Every reproductive endocrinologist knows that ovulation is triggered by estradiol. In our textbooks, the sequence is clear: Estradiol rises, triggers an LH surge, and ovulation follows, culminating in the formation of a corpus luteum, which produces progesterone to support implantation and pregnancy. It is straightforward and reassuringly precise, and it forms the backbone of our clinical practice.
Yet, from the very beginning of training, we are instructed to use artificial ovulation triggers, hCG or GnRH agonists. Estradiol itself is not used clinically as a trigger for the simplest of reasons: In practice, it does not work. Thus, the true physiological trigger has remained elusive.
Since the ovarian cycle is the foundation of reproductive medicine, and the ovulation trigger is its holy grail, this contradiction matters. If estradiol is not the true physiological trigger, our entire clinical framework rests on a questionable assumption. This helps explain why we still cannot answer basic questions, such as why a woman’s cycle is so consistent within the same individual yet varies widely between women, or why cycle length shortens so predictably with age.
The cost of artificial triggers
For lack of a physiological trigger, we rely on artificial ones. Their most significant limitation is the unreliable formation of a competent corpus luteum. To compensate, we create a chemically defined luteal phase, often relying on painful intramuscular progesterone injections to replace what the corpus luteum failed to produce on its own.
This approach works. But “working” is not the same as being physiological. The corpus luteum is not merely a producer of progesterone; it is a complex, transient endocrine organ, still not fully understood, that plays a central role in establishing a competent pregnancy.
Increasing evidence suggests that the elevated rates of adverse maternal, placental, and fetal outcomes observed in ART pregnancies may be linked, at least in part, to the absence of a truly physiological corpus luteum.
At some point, it becomes reasonable to ask a fundamental question: If estradiol does not trigger ovulation, what does?
The Dozortsev-Diamond ovulation paradigm
This question was recently revisited by Dmitri Dozortsev and Michael P. Diamond, physician-scientists who proposed a new ovulation paradigm. Their work, published between 2020 and 2024, including a landmark paper featured under the “Sea Changes in Reproductive Physiology” editorial in Fertility and Sterility, represents an entirely new synthesis of existing experimental and clinical data.
One of their key insights was the identification of an interpretation error in the experiment that cemented estradiol as the ovulation trigger, demonstrating that estradiol could elicit an LH surge in postmenopausal women. Finally, after several decades, the new paradigm explained why this effect could never be reproduced in normally cycling females.
Within the Dozortsev-Diamond paradigm, ovulation timing is determined not by the estradiol level, but by woman-specific properties of the ovarian cortex. It takes place when the dominant follicle reaches a size that the ovarian cortex can no longer accommodate and begins to lose structural integrity, much like an inflamed hair follicle. This loss of integrity allows some granulosa cells to escape the luteinization block, which switches them from estradiol to progesterone production.
As a result, estradiol and progesterone levels in the blood begin to move simultaneously but in opposite directions: Progesterone is rising and estradiol is falling.
This, according to the new theory, creates a fail-safe mechanism for ovulation: Rising progesterone will eventually trigger an LH surge by interacting with its hypothalamic receptors through the GnRH signaling pathway. Meanwhile, falling estradiol weakens its direct negative feedback on the pituitary, allowing some LH to escape into the circulation, augmenting spontaneous luteinization within the follicle and assuring the inevitability of the progesterone rise to a triggering level.
Because this hormonal interplay is somewhat unpredictable, a woman may have a single surge or what may appear to be multiple LH surges. However, only one of them, the final one, will be effective, and that surge will be driven by the action of progesterone.
The new paradigm not only identifies a physiological ovulation trigger but also explains cycle length consistency within individuals, variability between women, cycle shortening with age, random ovulation from either ovary, mono-ovulation, and even offers a new framework for understanding the origin of PCOS.
Progesterone is ingrained in our collective mind as the hormone of pregnancy. Its name translates from Latin as “for gestation”; it is vital for maintaining pregnancy, it blocks ovulation during pregnancy, and this property is used in birth control pills to block the LH surge and in ovarian stimulation protocols. The idea that it can also trigger ovulation at levels as low as 0.5 ng/ml is shocking to the established view. This is one of those cases where we do not see what we do not understand. It took the new paradigm to provide the understanding; now, we can finally see.
As paradoxical as it is, this completely opposite effects are not without a precedent within the same signaling pathway. Progesterone, similarly to Lupron (GnRH agonist), will block LH surge if present for an extended time at high level, but elicit the surge if its circulating level rises from a low baseline.
When theory met a patient
Our first clinical experience using progesterone as an ovulation trigger was published as two case reports in the Journal of Assisted Reproduction and Genetics. In both cases, ovulation resulted in the formation of a competent corpus luteum, confirmed by hormonal profiles and ultrasound findings.
These patients were not selected to prove a concept. They were chosen because they had already failed conventional cycles with artificial luteal phases and had only one remaining embryo of suboptimal quality left for transfer. In one case, implantation failed; in the other, the patient conceived and delivered at term without adverse maternal or fetal outcomes, requiring only minimal luteal support, a short course of oral progesterone as a precaution.
A call for physiological humility
Progesterone is not new. It is inexpensive, familiar, and widely available. What is new is the realization that we may be able to align better with the physiology of implantation and improve both patients’ experience and outcomes without increasing the cost. Reproductive specialists should consider exploring progesterone triggers in select cases, and larger trials are urgently needed.
Michael Allon, Lina Villar, and Beata Tralik are reproductive specialists.
