Metabolic clearance of biologically active luteinizing hormone in man.

Veldhuis, Johannes D.; Fraioli, F; Rogol, Alan D.; Dufau, Maria L.

doi:10.1172/jci112411

Cited by 130 publications

(54 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These outcomes would be consistent with saturable mechanisms of LH's metabolism or removal, thus attenuating clearance of infused LH peaks per se. The notion was proposed earlier for high doses of pituitary LH extracts infused in men as well as for large GH pulses injected in women (13,41,50). The present data indicate that even within the physiologically normal range of LH concentrations in men (1.8 -8.6 IU/l), the metabolic clearance of LH from the circulation falls by 50% as LH concentrations double.…”

Section: R998 Pulsatile Versus Continuous Lh Stimulationsupporting

confidence: 70%

See 1 more Smart Citation

Analysis of the impact of intravenous LH pulses versus continuous LH infusion on testosterone secretion during GnRH-receptor blockade

Veldhuis¹,

Liu

Takahashi

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Analysis of the impact of intravenous LH pulses versus continuous LH infusion on testosterone secretion during GnRH-receptor blockade. Am J Physiol Regul Integr Comp Physiol 303: R994 -R1002, 2012. First published September 19, 2012 doi:10.1152/ajpregu.00314.2012.-Gonadotrophin-releasing hormone (GnRH) pulsatility is required for optimal luteinizing hormone (LH) secretion, but whether LH pulsatility is required for physiological testosterone (T) secretion is not known. To test the postulate that pulses of recombinant human (rh) LH stimulate greater T secretion than continuous infusion of the same dose, a potent selective GnRH antagonist was administered overnight to 19 healthy men ages 18 -49 yr. Subjects then received saline or rhLH intravenously continuously or as 6-min pulses intravenously every 1 or 2 h at the same total dose. Blood was sampled every 10 min for 10 h to quantify T responses. For the four interventions, the descending rank order of mean LH and mean T concentrations was 1-h ϭ 2-h rhLH pulses Ͼ continuous rhLH Ͼ saline (P Ͻ 10 Ϫ3 ). Plateau LH and T concentrations correlated positively (R 2 ϭ 0.943, P ϭ 0.029) as did LH concentrations and LH half-lives (R 2 ϭ 0.962, P ϭ 0.019). Percentage pulsatile T secretion assessed by deconvolution analysis (Keenan DM, Takahashi PY, Liu PY, Roebuck PD, Nehra AX, Iranmanesh A, Veldhuis JD. Endocrinology 147: 2817-2828, 2006) was the highest (P ϭ 0.019), and half-time to attain peak T concentrations was the shortest (P Ͻ 10 Ϫ6 ), for 1-h rhLH pulses. Approximate entropy (a pattern-regularity measure) revealed more orderly T secretion for 1-than 2-h rhLH pulses (P ϭ 0.0076). Accordingly, a pulsatile LH signal, while not obligatory to maintain mean T concentrations, controls the mean plasma LH concentration and determines quantifiable patterns of T secretion. These data introduce the question whether blood T patterns in turn supervise distinctive target-tissue responses.pulse; gonadotropin; human; testis; testosterone LOW TESTOSTERONE (T) concentrations increase the clinical risk of sarcopenia, osteopenia, diminished libido and potentia, visceral adiposity, decreased aerobic capacity, and (possibly) impaired cognitive function (30). Reduced T availability may result from reduced gonadotrope stimulation by hypothalamic gonadotrophin-releasing hormone (GnRH), attenuated biosynthesis of luteinizing hormone (LH), heightened T clearance, greater T negative feedback, and/or blunted testicular responses to LH (32,33). In addition, hypoandrogenemia in some conditions such as aging is associated with disorderly LH secretion patterns (30 -32, 36, 51) and smaller more frequent circhoral LH pulses (18,32,36). Whether small frequent LH pulses or continuous LH delivery into the bloodstream is less effective than larger infrequent LH pulses in driving T secretion is not known. The issue is central to the broader theme of pulsatility regulation and action in endocrine systems (17,20,54). Indeed, growth hormone (GH), ACTH, parathyroid hormone (PTH), insulin, and oxytocin driv...

show abstract

Section: R998 Pulsatile Versus Continuous Lh Stimulationsupporting

confidence: 70%

“…Exponential curve fitting (monoexponential ascending curve) and kinetic analysis were used to estimate the rate of rise of measured T concentrations and the metabolic clearance rate of infused LH, respectively (50,52). Deconvolution analysis was applied to assess the half-life of disappearance of infused LH (26).…”

Section: Methodsologymentioning

confidence: 99%

Analysis of the impact of intravenous LH pulses versus continuous LH infusion on testosterone secretion during GnRH-receptor blockade

Veldhuis¹,

Liu

Takahashi

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

show abstract

“…No demonstrable change in the calculated elimination rate of LH occurs during androgen-receptor antagonism. The derived estimate of serum LH half-life in our subjects agrees closely with the range of 74 to 1 1 1 min observed for the slow component disappearance of exogenously administered purified human pituitary LH (immunoassayable and bioassayable gonadotropin) in the adult male (29). The net result of antiandrogen administration is higher 24-h mean serum LH concentrations.…”

Section: Discussionsupporting

confidence: 86%

Androgen-Receptor Blockade Enhances Pulsatile Luteinizing Hormone Production in Late Pubertal Males: Evidence for a Hypothalamic Site of Physiologic Androgen Feedback Action

1994

View full text Add to dashboard Cite

ABSTRACT. To determine potential mechanisms by and frequency of hypothalamic GnRH release in late puwhich androgens alter gonadotropin secretion and elimibertal boys. (Pediatr Res 35: 102-106,1994) nation in the pubertal male, we administered the potent nonsteroidal androgen receptor blocking agent, flutamide, to eight males with Tanner IV or V genital development.AbbreviationsVenous blood samples were obtained every 10 min for 24 GnRH, gonadotropin-releasing hormone h and assayed for LH by a sensitive and high-precision L,, body distribution volume in liters fluorimmunoassay. Subjects were studied before and after the administration of flutamide. Deconvolution analysis was used to assess specific pulsatile LH secretory characteristics and estimate LH production and metabolic clearance rates quantitatively. After antagonism of endogenous androgen action, mean 24-h serum LH concentrations increased significantly. An increased mean 24-h LH production rate, without evident changes in serum LH half-life, accounted for the increase in average serum LH levels. The increased daily secretion rate of LH was in turn due to both an augmented mass of LH released per secretory episode and increased frequency of secretory events. There was no demonstrable change in the maximal rate of LH secretion attained within each secretory event. Serum concentrations of total testosterone, free-testosterone, and 17@-estradiol all increased during blockade of androgen action. Administration of the antiandrogen had no measurable effect on the pituitary response to a single maximally effective dose of exogenous gonadotropin releasing hormone (GnRH). These results indicate that, in the late pubertal male, endogenous androgen exerts negative feedback control of gonadotropin secretion primarily at a hypothalamic site reflected by regulation of the frequency of pulsatile LH secretion. Antiandrogen had no discernible effects on exogenous GnRH-stimulated pituitary LH release or on the elimination rate of LH, but amplified the mass of LH secreted in response to endogenous GnRH. Assuming that pituitary response to exogenous GnRH reflects responsivity to endogenous releasing factor, we can infer an augmentation of the endogenous GnRH stimulus when androgen negative feedback is withdrawn. Accordingly, we suggest that endogenous androgen acting via androgen receptors negatively regulates both the amount The dynamic process of normal human puberty is heralded by dramatic increases in nocturnal gonadotropin secretion (1-3). This awakening of the CNS-hypothalamic-pituitary axis then augments gonadal steroidogenic activity, manifested as increasing serum levels of sex steroid hormones. As the adolescent matures, a feedback control system develops whereby gonadal steroid hormones modulate pulsatile gonadotropin secretion. Although it appears that androgens inhibit gonadotropin release by acting at both the hypothalamus and pituitary gland (4, 5 ) , evidence exists supporting a developmental process of such feedback control.In the pubertal male, androgens m...

show abstract

“…injection of FSH (250 IU). With regard to the applicability of these parameters to the present data, note that the disappearance profiles in the earlier studies (10,11) have the same order of magnitude as the responses analysed in the present study (compare, for instance In the analysis, only measured (noisy) values of plasma concentration y k (IU/l), k ¼ 1, …, n, are available:…”

Section: Deconvolution Analysismentioning

confidence: 62%

“…These are population parameters estimated in a previous study (10) by fitting the two-exponential model to the plasma disappearance profiles observed after bolus i.v. injection of 35 mg LH.…”

Section: Deconvolution Analysismentioning

confidence: 99%

LH and FSH secretory responses to GnRH in normal individuals: a non-parametric deconvolution approach

Nicolao

Liberati²,

Veldhuis

et al. 1999

European Journal of Endocrinology

View full text Add to dashboard Cite

Objective: To reconstruct the instantaneous secretion rate (ISR) of LH and FSH after GnRH administration in normal volunteers using non-parametric deconvolution, and to derive a direct integration formula to evaluate the amount of LH and FSH secreted during the first 60 min after the stimulus. Design and methods: First, the deconvolution method was validated in vivo by reconstructing doses ranging from 7.5 IU to 75 IU injected in three healthy adult volunteers whose endogenous LH had previously been downregulated by pretreating them, 3-4 weeks earlier, with 3.75 mg GnRH agonist i.m. Then, 40 healthy adult male volunteers were tested with a single 100 mg GnRH bolus, administered at 0 min. LH and FSH concentrations were determined at ¹30, 0, 15, 30, 45, 60, 90, and 120 min. Results and conclusions:The validation study, conducted over a 10-fold range of doses, demonstrated that non-parametric deconvolution provided a reasonably accurate estimate of the amount of hormone entering the circulation. Applying deconvolution to the LH and FSH responses to GnRH, the ISRs of both hormones were shown to have a similar pattern, with a clearly delimited pulse after the GnRH bolus. In conjunction with earlier analyses of estimates of GHRH-stimulated GH secretion, we conclude that secretagogues evoke discrete LH, FSH, and GH secretory bursts of about 60 min total duration, despite markedly unequal (glyco-)protein hormone half-lives (18-500 min). With respect to the assessment of total hormone release during the first 60 min after the stimulus, the integration formula provided a reliable approximation of the result obtained by deconvolution, and had a negligible dependence on the samples at times 90 and 120 min.

show abstract

Metabolic clearance of biologically active luteinizing hormone in man.

Abstract: The plasma metabolic clearance of biologically active luteinizing hormone (bioactive LH) was studied using the rat interstitial cell testosterone (RICT)

Cited by 130 publications

References 19 publications

Analysis of the impact of intravenous LH pulses versus continuous LH infusion on testosterone secretion during GnRH-receptor blockade

Analysis of the impact of intravenous LH pulses versus continuous LH infusion on testosterone secretion during GnRH-receptor blockade

Androgen-Receptor Blockade Enhances Pulsatile Luteinizing Hormone Production in Late Pubertal Males: Evidence for a Hypothalamic Site of Physiologic Androgen Feedback Action

LH and FSH secretory responses to GnRH in normal individuals: a non-parametric deconvolution approach

Contact Info

Product

Resources

About