Orchidectomy unleashes pulsatile luteinizing hormone secretion in the rat

Ellis, Gary B.; Desjardins, Claude

doi:10.1095/biolreprod30.3.619

Cited by 74 publications

(31 citation statements)

References 33 publications

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“…Removal of the testes produces a model with GnRH-mediated elevations of circulating LH. This mechanism of action of the hypothalamic-pituitary-gonadal axis is well defined (Ellis and Desjardins, 1984). Suppression of LH in this model following administration of a GnRH receptor antagonist reflects blockade of the GnRH receptor.…”

Section: Discussionmentioning

confidence: 70%

Biological Characterization of a Novel, Orally Active Small Molecule Gonadotropin-Releasing Hormone (GnRH) Antagonist Using Castrated and Intact Rats

Anderes¹,

Luthin²,

Castillo³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

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Gonadotropin-releasing hormone (GnRH) receptor antagonists have potential in treating numerous hormone-dependent pathologies including cancers of the prostate, breast, and ovary, endometriosis, and fertility disorders. An unmet clinical need exists for an orally available GnRH receptor antagonist. Guided by structure-activity relationships, ligand-based targeted library designs, and biomarker measurements, our discovery efforts have yielded a novel, small molecule GnRH receptor antagonist, 5- [(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-N-(2,4,6-trimethoxyphenyl)-2-furamide (CMPD1). CMPD1 bound with low nanomolar affinities to human, rat, and mouse GnRH receptors (6.0, 3.8, and 2.2 nM, respectively). CMPD1 was more than 100-fold selective for GnRH receptors versus various G-protein-coupled receptors and other enzymes and ion channels. In cells expressing recombinant rat GnRH receptors, CMPD1 was a competitive antagonist of GnRHstimulated increases in extracellular acidification rates in Cytosensor microphysiometer assays. In cells expressing recombinant human GnRH receptors, CMPD1 was a potent inhibitor of GnRH-stimulated total inositol phosphate accumulation. The effects of CMPD1 on circulating levels of luteinizing hormone (LH) and testosterone were studied in castrated and intact male rats, respectively. Intravenous and oral administration of CMPD1 dose dependently suppressed GnRH-mediated elevations of LH in castrated male rats and testosterone in gonadintact male rats. Moreover, CMPD1, when given at 20 mg/kg i.v. to intact male rats, inhibited the elevations of LH and testosterone stimulated by the superagonist of GnRH, [D-Ala 6 , desGly 10 ]GnRH (GnRH-A). These data suggest that CMPD1 is a potent, selective, orally active GnRH receptor antagonist that may have potential application as a therapeutic agent for treating hormone-dependent cancers and diseases.Gonadotropin-releasing hormone (GnRH) is a neuroendocrine decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-ProGly-NH 2 ) synthesized in the neurovascular terminals of the hypothalamus and is secreted in a pulsatile manner directly into the hypophyseal portal blood supply. GnRH selectively binds specific receptors on the membranes of the anterior pituitary gonadotroph cells to stimulate synthesis and release of the gonadotropic hormones [luteinizing hormone (LH) and follicle-stimulating hormone (FSH)]. LH and FSH stimulate gonadal production of sex steroids and gametogenesis, respectively. GnRH, as the primary regulator of LH, is consequently the primary regulator of the sex hormones testosterone and estrogen. GnRH and its analogs have stimulated much interest because of their potential therapeutic benefit in treating sex hormone-dependent diseases such as prostate, ovarian, and breast cancer, as well as endometriosis, uterine fibroids, benign prostate hyperplasia, fertility disorders, and precocious puberty (Huirne and Lambalk, 2001). In contrast to GnRH agonists, which are associated with an initial surge in LH and testosterone ...

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Section: Discussionmentioning

confidence: 70%

Biological Characterization of a Novel, Orally Active Small Molecule Gonadotropin-Releasing Hormone (GnRH) Antagonist Using Castrated and Intact Rats

Anderes¹,

Luthin²,

Castillo³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

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“…Three to five days after catheterization, animals were attached to extension tubing to minimize disruption during sampling. Sequential blood samples were taken at 12-or 6-min intervals between 1300 and 1600, an interval during which episodic LH secretion has been demonstrated in male rats (4,5). Sampling intervals were selected on the basis of insight from earlier studies in rats (6).…”

Section: Methodsmentioning

confidence: 99%

“…Surgical and sampling procedures were performed as described above. However, samples were taken at 6-min intervals to capture the initial increase in LH pulses that occurs following short-term castration (5).…”

Section: Methodsmentioning

confidence: 99%

Hormone secretion in transgenic rats and electrophysiological activity in their gonadotropin releasing-hormone neurons

Hemond

Schmidt

O’Boyle

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…In particular, both steroidal and nonsteroidal feedback effectors are produced by various gonadal compartments. Feedback from the testis is important, because rodents and men with bilateral orchidectomy and/or primary testicular failure exhibit increased serum LH (and FSH) concentrations, defined as a castration response (1)(2)(3)(4)(5). Conversely, the administration of synthetic androgens or testosterone will suppress blood gonadotropin concentrations (6 -13).…”

Section: G Onadal Hormones Participate In Regulating Thementioning

confidence: 99%

Disparate Serum Free Testosterone Concentrations and Degrees of Hypothalamo-Pituitary-Luteinizing Hormone Suppression Are Achieved by ContinuousVersusPulsatile Intravenous Androgen Replacement in Men: A Clinical Experimental Model of Ketoconazole-Induced Reversible Hypoandrogenemia with Controlled Testosterone Add-Back¹

Zwart

Iranmanesh

Veldhuis

1997

The Journal of Clinical Endocrinology & Metabolism

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To investigate the neuroendocrine mechanisms underlying the negative feedback actions of testosterone on both the pulsatile mode of LH release and the entropy or disorderliness of the LH release process, we blocked testicular androgen biosynthesis using oral high dose ketoconazole treatment with concomitant low dose glucocorticoid replacement for 48 h in six healthy young men. Volunteers were then infused iv with saline or a total of 8.0 mg testosterone base over the second 24 h via either a continuous or a pulsatile (90-min boluses) delivery pattern. Discrete peak detection (Cluster analysis) was applied to obtain a model-independent estimate of the frequency of serum LH concentration peaks, maximal and incremental LH peak amplitudes, peak area, and interpeak nadir serum LH concentrations. Approximate entropy was used to quantify the relative orderliness/disorderliness of the LH release process over 24 h. Ketoconazole treatment markedly lowered 24-h mean serum total and free testosterone concentrations (by 17-and 9-fold respectively), and significantly increased LH pulse frequency, maximal LH peak height, and interpeak nadir serum LH concentrations. Continuous iv testosterone add-back increased 24-h pooled serum free testosterone concentrations 3-fold more and concomitantly reduced mean (24-h) serum LH concentrations by at least 2-fold more than pulsatile delivery of the same total daily amount of androgen. Both modes of testosterone infusion suppressed pulsatile LH release, but the effects were distinguishable; namely, treatment with continuous vs. intermittent androgen add-back, respectively, decreased LH pulse frequency and incremental LH pulse amplitude. Ketoconazole treatment alone also significantly increased approximate entropy values, indicating greater disorderliness of LH release during androgen removal. Approximate entropy/orderliness was restored to baseline by continuous, but not pulsatile, iv testosterone replacement.In conclusion, the present novel testosterone add-back clinical experimental paradigm indicates that 1) remarkably different 24-h mean serum free testosterone concentrations can result from continuous vs. pulsatile testosterone delivery into the bloodstream; 2) androgen negative feedback can exert frequency-as well as amplitudedependent suppression of pulsatile LH release; and 3) testosterone is required to maintain an orderly 24-h LH release process in young men. (J Clin Endocrinol Metab 82: 2062-2069, 1997 G ONADAL HORMONES participate in regulating the pulsatile output of the hypothalamo-pituitary-gonadotroph unit in men and women. In particular, both steroidal and nonsteroidal feedback effectors are produced by various gonadal compartments. Feedback from the testis is important, because rodents and men with bilateral orchidectomy and/or primary testicular failure exhibit increased serum LH (and FSH) concentrations, defined as a castration response (1-5). Conversely, the administration of synthetic androgens or testosterone will suppress blood gonadotropin concentrations (6...

show abstract

Orchidectomy unleashes pulsatile luteinizing hormone secretion in the rat

Cited by 74 publications

References 33 publications

Biological Characterization of a Novel, Orally Active Small Molecule Gonadotropin-Releasing Hormone (GnRH) Antagonist Using Castrated and Intact Rats

Biological Characterization of a Novel, Orally Active Small Molecule Gonadotropin-Releasing Hormone (GnRH) Antagonist Using Castrated and Intact Rats

Hormone secretion in transgenic rats and electrophysiological activity in their gonadotropin releasing-hormone neurons

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