Acute and chronic effects of human recombinant GH (hrGH) on adrenal steroidogenesis in children affected with isolated GH deficiency (IGHD).

In a previous study we demonstrated that, in children affected with isolated GH deficiency, an acute high-dose human recombinant GH (hrGH) treatment increases the 11-deoxycortisol and induces an IGF-I responsiveness to ACTH. The aim of the present study was to reevaluate, in the same children, the adrenal and IGF-I responsiveness to ACTH after a chronic replacement-dose GH therapy. Ten children (seven males and three females, mean age 7 years) affected with isolated GH deficiency underwent a synthetic ACTH 1-17 test before and after sc administration of human recombinant GH at a dose of 0.6 UI/kg/week for 3 months. After therapy, the 11-deoxycortisol responsiveness to ACTH significantly decreased compared with that observed after acute treatment (P < 0.001), and so it returned to baseline. No differences were detected in the responsiveness to ACTH of cortisol, dehydroepiandrosterone-sulphate, D4-androstenedione, and 17-hydroxyprogesterone. On the other hand, the chronic treatment induced an IGF-I responsiveness to ACTH (P < 0.001). In conclusion, our study demonstrates that, in isolated GH deficiency, replacement doses of hrGH do not modify the adrenal steroid basal levels or its responsiveness to ACTH, whereas both replacement and high doses of hrGH induce an IGF-I responsiveness to ACTH.

Partial deficiency of adrenal 11-hydroxylase. A possible cause of primary hypertension.

Results of supraphysiological adrenocorticotropic hormone (ACTH) stimulation of biosynthetic pathways of adrenal zona fasciculata indicate that a deficiency of 11-hydroxylase exists in patients with essential hypertension. The deficiency is suggested by the much greater stimulus of synthesis of deoxycorticosterone (DOC) and deoxycortisol in hypertensive subjects than in controls (p less than 0.001). No significant difference in the synthesis of cortisol, corticosterone, progesterone, 17-hydroxyprogesterone (17-OHP), and delta-4-androstenedione (D4) was observed between the two groups. The ratios for synthesis of DOC and corticosterone and for deoxycortisol and cortisol found in hypertensive patients were significantly higher than those found in controls (p less than 0.001); no significant difference was observed in the synthesis of 17-OHP and progesterone. The synthesis of DOC and deoxycortisol was not significantly correlated with either blood pressure or plasma renin activity. Plasma renin activity was significantly lower in hypertensive subjects than in normotensive subjects (p less than 0.0001), while no difference was found in aldosterone secretion between the two groups. The 11-hydroxylase deficiency in the adrenal zona fasciculata may be one of the genetic factors causing hypertension together with environmental factors (particularly salt intake and work-related stress). The investigation performed in our study may be useful for the evaluation of adrenal zona fasciculata enzymatic activities during the study of hypertensive patients.

The influence of intense ballet training on trabecular bone mass, hormone status, and gonadotropin structure in young women.

A cross-sectional study on young dancers and exdancers was performed to evaluate the effects of intense weight-bearing exercise and dietary restriction, started during puberty, on bone mineral density (BMD), menarche age, menstrual function, and gonadotropin structure. Twenty current dancers (group 1) and 9 exdancers (group 2) were compared with a control group of 30 age-matched, regularly cycling women. Body weight, body mass index, total daily caloric intake, and nutritional markers were significantly lower (P < 0.05) in groups 1 and 2 than in controls. Using Quantitative Computed Tomography for the BMD evaluation, 12 dancers and 5 exdancers had Z-scores less than 2.5 SD below the mean of the controls; whereas, in 6 dancers and in 2 exdancers, BMD was between 1 and 2.5 SD. Groups 1 and 2 had a delay of menarche, which correlated positively with years of dance before menarche (r = 0.8; P < 0.001). Dancers had low levels and altered structure of circulating gonadotropins, which improved after GnRH stimulation. In conclusion, ballet training performed by dancers during puberty, dietary restriction, and low body mass index can all be associated with reduction in BMD and altered gonadotropin isoforms, with subsequent delay of menarche, menstrual dysfunctions, and insufficient peak bone mass. A longitudinal study must be conducted to confirm the persistence of low lumbar spine bone density in adult age.

Usefulness of 123I-metaiodobenzylguanidine (MIBG) scintiscan in the diagnosis of juxta-adrenal schwannoma.

The adrenal scintiscan with 123I-metaiodobenzylguanidine (MIBG), a reliable morphofunctional technique to evaluate catecholamine turnover in adrenal tumors, can be a useful method to investigate adrenal incidentalomas with arterial hypertension. A male patient, 44 yr old with diabetes, unstable arterial hypertension, and sudden paroxysms of tachycardia is described. The presence of a disomogeneous right juxta-adrenal neoplasm with calcifications was evidenced with ultrasound tomography and confirmed by computerized tomography (CT) scan. Adrenal 123I-MIBG scintiscan revealed a unilateral uptake at level of the right juxta-adrenal region, sized similarly to the neoplasm previously evidence by CT scan. Histological findings of the surgically removed neoplasm were consistent with an ancient schwannoma. Apart from pheochromocytomas, the MIBG uptake is commonly reported in neuroblastomas. In neuroblastoma, a bidirectional process of transdifferentiation has been previously reported in vitro between two coexistent cells: cells with specific uptake system for norepinephrine, with 123I-MIBG uptake capability, and cells oriented toward schwann/melanocytic line. The evidence of in vivo MIBG uptake in our schwannoma may be caused by the same possible phenotypic interconversion of above mentioned cell types. In conclusion, the presence of adrenal tumors with MIBG uptake capability, apart from pheochromocytomas, neuroblastomas, ganglioneuroblastomas, and ganglioneuromas, must be considered in the diagnosis of adrenal tumors.

A role for steroid hormones in the variability of blood pressure determination.

Blood pressure variability was studied in eight patients with renovascular hypertension (group 1) and eight patients with hypertension and partial deficiency of adrenal zona fasciculata 11-hydroxylase (group 2). Systolic, diastolic and mean blood pressure were found to be higher in group 1 than in group 2 when measured at home (P less than 0.001), while no difference was measured when blood pressure was taken in the outpatient clinic. Heart rate was higher in group 1 than in group 2 both at home and in the clinic (P less than 0.005 and P less than 0.05, respectively); a significant increase was observed only in the hospital clinic for group 2 (P less than 0.001). No difference in systolic function and left ventricular mass was found between the two groups. Finally, group 2 exhibited a significant increase (P less than 0.0001) in systolic, diastolic and mean blood pressure in the clinic, compared with that found at home, while group 1 showed a poor increase (P less than 0.05) in systolic blood pressure only. It is suggested that the enzymatic impairment of adrenal glands in group 2 may play a role in the disparity of blood pressure levels determined at home and in the outpatient clinic. Furthermore, our data suggest that differences in blood pressure measurement at home and in the hospital clinic should be taken into account when screening patients with partial deficiency of 11-hydroxylase.

Percutaneous computed tomography-guided ethanol injection in aldosterone-producing adrenocortical adenoma.

The feasibility, safety and effectiveness of percutaneous computed tomography-guided ethanol injection (PEI-CT) was investigated in a patient affected by aldosterone-producing adenoma (APA). A 42-year-old male patient with typical features of hyperaldosteronism presented a solitary left adrenal adenoma measuring 2 cm, with a normal contralateral gland, evidenced by both CT scan and adrenal [75Se-19]-nor-cholesterol scintigraphy. After normalization of potassium plasma levels, 4 ml of sterile 95% ethanol with 0.5 ml of 80% iothalamate sodium was injected. The procedure was completed in about 30 min. No severe pain or local complication was noted. Five hours after PEI, a fourfold and a twofold increase in aldosterone and cortisol plasma levels were observed, respectively. After 11 days on a normal sodium and potassium diet, normal potassium plasma levels and reduced aldosterone plasma levels were present, with reappearance of an aldosterone postural response. Plasma renin activity and aldosterone plasma levels normalized 1 month later, with reappearance also of a plasma renin activity postural response and maintenance of normal potassium plasma levels even on a high sodium and normal potassium diet. The patient has remained hypertensive, although lower antihypertensive drug dosages have been employed. After 17 months, normal biochemical, hormonal and morphological findings were still present. Thus, we suggest PEI-CT as a further alternative approach to surgery in the management of carefully selected patients with APA.

Altered glycosylation of pituitary gonadotropins in anorexia nervosa: an alternative explanation for amenorrhea.

To investigate the relevance of glycoprotein polymorphism to gonadotropin bioactivity in vivo, plasma follicle-stimulating hormone (FSH) and luteinizing hormone (LH), 17 beta-estradiol (E2), testosterone and sex hormone binding globulin (SHBG) levels in 17 amenorrheic women affected with anorexia nervosa (14-29 years) and 10 age-matched normally cycling women were evaluated. Plasma FSH and LH levels were assayed using radioimmunoassay (RIA) and immunoradiometric assay (IRMA) methods, before and after concanavalin A-Sepharose (Con A) affinity chromatography. Significant RIA-IRMA differences in FSH and LH plasma values were present only in women with anorexia nervosa (p < 0.005). Moreover, in these patients both FSH and LH showed a reduced binding to the Con A, expressed as a percentage of unbound, suggesting altered glycosylation of these moieties. In conclusion, these findings hypothesize the involvement of glycosylation polymorphism in RIA-IRMA differences; support the usefulness of both RIA and IRMA methods in FSH and LH evaluation, before and after Con A chromatography; and suggest a new pathogenetic pathway to explain amenorrhea in anorexia nervosa.

Changes in the glycosylation pattern of circulating gonadotropins after acute administration of gonadotropin-releasing hormone in patients with anorexia nervosa.

To study the involvement of gonadotropin-releasing hormone (GnRH) in glycosylation of circulating gonadotropin isoforms in anorexia nervosa (AN), 14 amenorrhoic patients with AN, 14 age-matched volunteers in early follicular phase, and five normal-weight re-fed patients with AN were investigated under baseline conditions and after acute administration of GnRH. Plasma gonadotropins were assayed using IRMA before and after concanavalin A affinity chromatography. Baseline plasma gonadotropin levels were lower for both AN and re-fed AN patients than in controls (P<0.005). The increase in FSH and LH after GnRH administration was lower than in controls for AN (P<0.005) and re-fed AN (P<0.005 and P<0.05 respectively) patients. Percentages of total gonadotropin not bound to concanavalin A (complex carbohydrate chains) under baseline conditions were higher in patients with AN than in controls (P<0.005) but decreased after GnRH administration (P<0.001). In re-fed AN patients, the percentage of unbound FSH was higher than in controls (P<0.05), and decreased after GnRH administration (P<0.001), whereas the percentages of unbound LH were not significantly different from controls either before or after GnRH administration. These data suggest that: (a) the acute administration of GnRH induces quantitative and qualitative changes in circulating gonadotropin isoforms in both normal controls and AN patients; (b) during recovery the LH response in re-fed AN patients is associated with a glycosylation pattern that is the same as that for controls.

Different dysregulations in adrenal steroid biosynthesis as a prevalent cause of hyperandrogenism in women from southern Italy.

OBJECTIVE: To investigate the presence of a dysregulation in steroid biosynthesis in women from southern Italy. DESIGN: Controlled clinical study. SETTING: Normal and hyperandrogenic women referred to the Endocrinology Unit of Federico II University Medical School of Naples. PATIENT(S): One hundred fifty untreated young hyperandrogenic women and 50 normal age-matched women. INTERVENTION(S): Morning (basal) blood samples obtained in the early follicular phase and after a long (360 minute) ACTH stimulation test. MAIN OUTCOME MEASURE(S): The adrenal maximal response was calculated as stimulus under curve areas (AUCa), and all steroids were assayed using RIA methods. RESULT(S): A dysregulation of 21-hydroxylase was found in 22 patients (14.7%), with a prevalent increase of 17 alpha-hydroxyprogesterone AUC, whereas in 9 hirsute women (6%), there was a prevalent significant increase in 11-deoxycortisol AUC. In 5 women (3.3%), DHEA and DHEAS basal and AUCs plasma levels were increased, suggesting an impaired 3 beta-olo-dehydrogenase activity. The remaining 114 hyperandrogenic women (76%) compose the nonadrenal group, with a probable diagnosis of primitive functional ovarian hyperandrogenism. CONCLUSION(S): Considering the high prevalence of hirsutism and oligomenorrhea in our female hyperandrogenic population, we suggest an adrenal hyperresponsiveness likely due to a dysregulation in enzymes related to androgen adrenal steroidogenesis.

Derangement of the hypothalamic GnRH pulse generator in women with epilepsy.

An increased frequency of reproductive endocrine diseases has been described in women with epilepsy and a subclinical reproductive dysfunction has been suggested in normally menstruating epileptic women. We assessed the reproductive endocrine function in 11 normally menstruating, drug-free epileptic women, evaluating the basal hormonal profile and LH pulsatile secretion during continuous EEG monitoring. A significant LH hyperpulsatility was observed in epileptic women compared with controls; moreover, a significant increase of gonadotropin basal secretions was observed when inter-ictal paroxysmal activity increased. The derangement of the hypothalamic GnRH pulse generator may represent a subclinical condition associated with epilepsy, not necessarily affecting the regularity of menstrual function. However, it is possible that the alteration of LH pulsatile pattern might eventually cause reproductive endocrine diseases. Paroxysmal activity seems to be an important additional factor in the derangement of gonadotropin secretion.

Effect of a combination of ethinylestradiol and desogestrel in adolescents with oligomenorrhea and ovarian hyperandrogenism.

Nine oligomenorrheic adolescent girls with a clinical and hormonal picture of ovarian hyperandrogenism were treated with a monophasic oral contraceptive (OC) containing 0.03 mg ethinylestradiol (EE) plus 0.150 mg desogestrel (DOG) for six months. The same treatment was administered in eight eumenorrheic adolescents. In both groups the treatment induced a decrease in LH, FSH, androstenedione (delta 4-A), testosterone (T) and dehydroepiandrosterone sulphate (DHEA-S) levels associated with a significant sex-hormone-binding globulin (SHBG) increase. In oligomenorrheic adolescents a marked decrease in both the total ovarian volume and the number of cystic follicles was observed. All parameters, except SHBG and ovarian volume in hyperandrogenic girls, returned to pre-treatment values 3 months after treatment. Subjective improvement of skin problems occurred in six of the nine oligomenorrheic girls. Although temporary, the EE + DOG formulation pill is effective in the treatment of ovarian hyperandrogenism in adolescents. It may also be useful for the prevention of the progressive transformation in the 'classical' and 'irreversible' micropolycystic ovary of adult age.

PIP: The hormonal effects of a combined, monophasic oral contraceptive (OC) containing 0.03 mg of ethinyl estradiol and 0.150 mg of desogestrel were compared in 9 adolescents with oligomenorrhea and ovarian hyperandrogenism and 8 controls with regular menstrual periods. All adolescents were treated for 6 consecutive months. Before treatment, the females with irregular periods had significantly higher basal luteinizing hormone (LH), delta 4-androstenedione (A), testosterone (T), and dehydroepiandrosterone sulfate (DHEA-S) levels than controls. In addition, the oligomenorrheic females had significantly lower sex hormone binding globulin (SHBG) levels and greater mean ovarian volume. OC treatment produced a decrease in all hormones (LH, follicle-stimulating hormone, delta-4 A, T, and DHEA-S) in girls in both groups and a significant increase in SHBG levels. Oligomenorrheic subjects further manifested a significant decrease in total ovarian volume, with reduced number or disappearance of all echo-free cystic follicles in both ovaries. With the exception of SHBG and ovarian volume in hyperandrogenic subjects, all parameters returned to pretreatment values 3 months after discontinuation of the OC. 6 of the 9 oligomenorrheic subjects showed subjective improvement of skin problems; in addition, 6 reported a longterm decrease in hair growth. Post-treatment, oligomenorrhea and anovulation persisted in 7 of the 9 subjects. Although the effect of this treatment is temporary, the ethinyl estradiol-desogestrel OC appears to be effective in hyperandrogenic adolescents and may delay the progression of hirsutism and prevent adult micropolycystic ovarian disease.

Evaluation, by noninvasive methods, of the effects of acute loss of thyroid hormones on the heart.

To evaluate the effects of the acute loss of thyroid hormones on the heart the authors studied 11 women with acute hypothyroidism. The cardiac study was performed by means of electrocardiography (ECG), radionuclide ventriculography (RNV) at rest and under effort, and monodimensional echocardiography (MD-echo) and was repeated with ECG and MD-echo after six months of thyroxine suppressive therapy. The ECG showed a significant prolongation of QT interval and flattening and inversion of T wave with normal heart rate. The MD-echo revealed left ventricular function in the normal range and normal left ventricular dimensions. RNV showed the ejection fraction in the lower normal range at rest, which increased to a smaller extent under effort in comparison with a control group. The ECG performed during suppressive therapy with L-thyroxine yielded normal findings with an increase of heart rate and of R wave amplitude, and the MD-echo showed no significant variations of cardiac function due to the increase of heart rate.

[Does the therapy with indomethacin interfere with growth in Bartter's syndrome in childhood?]. / La terapia con indometacina interferisce con l'accrescimento nella sindrome di Bartter dell'infanzia?

The authors describe a new-born form of Bartter's syndrome treated for about 6 years with Indomethacin in a quantity of 2 mg/Kg/die except short periods, during which it was given triamterene in a quantity of 2 mg/Kg/die. While with the first medicine the growth of height has had an average increase of about 9 cm a year, with the second one there hasn't been any result neither on growth nor on the rest of symptomatology. The A.A. on the base of recent experimental data think that the deficiency of height could be due to a scanty affinity of peripherical receptors and SmC, that could be removed from the provision of Indomethacin.

A pilot study for neonatal screening of congenital adrenal hyperplasia due to 21-hydroxylase and 11-beta-hydroxylase deficiency in Campania region.

A neonatal screening for both 21-hydroxylase and 11-beta-hydroxylase deficiencies, responsible for congenital adrenal hyperplasia (CAH), has been conducted in Campania Region, Southern Italy. In 4380 neonates, aged 2-10 days, capillary blood from a heel prick was collected on microfilter paper, and 17-alpha-hydroxyprogesterone (17OHP) measured by radioimmunoassay (RIA) using a highly specific antibody (Ab A). In addition, in 295 of these samples, both 17OHP and 11-deoxycortisol (S) were measured using an anti-deoxycortisol antibody (Ab B) cross-reacting with 17OHP 100%. All results were compared with plasma 17OHP and S levels in 21 patients with diagnosed 21-hydroxylase deficiency and in 5 healthy volunteers on metyrapone test used for blocking the 11-beta-hydroxylase activity. CAH due to 21-hydroxylase deficiency was diagnosed in a female newborn. The assay, based on the antibody reacting with both 17OHP and S, is particularly suitable for wide-scale screening programs enabling the simultaneous detection of two congenital enzyme defects.

A quick method to detect circulating anti-thyroid hormone autoantibodies.

The aim of this study was to evaluate the feasibility of a chromatographic method to easily detect circulating anti-thyroid hormone autoantibodies (THBA), to calculate their affinity constant and the total thyroid hormone (TH) levels in presence of THBA. This method was applied to sera from 4 subject with suspected THBA and 20 controls (10 normal subjects and 10 patients with thyroid dysfunctions). After a short incubation with 125I-T3 or T4 tracer solution containing 8-anilino-1-naphthalenesulfonic acid as inhibitor of the binding of TH to plasma proteins without affecting THBA binding, the samples were chromatographied on prepacked Sephadex LH 20 columns and eluted with TRIS buffer to separate free TH from THBA-bound TH. Samples were considered THBA positive when radioactivity values in TRIS eluates were higher than in controls. THBA-bound TH were subsequently eluted with methanol and used to calculate the total TH present in patients with THBA. After a validation test using two standardized methods, we propose this method to quickly detect TH-BA in samples with suspected spuriously high values of free and total TH.

Interleukin-1 beta plasma secretion during diurnal spontaneous and induced sleeping in healthy volunteers.

We previously reported nocturnal plasma IL-1 beta (beta) increases during sleep in absence of stress-induced activation of hypothalamic-pituitary-adrenal (HPA) axis. In this paper we evaluate the presence of plasma IL-1 beta secretion in nine healthy volunteers (mean age 31.2 +/- 4.2) during post-prandial naps, after the administration of zolpidem, a benzodiazepine receptorial agonist. Although a significant increase in IL-1 beta plasma levels during spontaneous sleep was present in only four subjects when compared to those obtained during wake and induced-sleep, spontaneous sleep IL-1 beta mean plasma levels appeared slightly higher than both wake and induced-sleep values. Moreover, a negative correlation was present between IL-1 beta and cortisol (F) values obtained during the early afternoon (r = 7; p < 0.05). Our findings are consistent with a possible association of IL-1 beta secretion to physiologic sleep also during daytime spontaneous naps, with the presence of F influence on this phenomenon, and with the lack of IL-1 beta association to daytime naps after sleep-inducer pharmacological agents.

Interleukin-1 beta and beta-endorphin circadian rhythms are inversely related in normal and stress-altered sleep.

Normal sleep is associated to physiological nocturnal rises in Interleukin 1 beta (IL 1 beta) secretion. The 24 h pattern of IL 1 beta, beta-Endorphin (beta-EPH), ACTH and cortisol (F) production was evaluated in four male healthy volunteers. Two subjects were unable to sleep, due to the stress of the experiment; in these cases, no detectable plasma IL 1 beta secretion, both diurnal and nocturnal, was present, beta-EPH plasma levels were significantly higher (p < 0.01) than in the subjects who slept regularly and, in one case, increased F plasma levels were also reported. A strong negative correlation between IL 1 beta and beta-EPH plasma levels was present in all the cases. In conclusion, stress-induced sleep alterations might deeply affect both diurnal and nocturnal IL 1 beta plasma secretion, probably due to the hypothalamus-pituitary-adrenal axis (HPAA) activation, and beta-EPH might be the reliable marker of the stress-induced HPAA activation level.

Unusual association of thyroiditis, Addison's disease, ovarian failure and celiac disease in a young woman.

The coexistence of autoimmune endocrine diseases, particularly autoimmune thyroid disease and celiac disease (CD), has recently been reported. We here present a 23-year-old woman with a diagnosis of hypothyroidism due to Hashimoto's thyroiditis, autoimmune Addison's disease, and kariotypically normal spontaneous premature ovarian failure. Considering the close association between autoimmune diseases and CD, we decided to search for IgA anti-endomysium antibodies (EmA) in the serum. The positivity of EmA and the presence of total villous atrophy at jejunal biopsy allowed the diagnosis of CD. On a gluten-free diet the patient showed a marked clinical improvement accompanied, over a 3-month period, by a progressive decrease in the need for thyroid and adrenal replacement therapies. After 6 months, serum EmA became negative and after 12 months a new jejunal biopsy showed complete mucosal recovery. After 18 months on gluten-free diet, the anti-thyroid antibodies titre decreased significantly, and we could discontinue thyroid substitutive therapy. This case emphasizes the association between autoimmune polyglandular disease and CD; the precocious identification of these cases is clinically relevant not only for the high risk of complications (e.g. lymphoma) inherent to untreated CD, but also because CD is one of the causes for the failure of substitute hormonal therapy in patients with autoimmune thyroid disease.