Hypothalamic-pituitary Activity Research Articles

Neurobiology of Psychotic Disorders

Efforts to prevent or lessen the functional impact of psychosis can be informed by a better understanding of the neurobiological underpinnings at the earliest stages of the disorder. Understanding these processes early in the psychosis spectrum will in turn allow more targeted efforts to prevent or minimize functional limitations among patients with psychosis. Advances in technology have enabled the study of a host of biomarkers implicated in the neurobiology of psychosis offering unique avenues to investigate mechanisms of disease while at the same time shedding some light on more patient-tailored treatments and setting the foundation for personalized medicine in psychosis. Insights into the neurobiology of psychosis are reviewed, including findings from neuroimaging, neurocognitive, and electrophysiologic studies and findings related to the role of hypothalamic-pituitary axis activity and neuroinflammation in the emergence of psychosis. Biomarker-informed treatments are discussed, and potential promising biomarkers and related treatments are proposed. This review contains 5 figures, 13 tables, and 85 references. Key words: attenuated risk syndrome, biomarkers, prodrome, psychosis, schizophrenia, treatment

Neurobiology of Psychotic Disorders

Efforts to prevent or lessen the functional impact of psychosis can be informed by a better understanding of the neurobiological underpinnings at the earliest stages of the disorder. Understanding these processes early in the psychosis spectrum will in turn allow more targeted efforts to prevent or minimize functional limitations among patients with psychosis. Advances in technology have enabled the study of a host of biomarkers implicated in the neurobiology of psychosis offering unique avenues to investigate mechanisms of disease while at the same time shedding some light on more patient-tailored treatments and setting the foundation for personalized medicine in psychosis. Insights into the neurobiology of psychosis are reviewed, including findings from neuroimaging, neurocognitive, and electrophysiologic studies and findings related to the role of hypothalamic-pituitary axis activity and neuroinflammation in the emergence of psychosis. Biomarker-informed treatments are discussed, and potential promising biomarkers and related treatments are proposed. This review contains 5 figures, 13 tables, and 85 references. Key words: attenuated risk syndrome, biomarkers, prodrome, psychosis, schizophrenia, treatment

CIRCADIAN DYNAMICS OF OPTIC DENSITY OF MELATONIN RECEPTORS IN THE NEURONS OF HYPOTHALAMIC SUPRAOPTIC NUCLEUS IN RATS UNDER ALTERED PHOTOPERIOD

Introduction. Melatonin production is considerably suppressed by light and affects the ability to transfer daily rhythm information from the hypothalamus to other neural target sites and thus alters the expression of some biological rhythms. The hormone controls the state of the hypothalamic-pituitary system and endocrine gland activity through melatonin receptors (membrane, cytosolic and nuclear ones). In addition, using a mechanism of the feedback, it interferes with the activity of supraoptic nucleus of the hypothalamus, which regulates water-salt metabolism and responses to stress. Objective: to provide quantitative circadian characteristics of melatonin receptors density in the neurons of the hypothalamic supraoptic nucleus of rats being under light stimulation as well as the correction of changes after injecting exogenous melatonin. Material and methods. The experiments were conducted on 60 white mongrel mature male rats weighing 150 – 180 g. The test animals were divided into 3 parts each with 2 groups, kept under the conditions of standard light regime, hyperilluminated and the injection of exogenous melatonin and day-round lighting within 7 days. To perform immunohistochemical methods, we used polyclonal antibodies to melatonin 1A receptors produced by Abcam and streptavidin biotin visualization system LSAB2 (peroxidase mark + diaminobenzidine) produced by Chemicon International Inc. We adhered to protocol standardization of methods for all sections. Additional staining of nuclei was performed with Mayer hematoxylin. Results. The indices of optical density of specific melatonin 1A receptors of supraoptic neurocytes staining obtained in the intact group (at 02.00 AM- 0,488 ± 0,0024, at 02.00 P.M. - 0,464 ± 0,0023, p = 0.002) and in animals subjected to light stress (at 02.00 AM-0,295 ± 0, 0019, at 02.00 P.M.- 0,286 ± 0,0018, p = 0,012) had a probable value and were characterized by a clear diurnal periodicity. In the group of animals with pineal gland hypofunction modulation (at 02.00 A.M.- 0,216 ± 0,0017, at 02.00 P.M. - 0,214 ± 0,0021, p> 0,05). Conclusions The density of 1A melatonin receptors in rat’s hypothalamic supraoptic neurons are normally characterized by an accurate circadian rhythm. The highest density of receptors is observed at 02.00 AM, and at 02.00 PM it is significantly lower (p = 0.002). Immunohistochemical studies revealed that under inhibition of pineal gland activity the circadian rhythm of melatonin receptors density in neurons of supraoptic nuclei of the hypothalamus gets disturbed, which is characterized by an incredible difference of indices in the tested periods of the day.

Enhancement of hypothalamic-pituitary activity in male athletes: evidence of a novel hormonal mechanism of physical conditioning

BackgroundExercise is known to induce multiple beneficial conditioning processes. Conversely, although exercise may generate several hormonal effects, an intrinsic hormonal conditioning process has not been reported. In the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study, we observed inherent and independent conditioning processes of the hypothalamic-pituitary axes in athletes. Our objective is to describe the theory of the novel hormonal conditioning mechanism using the findings from the EROS study.MethodsIn this cross-sectional study, we selected 25 healthy athletes (ATL) and 12 non-physically active healthy controls (NPAC), 18–50 years old, males, with BMI 20–30 kg/m2, with similar baseline characteristics, who underwent gold-standard exercise-independent tests: cosyntropin stimulation test (CST) and insulin tolerance test (ITT), to evaluate cortisol response to CST, and ACTH, cortisol, GH, and prolactin responses to an ITT.ResultsResponses to ITT were significantly earlier and higher in ATL than NPAC for cortisol [Mean ± SD: 21.7 ± 3.1 vs 16.9 ± 4.1 μg/dL; p < 0.001], GH [Median (95% CI): 12.73 (1.1–38.1) vs 4.80 (0.33–27.36) μg/L; p = 0.015], and prolactin [24.3 (10.5–67.45) vs 10.50 (6.21–43.44) ng/mL; p = 0.002]. Cortisol response to CST was similar between ATL and NPAC. During ITT, cortisol, GH, and ACTH mean increase in ATL were 52.2, 265.2, and 18.6% higher than NPAC, respectively. Prolactin response was absent in NPAC, while present in ATL.ConclusionsWe found sufficient evidence to propose the existence of a diffuse enhancement of the hypothalamic-pituitary activity in athletes, not restricted to any axis, showing an intrinsic and independent process of “hormonal conditioning” in athletes, similar to those observed in the cardiovascular and neuromuscular systems. This novel conditioning process may be the missing link for understanding the improved responses observed in athletes to harmful situations, traumas, infections, inflammations, and psychiatric conditions.

Prolactin acts on the hypothalamic–pituitary axis to modulate follicle-stimulating hormone gene expression in the female brushtail possum ( Trichosurus vulpecula)

Brushtail possums exhibit a distinct preovulatory pattern of prolactin (Prl) secretion suggesting that Prl is involved in normal reproductive function. In some mammals, Prl is essential for corpus luteum (CL) function and/or modulation of steroidal effects on hypothalamic–pituitary activity. The aim of this study was to test the effects of biologically active recombinant possum Prl (recPosPrl) on both pituitary gland and CL function in possums. To confirm biological activity, administration of recPosPrl-N2C1 (10 μg) resulted in an 18-fold stimulation ( P < 0.05) of progesterone (P 4) production by possum granulosa cells in vitro. Based on these findings, minipumps containing either recPosPrl-N2C1 ( n = 10) or saline ( n = 8) were inserted into lactating female possums. The expression levels of pituitary-derived PRL, LHB, FSHB and GNRHR and CL-derived LHR mRNA were quantified. Following a resumption of reproductive activity, no differences in ovulation incidence or plasma Prl concentrations were observed. Plasma Prl levels were less variable ( P < 0.001) in Prl-treated possums, confirming a self-regulatory role for Prl in this species. There was a marked down-regulation ( P < 0.001) of FSHB mRNA at the mid-luteal stage in Prl-treated possums, whereas mean PRL, LHB, GNRHR and LHR mRNA expression levels were not different between experimental groups. Plasma P 4 concentrations were not different ( P = 0.05) in Prl-treated possums, although tended to be higher in the peri-ovulatory and early-luteal phase. We conclude in the brushtail possum that Prl is self-regulated via a short-feedback loop common to all mammals studied and is able to modulate FSHB expression probably at the level of the hypothalamus and/or pituitary gland.

Evidence of reduced sympatho-adrenal and hypothalamic-pituitary activity during static muscular work in patients with fibromyalgia

To assess activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenocortical axis during static exercise in patients with fibromyalgia. Sixteen patients with fibromyalgia and 16 healthy controls performed a static knee extension until exhaustion. Plasma catecholamines, adrenocorticotropic hormone and cortisol, as well as blood pressure and heart rate, were assessed before, during and following contraction. Plasma C reactive protein was analysed at baseline. Blood pressure and heart rate increased during contraction (p < 0.001) and decreased following contraction (p < 0.001) in both groups alike. Compared with baseline, plasma catecholamines increased during contraction in both groups (p < 0.001), but patients with fibromyalgia had lower levels of plasma adrenaline (p < 0.04) and noradrenaline (p < 0.08) at all times. Adrenocorticotropic hormone increased at exhaustion in controls (p < 0.001), but not in patients with fibromyalgia, who also had lower adrenocorticotropic hormone at exhaustion (p < 0.02) compared with controls. There were no group differences, or changes over time in plasma cortisol. High sensitivity C reactive protein was higher in patients with fibromyalgia compared with controls (p < 0.02). Patients with fibromyalgia exhibited a hypoactive sympatho-adrenal system as well as a hypo-reactive hypothalamic-pituitary axis during static exercise.

Pituitary response to metyrapone in Gulf War veterans: Relationship to deployment, PTSD and unexplained health symptoms

Gulf War deployment has been associated with a distinct neuroendocrine profile characterized by low 24h basal ACTH levels and enhanced cortisol and ACTH suppression to low-dose dexamethasone. The metyrapone stimulation test was performed to further characterize hypothalamic-pituitary activity in Gulf War veterans (GWV) and its relationship to unexplained medical symptoms and post-traumatic stress disorder (PTSD). Eleven GWV without PTSD, 18 GWV with PTSD and 15 healthy subjects not exposed to the Gulf War theater (non-exposed) underwent the metyrapone stimulation test, which inhibits cortisol synthesis, impairs cortisol-mediated negative feedback inhibition and in turn increases levels of ACTH and 11-deoxycortisol, a cortisol precursor. These hormones were measured at baseline (7:00 a.m.) and at intervals (from 8:00 a.m. to 4:00 p.m.) following the administration of metyrapone 750mg orally at 7:05 a.m. and at 10:05 a.m. There were group differences in the ACTH response despite similar cortisol and 11-deoxycortisol responses to metyrapone. GWV without PTSD had a significantly attenuated ACTH response compared to non-exposed subjects; GWV with PTSD had a significantly higher ACTH response than GWV without PTSD but did not differ from non-exposed subjects. Among GWV, unexplained medical health symptoms (e.g., neurological, musculoskeletal, cardiac, and pulmonary symptoms) and PTSD symptoms were significantly positively associated with the ACTH response to metyrapone. Gulf War deployment is associated with a substantially lower ACTH response to metyrapone. In contrast, unexplained health symptoms and PTSD in Gulf War veterans are associated with relatively greater hypothalamic-pituitary activity which may reflect increased CRF activity and is evident only in consideration of deployment effects. This pattern of differences suggests either that Gulf War deployment and its associated exposures results in enduring changes in pituitary function or that reduced hypothalamic-pituitary activity protects against the development of PTSD and other deployment-related health problems.

A Case of Pediatric Virilizing Adrenocortical Tumor Resulting in Hypothalamic-pituitary Activation and Central Precocious Puberty Following Surgical Removal

We present a 6-year-old boy with a virilizing adrenocortical tumor who initially presented with peripheral precocious puberty. Development of facial acne, pubic hair and a growth spurt were noted at the age of five. A low-pitched voice as well as maturation of external genitalia was noted at the age of six. Both serum and urinary levels of adrenal androgens were elevated. Abdominal computed tomography revealed a large right suprarenal mass and he underwent surgical resection without any complications. The histological diagnosis was adrenocortical carcinoma according to the criteria of Weiss. Following surgical removal of the androgen-producing tumor, the patient subsequently developed hypothalamic-pituitary activation and demonstrated central precocious puberty. He was treated with a gonadotropin-releasing hormone agonist in order to delay further pubertal progression. Clinical follow-up of potential secondary effects of excess hormone secretion after removal is important in some pediatric patients with virilizing adrenocortical tumor.

Plasma Leptin Concentrations Correlate with Luteinizing Hormone Secretion in Early Postpartum Holstein Cows

We tested the hypothesis that hypothalamic-pituitary activity, bioassayed by LH pulse frequency, in dairy cattle during early lactation is related to measures of energy status and to circulating profiles of free fatty acids (FFA), insulin, insulin-like growth factor-I (IGF-I), leptin, and growth hormone (GH). On d 14 postpartum, before first ovulation and during the period of negative energy balance (−23.4±2.4 Mcal/d of metabolizable energy), blood plasma was sampled from 18 multiparous cows at 10-min intervals for 8h. All samples were assayed for LH and GH and hourly samples were assayed for FFA, insulin, IGF-I, and leptin. Milk yield and composition, body condition score, and energy balance were also measured. Frequency of LH pulses was correlated positively with energy balance (r = 0.51) and plasma leptin concentrations (r = 0.73), and negatively with milk fat content (r = −0.52). Amplitude of the LH pulses was correlated only with leptin (r = 0.53). Frequency of GH pulses was not correlated with any measure of LH secretion, but was correlated negatively with plasma concentrations of insulin (r = −0.62) and IGF-I (r = −0.61). First ovulation was observed 34±4 d after parturition. These observations reveal an important linkage between pulsatile LH secretion and blood leptin concentrations during the early postpartum period in dairy cows, when their energy balance is negative, and may explain the delay in ovulation.

Chronic Treatment with the Monoamine Oxidase Inhibitor Phenelzine Increases Hypothalamic-Pituitary-Adrenocortical Activity in Male C57BL/6 Mice: Relevance to Atypical Depression

Atypical depression has been linked to low hypothalamic-pituitary-adrenocortical axis activity and exhibits physical and affective symptoms resembling those of glucocorticoid deficiency. Because atypical depression has also been defined by preferential responsiveness to monoamine oxidase inhibitors (MAO-I), we hypothesized that MAO-I reverse these abnormalities by interfering with glucocorticoid feedback and increasing hypothalamic-pituitary-adrenocortical activity. To test this hypothesis, we measured plasma hormones and ACTH secretagogue gene expression in male C57BL/6 mice treated chronically with saline vehicle or phenelzine, a representative MAO-I. Changes in glucocorticoid feedback were evaluated using adrenalectomized (ADX) mice with and without corticosterone replacement. Antidepressant efficacy was confirmed by decreased immobility during forced swim testing. Phenelzine significantly increased circadian nadir and postrestraint plasma corticosterone levels in sham-operated mice, an effect that correlated with increased adrenocortical sensitivity to ACTH. Phenelzine increased circadian nadir, but not poststress ACTH in ADX mice, suggesting that phenelzine augmented corticosterone secretion in sham-operated mice by increasing stimulation and decreasing feedback inhibition of hypothalamic-pituitary activity. Consistent with the latter possibility, phenelzine significantly increased plasma ACTH and paraventricular hypothalamus CRH mRNA in ADX, corticosterone-replaced mice. Phenelzine did not increase paraventricular hypothalamus CRH or vasopressin mRNA in ADX mice lacking corticosterone replacement. We conclude that chronic phenelzine treatment induces sustained increases in glucocorticoids by impairing glucocorticoid feedback, increasing adrenocortical responsiveness to ACTH, and increasing glucocorticoid-independent stimulation of hypothalamic-pituitary activity. The resulting drive for adrenocortical activity could account for the ability of MAO-I to reverse endocrine and psychiatric symptoms of glucocorticoid deficiency in atypical depression.

Puberdade precoce: dilemas no diagnóstico e tratamento

Novos critérios para o diagnóstico e tratamento da puberdade precoce (PP) central (GnRH-dependente) têm sido propostos. Frente a uma menina com desenvolvimento sexual precoce o médico deve considerar: 1) O que é o desenvolvimento puberal normal e quando ele se inicia? O início puberal em meninas normais aparentemente tem ocorrido cada vez mais cedo. A idade limite para o desenvolvimento puberal normal é de 9 anos nos meninos e 8 anos nas meninas. Entre 6 e 8 anos, muitas meninas apresentam sinais puberais isolados, associados apenas a discreto avanço da velocidade de crescimento (VC) e da idade óssea (IO). O quadro representa uma aceleração constitucional do crescimento e puberdade e não necessita tratamento. A puberdade precoce GnRH-dependente patológica cursa com progressão dos caracteres puberais, aumento significante da VC e avanço desproporcional da IO, determinando redução da estatura final prevista. 2) Quais os valores normais de LH e FSH? Com o advento de novas técnicas os valores do normal devem ser cuidadosamente interpretados. 3) Por que devemos tratar a PP? Devido à perda estatural e comprometimento psicossocial. 4) Todas as crianças com PP necessitam tratamento? Quem deve ser tratado? Apenas as crianças com PP que apresentam avanço significante da IO e da VC com previsão de perda da estatura final e resposta puberal do LH. A etiologia do processo é investigada com a RM de crânio. Deve ser tratada com agonistas hiperativos do GnRH. Pode-se utilizar leuprolide ou triptorelina, na dose de 3,75mg IM, uma vez a cada 4 semanas. Habitualmente, obtem-se bom controle dos caracteres puberais. 5) Quais são os resultados do tratamento? Os resultados sobre a estatura final dependem do diagnóstico e tratamento precoces, preferencialmente antes dos 6 anos, e praticamente não existem efeitos colaterais importantes. 6) Quando associar o GH? Durante o tratamento com GnRHa, parte dos pacientes apresenta grande redução da VC e intenso comprometimento da previsão estatural. Nesta situação, a associação com GH pode ser considerada.

Effects of ECT on hypothalamic-pituitary activity: TSH, GH, ACTH and PRL

Effects of ECT on hypothalamic-pituitary activity: TSH, GH, ACTH and PRL

Fetal Hypothalamic-Pituitary Adrenal (HPA) Development and Activation as a Determinant of the Timing of Birth, and of Postnatal Disease

Birth in most animal species is triggered by the fetus through activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis. Preterm birth, may be associated with precocious activation of fetal HPA function, reflecting the fetal response to an adverse intrauterine environment.There is a progressive and concurrent increase of ACTH1–39 and cortisol (F) in the circculation of fetal sheep during the last 15–20 days of pregnancy (term, day 145–150) associated with increased expression of hypothalamic CRH pituitary POMC and adrenal ACTH receptor and steroidogenic enzymes, particularly P450 C17. Similar changes occur with fetal hypoxemia. Negative feedback is ameliorated by decreased pituitary and hypothalamic glucocorticoid receptor, increased CBG, and altered fetal pituitary 11B-hydroxysteroid dehydrogenase type 1. Repeated fetal hypoxemia, diminishes the fetal-pituitary ACTH response, but increases fetal adrenal responsiveness. Fetuses exposed to maternal glucocorticoid in late gestation are growth restricted with altered postnatal HPA responsiveness and glycemic responses that reproduce the insulin resistance of type 2 diabetes. We conclude that the level of fetal HPA activity is crucial not only for determining gestation length, but also predicts pathophysiologic adjustment in later life.

Three novel mutations and a de novo deletion mutation of the DAX-1 gene in patients with X-linked adrenal hypoplasia congenita.

The DAX-1 [DSS (dosage sensitive sex)-AHC critical region on the X, gene 1] gene is responsible for X-linked adrenal hypoplasia congenita (AHC). However, DAX-1 protein structure-function relationships are not well understood. Identification of missense mutations may help to reveal these relationships. We analyzed the DAX-1 gene from seven patients in six kindreds with X-linked AHC and identified one frameshift mutation, two missense mutations, and three deletion mutations. Case 1 had a 388delAG frameshift mutation, inducing a premature stop codon at position 70. Case 2 had a missense mutation, Lys382Asn, which encodes an asparagine (Asn) for lysine (Lys) at position 382. Sibling cases of 3-1 and 3-2 had a missense mutation of Trp291 Cys, which encodes a substitution of cysteine (Cys) for tryptophan (Try) at position 291. The tryptophan (Trp) at position 291 and lysine (Lys) at position 382 in human DAX-1 protein are highly conserved among other related orphan nuclear receptor superfamily members. Cases 4, 5, and 6 showed deletion mutation. In case 6, a de novo deletion mutation was revealed by both southern hybridization and polymerase chain reaction (PCR) of a GGAA tetranucleotide tandem repeat. These findings suggest that: 1) Trp at position 291 and Lys at position 382, located in the C-terminal presumptive ligand binding domain, are important to the functional role of the DAX-1 protein in adrenal embryogenesis and/or in hypothalamic-pituitary activity; and 2) molecular analysis of the DAX-1 gene may help genetic counseling, even in cases with deletion mutation, because a detection of de novo deletion may exclude another affected or carrier child.

Neuroendocrine and immunological functions in depressed patients: a follow-up study

The development, evaluation and use of biological markers with a diagnostic purpose in psychiatry is extremely important. However, with certain exceptions, truly sensitive and specific markers have not yet emerged. In order to investigate the relationship between the immune apparatus and the hypothalamic-pituitary activity on the one hand, and the psychopathological state of the patients on the other, we used a longitudinal design and assessed monocyte parameters (HLA-DR, CD 35, vimentin filaments, and phagocytosis index) and neuroendocrine tests (dexamethasone suppression test [DST] and thyrotropin-releasing hormone [TRH] stimulation test) at intake and at follow-up in 49 depressed patients. Immunological parameters were compared with neuroendocrine tests in both phases of the study. The combined use of both immunological and neuroendocrine tests did not add sensitivity to the immunological identification of depressed patients. The findings lead us to consider the role of the monocyte parameters as sensitive depressive state markers, while the combined use of both neuroendocrine and immunological tests in current clinical practice would be debatable.

Behavioral Toxicology of Volatile Organic Solvents V. Comparisons of the Behavioral and Neuroendocrine Effects Among n-Alkanes

Four homologous n-alkanes were compared for their ability to impair performance and stimulate hypothalamic-pituitary activity in mice. Performance was assessed using operant responding maintained under a fixed interval 60-sec schedule of milk presentation. Cumulative concentration-effect functions for octane, heptane, hexane, and pentane were obtained by incrementally increasing exposure concentrations until responding was abolished. Recovery from these rate-decreasing effects was determined 30 min after exposure to the highest concentration. Rate-decreasing potency (EC50) was greatest for octane (2474 ppm), and progressively less for heptane (3872 ppm), hexane (7051 ppm), and pentane (36130 ppm). Responding recovered completely 30 min after exposure for pentane and hexane, to 75% of pre-exposure levels for heptane, but to only 15% of pre-exposure levels for octane. The risk of obtaining a small effect with these agents (the concentration expected to decrease performance 10% in 1 out of 1000 mice) exhibited a similar order. The effect was predicted to occur at 227 ppm for octane, 331 ppm for heptane, and 1429 ppm for pentane. However, this prediction occurred at an unusually low dose for hexane (68 ppm). These n-alkanes also stimulated up to 2000-fold increases in adrenocorticotropin hormone (ACTH) release. n-Hexane was slightly more potent and produced larger effects. These studies demonstrate a direct relationship between aliphatic carbon chain length and the potency of n-alkanes in impairing performance.

Alterations in the pulsatile mode of growth hormone release in men and women with insulin-dependent diabetes mellitus.

The mechanisms responsible for the elevated levels of circulating GH observed in diabetes mellitus (DM) remain incompletely defined. To assess the episodic fluctuations in serum GH as a reflection of hypothalamic-pituitary activity, we accumulated GH concentration-time series in a total of 48 adult men and women with and without insulin-dependent DM by obtaining serum samples at 10-min intervals over 24 h. Significant pulses of GH release were subsequently identified and characterized by an objective, statistically based pulse detection algorithm (Cluster) and fixed circadian (24-h) periodicities of secretory activity, resolved using Fourier expansion time-series analysis. Compared to those in age-matched controls, integrated 24-h concentrations of GH were 2- to 3.5-fold higher in diabetic men (P = 0.002) and women (P = 0.0005). Both men and women with DM had over 50% more GH pulses per 24 h than their non-DM counterparts. In addition, maximal GH pulse amplitude was markedly elevated in the men and women with DM (P = 0.0019 and 0.0189, respectively). That the increase in maximal pulse amplitude was accounted for by greater baseline levels was documented by a higher interpulse valley mean GH concentration in the diabetics compared to the controls (P = 0.0437 and 0.0056, men and women, respectively) and the absence of any difference in incremental pulse amplitude for either sex (P greater than 0.05). DM men had larger GH pulse areas (P = 0.039) than control men, apparently accounted for by greater pulse width (P = 0.0037). Pulse areas in DM and non-DM women were indistinguishable. Time-series analysis revealed that the 24-h (circadian) rhythms of serum GH concentrations exhibited significantly increased amplitudes in the diabetic group as a whole (compared to the controls, P = 0.011). However, the times of maximal GH concentrations (acrophases) were not significantly different. As a group, serum insulin-like growth factor-I was lower in DM vs. non-DM individuals (P = 0.0014), although when separated by sex this difference did not reach statistical significance in women (P = 0.317). The present data confirm the higher circulating levels of GH previously reported to occur in individuals with poorly controlled DM. The altered frequency of GH pulses together with enhanced interpulse GH concentrations and an amplified circadian GH rhythm are compatible with hypothalamic dysfunction associated with dysregulation of somatostatin and/or GHRH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Selective effects of ECT on hypothalamic-pituitary activity.

The hypothesis that ECT produces selective effects on hypothalamic-pituitary activity was investigated by determining the effect of ECT on pituitary hormone release in nine depressed patients. After ECT there were massive and rapid increases in the plasma concentrations of nicotine- and oestrogen-stimulated neurophysin (NSN and ESN), prolactin (PRL) and adrenocorticotropin (ACTH), smaller increases in plasma luteinizing hormone (LH) and cortisol, a significant decrease in plasma growth hormone (GH) concentration but no change in plasma thyrotropin (TSH). There was significant attenuation of PRL responses with repeated ECT. The hormonal responses to ECT cannot simply be attributed to stress, since a similar pattern of increases in plasma hormone concentrations did not occur in psychologically normal patients in whom plasma hormone concentrations were measured during induction of anaesthesia and abdominal incision for cholecystectomy. Analysis of these hormonal responses in terms of the knowledge available on the neurotransmitter control of pituitary hormone release suggests that some of these hormonal responses to ECT may be mediated by the activation of serotonergic neurones, while others are probably due to direct stimulation of the neuroendocrine neurones themselves.

MECHANISM OF PRECOCIOUS PUBERTY IN GIRLS WITH McCUNE-ALBRIGHT SYNDROME (MAS)

We studied 7 girls, ages 1.3 to 10 yrs., with precocious puberty associated with MAS. In 6 of the 7 girls, basal and LHRH-stimulated gonadotropins and bioactive LH were prepubertal. In one girl, gonadotropins and bioactive LH were in the pubertal range. Ovarian volumes (mean 6.4, range 1.4 - 12.9 ml) were increased in all 7 girls compared to prepubertal girls (nl < 0.9 ml - Radiology 125:477(1977)). The girls with MAS had greater asymmetry in ovarian volume than did girls with true precocious puberty (TPP) (R to L difference 5.9 ± 1.9 ml vs. 1.5 ± 0.2 ml in TPP; p<0.05). The logarithm of plasma estradiol correlated significantly with ovarian volume (p< 0.05). Ovarian volumes and plasma estradiol fluctuated markedly over time. LHRH-analog treatment, given to 6 of the 7 girls, failed to suppress menses, ovarian cyst volume, or estradiol levels in the five girls who had low gonadotropins. The girl who had true puberty responded to LHRH-analog treatment. She had a bone age of 13.5 years, which is within the range when puberty normally occurs. Thus, we cannot exclude the possibility that her gonadotropins were also low when secondary sex characteristics first appeared. We conclude that the mechanism of precocious puberty in the majority of girls with MAS is intermittent ovarian estrogen secretion independent of pubertal hypothalamic-pituitary activation.

Evidence for the existence of extra-hypophyseal neural mechanisms controlling ovarian steroid secretion

The effects of electrical stimulation of various brain regions on the ovarian venous plasma concentrations of oestradiol and progesterone (OVP E 2 and P) were investigated in female rats hypophysectomized and adrenalectomized at 10.00 h on the day of pro-oestrus. Stimulation was applied during the critical period of pro-oestrus under pentobarbital anesthesia, and contralateral ovarian venous blood was collected at 105–120 min after the stimulation. OVP E; and P were estimated by radioimmunoassay. OVP E 2 and P were significantly increased by stimulation of the preoptic periventricular area (PVA) or some regions in the mesencephalic area, while decreased by stimulation of the dorsal hippocampus, lateral amygdala or a part of the mesencephalic reticular formation and central grey area. Since ovarian venous plasma volume and peripheral plasma gonadotrophins (GTH) were not affected by the stimulations, present results suggest the existence of extra-hypophyseal central influences on the ovarian secretory function independent of pituitary GTH. In intact pro-oestrous rats, all the stimulations of the PVA and preoptic suprachiasmatic area (POSC) commonly potentiated GTH secretion. However, only the stimulation of the PVA increased ovarian steroid secretion, while POSC stimulation was not effective. Moreover, it has been reported that stimulation of the dorsal hippocampus causes a change in ovarian biosynthetic activity without any alteration of hypothalamic-pituitary activity. The present study also revealed that dorsal hippocampal stimulation in hypophysectomized and adrenalectomized rats diminished LH-induced E 2 secretion and enhanced LH-induced P secretion. All these findings suggest that the ovarian secretory function is regulated not only through the pituitary GTH but additionally through an extrahypophyseal neural mechanism. The later mechanism is thought to modulate the sensitivity and responsiveness of the ovarian steroidogenetic structures to GTH.