Progesterone is a trigger of ovulation

For several decades the sustained elevation of estradiol toward the end of the follicular phase was accepted as a trigger of ovulation. We recently provided compelling lines of evidence establishing that the role of estradiol in the process was misunderstood and that the true physiological trigger of ovulation is progesterone.

This page is an update to the manuscripts by Dozortsev, Pellicer, and Diamond:  

Progesterone is a physiological trigger of ovulatory gonadotropins. Dozortsev D, Pellicer A, Diamond MP. Fertil Steril. 2020 Luteinizing hormone-independent rise of progesterone as the physiological trigger of the ovulatory gonadotropins surge in the human. Dozortsev DI, Diamond MP. Fertil Steril. 2020 

The easiest way to understand the paradoxical action of progesterone, which apparently can do both, block and trigger ovulation, is to think about it as a GnRH agonist, which acts upstream, at the level of the hypothalamus. It can be perhaps referred to as a GnRH release agent. If it is sustainably high (usually above 10 ng/ml), as during the pregnancy or taken continuously in the form of a progestin as a birth control pill it drains hypophysis of LH and blocks FSH synthesis, and also desensitizes its own receptors. However, when it rises from a low baseline level during the follicular phase to about 0.5 ng/ml, it triggers ovulation through the GnRH signaling pathway.  

An additional reason to rule E2 out as a possible trigger of gonadotropins comes from an observation we made while reviewing the data from Inito, Inc, a company making a device for home monitoring of hormones during the follicular cycle. There is no pattern of E2 surging or being sustained at a high level before LH surge. Instead, the level of E2 relative to the start of the LH surge seems to be random. In the representative example below, the peak of LH begins well before the peak of E2, when E2 is almost at a baseline level.  

Further, the new interpretation of Leyendecker et al experiment goes as follows:

When the patient is started on E2, the assumption is made that both, LH and FSH secretion is suppressed. We have learned since then that the LH synthesis is in fact continued, only its release is prevented. Metaphorically, the basin above the dam (pituitary) is being filled and filled and filled (generously, since the female has no ovaries and the baseline level of LH synthesis level before E2 suppression was high). As E2 drops, it gently opens the dam, without damaging the infrastructure (draining LH directly from the pituitary, bypassing the GnRH signaling pathway). When P4 is injected, it destroys the dam (activates GnRH signaling pathway), the basin is empty and E2 has nothing left to drain. 

When the Inito, Inc natural cycle data are extrapolated on the graph from Leyendecker’s experiment (below), it is possible to observe LH peaks produced by two distinctively different mechanisms.   

Summary of changes in the new ovulation paradigm (graph below):

  1. There are seem to be no linear slops of E2 and FSH. Instead, both hormone levels oscillate with a periodicity of about 48 hrs due to positive and negative feedback on each other through receptors on the mural granulosa and hypothalamus. 
  2. The level of E2 at the start of the LH surge is not relevant and is random. 
  3. Gonadotropins surge is triggered by LH independent rise of progesterone in circulation (signalling inflamed follicle loss of integrity) to about 1 ng/ml or about x3 of the average baseline level through a GnRH signalling pathway
  4. Dropping E2 can release LH directly from the pituitary bypassing the GnRH signalling pathway and produce an additional LH peak

We recently published a hypothesis explaining the origin of E3G oscillations in the urine. However, it still needs to be confirmed that E2 levels in serum also oscillate.  

Triple redundancy for triggering GnRH activating pathway

One of the reasons for confusion surrounding the identification of a physiological trigger of ovulation is the surge for a single mechanism. While the mechanism seems to be indeed only one, there are multiple redundancies, making it difficult to elucidate. 

The first and second redundancies are created by a fork of dropping E2 and rising P4. As we can see they always move in the opposite directions, possibly because their pathways compete for the same substrate, but could be a host of other mechanisms as when the follicle begins to lose integrity, there is a chaos of uncertainties. Both, rising P4 or dropping E2 will initiate LH surge with eventual activation of the GnRH signaling pathway. Refer to the “Summary of changes in the new ovulation paradigm” (above).

Bifurcation of P4 and E2
Hoff, Quigley and Yen , 1983

A third redundancy is provided through the threshold of the P4 receptor in the hypothalamus. As long as E2 is present at any level, it will continue inducing P4 receptors in the hypothalamus. Therefore, even if the P4 remains at a baseline level, the number of P4 receptors at some point in time will cross the gonadotropins triggering threshold. 

Rather than hammering the hypothalamus with a high level of E2, the new paradigm teaches that P4 “tickles” it while remaining at a low level until the hypothalamus can’t take any more. 

Case report of using progesterone as a trigger. Dozortsev, Allon, Tralik and Diamond, 2020, unpublished. A single i/m injection of 5 mg of progesterone was given. 

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