Walter Bloise

THE ESSENTIAL ROLE OF ZINC IN GROWTH

Zinc is known to play a relevant role in growth and development. The basic mechanisms of action of this trace element are intimately linked to the structure and action of countless enzymes involved in many different metabolic processes. In this respect, when zinc specifically acts on cartilage growth it is involved in multiple enzymatic reactions which make this a multifactorial event. Thus, we may divide the actions of zinc into three distinct types: 1) action on taste and smell acuity, appetite regulation, and food consumption and regulation; 2) action on DNA and RNA synthesis stimulating a) cell replication and differentiation of chondrocytes, osteoblasts and fibroblasts; b) cell transcription culminating in the synthesis of somatomedin-C (liver), alkaline phosphatase, collagen and osteocalcin (bone), and c) protein, carbohydrate and lipid metabolism, that is intimately related to the mechanisms of smell, taste, appetite, and food consumption and utilization; 3) action on hormonal mediation by participating in a) GH synthesis and secretion in somatomammotroph cells, b) the action of GH on liver somatomedin-C production, and c) somatomedin-C activation in bone cartilage. In addition to these multiple functions, zinc also interacts with other hormones somehow related to bone growth such as testosterone, thyroid hormones, insulin, and vitamin D,. On the basis of the above considerations, we conclude that the integration of these mechanisms contributes to the perfect physiological functioning of bone. In the presence of zinc deficiency, this homeostasis is impaired, causing the weight-height deficiency detected in several species studied, the human species in particular.

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.

Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase 3 deficiency. Diagnosis, psychological evaluation, and management.

Ten male pseudohermaphrodites with 17 beta-hydroxysteroid dehydrogenase 3 (17 beta-HSD3) deficiency were evaluated in 1 clinic with an average follow-up of 10.1 years. The diagnoses were made by demonstrating low to normal serum testosterone levels, high androstenedione levels, and high ratios of serum androstenedione to testosterone in the basal state or after treatment with human chorionic gonadotropin. The molecular features of the underlying mutations were identified in all 7 families. Two additional males in the same families are believed to be affected on the basis of history obtained from family members. All of the 46,XY individuals in these families were registered at birth and raised as females (despite the presence of ambiguous genitalia in all or most), and all virilized after the time of expected puberty due to a rise in serum testosterone to or toward the normal male range. The age at diagnosis varied from 4 to 37 years. Ten individuals were studied by the same psychologist, and change of gender role (social sex) from female to male occurred in 3 subjects and in the 2 presumed affected subjects not studied. The individual with the highest serum testosterone level maintained female sexual identity, and in 2 families some of the affected males changed gender role and others did not. Thus, while androgen action plays a role in the process, additional undefined psychological, social, and/or biologic factors must be determinants of gender identity/role behavior. Management of the 7 individuals who chose to maintain female sex roles included castration, clitoroplasty, vaginal enlargement procedures when appropriate, treatment of hirsutism, cricoid cartilage reduction, and estrogen replacement. Three of the 7 are married (2 twice), 1 is involved in a long-term heterosexual relationship, 1 is engaged to be married, and the other 2 are not married and not believed to be sexually active. The 3 subjects who changed gender role behavior to male underwent hypospadias repair, and 1 was given supplemental testosterone therapy. One of these men is divorced, and the other 2 (aged 29 and 35 years) are unmarried. The diagnosis in 8 of these subjects was made after the time of expected puberty; it is unclear whether the functional and social outcomes would have been different if the diagnosis had been made and therapy begun earlier in life.

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.

Low Frequency of CYP21B Deletions in Brazilian Patients with Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

The frequency of large mutations was determined in 131 Brazilian patients with different clinical forms of 21-hydroxylase deficiency, belonging to 116 families. DNA samples were examined by Southern blotting hybridization with genomic CYP21 and C4cDNA probes after TaqI and BglII restriction. Large gene conversions were found in 6.6% and CYP21B deletions in 4.4% of the alleles. The breakpoint in these hybrid genes occurred after exon 3 in 92% of the alleles. All rearrangements involving CYP21B gene occurred in the heterozygous form, except in a patient with simple virilizing form who presented homozygous CYP21B deletion. Our data showed that in these Brazilian patients, CYP21B deletions were less frequent than in most of the large series previously reported.

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.

Severe and Mild Neonatal Hypothyroidism Mediate Opposite Effects on Leydig Cells of Rats

The effects of neonatal hypothyroidism on the number of Leydig cells were studied in neonatal Wistar rats. Moderate or severe hypothyroidism were induced during neonatal life by giving different amounts of methimazole (MMI; 0.05% or 0.1%) in the drinking water of pregnant and lactating dams. Rats were sacrificed on day 21 of postnatal life. Severely hypothyroid rats had approximately 45-fold higher serum thyrotropin (TSH) values and demonstrated approximately a 65% decrease in testes weight (p < 0.05) and the number of Leydig cells. However, in moderately hypothyroid rats, in which serum TSH was only approximately 16-fold higher, testicular weight was normal and the number of Leydig cells almost doubled (p < 0.01). There were no significant differences between the serum-free testosterone levels of the moderately and severely hypothyroid rats versus controls. Serum levels of 3alpha-androstanediol glucuronide, although decreased to less than 10% in severely hypothyroid rats (p < 0.01), were not changed by mild hypothyroidism. The number of Sertoli cells was increased in moderately hypothyroid rats versus controls (p < 0.05) and even further increased in severely hypothyroid rats (p < 0.05). We conclude that (1) severe neonatal hypothyroidism impairs the development and function of the testes and (2) moderate neonatal hypothyroidism stimulates the proliferation of Leydig cells.

Prepubertal male pseudohermaphroditism due to 17-ketosteroid reductase deficiency: diagnostic value of a hCG test and lack of HLA association.

Most patients with male pseudohermaphroditism (MPH) due to 17-ketosteroid reductase (17-KSR) deficiency were diagnosed at or after puberty when significant virilization occurred. We report 2 prepubertal sibs (Case 1, 4 yr and Case 2, 10 yr) unambiguously raised as females, with clitoral enlargement, separate urethral and vaginal orifices and gonads palpable at the inguinal canal bilaterally. Basal serum LH, FSH, 17-hydroxyprogesterone, testosterone (T), Dihydrotestosterone and dehydroepiandrosterone (DHEA) were normal for age. †4-Androstenedione (†4-A) was slightly elevated in Case 2 but nondiagnostic. Steroid measurements after human chorionic gonadotropin (hCG) stimulation were compared with those of boys with male external genitalia submitted to the same hCG protocol: peak T was subnormal (Case 1, 80, Case 2, 91, vs normal 329 ± 129 ng/dl, mean ± 1SD), peak †4-A elevated (Case 1, 477, Case 2,264, vs normal 44 ± 26 ng/dl) resulting in an abnormally elevated †4-A/T ratio (Case 1, 6.0, Case 2,2.9, vs normal 0.12 ± 0.09) and establishing the diagnosis of 17-KSR deficiency. This diagnosis was confirmed in vitro by minimal T production when testicular tissue of both patients was incubated with tritiated †4-A. The 2 sibs did not share a single haplotype for the HLA complex indicating lack of association between HLA and the locus of the gene for 17-KSR. In conclusion, in 2 sibs with MPH the subnormal T and elevated †4-A response to the hCG test indicated the diagnosis of 17-KSR deficiency followed by orchiectomy to avoid later virilization at puberty.

ENDOCRINE INTERACTION BETWEEN ZINC AND PROLACTIN : AN INTERPRETATIVE REVIEW

Zinc plays a very important role in animal and human metabolism. Nowadays, it is one of the most extensively studied trace element, since its sphere of action has been demonstrated to be very broad. From the biochemical standpoint, it controls more than 300 different enzymes, many of them involved with intermediary metabolism, DNA and RNA synthesis, gene expression, and immunocompetence. It also plays a significant role in hormonal homeostasis, since it can interact with almost all hormones. Zn2+ is closely related to the thyroid and steroid hormones, insulin, parathormone, and pituitary hormones, particularly prolactin (PRL). Zn2+ can inhibit PRL secretion within a range of physiologically and pharmacologically relevant concentrations. This property has raised the possibility of clinical applications of zinc. In this article, we review the literature on the subject in an attempt to provide a comprehensible general view.

Identification of nonclassical 21-hydroxylase deficiency in girls with precocious pubarche

Recent studies have described mild adrenal enzymatic defects in patients presenting with precocious pubarche. In order to identify these defects we have evaluated basal and ACTH — (25 IU iv) stimulated serum adrenal steroid levels in 19 girls, 2 - to 8.3-year-old, with precocius pubarche (pubic hair Tanner II–III). Two patients had clitorial enlargement. Bone age was moderatly advanced in 10 patients and 2 to 3.7 yr in four others. Four patients had high basal serum levels of 17-hydroxyprogesterone (17OHP) (525+202 ng/dl, mean +SD), compatible with the diagnosis of nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCCAH-21OH), which was confirmed by an increased response of 17OHP to ACTH (3425±953 ng/dl). Fifteen patients had moderatly elevated basal 17OHP levels (56+38 ng/dl) but a normal 17OHP response (191±71 ng/dl) to ACTH, compatible with the diagnosis of idiopathic precocious pubarche (IPP). The Cortisol response to ACTH was normal in both groups. Basal values of DHEA-S were 651 ±256 and 506+462 ng/ml and of DHEA 380±24 ng/dl and 205±102 ng/dl, in NCCAH- 21OH and IPP, respectively. We conclude that: i) clinical findings and baseline levels of DHEA-S and DHEA in IPP can be indistinguishable from the late onset 21 hydroxylase deficiency; ii) baseline levels of 17OHP are sufficient for the diagnosis of NCCAH-21OH; iii) the ACTH stimulation test is indicated only when baseline levels of 17OHP are moderately elevated (100–300 ng/dl).