Luteinizing hormone–independent rise of progesterone as the physiological trigger of the ovulatory gonadotropins surge in the human

Abstract

The current ovarian cycle paradigm postulates that ovulation is triggered by a critically sustained elevation of estradiol. However, an in-depth look into the published data reveals considerable uncertainty about the relative roles of progesterone and estradiol in the ovulation process.This review provides compelling evidences that the role of estradiol in ovulation has been misinterpreted and that the true physiological trigger of ovulation is a luteinizing hormone–independent preovulatory progesterone surge in the circulation to approximately 0.5 ng/mL. Furthermore, the current work reconciles the ability of progesterone to trigger ovulation, with its well-established ability to block ovulation during pregnancy, or when administered in the form of a synthetic progestin in birth control formulations and with experimental data that estradiol benzoate triggers ovulation in the complete absence of progesterone. The current ovarian cycle paradigm postulates that ovulation is triggered by a critically sustained elevation of estradiol. However, an in-depth look into the published data reveals considerable uncertainty about the relative roles of progesterone and estradiol in the ovulation process.This review provides compelling evidences that the role of estradiol in ovulation has been misinterpreted and that the true physiological trigger of ovulation is a luteinizing hormone–independent preovulatory progesterone surge in the circulation to approximately 0.5 ng/mL. Furthermore, the current work reconciles the ability of progesterone to trigger ovulation, with its well-established ability to block ovulation during pregnancy, or when administered in the form of a synthetic progestin in birth control formulations and with experimental data that estradiol benzoate triggers ovulation in the complete absence of progesterone. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/30083 Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/30083 The current ovulation paradigm postulates that the rise of estradiol (E2) into the range of above 200 to 300 pg/mL for a minimum of 50 hours is what triggers gonadotropin-releasing hormone (GnRH) to surge. GnRH in turn binds to its receptors in the anterior hypophysis, causing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) into the circulation and culminating in the rupture of the developing ovarian follicle (Fig. 1) (1Christensen A. Bentley G.E. Cabrera R. Ortega H.H. Perfito N. Wu T.J. et al.Hormonal regulation of female reproduction.Horm Metab Res. 2012; 44: 587-591Crossref PubMed Scopus (82) Google Scholar). However, a recent 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 (2Hurst B.S. Merriam K.S. Elliot M. Matthews M.L. Marshburn P.B. Usadi R.S. A sustained elevated estradiol is not the trigger for the preovulatory luteinizing hormone surge.Women’s Health & Gynecology. 2015; 1: 1-3Google Scholar). Notably, this is by far not the first observation questioning the role of the estradiol rise as a trigger of ovulation. Indeed, it has long been known that 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 (3Messinis I.E. Templeton A. Effect of high dose exogenous oestrogen on midcycle luteinizing hormone surge in human spontaneous cycles.Clin Endocrinol (Oxf). 1987; 27: 453-459Crossref PubMed Scopus (10) Google Scholar). 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 (3Messinis I.E. Templeton A. Effect of high dose exogenous oestrogen on midcycle luteinizing hormone surge in human spontaneous cycles.Clin Endocrinol (Oxf). 1987; 27: 453-459Crossref PubMed Scopus (10) Google Scholar). Reviewing published data on the role of estradiol in ovulation, Zalanyi (4Zalányi S. Progesterone and ovulation.Eur J Obstet Gynecol Reprod Biol. 2001; 98: 152-159Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar) concluded that the idea that E2 causes ovulation has to be discarded. Another agent long known to cause the LH surge is progesterone (P4). Back in 1964, Buchholtz et al. (5Buchholz 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: 231-251PubMed Google Scholar) were the first to show that the intramuscular injection of P4 causes an immediate rise in urinary gonadotropins, similar to the gonadotropin peak seen during ovulation. Consistent with that observation, Odell and Swerdloff (6Odell 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; 61: 529-536Crossref PubMed Scopus (146) Google Scholar) demonstrated that P4 injection elicits an LH and FSH surge in postmenopausal women after FSH downregulation with an estradiol regimen. Despite those early findings clearly demonstrating the ability of P4 to induce an ovulatory peak of gonadotropins, its role as a physiological ovulation trigger has not been recognized to this day. Likely this is largely because Leyendecker et al. (7Leyendecker 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; 71: 160-178Crossref PubMed Google Scholar) demonstrated that estradiol benzoate can induce an LH surge in castrated women who completely lack any ovarian-derived P4. Furthermore, P4 has been historically known as an LH suppressor (4Zalányi S. Progesterone and ovulation.Eur J Obstet Gynecol Reprod Biol. 2001; 98: 152-159Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar), and its artificial derivatives–progestins–are the primary components of birth control regiment. Also, the preovulatory peak of P4 is seemingly small, only approximately 0.5 ng/mL (8Hoff J.D. Quigley M.E. Yen S.S.C. Hormonal dynamics at midcycle: a reevaluation.J Clin Endocrinol Metab. 1983; 57: 792-796Crossref PubMed Scopus (419) Google Scholar) compared with the postovulatory rise, which is about 10 times higher. The relatively low level of the preovulatory peak makes it difficult to recognize its clinical significance. It is also easy to miss because it occurs within hours, whereas virtually all relevant clinical studies sample P4 daily. Only when Hoff et al. (8Hoff J.D. Quigley M.E. Yen S.S.C. Hormonal dynamics at midcycle: a reevaluation.J Clin Endocrinol Metab. 1983; 57: 792-796Crossref PubMed Scopus (419) Google Scholar) sampled blood every 2 hours in the days preceding ovulation was it possible to observe that the P4 surge precedes both the estradiol peak and the gonadotropins flare by approximately 12 hours. Another intrinsic challenge in dissecting the roles of estradiol and P4 is their intimate cooperation, whereby the former is required to induce P4 receptors in the hypothalamus (9Leavitt W.W. Chen T.J. Allen T.C. Regulation of progesterone receptor formation by estrogen action.Ann N Y Acad Sci. 1977; 286: 210-225Crossref PubMed Scopus (149) Google Scholar). This review is narrowly focused on bringing together the evidence for the role of P4 as the trigger for the gonadotropin surge: evidence that we believe is credible. We put forth what we believe is compelling evidence that under physiological conditions, there are two waves of P4. The first wave is an LH-independent, precipitous rise of P4 12 hours before the gonadotropin surge to approximately 0.5 ng/mL, which signals to the hypothalamus that a follicle is ready to rupture. This rise activates the GnRH signaling pathway, with an ensuing LH/FSH surge, which causes the follicle to rupture and its granulosa cells to luteinize. Evolutionarily, luteinization first appeared at least 500 million years ago and has survived to this day as a locally controlled event in lower animals (Fig. 2) (10Stout E.P. La Clair J.J. Snell T.W. Shearer T.L. of progesterone hormone in Natl Acad Sci U S A. Scopus Google Scholar). have a level of luteinization there is evidence that the ability of all granulosa to was in of PubMed Scopus Google Scholar). the granulosa cells are to luteinization are luteinization a that is not However, of the the of the block an of the follicle luteinization of in PubMed Scopus Google Scholar). the is by or by of follicle rupture during Sci. Scopus Google Scholar), the granulosa cells are the block and as a luteinization of granulosa progesterone of both P4 formation and PubMed Google Scholar). the of luteinization of the follicle the is similar in the or absence of This the that the release the block is to in the to an of luteinization by LH luteinization of in PubMed Scopus Google Scholar). Consistent with this in completely the ovulation and luteinization after an injection of FSH luteinization and ovulation in the a possible role for the PubMed Scopus Google Scholar). a the for during the Biol. PubMed Scopus Google Scholar) that the ability to after the of and at the during follicular the the ability to at least days before ovulation and before it G. G. N. for and in effect of follicle and 57: PubMed Scopus Google Scholar), which we as the ability to to physiological conditions, the LH surge triggers of the by cells with the and the can be as under the (Fig. However, any in the follicular to the follicle its to spontaneous luteinization and of the with the be as long as the has ability randomized study of human before women with ovarian PubMed Scopus Google Scholar). The timing of in this is the physiological of which for all granulosa cells after an LH flare M. et hormone causes and of in ovarian of two to PubMed Scopus Google Scholar). for a follicle does not and the the of it have a at the of (Fig. This is a as a can be of normally with LH (Fig. The ability of the ovarian to rupture an LH surge has been demonstrated in luteinization and ovulation in the a possible role for the PubMed Scopus Google Scholar). in this is known as and occurs in during S. The follicle in women luteinization low PubMed Scopus Google Scholar). The of the follicle is by an in circulating P4 to the when the LH surge is S. The follicle in women luteinization low PubMed Scopus Google Scholar). It be that rupture of the follicle that has not been to LH human gonadotropin be ovulation it in an being and for by a FSH can cause follicle it is not known to the of which in the the or ovulation of an or an by cells that is not rupture of the of and luteinization of granulosa cells can all in the absence of what is by an LH ovulatory can have an low to in in because of a relatively that can to a S. A. et for injection in the human is to hours after administration of human Full Text Full Text PDF PubMed Scopus Google Scholar). The of the in the human is the with day injection clearly that it is no hours after injection in after or Full Text Full Text PDF PubMed Scopus Google Scholar) or approximately hours after et al. S. A. et for injection in the human is to hours after administration of human Full Text Full Text PDF PubMed Scopus Google Scholar) demonstrated that the of an developing to is hours after the of to the other the of the hours after both and S. A. et for injection in the human is to hours after administration of human Full Text Full Text PDF PubMed Scopus Google Scholar). This that the human has the for within only to hours after ovulation. that ovulation to hours after it is to the which that the the rupture and it to the GnRH to trigger an LH surge. a the physiological LH surge is by the surge of FSH and is often to as an LH/FSH surge. It is not known FSH is for the follicle rupture at this or is a of an LH surge, which is to both follicle rupture and ovulation. The of an FSH surge being a effect is by of FSH in the in the of their administration Y of luteinizing hormone LH in PubMed Scopus Google Scholar). The of their release is not by GnRH by other as Y administration Y of luteinizing hormone LH in PubMed Scopus Google Scholar), a very for of with that the role of LH in ovulation is a of of of the and rupture of the The follicle before its into an is hormone and is controlled by the by the control both the granulosa cells and the follicle that there is a of both J.J. The the of ovarian follicular Natl Acad Sci U S A. PubMed Scopus Google M. of and Reprod PubMed Scopus Google A. and the follicle Reprod Scopus Google Scholar). The within the follicle is by of granulosa The of granulosa cells with the this all granulosa cells are to the into the all granulosa cells are to FSH receptors and into However, continued of other and by an granulosa cells FSH The within the follicle J.J. in ovarian Sci. PubMed Scopus Google Scholar), a with the to the and the at the follicular (Fig. a is within the follicle and its the granulosa cells control and FSH This makes the follicle to FSH at the of the phase of the cycle A. follicular and Google Scholar). The of the during the follicular phase under control of the However, of the which is the of granulosa and be controlled by FSH and by both FSH and by the anterior Full of this control that the for the and the for the release the follicle are by completely and which have for A. Progesterone is a physiological trigger of ovulatory Full Text Full Text PDF Scopus Google A. and ovarian impact on Full Text Full Text PDF PubMed Scopus Google Scholar). the of the granulosa cells to FSH receptors is their intrinsic and be controlled However, the into and granulosa cells is a because it is by of the and FSH J.J. in ovarian Sci. PubMed Scopus Google Scholar). those cells in the and be to the follicular and estradiol. evidence to the that high FSH levels granulosa into cells to with an J.J. The the of ovarian follicular Natl Acad Sci U S A. PubMed Scopus Google J.J. in ovarian Sci. PubMed Scopus Google Scholar). It is not known cells with the to its a lower This a that FSH the of the studies demonstrating of with ovarian an L. S. ovarian for and Full Text Full Text PDF PubMed Scopus Google Scholar). Another possible of of the granulosa into an of cells is to the is a which rupture of the of this is that does not control the cycle of the follicle and not be to by the the follicle A. and ovarian impact on Full Text Full Text PDF PubMed Scopus Google Scholar). in the early days of ovulation the role of the E2 as an ovulation trigger was when a in circulating P4 was as early as 12 hours before any in LH or E2 (8Hoff J.D. Quigley M.E. Yen S.S.C. Hormonal dynamics at midcycle: a reevaluation.J Clin Endocrinol Metab. 1983; 57: 792-796Crossref PubMed Scopus (419) Google Scholar). the preovulatory P4 relatively throughout the follicular phase, and its are to the of the which is a of rupture of the its rise can as an signaling to the hypothalamus the to ovulation (Fig. et al. (5Buchholz 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: 231-251PubMed Google Scholar) demonstrated that intramuscular injection of P4 an immediate rise in gonadotropins similar to the rise with ovulation at the were by and Swerdloff (6Odell 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; 61: 529-536Crossref PubMed Scopus (146) Google Scholar) and by Leyendecker et al. (7Leyendecker 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; 71: 160-178Crossref PubMed Google Scholar). and Yen Yen of midcycle gonadotropin surge by ovarian in women: a Clin Endocrinol Metab. 1983; 57: PubMed Scopus Google Scholar) that P4 is to the of the LH the surge by estradiol. et al. Merriam for a role of progesterone in the regulation of the midcycle gonadotropin surge and Clin Endocrinol Metab. PubMed Scopus Google Scholar) demonstrated in that injection of P4 the ovulation block by administration of in a whereas administration of a LH surge R. et is an for the of luteinizing hormone luteinization in women controlled ovarian for in Clin Endocrinol Metab. PubMed Scopus Google Scholar). Consistent with P4 being an ovulation P4 to normally is other evidence to the role of P4 as the ovulation agent (4Zalányi S. Progesterone and ovulation.Eur J Obstet Gynecol Reprod Biol. 2001; 98: 152-159Abstract Full Text Full Text PDF PubMed Scopus (31) Google et progesterone receptor 9: PubMed Scopus Google of the progesterone receptor 2001; PubMed Scopus Google Scholar). The of the preovulatory rise in P4 level can be difficult to because it is approximately 0.5 with the levels of P4 relevant in an and However, we it within the of P4 during the follicular phase, this a precipitous of to 12 hours before the peak of the E2 or LH before ovulation, the follicle and G. R. G. ovulatory with the of in women with J PubMed Scopus (82) Google Scholar), which the (Fig. This is very relevant because it the for two possible of P4 The first is that the in the release of the granulosa cells luteinization The does not luteinization a in P4 it has been that under conditions, P4 and the is P4 as a luteinization of granulosa progesterone of both P4 formation and PubMed Google Scholar). We believe that this is the of the P4 surge that binds to receptors in the This has been to be required for the GnRH that in the LH flare progesterone gonadotropin and in female PubMed Scopus Google Scholar). Regulation of P4 not be completely that is in N. L. et and the of human Biol. PubMed Google Scholar), of which has been recognized with a in It was that the surge of circulating P4 preceding ovulation is not to P4 in the follicle progesterone and the and in the control of ovulation and the regulation of progesterone Google Scholar). This that the preovulatory P4 surge is not to also to in of the follicular a this also the preovulatory surge of which has a lower P4 and has other it to the follicle into the of the of the preovulatory P4 when it approximately 0.5 ng/mL times the this signals to the the the rupture of the to the of It is also possible that of the in a (Fig. release of LH and FSH in the to the of the the and and into the of the in the within an of the LH surge that the is with the follicle rupture to hours at the of the controlled ovarian P4 can above 0.5 ng/mL the LH surge, because GnRH is its receptors that the GnRH signaling pathway, is the gonadotropin flare at any P4 has been as an ovulation agent (7Leyendecker 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; 71: 160-178Crossref PubMed Google Scholar). This ability of P4 is known and is by with the of in birth control first this is with the of P4 inducing LH to surge and induce ovulation, because the circulating level of in birth control formulations is the preovulatory 0.5 ng/mL level of P4. The first in this is that a gonadotropin surge the of LH and FSH within the during the preceding follicular an there is to surge. as seen in the of is that of P4. with P4 by the in the circulation is We to by their The of all progestin in the circulation is an of 0.5 of preovulatory P4 of to 200 progesterone to in the phase of the of administered in Full Text PDF PubMed Scopus Google in a a in a birth control of has P4 to that of 200 of P4 of the of administered in Full Text PDF PubMed Scopus Google Scholar). an of 10 of in an circulating P4 at least times its gonadotropin level and above the ng/mL to Leyendecker et al. (7Leyendecker 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; 71: 160-178Crossref PubMed Google Scholar) it no a on LH release We the P4 by that when P4 is very as during the follicular phase, it gonadotropins to and P4 receptors to when P4 to rise, to a relatively low it is to trigger GnRH and cause LH/FSH to be when P4 elevated above the gonadotropin surge as is the with birth control during pregnancy, or the phase, it causes of its or by also GnRH receptors W. G. A. of gonadotropin-releasing hormone in the PubMed Google Scholar), that LH or its surge is not and ovulation is The of P4 as a physiological ovulation trigger be complete its role with an LH surge was by the injection of estradiol in castrated who completely lack any ovarian-derived P4 (7Leyendecker 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; 71: 160-178Crossref PubMed Google Scholar). We believe that a in this is that estradiol not the of only its release into the blood L. The of FSH and regulation and 61: Google Scholar), E2 similar to those in the release of pituitary of estrogen of levels and release in a pituitary J Endocrinol Metab. Scopus Google Scholar). it is to that when estradiol is administered to a LH level in blood because of its in the that E2 the circulation the release of LH into the This the by et al. (7Leyendecker 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; 71: 160-178Crossref PubMed Google Scholar), after the injection of estradiol benzoate in a castrated there was an levels of E2 and LH in the We believe that the LH peak seen on day after injection in their is to the E2 to 200 at which it can no block the release of LH into the the LH surge by E2 the circulation does not the of a LH surge by P4 (7Leyendecker 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; 71: 160-178Crossref PubMed Google Scholar), which that signaling This is by the observation that estradiol induce an LH surge after a LH surge (7Leyendecker 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; 71: 160-178Crossref PubMed Google Scholar). Furthermore, only the gonadotropin surge is with a physiological LH/FSH (7Leyendecker 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; 71: 160-178Crossref PubMed Google Scholar). we believe that together P4 and E2 a to an LH surge, only P4 a on the GnRH signaling We that as a follicle to the of P4 elevation and E2 and also the of their the of periovulatory P4 first the level in the a have a LH E2 first the required to block LH it the first LH which in turn the P4 level by luteinizing granulosa and in a LH surge P4 triggers It be that is the of a physiological LH surge to E2 be to be those in the study by et al. (7Leyendecker 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; 71: 160-178Crossref PubMed Google Scholar), because the LH levels in castrated women are an of higher. ovulation is a in the of the controlled ovarian in in and other of only is the ovulation trigger for the of and rupture of the also it its granulosa to P4 the for is the only by the S. and as an ovulation However, its is because of the relatively high of the ovarian is as an ovulation of because of its lower of ovarian of and and relatively low of are in the of for ovulation. However, are to be on the the A. S. R. S. et dose of in women at high of ovarian a phase 2 randomized controlled PubMed Scopus Google Scholar). The of all is their to the of GnRH which is to be a of the This the phase and the to it with P4. for this for has to be Also, to the of GnRH a of the has been et GnRH in with pituitary hormone a Clin Endocrinol Metab. Scopus Google Scholar). is for in a P4 is the ovulation it a very of which ovulation. experimental and clinical evidence to the preovulatory rise in P4 as a trigger for the flare of ovulatory However, the of the paradigm has been as is often the in and We that this review a to an look at the role of P4 in ovulation. The authors and for their and

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