Potential diagnostic utility of intermittent administration of short-acting gonadotropin-releasing hormone agonist in gonadotropin deficiency

Zimmer, C; Ehrmann, David A.; Rosenfield, Robert L.

doi:10.1016/j.fertnstert.2010.04.019

Cited by 20 publications

(8 citation statements)

References 29 publications

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“…In consultation with our endocrinologists, we determined that both assays are analytically and clinically equivalent, and the existing reference intervals established by the classic RIA method developed in our institution and published by our endocrinologists in the literature (34)(35)(36)(37)(38) are transferrable to the LC-MS/MS assay. The bias of this assay at the LOQ level was also not assessed, since there are currently no low E 2 reference materials available, and bias study by spiking standards and serially diluting up to 200-fold could result in large variation at the low end.…”

Section: Limitationsmentioning

confidence: 99%

High-Sensitivity Micro LC-MS/MS Assay for Serum Estradiol without Derivatization

Leung

Bridgman

et al. 2016

The Journal of Applied Laboratory Medicine

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Background: There are considerable demands to accurately measure estradiol (E 2 ) at low concentrations (<20 pg/mL) in postmenopausal women, men, pediatric patients, and patients receiving breast cancer treatment. Most current high-sensitivity LC-MS/MS E 2 methods require large sample volumes and involve complex sample preparations with dansyl chloride derivatization. Our study aims to develop a high-sensitivity, underivatized method using micro LC-MS/MS to reliably measure E 2 concentrations below 5 pg/mL by the use of low sample volume. Methods: A total of 290 μL of sample was mixed with internal standard (IS), E 2 -d4, and extracted with a mixture of hexane/ethyl acetate (90/10) (v/v). After extraction, sample was separated by Eksigent Ekspert™ micro LC 200 system with a flow rate of 35 μL/min in a total run time of 3.5 min and detected by SCIEX QTRAP 6500 mass spectrometer in a negative mode using transitions: 271/145 (quantifier) and 271/143 (qualifier). In this method, it was crucial to use HPLC columns with stability at a pH >10. Results:The validation study demonstrated broad linear ranges (3.0 -820.0 pg/mL) with r 2 > 0.999. Total precision was below 15% at all QC levels, and limit of quantification (LOQ) was 3.0 pg/mL. Our method showed good correlation with E 2 RIA (r 2 = 0.96, bias = −1.0 pg/mL) and modest correlation with E 2 Roche Cobas automated immunoassay (r 2 = 0.86, bias = 6.0 pg/mL). Conclusions:In conclusion, we developed and validated a routinely applicable micro LC-MS/MS method without derivatization for E 2 in blood samples with an LOQ of 3.0 pg/mL. IMPACT STATEMENTPatients under assessment of puberty delays, pubertal growth, gynecomastia, and efficiency of aromatase inhibitor (AI) treatment will benefit from the information presented here. Evidence presented on high-sensitivity LC-MS/MS assay for E 2 will allow better characterization of E 2 concentration in blood in the low measurement range. Knowledge in the field of LC-MS/MS method development for E 2 will be advanced by the information presented.

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Section: Limitationsmentioning

confidence: 99%

High-Sensitivity Micro LC-MS/MS Assay for Serum Estradiol without Derivatization

Leung

Bridgman

et al. 2016

The Journal of Applied Laboratory Medicine

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“…This important observation led Plant and colleagues [64,65,66,67,68]to employ a standard GnRH priming protocol in their studies where gonadotropin secretion is measured in response to various factors. Studies have also been conducted in men exhibiting gonadotropin deficiency, and in the absence of any pituitary defects it has been reported that GnRH priming improves gonadotropin secretion [69,70]. More detailed studies in human male patients are generally lacking because males who are diagnosed with GnRH and gonadotropin deficiency often exhibit pituitary and testicular defects [71].…”

Section: Kiss1r Displays Basal Constitutive Signaling and Kp-independmentioning

confidence: 99%

KISS1R: Hallmarks of an Effective Regulator of the Neuroendocrine Axis

Millar

Babwah

2015

Neuroendocrinology

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Kisspeptin (KP) is now well recognized as a potent stimulator of gonadotropin-releasing hormone (GnRH) secretion and thereby a major regulator of the neuroendocrine-reproductive axis. KP signals via KISS1R, a G protein-coupled receptor (GPCR) that activates the G proteins Gα_q/11. Modulation of the interaction of KP with KISS1R is therefore a potential new therapeutic target for stimulating (in infertility) or inhibiting (in hormone-dependent diseases) the reproductive hormone cascade. Major efforts are underway to target KISS1R in the treatment of sex steroid hormone-dependent disorders and to stimulate endogenous hormonal responses along the neuroendocrine axis as part of in vitro fertilization protocols. The development of analogs modulating KISS1R signaling will be aided by an understanding of the intracellular pathways and dynamics of KISS1R signaling under normal and pathological conditions. This review focuses on KISS1R recruitment of intracellular signaling (Gα_q/11- and β-arrestin-dependent) pathways that mediate GnRH secretion and the respective roles of rapid desensitization, internalization, and recycling of resensitized receptors in maintaining an active population of KISS1R at the cell surface to facilitate prolonged KP signaling. Additionally, this review summarizes and discusses the major findings of an array of studies examining the desensitization of KP signaling in man, domestic and laboratory animals. This discussion highlights the major effects of ligand efficacy and concentration and the physiological, developmental, and metabolic status of the organism on KP signaling. Finally, the potential for the utilization of KP and analogs in stimulating and inhibiting the reproductive hormone cascade as an alternative to targeting the downstream GnRH receptor is discussed.

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“…LH pulse amplitude is also increased (Kazer et al, 1987; Waldstreicher et al, 1988), which is reflected in the size of the pulse induced promptly by GnRH (Arroyo et al, 1997) or GnRH agonist administration (Barnes et al, 1989). LH secreted early (30–60 min) in response to GnRH or GnRH agonist injection subcutaneously represents the readily releasable gonadotrope pool of preformed LH (GnRH agonist, being long-acting, then stimulates synthesis and release of a second, slowly releasable gonadotropin pool) (Bremner and Paulsen, 1974; Redding et al, 1972; Rosenfield et al, 1996; Zimmer et al, 2010). …”

Section: Relationship Of Nutritional Status To Neuroendocrine Funcmentioning

confidence: 99%

“…There is also a sexual dimorphism in gonadotropin production that indicates a net testosterone stimulatory effect on LH pulse amplitude in response to GnRH (Rosenfield et al, 1996; Zimmer et al, 2010). Normal men have a higher LH response than women within the first hour after a GnRH agonist injection, although baseline LH levels are similar between the sexes; then men’s LH plateaus.…”

Section: The Relationship Of Androgen Status To Neuroendocrine Funmentioning

confidence: 99%

Evidence that obesity and androgens have independent and opposing effects on gonadotropin production from puberty to maturity

Rosenfield

Bordini

2010

Brain Research

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Optimal fat mass is necessary for normal gonadotropin levels in adults, and both undernutrition and overnutrition suppress gonadotropins: thus, the gonadotropin response to relative adipose mass is biphasic. Adult obesity is associated with blunted luteinizing hormone (LH) pulse amplitude that is partially attributable to increased LH clearance rate. Testosterone appears to have a biphasic effect on gonadotropin production in females. Moderate elevations of testosterone appear to stimulate LH production at both the hypothalamic and pituitary level, while very high levels of testosterone suppress LH. Thus, obesity per se appears to suppress gonadotropin production, and moderate hyperandrogenemia in women appears to stimulate LH. The ordinary hypergonadotropic hyperandrogenism of obese women appears to be an exception to this model because it is usually due to polycystic ovary syndrome (PCOS), a condition in which intrinsic functional ovarian hyperandrogenism and excess adiposity share a common origin that involves insulin-resistant hyperinsulinemia. LH elevation seems to be secondary to hyperandrogenemia and is absent in the most obese cases. Overweight early pubertal girls have significant blunting of sleep-related LH production, which is the first hormonal change of puberty. The data are compatible with the possibility that excess adiposity may paradoxically subtly suppress hypothalamic-pituitary-gonadal function in early puberty although it is known to contribute to the early onset of puberty.

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Potential diagnostic utility of intermittent administration of short-acting gonadotropin-releasing hormone agonist in gonadotropin deficiency

Cited by 20 publications

References 29 publications

High-Sensitivity Micro LC-MS/MS Assay for Serum Estradiol without Derivatization

High-Sensitivity Micro LC-MS/MS Assay for Serum Estradiol without Derivatization

KISS1R: Hallmarks of an Effective Regulator of the Neuroendocrine Axis

Evidence that obesity and androgens have independent and opposing effects on gonadotropin production from puberty to maturity

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