Physiological effects of nonthyroidal illness syndrome in patients after cardiac surgery.

In a prospective randomized placebo-controlled study, we assessed potential physiological effects of nonthyroidal illness syndrome (NTIS) in acute illness. Coronary artery bypass graft surgery was employed as a prospective model of acute illness and NTIS. Triiodothyronine (T(3)) or placebo was infused for 24 h after surgery, with a T(3) dose selected to maintain postoperative serum T(3) concentrations at preoperative levels. Patients were evaluated before coronary artery bypass graft and during the postoperative period. Cardiovascular function was monitored with Swan-Ganz catheter measurements and ECG. Urinary nitrogen excretion and L-[1-(13)C]leucine flux were used to evaluate protein metabolism. Serum measurements of relevant hormones, iron, and total iron-binding capacity were used to assess effects on sex steroid, growth hormone axis, and iron responses to illness. Cardiovascular function was not affected by T(3) infusion, except for a transient higher cardiac index in the T(3) group 6 h after surgery (3.04 +/- 0.12 for T(3) and 2.53 +/- 0.08 for placebo, P = 0.0016). Protein metabolism was not affected; changes in urinary nitrogen excretion and L-[1-(13)C]leucine flux were equivalent in the two groups (P = 0.35 and P = 0.95, respectively). No differences were observed in changes in testosterone, estrogens, growth hormone, insulin-like growth hormone I, iron, or total iron-binding capacity between T(3) and placebo groups. We conclude that, in the early stages of major illness, the decrease in circulating T(3) concentrations in NTIS has only a minimal transient physiological impact on cardiac function and plays no significant role in protecting against protein catabolism or modulating other endocrine responses or iron responses to illness.

Altered gonadal steroidogenesis in critical illness: is treatment with anabolic steroids indicated?

The physiology of the reproductive system changes dramatically with the onset of major illness. The serum testosterone concentrations fall to pre-pubertal levels secondary to a decreased secretion of gonadotropins and a decreased Leydig cell response to luteinizing hormone. At the same time, the serum oestrogen concentration rises as the result of an increased rate of peripheral aromatization. The clinical consequences of these marked changes are not yet well understood. One line of evidence argues for the administration of anabolic steroids (derivatives of testosterone) to critically ill patients to improve their catabolic state. Another line of evidence in animal models suggests that testosterone may suppress the immune system and myocardial function in critical illness. No clinical trials of oestrogen administration to critically ill patients have been reported, although two animal studies suggest that oestrogen may have a positive effect on survival. This chapter reviews changes in the physiology of the reproductive system in major illness as well as current evidence regarding the clinical effects of androgens and oestrogens in critical illness and their potential therapeutic roles.

Mealtime glucose regulation by nateglinide in type-2 diabetes mellitus.

OBJECTIVES: Pharmacodynamic effects of nateglinide, a novel antidiabetic agent, were investigated in patients with type-2 diabetes mellitus. METHODS: Ten patients participated in this single-center, double-blind, crossover study. Plasma glucose and insulin levels were measured over 24 h following five 7-day treatment periods with nateglinide (30, 60, or 120 mg) or placebo given three times daily before breakfast, lunch, and dinner. A fifth treatment consisted of 120 mg nateglinide four times daily, with the fourth dose given before an evening snack. RESULTS: Taken 10 min before meals, doses of 30-120 mg nateglinide caused dose-dependent increases in plasma insulin levels that were significantly greater than with placebo. Higher doses were more effective and had a longer duration of action than lower doses. Nateglinide was also significantly better than placebo in lowering plasma glucose levels; the 60-mg and 120-mg doses were similarly effective and superior to the 30-mg nateglinide treatment. Following the fourth 120-mg dose, the glucose-lowering effects of treatment were maintained through the night. No serious adverse events occurred during the study. There were no events of hypoglycemia and no clinically meaningful changes in safety parameters. CONCLUSIONS: Nateglinide produced rapid, short-lived, dose-related increases in plasma insulin that significantly lowered mealtime glucose excursions compared with placebo with no incidence of hypoglycemia. The decrease in mealtime glucose levels produced a significant improvement in overall 24-h glycemia.

Differential changes in serum concentrations of androgens and estrogens (in relation with cortisol) in postmenopausal women with acute illness.

Previous studies of adrenal androgens and estrogens in critical illness were limited by measuring only selected sex steroids and by including men (who have confounding simultaneous changes in gonadal steroids). We evaluated relationships between changes in serum levels of cortisol (F), androgens, estrogens, and gonadotropins in 20 postmenopausal women with acute critical illness to determine if changes in adrenal androgens and estrogens paralleled gonadal axis suppression or adrenal stimulation. Two patterns of changes in sex steroids were observed. Admission serum levels of androstenedione (delta 4-A), estradiol, and estrone, like F, were increased compared to healthy controls (P < 0.0001). delta 4-A and estrone then decreased toward normal by day 5 in parallel with cortisol (r = 0.56 and 0.60). In contrast, admission serum dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) were not elevated and testosterone (T) was decreased in our patients compared to controls (P < 0.0005) in parallel with serum gonadotropin levels. Serum levels of DHEA and T continued to decrease by day 5 in parallel with gonadotropins. We conclude that in agonadal patients with acute critical illness, serum levels of DHEA-S and T are selectively decreased in relation to F, delta 4-A, and estrogens. The decreased serum T levels suggest inhibition of 17 beta-OH-dehydrogenase and/or increased aromatization to estradiol. The marked increase in serum estrogen levels also suggests increased aromatization. The absence of increases in DHEA and DHEA-S suggest enhanced activity of 3 beta-hydroxysteroid dehydrogenase and/or inhibition of C17,20-lyase activity of P-450c17. The clinical significance of this marked increase in the ratio of estrogens to androgens in acute illness requires further investigation.

Reproductive axis suppression in acute illness is related to disease severity.

Changes in the adrenal and thyroid axes in critically ill patients are accentuated by increasing disease severity. However, the relationship of gonadal axis suppression to severity of illness is not well defined. We evaluated serial serum levels of LH, FSH, and testosterone (T) in 59 men and 42 postmenopausal women admitted to critical care units with a spectrum of disease severity. Patients were grouped according to severity of illness by the Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores and by survival. Patients with surgery, renal or hepatic failure, alcohol abuse, endocrine disease, or head trauma were excluded to avoid these confounding factors. In men, mean admission serum T levels in all groups were lower than in healthy controls (P < 0.005). In addition, T levels in men with severe illness (APACHE > 15) were lower than in men with relatively mild (APACHE < 10; P < 0.01) or moderate illness (APACHE 10-15; P < 0.05). These differences were accentuated as hospitalization progressed. In postmenopausal women and men, nadir serum FSH but not LH levels during hospitalization were lower in patients with APACHE greater than 15 than in patients with APACHE scores of 10-15 or less than 15 (P < 0.05). Grouping patients by survival yielded similar results. Analysis of drug effects, age, and PRL did not explain these relationships. We conclude that the degree of both central and peripheral suppression of the reproductive axis in acute illness is related to disease severity. This suppression could not be attributed to other factors known to alter the reproductive axis independently from critical illness (e.g. age, drugs, head trauma, hepatic failure, etc.). These findings further document a general endocrine response to acute illness involving several axes which is graded according to disease severity.

Both hyper- and hypogonadotropic hypogonadism occur transiently in acute illness: bio- and immunoactive gonadotropins.

Previous reports of hypogonadotropic hypogonadism in critically ill men may not reflect the complexity of changes in the hypothalamic-pituitary-gonadal (HPG) axis during acute illness. We sampled blood throughout hospitalization in 55 men admitted to acute care units to delineate the spectrum of changes in circulating gonadotropin and sex steroid levels at the onset and during recovery from acute illness. Bioactive LH and FSH were measured in a subset of patients. Percent free testosterone was measured to assess changes in binding to sex hormone binding globulin. Medications and serum estrogen and prolactin levels were monitored as potential causes of hypogonadotropism. Sustained suppression of serum testosterone levels below the normal range occurred in 62% of men with varying diagnoses and disease severity. Percent free testosterone remained constant. Hypogonadotropism was observed in most men (60%) and occurred independently from head injury, surgery, medications, or hyperprolactinemia. In a subset of men (n = 16), LH and/or FSH rose transiently above the normal range. Bioactivity of both LH and FSH remained constant while serum testosterone levels decreased. In contrast to serum testosterone levels, mean serum levels of E1, E2 and androstenedione were not less than control values. We conclude that both primary and secondary hypogonadism occur transiently in acutely ill men and cannot be explained solely by medications, hyperprolactinemia, or hyperestrogenemia. Neither biopotency of gonadotropins nor binding of testosterone to SHBG change across the course of acute illness. The hypogonadism, often severe and prolonged, may contribute to the persistent catabolic state observed in many critically ill patients.

Serum estradiol but not gonadotropin levels decrease acutely after insulin-induced hypoglycemia in cycling women.

Although corticotropin-releasing hormone (CRH) acutely suppresses gonadotropin-releasing hormone (GnRH) secretion in animal models, its effect on the hypothalamic-pituitary-gonadal axis in humans is not well defined. To further evaluate the acute effects of adrenal axis activation on the hypothalamic-pituitary-gonadal axis in humans, we employed a model of insulin-induced hypoglycemia to stimulate endogenous CRH secretion in eight cycling women. Serum samples were obtained immediately before and 15, 30, 45, 60, 75, 90, and 120 min following iv insulin (0.15 U/kg) or saline injection. To ensure that the degree of hypothalamic-pituitary-adrenal activation in our subjects was similar to that observed in severely ill patients with hypogonadotropism, serum cortisol (F) levels were also measured in a group of acutely ill patients selected to have hypogonadotropism. All women experienced symptomatic hypoglycemia after insulin injection. Differences between serum F levels in hypoglycemic vs. control sessions were evident at 30 min (P < 0.01) and maximum at 120 min (P < 0.0001) after insulin injection. Serum estradiol levels were significantly lower following hypoglycemia than during control sessions (P < 0.001). In contrast, serum LH and FSH levels were not significantly different between control and hypoglycemic sessions. Peak serum F levels in these hypoglycemic women were similar to F levels in critically ill patients with hypogonadotropism. These results demonstrate that stress and/or hypoglycemia can acutely decrease circulating estradiol levels. In addition, these data suggest that endogenous CRH does not play a major role in acute suppression of GnRH (over 2 h) in humans. Further studies are required to identify longer term effects of CRH on GnRH secretion which may be present in hypothalamic amenorrhea or hypogonadotropic hypogonadism of critical illness.

Osteopenia in women with hypothalamic amenorrhea: a prospective study.

Hypothalamic amenorrhea, a common disorder associated with abnormalities in gonadotropin pulsatility and subsequent estrogen deficiency, is usually transient, and treatment indications are unclear unless fertility is desired. To determine whether this disorder is associated with progressive bone loss, we studied 24 women with primary or secondary amenorrhea related to stress or simple weight loss, compared with 31 normal women of the same age. Amenorrheic women had significantly lower (P = .01) body fat (26.4 +/- 7.3 versus 30.6 +/- 4.7%) and higher (P = .0001) urine free cortisol levels (250 +/- 100 versus 140 +/- 50 nmol/day) than normals. Trabecular bone density in women with hypothalamic amenorrhea as assessed by spinal computed tomography was significantly (P = .001) lower than in normals (140.2 +/- 27.3 versus 175.1 +/- 24.6 mg K2HPO4/mL, respectively). Twenty of the 24 amenorrheic women had initial spinal bone density below the mean in normals, and in eight it was 2 standard deviations or more below the normal mean. Initial bone density correlated negatively with duration of amenorrhea (r = -0.489, P = .02) and positively with serum free testosterone levels (r = 0.517, P = .02). Prospective evaluation showed a decline in spinal bone density in those who were amenorrheic for fewer than 5 years. The slope of change in bone density correlated with initial weight, percent ideal body weight, and percent body fat (R2 = 0.597, P = .0003; R2 = 0.549, P = .0007; and R2 = 0.618, P = .0002, respectively).(ABSTRACT TRUNCATED AT 250 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.

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.

Pituitary and gonadal responsiveness is enhanced during GnRH-induced puberty.

We hypothesized that the hypothalamic gonadotropin-releasing hormone (GnRH) signal that initiates sexual maturation is further amplified at both the pituitary and gonadal levels during puberty. To test this theory, six GnRH-deficient men were monitored during administration of exogenous GnRH at a physiological frequency for greater than or equal to 9 mo. GnRH doses were progressively increased until normal testosterone (T) concentrations and secondary sexual development were achieved. This "optimized" dose of GnRH was then sustained for at least 6 mo to allow maturation of the hypothalamic-pituitary-gonadal axis. The GnRH dose was then progressively decreased to a level that had been unable to stimulate normal T secretion before sexual maturation. Changes in pituitary responsiveness were analyzed in four of the six men by comparing gonadotropin responses to identical doses of GnRH before and after sexual maturation. Mean serum luteinizing hormone and follicle-stimulating hormone levels as well as luteinizing hormone pulse amplitudes were greater after the induction of sexual maturation than before despite identical doses of GnRH. Both pituitary and gonadal responsiveness was then analyzed in the remaining two subjects by choosing periods of evaluation where endogenous gonadotropin levels were matched before and after the period of sexual maturation. Serum T concentrations were greater after sexual maturation than before despite equivalent gonadotropin input to the testes and LH pulse amplitudes. Thus the testicular responsiveness to gonadotropins increased during sexual maturation. After initiation of puberty by GnRH secretion, amplification at both the pituitary and gonadal levels contributes to sexual maturation in the human.

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).

Effects of increasing the frequency of low doses of gonadotropin-releasing hormone (GnRH) on gonadotropin secretion in GnRH-deficient men.

The effects of increasing the frequency of pulsatile GnRH administration on LH and FSH responsiveness were studied in five GnRH-deficient men who had achieved normal sex steroid levels during prior long term GnRH replacement. Intravenous doses of GnRH were employed that had previously been demonstrated to produce LH and FSH levels in each subject similar to those in normal men. Both acute and chronic changes in pituitary responses were studied after progressive increases in GnRH frequency (from every 120 to 60 min, from 60 to 30 min, and from 30 to 15 min) during three 12-h admissions, each separated by 7 days. During the two intervals between the studies GnRH frequency was 60 and 30 min, respectively. Pituitary responses were characterized by determining the mean serum LH and FSH levels, LH pulse amplitudes, and mean LH and FSH levels which were normalized for the frequency of GnRH administration (nLH and nFSH). As the frequency of GnRH stimulation was increased acutely, mean serum LH levels rose progressively, in contrast to both LH pulse amplitude and nLH levels which decreased, while serum testosterone (T) concentrations remained constant. No further evidence of gonadotroph desensitization occurred after chronic GnRH administration at either 60- or 30-min intervals. At higher frequencies of GnRH stimulation, discrete pulses of LH were not always apparent after injections of GnRH, and in two men, marked destabilization of the gonadotroph responses occurred. Even without detectable LH pulses, serum T levels did not decline during administration of GnRH at intervals as rapid as 15 min. In contrast, there was no change in mean FSH concentrations, although nFSH values decreased progressively as the GnRH frequency was increased. nFSH levels fell to a greater degree than nLH after each increase in GnRH frequency. Thus, pituitary gonadotroph responsiveness to a fixed dose of GnRH decreased as the frequency of GnRH stimulation increased. FSH responsiveness decreased to a greater degree than did LH. Gonadotropin secretory responses are destabilized at higher frequencies of GnRH administration. Pulsatile LH stimulation of the testes does not appear necessary to maintain T secretion.

The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations.

Several lines of evidence indicate that hypothalamic-pituitary-gonadal activity varies among men with idiopathic hypogonadotropic hypogonadism (IHH). To test the hypothesis that a spectrum of abnormalities of GnRH secretion underlies the syndrome of IHH, we characterized the patterns of GnRH-induced gonadotropin secretion during periods of frequent sampling in 50 consecutive men with IHH and contrasted them with those in 20 normal men. The largest group of IHH patients (n = 42) had no detectable LH or FSH pulsations and could be categorized into 2 subsets according to the presence or absence of evidence of spontaneous puberty. The most severely affected subset (n = 32), who recalled no history of puberty, had testes with a mean volume of 3.3 +/- 0.5 (+/- SEM) ml, with a prepubertal appearance on biopsy, and often were anosmic (n = 17). The second subset of apulsatile IHH men (n = 10) had histories of partial or complete spontaneous sexual development with subsequent isolated loss of sexual function, testes with a mean volume of 13.3 +/- 1.9 ml (P less than 0.01 compared to the first subset), a pubertal or adult appearance of the testes on biopsy, and an intact sense of smell. In a second group of IHH patients (n = 3), LH was secreted predominantly in a nighttime pattern similar to that of normal children during early puberty. These men were aged 18-24 yr, had a mean testicular volume of 10.5 +/- 2.3 ml, pubertal changes on testicular biopsy, and an intact sense of smell. A third group of IHH men (n = 4) had LH pulses of abnormally low amplitude. Only one patient in this group had a history of spontaneous sexual development. The mean testicular volume of these patients was 5.6 +/- 1.9 ml, and the testes appeared prepubertal (n = 3) or pubertal (n = 1) on biopsy. In addition to these groups, another patient had apparent LH pulsations and nearly normal amplitude, but the LH was bioinactive and appeared to consist chiefly of alpha-subunit. Testing of other anterior pituitary hormone functions did not distinguish IHH men from normal men. However, those IHH patients with some evidence of endogenous GnRH secretion had higher basal and stimulated serum PRL levels than IHH men without such evidence (P less than 0.05), suggesting an influence of GnRH on PRL secretion.

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.

Bio- and immunoactive luteinizing hormone responses to low doses of gonadotropin-releasing hormone (GnRH): dose-response curves in GnRH-deficient men.

Previous investigations of the effects of GnRH on pituitary LH responses in normal men required pharmacological doses of GnRH to avoid the confounding effects of endogenous GnRH secretion and employed nonphysiological dose intervals. To examine the role of GnRH in determining both the qualitative and quantitative nature of physiological LH responses, we studied five GnRH-deficient men in whom pituitary and gonadal function had been normalized with GnRH replacement. Both bio- and immunoactive LH responses were evaluated in these men after a wide range of GnRH doses (7.5-250 ng/kg) administered at a physiological frequency (every 2 h), while gonadal steroid levels were within the normal adult male range. In addition, the amplitude and contour of the immunoactive LH pulses were compared to those of 15 normal men to assure that these experiments achieved physiological pituitary responses. The relationship between bio- and immunoactive LH was compared between patients, between doses as the amount of GnRH was increased, and within pulses of LH. As the dose of GnRH was increased, both bio- and immunoactive LH responses increased in a log-linear fashion when assessed by both amplitude (r = 0.96 for bioactive LH and r = 0.98 for immunoactive LH) and area under the curve (r = 0.99 for bioactive LH and r = 0.97 for immunoactive LH). GnRH doses of 7.5 and 25 ng/kg produced LH responses with amplitudes similar to those in normal men. The relationship between bio- and immunoactive LH between patients and between differing doses of GnRH was analyzed by comparing the slopes of lines fit to individual bioactive vs. immunoactive LH plots after each dose of GnRH in each patient. There was a marked variation in the relationship of bio- to immunoactive LH between patients (P less than 0.005). No change was found in the biopotency of LH as the dose of GnRH was increased (P less than 0.10). Finally, no variation of the bioactivity of LH was evident within individual pulses. We conclude that a log-linear relationship exists between doses of GnRH that produce physiological LH pulses and both bio- and immunoactive LH responses; the bioactivity of secreted LH varies markedly between patients; the relative bioactivity of LH in an individual does not change as the dose of GnRH is increased; and no change in bioactivity of LH responses was demonstrated within pulses of LH.

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.

Administration of low dose pulsatile gonadotropin-releasing hormone (GnRH) to GnRH-deficient men regulates free alpha-subunit secretion.

Although pharmacological doses of GnRH and TRH stimulate free alpha-subunit (alpha-subunit) secretion from the pituitary, little is known about the pattern and control of alpha-subunit release under physiological circumstances. Euthyroid men with idiopathic hypogonadotropic hypogonadism, a condition of deficient GnRH release, provide a unique opportunity to study alpha-subunit secretion before and during administration of a physiological regimen of GnRH administration. Before GnRH therapy, six euthyroid IHH men with normal endogenous TSH secretion had circulating alpha-subunit levels close to or below assay detection limits, with a mean level less than 0.5 ng/ml. During 12-42 weeks of physiological GnRH replacement, serum alpha-subunit concentrations rose to a mean value of 2.07 +/- 0.3 (+/- SEM) ng/ml (P less than 0.01). After GnRH administration, alpha-subunit was released in a pulsatile pattern following each dose of GnRH and mirrored the secretory pattern of LH. Increases in serum alpha-subunit concentrations during GnRH administration were closely correlated with increases in LH (r = 0.91; P less than 0.01), but not FSH (r = 0.24; P = NS), levels. In addition, a situation in which LH secretion was clearly predominant and FSH levels were barely detectable was created by increasing the frequency of GnRH administration to every 30 min. In this circumstance, free alpha-subunit concentrations increased in conjunction with LH levels in the face of decreased FSH levels. We conclude that replacement of GnRH regulates both the level and pattern of alpha-subunit secretion in GnRH-deficient men, and that there is tight correlation of alpha-subunit with LH, but not with FSH, secretion.

Pituitary luteinizing hormone responses to intravenous and subcutaneous administration of gonadotropin-releasing hormone in men.

Although differences in plasma GnRH concentrations have been identified after iv and sc injection of this peptide, differences in pituitary LH responses to iv and sc GnRH have not been evaluated in detail. We studied the magnitude and contour of plasma GnRH and LH responses after low doses of iv and sc GnRH administered to men with idiopathic hypogonadotropic hypogonadism and compared them to LH pulses in normal men after endogenous GnRH secretion. Mean areas under the LH response curves differed significantly (P less than 0.01) after 25 ng/kg, but not 250 ng/kg, iv and sc GnRH doses. The mean time from basal to peak plasma LH concentrations was significantly longer with sc than iv GnRH (P less than 0.02). In addition, individual LH responses were more variable with sc GnRH. Intravenous administration produced greater GnRH amplitude (P less than 0.001) and area under the curve (P less than 0.005) and shorter time to peak (P less than 0.01) GnRH concentrations. When plasma LH responses of similar area and amplitude were compared, the contour of LH responses after iv GnRH more closely simulated the LH pulses in normal men. These data demonstrate that 1) significant differences exist in the amplitude, contour, and variability of plasma LH and GnRH pulses after iv and sc GnRH; and 2) iv GnRH elicits LH secretory episodes which closely resemble endogenous pulsations of normal men. These results suggest that iv GnRH administration may be preferred in physiological studies and, if the data can be extrapolated to women, may account for the greater success of ovulation induction reported with iv GnRH.