In the end, and as suggested by Professor Thibeault nearly 50 years ago now, folliculogenesis and oogenesis are inseparably intertwined to guarantee that the success of one (good egg) is aligned with the success of the other (corpus luteum) [8]. At the heart of this bidirectional dialog is the matter of how the array of factors related to the TGFβ family of signaling molecules interfaces with our traditional and well-worn notions of FSH and LH doing their respective duties in the quest for high-quality eggs.

So it is that a small chapter of the increasingly evocative story of AMH enters the plot in this issue of JARG with the work of Liuzzi and colleagues implicating LH as a modulator in granulosa cells at the receptor level (LH prevents AMH action via receptor downregulation in human primary granulosa lutein cells; 10.1007/s10815-025-03635-x). And, Pankhurst offers our readership a contextualizing treatment of where this work fits relative to much of the extensive background commanded toward AMH over the years (The elusive function of AMH signaling in folliculogenesis; 10.1007/s10815-025-03657-5). But “appetizers” like this only serve to tease given what is an unavoidable series of events elicited within the follicle having to do with multiple rate-limiting steps associated with the actions of AMH and other TGFβs at the level of ligand processing and beyond [9].

Among examples of increasing complexity are the interaction of AMH with follicular fluid heat shock proteins [10], and from the same group evidence that high doses of AMH can block PL in an experimental model system [11]. Given the recognized role of OSFs in preventing luteinization mentioned above, it comes as no surprise that such factors have among their modes of action direct or indirect influences on FSH or LH as intrafollicular modulators of both oocyte status and granulosa cell differentiation [12]. Will studies on animal models enable translation to clinical ARTs? Progress is indeed pointing out the way to preventing PL in the context of COS [13]. And with studies of the kind reported by Wang et al., where quantitative evaluation of follicular levels of signaling molecules is used to define trends according to patient age, insights into the management of older patients enduring infertility may be at hand in the near future [14].

In closing, we wish to welcome our newest Editorial Board members Dahlia Abramovich, Lucia De Santis, and Maria Gracia Gervasi, who expand our coverage of many research areas within JARG’s purview, and thank the following individuals for their past editorial support: Demian Glujovsky, Randi Goldman, Juan Enrique Schwarze, Christoph Sifer.