New Ovulation paradigm
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Evidences confirming progesterone is a physiological trigger of ovulation
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New Ovulation paradigm
- 1. Regulation of ovulation in the human Dmitri Dozortsev, MD, PhD 2020
- 2. This lecture is based on:
- 3. Current ovulation paradigm Dozortsev and Diamond, Fertility and Sterility, 2020 Sustained high estradiol level triggers LH surge by activating GnRH signaling pathway after 12 to 48 hrs Progesterone begins to rise after LH surge as a result of granulose luteinization in the follicle (activin and inhibin are not shown)
- 4. Leyendecker et al crucial experiment Leyendecker et al (1972) interpret the data as an evidence that estradiol is a physiological ovulation trigger. Progesterone can also trigger LH surge. However Leyendecker rules out the possibility that it can be a physiological ovulation trigger:
- 5. Anomalies A prospective randomized study has clearly demonstrated that the continued administration of letrozole throughout the follicular phase, with well-documented suppression of estradiol, did not have any effect on the timing of ovulation in normally menstruating women. This led the authors to conclude that the role of estradiol in ovulation has been misinterpreted. During ovarian stimulation, a supraphysiological E2 level is reached very early in the follicular phase, yet, does not trigger ovulation. Furthermore, when the LH surge does occur, it is often markedly reduced, inconsistent with E2 being a trigger. Furthermore, increasing the circulating E2 levels 10-fold (to ∼13,000 pmol/L) compared with control by the administration of exogeneous estradiol before ovulation had no impact on inducing an LH surge, or ovulation, in normally menstruating women.
- 6. One more curious anomaly Vanishing follicle is accompanied by luteinization (and P4 elevated to the ovulatory level) without any evidences of failed LH suppression.
- 7. Real life estradiol profile during ovarian cycle Courtesy of
- 8. Progesterone has been known to induce LH surge
- 9. Progesterone as LH trigger in the humans But is it a physiological trigger of ovulation? Odell W.D. Swerdloff R.S. Progestogen-induced luteinizing and follicle-stimulating hormone surge in postmenopausal women: a simulated ovulatory peak. Proc Natl Acad Sci U S A. 1968 Leyendecker G. Wardlaw S. Nocke W. Experimental studies on the endocrine regulations during the periovulatory phase of the human menstrual cycle: the effects of exogenous 17-oestradiol and progesterone on the release of pituitary luteinizing and follicle stimulating hormones. Acta Endocrinol (Copenh). 1972 Buchholz R, Nocke L., Nocke W. The influence of gestagens on the urinary excretion of pituitary gonadotropins, estrogens, and pregnanediol in women in the postmenopause and during the menstrual cycle.Int J Fertil. 1964; 9: 231-251
- 10. Barriers to accepting progesterone as a natural trigger Estradiol can be used to trigger ovulation in ovariectomized female (complete absence of ovarian derived progesterone) 1) Progesterone is high during pregnancy (when ovulations are blocked) 2) Main component of birth control pills 3) Blocks LH surge during progesterone-primed controlled ovarian stimulation Progesterone does not begin to rise until after LH surge
- 11. Lack of a relevant case reports Lack of evidences that P4 can trigger LH surge at the circulating levels observed during natural follicular phase i.e. ~ 1 ng/ml
- 12. Hoff, Quigley and Yen experiment Journal of Clinical endocrinology and Metabolism, 1983 LH peak Progesterone DOES rise before LH surge LH peak E2 P4 Progesterone LH triggering level is only 0.5 ng/ml
- 13. McNeilly et al, crucial findings McNeilly et al, Reproduction Supplement, 2010 Increasing E2 level prevents LH release, but does not affect its synthesis, causing LH during follicular phase to accumulate. Its action on FSH is more complex, affecting both, the synthesis and release.
- 14. E2 action directly on the pituitary
- 15. Leyendeker’s crucial experiment When the patient is started on E2, the assumption is made that both, LH and FSH secretion is suppressed. But we now know that the LH synthesis is continued, but 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. When P4 is injected, it destroys the dam, the basin is drained and E2 has no dam to open. Our interpretation:
- 16. Example of E2 profiles in natural cycles Courtesy of
- 17. Leyendeker's LH “surge” as E2 falls in a natural cycle Real LH surge (GnRH pathway) Falling estradiol artefact Falling estradiol artefact LH E2 Courtesy of
- 18. P4 as a physiological trigger of gonadotropins Ultrasound observation P4 (ng/ml) LH (IU/L) Baseline Clear, no cyst (Figure 1 A, B) 0.4 Not measured First follicular ultrasound 2 leading follicles, 14 mm and 13 mm. Lining 6.5mm 0.49 9.47 Stimulation day 10 2 follicles leading 17 mm and 16mm. 0.38 5.09 Stimulation day 12 Day of a progesterone trigger shot 2 leading follicles 22 mm each and 19 mm (Figure 1 C,D) Uterine lining 8.8 mm (Figure 2) 0.62 4.26 17 hours 30 minutes after trigger shot Not performed 8.01 37.01 Day 3 after trigger shot Fluid behind uterus (Figure 3-D); all follicles ruptured (Figure 3- A,B); Uterine lining – 15.2 mm (Figure 3 -C) Not measures Not measured 7 days after trigger shot Not performed 38.39 Not measured Dozortsev, Tralik, Allon and Diamond, 2020 (unpublished case report) Estimated peak plasma concentration ~ 1 ng/ml
- 19. Redundancy of the LH triggering mechanism If E2 drops below the thresholds first – two LH peaks IF P4 rises above the threshold first – one LH peak Move of P4 and E2 in opposite directions during impending follicular rapture makes LH surge immanent. Dropping E2 releases LH directly from the pituitary, bypassing GnRH signaling pathway. Rising P4 acts on its receptors in the hypothalamus activating GnRH signaling pathway.
- 20. Third putative redundancy for LH trigger mechanism With sufficiently high E2 level the number of P4 receptors can be increased to the threshold, where GnRH signaling pathway becomes sensitive to the base level of P4 This would explain LH surge in sheep and premature LH surge in females with PCOS E2 P4 P4 receptors This would be similar to granulosa cells becoming responsive to baseline level of LH once they acquire critical number of LH receptors after FSH priming LH triggering threshold
- 21. Reconciling with progestins in BCP Progestin Consensus value (mg) Norethindrone 0.35 D/L norgestrel 0.075 Medroxyprogesterone acetate 5 Dydrogesterone 10 The equivalent amount of progestines to 200 mg progesterone to elicit endometrial changes observed in the premenopausal, secretory phase (King and Whitehead, 1986). A single pill in a birth control formulation of dydrogesterone has P4 activity equivalent to that of 200 mg of injected P4. Since 5 mg of injected P4 is already sufficient to induce LH surge, an oral intake of 10 mg of dydrogesterone (200 mg of injected P4) would result in an estimated circulating P4 activity several times higher than its putative gonadotropin triggering level. (this would explain why women who starts her BC regiment by taking the first pill in the end of the follicular phase will induce her to ovulate and may become pregnant). Progestins prevent premature LH surge by draining pituitary and desensitizing P4 receptors in hypothalamus – the same way it happens during the pregnancy. P4 can act as a trigger only within a narrow time window
- 22. Reconciling with progestins-primed COS Requirements: 1. baseline E2 < 70 pg/ml 2. start on day 3 (starting later did not block LH surge) Hypothalamus Follicle Pituitary hCG LH Agonist GnRH Progestin desensitizes P4 receptors before E2 has induced enough P4 receptors in hypothalamus to trigger GnRH, thereby blocking physiological trigger mechanism Agonist can be used to trigger LH since it acts directly on the pituitary It is all about the timing
- 23. If P4 is the trigger, what causes it to rise, before LH? LH is not required for luteinization From Stout et all (2007). Note that cells surrounding the egg (e) of Brachionus Manjavacas are stained by antibodies to progesterone (blue). Organelles are noted by: vit, vitellarium (yolk gland); o, ovaries; ov, oviduct; e, egg; Scale bar: 100 μm; Reproduced from PNAS. Odell and Swerdloff , 1968 “Pituitary-ovarian system would be most efficient if the ovary could signal exactly when a follicle were ready for ova discharge” Granulose cells are committed to luteinize spontaneously
- 24. Inflammation and luteinization Odell and Swerdloff , 1968 “Pituitary-ovarian system would be most efficient if the ovary could signal exactly when a follicle were ready for ova discharge”
- 25. The new ovulation paradigm Not PR-A and PR-B,, but a rapid action G-protein coupled P4 receptors. These type of receptors are involved in opioids and insulin pathways.
- 26. Conclusion As follicle is losing integrity, changes in the intrafollicular milieu cause P4 to rise and E2 to drop making LH surge immanent P4 level above 0.5 ng/ml during follicular phase is clinically significant The ovulatory surge of gonadotropins is triggered by P4 through GnRH signaling pathway
- 27. New theory of PCOS origin Term stimulation New approach to creating a natural luteal phase for frozen transfers Ramifications
- 28. Acknowledgements Pasha Itskson, PhD and Nabil Arrach, PhD (Progenesis) For donating funds to make publication free and open-access
- 29. The beauty of virgin endocrinology PNAS, 1968
Editor's Notes
- In this lecture we will look at the current ovulation paradigm in the human, review the anomalies that it can’t explain and discuss a new paradigm, which resolves those anomalies
- This lecture is based on two manuscripts published in fertility and sterility in 2020 in co-authorship with
- According to the current paradigm sustained elevation of estradiol triggers LH surge. Rising LH luteinizes granulose cells resulting in progesterone elevation, which terminates LH surge.
- The cornerstone of the current paradigm are experiments by Leyendecker. At the time, it was generally accepted that regulation of the obavrian cycle is a purely hormonal interaction. When women enters menopause, she looses ovarian derived estradiol. It was reasoned therefore, that restoring estradiol in circulation, would restore the cycle. To prove this, Leyendecker’s primed a postmenopausal woman with oral estradiol for a few days and then administered an injection of estradiol. After a latent period of about a day, an LH surge is detected. … Even though progesterone in his experiments also induced LH surge, it was ruled out as physiological ovulation trigger because in a natural cycle it does not begin to rise until after LH surge.
- There are many unexplained anomalies that do not fit into the current paradigm, here are a couple of examples ./… Injection of E2 before ovulation, which increased E2 level 10 folds! in normally menstruating females did not have any impact on inducing LH surge
- Another curious anomaly is well known phenOmenon of the so-called vAnishing follicles. They are essentially spontaneously rupturing follicles which disappear on the ultrasound and spontЭneously luteinize without any evidences of LH surge, which remains well suppressed. This phenomenon not only undermines that idea that sustained E2 elevation is required to trigger gonadotropins surge, but also clearly demonstrate that LH is not required neither for follicle’s rupture not for luteinization.
- recently, Inito corporation, a Silicone Valey funded startup from India, gave us an opportunity to review E2 profiles of normally menstruating females collected using home ovulation tracking kit and software. Only in about 30% of the cases we saw a correlation between peak of E2 and LH surge. In the vast majority of cases this relationship looked random. In this representative case, E2 goes up and down and LH surges when E2 is barely elevated above the baseline. it is very different from the expected slop.
- Another hormone that has been considered as a physiological trigger of gonadotropins – progesterone. Back in 1940th Everet wrote the following, interpreting his experimental findings:
- There are several highly credible publications in the human suggesting that progesterone can trigger LH surge:
- There are several barriers in a way of accepting that progesterone is a physiological ovulation trigger. Leyendeker ..
- Finally, there are no ..
- Now, lets look at the relevant experimental data, not available to Lyendecker at the time. Then we will go back to his data and try to re-interpret them within the new context. As we already discussed, it is usually believed that P4 begins to rise only after LH surge. But this was based on daily hormones measurements in the circulation. However, Hoff, Quigleo and Yen for their experiments admitted several normally menstruating females into the hospital a few days before expected LH surge. They draw their blood for hormonal measurements every two hrs. By doing this, they detected P4 rise about 12 hrs before the peack of E2 and the start of LH surge. They also noticed that P4 and E2 begin to move in sharply different directions
- Another important piece of information not available to Leyendecker is related to E2 action on LH and FSH synthesis. At the time, it was assumed that E2 suppresses the synthesis of both LH and FSH, because its administration to menopausal woman reduces the level of both hormones in the circulation. However, McNeilly’s experimetns have clearly demonstrated that during the follicular phase, while rising E2 prevents LH release, but does not affect its synthesis, which causes LH to accumulate within the gonadotrophs in pituitary.
- Furthermore, it was not known at the time of leyendeker’s experimetns that E2 has a direct negative feedback on LH release from the pituitary, which becomes stronger with age.
- Now lets look at the Leyendecker’s experiments. When the menopausal patient is started on oral estradiol, The artefact observed by Leyendecker is more likely to be seen in the post-menopausal women, because they have a higher baseline level of LH production, but as we recently found out can also be observed in a normally cycling females.
- What determines the duration of the follicular phase is a subject of a separate lecture. Evolutionary
- Just as 50 years ago we think of regulation of the follicular cycle as a beautiful interplay of hormones. Even though already at the time, Odell and Swerdloff felt that something is wrong. They reasoned that if that is the case, they should be able to restore the cycle by giving post menopausal woman estrogens. But it did not work. They did suggest that follicle must give a signal to hypothalamus that it is ready to rupture and were actually one of the first to propose that progesterone may be that signal.