Gonadotrophin surge-inhibiting/attenuating factor governs luteinizing hormone secretion during the ovarian cycle: physiology and pathology.
The stabilization of low luteinizing hormone (LH) concentrations during the period of the ovarian cycle preceding the mid-cycle LH surge seems to be of importance for embryo viability and survival. Several studies have stressed the importance of the timely excess of threshold levels of LH for optimal oocyte quality: LH already initiates the resumption of meiosis when a relatively low threshold level is reached, whereas a further outburst of LH release is necessary to reach the threshold level to induce ovulation. Hence, the mechanism of LH release should have the ability, on the one hand, to limit the LH secretion rate, and on the other, to allow an increased secretion rate, as during the LH surge. The functional antagonistic coupling of gonadotrophin-releasing hormone (GnRH) and the ovarian protein gonadotrophin surge-inhibiting factor or -attenuating factor (GnSIF/AF) provides such a mode of action for the control of LH concentration during the ovarian cycle. One of the important regulatory steps in this process is the de-novo synthesis of the so far unidentified pituitary proteins induced by GnRH. The induction of these proteins is a prerequisite for the increase in the rate of LH release. Because their synthesis is a time-consuming process, the effect becomes visible in the typical biphasic pituitary LH responses to the pulsatile or continuous administration of GnRH: initially low, with an increase after some time. This phenomenon is also known as the GnRH self-priming action. It is assumed that the synthesis of these self-priming-associated proteins is necessary to eliminate the inhibitory effect of GnSIF/AF. GnSIF/AF eliminates the effect of self-priming by neutralizing the biological activity of the pituitary proteins, which are responsible for the increased rate of LH release. Thus, the pituitary gland is kept in a GnRH-hyporesponsive state. The major advantage of such a slow protein synthesis-dependent regulatory mechanism is that it prevents sudden increases in the LH secretion rate in response to GnRH. Thus it stabilizes low LH concentrations to prevent the premature reinitiation of meiosis. However, the enhanced secretion of GnRH and/or the suppressed release or action of GnSIF/AF may finally lead to the restoration of the intrinsic LH responsiveness of the gonadotrophs at the start of the mid-cycle LH surge. The antagonistic interaction between GnRH and GnSIF/AF, and its implication in the control of LH release under physiological and pathological conditions, are discussed.
de Koning
J
J
Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratory, University of Leiden, The Netherlands.
D000818:Animals; D005260:Female; D005498:Follicular Phase / Q000187:drug effects* / Q000502:physiology*; D042341:Gonadal Hormones; D012739:Gonadal Steroid Hormones / Q000494:pharmacology* / Q000502:physiology; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D007986:Luteinizing Hormone / Q000378:metabolism*; D008597:Menstrual Cycle / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D011085:Polycystic Ovary Syndrome / Q000503:physiopathology; D011506:Proteins / Q000494:pharmacology* / Q000502:physiology
D042341:Gonadal Hormones; D012739:Gonadal Steroid Hormones; D011506:Proteins; C080538:attenuin; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone