Luteinizing Hormone Half-life Research Articles

Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic–pituitary–gonadal axis following treatment with GnRH analogues

To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the hypothalamic-pituitary-gonadal (HPG) axis describing the changes in luteinizing hormone (LH) and testosterone concentrations following treatment with the gonadotropin-releasing hormone (GnRH) agonist triptorelin and the GnRH receptor blocker degarelix. Fifty-eight healthy subjects received single subcutaneous or intramuscular injections of 3.75 mg of triptorelin and 170 prostate cancer patients received multiple subcutaneous doses of degarelix of between 120 and 320 mg. All subjects were pooled for the population PK/PD data analysis. A systematic population PK/PD model-building framework using stochastic differential equations was applied to the data to identify nonlinear dynamic dependencies and to deconvolve the functional feedback interactions of the HPG axis. In our final PK/PD model of the HPG axis, the half-life of LH was estimated to be 1.3 h and that of testosterone 7.69 h, which corresponds well with literature values. The estimated potency of LH with respect to testosterone secretion was 5.18 IU l(-1), with a maximal stimulation of 77.5 times basal testosterone production. The estimated maximal triptorelin stimulation of the basal LH pool release was 1330 times above basal concentrations, with a potency of 0.047 ng ml(-1). The LH pool release was decreased by a maximum of 94.2% by degarelix with an estimated potency of 1.49 ng ml(-1). Our model of the HPG axis was able to account for the different dynamic responses observed after administration of both GnRH agonists and GnRH receptor blockers, suggesting that the model adequately characterizes the underlying physiology of the endocrine system.

Semi-Mechanistic Pharmacodynamic Modeling for Degarelix, a Novel Gonadotropin Releasing Hormone (GnRH) Blocker

An integrated semi-mechanistic pharmacodynamic (PD) model describing the relationship between luteinizing hormone (LH) and testosterone (T) after short-term administration of degarelix was developed. Data from three clinical studies involving, intravenous (IV) and subcutaneous (SC) dosing, in healthy male subjects were available. Degarelix pharmacokinetic (PK) data from all studies were modeled simultaneously. One intravenous study was used to develop the PD model and the two other studies (IV and SC dosing) were used to qualify the model. Degarelix PK follows a two-compartment model and exhibits flip-flop kinetics after subcutaneous dosing. Based on physiological mechanism, the gonadotropin releasing hormone (GnRH) time course was described using a pulsatile release model. A precursor-dependent pool model was used to describe the kinetics of LH in the pituitary and plasma compartment. In males, LH regulates T production in leydig cells. Degarelix inhibits the release of LH from the pool compartment to the plasma compartment leading to decreased T production. The plasma half-life of LH (2.6-3.3 hr) and T (2.7 hr) match well with the literature reports. The proposed PD model reasonably described the time course of LH and T including the LH rebound for short-term studies. The model predicted the time course of LH and T for the second IV and SC dosing studies very well. However, the long term simulations from the final model did not match with literature reports. A modification is suggested based on the physiological understanding of the system. The proposed novel modification to precursor models can be of general use for predicting long term responses.

LH secretion and testosterone concentrations are blunted after resistance exercise in men.

This study examined the hypothesis that exercise-induced changes in circulating testosterone would be centrally mediated via hypothalamic-pituitary release of luteinizing hormone (LH). We tested this hypothesis by examining overnight LH, total and free testosterone (TT and FT), and cortisol (C) concentrations in 10 young healthy men (21 +/- 1 yr) during two experimental sessions: a control and an acute heavy-resistance exercise bout (50 total sets consisting of squats, bench press, leg press, and latissimus dorsi pull-down). Exercise was performed from 1500 to 1700, and blood sampling began at 1700 and continued until 0600 the next morning. Blood was sampled every 10 min for LH and every hour for TT, FT, and C. Hormonal concentrations were determined via RIA, and the secretion characteristics of LH were analyzed with deconvolution analysis. When overnight postexercise concentrations were compared with control concentrations, no statistically significant (P < or = 0.05) differences were observed for LH half-life, LH pulse frequency, interpulse interval, pulse amplitude, or pulse mass. Significant differences were observed for LH production rate (13.6 +/- 4 and 17.9 +/- 5 IU. l distribution volume(-1) x day(-1) for exercise and control, respectively, a 24% reduction). For the ANOVA marginal main effect means due to condition, C was significantly elevated (5.9 +/- 0.7 vs. 4.0 +/- 0.4 microg/dl), while TT (464 +/- 23 vs. 529 +/- 32 ng/dl) and FT (15.6 +/- 0.7 vs. 18.3 +/- 0.9 pg/ml) were significantly decreased for the exercise condition. These data demonstrate that the decline in overnight testosterone concentrations after acute heavy-resistance exercise is accompanied by a blunted LH production rate and elevated C concentrations.

Alteration in the hypothalamic-pituitary-ovarian axis in depressed women.

Stress and corticotropin-releasing hormone inhibit the reproductive axis. We hypothesized that reproductive axis hormone secretion, particularly luteinizing hormone secretion, is inhibited in women with depression, similar to what has been observed to be caused by stress in numerous species. Blood samples were collected every 10 minutes for 12 hours in 25 untreated premenopausal women with depression and 25 nondepressed women who were matched by age and menstrual cycle day. Samples were assayed for luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone. The mean plasma estradiol level was 30% lower in the follicular phase in women with depression than in their matched controls: 191 + 136 vs 261 + 169 pmol/L (52 + 37 vs 71 + 46 pg/mL). The half-life of luteinizing hormone was significantly shorter in women with depression than in their matched controls during both the follicular (22% shorter) and luteal (15% shorter) phases. The blood levels of reproductive hormones were mostly normal in women with depression, but the blood level of estradiol was significantly lower. Estradiol is known to affect a number of neurotransmitter systems in the brain. Arch Gen Psychiatry. 2000;57:1157-1162.

Le rôle de l’hormone lutéinisante dans la physiologie du follicule et du corps jaune

Luteinizing hormone (LH) is an hypophyseal glycoprotein involved in both follicular maturation and corpus luteum function. During the follicular phase, effects of LH must be considered according to the stages of follicular development: in the early follicular phase, LH acts through specific receptors, constitutively present on thecal cells, for stimulating androgen production. Androgens seem to be positively involved in the folliculogenesis in primates. Indeed, a positive correlation has been recently established between androgen receptor expression and follicular cell proliferation. Furthermore, androgens are active through a conversion to estrogens in granulosa cells. Estrogens are needed for achieving pregnancy. Thus, a question remains: what in the minimal amount of endogenous LH required for an optimal production of oestradiol? Several models have been investigated in clinical situations with hypogonadotrophic hypogonadism: WHO type I anovulation or GnRH analog-induced hypogonadisms. A large majority of these studies conclude that the minimal amount of LH needed during the follicular phase is probably low (<1.5 IU/L of plasma LH level). Recent availability of GnRH antagonist will give a new opportunity for evaluating this minimal LH threshold. During the late follicular phase, LH plays a biphasic role, with a positive effect on steroidogenesis but a negative effect on cell proliferation. As suggested by S. Hillier, this negative effect on cell proliferation may be relevant to control the rate of follicular growth. One study, performed in WHO type I anovulatory patients, seems to confirm this assumption but further evaluation is needed to give support to this concept. Finally, LH is also involved in corpus luteum function. Due to the short half-life of LH as compared to hCG, the role of LH must be evaluted according to the adjunct therapies. For example, following a long-term GnRH agonist administration that constantly induces a profound hypophyseal desensitization, LH administration must be repeated to adequately sustain the corpus luteum function. This conclusion must be reconsidered with the recent introduction of GnRH antagonists. Indeed, according to their short-term effects on LH secretion, it may be presumed that a single injection of LH may be effective to maintain an adequate corpus luteum function.

A preponderance of basic luteinizing hormone (LH) isoforms accompanies inappropriate hypersecretion of both basal and pulsatile LH in adolescents with polycystic ovarian syndrome.

We recently demonstrated that adolescent girls with polycystic ovarian syndrome (PCOS) exhibit augmented LH secretion due to an increase in immunofluorometric and deconvolution-estimated LH secretory burst mass and pulse frequency. Concurrently, we inferred either a prolongation of apparent (endogenous) LH half-life or elevated basal (nonpulsatile) LH release in PCOS. The in vivo half-life of LH molecules can be affected by the oligosaccharide side-chains, which also modify in vitro bioactivity and electrostatic change. Accordingly, as a surrogate estimator of altered endogenous LH half-life and/or biopotency in PCOS, we characterized the isoelectric properties of secreted LH isoforms and determined their in vitro biological activity in adolescent girls with PCOS compared with healthy age-matched eumenorrheic controls. To this end, 12-h (overnight) serum samples from PCOS patients (n = 12) and normal adolescents (n = 10) were pooled by subject. Bioactive LH concentrations were then quantitated in a rat Leydig cell in vitro bioassay, and immunological activity was determined by immunofluorometry. The distribution of LH isoforms was evaluated by preparative chromatofocusing (pH window, 10.5 to <4.0) of samples further combined to yield three independent serum pools for each of the patient and control groups. Fasting serum concentrations of 17-hydroxyprogesterone (17-OHP), androstenedione, testosterone, estrone, estradiol, and sex hormone-binding globulin were determined as possible endocrine correlates of LH isotypes. Mean serum concentrations of immunoreactive and bioactive LH in adolescents with PCOS were 3 and 2 times higher than values in controls: immunoreactive: PCOS, 7.8+/-0.9; controls: 2.6+/-0.3 IU/L (P < 0.001); and bioactive: PCOS, 52+/-10; controls, 25+/-4.1 IU/L (P = 0.002), respectively. Bioactive LH concentrations correlated positively with 17-OHP (P = 0.022), androstenedione (P = 0.012), and testosterone (P = 0.046) concentrations in PCOS. Chromatofocusing of LH isoforms disclosed greater LH immunoreactivity at pI values greater than 8 and 7.99-7.0 in adolescents with PCOS compared with controls (P = 0.031). The percentage of basic LH isoforms was related positively to serum concentrations of 17-OHP (P = 0.032), androstenedione (P = 0.046), and testosterone (P = 0.040). In conclusion, the present isotype analysis demonstrates elevated in vitro LH bioactivity and a preponderance of basic LH isoforms in girls with PCOS. Since previously reported heterologous in vivo assays of LH kinetics point toward accelerated removal of such alkaline isotypes, our findings would favor the earlier alternative hypothesis of inappropriate hypersecretion of basal (interpulse) LH rather than prolongation of the LH half-life as the mechanism for elevated interpulse serum LH concentrations in adolescents with PCOS. In ensemble, the foregoing data thus suggest 3-fold amplification of basal LH secretion as well as both a heightened amplitude and frequency of the pulsatile mode of LH release in PCOS.

Evaluation of LH secretory dynamics during the rat proestrous LH surge.

The preovulatory luteinizing hormone (LH) surge results from the integration of complex interactions among gonadal steroids and hypothalamic and pituitary hormones. To evaluate changes in LH secretory dynamics that occur during the rat LH surge, we have 1) obtained frequently sampled serum LH concentration time series, 2) used both waveform-dependent and waveform-independent convolution analyses, and 3) independently assessed proestrous LH half-life and basal non-gonadotropin-releasing hormone (GnRH)-dependent LH secretion during the LH surge. Waveform-independent pulse analysis revealed a 24-fold increase in the maximal pulsatile LH secretory rate attained during late proestrus compared with early proestrus. A 15-fold increase was quantified for the mean LH secretory rate. In complementary analyses, we applied a measured LH half-life of 17 +/- 2.7 min and a median basal LH secretion rate of 0.0046 microgram. l-1. min-1 for convolution analysis, revealing a 16-fold increase in the mass of LH released/burst and more than sixfold rise in the amplitude of the secretory peaks. Evaluation of the approximate entropy of the LH surge profiles was performed, showing an increase in the orderliness of the LH release process during the surge. We conclude that both quantitative (mass/burst) and qualitative (approximate entropy) features of LH release are regulated during the proestrous LH surge.

Joint recovery of pulsatile and basal hormone secretion by stochastic nonlinear random-effects analysis.

We present a nonlinear random-effects stochastic differential equation (SDE) model of combined basal and pulsatile hormone secretion with a series-specific hormone half-life and conditional pulse times. The construct uses a three-parameter pulse shape (generalized gamma function) to allow variably skewed secretory bursts superimposed on a finite basal hormone secretion rate. The analysis imbeds stochastic elements at three levels: a variable mass of hormone accumulation (of which the random effect is a part) during interpulse intervals, nonuniform secretion with hormone admixture into the circulation, and technical (sampling and assay) experimental uncertainty. We implement maximum likelihood estimates of secretory parameters (basal and pulsatile secretion and half-life) with asymptotic standard errors. The model applied to illustrative human luteinizing hormone (LH) time series suggests contrasts in basal LH secretion rates (e.g., greater in postmenopausal women than men) and LH secretory burst mass (e.g., higher in older women), but not LH burst frequency or distributional LH half-lives (7-40 min). For validation, in two infused (human recombinant) LH profiles, we implement partially constrained mono- and biexponential versions of the model with fixed (a priori assumed) versus variable LH basal secretion rates. We conclude that a statistically supported, nonlinear, random effects, SDE-based construct can evaluate jointly basal and pulsatile LH secretory rates and LH half-life in 24 h, episodically varying serum LH concentration profiles. This new reduced-parameter analytic strategy should be useful to explore further the pathophysiological mechanisms of altered neurohormone secretion.

Fasting suppresses pulsatile luteinizing hormone (LH) secretion and enhances orderliness of LH release in young but not older men.

Pulsatile gonadotropin secretion and sex-steroid concentrations are suppressed reversibly in young fasted or malnourished human subjects. In this study, we investigated the impact of age on the dynamic neuroendocrine mechanisms underlying this stress response in healthy young (age, 28 +/- 3 yr, n = 8) vs. older (age 67 +/- 2 yr, n = 8) men with similar body mass indices (mean, 26 +/- 0.6 vs. 26 +/- 1.3 kg/m2, respectively). Serum LH concentrations were measured by immunoradiometric assay (IRMA) in blood collected at 10-min intervals over 27 h on a control (fed) day and on the third day of a 3.5-day fast (water only) assigned in randomized order. After 24 h of basal sampling, GnRH (10 micrograms i.v. bolus) was administered to test gonadotrope responsiveness. Cortisol, dehydroepiandrosterone sulfate, androstenedione, testosterone, FSH, GH, and PRL were measured in 24-h pooled serum as positive and negative control hormones. Approximate entropy was used to quantitate the orderliness of LH release over 24 h, and a multiple-parameter deconvolution method was applied to quantify pulsatile LH secretion and LH half-life. In the fed state, older men exhibited elevated mean (24-h pooled) serum FSH and cortisol concentrations compared with young controls but equivalent serum LH concentrations and reduced serum GH, free testosterone, androstenedione, and dehydroepiandrosterone sulfate concentrations. Fed older men also manifested a lower frequency and amplitude of 24-h pulsatile LH secretion, and, by approximate entropy calculations, a more disorderly pattern of basal LH release than younger individuals. Three- and one-half days of fasting evoked 40% and 47% increases in mean (24-h) serum cortisol concentrations in young and older men, respectively (P < 0.01 vs. fed, but P = not significant for percentage rise in older vs. young men). Concurrently, fasting induced a 2.1-fold fall in the 24-h endogenous LH production rate in young men (fed 36 +/- 9.7 vs. fasted 17 +/- 2.0 IU/L of distribution volume/day, P < 0.01), but did not significantly affect the daily LH secretion rate in older men (fed 27 +/- 4.5 vs. fasted 21 +/- 3.4 IU/day). The reduced LH production rate in fasting young men was accounted for by a 1.7-fold decline in the mass of LH secreted per burst (fed 2.5 +/- 0.45 vs. fasted 1.5 +/- 0.16 IU/L, P < 0.05), whereas LH burst mass in older men remained unchanged (and low) during fasting. In addition, in young men, during the 3.5-day fast the number of computer-resolved LH secretory bursts per 24 h decreased (fed 15 +/- 0.7 vs. fasted 11 +/- 0.7, P < 0.01), and the interburst interval increased (fed 94 +/- 4.2 vs. fasted 125 +/- 8.7 min, P < 0.05). In contrast, in older men in the fed state, basal LH peak frequency and serum free testosterone concentrations were reduced compared with corresponding values in young men, and did not decline further with fasting. Whereas the orderliness of LH release patterns increased significantly during fasting in the young men, the approximate entropy measure failed to change significantly in unfed older subjects. By cosinor analysis, young men showed lower 24-h mesor (mean of nyctohemeral rhythm of) serum LH concentrations than older volunteers during fasting. Moreover, young but not older men manifested preserved 24-h variations in LH interpulse intervals when fasting. Exogenously stimulated LH release (mean 3-h serum LH concentration or calculated mass of LH secreted) following a single i.v. injection of 10 micrograms GnRH was independent of age and fasting status. We conclude that the metabolic stressor of short-term fasting unmasks specific age-related neuroendocrine contrasts in the stress-responsive control of both the pulsatile and nyctohemeral regulation of the male hypothalamo-pituitary-gonadal-axis.

Neuroendocrine mechanisms by which selective Leydig cell castration unleashes increased pulsatile LH release

A novel pharmacological model of acute reversible Leydig cell "castration" induced by a steroidogenic enzyme inhibitor, ketoconazole, achieves marked hypoandrogenemia in healthy men with an attendant 2.5-fold increase in 24-h mean serum luteinizing hormone (LH) concentrations. Mechanistically, the unleashing of amplified pulsatile LH release can be accounted for by any of three distinct models of deconvolution-estimated gonadotropin secretion, all of which are marked by a nearly twofold acceleration in LH secretory burst frequency. In addition, the models variously also predict concomitant prolongation of the endogenous LH half-life, an augmented LH secretory burst mass and duration, and/or the emergence of significant basal LH secretion. The nyctohemeral (cosinor analysis) rhythmicity of serum LH concentrations is not disturbed when androgenic negative-feedback signaling is withdrawn abruptly, but the apparent process randomness of LH release increases, as quantified by higher approximate entropy values. Thus we conclude that an intact (closed loop) androgen-mediated negative-feedback network in the adult human male is required to sustain low-frequency pulsatile LH release in a quantifiably orderly manner.

Variability of pulsatile luteinizing hormone secretion in young male volunteers.

Characteristics of spontaneous pulsatile luteinizing hormone secretion were compared in ten young healthy men in three 24-h profiles obtained at intervals of 14 days and 3 months. The ages of the volunteers ranged from 19 to 25 years, and heights and weights were within normal limits. Blood samples were taken at 10-min intervals and plasma luteinizing hormone (LH) was determined in the same immunoradiometric assay using monoclonal antibodies. Conventional pulse detection was carried out with PULSAR and CLUSTER programs. In addition, a simultaneous multiple parameter DECONVOLUTION was applied. As a group, no significant differences between the three profile series were found for any of the calculated parameters of LH concentration or LH secretion. However, most parameters showed low correlation coefficients between the three study periods, suggesting that substantial individual variations might contribute to the more reliable group results. Median coefficients of variation (cv) for the individual subject ranged from 9.7% (interpulse interval and endogenous half-life) to 37.7% (mass per burst). However, the maximal individual cv observed was 78.4%. Intra-individual variability was lower than the variability between subjects for quantitative properties of LH concentration and secretion, although not significantly so for all parameters. In conventional pulse detection, the highest individual reliability was found for mean and integrated LH concentrations (median cv 10.2 and 13.7%, respectively), number of pulses per 24h (CLUSTER, median cv 12.2%), mean pulse amplitude (PULSAR, median cv 10%) and interpulse interval (CLUSTER, median cv 9.7%). In DECONVOLUTION analysis, the endogenous LH half-life (median cv 9.7%), secretory burst amplitude (median cv 14.8%) and interburst interval (median cv 14.5%) revealed the lowest intra-individual variation. In contrast, the half-duration of a secretory episode and the mass of LH secreted per burst proved to be the least reliable measures (median cv 32.7% and 37.7%, respectively). Calculated endogenous LH production rates correlated highly (p < 0.01) across all three sessions. The relative frequencies of the LH peak amplitudes/heights and peak widths (durations) showed almost identical distribution curves for all three sampling periods. In conclusion, a high reproducibility of group results for both integrative parameters and pulse characteristics of LH concentrations and secretion were found in normal men. However, intra-individual reliability was variable and at times considerable, depending on the parameter chosen. These observations suggest caution in the interpretation of single LH profiles from individual subjects or patients unless the variation reported herein is considered.

Validation of deconvolution analysis of LH secretion and half-life.

Deconvolution methods constitute a class of analytic tools to quantitate hormone secretion and/or clearance in vivo. Although mathematically rigorous, deconvolution techniques have assumed, rather than proven, validity. Accordingly, we tested the validity of deconvolution analysis on true-positive human, animal (sheep and monkey), and computer-simulated data using the luteinizing hormone (LH) pulse signal as a relevant paradigm. We found that multiparameter deconvolution analysis has high discriminative sensitivity (human data 91%, animal 81%, computer-stimulated 95%) and specificity (human 90%, animal 81%, computer-simulated 100%). Sensitivity was impaired by low secretory burst amplitude (< 0.1 IU.l-1.min-1), short interpulse interval (< 60 min), infrequent venous sampling (every 20-30 min), and high random experimental variation (e.g., noise > 15%). Specificity was hindered by noise. Deconvolution accurately characterized the unknown hormone half-life (r = +0.994) and production rate (r = +0.990). Interoperator reliability was high when statistically based criteria for secretory pulse detection were applied. We conclude that multiparameter deconvolution, within recognizable constraints, is a valid and reliable tool for in vivo investigation of hormone secretion and half-life.

Reanalysis of the rat proestrous LH surge by deconvolution analysis.

To evaluate the temporal mechanisms that give rise to the spontaneous proestrous surge of luteinizing hormone (LH) in the rat, we have applied deconvolution analysis to earlier immunoreactive LH concentration vs. time profiles obtained by sampling blood in proestrus at 2- to 3-min intervals in 10 animals over a span of 160-300 min. Six other animals were bled in 6-min intervals on day 1 of diestrus. Deconvolution analysis permitted us to calculate the number, duration, amplitude (maximal release rates), and mass of underlying LH secretory bursts and to simultaneously estimate basal secretion and the half-life of endogenous LH in each animal. Proestrus rats exhibited a significant increase in the number of computer-identified LH secretory bursts per hour (1.8 +/- 0.2 vs. 1.1 +/- 0.01 on diestrus, P < 0.01), with a corresponding reduction in the LH intersecretory burst interval from 61 +/- 6.4 min (diestrus) to 25 +/- 2.7 min (proestrus, P < 0.01). There was a remarkable 16-fold increase in the mass of LH secreted per burst, which rose from 72 +/- 5.2 to 1,230 +/- 200 ng/ml (P < 0.01). This resulted from a sixfold increase in LH secretory burst amplitude and a doubling of burst duration. The total amount of LH released in a burstlike fashion during the proestrous LH surge rose 20-fold, and calculated basal LH secretion increased to approximately 25% of this value. Of interest, the computed half-life of endogenous LH also increased from 10 +/- 1.1 to 19 +/- 3.7 min (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Specific Physiological Regulation of Luteinizing Hormone Secretory Events Throughout the Human Menstrual Cycle: New Insights into the Pulsatile Mode of Gonadotropin Release

Abstract To investigate the physiological regulation of luteinizing hormone (LH) secretory events and the endogenous clearance of this hormone, we applied multiple-parameter deconvolution analysis to serum LH concentration-time series obtained from normal women during three phases of the menstrual cycle. The number of significant LH secretory bursts (/24 h) was maximal in the late follicular (LF) phase (27 +/- 1.6; mean +/- SEM), minimal in the mid-luteal (ML) phase (10 +/-1.0) and intermediate in the early follicular (EF) phase (18 +/- 1.4). Similarly, the half-duration of the secretory impulse (min) was different at each phase of the cycle with values of 6.5+/-1.0, 3.5+/-0.9 and 11 +/- 1.1 during the EF, LF and ML phases, respectively. In contrast, there were no cycle-dependent differences in the LH half-life or in the total daily secretion of LH. When maximal secretory impulse amplitudes were examined, a putative bimodal distribution was found in the ML but not the EF or LF phases. The amplitudes for the large ML impulses, the LF and EF impulses and the small ML impulses were 0.95 +/- 0.05, 070 +/- 0.03, 0.43 +/- 0.02 and 0.26 +/- 0.02, respectively. The mass (mlU/ml) of hormone secreted within bursts was minimal in the LF phase (2.1 +/- 0.1), maximal in the large ML impulses (10.2 +/- 0.5) and intermediate in the EF (2.8 +/- 0.1) and small ML (3.1 +/-0.3) secretory impulses. There was no evidence of tonic (i.e. inter-secretory burst) LH secretion during any phase of the menstrual cycle. The early morning hours of the EF phase were characterized by fewer secretory bursts of greater amplitude. During the ML phase, autocorrelation analysis of inter-secretory burst intervals revealed a negative association indicating that high frequency events both precede and follow secretory pauses. In addition, secretory burst amplitude and both the preceding and following inter-secretory burst interval was correlated to secretory burst amplitude. These new data on the nature of regulated LH secretion indicate that specific facets of spontaneous LH secretory events are controlled throughout the menstrual cycle. Such observations offer a basis for defining altered secretory dynamics in a variety of pathophysiologic situations.

Clearance Rate of Luteinizing Hormone and Follicle Stimulating Hormone from Peripheral Circulation in the Pig2

Passive immunization of chronically ovariectomized gilts against gonadotropin releasing hormone (GnRH) resulted in an abrupt cessation of pulsatile secretion of luteinizing hormone (LH) accompanied by clearance from serum with a mean half-life of 30.9 +/- 2.3 (mean +/- SE) and 918 +/- 200 min for the first and second compartment, respectively. Serum follicle stimulating hormone (FSH) was unaffected immediately by passive immunization against GnRH and declined slowly with a half-life of 4.9 +/- .7 d. After LH and FSH had declined to basal levels in passively immunized gilts, injection of a bolus of LH and FSH resulted in peak values within 5 min and depletion curves with half-lives for the first compartment of 28.0 +/- 1.3 and 36.4 +/- 2.6 min and for the second compartment of 679 +/- 98 and 1,230 +/- 54 min, for LH and FSH respectively. These results show that the half-life of LH is similar following immunoneutralization of GnRH or administration of a bolus of LH in immunized gilts and a difference in clearance rates of LH and FSH after initial passive immunization. These results suggest that secretion of FSH in the ovariectomized gilt is controlled by factors in addition to hypothalamic GnRH.

Acute Inhibitory Effects of Antiserum to Gonadotropin-Releasing Hormone in Ovariectomized Rats

To evaluate the dependence of pulsatile secretion of luteinizing hormone (LH) on gonadotropin-releasing hormone (GnRH), the acute effects of immunoneutralization of endogenous GnRH on plasma LH were compared in ovariectomized rats with phenobarbital treatment and hypophysectomy. Anti-GnRH produced a rapid dose-dependent decrease in plasma LH and LH pulse amplitude. Pulsatile secretion of LH was eliminated in 6 of 12 rats treated with the highest dose of anti-GnRH, but plasma LH was still 50% of control values 3 h after treatment. Frequency of LH pulses was unchanged in animals which had persistence of pulsatile secretion of LH. Phenobarbital eliminated pulsatile secretion of LH transiently. Hypophysectomized rats displayed a striking decrease in plasma LH which could be resolved into two exponential components with half-lives of 16 and 70 min. The initial half-life of plasma LH from untreated rats determined after LH pulses was also 16 min. These studies support the hypothesis that pulses of GnRH induce the pulsatile pattern of plasma LH and may be responsible for all LH secretion in ovariectomized rats.

The Half-Life of Luteinizing Hormone in Intact and Castrated Quail During Fhotoferiodic Stimdlation

In the Japanese quail (Coturnix coturnix japonica) the plasma concentration of luteinizing hormone (LH) depends on the physiological state of the animal. Low levels are found in sexually immature birds on short days (0.8 +/- 0.1 (n = 20) ng/ml) while after exposure to long days, sexually mature birds have a significantly higher LH level (4.4 +/- 0.4 (n = 20) ng/ml). Castration of long day males results in an even higher rise in LH concentration to 16.8 +/- 1.8 (n = 16) ng/ml. When the half-life (t1/2) of circulating LH was determined it was found to have two components: a fast t 1/2 of about 6 min and a slower component of either 20 min (determined by a radioisotope method), or 40 min (following hypophysectomy). No significant difference was observed in either of these components between birds in the three physiological states (short days, long days, castration plus long days). It would appear, therefore, that since the half-life of plasma LH remains constant, the difference in circulating LH observed under the various physiological conditions results solely from a change in the rate of LH secretion.

Rates of disappearance from blood and biological potencies of mammalian gonadotropins (HCG and ovine LH) in the toad Bufo bufo bufo (L.)

In hypophysectomized toads Bufo bufo bufo (L.), daily subcutaneous injections of human chorionic gonadotropin (HCG) effectively stimulate vitellogenic growth of oocytes whereas ovine luteinizing hormone (LH) is almost inactive. This difference in potency of the two chemically closely related hormones is correlated with the rates at which the hormones disappear from the blood. In hypophysectomized toads the circulatory half-life of ovine LH was about 40 min. Injected HCG disappcared at decreasing rates, from half-lives of about 3 hr to about 30 hr. It is suggested that the different potency of HCG and LH in stimulating vitellogencsis in hypophysectomized female toads can be due to the different length of time hormone is available to the organism, rather than to different affinities of the ovarian receptors toward the two hormones.

Role of the kidney in the metabolism of luteinizing hormone.

SUMMARY Autoradiographic localization of 125I-labelled luteinizing hormone (LH) in the renal proximal convoluted tubule of rats initiated a study of the role of the kidney in the metabolism of LH. Incubation of 131I-labelled LH with rat renal homogenates for 90 min failed to destroy its immunological reactivity. The plasma half-life of 131I-labelled LH injected i.v. was investigated in normal ewes and rams. Preliminary studies indicated that the use of a preparation containing a high proportion of 'damaged' iodinated hormone could erroneously prolong the plasma half-life. Before use, 131I-labelled LH was purified by gel filtration and column chromatography using DEAE-cellulose. The mean plasma half-life of 131I-labelled LH in normal ewes was 26·7 min and was not significantly altered after oophorectomy (31·1 min). After bilateral oophorectomy and nephrectomy, marked prolongation of the plasma half-life was observed (mean 70·7 min). In normal rams, mean plasma half-life of 131I-labelled LH was 32·0 min, after orchidectomy 44·0 min and after orchidectomy and nephrectomy 82·0 min. The plasma half-life of 131I-labelled LH in a nephrectomized ewe maintained on haemodialysis was also prolonged (67·5 min), the determination being performed 24 h after the last haemodialysis. Although the kidney does not degrade LH, the plasma half-life was significantly increased after nephrectomy. This suggests that the localization of 125I-labelled LH in the proximal convoluted tubule may represent a secretory mechanism allowing renal excretion of LH.

The half-life of luteinizing hormone in the circulation of domestic fowl and Japanese quail.

The rate of disappearance of luteinizing hormone (LH) from the circulation is an important parameter in studying the dynamics of the hormone and in interpreting the significance of both circulating and pituitary hormonal levels. This rate is most frequently expressed in terms of the half-life of LH in the circulation (see Parlow, 1968). The estimation of the half-life of circulating LH in birds has been made feasible by the availability of purified chicken gonadotrophins (Stockell Hartree & Cunningham, 1969; Scanes & Follett, 1972), together with a radioimmunoassay for avian LH (Follett, Scanes & Cunningham, 1972). The half-life of LH in the domestic fowl was determined by following the dis-appearance of either unlabelled LH or 125I-labelled LH from the circulation of the bird. In the case of the labelled hormone, a chicken LH fraction of high ovarian ascorbic acid depleting activity and low thyrotrophin content (fraction AEI, Scanes & Follett,