Adolesc Pediatr Gynecol (1992) 5:89-91
Adolescent and Pediatric Gynecology © 1992 Springer-Verlag New York Inc.
World Literature Reviewed by: Selma F. Siegel, M.D., and Peter A. Lee, M.D., Ph.D., University of Pittsburgh, School of Medicine, Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA.
Adult Height in Precocious Puberty after Long-Term Treatment with Deslorelin. Oerter KE, Manasco P, Barnes KM, Jones J, Hill S, Cutler GB, Jr. J Clin Endocrinol Metab 1991; 73:1235. One goal in the treatment of precocious puberty with gonadotropin-releasing hormone (GnRH) agonists is improved adult height. Actual data examining this aim are just becoming available. These authors report proximate (;;;;.98.6% predicted height by Bayley-Pinneau height prediction method) or final height for 44 children treated with daily subcutaneous Deslorelin at a dose of 4 fLg/kg/day. Of the 38 girls and 6 boys enrolled in this study, 14 had achieved their final adult height and 30 had achieved their proximate adult height. Etiologies of isosexual central precocious puberty in these patients were hypothalamic hamartoma (four girls and three boys), other central nervous system abnormalities (four girls and two boys), and idiopathic precocious puberty (30 girls and 1 boy). At initiation of therapy, the mean age was 7.1 ± 1.2 years following a mean duration of puberty of 3.0 ± 1.5 years. Mean duration of therapy was 4.1 ± 1.3 years. Mean chronologic age at discontinuation of therapy was 11.3 ± 0.8 years. For the girls, the mean adult height was 157.0 ± 5.9 em. For the boys, the mean adult height was 168.0 ± 8.3 cm. The proximate adult height was significantly greater than the pretreatment predicted height by 5.2 ± 8.4 cm for the girls and 6.7 ± 3.0 cm for the boys. Heights of 36 patients surpassed the pretreatment predicted height and were between the pretreatment predicted height and target height. The proximate adult height inversely correlated with the pretreatment bone age (r = - 0.35, p = 0.02). The authors have shown that GnRH analogue therapy improved the adult height of this group of patients, but their heights were considerably below their genetically predicted target heights (based on sex and parental heights). Heights were improved, on the average, by 2 inches for females and 2.5
inches for males, with adult heights being substantially less than the average population. This finding suggests loss of growth potential perhaps related to the time of untreated sexual precocity. The authors appropriately caution that these patients had a greater delay between the onset of puberty and the initiation of treatment, and more advanced skeletal maturation than many patients currently undergoing treatment for central precocious puberty. This would suggest better height potential for current patients. It is important to note that using the BayleyPinneau method, predicted adult heights were overestimated when GnRH analogue therapy was discontinued. Actual final height measurements need to be accrued and analyzed to confirm this report. Further data from patients treated earlier during premature pubertal development are necessary to determine if GnRH analogue treatment can restore height to its full genetic potential. Androgen-Dependent Stimulation of Aromatase Activity in Genital Skin Fibroblasts from Normals and Patients with Androgen Insensitivity. Stillman SC, Evans BAJ, Hughes IA. Clin Endocrinol 1991; 35:533. Cytochrome P450 aromatase is the enzyme that converts testosterone to estradiol and androstenedione to estrone. Aromatase activity is increased by follicle-stimulating hormone and androgens. The androgen effect, mediated through androgen receptors, provides an index of in vitro androgen action which was used to assess androgen action in genital skin fibroblasts of patients with androgen insensitivity syndromes. Cell culture explants from normal genital skin were obtained at the time of circumcision_ Genital skin fibroblasts were obtained from 14 patients with complete androgen insensitivity and 22 with partial androgen insensitivity at the time of gonadectomy or reconstructive surgery of the external genitalia. In addition, each patient was characterized as being androgen receptor-positive or negative. Testosterone, dihydrotestosterone, and mibolerone (a synthetic androgen) increased aromatase activity in normal genital skin fibroblasts. The mibolerone effect was inhibited when the cells were co-incubated with cyproterone acetate or hydroxyflutamide anti-
androgens. Fifteen individuals with partial androgen insensitivity who were receptor positive had miberolone-stimulated aromatase activity that was similar to that of normal genital skin fibroblasts. Seven individuals with partial androgen insensitivity (three receptor positive and four receptor negative) had subnormal stimulated aromatase activity. Of those individuals with complete androgen insensitivity, all 10 receptor-negative individuals and three of four receptor-positive individuals had subnormal stimulated aromatase activity. Two of these three receptor-positive individuals had deletion of an exon which codes for the second zinc finger. As expected, those who are receptor negative had subnormal stimulated aromatase activity. However, one promising aspect of this report is the ability to assess androgen responsiveness in individuals with partial androgen insensitivity. This would be important in 46,XY individuals with ambiguous genitalia but sufficiently developed phallic structures so that genital reconstructive surgery would allow for male sex of rearing. Such androgen responsiveness should be of a magnitude that adequate male genital development will ensue at puberty. Further studies are necessary to correlate this in vitro assessment with the clinical evaluation of androgen responsiveness. Activating Mutations of the Stimulatory G Protein in the McCune-Albright Syndrome. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Speigel AM. N Engl J Med 1991; 325:1688. The McCune-Albright Syndrome--the Whys and Wherefores of Abnormal Signal Transduction. Levine MA. N Engl J Med 1991; 325:1738. McCune-Albright syndrome is characterized by polyostotic fibrous dysplasia, cafe-au-Iait spots with irregular margins, and endocrinopathies, frequently gonadotropin-independent precocious puberty. Hyperthyroidism, hypercortisolism, or excessive growth hormone secretion due to autonomous hyperfunction are recognized features. The common attribute of the endocrine abnormalities of McCune-Albright syndrome is that cyclic AMP is the second messenger for the signal transduction pathway in these endocrine glands. This signal transduction pathway involves G proteins and guanosine triphosphate. Following binding of the hormone ligand to the receptor, the 0: subunit dissociates from the other two subunits of the G protein to stimulate adenylate cyclase activity and increase the intracellular concentration of cAMP. This 0: subunit has intrinsic GTPase activity which terminates the "signaL" Modification of a specific amino acid, arginine 201 (Arg 201 ), in cholera toxin
leads to constitutive activation of GsO: with massive diarrhea secondary to altered transport of water and electrolytes across intestinal cells. These authors have examined DNA from four patients with typical clinical features of McCuneAlbright syndrome. DNA was isolated from frozen tissue, paraffin-embedded sections, or blood. Following polymerase chain reaction amplification of exon 8 of the GsO: gene which codes for Arg201 , DNA was analyzed by denaturing gradient gel electrophoresis. Allele-specific oligonucleotide hybridization with oligonucleotides that contained the wild type sequence, substitution of cysteine for Arg 201 , or substitution of histidine for Arg201 was also performed. Substitution of cysteine or histidine for Arg 201 was found in varying amounts in most tissues of these patients. The authors concluded that these "activating mutations" may be the pathophysiologic basis for this disease because a single mutation was found in each patient, the apparent presence of a single type of abnormal somatic cell line was found in each patient, and because of the similarity of these results to G s protein (gsp) oncogenes which have been described in growth hormone secreting pituitary adenomas. These results are interpreted as consistent with the speculation that McCune-Albright syndrome is due to an early somatic mutation. This exciting circumstantial evidence strongly suggests a possible pathophysiologic mechanism for the endocrine manifestations of McCune-Albright syndrome. However, the relationship of this mutation in the G s protein to the manifestations of McCune-Albright syndrome, which are not clearly endocrine in nature, remains to be eludicated. If the bone lesions are due to a parathyroid-related mechanism and the skin pigmentation to melanocyte stimulating hormone (MSH), the same pathophysiologic relationship may be present locally. Importantly, in the process of investigating this mechanism at the molecular level, this paradigm may provide insight into the Gs signal transduction system and its role in human disease. Middle-Aged Women with Turner's Syndrome. Medical status, hormonal treatment and social life. Sylven L, Hagenfeldt K, Brondum-Nielsen K, von Schoultz B. Acta Endocrinologica 1991; 125:359 This article reports on the medical and social status of older women with Turner's syndrome diagnosed at the Department of Clinical Genetics at the Karolinska Hospital in Stockholm, Sweden. Forty-nine women participated in this study; their karyotypes were as follows: 45,X (n = 20); 45,Xl46,X,i(Xq) (n
= 8);45,Xl46,XX(n = 15); 45,Xl46,XXl47,XXX (n = 3); and 45,Xl46,XY (n = 3). Heights ranged from 139 to 170 cm. The median height ofthose with 45,X karyotype was 148.5 cm; those with 45,Xl46,XXI 47,XXX karyotype were the tallest, with median height 166 cm. Thirteen women had spontaneous menarche including one with 45,X karyotype who had regular menses for 9 years. Gonadectomy had been performed in the women with 45,X/46,XY karyotype. Only 19 women had received hormone therapy at any time. There were 18 pregnancies resulting in eight normal children among the women with mosaic karyotypes. Although there was no formal assessment of mental development, the women had attended school and were working outside of their homes. Thirty-one (63%) were married, but some women were "without the experience of a sexual relationship." Eight women had adopted children, but some had been refused adoptions. Infertility was an issue of great distress to these women. Hearing loss was the most frequent medical complication (63%). Hypertension, fractures, and elevated liver enzymes were also noted. There were no urinary tract problems apart from lower urinary tract infections. Twelve (24%) had thyroid disorders. This descriptive report of the natural history of a group of women with Turner's syndrome in adulthood, including educational and occupational outcome, provides further evidence of the overall normal cognitive development of individuals with Turner's syndrome. Issues regarding reproductive function, the need for hormone replacement therapy, and individualized care by knowledgeable physicians and ancillary medical personnel are major common concerns. The authors speculate that the incidence of fractures may be related to the lack of hormone replacement therapy. "Clearly we, patients as well as physicians, need to enhance our knowledge and understanding about the variety of medical and social problems associated with Turner's syndrome." The Product of the CYPllB2 Gene is Required for Aldosterone Biosynthesis in the Human Adrenal Cortex. Curnow KM, Tusie-Luna M-T, Pascoe L, Natarajan R, Gu J-L, Nadler JL, White PC. Mol Endocrinol1991; 5:1513
The steroid 11 l3-hydroxylase (P450c11) enzyme converts II-deoxycortisol to cortisol. This enzyme
or a closely related isozyme also appears to have 18-hydroxylation and 18-oxidation activity such that it converts deoxycorticosterone to aldosterone. Two genes, CYPIIBI and CYPllB2, encoding highly homologous proteins, have been described. The purpose of this article was to investigate the roles of these genes. Using reverse transcription of adrenal cell mRNA followed by polymerase chain reaction, CYPllB 1 and CYPIIB2 products were detected on ethidium bromide-stained agarose gels and autoradiographic blots with internal specific probes. Zona glomerulosa cells were dissected from the adrenal gland and cultured in the presence of angiotensin-II or ACTH. As there is minimal 17ahydroxylase activity in the zona glomerulosa, CYP17 was used as a control for the presence of fasciculata cells. Angiotensin-II increased mRNA transcripts for both CYPllBl and CYPllB2, but only ACTH increased CYPllBl transcripts. There was a minimal increase in CYP17 transcripts following incubation with angiotensin-II. The coding sequences of both mRNAs obtained from an aldosterone-secreting tumor were cloned into the eukaryotic expression vector, pCMV4, sequenced, and transfected into COS-l cells. An expression vector containing cDNA for bovine adrenodoxin was co-transfected. When cells were incubated with II-deoxycortisol, cells transfected with pCMV -B 1 converted ll-deoxycortisol to cortisol and cortisone and those transfected with pCMV-B2 also produced a compound with the mobility of 18hydroxy cortisol. The molecular genetics of the 21-hydroxylase genes have been well characterized. It is recognized that there are two genes: a one functional gene and a pseudogene which has deleterious mutations that render its product nonfunctional. In contrast, two genes have been described for 1113-hydroxylase with no apparent deleterious mutations detected in either gene. This article provides preliminary data that suggest functional roles for both 1113hydroxylase genes with differing regulation. The authors speculate that defects in these genes might be involved in the pathogenesis of the disorders corticosterone methyl oxidase-II deficiency and glucocorticoid-suppressible hyperaldosteronism. Further investigation into the expression and function of these genes is necessary to confirm the apparent dissimilar expression in different zones of the adrenal cortex.