Differential Suppression of Follicle-Stimulating Hormone and Luteinizing Hormone Secretion in vivo by a Gonadotropin-Releasing Hormone Antagonist

Grady, Rosemary R.; Shin, Lauren; Charlesworth, M. Cristine; Cohen-Becker, Ilene R.; Smith, Matthew J.; Rivier, Catherine; Rivier, J.; Vale, Wylie; Schwartz, Neena B.

doi:10.1159/000124081

Cited by 60 publications

(25 citation statements)

References 14 publications

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“…These observations support the contention that FSH secretion may be less dependent on GnRH than LH, utilizing evidence that GnRH antagonists in vivo lower serum LH more than FSH, whether given to gonadectomized rats or intact rats at metestrus and proestrus [23,24]. In dispersed cell cultures the effect of Antag on LH and FSH is equal when given against a back ground of GnRH stimulation [8], but others have seen discre pancies using pituitary fragments [10], A GnRH antagonist si milar to the one used in the present experiments causes a drop in bioassayable FSH when given to male patients [25], while immunoassayable FSH shows the minor drop we have seen in rats [8,23]. Since we did not measure bioassayable FSH we do not know whether the differences in FSH:LH ratios seen in this study as a function of Antag are partly due to failure of the RIA to pick up changes in bioactive FSH.…”

Section: Discussionsupporting

confidence: 74%

“…Not only was a paradoxical suppression of BSR caused by the Antag, but the suppressive effect was more marked for LH se cretion rates than FSH, and more effective in pituitaries from proestrous rats than from metestrous animals. These results ob tained with perifused pituitary fragments are discussed in light of previous reports [8][9][10] of suppression by such antagonists in dispersed pituitary cell cultures and after in vivo administration. Implications for regulation of gonadotropin secretion during the estrous cycle are also considered.…”

supporting

confidence: 65%

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Suppression of Basal and GnRH-Stimulated Gonadotropin Secretion Rate in vitro by GnRH Antagonist: Differential Effects on Metestrous and Proestrous Pituitaries

Hiatt¹,

Schwartz²

1989

Neuroendocrinology

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LH and FSH basal secretion rates (BSR) in vitro of pituitary fragments from female rats at metestrus or following ovariectomy parallel changes seen in serum gonadotropins. These findings led us to suspect that in vitro BSR of fragments depended on prior exposure to GnRH or lingering GnRH in the culture. We compared pituitaries removed from rats in two cycle stages, proestrus (PRO) and metestrus (MET). Rats were given a single injection of a potent GnRH antagonist, Antag – WY 45760 -[Ac-β(2)-D-Nal¹, 4-F-D-Phe², D-Trp³, D-Arg⁶]-LHRH, or oil prior to sacrifice at 09.00 h on PRO or MET. Pituitary fragments were perifused for 8 h. To test the effects of Antag in vitro some pituitaries from oil-injected rats were perifused with medium containing 1 µM Antag for the first 4 h. Starting at 5 hall chambers received hourly 10-min pulses of 1 µM GnRH. In PRO rats Antag injection in vivo lowered LH BSR to 50% and FSH to 70% of oil-treated controls. Surprisingly, Antag administered in vitro suppressed LH BSR to 30% and FSH to 55% of controls. In pituitaries from MET rats, BSR of LH and FSH were 20 and 70% of control PRO values and were unaffected by Antag treatment in vivo or in vitro. In PRO pituitaries LH and FSH responses to the first GnRH pulse were blunted by Antag in vivo but responses to subsequent pulses were unaffected; MET responses were not different from controls. In vitro Antag suppressed GnRH-stimulated release to 10–20% of controls at both cycle stages. The lower effectiveness of Antag in suppressing FSH has not been shown previously in vitro, but is consistent with in vivo studies in this laboratory. The relative ineffectiveness of the Antag in lowering BSR in MET compared to PRO pituitary fragments suggests that there is less GnRH present, consonant with data showing lower in vivo GnRH release and pituitary receptor levels in MET rats. Our findings suggest that pituitary fragments retain an appreciable amount of endogenous GnRH that stimulates apparent ‘basal’ gonadotropin secretion and that the concept of basal in vitro secretion rate in fragments needs reexamination.

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Section: Discussionsupporting

confidence: 74%

supporting

confidence: 65%

Suppression of Basal and GnRH-Stimulated Gonadotropin Secretion Rate in vitro by GnRH Antagonist: Differential Effects on Metestrous and Proestrous Pituitaries

Hiatt¹,

Schwartz²

1989

Neuroendocrinology

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“…The FSH response to GnRH suppression in vivo is known to be more sluggish than the LH response. Thus, Grady et al (20) did not observe any changes in FSH levels until 12 h after suppression by a GnRH antagonist, whereas LH levels showed a dose-dependant 20 -50% decrease by 2 h. As our clamp lasted for 6 h, glycemiainduced suppression of GnRH could well be responsible for the selective decrease in LH concentration, leaving FSH levels unaffected.…”

Section: Discussionmentioning

confidence: 45%

Hypoglycemia, But Not Insulin, Acutely Decreases LH and T Secretion in Men

Oltmanns¹,

Fruehwald‐Schultes²,

Kern³

et al. 2001

The Journal of Clinical Endocrinology & Metabolism

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Hypoandrogenemia is frequently associated with hyperinsulinemia in men with the metabolic syndrome. We questioned whether insulin or changes in blood glucose levels influence pituitary gonadotropin secretion or testicular steroidogenesis in healthy men. Also, the relationship between hypoglycemia-induced activation of the hypothalamus-pituitaryadrenal axis and altered steroidogenesis was examined.Euglycemic and hypoglycemic clamp experiments were performed in 30 healthy men over a period of 6 h. Half of the men were infused with insulin at a rate of 1.5 mU/min⅐kg; the other half were infused at a rate of 15.0 mU/min⅐kg. Plasma glucose was held constant during a euglycemic clamp session and was decreased stepwise in a hypoglycemic clamp session.LH and total/free T concentrations decreased under hypoglycemic conditions regardless of the rate of insulin infusion. With euglycemic conditions, LH and T levels remained un- H YPERINSULINEMIA AND increased glucose concentrations are both negatively correlated with total and free T levels in men (1). Although it has been suggested that low levels of T play a role in the development of insulin resistance and type 2 diabetes (2), the cause of the decrease in T remains obscure. Insulin-induced hypoglycemia is known to suppress the pulsatile secretion of LH in rats and sheep (3-6) as well as the pulse generator frequency of hypothalamic GnRH in rats and rhesus monkeys (3, 7). In men, insulin-induced hypoglycemia was followed by a rapid decrease in serum T levels (8). However, it remains unclear whether this is an effect of insulin or of changes in blood glucose levels.Additionally, decreased T levels in patients with the metabolic syndrome could be a direct consequence of perturbed function of the hypothalamic-pituitary-adrenal (HPA) axis (9, 10). It is known that a counterregulatory response of the HPA axis, including cortisol release, to hypoglycemia begins at normoglycemic ranges in poorly controlled type 2 diabetes (11), and the epinephrine response during hypoglycemia is enhanced (12). In vitro, glucocorticoids caused a decrease in LH and an increase in FSH in rat pituitary cells (13,14), and ACTH directly reduced T secretion in testicular cells of guinea pigs (15). In men, elevation of cortisol levels resulting from insulin-induced hypoglycemia or administration of hydrocortisone was followed by a rapid decrease in serum T levels without accompanying changes in LH secretion (8).This study determined whether insulin, or rather hypoglycemia, suppresses pituitary gonadotropin secretion and testicular steroidogenesis in men. Furthermore, it was examined to which extent these effects coincide with alterations of pituitary ACTH and adrenal dehydroepiandrosterone (DHEA) as well as cortisol release. Subjects and Methods SubjectsThirty young healthy men participated in the experiments. Exclusion criteria were chronic or acute illness, current medication of any kind, smoking, alcohol or drug abuse, adiposity, and diabetes or hypertension in first degree relatives. Each volunteer ...

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“…Antagonists of LH-RH have been originally developed for contraception [1][2][3][4][5][26][27][28][29][30]. Other uses, such as treatment of endometriosis and cancer therapy were later proposed [ 1,3,4,26,27].…”

Section: Discussionmentioning

confidence: 99%

Recovery of Pituitary-Gonadal Function in Male and Female Rats after Prolonged Administration of a Potent Antagonist of Luteinizing Hormone-Releasing Hormone (SB-75)

Bokser¹,

Srkalović

Szepesházi

1991

Neuroendocrinology

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The reversibility of the antifertility effects induced by long-term administration of the LH-RH antagonistic analog [Ac-D-Nal(2)’, D-Phe(4Cl)², D-Pal(3)³, D-Cit⁶, D-Ala¹⁰]-LH-RH (SB-75) was investigated in male and female rats. Male rats were implanted with osmotic minipumps releasing 50 µg of SB-75/day for 60 days. The control rats were implanted with minipumps containing only vehicle. The treatment with the antagonist caused a significant decrease in the weights of the testes, seminal vesicles and ventral prostates (p < 0.01) and reduced serum LH and testosterone levels (p < 0.01). The histology of the testes from the treated rats showed that spermatogenesis was totally depressed. No mature elongated or round spermatids were found in the seminiferous tubules, spermatocytes being the most advanced germ cell form in 100% of the testicular tubules. These changes indicate that a total spermatogenetic arrest occurred in the treated animals. Ninety days after cessation of treatment with the LH-RH antagonist, there was a complete recovery of the weights of the testes, seminal vesicles and ventral prostates and LH and testosterone returned to control levels. Histological studies revealed a complete recovery of spermatogenesis, with 99.2% of seminiferous tubules containing mature elongated spermatids. Immediately after the discontinuation of treatment with SB-75, a significant down-regulation of the pituitary LH-RH receptors was found, but 90 days later, this phenomenon was completely reversed. Female rats were injected every 3 weeks for 6 weeks with SB-75 microcapsules, at a dose calculated to release 27 µg/day of the antagonist. The treatment with SB-75 disrupted the normal estrous cycle. Body weights were not affected, but ovarian and uterine weights were significantly decreased (p < 0.01 and p < 0.05, respectively) in the animals treated with the antagonist. Treated rats had significantly lower LH (p < 0.05) and estradiol (p < 0.01) levels than controls. The histology of the ovaries from the SB-75-treated group showed that the ratio of small to large maturing follicles increased significantly (p < 0.01) and corpora lutea were absent. Two months after the cessation of treatment, a complete recovery in the organ weights and in hormonal levels was observed and no histological differences were found between the ovaries in treated and untreated rats. These collective results indicate that the suppression of gonadal function induced by the treatment with LH-RH antagonist SB-75 is completely reversible both in male and female animals. These findings should facilitate the use of modern LH-RH antagonists, free of side effects, for the treatment of hormone-sensitive cancers, gynecologic conditions and other disorders where inhibition of the pituitary-gonadal axis is desirable.

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Differential Suppression of Follicle-Stimulating Hormone and Luteinizing Hormone Secretion in vivo by a Gonadotropin-Releasing Hormone Antagonist

Cited by 60 publications

References 14 publications

Suppression of Basal and GnRH-Stimulated Gonadotropin Secretion Rate in vitro by GnRH Antagonist: Differential Effects on Metestrous and Proestrous Pituitaries

Suppression of Basal and GnRH-Stimulated Gonadotropin Secretion Rate in vitro by GnRH Antagonist: Differential Effects on Metestrous and Proestrous Pituitaries

Hypoglycemia, But Not Insulin, Acutely Decreases LH and T Secretion in Men

Recovery of Pituitary-Gonadal Function in Male and Female Rats after Prolonged Administration of a Potent Antagonist of Luteinizing Hormone-Releasing Hormone (SB-75)

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