Is GnRH Reduced at the Midcycle Surge in the Human?

Recent studies indicate that the midcycle gonadotropin surge in the human occurs without an increase in hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency. In addition, previous studies employing a GnRH antagonist to provide a semiquantitative estimate of endogenous GnRH secretion suggest that the overall amount of GnRH secreted is decreased at the time of the surge. To investigate the hypothesis that a normal gonadotropin surge can be generated in the human with a decreased amount of GnRH at the midcycle, 7 GnRH-deficient subjects underwent two cycles of a physiologic regimen of intravenous pulsatile GnRH therapy. In the control cycle, 75 ng/kg/bolus of GnRH, a dose known to be sufficient for folliculogenesis, was administered throughout the cycle, using physiological frequencies. In a second cycle, the bolus dose of GnRH was decreased by one-half log order to 25 ng/kg just prior to the luteinizing hormone surge and returned to 75 ng/kg after documented ovulation. All cycles were ovulatory. The peak luteinizing hormone level (77.4±9.7 vs. 67.5±17.6 IU/l) did not differ between the control and decreased GnRH cycles. There was no difference in the peak serum estradiol level (475.8±144.1 vs. 493.2±93.0 pg/ml), follicular phase length (15.0±1.3 vs. 14.8±0.6 days), or progesterone level (22.4±5.1 vs. 34.8±5.7 ng/ml) on day 6 of the luteal phase in the control and decreased GnRH cycles, respectively. Three pregnancies were achieved in each of the control and reduced GnRH cycles. We conclude that a decreased overall amount of GnRH generates a normal midcycle gonadotropin surge and has no significant impact on luteal phase adequacy or fertility. These results provide further evidence that a decrease in endogenous hypothalamic GnRH secretion may occur at the midcycle in normal women. This study also provides evidence that the GnRH requirements for normal follicular and luteal phase dynamics may well be greater than those required for generation of a normal midcycle gonadotropin surge and ovulation in women.

[1]  S. Moenter,et al.  Gonadotropin-releasing hormone requirements for ovulation. , 1997, Biology of reproduction.

[2]  V. Padmanabhan,et al.  How much of the gonadotropin-releasing hormone (GnRH) surge is required for generation of the luteinizing hormone surge in the ewe? Duration of the endogenous GnRH signal. , 1996, Endocrinology.

[3]  D. Schoenfeld,et al.  The midcycle gonadotropin surge in normal women occurs in the face of an unchanging gonadotropin-releasing hormone pulse frequency. , 1994, The Journal of clinical endocrinology and metabolism.

[4]  D. Schoenfeld,et al.  Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[5]  B. Charbonnel,et al.  Effect of administration of a gonadotropin-releasing hormone (GnRH) antagonist (Nal-Glu) during the periovulatory period: the luteinizing hormone surge requires secretion of GnRH. , 1994, The Journal of clinical endocrinology and metabolism.

[6]  K. Pau,et al.  Preovulatory gonadotropin-releasing hormone surge in ovarian-intact rhesus macaques. , 1993, Endocrinology.

[7]  I. Clarke.  Variable patterns of gonadotropin-releasing hormone secretion during the estrogen-induced luteinizing hormone surge in ovariectomized ewes. , 1993, Endocrinology.

[8]  M. Ferin,et al.  A surge of gonadotropin-releasing hormone accompanies the estradiol-induced gonadotropin surge in the rhesus monkey. , 1992, Endocrinology.

[9]  W. Vale,et al.  Abrogation by a potent gonadotropin-releasing hormone antagonist of the estrogen/progesterone-stimulated surge-like release of luteinizing hormone and follicle-stimulating hormone in postmenopausal women. , 1992, The Journal of clinical endocrinology and metabolism.

[10]  S. Moenter,et al.  Dynamics of gonadotropin-releasing hormone (GnRH) secretion during the GnRH surge: insights into the mechanism of GnRH surge induction. , 1992, Endocrinology.

[11]  S. Moenter,et al.  Pattern of gonadotropin-releasing hormone (GnRH) secretion leading up to ovulation in the ewe: existence of a preovulatory GnRH surge. , 1991, Endocrinology.

[12]  W. Crowley,et al.  Clinical review 15: Management of ovulatory disorders with pulsatile gonadotropin-releasing hormone. , 1990, The Journal of clinical endocrinology and metabolism.

[13]  W. Crowley,et al.  Utility of free alpha-subunit as an alternative neuroendocrine marker of gonadotropin-releasing hormone (GnRH) stimulation of the gonadotroph in the human: evidence from normal and GnRH-deficient men. , 1990, The Journal of clinical endocrinology and metabolism.

[14]  S. Yen,et al.  RELATIVE CHANGES IN LH PULSATILITY DURING THE MENSTRUAL CYCLE: USING DATA FROM HYPOGONADAL WOMEN AS A REFERENCE POINT , 1990, Clinical endocrinology.

[15]  W. Chin,et al.  Molecular biology of the pituitary gonadotropins. , 1990, Endocrine reviews.

[16]  A. Caraty,et al.  Biphasic response in the secretion of gonadotrophin-releasing hormone in ovariectomized ewes injected with oestradiol. , 1989, The Journal of endocrinology.

[17]  C. Flamigni,et al.  Evidence for a specific role of GnRH pulse frequency in the control of the human menstrual cycle. , 1989, The American journal of physiology.

[18]  A. Murdoch,et al.  Is changing hypothalamic activity important for control of ovulation. , 1987, British medical journal.

[19]  W. Crowley,et al.  Characterization of the physiological pattern of episodic gonadotropin secretion throughout the human menstrual cycle. , 1986, The Journal of clinical endocrinology and metabolism.

[20]  P. Steele,et al.  Activity of gonadotropin-releasing hormone neurons during the preovulatory luteinizing hormone surge. , 1986, Fertility and sterility.

[21]  D. Bangsberg,et al.  In vivo gonadotropin-releasing hormone release and serum luteinizing hormone measurements in ovariectomized, estrogen-treated rhesus macaques. , 1985, Endocrinology.

[22]  J. Marshall,et al.  Pulsatile gonadotropin secretion during the human menstrual cycle: evidence for altered frequency of gonadotropin-releasing hormone secretion. , 1984, The Journal of clinical endocrinology and metabolism.

[23]  J. Butler,et al.  Neuroendocrine regulation of the corpus luteum in the human. Evidence for pulsatile progesterone secretion. , 1984, The Journal of clinical investigation.

[24]  D. Baird,et al.  PULSATILE RELEASE OF LH AND OESTRADIOL DURING THE PERIOVULATORY PERIOD IN WOMEN , 1984, Clinical Endocrinology.

[25]  T. Cicero,et al.  Morphine-induced supersensitivity to the effects of naloxone on luteinizing hormone secretion in the male rat. , 1983, The Journal of pharmacology and experimental therapeutics.

[26]  H. Spies,et al.  Reinitiation of ovulatory cycles in pituitary stalk-sectioned rhesus monkeys: evidence for a specific hypothalamic message for the preovulatory release of luteinizing hormone. , 1982, Endocrinology.

[27]  J. Levine,et al.  Simultaneous measurement of luteinizing hormone-releasing hormone and luteinizing hormone release in unanesthetized, ovariectomized sheep. , 1982, Endocrinology.

[28]  J. Levine,et al.  Luteinizing hormone-releasing hormone release during the rat estrous cycle and after ovariectomy, as estimated with push-pull cannulae. , 1982, Endocrinology.

[29]  H. Spies,et al.  Gonadotropin-releasing hormone receptor binding and pituitary responsiveness in estradiol-primed monkeys. , 1982, Science.

[30]  H. Spies,et al.  Gonadotropin-releasing hormone receptor binding and pituitary responsiveness in estradiol-primed monkeys. , 1981, Science.

[31]  L. Wildt,et al.  Estradiol as a gonadotropin releasing hormone in the rhesus monkey. , 1981, Endocrinology.

[32]  L. Wildt,et al.  Control of the rhesus monkey menstrual cycle: permissive role of hypothalamic gonadotropin-releasing hormone. , 1980, Science.

[33]  J. Marshall,et al.  Pituitary gonadotropin-releasing hormone receptors during the rat estrous cycle. , 1980, Science.

[34]  W. Crowley,et al.  Simulation of the normal menstrual cycle in Kallman's syndrome by pulsatile administration of luteinizing hormone-releasing hormone (LHRH). , 1980, The Journal of clinical endocrinology and metabolism.

[35]  W. Crowley,et al.  The biologic activity of a potent analogue of gonadotropin-releasing hormone in normal and hypogonadotropic men. , 1980, The New England journal of medicine.

[36]  D. Hess,et al.  On the sites of the negative and positive feedback actions of estradiol in the control of gonadotropin secretion in the rhesus monkey. , 1978, Endocrinology.

[37]  D. Sarkar,et al.  Gonadotropin-releasing hormone surge in pro-oestrous rats , 1976, Nature.

[38]  S. Araki,et al.  Pituitary stalk portal blood collection in rhesus monkeys: evidence for pulsatile release of gonadotropin-releasing hormone (GnRH). , 1976, Endocrinology.

[39]  R. Jaffe,et al.  Estradiol augmentation of pituitary responsiveness to gonadotropin-releasing hormone in women. , 1974, The Journal of clinical endocrinology and metabolism.

[40]  A. Scialli.  Goodman and Gilman's the pharmacologic basis of therapeutics , 1991 .

[41]  R. Clayton,et al.  Gonadotrophin-releasing hormone: its actions and receptors. , 1989, The Journal of endocrinology.

[42]  N. Wayne,et al.  Importance of pituitary and neural actions of estradiol in induction of the luteinizing hormone surge in the ewe. , 1988, Neuroendocrinology.

[43]  I. Clarke,et al.  GnRH secretion throughout the ovine estrous cycle. , 1987, Neuroendocrinology.

[44]  W. Crowley,et al.  Intravenous administration of pulsatile gonadotropin-releasing hormone in hypothalamic amenorrhea: effects of dosage. , 1986, The Journal of clinical endocrinology and metabolism.

[45]  M. Ferin,et al.  The hypothalamic control of the menstrual cycle and the role of endogenous opioid peptides. , 1984, Recent progress in hormone research.

[46]  G. Hodgen,et al.  Folliculogenesis in the primate ovarian cycle. , 1981, Endocrine reviews.

[47]  M. Ferin,et al.  Estrogen-induced gonadotropin surges in female rhesus monkeys after pituitary stalk section. , 1979, Endocrinology.

[48]  B. Lasley,et al.  The effects of estrogen and progesterone on the functional capacity of the gonadotrophs. , 1975, The Journal of clinical endocrinology and metabolism.

[49]  S. Yen,et al.  Direct evidence of estrogen modulation of pituitary sensitivity to luteinizing hormone-releasing factor during the menstrual cycle. , 1975, The Journal of clinical investigation.