Clomipramine hypersensitivity with predominantly pulmonary involvement

Drug hypersensitivity (DRESS syndrome) is a rare disorder with diverse systemic and visceral manifestations. Pulmonary involvement is uncommon and is mainly characterized by eosinophilic infiltration. We report a case of DRESS syndrome induced by clomipramine with predominant pulmonary involvement.     

Hypogonadotropic hypogonadism in nephrotic rats: increased sensitivity to negative feedback effects of testosterone

Pituitary-testicular function was examined in adult male rats with aminonucleoside-induced nephrotic syndrome as a model for similar disease in humans. Nephrotic rats developed androgen deficiency, as manifested by decreased prostate and seminal vesicle weights, lower serum total and free testosterone levels, and reduced testosterone release from testes incubated in vitro. Despite hypoandrogenism, the weight and histologic appearance of the testes (light microscopy) were not affected in nephrotic rats. This androgen deficiency seemed to be a consequence of decreased gonadotropin output rather than primary testicular failure, since both pituitary gonadotropin content and serum gonadotropin levels (basally and after luteinizing hormone releasing factor; LHRH) were reduced in nephrotic rats. In addition, the percentage increase in testosterone release by testes incubated in vitro after addition of exogenous gonadotropin was similar in nephrotic and control groups. However, gonadotropin output in nephrotic rats was not impaired in the absence of testis, since no reduction was seen in either post-castration serum gonadotropin levels in vivo or gonadotropin release from pituitaries incubated in vitro. This presumed inhibitory effect of the testis on gonadotropin output in nephrotic rats was confirmed directly by demonstrating an increased sensitivity to testosterone-mediated suppression of gonadotropins in castrate animals in vivo. The presence or absence of albumin also seemed to modulate the suppressive effect of testosterone on gonadotropin output from normal pituitaries incubated in vitro. We conclude that nephrotic male rats develop hypogonadotropic hypogonadism secondary to an increase in sensitivity of the pituitary to the negative feedback effects of testosterone.     

Chronic morphine treatment induces hypersensitivity to testosterone-negative feedback in castrated male rats

Studies were undertaken to determine the effects of chronic stimulation of opiate receptors on the negative feedback effects of testosterone (T) on luteinizing hormone (LH) secretion in the male rat. In an initial study, castrated male rats received replacement levels of T (2 ng/ml) or chronic morphine (M) treatment for 7 days. When initiated at the time of castration, both T and M treatments prevented the castration-induced hypersecretion of LH. However, when the treatments commenced 2 weeks after castration, only T restored LH secretion to the low levels seen in intact rats. In a second study, rats castrated 2 weeks previously were exposed to chronic M or placebo (control) treatment in the presence of various dosages of T. In rats receiving T alone, LH secretion was unaffected at T levels up to 600 pg/ml serum, but thereafter there was a dose-dependent suppression of LH release by T. Serum T levels which reduced LH secretion by 50% were estimated to be 966 pg/ml. In contrast, in castrated rats receiving both M and T treatment, a 50% reduction in LH secretion was estimated to be at 300 pg T/ml serum and maximal inhibition of LH secretion was achieved at serum T levels of greater than 600 pg/ml. Neither T alone nor M plus T treatment altered the responsiveness of the anterior pituitary to LHRH in vitro. These findings indicate that M may enhance the sensitivity of the hypothalamus to T feedback by approximately 3-fold and raise the possibility of the existence of an opioid-sensitive neural component which may modulate the negative feedback effects of T on LH secretion.     

Does prolactin modify testosterone feedback in the hamster? Suppression of plasma prolactin inhibits photoperiod-induced decreases in testosterone feedback sensitivity

The hormonal changes during the photoperiodically driven annual reproductive cycle of the male golden hamster can be explained partially by a change in the sensitivity of the hypothalamo-pituitary axis to negative feedback by testosterone (T). The present studies test the hypothesis that the increases in plasma levels of LH and FSH that follow photo-stimulation are due to decreasing feedback sensitivity and examine if this change in sensitivity is dependent upon increasing PRL levels. Adult males were exposed to a lighting schedule of 5 h of light, 19 h of darkness (5:19) for 12 weeks to induce gonadal regression. The animals were castrated; treated with an inhibitor of PRL release, bromocriptine (CB-154), or oil; and received a Silastic capsule that was empty or filled with T. Subsequently, the animals were transferred to 14:10 and killed 9 or 31 days later. There were no significant changes in FSH and LH in animals receiving oil injections and empty implants between days 9 and 31, suggesting no steroid-independent changes in gonadotropin secretion during this time period. However, 4-mm T implants were more effective in suppressing LH and FSH levels on day 9 than on day 31. This suggests that there is a gradual decrease in feedback sensitivity to T following photostimulation. T was more effective in inhibiting LH and FSH levels in CB-154-treated than in oil-treated animals on both day 9 and day 31. Thus, increases in PRL release are instrumental in causing decreases in feedback sensitivity following photostimulation.     

Anterior pituitary involvement in Wegener's granulomatosis

Wegener's granulomatosis rarely involves the pituitary, and is limited to the posterior gland. A young woman developed sinusitis, otitis media, asymptomatic pulmonary density, blindness, and anterior pituitary hormone deficiency over 7 years. Mucosal biopsies showed only chronic necrotizing inflammation without vasculitis. Since her clinical course suggested an atypical presentation of Wegener's granulomatosis, cyclophosphamide was finally added to corticosteroid therapy. All symptoms but monocular blindness and hypopituitarism remitted.     

Retinal modulation of the hypothalamic sensitivity to testosterone feedback in photoperiodism of quail

This experiment was performed on two groups of male Japanese quail. One had been maintained in our laboratory as a closed colony (S-group), and the other had been obtained from a commercial source (R-group). Different responses of gonadal function were found between two groups following either testosterone treatment or exposure to short days. Immature birds of these groups responded to long days with rapid gonadal growth, but after sexual maturity, exposure to short days for 3 weeks induced testicular atrophy only in S-group. Involvement of the feedback effect of androgen in the photoperiodic response was then examined. Under long-day conditions, intraperitoneal placement of testosterone propionate (TP)-filled Silastic tube for 2 weeks decreased testicular weights in S-group but not in R-group. Apparently, sensitivity to short days is closely correlated with sensitivity to testosterone in the adult male. By bilateral enucleation, quail of S-group became less sensitive to both gonad inhibitory effect of short days and the negative feedback effect of TP. These results suggest that the photoperiodic mechanisms that are primarily mediated by the retinal system play a role in altering sensitivity to steroid feedback at the hypothalamus.     

Effects of testosterone mediated or modulated by pituitary factors.

Adult rats of both sexes were either gonadectomized or hypophysectomized and gonadectomized. Three to eight weeks later they were treated for 14 consecutive days with oil or with 75 or 200 mug testosterone propionate (TP) per 100 g body weight. The animals were killed and for each sex the gonadectomized animals were compared with the hypophysectomized-gonadectomized animals as far as their NADPH- and NADH-dependent 3alpha-hydroxy-steroid dehydrogenases (3alpha-HSD) in renal microsomes, transcortin levels in serum and five organ weights relative to total body weight were concerned. For two of the latter, i.e. the relative kidney and prostatic weights, no significant differences were found. Transcortin levels, relative adrenal weights and renal NADPH-dependent 3alpha-HSD activities were higher in oil-treated gonadectomized animals than in oil-treated hypophysectomized-gonadectomized animals. The opposite was found for the relative weights of uterus and seminal vesicles and renal NADH-dependent 3alpha-HSD activities. These differences between gonadectomized and hypophysectomized-gonadectomized animals disappeared after TP treatment as far as transcortin levels were concerned but remained for the five other parameters. After gonadectomy sexual differences subsisted for all parameters studied. But whereas intact male rats had higher NADH-dependent 3alpha-HSD activities than female rats the opposite was found after gonadectomy. After gonadectomy plus hypophysectomy the between sex differences disappeared as far as transcortin levels were concerned but remained in the other parameters studied.     

Short-term testosterone supplementation relieves growth hormone autonegative feedback in men

The present study tests the postulate that testosterone (Te) stimulates GH secretion, in part, by attenuating autonegative feedback. To this end, 13 healthy men (ages 43-71 yr) received three consecutive weekly im injections of placebo (Pl) (n = 7) or Te (200 mg) (n = 6) in a prospectively randomized, double-blind, parallel-cohort design. An iv pulse of saline or recombinant human (rh)GH (3 micro g/kg.6 min) was infused 2 h before bolus saline or GH-releasing peptide (GHRP)-2 (1 micro g/kg) in the fasting state. Blood was withdrawn every 10 min, GH concentrations were quantitated by chemiluminometry, secretion was determined by deconvolution analysis, and outcomes were compared by ANOVA. After Pl, rhGH suppressed basal, pulsatile, and GHRP-2-stimulated GH secretion by 2.6-, 2.4-, and 2.1-fold, respectively (each P < 0.03), and truncated GHRP-2-stimulated GH secretory bursts (P < 0.005). Compared with Pl, Te: 1) stimulated basal and pulsatile GH secretion by 1.9 and 2.4-fold (P < 0.01 and P < 0.02), respectively; 2) reduced feedback on basal GH secretion (P < 0.01); 3) blunted GHRP-2-stimulation by 1.9-fold (P < 0.01); and 4) facilitated initial recovery of rhGH-suppressed GH concentrations (P < 0.005). The foregoing actions were selective, inasmuch as Te did not relieve autoinhibition of pulsatile GH secretion. In summary, short-term Te supplementation decreases rhGH-imposed negative feedback on basal GH secretion and enhances early escape of GH from autoinhibition. In principle, such actions could potentiate the renewal of high-amplitude pulses of GH in androgen-replete individuals.     

Pituitary-thyroid feedback hypersensitivity as a novel cause of hypothyroidism in children

Recognition and treatment of childhood hypothyroidism is essential to prevent serious developmental abnormalities, and neonatal screening based on detection of raised thyrotropin concentrations is routine. We investigated an adolescent who had developmental retardation because of an undiagnosed and novel cause of childhood hypothyroidism associated with normal circulating thyrotropin concentrations. Dynamic testing showed a hypersensitive pituitary-thyroid feedback axis with no evidence of other pituitary or hypothalamic disease, and sequence analysis of four candidate causative genes was negative. A high index of suspicion is required to diagnose and treat this disorder to prevent the consequences of long-term hypothyroidism on development.     

Hypogonadotropic hypogonadism in idiopathic hemochromatosis: evidence for combined hypothalamic and pituitary involvement

Hypogonadism is a common finding in idiopathic hemochromatosis. Most studies have localized the defect to either the pituitary gland or the testes. We describe a case with evidence that favors the likely concomitant involvement of the hypothalamus as a factor in the observed hypogonadism. A clinically hypogonadal male with hemochromatosis had a low testosterone concentration with inappropriately normal serum LH levels. Leydig cell function was intact, as demonstrated by a normal increase in serum testosterone following HCG administration. However, although the pituitary secretion of LH was normal in response to GnRH stimulation, clomiphene administration did not produce an increase in LH and FSH, suggesting that there was a defect in the hypothalamic GnRH response. Since the FSH and prolactin responses to stimulatory testing were inadequate, coexisting pituitary dysfunction was likely also present. We conclude that this man had hypogonadism with laboratory evidence for a combined defect in hypothalamic and pituitary function.