Phosphatidylinositol-glycan anchors of membrane proteins: potential precursors of insulin mediators.

BC3H1 myocytes release membrane-bound alkaline phosphatase to the incubation medium upon stimulation with insulin, following a time course that is consistent with the generation of dimyristoylglycerol and the appearance of a putative insulin mediator in the extracellular medium. The use of specific blocking agents shows, however, that alkaline phosphatase release and dimyristoylglycerol production are independent processes and that the blockade of either event inhibits the production of insulin mediator. These experiments suggest a new model of insulin action.

Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis.

Congenital lipoid adrenal hyperplasia is an autosomal recessive disorder that is characterized by impaired synthesis of all adrenal and gonadal steroid hormones. In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional, providing genetic evidence that this protein is indispensable normal adrenal and gonadal steroidogenesis.

A correlation between platelet monoamine oxidase activity and plasma prolactin concentrations in man.

Increases in plasma prolactin concentrations produced by alpha-methyl-p-tyrosine, a catecholamine synthesis inhibitor, varied inversely with baseline platelet monoamine oxidase activity in 12 patients with chronic schizophrenia. In normal volunteers with low monoamine oxidase activity and in unmedicated patients with chronic schizophrenia, plasma prolactin concentrations varied directly with platelet monoamine oxidase activity. No such relationship was found in normal subjects with high platelet monoamine oxidase activity. These data suggest that platelet monoamine oxidase activity reflects monoaminergic activity in the tubero-infundibular system, which in turn affects plasma prolactin concentrations. This relationship may be important in patients with low platelet monoamine oxidase activity, such as some chronic schizophrenics.

Use of Gonadotropin-Releasing Hormone Analogs in Children: Update by an International Consortium.

This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses topics related to changes in GnRHa usage in children and adolescents over the last decade. Topics related to the use of GnRHa in precocious puberty include diagnostic criteria, globally available formulations, considerations of benefit of treatment, monitoring of therapy, adverse events, and long-term outcome data. Additional sections review use in transgender individuals and other pediatric endocrine related conditions. Although there have been many significant changes in GnRHa usage, there is a definite paucity of evidence-based publications to support them. Therefore, this paper is explicitly not intended to evaluate what is recommended in terms of the best use of GnRHa, based on evidence and expert opinion, but rather to describe how these drugs are used, irrespective of any qualitative evaluation. Thus, this paper should be considered a narrative review on GnRHa utilization in precocious puberty and other clinical situations. These changes are reviewed not only to point out deficiencies in the literature but also to stimulate future studies and publications in this area.

Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop.

OBJECTIVE: Our objective was to summarize important advances in the management of children with idiopathic short stature (ISS). PARTICIPANTS: Participants were 32 invited leaders in the field. EVIDENCE: Evidence was obtained by extensive literature review and from clinical experience. CONSENSUS: Participants reviewed discussion summaries, voted, and reached a majority decision on each document section. CONCLUSIONS: ISS is defined auxologically by a height below -2 sd score (SDS) without findings of disease as evident by a complete evaluation by a pediatric endocrinologist including stimulated GH levels. Magnetic resonance imaging is not necessary in patients with ISS. ISS may be a risk factor for psychosocial problems, but true psychopathology is rare. In the United States and seven other countries, the regulatory authorities approved GH treatment (at doses up to 53 microg/kg.d) for children shorter than -2.25 SDS, whereas in other countries, lower cutoffs are proposed. Aromatase inhibition increases predicted adult height in males with ISS, but adult-height data are not available. Psychological counseling is worthwhile to consider instead of or as an adjunct to hormone treatment. The predicted height may be inaccurate and is not an absolute criterion for GH treatment decisions. The shorter the child, the more consideration should be given to GH. Successful first-year response to GH treatment includes an increase in height SDS of more than 0.3-0.5. The mean increase in adult height in children with ISS attributable to GH therapy (average duration of 4-7 yr) is 3.5-7.5 cm. Responses are highly variable. IGF-I levels may be helpful in assessing compliance and GH sensitivity; levels that are consistently elevated (>2.5 SDS) should prompt consideration of GH dose reduction. GH therapy for children with ISS has a similar safety profile to other GH indications.

Idiopathic short stature: definition, epidemiology, and diagnostic evaluation.

Idiopathic short stature is a condition in which the height of the individual is more than 2 SD below the corresponding mean height for a given age, sex and population, in whom no identifiable disorder is present. It can be subcategorized into familial and non-familial ISS, and according to pubertal delay. It should be differentiated from dysmorphic syndromes, skeletal dysplasias, short stature secondary to a small birth size (small for gestational age, SGA), and systemic and endocrine diseases. ISS is the diagnostic group that remains after excluding known conditions in short children.

Idiopathic short stature: management and growth hormone treatment.

In the management of ISS auxological, biochemical, psychosocial and ethical elements have to be considered. In boys with constitutional delay of growth and puberty androgens are effective in increasing height and sexual characteristics, but adult height is unchanged. GH therapy is efficacious in increasing height velocity and adult height, but the inter-individual variation is considerable. The effect on psychosocial status is uncertain. Factors affecting final height gain include GH dose, height deficit in comparison to midparental height, age and first year height velocity. In case of a low predicted adult height at the onset of puberty, addition of a GnRH analogue can be considered. Although GH therapy appears safe, long-term monitoring is recommended.

Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society.

OBJECTIVE: Low birth weight remains a major cause of morbidity and mortality in early infancy and childhood. It is associated with an increased risk of health problems later in life, particularly coronary heart disease and stroke. A meeting was convened to identify the key health issues facing a child born small for gestational age (SGA) and to propose management strategies. PARTICIPANTS: There were 42 participants chosen for their expertise in obstetrics, peri- and neonatal medicine, pediatrics, pediatric and adult endocrinology, epidemiology, and pharmacology. EVIDENCE: Written materials were exchanged, reviewed, revised, and then made available to all. This formed the basis for discussions at the meeting. Where published data were not available or adequate, discussion was based on expert clinical opinions. CONSENSUS PROCESS: Each set of questions was considered by all and then discussed in plenary sessions with consensus and unresolved issues identified. The consensus statement was prepared in plenary sessions and then edited by the group chairs and shared with all participants. CONCLUSIONS: The diagnosis of SGA should be based on accurate anthropometry at birth including weight, length, and head circumference. We recommend early surveillance in a growth clinic for those without catch-up. Early neurodevelopment evaluation and interventions are warranted in at-risk children. Endocrine and metabolic disturbances in the SGA child are recognized but infrequent. For the 10% who lack catch-up, GH treatment can increase linear growth. Early intervention with GH for those with severe growth retardation (height sd score, <-2.5; age, 2-4 yr) should be considered at a dose of 35-70 microg/kg x d. Long-term surveillance of treated patients is essential. The associations at a population level between low birth weight, including SGA, and coronary heart disease and stroke in later life are recognized, but there is inadequate evidence to recommend routine health surveillance of all adults born SGA outside of normal clinical practice.

Endogenous opiates modulate the pulsatile secretion of biologically active luteinizing hormone in man.

We studied the secretion of physiological pools of immunoreactive and biologically active luteinizing hormone in response to endogenous pulses of gonadotropin-releasing hormone (GNRH) in eugonadal men. Concentrations of immunoactive and bioactive luteinizing hormone (LH) were determined in blood drawn at 20-min intervals for 8 h in eight normal men under two conditions: (a) after placebo, in order to evaluate spontaneous LH pulsations in the basal state, and (b) after administration of the opiate-receptor antagonist, naltrexone, which is believed to amplify the pulsatile release of endogenous GNRH. Spontaneous and naltrexone-stimulated secretion of LH occurred in pulses of high biological activity, as measured in the RICT (rat interstitial cell testosterone bioassay), i.e., bioactive:immunoactive LH ratios within both spontaneous and naltrexone-stimulated LH pulses were higher than corresponding interpulse ratios (P less than 0.001). Quantitative characterization of the pulsatile release of bioactive LH revealed the following specific effects of opiate-receptor blockade: increased 8-h mean and integrated serum concentrations of bioactive LH (P less than 0.002), enhanced pulse frequency of bioactive LH release (P less than 0.001), and augmented peak amplitude of bio-LH pulses (P less than 0.01). Moreover, this increase in episodic secretion of bioactive LH was associated with increased 8-h mean and integrated serum testosterone concentrations in these men (P less than 0.05). We conclude the following: (a) LH is normally released in spontaneous pulses of high biological activity in men; (b) when the endogenous GNRH signal is amplified by opiate-receptor blockade, the pituitary gland releases more frequent bioactive LH pulses, which are of high amplitude and contain a high bioactive:immunoactive LH ratio. This increase in pulsatile release of bioactive LH quantitated in the RICT assay in vitro is reflected by acutely increased serum testosterone concentrations in vivo. We infer that modulation of the episodic GNRH signal by endogenous opiates provides another significant mechanism by which the hypothalamus can alter the biological activity of circulating gonadotropic hormone in man. Moreover, observed alterations in the pulsatile pattern of bioactive LH release were associated in turn with significant changes in testosterone concentrations. Thus, we hypothesize that alterations in the properties of the bioactive LH pulse signal can provide an important mechanism for regulating target-cell function within the gonad in states of health or disease.

Metabolic clearance of biologically active luteinizing hormone in man.

The plasma metabolic clearance of biologically active luteinizing hormone (bioactive LH) was studied using the rat interstitial cell testosterone (RICT) bioassay in six hypogonadotropic men after single bolus injection of highly purified human LH and during continuous steady-state infusions of three graded doses of LH. The LH bolus disappearance curves provided estimates of metabolic clearance rates (MCR) of 24.1 +/- 4.7 (+/- SD) ml/min for bioactive LH vs. 56.2 +/- 12 ml/min for immunoactive LH in the same men (P = 0.03). A lower MCR of bioactive LH compared with immunoactive LH was also observed during continuous infusions of physiological doses of LH; for example, the mean steady-state MCRs for bioactive and immunoactive LH were, respectively, 26.1 +/- 3.1 and 34.2 +/- 3.2 ml/min (P = 0.02). Moreover, the stepped-dose infusion regimens permitted us to demonstrate that increasing doses of pure human LH resulted in progressive and parallel decreases in the apparent MCRs of both bioactive and immunoactive LH. Based on the respective steady-state MCRs calculated at physiological plasma concentrations of immunoactive and bioactive LH, we estimate a mean endogenous production rate for bioactive hormone of 1,937 IU/24 h, and for immunoactive LH of 589 IU/24 h in normal men. These results indicate that previous estimates of LH production rates from immunoassay data alone markedly underestimate the quantity of biologically active hormone secreted in man.

Role of endogenous opiates in the expression of negative feedback actions of androgen and estrogen on pulsatile properties of luteinizing hormone secretion in man.

We have tested the participation of endogenous opiate pathways in the negative feedback actions of gonadal steroids on pulsatile properties of luteinizing (LH) hormone release in normal men. To this end, sex steroid hormones were infused intravenously at dosages that under steady state conditions selectively suppressed either the frequency or the amplitude of the pulsatile LH signal. The properties of pulsatile LH secretion were assessed quantitatively by computerized analysis of LH series derived from serial blood sampling over 12 h of observation. When the pure (nonaromatizable) androgen, 5-alpha-dihydrotestosterone, was infused continuously for 108 h at the blood production rate of testosterone, we were able to achieve selective inhibition of LH pulse frequency akin to that observed in experimental animals after low-dosage androgen replacement. Under these conditions, serum concentrations of testosterone and estradiol-17 beta did not change significantly, but serum 5 alpha-dihydrotestosterone concentrations increased approximately two- to threefold, with a corresponding increase in levels of its major metabolite, 5 alpha-androstan-3 alpha, 17 beta-diol. In separate experiments, the infusion of estradiol-17 beta at its blood production rate over a 4.5-d interval selectively suppressed LH pulse amplitude without influencing LH pulse frequency. Estrogen infusion increased serum estradiol-17 beta levels approximately twofold without significantly altering blood androgen concentrations. We then used these schedules of selective androgen or estrogen infusion to investigate the participation of endogenous opiates in the individual inhibitory feedback actions of pure androgen or estrogen on pulsatile LH release by administering a potent and specific opiate-receptor antagonist, naltrexone, during the infusions. Our observations indicate that, despite the continuous infusion of a dosage of 5 alpha-dihydrotestosterone that significantly suppresses LH pulse frequency, co-administration of an opiate-receptor antagonist effectively reinstates LH pulse frequency to control levels. Moreover, during the infusion of a suppressive dose of estradiol-17 beta, opiate receptor blockade significantly augments LH pulse frequency and increases LH peak amplitude to control levels. Thus, the present studies in normal men demonstrate for the first time that the selective inhibitory action of a pure androgen on LH pulse frequency is effectively antagonized by opiate-receptor blockade. This pivotal observation indicates that opiatergic and androgen-dependent mechanisms specifically and coordinately control the hypothalamic pulse generator for gonadotropin-releasing hormone (GnRH)

Actions of estradiol on discrete attributes of the luteinizing hormone pulse signal in man. Studies in postmenopausal women treated with pure estradiol.

We assessed the time-dependent impact of estradiol on properties of the luteinizing hormone (LH) pulse signal in 12 hypoestrogenemic postmenopausal volunteers studied basally and after 1, 5, 10, and 30 d of estradiol delivery via an intravaginal Silastic ring. Computerized analysis of the plasma LH time series revealed a significant decrease in LH pulse frequency within 24 h of estrogen treatment, followed by a secondary increase (days 5 and 10), and then a sustained decline (day 30) in LH pulsatility. Estradiol also significantly suppressed incremental and maximal (but not fractional) LH pulse amplitudes in a biphasic manner. In contrast, LH peak duration was invariant until day 30 of estradiol replacement. These observations indicate that the well recognized biphasic actions of estradiol on mean serum LH concentrations can be modeled in relation to specific and time-dependent alterations in LH pulse frequency and amplitude.

Pituitary self-priming actions of gonadotropin-releasing hormone. Kinetics of estradiol's potentiating effects on gonadotropin-releasing hormone-facilitated luteinizing hormone and follicle-stimulating hormone release in healthy postmenopausal women.

We examined the kinetically distinct characteristics of estradiol's effects upon pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release in response to pulses of exogenous gonadotropin-releasing hormone (GnRH) in healthy postmenopausal individuals. The putative self-priming actions of GnRH on LH and FSH release were tested by intravenous injections of equal paired doses of GnRH (10 micrograms) before and after 1, 5, 10, and 30 d of pure estradiol-17 beta delivery via an intravaginal silastic ring. Self-priming actions of GnRH, as defined by heightened gonadotropin release in response to the second pulse of GnRH compared with the first, were completely absent in the hypoestrogenemic state. However, estradiol administration unmasked GnRH self-priming in a time-dependent fashion, with maximal expression after 5 and 10 d of steroid replacement, followed by attenuation by 30 d. Since estradiol's modulation of GnRH action was expressed differentially on LH and FSH release, we suggest that such facilitation of GnRH-stimulated pituitary LH and FSH release may provide an additional mechanism for dissociated secretion of gonadotropic hormones in health or disease.

Somatotroph hyperplasia. Successful treatment of acromegaly by removal of a pancreatic islet tumor secreting a growth hormone-releasing factor.

A 21-yr-old woman with Turner's syndrome presented with signs and symptoms of acromegaly. The serum growth hormone (GH) (95+/-9.4 ng/ml; mean+/-SEM) and somatomedin C (11 U/ml) levels were elevated, and an increase in GH levels after glucose instead of normal suppression, increase after thyrotropin-releasing hormone (TRH) administration instead of no change, and decrease after dopamine administration instead of stimulation were observed. The pituitary fossa volume was greater than normal (1,440 mm(3)) and the presence of a pituitary tumor was assumed. After tissue removal at transsphenoidal surgery, histological study revealed somatotroph hyperplasia rather than a discrete adenoma. Postoperatively, she remained clinically acromegalic and continued to show increased GH and somatomedin levels. A search was made for ectopic source of a growth hormone-releasing factor (GRF). Computer tomographic scan revealed a 5-cm Diam tumor in the tail of the pancreas. Following removal of this tumor, serum GH fell from 70 to 3 ng/ml over 2 h, and remained low for the subsequent 5 mo. Serum somatomedin C levels fell from 7.2 to normal by 6 wk postoperatively. There were no longer paradoxical GH responses to glucose, TRH, and dopamine. Both the medium that held the tumor cells at surgery and extracts of the tumor contained a peptide with GRF activity. The GRF contained in the tumor extract coeluted on Sephadex G-50 chromatography with rat hypothalamic GH-releasing activity. Stimulation of GH from rat somatotrophs in vitro was achieved at the nanomolar range, using the tumor extract. The patient's course demonstrates the importance of careful interpretation of pituitary histology. Elevated serum GH and somatomedin C levels in a patient with an enlarged sella turcica and the characteristic responses seen in acromegaly to TRH, dopamine, and glucose do not occur exclusively in patients with discrete pituitary tumors and acromegaly. This condition can also occur with somatotroph hyperplasia and then revert to normal after removal of the GRF source. Thus, in patients with acromegaly a consideration of ectopic GRF secretion should be made, and therefore, careful pituitary histology is mandatory. Consideration for chest and abdominal computer tomographic scans before pituitary surgery, in spite of their low yield, may be justified.

Natesto™ , a novel testosterone nasal gel, normalizes androgen levels in hypogonadal men.

Advantages of testosterone nasal gel include ease of administration, low dose, and no risk of secondary transference. The efficacy and safety of testosterone nasal gel was evaluated in hypogonadal males. The ninety-day, randomized, open-label, dose-ranging study, included potential dose titration and sequential safety extensions to 1 year. At 39 US outpatient sites, 306 men (mean age 54.4 years) with two fasting morning total serum testosterone levels <300 ng/dL were randomized (n = 228, b.i.d. dosing; n = 78, t.i.d. dosing). Natesto(™) Testosterone Nasal Gel was self-administered, using a multiple-dose dispenser, as two or three daily doses (5.5 mg per nostril, 11.0 mg single dose). Total daily doses were 22 mg or 33 mg. The primary endpoint was the Percentage of patients with Day-90 serum total testosterone average concentration (C(avg)) value within the eugonadal range (≥300 ng/dL, ≤1050 ng/dL). At Day 90, 200/273 subjects (73%; 95% CI 68, 79) in the intent-to-treat (ITT) population and 180/237 subjects (76%; 71, 81) in the per-protocol (PP) population were in the normal range. Also, in the normal range were 68% (61, 74) of ITT subjects and 70% (63, 77) of PP subjects in the titration arm, as well as, 90% (83, 97) of ITT subjects and 91% (84, 98) of PP subjects in the fixed-dose arm. Natesto(™) 11 mg b.i.d. or 11 mg t.i.d. restores normal serum total testosterone levels in most hypogonadal men. Erectile function, mood, body composition, and bone mineral density improved from baseline. Treatment was well tolerated; adverse event rates were low. Adverse event discontinuation rates were 2.1% (b.i.d.) and 3.7% (t.i.d.). This study lacked a placebo or an active comparator control which limited the ability to adequately assess some measures.

Insulin and phorbol ester induce distinct phosphorylations of pp60c-src in the BC3H-1 murine myocyte cell line.

Insulin and phorbol esters have been shown to produce similar, non-additive metabolic effects in BC3H-1 murine myocytes. Recently, it has been demonstrated that insulin stimulation of these cells increases production of diacylglycerol, a known activator of protein kinase C (PK-C). To determine if insulin stimulation results in the activation of PK-C, we have examined the effects of insulin and the tumor promoting phorbol ester, 12-0-tetradecanoyl-phorbol-13-acetate (TPA), on the phosphorylation of a known PK-C substrate in vivo, the cellular proto-oncogene product, pp60c-src. Differentiated BC3H-1 monocytes showed an approximate twofold elevation in the [32P] content of pp60c-src following stimulation with insulin or TPA for 20 min, with no detectable change in the level of immunoprecipitable c-src protein. The enhanced phosphorylation in response to each agent localized to serine residues in the amino terminal 16 kD staphylococcal V8 proteolytic fragment. Tryptic phosphopeptide analysis revealed that TPA stimulation resulted in an approximate 18-fold increase in phosphorylation of the serine 12-containing tryptic fragment. Insulin stimulation, however, resulted in an approximate 10-fold increase in phosphorylation of the serine 17-containing tryptic fragment with little or no accompanying increase in serine 12 phosphorylation. In cells exposed to high concentrations of TPA for 16 h to deplete PK-C activity, insulin, but not TPA, stimulated phosphorylation of pp60c-src. These data suggest that insulin and phorbol ester induce phosphorylation of pp60c-src by distinct protein kinases.

Rh/IGF-I/rhIGFBP-3 administration to patients with type 2 diabetes mellitus reduces insulin requirements while also lowering fasting glucose.

Administration of insulin-like growth factor-I to patients with diabetes enhances insulin action and reduces the degree of hyperglycemia but it is associated with a high rate of adverse events. Infusion of the combination of rhIGFBP-3 (the principal binding protein for IGF-I in plasma) with rhIGF-I to patients with type I diabetes improved insulin sensitivity and was associated with a low incidence in side effects. In this study, 52 patients with insulin-treated type 2 diabetes received recombinant human IGF-I plus rhIGFBP-3 in one of four dosage regimens for 14 days. The four groups were: (1) continuous subcutaneous infusion of 2 mg/kg/day; (2) the same 2 mg/kg dose infused subcutaneously over 6 h between 2000 and 0200 h; (3) 1 mg/kg twice a day by bolus subcutaneous injection; (4) a single bedtime subcutaneous injection of 1 mg/kg. Across these four groups rhIGF-I/rhIGFBP-3 decreased insulin requirements between 54% and 82%. Fasting glucose decreased by 32-37%. Mean daily blood glucose (4 determinations per day) declined in all 4 groups (range 9-23% decrease). Frequent sampling for total IGF-I, free IGF-I and IGFBP-3 was performed on days 0,1,7,14 and 15. The peak total IGF-I values were increased to 4.0-4.8-fold at 16-24 h. For free IGF-I the increase varied between 7.1 and 8.2-fold and peak values were attained at 16-20 h after administration. Both the time to maximum concentration (Tmax) and the maximum free IGF-I levels (Cmax) on day 1 for all groups were substantially less than previously published studies, wherein lower doses of rhIGF-I were given without IGFBP-3. The improvement in glucose values and the degree of reduction in insulin requirement were the greatest in groups 2 and 3 and the patients in those groups had the highest free IGF-I levels. The frequency of side effects such as edema, jaw pain and arthralgias was 4% which is less than that has been reported in previous studies wherein IGF-I was administered without IGFBP-3. We conclude that rhIGF-I/rhIGFBP-3 significantly lowers insulin requirements yet improves glucose values and these changes may reflect improvement in insulin sensitivity. Coadministration of IGFBP-3 with IGF-I produces lower free IGF-I (Tmax and Cmax) levels compared to administration of IGF-I alone and is associated with relatively low incidence of side effects during 2 weeks of administration.

Plasma prolactin concentrations and psychopathology in chronic schizophrenia.

Plasma prolactin concentrations in 17 drug-free chronic schizophrenic patients correlated inversely with ratings of their psychopathology. An inverse relationship between psychotic symptoms and plasma prolactin concentrations was particularly clear in patients with normal cerebral ventricular size as determined by computed tomography. The psychosis-prolactin relationship did not hold for schizophrenic patients with large ventricular size. These data suggest that the degree of psychosis is related to dopaminergic activity insofar as this is reflected by plasma prolactin concentrations, especially in schizophrenic patients with normal ventricular size. These findings lend further support to the hypothesis that ventricular size is a meaningful factor in subtyping chronic schizophrenic patients.

Inhibition of dopamine synthesis in chronic schizophrenia. Clinical ineffectiveness of metyrosine.

According to the dopamine (DA) hypothesis of schizophrenia, there is a functional excess of dopaminergic activity within unspecified areas of the brain in schizophrenic patients. As a clinical test of this hypothesis, we administered metyrosine for three weeks to symptomatic chronic male schizophrenic patients who were maintained on suboptimal doses of neuroleptic agents. Metyrosine inhibits tyrosine hydroxylase, the rate-limiting enzymatic step in the synthesis of DA. No clinical improvement was observed, using the National Institute of Mental Health Inpatient Behavioral Rating Scale or the Brief Psychiatric Rating Scale. Central inhibition of DA synthesis by metyrosine was suggested, however, by (1) the development of extrapyramidal side effects and (2) a significant increase in plasma prolactin concentrations. Plasma chlorpromazine concentrations remained unchanged during metyrosine treatment. There was, nevertheless, a significant improvement on the scores of the Wechsler Adult Intelligence Scale Comprehension subtest, which measures judgment and common sense. This finding suggests that DA may be involved in the regulation of subtle psychological processes. The results are discussed in light of the DA hypothesis of schizophrenia and previous reports suggesting that metyrosine potentiates the antipsychotic effect of neuroleptics in schizophrenia.

Gonadal steroid hormone regulation of the somatotropic axis during puberty in humans Mechanisms of androgen and estrogen action.

The adolescent growth spurt is associated with a sex steroid hormone-dependent rise in GH production; both androgens and estrogens are implicated as positive regulators of the somatotropic axis during puberty. The issue is complicated by the fact that testosterone may act both directly via the androgen receptor and indirectly, after its aromatization to 17beta-estradiol, through the estrogen receptor. Recently, a number of investigators have studied the effects of the administration of androgen and estrogen receptor antagonists, as well as nonaromatizable androgens, on GH secretion. These reports suggest that estrogen receptor-dependent processes play a facilitatory role in the pubertyassociated rise in GH secretion. If androgen receptor-mediated events are involved in the control of the somatotropic axis, their role is likely inhibitory. A hypothalamic site of action of the sex steroids is postulated.