Faculty Bibliography

Osteoporosis in men is a disease that is increasing in incidence, and with an increasing elderly population it poses a serious health problem. Since both testosterone (T) and growth hormone (GH) have an anabolic effect on bone and both decrease with aging, we were prompted to test whether the administration of these hormones in combination would increase bone mass in orchiectomized (orx) senile rats more than administration of either agent alone. Twenty-month-old male Wistar rats were divided into five groups with seven animals each: (a) age-matched intact control, (b) orx, (c) orx+GH (2.5 mg/kg/day), (d) orx+T [10 mg/kg, subcutaneous (s.c.), injection given twice a week], and (e) orx+GH+T. Testosterone and GH were given subcutaneously for 4 weeks. Bone histomorphometry of the tibial shaft showed that the orx group had lower cortical bone area than the intact control group. The decrease in cortical bone area was due to increased intracortical porosis as well as decreased periosteal bone formation rate (BFR). Administration of T to the orx animals prevented the development of the porosis and the decrease in periosteal BFR. The bone mineral content (BMC) and bone mineral density (BMD) of the femur as tested by dual-energy X-ray absorptiometry were significantly higher in the orx+T than in the orx group and were not significantly different from that of the intact control group. Administration of GH to the orx rats increased periosteal BFR significantly; however, the BMC and BMD measured were not increased significantly in comparison to the orx group. When GH and T were combined in treatment, the cortical bone area, periosteal BFR, and femoral BMD were all significantly higher than that of the orx and even higher than the intact control rats. Two-way analysis of variance shows that the individual effect of GH and T treatment on the periosteal BFR and cortical bone area was significant. The effect of T, but not GH, on femoral BMC and BMD was also significant; however, there is no synergistic interaction between the two treatments. Four weeks of orx with or without GH or T administration had no significant effect on tibial metaphyseal cancellous bone volume. In conclusion, this short-term study suggests that the combined intervention of GH and T in androgen-deficient aged male rats may have an independent effect in preventing osteopenia. The significant effect of GH+T may be attributed to the prevention of intracortical porosis, and an increase in periosteal bone formation and cortical bone mass.

Prolactin secreting pituitary adenomas are a rare finding in prepubertal children /1/. As in adults, their incidence is higher in girls than in boys; however, the macroadenomas are predominant in boys /20-16/. Two prepubertal boys who presented with short stature and linear growth deceleration were diagnosed to have prolactin secreting pituitary macroadenoma associated with growth hormone (GH) deficiency. They were treated with bromocryptine and exogenous recombinant hGH. They achieved a normal adult stature, full sexual maturation and tumor regression on the therapy. In addition, both boys developed macrotestes. Further evaluation ruled out other etiologies for macrotestes. We presume that the elevated prolactin caused local testicular growth factors to induce testicular cell division and/or hypertrophy resulting in an increased testicular volume.

We studied the testicular function and some androgen-mediated events in 22 males (16-30 years of age) with male pattern baldness that was treated with finasteride (10 mg once daily) for 2 years. Patients were evaluated every 3 months. Prostatic volume was determined in six subjects by endorectal ultrasound scans. Serum gonadotropin, prostate-specific antigen (PSA), and sex hormone levels were determined basally and periodically during the treatment period. Fourteen subjects underwent gonadal stimulation with human chorionic gonadotropin (hCG), and the gonadotropin response to gonadotropin releasing hormone (GnRH) was determined in eight subjects, prior to and after 2 years of therapy. Finasteride treatment resulted in an improvement in the male pattern baldness and prostatic shrinkage that was associated with an increase in serum testosterone levels (17.2 +/- 2.5 vs. 26.3 +/- 1.7 nmol/L) and a decrease in dihydrotestosterone (DHT) levels (1.45 +/- 0.41 vs. 0.38 +/- 0.10 nmol/L), causing a marked increase in that testosterone/DHT ratio. A significant increase in the serum levels of androstenedione (3.67 +/- 0.49 vs. 7.05 +/- 0.70 nmol/L) and estradiol (132 +/- 44 vs. 187 +/- 26 pmol/L) was also noted, whereas androstanediol glucoronide (33.3 +/- 6.4 vs. 10.7 +/- 4.5 pmol) and PSA (1.6 +/- 0.6 vs. 0.4 +/- 0.1 ng/ml) were significantly decreased. No changes in basal or stimulated levels of gonadotropin were observed. There was a significant increase in the testosterone response to hCG during finasteride therapy (delta: 16.7 vs. 35.5 nmol/L) that could be explained, at least in part, by the reduction of testosterone metabolism resulting from the blockage induced by finasteride. The decrease in the androstenedione to testosterone and estrone to estradiol ratios observed after hCG treatment, however, strongly suggests increased activity of the 17-ketosteroid reductase enzyme and an improvement of the testicular capacity for testosterone production.

Obesity, short stature, decreased growth rate and delayed skeletal maturation are common features of children with Prader-Willi syndrome (PWS). In contrast to PWS, children with simple exogenous obesity have normal or increased growth rate and normal or advanced skeletal maturation. Decreased growth hormone (GH) secretion evaluated by pharmacological or physiological testing associated with increased plasma insulin-like growth factor (IGF-I) and GH-binding protein (GH-BP) levels are also characteristic of simple obesity. In order to understand whether the suboptimal GH secretion in PWS is an artifact of the obesity, we studied 33 obese and 11 non-obese PWS children, aged 2-16 years.GH secretion was evaluated with three pharmacological stimuli (insulin, clonidine and L-dopa) and by spontaneous 24-hour GH secretion. Skeletal maturation was delayed in 70% whereas plasma IGF-I and GH-BP were either low or normal. Forty subjects, including ten non-obese children, had GH deficiency by standard testing (failure to respond to two pharmacological stimuli), and all but one had blunted spontaneous 24-h GH secretion. No significant correlation between body mass index (wt/ht2) and spontaneous 24-h GH secretion (r = 0.145), p > 0.06) or GH-BP levels (r = 0.19, p > 0.07) was found. Thirty documented GH deficient children have completed at least two years of GH therapy. With treatment the overall mean height SD and weight SD changed from -2.2 to -0.8 and from 3.5 to 2.4 respectively (p < 0.0001). No patient has developed diabetes mellitus. In conclusion, growth velocity, skeletal maturation, GH secretion and GH dependent proteins in PWS resemble GH deficiency more than simple obesity. Our ongoing study suggests that GH deficiency in PWS is not an artifact of obesity. Although it is unlikely that GH deficiency is the only cause of decreased growth velocity and increased adiposity in PWS, it is a common feature and significant contributory factor. Long term observation will be required until achievement of adult height to determine whether GH therapy actually improves final height.

We describe a boy who developed precocious puberty resulting from chorionic gonadotropin produced by a mediastinal germ cell tumor. Following tumor removal he began spontaneous precocious sexual development which was treated and then arrested spontaneously. Investigation of this arrested puberty established that he had Klinefelter syndrome (KS) mosaicism. He represents the first instance of KS mosaicism reported with a mediastinal germ cell tumor, a neoplasm commonly reported in males with a 47,XXY karyotype. We recommend that all males with KS and early sexual development or with "normal" testicular growth be screened with measurement of germ cell tumor markers including beta-subunit of human chorionic gonadotropin and alpha-fetoprotein.

The function of the adrenal zona glomerulosa was studied in 18 patients with 11-hydroxylase deficiency confirmed by elevated plasma levels of 11-deoxycortisol. Patients were divided into two groups. Group I (4 males, 7 females; aged 1.2-2.8 yrs) had symptoms at birth or shortly after (classic form), and Group II (4 males, 3 females; aged 7.3-20.1 yrs) had their first clinical manifestation during childhood (non-classic form). To study zona glomerulosa function, patients were given dexamethasone p.o. 2 mg/m2/day x6 days, thus suppressing the zona fasciculata. Six hours after the last dose of dexamethasone, the zona glomerulosa was stimulated by i.v. administration of furosemide 1.0 mg/kg as a single dose. Blood was drawn 2 h later. In the untreated state, all patients had striking elevation of ACTH (Group I: 1,070 +/- 380 pg/ml; Group II: 764 +/- 180 pg/ml), 11-deoxycortisol (Group I: 63,000 +/- 22,000 ng/dl; Group II: 17,200 +/- 5,200 ng/dl) and deoxycorticosterone (Group I: 1,100 +/- 67 ng/dl; Group II: 499 +/- 27 ng%) while plasma renin activity (< 0.5 ng/ml/h in both groups) and aldosterone (Group I: 3.0 +/- 1.8 ng/dl; Group II: 2.3 +/- 1.8 ng/dl) were markedly suppressed. After the administration of furosemide 4 patients in Group I were unable to increase aldosterone (2.8 +/- 0.9 ng/dl) secretion in spite of marked elevation of plasma renin activity (28 +/- 7 ng/ml/h), suggesting an impairment of 11-hydroxylase in the zona glomerulosa.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND:17-Ketosteroid reductase deficiency results in male pseudohermaphroditism because conversion of the weak androgen androstenedione to the more potent androgen testosterone is impaired. If a late-onset form exists, hypogonadism and gynecomastia caused by decreased testosterone production and increased estrogen production, respectively, would be expected as the major clinical manifestations in men. METHODS:We studied 48 male subjects, ranging from 14 to 26 years of age, who had idiopathic pubertal gynecomastia. Serum concentrations of gonadal and adrenal steroid hormones were measured before and after the administration of corticotropin and after the combined administration of chorionic gonadotropin and dexamethasone for three days. RESULTS:We identified three unrelated subjects (ages, 16, 17, and 26 years) with results indicative of a partial deficiency of testicular 17-ketosteroid reductase. The three subjects had gynecomastia as well as decreased libido and impotence. Their mean (+/- SD) base-line serum androstenedione and estrone concentrations were elevated as compared with the levels in the 45 subjects without this enzyme deficiency (androstenedione, 380 +/- 70 vs. 110 +/- 70 ng per deciliter [13 +/- 2 vs. 4 +/- 2 nmol per liter]; estrone, 138 +/- 12 vs. 46 +/- 9 pg per milliliter [511 +/- 44 vs. 170 +/- 33 pmol per liter]). After the administration of chorionic gonadotropin, the mean serum androstenedione concentration in these three subjects was 910 +/- 48 ng per deciliter (32 +/- 2 nmol per liter) and the mean serum estrone concentration was 260 +/- 16 pg per milliliter (962 +/- 59 pmol per liter). The mean serum testosterone concentration at base line was 210 +/- 80 ng per deciliter (7.4 +/- 2.8 nmol per liter) in the 3 subjects, as compared with a value of 410 +/- 12 ng per deciliter (14.4 +/- 0.42 nmol per liter) in the 45 other subjects, and it did not increase in response to the administration of chorionic gonadotropin. The concentrations of androstenedione and estrone in spermatic venous serum were 19 times higher and 73 times higher, respectively, than in normal men. The serum concentrations of follicle-stimulating hormone and luteinizing hormone in these three subjects were inappropriately low, suggesting the presence of hypogonadotropic hypogonadism. CONCLUSIONS:A late-onset form of testicular 17-ketosteroid reductase deficiency can cause gynecomastia and hypogonadism in men.