Wilian Nicolau

Male pseudohermaphroditism due to steroid 5α-reductase 2 deficiency. Diagnosis, psychological evaluation, and management

Sixteen subjects (from 10 Brazilian families) with male pseudohermaphroditism due to steroid 5alpha-reductase 2 deficiency have been evaluated in 1 clinic. The diagnoses were made on the basis of normal plasma testosterone values, normal or low plasma dihydrotestosterone levels and high testosterone/dihydrotestosterone ratios in the basal state in postpubertal subjects or after treatment with either human chorionic gonadotropin or testosterone in prepubertal subjects. The analysis of the ratios of etiocholanolone to androsterone in urine confirmed the diagnosis in all subjects who were tested, and the molecular basis of the underlying mutations was established in 9 of the families. Fourteen of the individuals were evaluated by the same psychologist. All subjects but 1 were given a female sex assignment at birth. Three of the subjects (1 the sibling of an individual who has undergone female to male social behavior) maintain a female social sex; they have been gonadectomized and treated with exogenous estrogens. Ten of 13 subjects of postpubertal age underwent a change of social sex from female to male, had surgical correction of the hypospadias, and were treated with high-dose testosterone esters by parenteral injection and subsequently with dihydrotestosterone cream. These regimens brought serum dihydrotestosterone levels to the normal male range (or above) but resulted only in limited growth of the prostate and penis and, in some, increase in body and facial hair and enhancement of libido and sexual performance. Treatment of the prepubertal boys with testosterone and/or dihydrotestosterone resulted in a doubling of penis size.

Clinical, Hormonal and Pathological Findings in a Comparative Study of Adrenocortical Neoplasms in Childhood and Adulthood

PURPOSE We reviewed clinical and laboratory findings in 6 male and 32 female patients with functional adrenocortical neoplasms, and compared pediatric and adult data. MATERIALS AND METHODS Hormonal measurements were performed by radioimmunoassay, histological analysis was based on Weiss criteria and staging was done according to previously established guidelines. RESULTS Children had a higher incidence of virilization (72%), whereas in adults the predominant feature was Cushings syndrome (60%). A high testosterone level was the most common finding in adults and children with virilization followed by high dehydroepiandrosterone sulfate, androstenedione and dehydroepiandrosterone levels. High 11-deoxycortisol levels were frequently associated with tumor recurrence. Cortisol suppression after dexamethasone was altered in 93% of patients with virilization and no clinical features, suggesting autonomous cortisol secretion. CONCLUSIONS No statistically significant relation was noted between tumor weight and prognosis but there was a negative correlation between patient age and prognosis since children had a more favorable followup than adults. Mixed features in both groups resulted in the worst prognosis. A Weiss criteria grade IV or greater correlated well with a poor prognosis in adults but not children, while staging was more reliable in children.

Spironolactone-reversible rickets associated with 11β-hydroxysteroid dehydrogenase deficiency syndrome

A 7-year-old girl had growth retardation, hypertension, and hypokalemic alkalosis. Baseline serum aldosterone concentration and plasma renin activity were low and unresponsive to sodium deprivation and to orthostatic changes. Baseline serum progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, and cortisol levels were normal and adequately responsive to ACTH stimulation. No steroid was found abnormally elevated. A diagnosis of 11 beta-hydroxysteroid dehydrogenase deficiency was established on the basis of elevated urinary tetrahydrocortisol plus allotetrahydrocortisol/tetrahydrocortisone ratio, determined by gas chromatography-mass spectrometry. Evaluation of bone mineral metabolism and parathyroid function, and skeletal radiographs, revealed the presence of rickets and secondary hyperparathyroidism. Treatment with spironolactone alone for 2 months corrected hypertension, hypokalemic alkalosis, and all laboratory and radiologic evidence of rickets and hyperparathyroidism, resulting in acceleration of growth rate. The response to spironolactone suggests that a hypermineralocorticoid state is responsible for the hypertensive syndrome and that rickets and hyperparathyroidism could be a consequence of excess mineralocorticoid activity.

Normal Expression of the Serologically Defined H-Y Antigen in Leydig Cell Hypoplasia

H-Y antigen, the proposed inducer of testicular organogenesis, was determined serologically in 3 patients with male pseudohermaphroditism due to Leydig cell hypoplasia, a pathological model with lack of Leydig cell differentiation but normal seminiferous tubule embryogenesis. One patient was the offspring of consanguineous parents and 2 siblings presented as women with a lack of breast development and primary amenorrhea. Gonads were palpable in the inguinal canal, except for the right intra-abdominal testis in 1 patient. Two patients had female external genitalia and 1 had partial labial fusion. Karyotypes were 46XY. Gonadotropin levels were elevated, and testosterone was low and failed to increase after stimulation with human chorionic gonadotropin. Testosterone precursors were not elevated. Testicular histology showed absence of mature Leydig cells but relatively preserved seminiferous tubules. Family history was consistent for autosomal recessive inheritance. H-Y antigen expression measured by an enzyme-linked immunosorbent assay was normal, indicating that lack of other inductive factors for Leydig cell differentiation are responsible for Leydig cell hypoplasia.

Pulsatile release and circadian rhythms of thyrotropin and prolactin in children with growth hormone deficiency.

We have measured mean concentrations and have appraised the pulsatile nature of thyrotropin (TSH) and prolactin (PRL) release in children with classical GH deficiency (GHD; n = 4) and neurosecretory GH dysfunction (NSD; n = 4) and have compared the results with those obtained in children with constitutional delay (control; n = 4). Blood samples were obtained at 20-min intervals for 24 h. Pulse analysis of TSH and PRL was undertaken using the Cluster pulse detection algorithm. Circadian rhythmicity of TSH and PRL was assessed using cosinor analysis. The mean 24-h concentration of GH in the control subjects was significantly higher than that obtained in the GHD and NSD groups. With regard to TSH, the mean serum concentration in the GHD and NSD group were higher than that of the control subjects. This augmentation reflects TSH pulses of large amplitude and area, and a higher interpulse valley mean rather than a difference in peak number or peak duration. No differences in mean PRL concentration or characteristics of PRL pulses were found between the control and GHD and NSD subjects. When the 24 h data sets were divided into day (0800-2000 h) and night (2000-0800 h), the mean nighttime TSH concentration was higher than the daytime concentration in the control, GHD, and NSD groups. Although there were no day versus night differences in TSH pulse frequency in either group, peak amplitude, area, and interpulse valley means were increased during the night in the control group, and peak area, duration, and amplitude mean in the NSD group. The nighttime mean PRL concentrations in the control, GHD, and NSD subjects were higher than those found during the day. This increase was accounted for by increases in PRL peak amplitude, area in the control group, and peak area, amplitude, and interpulse valley mean in the GHD and NSD groups. Cosinor analysis of the 24-h TSH and PRL data revealed clear circadian rhythmicity in all groups of subjects. These data suggest that GHD and NSD are associated with an increase in pulsatile TSH secretion due to an increase in pulse amplitude and interpulse valley mean.

Effects of acute and chronic zinc administration on growth velocity in patients with hypopituitarism

Zinc is a metal that plays an important role in growth and development. It is capable of releasing growth hormone (GH) in vitro as well as in vivo and to promote an increase in the synthesis of insulin-like growth factor (IGF-I). We studied 16 prepubertal patients with hypopituitarism with the objective of evaluating serum zinc levels and the effect of its acute and chronic administration on growth velocity, pubertal development, pituitary hormones release and on the levels of IGF-I and sexual steroid hormones. We compared the serum zinc levels of patients with hypopituitarism with the levels of 15 children with constitutional short stature. We observed that patients with hypopituitarism, like patients with constitutional short stature, did not have abnormal serum zinc levels. After acute and chronic zinc administration, hormone levels (GH, IGF-I, PRL, TSH, T3, T4, CORTISOL, TESTOSTERONE, ESTRADIOL, and DHEA-S) did not change, in spite of the significant increase in zinc serum levels. The chronic use of zinc, alone, did not increase growth velocity, which happened during growth hormone therapy and was more intense after zinc association. After the withdrawal of the metal and continuing growth hormone therapy, we observed a significant decrease in growth velocity. All patients remained clinically and laboratorially prepubertal during all the study period. We conclude that the effect of zinc on growth depends on the level of growth hormone and that it can be used as an auxiliary therapy for hypopituitarism, even in patients who do not present with low serum zinc levels.

DETECTION OF THE SRY AND ZFY SLQUENCES IN PATIENTS WITH ABNORMAL GORADAL DIFFERENTIATION

Thirteen patients with abnormal gondal differentiation confirmed by pathology were studied. Seven with 46,XY karyotype (six with dysgenetic gonads and one with gonadal agenesis) and six with 46,XY karyotype: three 46,XY true hermaphrodites, two genitalia and gynecomastia) and one 46,XX patient with primary gonadal failure, born from a consanguineous marriage and sister of the 46,XY patient with gonadal agenesis. The SRY sequence was amplified by PCR with the primers EA and EB located within the SRY conserved sequence, amplifying a 317-bp fragment. The Y-specific DNA sequence ZFY was detected by Southern hybridizations using the pDP1007 probe, which corresponds to a Y-chromosome segment mapping close to the testis determining factor corresponds to a Y-chromosome segment mapping close to the testis determining factor region. The ZFY sequence was analysed in 8 cases (three 46,XX and five 46,XY patients) and found to be present in all 46,XY patients being absent in the 46,XX patients. The SRY sequence was analysed by PCR in 8 cases (four 46,XX patients and four 46,XY patients) being present in one 46,XX patient (a true hermaphrodite) and in all 46,XY (gonadal dysgenesis patients) and absent in three 46,XX patients. It was concluded that: a)-testicular differentiation can occur in the absence of the Y-chromosome sequences SRY and ZFY; b)-gonadal dysgenesis in SRY and ZFY-positive patients could be caused by mutations, Out of the SRY and ZFY loci; c)-46,XX and 46,XY gonadal agenesis present in two sisters born from consanguineous marriage suggest a role for autosomal loci in gonadal differentation.

ANALYSIS OF CLINICAL DATA OF 107 PATIENTS WITH GROWTH HORMONE DEFICIENCY

Clinical and radiological data and associated hormonal deficiencies were studied in 107 patients, with growth hormone deficiency: 46 had isolated growth hormone deficiency (1GHD)(25 males, 21 females) and 61 had multiple hypothalamic-pituitary hormone deficies (MHPD) (45 males, 16 females).Of the patients with IGHD, 82.2% were prepubertal, 40% had micropenis, 21.4% cryptorchidism, 61.4% were born by normal delivery (1 forceps), 29.5% delivered by cesarean section, 9.1% pelvic presentation and 2 pairs of twins. 17.5% had neonatal problems, 27.3% associated anomalies, 9.1% parental consanguinity and 13.3% affected siblings.In the group with MHPD 91.8% were prepubertal, 38.6% had micropenis, 11.1% cryptochidism, 51.8% normal delivery (4 forceps), 17.8% delivered by cesarean section, 30.4% with pelvic presentation at bird, 61.5% had neonaltal problem, 12.5% associated anomalies, 10.9% parental consanguinity and only 1 affected sibling. 14 patients with IGHD and 25 with MHPD had cranial CI-scans; abnormalities were described by the radiologist in 50% and 68%, respectively: 7.7% had empty sella, changes. The high incidence of empty sella is probably due to the small dimension of the sella in this condition. Associated hormonal deficiencies: GH + TRH (21.1%) GH +TRH + LHRH + CRF (14.0%), GH + TRH + LHRH (10.5%), GH + LHRH (10.5%), GH + TRH + CRF (8.8%).

“Effect of Gonadal Supression Treatment on Predicted Height in Growth Hormone Deficient (Ghd) Children.” 23

“Effect of Gonadal Supression Treatment on Predicted Height in Growth Hormone Deficient (Ghd) Children.” 23

Diagnostic Value of Basal and Stimulated Levels of Gonadotropins Measured By An Immunofluorometric Assay (Ifma) in the Differential Diagnosis of Precocious Puberty. 20

The new immunofluorometric kits such as DELFIA (Wallac, Turku, Finland) have an improved sensitivity and may allow a better discrimination between patients with gonadotropin dependent (GDPP) and independent (IGPP) precocious puberty. Normal prepubertal girls had gonadotropin levels measured by DELFIA kits under basal conditions (n = 20) and after stimulation with 100 μg iv GnRH (n = 10). Basal LH and FSH levels were 0.7 U/L) and FSH (> 3.4 U/L) may establish the diagnosis of GDPP, precluding the use of GnRH stimulation tests. In contrast, basal prepubertal concentrations of LH and FSH may occur in both GDPP and IGPP, indicating the need to perform GnRH stimulation tests.