High prevalence of adrenal cortical adenomas in patients with cerebral meningiomas.

PURPOSE: Adrenal cortical adenomas (ACAs) represent one of the most common endocrine neoplasms. Recently, a genetic syndrome, characterized by tumor-suppressor ARMC5-gene mutations and causing primary macronodular bilateral adrenal hyperplasia with concomitant meningiomas of the central nervous system, has been described. Apart from this rare disorder and despite the well-known influence of steroid hormones on meningiomas, no data are available about the association between ACAs and meningiomas. METHODS: We investigated the prevalence of ACAs in a group of patients with cerebral meningioma undergoing unenhanced chest CT scans before attending surgical treatment. Patients with meningioma were age- and sex-matched in a 1:3 ratio with hospitalized patients for COVID-19. RESULTS: Fifty-six patients with meningioma were included and matched with 168 control patients with COVID-19. One-hundred forty-four (66.1%) were female and the median age was 63 years. Twenty ACAs were detected in the overall population (8.9% of the subjects): 10 in patients with meningioma (18%) and the remaining 10 (6%) in the control group (p = 0.007). Multivariate analysis showed that age and presence of meningioma were statistically associated with the presence of ACAs (p = 0.01, p = 0.008). CONCLUSION: We report, for the first time, a higher prevalence of ACAs in patients with meningioma as compared to age- and sex-matched controls. Larger studies are needed to confirm our data and to clarify the characteristics of the ACAs in patients with meningioma. Whether the detection of ACAs should prompt a neuroimaging evaluation to exclude the presence of meningiomas needs also to be considered.

"Let's take that [stop sign] down." Provider perspectives on barriers to and opportunities for PrEP prescription to African American girls and young women in Alabama.

HIV disproportionately impacts many groups, including Black adolescent girls and young women (AGYW) aged 13-24 living in the Deep South. Current prevention efforts have the potential to further exacerbate disparities within this population as HIV pre-exposure prophylaxis (PrEP) remains underutilized by Black AGYW in the South. We conducted in-depth interviews (IDIs) grounded in Andersen's Model of Healthcare Utilization exploring providers' PrEP prescribing practices to Black AGYW in Alabama. Eleven providers completed IDIs exploring providers' PrEP prescription knowledge and experiences. Cross-cutting themes included: (1) Community and provider-level stigmas (including those propagated by legislation) relating to HIV and sexuality limit sexual health discussions with Black AGYW clients; (2) Low PrEP knowledge and comfort with guidelines limits PrEP conversations and reinforces low uptake and prescriptions; (3) Healthcare systems and structural barriers impede PrEP access for youth. Multi-level (structural, community, and provider) barriers to PrEP prescription demands high activation energy for providers to prescribe PrEP. We present recommendations in training in sexual health assessment, updates to PrEP guidelines to accommodate risk assessment appropriate for AGYW, and increased implementation science focused on PrEP prescription for Black AGYW in order to reduce HIV incidence for this population.

The prevalence of silent acromegaly in prolactinomas is very low.

PURPOSE: The aim of this study was to evaluate the somatotroph axis in a large series of patients with prolactinoma to verify the prevalence of silent acromegaly in this population. METHODS: A hundred and forty-four patients were enrolled in a multicenter study: 90 were already on cabergoline (CAB) and enrolled in a cross-sectional arm (group A) with random PRL, GH and IGF-I determination on treatment (≥ 3 months), whereas 54 untreated patients were enrolled at diagnosis in a prospective arm (group B) with PRL, GH and IGF-I measurement before and after 6 and 12 months of treatment. In the presence of high IGF-I, CAB was withdrawn for 3 months and GH, IGF-I, PRL and GH during an oral Glucose Tolerance Test (OGTT) were obtained. RESULTS: High IGF-I levels (ULN 1.01-1.56) were observed in 9 patients (6.25%, 5F). After CAB withdrawal, IGF-I levels normalized in 5/9 patients, GH was < 0.4 ng/ml after OGTT in 7/9 cases or at random GH determination in one case. After CAB re-introduction, IGF-I levels re-increased in a single case. Overall, a single young female patient harboring a macroadenoma in group A was diagnosed with silent acromegaly and underwent successful transsphenoidal removal of a GH/PRL-secreting adenoma. CONCLUSION: The prevalence of silent acromegaly in prolactinomas (0.7%) is lower than previously reported and OGTT is helpful to recognize silent acromegaly. We suggest that the somatotroph axis should be evaluated at diagnosis in all cases and not systematically during follow-up.

Growth hormone stimulates osteoprotegerin expression and secretion in human osteoblast-like cells.

It is presently thought that osteoprotegerin (OPG) is a cytokine involved in the regulation of osteoblast/osteoclast crosstalk and maintenance of bone mass. Recent studies showed that GH replacement therapy in GH-deficient patients was able to induce a significant increase of OPG in the plasma, as well as in the cortical and the trabecular bone. In order to determine whether GH could directly modulate OPG secretion, the effect of GH on human osteoblast-like cells (hOB) in primary culture was studied. After detecting the presence of the mRNA for the GH receptor (GHR) by RT-PCR, hOB were exposed to increasing concentrations of GH, from 0.1 to 25 ng/ml, for 24 h. The results showed that GH exposure was able to stimulate OPG secretion in a concentration-dependent manner. In addition, the OPG mRNA levels were increased, indicating that the hormone has a stimulatory effect on gene expression. The stimulatory effect on OPG expression and production was prevented by exposing the cells to tyrphostin AG490 (10 muM), an inhibitor of Janus kinase 2, which is one of the kinases involved in the intracellular pathway activated by the binding of GH to its receptor. Similar results were obtained when the cells were exposed to a receptor antagonist of GH, pegvisomant at 50 nM. GH exposure neither induced an increase in IGF-I expression nor secretion in hOB. These results suggest that the stimulation of OPG production induced by GH in hOB is specific and receptor mediated and further support the view that GH is able to modulate bone remodeling by directly influencing osteoblast-osteoclast crosstalk.

Hypokalemic periodic paralysis in a patient with acquired growth hormone deficiency.

CONTEXT: Hypokalemic periodic paralysis (HypoPP) is a rare disorder consisting of sudden episodes of muscle weakness with areflexia involving all four limbs, which spontaneously resolve within several hours or days. Primary HypoPP is genetically determined, while secondary acquired HypoPP has been described in association with thyreotoxycosis, hyperaldosteronism, kidney diseases, diuretics and liquorice abuse, gastrointestinal potassium loss, or cysplatinum therapy. OBJECTIVE: To report a case of HypoPP associated with GH deficiency. PATIENT: A 33 yr-old man with hypopituitarism and diabetes insipidus secondary to pituitary stalk-localized sarcoidosis, and documented HypoPP episodes. CLINICAL PRESENTATION: Neurologic exam outside HypoPP episodes was normal. Needle electromyography was normal without myotonia or other spontaneous electric activity. Muscle biopsy documented a vacuolar myopathy with tubular aggregates. However, genetic analysis ruled out common mutations of the voltage-gated calcium channel observed in primary HypoPP. Common causes of secondary HypoPP were also ruled out. The patient was diagnosed with severe GH deficiency with modest fasting hyperinsulinemia and insulin resistance and started on GH replacement therapy, an alpha-glucosidase inhibitor (acarbose) and a diet low in simple carbohydrates. CONCLUSIONS: GH replacement therapy, acarbose and a diet low in simple carbohydrates resulted in the complete long-term (>2 yr) remission of HypoPP episodes. This is consistent with the hypothesis that the hyperinsulinemia associated to GH deficiency may trigger HypoPP episodes by increasing Na+/K+ ATPase activity and K+ transport into the intracellular compartment with subsequent hypokalemia.

Time-dependent reduction and potentiation of growth hormone (GH) responsiveness to GH-releasing factor induced by exogenous GH: role for somatostatin.

Exogenous GH is known to exert a negative feedback effect on its own responsiveness to GH-releasing factor (GRF); however, the mechanism is not known. In the present study we examined the time course of effects of a single sc administration of recombinant human (rh) GH on GH responsiveness to GRF and investigated the possible involvement of somatostatin (SRIF) in this response. Free-moving adult male rats were administered 200 micrograms rhGH, sc, at 0800 h and subsequently challenged with 1 microgram GRF-(1-29)NH2, iv, at times of spontaneous peaks (1100 and 1500 h) and troughs (1300 h) in GH secretion during a 6-h (1000-1600 h) sampling period. H2O-injected control rats exhibited the typical cyclic responsiveness to GRF stimulation, with GRF-induced GH release significantly greater during peak compared to trough periods of the GH rhythm. Pretreatment with rhGH 3 h before GRF injection markedly inhibited the GH response to GRF at a peak time [integrated GH release over 30 min, 1135 +/- 271 vs. 6372 +/- 1185 ng/ml.30 min in H2O-injected controls (mean +/- SE); P less than 0.01]. In striking contrast, 5 h after rhGH administration, there was a 6-fold augmentation of GH responsiveness to GRF compared to that in H2O-injected controls at a trough time (7032 +/- 1622 vs. 1128 +/- 216 ng/ml.30 min; P less than 0.01). High GH responsiveness to GRF was preserved 7 h after rhGH injection. Passive immunization of rhGH-treated rats with SRIF antiserum reversed the rhGH-induced blunted GH response at 3 h (7985 +/- 366 vs. 1705 +/- 431 ng/ml.30 min in rhGH-treated control rats given normal sheep serum; P less than 0.01) and completely restored GH responsiveness to levels as high as those in H2O-injected controls. These results demonstrate that 1) a single sc injection of rhGH markedly attenuates GH responsiveness to GRF acutely for about 3 h, but subsequently enhances somatotroph sensitivity to the stimulatory actions of GRF; and 2) the short term blunting of GRF-induced GH release by rhGH is due at least in part to increased release of endogenous SRIF. The subsequent potentiation of GH responsiveness to GRF is probably due to a SRIF-mediated build-up of pituitary GH stores in a readily releasable pool. Such a mechanism of GH autofeedback may play a physiological role in the genesis of pulsatile GH secretion.

Time course and mechanism of growth hormone's negative feedback effect on its own spontaneous release.

Endogenous pulsatile GH secretion is blunted by the administration of exogenous GH; however, few data are available on the time course of GH negative feedback, and the mechanism by which this occurs still remains unclear. In the present study, we examined the temporal pattern of the inhibitory effect induced by an acute (single) and chronic (5 days) sc recombinant human (rh) GH injection regimen on spontaneous GH release in the rat and assessed the possible involvement of the hypothalamic GH-inhibitory peptide, somatostatin (SRIF), in this response. Eight-hour (0800-1600 h) GH secretory profiles, obtained from free-moving adult male rats administered a single sc injection of 200 micrograms rhGH at 0800 h, revealed a marked suppression of spontaneous GH pulses (GH peak amplitude: 45.7 +/- 10.9 vs. 207.8 +/- 31.7 ng/ml in H2O-injected control rats; P less than 0.001) lasting for up to 4.1 +/- 0.1 h after the injection (mean 4-h plasma GH level: 13.6 +/- 3.6 vs. 49.4 +/- 7.0 ng/ml in H2O-injected controls; P less than 0.01). During the subsequent 4- to 8-h period, recovery of spontaneous GH secretory bursts was evident, and neither the GH peak amplitude nor mean 4-h plasma GH level of rhGH-treated rats was significantly different from that of H2O-injected controls. The magnitude, time course, and recovery of the rhGH-induced inhibitory effect on pulsatile GH release after chronic rhGH treatment was similar to that after a single injection. Passive immunization of rhGH-treated rats with SRIF antiserum reversed the rhGH-induced inhibition of spontaneous GH pulses (peak amplitude: 131.7 +/- 53.7 vs. 7.1 +/- 3.4 ng/ml in rhGH-treated control rats given normal sheep serum; P less than 0.05) and restored both the GH peak amplitude and mean plasma GH level to values similar to those in H2O-injected controls. Taken together, these results demonstrate that: 1) the inhibitory effect of rhGH on endogenous pulsatile GH release is of short duration (approximately 4 h); 2) the time course of this response does not change after 5-day repeated rhGH administration; and 3) the feedback effect of GH on its own spontaneous release is exerted, at least in part, by increasing hypothalamic SRIF secretion. Such a mechanism of GH feedback may be important in the physiological control of pulsatile GH secretion.

Inhibition of the growth hormone (GH) response to GH-releasing hormone by constant Met-GH infusions.

GH release is controlled by hypothalamic hormones and insulin-like growth factor I, synthesized under the influence of GH, and perhaps also by GH itself. The availability of recombinant Met-GH was the basis for studies aimed at 1) obtaining constant serum GH levels by means of constant Met-GH infusions (40 and 80 ng/kg.min for 6 h), and 2) evaluating the metabolic effects of constant GH levels and, in particular, their effects on the serum GH response to GHRH. In six normal men, both Met-GH infusions increased plasma FFA levels, but did not alter the circulating levels of somatostatin, insulin-like growth factor I, insulin, glucose, cholesterol, and triglycerides. The Met-GH infusions did cause a dose-related inhibition of GHRH-induced GH release. These data indicate that it is possible to maintain constant serum GH levels by means of constant Met-GH infusions at different infusion rates, and that GH inhibits its own release.

Restoration of growth hormone (GH) response to GH-releasing hormone in elderly and obese subjects by acute pharmacological reduction of plasma free fatty acids.

GH induces lipolysis in vivo, increasing plasma free fatty acid (FFA) levels; in turn, FFA are able to reduce GH release, and acipimox, a nicotinic acid analog able to block lipolysis, enhances in normal subjects the GH response to GHRH. Obesity and old age are characterized by a blunted GH response to several stimuli, including GHRH; reports also indicate high plasma FFA levels in obesity and sometimes in the elderly. The aim of this study was to evaluate the possible role of FFA in GH release in obese and elderly subjects. According to a randomized, single blind, cross-over protocol, six healthy subjects, six obese subjects, and six elderly subjects received on 2 different days, with a 1-week interval, placebo or acipimox (250 mg, orally) at 0700 and 1100 h; GHRH [GHRH-(1-44)NH2; 50 micrograms in healthy subjects and in elderly subjects, 100 micrograms in obese subjects] was injected iv at 1300 h, and blood samples for evaluation of plasma FFA, blood glucose, serum insulin (IRI), and serum GH levels were taken from 1200 to 1500 h. Plasma FFA levels were always lower (P < 0.05) after acipimox than after placebo (0.03 +/- 0.01 vs. 0.13 +/- 0.02 g/L in healthy subjects, 0.09 +/- 0.01 vs. 0.27 +/- 0.02 g/L in obese, 0.02 +/- 0.005 vs. 0.17 +/- 0.01 g/L in elderly subjects); serum IRI levels were also lower (P < 0.05) after acipimox than after placebo in the three groups of subjects (16 +/- 3 vs. 30 +/- 5, 120 +/- 30 vs. 181 +/- 32, and 21 +/- 3 vs. 49 +/- 9 pmol/L); both FFA (P < 0.05) and IRI levels (P < 0.05) were higher in obese than in healthy or elderly subjects after placebo and acipimox. Blood glucose levels were not different in the three groups of subjects after either placebo or acipimox. The integrated GH response to GHRH-(GH delta area) was always greater (P < 0.05) after acipimox than after placebo (4677 +/- 633 vs. 1599 +/- 373 in healthy, 1469 +/- 230 vs. 343 +/- 114 in obese, 2304 +/- 759 vs. 325 +/- 133 micrograms/L.120 min in elderly subjects); after both placebo and acipimox, the GH delta area was greater (P < 0.05) in healthy subjects than in obese or elderly subjects. The GH delta area of elderly and obese subjects after acipimox was not different from the GH delta area of healthy subjects after placebo. Changes in GH delta areas were not significantly related to changes in FFA or IRI induced by acipimox; in contrast, absolute values of FFA and IRI as well as basal GH levels were all significantly related to the GH delta area. At multiple regression analysis, FFA was the only significant predictor of GH delta area. These data indicate that acute pharmacological reduction of plasma FFA levels restores the blunted GH response to GHRH commonly observed in obese and elderly subjects: however, when lipolysis is blocked to a similar extent, healthy subjects still show a higher GH delta area than obese or elderly subjects. As FFA are the best predictor of the GH delta area, we suggest that in obesity, the blunted GH release is due to high FFA levels, whereas in the elderly there might be an abnormal sensitivity to normal FFA levels.

The control on growth hormone release by free fatty acids is maintained in acromegaly.

Free fatty acids (FFA) physiologically regulate GH release via a negative feedback. The aim of this study was to examine whether such feedback is preserved in acromegaly, a condition in which alterations in other regulatory mechanisms of GH release occur. Eight acromegalic patients (group 1: five women and three men, 43.0 +/- 4.2 yr old, mean +/- SE) received per os on two different days, at a 3 day-interval, in a random order, placebo or 250 mg of acipimox, an inhibitor of lipolysis analogous to nicotinic acid, at 0700 and 1100 h. In both tests GHRH (1-29 NH2), 50 microg, was administered i.v. at 1300 h. Blood samples for GH, FFA, immunoreactive insulin (IRI), and glucose were taken from 0900 to 1500 h, and the time period considered for statistical analysis was 1200-1500 h, representative of steady-state condition for FFA, IRI, and glucose. Mean plasma FFA levels (1200-1500 h) were significantly lower after acipimox than after placebo (0.05 +/- 0.01 vs. 0.17 +/- 0.01 g/L, P < 0.01). In contrast, both mean basal GH levels (1200-1300 h) and the mean GH response to GHRH (GH delta area, 1300-1500 h) were significantly higher after acipimox than after placebo (12.0 +/- 1.9 vs. 7.8 +/- 1.2 microg/L, P < 0.01; 2937 +/- 959 vs. 1154 +/- 432 microg/L x 120 min, P < 0.01). The increase in both basal GH levels and GH delta area occurred in all eight patients. Acipimox also reduced mean serum IRI (83 +/- 12 vs. 112 +/- 14 pmol/L) and blood glucose (5.1 +/- 0.1 vs. 5.7 +/- 0.1 mmol/L) levels, as compared with placebo (P < 0.03 or less). Eight acromegalic patients (group 2: six women and two men, 46.6 +/- 5.7 yr old) underwent a constant i.v. 10% lipid infusion (150 mL/h), started at 0900 h and continued until 1500 h. Mean plasma FFA levels (1200-1500 h) were significantly higher during lipid infusion than after placebo (0.27 +/- 0.01 vs. 0.16 +/- 0.01 g/L, P < 0.02); in contrast, mean basal GH levels (1200-1300 h) were reduced by lipid infusion, as compared with placebo (9.9 +/- 3.1 vs. 16.6 +/- 4.4 microg/L, P < 0.01), and the same occurred for the GH delta area after GHRH (2498 +/- 1643 vs. 4512 +/- 1988 microg/L x 120 min, P < 0.01). Serum IRI and blood glucose levels were similar after placebo and during lipid infusion. These data indicate that, in acromegaly, the acute reduction of circulating FFA levels results in increased GH release, whereas the increase in circulating FFA levels is accompanied by a reduced GH release. Taken together, these findings suggest that, in acromegaly, the control of FFA on GH release is preserved.

Growth hormone (GH) autofeedback on GH response to GH-releasing hormone. Role of free fatty acids and somatostatin.

Methionyl-GH (met-GH) infusions inhibit the GH response to GH-releasing hormone (GHRH). Met-GH infusions induce lipolysis with a rise of plasma FFA that are known to suppress GH release, but the met-GH inhibition of the GH response to GHRH occurs also when lipolysis is pharmacologically blocked by acipimox. In addition, the inhibition of GH release might be due to an enhanced release of hypothalamic somatostatin. The aim of this study was to evaluate the effect of a met-GH infusion on the GH response to GHRH when lipolysis and hypothalamic somatostatin release are pharmacologically blocked. Twelve normal subjects, randomly allocated to two groups (A and B), received GHRH (50 micrograms, iv) at 1300 h after a 4-h saline infusion or met-GH infusion (80 ng/kg.min). To block lipolysis and hypothalamic somatostatin release, subjects in group B received acipimox, an antilipolytic agent (500 mg), and pyridostigmine, an acetylcholinesterase inhibitor (60 mg), during the 6 h before iv GHRH. GHRH induced a clear GH release during saline infusion in both groups, significantly higher in group B (43.6 +/- 4.8 micrograms/L) than in group A (20.1 +/- 6.1 micrograms/L; P less than 0.02 vs. A), and only a slight increase during met-GH infusions (10.4 +/- 4.1 micrograms/L in group A; 16.7 +/- 4.2 micrograms/L in group B; P = NS). These data indicate that the GH response to GHRH is inhibited by met-GH infusions when peripheral lipolysis and hypothalamic somatostatin release are pharmacologically blocked, suggesting the possibility of autoinhibition of GH at the pituitary level.

Evidence for an inhibitory effect of physiological levels of insulin on the growth hormone (GH) response to GH-releasing hormone in healthy subjects.

It has been previously reported that in healthy subjects, the acute reduction of free fatty acids (FFA) levels by acipimox enhances the GH response to GHRH. In the present study, the GH response to GHRH was evaluated during acute blockade of lipolysis obtained either by acipimox or by insulin at different infusion rates. Six healthy subjects (four men and two women, 25.8 +/- 1.9 yrs old, mean +/- SE) underwent three GHRH tests (50 micrograms iv, at 1300 h) during: 1) iv 0.9% NaCl infusion (1200-1500 h) after oral acipimox administration (250 mg) at 0700 h and at 1100 h; 2) 0.1 mU.kg-1.min-1 euglycemic insulin clamp (1200-1500 h) after oral acipimox administration (250 mg at 0700 h and at 1100 h); 3) 0.4 mU.kg-1.min-1 euglycemic insulin clamp (1200-1500 h) after oral placebo administration (at 0700 and 1100 h). Serum insulin (immunoreactive insulin) levels were significantly different in the three tests (12 +/- 2, 100 +/- 10, 194 +/- 19 pmol/L, P < 0.06), plasma FFA were low and similar (0.04 +/- 0.003, 0.02 +/- 0.005, 0.02 +/- 0.003, not significant), and the GH response to GHRH was progressively lower (4871 +/- 1286, 2414 +/- 626, 1076 +/- 207 micrograms/L 120 min), although only test 3 was significantly different from test 1 (P < 0.05). Pooling the three tests together, a significant negative regression was observed between mean serum immunoreactive insulin levels and the GH response to GHRH (r = -0.629, P < 0.01). Our results indicate that in healthy subjects, acipimox and hyperinsulinemia produce a similar decrease in FFA levels and that at similar low FFA, the GH response to GHRH is lower during insulin infusion than after acipimox. These data suggest that insulin exerts a negative effect on GH release. Because the insulin levels able to reduce the GH response to GHRH are commonly observed during the day, for instance during the postprandial period, we conclude that the insulin negative effect on GH release may have physiological relevance.

Assessment of growth hormone (GH) plasma clearance rate, half-life, and volume of distribution in acromegalic patients: the combined GH-octreotide infusion.

In acromegaly, high GH levels are primarily attributable to GH hypersecretion, but the contribution of GH clearance is still under debate and is difficult to assess. In the present study, GH plasma clearance rate (PCR), half-life (t1/2), and volume of distribution (VD) were assessed in seven acromegalic patients and seven normal lean subjects, after suppression of endogenous GH release by octreotide, with use of a constant GH infusion. An octreotide sc infusion was started the night before the day of the test (2100 h) and maintained throughout the study. On the day of the test, exogenous GH was constantly infused iv for 6 h (0900-1500 h) in order to achieve a new steady state of GH levels. After the cessation of GH infusion, the decay curve of serum GH levels was monitored for 1 h. In both groups, GH PCR was calculated from the steady state serum GH levels, and GH t1/2 was estimated from the monoexponential analysis of the GH disappearance curve. Estimates of VD were derived from PCR and t1/2. In acromegalic patients, GH PCR was 2.5 +/- 0.2 mL/kg.min-1, and GH t1/2 and VD were 15.7 +/- 1.0 min and 54.9 +/- 5.5 mL/kg, respectively. GH PCR and GH t1/2 of acromegalic patients were higher and lower, respectively, than those of normal subjects (PCR, 1.7 +/- 0.2 mL/kg.min-1, P < 0.02; t1/2, 18.4 +/- 0.6 min, P < 0.05). VD was not significantly different in the two groups. In summary, in acromegalic patients GH kinetic parameters can be reliably assessed by using a constant GH infusion after suppression of endogenous GH release by octreotide. Our results also indicate that the increased circulating GH levels observed in acromegaly are attributable only to GH overproduction and do not depend on an alteration in the processes of GH distribution or disappearance.

Evidence for a primary involvement of somatostatin in clonidine-induced growth hormone release in conscious rats.

The GH-releasing activity of the alpha 2-adrenergic agonist clonidine has been extensively studied in the rat, but the mechanism(s) by which clonidine stimulates GH release remains controversial. In the present study, we examined the effects of various doses of clonidine on spontaneous pulsatile GH secretion in conscious rats, and tested the hypothesis that the GH-releasing activity of clonidine is mediated primarily by an inhibition of hypothalamic somatostatin (SRIF) release. In the first experiment, free-moving adult male rats were given either saline or various doses of clonidine i.v. (30, 50 and 125 micrograms/kg) at times of spontaneous peaks (1100 h) and troughs (1300 h) in the GH rhythm. Clonidine, at all doses tested, failed to stimulate GH release when administered at the time of a spontaneous peak. In contrast, injection of clonidine at trough times (when SRIF tone is high) consistently augmented plasma GH levels (mean +/- S.E.M. integrated GH release; 30 micrograms/kg, 1843.0 +/- 484.0; 50 micrograms/kg, 1469.0 +/- 490.3; 125 micrograms/kg, 1675.6 +/- 513.4 vs 201.3 +/- 100.1 ng/ml per 45 min in saline-injected controls; p < 0.05 or less). No significant regression was observed between increasing doses of clonidine and GH release. In the second experiment, i.v. administration of 30 micrograms clonidine/kg during a GH trough period, 30 min prior to GH-releasing factor (GRF) challenge, significantly potentiated the GH response to GRF compared with rats given saline (7218.7 +/- 806.6 vs 4206.9 +/- 1068.1 ng/ml per 30 min; p < 0.05). Clonidine treatment, at all doses tested, resulted in hyperglycaemia and behavioural effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Laparoscopic bilateral adrenalectomy for persistent Cushing's disease after transsphenoidal surgery.

BACKGROUND: We performed bilateral laparoscopic adrenalectomies on four patients (three women and one man) with Cushing's disease (pituitary-dependent Cushing's syndrome) showing persistent hypercortisolism after transsphenoidal surgery. METHODS: The technique for bilateral transperitoneal laparoscopic adrenalectomy was derived from the one previously adopted by our group for unilateral adrenalectomy and previously described. Eight trocars were used, of which two were used for both left and right adrenalectomy. RESULTS: Bilateral laparoscopic adrenalectomy was performed in a one-stage procedure in the three women and, because of the abundant abdominal fat of the patient, in a two-stage procedure (after a 1-week interval) in the man. Operating times for the three women were 255 minutes, 230 minutes, and 220 minutes, and for the man 170 minutes for right adrenalectomy and 140 minutes for left adrenalectomy. No surgical or anesthesiologic complications were encountered. All patients were discharged from the hospital within 5 days after operation. At present, after follow-up periods of 23, 8, 6, and 18 months, all patients show remission of Cushing's disease and undetectable cortisol levels. CONCLUSIONS: Our experience suggests that bilateral laparoscopic adrenalectomy is a safe and effective procedure and a valid therapeutic option in patients with Cushing's disease showing persistent hypercortisolism after transsphenoidal surgery. However, the decision to remove both adrenal glands in such patients needs to be weighed against the risk of their having Nelson's syndrome or other long-term complications.

The growth hormone clamp technique: inhibition of growth hormone release by growth hormone occurs independently of free fatty acids.

It has been suggested that growth hormone (GH) can inhibit its own release: in fact it has repeatedly been shown that an acute methionyl-GH (met-GH) infusion blocks the GH response to GH-releasing hormone (GHRH). However, met-GH infusions are accompanied by a significant increase of free fatty acids (FFA), which can block GH release. The aim of this study was to evaluate whether the inhibition of GH response to GHRH also occurs when lipolysis is pharmacologically blocked. Therefore, six normal subjects received GHRH, 50 micrograms intravenously (IV), after a 4-hour saline infusion and a 4-hour met-GH infusion (80 ng/kg/min, yielding a constant GH level of 33.6 +/- 4.63 micrograms/L), and GH release was evaluated during the following 2 hours. To prevent lipolysis, all subjects received on both occasions acipimox, an antilipolytic agent, 500 mg during the 6 hours before IV GHRH. GHRH induced a clear GH release during saline infusion (46.6 +/- 2.70 micrograms/L) and a scanty GH release during met-GH infusion (9.3 +/- 1.52 micrograms/L; P less than .01). Plasma levels of FFA, somatostatin, insulin-like growth factor I (IGF-I), and glucagon and serum insulin levels were unaffected, while blood glucose levels slightly decreased during saline infusion, but not during GH infusion. These data confirm that met-GH inhibits GHRH-induced GH release, and demonstrate that this inhibition is not mediated by FFA levels.

Acute pharmacologic blockade of lipolysis normalizes nocturnal growth hormone levels and pulsatility in obese subjects.

Obesity is associated with blunted growth hormone (GH) levels and pulsatility and elevated plasma free fatty acids (FFA) levels. To evaluate whether the two phenomena are correlated, in the present study we investigated the effects of an acute pharmacologic blockade of lipolysis on nocturnal GH levels and pulsatility in 10 obese and 10 control subjects. At 9 PM on two different nights with a 1-night interval in between, all subjects received either a single oral tablet of placebo or acipimox slow release (ACX-SR, 500 mg) in randomized order. Blood samples were drawn from 10 PM to 6 AM for evaluation of FFA, glycerol, GH, immunoreactive insulin (IRI), glucose, and insulin-like growth factor-I (IGF-I) levels. After placebo, FFA and glycerol levels were higher (P < .02) and GH levels, areas, peak amplitude, and peak increment (assessed by the Cluster algorithm) were lower in obese than in control subjects (P < .01). After ACX-SR, FFA and glycerol levels were reduced in both groups (P < .02 v placebo), and in obese subjects they became similar to those observed in control subjects after placebo. ACX-SR had no effect on GH levels and pulsatility in control subjects. GH levels, areas, peak, amplitude, peak increment, and interpeak valley levels were all increased after ACX-SR in obese subjects (P < .05 or less v placebo) and became similar to those observed in normal subjects after placebo, but no correlation was found between the reduction in FFA levels and the increase in GH levels and pulsatility.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated insulin levels contribute to the reduced growth hormone (GH) response to GH-releasing hormone in obese subjects.

We have recently presented experimental evidence indicating that insulin has a physiologic inhibitory effect on growth hormone (GH) release in healthy humans. The aim of the present study was to determine whether in obesity, which is characterized by hyperinsulinemia and blunted GH release, insulin contributes to the GH defect. To this aim, we used a simplified experimental protocol previously used in healthy humans to isolate the effect of insulin by removing the interference of free fatty acids (FFAs), which are known to block GH release. Six obese subjects (four men and two women; age, 30.8 +/- 5.2 years; body mass index, 36.8 +/- 2.8 kg/m2 [mean +/- SE]) and six normal subjects (four men and two women; age, 25.8 +/- 1.9 years; body mass index, 22.7 +/- 1.1 kg/m2) received intravenous (i.v.) GH-releasing hormone (GHRH) 0.6 microg/kg under three experimental conditions: (1) i.v. 0.9% NaCl infusion and oral placebo, (2) i.v. 0.9% NaCl infusion and oral acipimox, an antilipolytic agent able to reduce FFA levels (250 mg at 6 and 2 hours before GHRH), and (3) euglycemic-hyperinsulinemic clamp (insulin infusion rate, 0.4 mU x kg(-1) x min(-1)). As expected, after placebo, the GH response to GHRH was lower for obese subjects versus normals (488 +/- 139 v 1,755 +/- 412 microg/L x 120 min, P < .05). Acipimox markedly reduced FFA levels and produced a mild reduction of insulin levels; under these conditions, the GH response to GHRH was increased in both groups, remaining lower in obese versus normal subjects (1,842 +/- 360 v 4,871 +/- 1,286 microg/L x 120 min, P < .05). In both groups, insulin infusion yielded insulin levels usually observed under postprandial conditions and reduced circulating FFA to the levels observed after acipimox administration. Again, the GH response to GHRH was lower for obese subjects versus normals (380 +/- 40 v 1,075 +/- 206 microg/L x 120 min, P < .05), and in both groups, it was significantly lower than the corresponding response after acipimox. In obese subjects, as previously reported in normals, the GH response to GHRH was inversely correlated with the mean serum insulin (r = -.70, P < .01). In conclusion, our data indicate that in the obese, as in normal subjects, the GH response to GHRH is a function of insulin levels. The finding that after both the acipimox treatment and the insulin clamp the obese still show higher insulin levels and a lower GH response to GHRH than normal subjects suggests that hyperinsulinemia is a major determinant of the reduced GH release associated with obesity.

Correlates of maternal depressive symptoms in a national Head Start program sample.

OBJECTIVE: To examine correlates of maternal depressive symptoms in a diverse, national sample of mothers whose kindergarten-aged children attended a Head Start program. DESIGN AND PARTICIPANTS: A cross-sectional study of 5820 mothers was conducted during their child's kindergarten year. MAIN OUTCOME MEASURE: Rates of maternal depressive symptoms were assessed by a validated 3-item depression screen. RESULTS: The ethnic makeup of the group of mothers was non-Hispanic white, 46%; African American, 30%; Hispanic, 13%; American Indian, 6%; Asian American, 1%; and other, 4%. The mean (SD) age of the mothers was 30.1 (5.55) years, 57% were unemployed, and 68% had at least a high school diploma or had earned a high school equivalency diploma. More than 40% of the mothers screened positive for depressive symptoms. The strongest associations after controlling for several biological and demographic variables were maternal chronic health problem (adjusted odds ratio, 2.77; 95% confidence interval, 1.98-3.87), homelessness (adjusted odds ratio, 2.00; 95% confidence interval, 1.45-2.77), and lowest income level (adjusted odds ratio, 1.56; 95% confidence interval, 1.30-1.88). CONCLUSIONS: Depressive symptoms were common among mothers of young children in this national sample. Interventions must be targeted at alleviating maternal depressive symptoms by decreasing poverty, providing support programs for single parents, and establishing accessible and affordable medical care for all parents and their children. Primary care physicians can play a key role in early identification and intervention.

Chronic exposure to aluminium decreases NADPH-diaphorase positive neurons in the rat cerebral cortex.

Aluminium (Al) exposure is neurotoxic and is considered a possible etiological factor for many neurodegenerative disorders. Since it is known that Al impairs the glutamate-nitric oxide-cGMP pathway in neurons, this study was carried out to monitor the expression of NADPH-d in some central nervous system areas of rats after chronic administration of Al in drinking water. We tested three different nervous areas known to contain NADPH-diaphorase positive neurons: two cortical area (somatosensory cerebral cortex and cerebral cortex), a deep brain area (dorsolateral periaqueductal gray matter) and a spinal area (lumbar enlargement of the spinal cord). Our data showed that Al significantly decreased NADPH-d positive neurons in the cerebral cortex and the NADPH-d staining of many granular neurons in the cerebellum. We also found that Al did not cause neuron loss or apoptosis in the cerebral cortex. These findings suggest that the cortical nitroxidergic neurons and granule cells were a specific target of Al neurotoxicity.