Recombinant LH (lutropin alfa) for the treatment of hypogonadotrophic women with profound LH deficiency: a randomized, double-blind, placebo-controlled, proof-of-efficacy study.

OBJECTIVE: To confirm the safety and efficacy of 75 IU lutropin alfa with concomitant follitropin alfa in inducing follicular development in women with profound gonadotrophin deficiency. DESIGN: Double-blind, randomized, placebo-controlled trial conducted in 25 medical centres in four countries. PATIENTS: Thirty-nine patients with LH < 1.2 IU/l and FSH < 5.0 IU/l were treated with concomitant 75 IU lutropin alfa and 150 IU follitropin alfa or concomitant placebo and 150 IU follitropin alfa. MEASUREMENTS: Primary efficacy end-point (intent-to-treat): follicular development defined by (i) at least one follicle >or= 17 mm; (ii) serum E(2) level >or= 400 pmol/l on day of hCG administration (DhCG); and (iii) mid-luteal phase progesterone level >or= 25 nmol/l. RESULTS: In the analysis of evaluable patients, 66.7% (16 of 24) of patients given lutropin alfa achieved follicular development compared with 20.0% (2 of 10) of patients receiving placebo (P = 0.023). In the intent-to-treat analysis, follicular development was achieved in 65.4% (17 of 26) of patients receiving lutropin alfa and 15.4% (2 of 13) of patients receiving placebo (P = 0.006). The statistical difference between treatment groups was preserved when over-response leading to cycle cancellation was analysed as a failed response (P = 0.034). Lutropin alfa was well tolerated. CONCLUSION: Subcutaneous co-administration of 75 IU lutropin alfa with follitropin alfa is safe and effective in inducing follicular development in women with profound gonadotrophin deficiency.

Effects of decreasing the frequency of gonadotropin-releasing hormone stimulation on gonadotropin secretion in gonadotropin-releasing hormone-deficient men and perifused rat pituitary cells.

The effects of decreasing the frequency of pulsatile gonadotropin-releasing hormone (GnRH) stimulation on pituitary responsiveness were studied in (a) men with isolated GnRH deficiency who had achieved normal sex steroid levels during prior long-term pulsatile GnRH replacement and (b) perifused dispersed pituitary cells from male rats in the absence of sex steroids. In three groups of four GnRH-deficient men, the frequency of GnRH stimulation was decreased at weekly intervals from (a) every 2-3-4 h (group I), (b) every 2-8 h without testosterone replacement (group II), or (c) every 2-8 h with testosterone replacement (group III). In three groups of three columns of perifused dispersed pituitary cells, pulses of GnRH were administered every 2, 4, or 8 h. In groups I and II, mean area under the luteinizing hormone (LH) curve increased (P less than 0.025) and serum testosterone levels fell (P less than 0.035) as the frequency of GnRH stimulation was decreased. In group III, the area under the LH curve also increased (P less than 0.01) although serum testosterone levels were constant, thereby demonstrating that the increase in pituitary responsiveness to slow frequencies of GnRH stimulation occurs independently of changes in the sex steroid hormonal milieu. The area under the LH curve also increased in the perifused dispersed rat pituitary cells when the frequency of GnRH administration was decreased to every 8 h (P less than 0.05), thus demonstrating that the enhanced pituitary responsiveness to slow frequencies of GnRH stimulation is maintained even in the complete absence of gonadal steroids. Nadir LH levels fell in all three groups (P less than 0.01) as the frequency of GnRH stimulation was decreased. In contrast, mean peak LH levels, the rate of LH rise, and the rate of endogenous LH decay were constant as the frequency of GnRH stimulation was decreased. Finally, as the GnRH interpulse interval increased, mean LH levels fell, and mean follicle-stimulating hormone levels were stable or fell. These results indicate that (a) pituitary responsiveness to GnRH increases at slower frequencies of GnRH stimulation in models both in vivo and in vitro, (b) these changes in pituitary responsiveness occur independently of changes in gonadal steroid secretion, and (c) the increases in LH pulse amplitude and area under the curve at slow frequencies of GnRH stimulation are due to decreases in nadir, but not peak, LH levels. Slowing of the frequency of GnRH secretion may be an important independent variable in the control of pituitary gonadotropin secretion.

Insulin binding and glucose transport in adipocytes in neonatal streptozocin-injected rat model of diabetes mellitus.

The neonatal streptozocin (STZ)-injected rat (NSIR) model of diabetes mellitus resembles human non-insulin-dependent diabetes mellitus (NIDDM) with respect to abnormalities in insulin secretory responses. The suggestion that insulin deficiency leads to insulin resistance, a prominent feature of human NIDDM, led us to examine insulin binding and glucose transport in the NSIR during the development of hyperglycemia. Male Wistar rats were injected at 2 days of age with STZ (90 mg/kg i.p.) or vehicle alone. Mild insulin deficiency, reflected by minimally decreased fed plasma insulin concentrations, was apparent at 4 wk (mean +/- SE, control vs. NSIR, 2.32 +/- 0.19 vs. 1.75 +/- 0.21 ng/ml) and at 8 wk. Pancreatic insulin content was dramatically reduced in NSIR to 12 and 5% of control values at 4 and 8 wk, respectively (P less than .001). Fed plasma glucose concentrations increased in the NSIR between 4 and 5 wk and were significantly elevated at 8 wk (251 +/- 25 vs. 527 +/- 52 mg/dl, P less than .001). 125l-labeled insulin binding showed a progressive increase as a function of adipocyte volume in control and NSIR. Epididymal fat pad weights and adipocyte volumes were significantly decreased in the NSIR. Thus, insulin binding did not differ when expressed per cell number but was increased in NSIR when corrected for cell size (percent specific binding X 10(2), 8.49 +/- 0.96 vs. 11.56 +/- 1.08/microliter cell vol; P less than .05, all ages combined).(ABSTRACT TRUNCATED AT 250 WORDS)

The nature of the gonadotropin-releasing hormone stimulus-luteinizing hormone secretory response of human gonadotrophs in vivo.

To examine the stimulus-secretion response of human pituitary gonadotrophs in vivo, we applied a new multiple parameter deconvolution technique to analyze (1) exogenous GnRH-stimulated LH secretory responses in 10 men with isolated hypogonadotropic hypogonadism (IHH), and (2) endogenous and exogenous GnRH-stimulated LH secretory responses in 8 normal men. The GnRH-deficient men were given 4 bolus doses of synthetic GnRH (7.5, 25, 75, and 250 ng/kg) iv at 2-h intervals in randomized order after long term pulsatile GnRH administration. The normal men were studied by sampling blood at 10-min intervals for 12 h basally and after 2 consecutive 10-micrograms iv GnRH doses. The serum LH peaks in both groups were subjected to quantitative deconvolution to resolve underlying LH secretory and clearance rates simultaneously. Such analyses revealed that exogenous GnRH-induced LH secretory episodes in GnRH-deficient men with IHH could be modeled as algebraically Gaussian distributions of instantaneous LH secretory rates with a mean half-duration of 14 +/- 2 min. The simultaneously resolved half-life of endogenous LH disappearance was 71 +/- 5 min. The log dose-response relationship for GnRH dose vs. maximal LH secretory rate or vs. calculated mass of LH released per secretory burst was linear. In contrast, varying GnRH doses did not alter the duration of LH secretory bursts, the half-time of LH disappearance, or the latency of LH secretory bursts after iv GnRH injections (viz. 7.6 min). Deconvolution analysis of the spontaneous (endogenous GnRH-stimulated) LH peaks in normal men revealed a mean half-duration of secretory bursts of 9.9 +/- 1.5 min, and a mean half-time of endogenous LH disappearance of 76 +/- 5 min. These values were not significantly different from those in the GnRH-treated normal or GnRH-deficient men. In summary, deconvolution analysis of LH release in men with IHH revealed a significant linear relationship between iv doses of pulsed GnRH and computer-resolved LH secretory rate and/or the mass of LH released per secretory event. In contrast, varying doses of GnRH did not alter the lag time between the GnRH stimulus and the LH secretory burst, the duration of LH secretion, or the calculated half-life of the LH released. We conclude that GnRH exerts dose-dependent effects on specific attributes of the secretory response of human gonadotrophs in vivo.

Sex steroid control of gonadotropin secretion in the human male. II. Effects of estradiol administration in normal and gonadotropin-releasing hormone-deficient men.

Although prior studies have suggested that estrogens exert their negative feedback effect at the pituitary level in men, these conclusions have been based on models that evaluate changes in LH pulse amplitude and frequency and, therefore, only provide indirect information concerning the site of action of estrogens. To assess whether estradiol (E2) inhibits gonadotropin secretion directly and solely at the pituitary level in men, we determined the pituitary responses to physiological doses of GnRH in six men with complete GnRH deficiency, whose pituitary-gonadal function had been normalized with long term pulsatile GnRH delivery, before and during a 4-day continuous E2 infusion (90 micrograms/day). To deduce whether E2 has an additional inhibitory effect on hypothalamic GnRH secretion, their responses were compared with the effects of identical E2 infusions on spontaneous gonadotropin secretion and the responses to a 100-micrograms GnRH bolus in six normal men. Both groups were monitored with 15 h of frequent blood sampling before and during the last day of the E2 infusion. In the GnRH-deficient men, the first three GnRH doses were identical and chosen to produce LH pulses with amplitudes in the midphysiological range of values in our normal men (i.e. a physiological dose), while the last four doses spanned 1.5 log orders (7.5, 25, 75, and 250 ng/kg). The 250-ng/kg dose was always administered last because it is known to be pharmacological. In the GnRH-deficient men, mean LH and FSH levels as well as LH pulse amplitude all decreased significantly (P less than 0.02) during E2 infusion, demonstrating a direct pituitary-suppressive effect of E2. Mean LH (P less than 0.01) and FSH (P less than 0.05) levels and LH pulse amplitude (P less than 0.01) also decreased significantly in the normal men. The degree of suppression of mean LH (52 +/- 3% vs. 42 +/- 12%) and FSH (49 +/- 10% vs. 37 +/- 10%) levels was similar in the two groups. These results provide direct evidence that E2 inhibits gonadotropin secretion at the pituitary level in men and suggest that the pituitary is the most important, and possibly the sole, site of negative feedback of estrogens in men.

Utility of free alpha-subunit as an alternative neuroendocrine marker of gonadotropin-releasing hormone (GnRH) stimulation of the gonadotroph in the human: evidence from normal and GnRH-deficient men.

To examine the hypothesis that the secretion of free alpha-subunit (FAS) can serve as an alternative to LH as a neuroendocrine marker of gonadotroph stimulation by GnRH in euthyroid humans, we have investigated the relationship of pulsatile FAS secretion in euthyroid GnRH-deficient men (n = 10) before and after exogenous GnRH stimulation and in normal men under the influence of endogenous GnRH secretion (n = 18). Before GnRH exposure, the GnRH-deficient men showed a complete absence of both LH and FAS pulses. During the initial 7 days of GnRH exposure, all GnRH-deficient men exhibited pulsatile release of FAS by the third day, whereas the appearance of pulsatile release of LH and FSH was more variable. Long term administration of GnRH led to pulses of LH and FAS that were 100% concordant with a demonstrable dose-response relationship between GnRH and FAS, which was quantitatively similar to but more exuberant than that for LH. All doses of GnRH that produced LH pulses within the normal adult range yielded supraphysiological FAS pulses. Analysis of distribution histograms of interpulse intervals and pulse amplitudes of LH and FAS in both normal and GnRH-deficient subjects demonstrated no significant difference between these glycoproteins in interpulse intervals in either the normal or GnRH-deficient groups or in the pulse amplitudes in the GnRH-deficient subjects. There was, however, a significant difference (P less than 0.01) between the distribution histogram of LH and FAS pulse amplitudes in normal men. We conclude that the pulsatile secretion of FAS in euthyroid men 1) is determined by GnRH secretion, 2) is the initial glycoprotein to be secreted in a pulsatile fashion from the gonadotroph during early GnRH exposure in GnRH-deficient men, 3) demonstrates a dose-response relationship to exogenous GnRH which is more robust than that of LH in GnRH-deficient men receiving GnRH, and 4) can, therefore, serve as a complementary and powerful tool with LH for the study of GnRH neurosecretory dynamics.

Sex steroid control of gonadotropin secretion in the human male. I. Effects of testosterone administration in normal and gonadotropin-releasing hormone-deficient men.

The precise sites of action of the negative feed-back effects of gonadal steroids in men remain unclear. To determine whether testosterone (T) administration can suppress gonadotropin secretion directly at the level of the pituitary, the pituitary responses to physiological doses of GnRH were assessed in six men with complete GnRH deficiency, whose pituitary-gonadal function had been normalized with long term pulsatile GnRH delivery, before and during a 4-day continuous T infusion (15 mg/day). Their responses were compared with the effects of identical T infusions on spontaneous gonadotropin secretion and the response to a 100-micrograms GnRH bolus in six normal men. Both groups were monitored with 15 h of frequent blood sampling before and during the last day of the T infusion. In the GnRH-deficient men, the first three GnRH doses were identical and were chosen to produce LH pulses with amplitudes in the midphysiological range of our normal men (i.e. a physiological dose), while the last four doses spanned 1.5 log orders (7.5, 25, 75, and 250 ng/kg). The 250 ng/kg dose was always administered last because it is known to be pharmacological. In the GnRH-deficient men, mean LH (P less than 0.02) and FSH (P less than 0.01) levels as well as LH pulse amplitude (P less than 0.05) decreased significantly during T infusion, demonstrating a direct pituitary-suppressive effect of T and/or its metabolites. Mean LH levels were suppressed to a greater extent in the normal than in the GnRH-deficient men (58 +/- 15% vs. 28 +/- 7%; P less than 0.05). In addition, LH frequency decreased significantly (P less than 0.01) during T administration in the normal men. These latter two findings suggest that T administration also suppresses hypothalamic GnRH release. T was unable to suppress gonadotropin secretion in one GnRH-deficient and one normal man. In both groups, the suppressive effect of T administration was present only in response to physiological doses of GnRH. Because the pituitary- and hypothalamus-suppressive effects of T could be mediated by its aromatization to estrogens, five GnRH-deficient and five normal men underwent identical T infusions with concomitant administration of the aromatase inhibitor testolactone (TL; 500 mg, orally, every 6 h). As an additional control, four GnRH-deficient and four normal men received TL alone. TL administration completely prevented the effect of T administration to suppress gonadotropin secretion in both the normal and GnRH-deficient men, and mean LH levels increased significantly in both the GnRH-deficient (P less than 0.01) and the normal (P less than 0.001) men who received TL alone. The increase in mean LH levels was greater (P less than 0.01) in the normal men who received TL alone than in the normal men who received T plus TL, thus revealing a direct effect of androgens in normal men. Measurements of T and estradiol production rates in three men demonstrated that TL effectively blocked aromatization.(ABSTRACT TRUNCATED AT 400 WORDS)

Pulsatile gonadotropin secretion after discontinuation of long term gonadotropin-releasing hormone (GnRH) administration in a subset of GnRH-deficient men.

Normal pituitary and gonadal function can be maintained with long term pulsatile GnRH administration in men with idiopathic hypogonadotropic hypogonadism (IHH), and both pituitary and gonadal priming occur during the process of GnRH-induced sexual maturation. Still, the long term effects of discontinuing GnRH therapy in IHH men have not been examined. Therefore, we evaluated the patterns of gonadotropin and alpha-subunit secretion before and after a prolonged period of pulsatile GnRH administration in 10 IHH men. Before exogenous GnRH stimulation, no patient had any detectable LH pulsations. In 6 of these men, who were typical of most of our IHH patients (group I), no LH pulsations were detectable after cessation of GnRH administration. However, in the other 4 men (group II), LH pulsations were easily detectable despite cessation of exogenous GnRH stimulation, and the amplitude (9.3 +/- 3.5 IU/L) and frequency (13.8 +/- 1.7 pulses/day) of these LH pulses were similar to those in 20 normal men (10.6 +/- 0.7 IU/L and 11.0 +/- 0.7 pulses/day). Three of these 4 men in group II maintained normal serum testosterone levels after discontinuation of GnRH delivery. To determine if there were any characteristics that might be useful in predicting which IHH men could maintain normal pituitary-gonadal function after long term GnRH administration, we evaluated various clinical and hormonal parameters at the time of initial presentation. Mean alpha-subunit levels (P less than 0.01) and alpha-subunit pulse amplitude (P less than 0.02) were significantly higher in the group II than the group I men, suggesting that the group II patients had partial, rather than complete, deficiency of endogenous GnRH secretion. None of the other parameters that were assessed distinguished the two groups. We conclude that gonadotropin and sex steroid levels return to their pretreatment state in the majority of IHH men when long term GnRH administration is discontinued. Normal pituitary-gonadal function can be maintained after discontinuation of long term GnRH administration in a rare subset of IHH men who present with higher levels of alpha-subunit. We hypothesize that these latter IHH men have an incomplete GnRH deficiency and that long term exogenous GnRH administration induces pituitary and gonadal priming, which subsequently enables them to sustain normal pituitary and gonadal function in response to their own enfeebled GnRH secretion.

Assessment of the role of serum luteinizing hormone and estradiol response to follicle-stimulating hormone on in vitro fertilization treatment outcome.

OBJECTIVE: To analyze the role of serum LH and of E2 secretion on IVF-ET outcome in patients stimulated with FSH. DESIGN: Using data from three studies, we analyzed ovarian response to FSH and IVF-ET outcome from two standpoints: [1] serum LH and [2] serum E2 on the day of hCG administration divided by the number of retrieved oocytes. SETTING: Twenty-six academic and private clinical centers. PATIENT(S): Three hundred twenty-three ovulatory patients eligible for IVF-ET. INTERVENTION(S): Patients were treated with a GnRH agonist and FSH and underwent IVF-ET. MAIN OUTCOME MEASURE(S): Follicular development, embryos, and pregnancy rate (PR). RESULT(S): Serum LH levels did not correlate significantly with number of oocytes retrieved, E2-oocyte ratio, fertilization rate, or PR. Five patient subpopulations were identified on the basis of E2-oocyte ratios: 0 to 70 (A), 70 to 140 (B), 140 to 210 (C), 210 to 280 (D), and > 280 (E) pg/mL per oocyte (conversion factor to SI unit, 3.671). Pregnancy rates were significantly different, i.e., 5.3%, 31.3%, 18.1%, 23.9%, and 20.4% for groups A, B, C, D, and E, respectively. Groups were not different in terms of baseline characteristics, number of follicles, fertilization rates, and number of embryos transferred. CONCLUSION: Patients with very low levels of LH respond to FSH alone as well as those with higher LH. The E2-oocyte ratio is a strong index of success rate.

Recombinant human chorionic gonadotropin (rhCG) in assisted reproductive technology: results of a clinical trial comparing two doses of rhCG (Ovidrel) to urinary hCG (Profasi) for induction of final follicular maturation in in vitro fertilization-embryo transfer.

OBJECTIVE: To compare the efficacy and safety of 250 microg and 500 microg of recombinant hCG with 10,000 U USP of urinary hCG in assisted reproduction technology. DESIGN: Open, comparative, randomized, prospective clinical study. SETTING: Twenty tertiary care U.S. infertility centers. PATIENT(S): Two hundred ninety-seven ovulatory infertile women undergoing a single cycle of assisted reproduction technology. INTERVENTION(S): Patients were randomized 1:1:1 to 250 microg of recombinant hCG SC, 500 microg of recombinant hCG SC, or 10,000 U USP urinary hCG IM after completing gonadotropin stimulation. MAIN OUTCOME MEASURE(S): Number of oocytes retrieved per patient receiving hCG. Also, measures of oocyte maturity, embryo development, and luteal function, as well as pregnancy and pregnancy outcome. Adverse safety events, laboratory changes, local tolerance, and immunogenicity were also assessed. RESULT(S): Mean numbers of oocytes retrieved per treatment group were equivalent, 13.6, 14.6, and 13.7 with 250 microg of recombinant hCG, 500 microg of recombinant hCG, and urinary hCG, respectively. The numbers of 2PN fertilized oocytes on day 1 after oocyte retrieval, and 2PN or cleaved embryos on the day of embryo transfer, were significantly higher with 500 microg of recombinant hCG than with the lower dose. However, the incidence of adverse events also tended to be higher with this dose. CONCLUSION(S): Recombinant hCG is effective and well tolerated in the induction of final follicular maturation and luteinization in women undergoing assisted reproduction technology. Recombinant hCG (250 microg) SC is equivalent to 10,000 U USP of urinary hCG in this indication.

Primary and secondary testicular insufficiency.

The possibility of testicular insufficiency is a common problem for the pediatric practitioner. Presentation varies with the severity of the defect, the developmental age achieved before onset, and the presence of associated other abnormalities. Most commonly, primary and secondary testicular insufficiency present at the time of puberty, but the presentation may be at birth or in the early neonatal period. Appropriate investigations may uncover the diagnosis at the time and allow intervention later at the appropriate age. Secondary testicular failure, although more difficult to diagnose and to differentiate from simple delay of development, offers the possibility of later development of spermatogenesis and the attainment of fertility through the use of gonadotropins or GnRH replacement programs. In primary testicular failure, because it implies an intrinsic abnormality of the functioning elements of the testis, spermatogenesis is not inducable by hormonal stimulation. Treatment of testicular failure in the neonatal period is unnecessary unless micropenis is associated. In the pubertal boy, testosterone replacement is the treatment of choice and should be initiated carefully, taking into consideration the age of the subject, his bone age, and the psychosocial circumstances. The goal of therapy is to achieve a normal progression of physical changes of puberty to physical maturity and the normal potential for sexual function.

Interpulse interval sequence of LH in normal men essentially constitutes a renewal process.

Luteinizing hormone (LH) is released from the anterior pituitary gland in an episodic pattern driven by pulses of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Autocorrelation analysis of the sequence of interpulse intervals of LH secretion in normal men supports the hypothesis that the underlying mechanism driving LH secretion is a renewal process. That is, whatever "memory" the GnRH pulse generator (i.e., the hypothalamus or its antecedent neural drive) may have, it does not go back in time further than the preceding secretory pulse. Thus the hypothalamic timer starts over again each time there is a GnRH secretory episode.

Recombinant follicle-stimulating hormone in a patient hypersensitive to urinary-derived gonadotropins.

Hypersensitivity reactions are a documented complication of urinary-derived gonadotropin therapy. In this report, a patient allergic to these older products is successfully treated with recombinant follicle-stimulating hormone.

Neuroendocrine control of human reproduction in the male.

The traditional difficulty in studying the neuroendocrine control of reproduction in the human male has been the inability to tease out the hypothalamic from the pituitary component of this neuroendocrine system. The use of multiple models, each with its own strength and weakness, represents an overlapping approach that has permitted further insights to be gained into the hypothalamic control of the neuroendocrine regulation of gonadotropin secretion in the human. Such an insight is an important prerequisite to the understanding of the pathophysiology of various disease states, the unraveling of a control of FSH secretion by GnRH vs other modulators, and the subsequent design of rational therapies for male reproductive disorders.

Neuroendocrine-gonadal axis in men: frequent sampling of LH, FSH, and testosterone.

Previous studies of episodic hormone secretion of the hypothalamic-pituitary-gonadal axis in normal men have produced conflicting results due to examinations of small cohorts of subjects or to limited sampling techniques. We evaluated gonadotropin and testosterone (T) secretory patterns in 20 normal men by sampling blood at 10-min intervals for luteinizing hormone (LH) and follicle-stimulating hormone (FSH). T concentrations were also analyzed at 20-min intervals in 10 subjects. A previously unappreciated spectrum of gonadotropin and T secretory patterns was observed in normal men. Both mean LH concentrations and mean LH pulse amplitudes varied fourfold between individuals. LH interpulse intervals varied from 30 to 480 min (mean 119 +/- 32). Results also suggested a relative refractory period at the level of the hypothalamus or pituitary. In three subjects, a striking nighttime accentuation of LH pulsations was noted. Through use of Fourier analysis, a diurnal variation in LH was observed in the population (P less than 0.02). Mean FSH levels showed marked variation between individual subjects, with discrete pulses rarely observed. No diurnal variation in FSH secretion was noted. Serum T concentrations determined at 6-h intervals ranged from 105 to 1,316 ng/dl between subjects. When T was measured at 20-min intervals, marked intermittent declines in the T concentrations to levels well below the normal range were observed in 3 of 10 subjects. T secretion was found to lag behind LH secretion by approximately 40 min (P less than 0.02).

Interpulse interval of GnRH stimulation independently modulates LH secretion.

To examine the importance of the interpulse interval of gonadotropin-releasing hormone (GnRH) stimulation in modulating gonadotroph responsiveness, a fixed individualized dose of GnRH was administered to eight GnRH-deficient men at intervals selected randomly from the distribution of luteinizing hormone (LH) interpulse intervals of normal men. The responses were compared with data derived from a study of LH pulses in 20 normal men. A positive relationship was found between LH pulse amplitude and the preceding interpulse interval both in the GnRH-deficient (P less than 0.05) and in the normal (P less than 0.003) men. The distributions of LH pulse amplitudes appeared to differ between the two groups with failure of the study paradigm to reproduce the distribution of low-amplitude pulses of the normal men in the GnRH-deficient men. There was significantly more variability about the line that related interpulse interval and LH amplitude in the normal men (P less than 0.004) in whom the amount of GnRH could vary physiologically. This difference remained significant both for pulses with amplitudes below (P less than 0.01) or above (P less than 0.03) the mean of the normal men. These studies demonstrate that the GnRH interpulse interval is an independent determinant of pituitary responsiveness and that alterations in the amount of GnRH secreted from the hypothalamus are an important determinant of LH pulse amplitude in men.

Long-term administration of gonadotropin-releasing hormone in men with idiopathic hypogonadotropic hypogonadism. A model for studies of the hormone's physiologic effects.

The effect of long-term administration of gonadotropin-releasing hormone (GnRH) for induction and maintenance of sexual maturation was characterized in 23 men with idiopathic hypogonadotropic hypogonadism. Twenty-two men achieved normal adult male serum testosterone concentrations (575 +/- 33 ng/dL; p less than 0.0001 compared with the baseline mean of 61 +/- 6 ng/dL) that were sustained in 21 men for up to 36 months with bolus doses of GnRH varying from 25 to 300 ng/kg body weight administered every 2 hours. Pulsatile luteinizing hormone (LH) secretion occurred in all 23 men, with mean levels of LH (14.7 +/- 1.3 mlU/mL) and follicle-stimulating hormone (11.3 +/- 1.3 mlU/mL) within or above the normal range for adult men. Mature sperm were observed in the ejaculates of 20 men, with counts ranging from less than 1 X 10(6) to 96 X 10(6)/mL. Increasing responsiveness of the pituitary-gonadal axis to GnRH was shown in 6 men. Men with idiopathic hypogonadotropic hypogonadism present a useful model to study the onset and maintenance of reproductive function in men.

Long-term therapy with recombinant human growth hormone (Saizen) in children with idiopathic and organic growth hormone deficiency.

In an open-label study, 69 children with organic or idiopathic growth hormone deficiency (GHD) were treated with recombinant human growth hormone (Saizen) for an average of 64.4 mo, with treatment periods as long as 140.9 mo. Auxologic measurements, including height velocity, height standard deviation score, and bone age, were made on a regular basis. The data suggest that long-term treatment with Saizen in children with GHD results in a positive catch-up growth response and proportionate changes in bone age vs height age during treatment. In addition, long-term Saizen therapy was well tolerated, with the majority of adverse events related to common childhood disorders or existing baseline medical conditions and not to study treatment. There were no significant changes in laboratory safety data or vital signs, and no positive antibody tests for Saizen.

Outcome of growth hormone therapy in children with growth hormone deficiency showing an inadequate response to growth hormone-releasing hormone.

Saizen (recombinant growth hormone [GH]), 0.2 mg/(kg x wk), was given in an open-label fashion for an average of 51 mo to 27 children with presumed idiopathic GH deficiency who had withdrawn from a trial of Geref (recombinant GH-releasing hormone [GHRH] 1-29) because of inadequate height velocity (HV) (25 children), the onset of puberty (1 child), or injection site reactions (1 child). Measurements were made every 3-12 mo of a number of auxologic variables, including HV, height standard deviation score, and bone age. The children in the study showed excellent responses to Saizen. Moreover, first-year growth during Saizen therapy was inversely correlated with the GH response to provocative GHRH testing carried out 6 and 12 mo after the initiation of Geref treatment. These findings indicate that GH is effective in accelerating growth in GH-deficient children who do not show or maintain a satisfactory response to treatment with GHRH. In addition, they suggest that the initial response to GH therapy used in this way can be predicted by means of provoc-ative testing.