Here's more info on GnRH
Gonadotropin-releasing hormone (GnRH), also known as Luteinizing-hormone-releasing hormone (LHRH) , is a peptide hormone responsible for the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. Gonadotropin-releasing hormone is created and released from within the hypothalamus.[1] *GnRH has the following amino acid structure: pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2. *GnRH plays an instrumental role in initiating pubertal changes, and depending on various other variables (physical environment, pulse amplitude, and pulse frequency) is responsible for many other functions within the body, including follicle growth, spermatogenesis in males, and ovulation in females. *Lower-frequency GnRH pulsatility lead to FSH release, whereas higher-frequency GnRH pulsatility stimulates LH release.[2]
*
Because of its short circulating half-life, GnRH therapy applied with a portable computerized infusion pump is the priary choice for long-term treatment of hypogonadism and fertility issues. *In a study by Skarin, et al, a 23-year-old male was successfully treated for hypogonadism with chronic treatment with GnRH:*
Spermatogenesis became close to normal and the subject 's wife became pregnant after 181 days of treatment. The prolonged treatment with the small infusion pump was well accepted and did not interfere with the patient's daily life activities. Thus, chronic pulsatile low dose GnRH treatment can restore normal pituitary-gonadal function in idiopathic male hypogonadotropic hypogonadism.[3]
*
As noted earlier, frequency and amplitude of GnRH pulses is the primary determinant of effect, both acute and long-term. *Bhasin et al demonstrate that "superactive analogues of gonadotrophin releasing hormone and testosterone, when administered together, synergistically inhibit gonadotrophin secretion and spermatogenesis in the rat."[4] When applied over the short-term, GnRH (with or *without testosterone administered adjunctly) resulted in initial stimulation with progressive decline over time in LH, FSH, and testosterone levels to below baseline in approximately ten days:
Daily administration of both 10 and 100 ***956;g of GnRH-A alone resulted in an early phase of stimulation followed by progressive decline in LH, FSH and testosterone to levels below baseline by day 10 despite continued administration of GnRH-A. Addition of testosterone to 10 ***956;g of GnRH-A resulted in hormonal responses identical to those seen with GnRH-A alone. Combined treatment of testosterone with 100 ***956;g of GnRH-A did not blunt the peak LH and FSH responses on day 2, but resulted in significantly lower LH (mean integrated responses: 187 ± 30 vs. 234 ± 42 mIU-d/ml) and FSH (mean integrated responses: 20·6 ± 3·3 vs. 32·8 ± 4·2 mIU-d/ml) responses from days 3 to 11. By day 11, all subjects receiving combined treatment (GnRH-A 100 ***956;g+testosterone oenanthate) had undetectable serum FSH levels....We conclude that addition of a suppressive dose of testosterone to an appropriate dose of GnRN-A significantly enhances gonadotrophin suppression by GnRH-A in the human male. Combined use of testosterone and GnRH-A might be of importance in the development of a male contraceptive to achieve the desired suppression of spermatogenesis while avoiding androgen deficiency.[4]
*
Counis et al do a good job of summarizing the various functions and coding mechanisms of GnRH and the systems it is involved in:
Brain control of the reproductive system is mediated through hypothalamic gonadotropin-releasing hormone (GnRH) which activates specific receptors (GnRHR) present at the surface of the pituitary gonadotropes to trigger secretion of the two gonadotropins LH and FSH. A unique feature of this system is the high dependence on the secretion mode of GnRH, which is basically pulsatile but undergoes considerable fluctuations in pulse frequency pattern in response to endogenous or external factors. [5]
*
Krsmanovic et al emphasize the resilience of the endogenous GnRH triggering system as a crucial system for most phases of life:*
The coexistence of multiple regulatory mechanisms for pulsatile GnRH secretion provides a high degree of redundancy in maintaining this crucial component of the mammalian reproductive process. These studies provide insights into the basic cellular and molecular mechanisms
involved in GnRH neuronal function.[6]
*
Garrel et al's "data suggest that the cAMP/PKA signaling pathway is preferentially recruited under sustained GnRH stimulation in vivo during proestrus, allowing the expression of a specific set of PKA-regulated proteins, including NOS1, in gonadotroph cells," which further highlights the integral nature of GnRH to the reproductive system in particular.[7]
In a study performed on healthy young men in a nutrient-deprived state, Aloi et al concluded that nutrient deprivation decreases endogenous GnRH output and that further, exogenous GnRH "rescue...hypogonadism."
*
Administration of a submaximal dose of exogenous GnRH (10 microg, i.v.) at the end of the fasting interval revealed statistically identical LH release in the three study groups, suggesting that pituitary responsiveness to GnRH was unchanged in this paradigm. In summary, a pulsatile iv GnRH infusion in young men averts completely the fasting-induced decline in LH secretory burst mass/amplitude and frequency, reinstates serum total and free testosterone concentrations, and restores the mesor of LH's nyctohemeral rhythmicity and the approximate entropy of LH release. Rescue of hypogonadism by pulsatile GnRH stimuli supports the thesis that nutrient withdrawal decreases the output of the human hypothalamic GnRH burst generator.[8]
*
Iranmanesh et al tentatively conclude that GnRH's decreased effect on FSH and LH output in men with age is related to the decreased sex steroid presence, namely testosterone:
In the face of eugonadal concentrations of total, bioavailable, and free T, young and older men exhibit remarkably similar LH responses to a 300-fold dose range of exogenous GnRH. Accordingly, previously reported disparate effects of age on GnRH action may reflect in part age-discrepant sex-steroid milieus.[9]
Finally, the therapeutic and treatment potential of exogenous GnRH treatment is highlighted well in the following abstract from Tsutsumi and Webster:
Fertility is impaired when GnRH pulsatility is inhibited by chronic malnutrition, excessive caloric expenditure, or aging. A number of reproductive disorders in women with including hypogonadotropic hypogonadism, hypothlamic amenorrhea, hyperprolactinemia and polycystic ovary syndrome (PCOS) are also associated with disruption of the normal pulsatile GnRH secretion.[10]
*
Citations:
[1] Campbell RE, Gaidamaka G, Han SK, Herbison AE. "Dendro-dendritic bundling and shared synapses between gonadotropin-releasing hormone neurons". Proc. Natl. Acad. Sci. U.S.A..
[2] Brown RM. An introduction to Neuroendocrinology. Cambridge, UK: Cambridge University Press, 1994.
[3]G. Skarin, SJ Nillius, L. Wibell, and L. Wide. Chronic Pulsatile Low Dose GnRH Therapy for Induction of Testosterone Production and Spermatogenesis in a Man with Secondary Hypogonadotropic Hypogonadism. Journal of Clinical Endocrinology & Metabolism Vol. 55, No. 4 723-726.
[4]S. Bhasin, D. Heber, B. Steiner, M. Peterson, B. Blaisch, L. A. Campfield, R. S. Swerdloff, Hormonal effects of GnRH agonist in the human male: Testosterone enhances gonadotrophin suppression induced by GnRH agonist. *Clinical Endocrinology, Volume 20 Issue 2, Pages 119 - 128.
[5]Counis R, Garrel G, Laverriere JN, Simon V, Bleux C, Magre S, Cohen-Tannoudji J. *Folia. *The GnRH receptor and the response of gonadotrope cells to GnRH pulse frequency code. A story of an atypical adaptation of cell function relying on a lack of receptor homologous desensitization. *Histochem Cytobiol. 2009;47(5):S81-7.
[6]Krsmanovic LZ, Hu L, Leung PK, Feng H, Catt KJ. The hypothalamic GnRH pulse generator: multiple regulatory mechanisms. Trends Endocrinol Metab. 2009 Oct;20(8):402-8.
[7]Garrel G, Simon V, Thieulant ML, Cayla X, Garcia A, Counis R, Cohen-Tannoudji J. *Sustained Gonadotropin-Releasing Hormone Stimulation Mobilizes the cAMP/PKA Pathway to Induce Nitric Oxide Synthase I Expression in Rat Pituitary Cells In Vitro and In Vivo at Proestrus. *Biol Reprod. 2010 Feb 24.
[8] Aloi JA, Bergendahl M, Iranmanesh A, Veldhuis JD. *Pulsatile intravenous gonadotropin-releasing hormone administration averts fasting-induced hypogonadotropism and hypoandrogenemia in healthy, normal weight men. *J Clin Endocrinol Metab. 1997 May;82(5):1543-8.
[9]Iranmanesh A, Mulligan T, Veldhuis JD. Age in Men Does Not Determine Gonadotropin-Releasing Hormone's Dose-Dependent Stimulation of Luteinizing Hormone Secretion under an Exogenous Testosterone Clamp. J Clin Endocrinol Metab. 2010 Mar 31.
[10]Tsutsumi R, Webster NJ. Endocr J. *GnRH pulsatility, the pituitary response and reproductive dysfunction. 2009 Dec;56(6):729-37.
*
