How a Semantic Trap and an Experiment That Was Just a Little Bit Too Perfect Led Reproductive Science Astray for 50 Years
This is the story of how the roles of progesterone, estradiol, and LH were misinterpreted for more than half a century. Only recently was this corrected, finally explaining the consistent duration of the menstrual cycle, why it shortens with age, why ovulation alternates randomly between sides, and many other previously unresolved questions, opening doors for new approach to treating infertility.
1. The Ancient Mystery of the Yellow Body
Since antiquity, it was known that a pregnant mammalian female possesses a round, yellow formation in her ovary. In 1903, Ludwig Fraenkel confirmed that this yellow body was essential for pregnancy, naming it the corpus luteum, Latin for yellow body.
2. Completing the Hormonal Picture (1913 to 1934)
It is crucial for our story that corpus luteum became a reference point for subsequently discovered of other reproductive hormones.
Estradiol (1923). Edward Doisy isolated the hormone that peaked before the formation of the corpus luteum.
LH and FSH (1931). Fevold, Hisaw, and Leonard isolated the pituitary signals known as LH and FSH. Luteinizing Hormone was named specifically for its role in creating the corpus luteum.
Progesterone (1934). Willard Allen and George Corner isolated the hormone produced by the corpus luteum.
By the 1940s, endocrinology had an ovulation mechanism described as an internally consistent interplay of ovarian and pituitary hormones, where one induces another: estradiol induces LH, which in turn induces progesterone.
3. The Semantic Trap of Luteinization
Since the main function of the corpus luteum is to produce progesterone, luteinization and progesterone production became virtually synonymous. In other words, Luteinizing Hormone became known as the hormone that induces progesterone production. This created a semantic trap solidifying the notion that the appearance of follicular ovarian progesterone must be preceded by LH surge.
4. Small but stubborn misfit
Despite its elegant appearance, insiders knew all along that something was not right with the ovulation paradigm, because achieving supraphysiologic level of estradiol failed to induce LH surge? This necessitated using hCG and Lupron as triggeres.
Furthermore, estradiol level varies greatly between females and between cycles of the same female. How can this translate into reproducible duration of the cycle from month to month? How does such variability ensure that LH is released precisely when the follicle is ready to rupture? Why does the cycle shorten with age while peak estradiol levels tend to decline? How does estradiol, known to suppress LH release in a dose-dependent manner, ends up triggering LH surge?
5. The Decisive Experiment
In the 1970s, a prominent reproductive endocrinologist, Dr. Gerhard Leyendecker, decided to design the cleanest possible experiment to elucidate the action of estradiol during ovulation. He choses what appeared at the time to be a perfect model, a postmenopausal female without ovaries, meaning she had no endogenous ovarian hormones. He reasoned that the absence of baseline estradiol would eliminate noise and help establish the estradiol profile required to trigger an LH surge. As we will see, for reasons that Leyendecker could not have known at the time, this choice was a mistake.
Postmenopausal females have very high baseline LH levels, similar to those seen during the ovulatory peak in non menopausal females. Therefore, he first had to suppress LH to levels expected before an ovulatory surge. To do this, he administered oral estradiol for several days. Once LH reached the desired range, he injected a high dose of estradiol benzoate. Throughout the experiment, blood estradiol levels were carefully monitored. Estradiol reached peak levels within a few hours of injection. Approximately forty eight hours later, when estradiol levels had fallen to about half of their peak value, the patient experienced an LH surge.
The conclusion was a small correction to the existing paradigm. The order of players remained unchanged, but the surge was now said to occur not at peak estradiol levels, but when estradiol began to decline. The apparent rigor of the experiment, combined with Leyendecker’s authority, sealed this paradigm for the next fifty years. Although not entirely wrong, as we will see was secondary to the true mechanism of LH surge.
6. How the Revision Arrived
In the early 2000s, Dr. Dozortsev and Dr. Diamond were trying to understand why a shorter follicular phase produces poor quality eggs in both natural cycles and IVF patients. This required understanding what determines follicular phase duration, which inevitably led them to revisit the mechanism of ovulation.
By that time, accumulating observations contradicted estradiol being a trigger. In particular, an observation that suppressing estradiol throughout the follicular phase with Letrozole did not shift the timing of the LH surge.
Another obscure candidate for physiological LH trigger, since 1940s was progesterone. Leyendecker himself, in the very experiment used to support estradiol as the physiological trigger, showed that progesterone induced an LH surge in the same patient. Yet he dismissed progesterone as a physiological trigger, since progesterone does not appear until after LH, it cannot be considered a physiological trigger. The semantics became a trap: we cannot have the product of luteinization before luteinization.
To Dozortsev and Diamond, progesterone appeared to be an ideal trigger candidate for several reasons. It remains very low throughout the follicular phase and begins to rise just before the LH surge. Its rise is predictable, unlike estradiol. They also knew that granulosa cells surrounding the oocyte can luteinize spontaneously when their environment changes. In 2008, Dr. Kol published a hypothesis based on vanishing follicles, proposing that complete luteinization can occur within the follicle without any LH participation.
What particularly intrigued Dozortsev and Diamond was that progesterone could coordinate follicular readiness with LH release. The ovarian follicle has a familiar analogue, a hair pimple. A pimple must be observed until the correct moment for evacuation. Too early, and removal is incomplete. Too late, and rupture is messy. At the right moment, evacuation is clean and healing is rapid.
They realized the ovarian follicle behaves similarly. If LH is released too early, the follicle fails to rupture and forms a cyst. If released too late, after spontaneous rupture has progressed too far, the ovulated egg is post mature. They hypothesized that as the follicular wall loses integrity, some granulosa cells spontaneously luteinize and produce small amounts of progesterone, which signals LH release at precisely the right moment.
7. Revealing the Interpretation Error of a Perfect Experiment
Yet Leyendecker’s experiment, apparently proving estradiol as the trigger, stood as a major obstacle. It was carefully performed and well documented. It clearly associated estradiol with an LH surge. Yet, Dozortsev and Diamond remained convinced that there must be an error in its interpretation.
Why could this effect never be reproduced in non menopausal females? They focused on one key question. How does estradiol suppress LH? LH is measured in blood, and estradiol clearly lowers circulating LH. But what if estradiol suppresses LH release rather than LH synthesis?
If so, administering estradiol to a postmenopausal female, who produces LH at a very high rate, would cause LH to accumulate in the pituitary far beyond physiological levels. When estradiol later declines, this accumulated LH would be released all at once, producing an artificial surge possible only in postmenopausal females.
After extensive searching, they found a 1985 PNAS publication confirming that estradiol suppresses LH release but not its synthesis. Thus, Leyendecker, striving for experimental purity with the knowledge available at the time, chose the worst possible model for sorting out role of estradiol in LH surge.
A Complete Picture
After the manuscript describing the new ovulation paradigm was published in the Fertility and Sterility, Sea Changes in Human Reproduction series, Dozortsev and Diamond were contacted by the founders of a California fertility startup, Inito. The company had developed a device for daily urinary hormone monitoring to predict ovulation.
While reviewing Inito’s data, Dozortsev and Diamond noticed that estradiol sometimes temporarily declines during the follicular phase, accompanied by a modest but unmistakable rise in LH. This led to another insight. The inverse relationship between estradiol and LH, which created an artifact in Leyendecker’s experiment, may in fact be a part of a fail-safe physiological mechanism.
Indeed, estradiol and progesterone are produced by the same granulosa cells. As follicular integrity declines, these cells shift from estradiol production toward progesterone, creating a fork where estradiol can only fall while progesterone can only rise.
If progesterone rises rapidly, it directly triggers an LH surge binding to its hypothalamus receptors and activating GnRH signaling pathway. But, if progesterone rises slowly or hypothalamic progesterone receptors fail to respond, declining estradiol will continue to allow LH escape directly from the pituitary, accelerating luteinization and eventually triggering a surge.
This explains why some patients experience multiple LH surges around ovulation.
In the Dozortsev Diamond ovulation paradigm, spontaneous luteinization of granulose cells creates a fail-safe mechanism to trigger LH surge with progesterone being responsible for activating GnRH signaling pathway and estradiol ensuring that progesterone continues to rise until its receptors respond.
New Trigger of Ovulation
Assisted reproduction now has a coherent and actionable ovulation paradigm and a new physiological trigger. Unfortunately, progesterone cannot be used during ovarian stimulation for IVF because it can’t overcome agonist or antagonist block. But, it is ideal for natural cycles and frozen embryo transfers.
The first live birth after progesterone triggered ovulation in a patient with prior implantation failure has already been reported. Another independent live birth was reported in 2024 at a Foundation for Reproductive Medicine conference. Dozortsev and Diamond are planning a clinical trial to formally introduce progesterone as a trigger. Progesterone is inexpensive and widely available, and one 0.5 ml injection may replace months of daily injections that many patients consider the most difficult part of IVF.
What Is Happening Now
Change takes time, especially in conservative fields such as medicine. However, this new understanding of ovulation is both actionable and intellectually satisfying, and its derivatives are already bearing fruit.
The new paradigm explains mono ovulation, random alternation between ovaries, cycle shortening with age, multiple LH surges, and paradoxical effects of Clomid. It has also generated a new theory of polycystic ovarian syndrome and more.