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Biomedical subjects

C J Migeon

Publications and source records attributed to C J Migeon.

At least 73 records · Page 4Linked to original sources
PubMed1986

Congenital adrenal hyperplasia: long-term results following vaginal reconstruction.

Forty-two women with virilizing congenital adrenal hyperplasia who had attempted coitus were studied retrospectively a mean of 23.6 years after vaginal repair. Satisfactory intercourse, as defined by the patient, was observed in 62% of the subjects. The functional success rate was higher if repeat operations were performed after the age of 16 years (61% versus 12%, P less than 0.05) or if the patient suffered from the non-salt-losing variety of the disorder (87% versus 46%, P less than 0.05). The outcome of the initial attempt to exteriorize the vagina did not differ significantly by age at surgery. In cases of moderate virilization, vaginal repair may be delayed until the patient's menarche, maturity, and desires for sexual activity are well established. Clitoroplasty should be performed as soon as possible.

Adolescent↗
PubMed1986

Elevation of serum gonadotropins establishes the diagnosis of anorchism in prepubertal boys with bilateral cryptorchidism.

Of more than 500 boys with bilateral cryptorchidism who presented during a 10-year period 28 prepubertal patients less than 11 years old who had no palpable testes after human chorionic gonadotropin therapy were studied to assess the ability of serum gonadotropin levels to identify patients with anorchism. Of the boys 21 had a normal testosterone response to human chorionic gonadotropin therapy and all of them had testes at exploration. The serum luteinizing hormone levels ranged from 2 to 6 mIU per ml., with a mean of 3.7 mIU per ml., and the serum follicle-stimulating hormone levels ranged from 1.6 to 6.2 mIU per ml., with a mean of 3.7 mIU per ml. Seven patients showed no testosterone response to human chorionic gonadotropin and all but 1 underwent exploration, at which time no testes were found. Of these 7 patients 6 had elevated gonadotropin levels that averaged 3 standard deviations above the mean. For comparison, 2 pubertal patients with nonpalpable gonads and 3 castrated prepubertal boys also were studied. From the study we concluded that in boys with nonpalpable gonads 1) abnormally elevated serum gonadotropin levels before puberty are indicative of anorchism, 2) neither exploration nor human chorionic gonadotropin stimulation tests are essential for diagnosis in these select patients, 3) serum gonadotropin levels alone are not sufficient for a definitive diagnosis after puberty and 4) all boys with normal serum gonadotropin levels must undergo exploration regardless of the outcome of a human chorionic gonadotropin stimulation test.

Adolescent↗
PubMed1986

Adrenal and testicular function in 14 patients with adrenoleukodystrophy or adrenomyeloneuropathy.

Testicular and adrenal function were evaluated in 12 patients with adrenoleukodystrophy and 2 patients with adrenomyeloneuropathy. Although only 5 subjects had clinical symptoms suggesting adrenal insufficiency, an additional 5 showed laboratory evidence of reduced adrenal reserve. 9 of the 14 patients developed neurological deficits prior to the onset of clinical or biological adrenal insufficiency. In the remaining 5 patients, adrenal insufficiency antedated the appearance of neurological symptoms; 2 of these 5 patients had only laboratory evidence of hypoadrenocorticism, and 3 had both clinical and laboratory abnormalities. None of the prepubertal patients had detectable signs of testicular insufficiency, while 3 of the 7 pubertal/adult patients had elevated serum LH or FSH levels. This mild testicular deficiency was seen only in association with clinical adrenal insufficiency and significant neurological impairment.

17-Hydroxycorticosteroids↗
PubMed1986

A retrospective evaluation of psychosocial impact of long-term growth hormone therapy.

Fifty-eight growth hormone (hGH) deficient adults who had received long-term hGH therapy and their families were contacted to assess their past and current status regarding peer relationships, educational and vocational achievements, and self-concepts. Both heterosexual and same-sex peer relationships were reported as troublesome; most reported problems with having been treated as younger than their chronologic ages. The majority reported average or above average academic performance; there were no significant differences between academic achievements of the expatients and their siblings; the greatest portion of the sample were employed at least part-time and were satisfied with their employment status. On self-concept measures, the sample rated themselves higher in self-satisfaction, personal work, and sociality, but lower on physical self and self-criticism than norms; most of the parents reported no significant differences between the patients' adjustment and that of their siblings. In addition, the recommendations from the group to others considering hGH treatment and to medical personnel working with such families are noted; implications for hGH intervention are discussed.

Adolescent↗
PubMed1986

Androgen binding in nuclear matrix of human genital skin fibroblasts from patients with androgen insensitivity syndrome.

Specific sex steroid-binding sites are associated with the salt-insoluble nuclear matrix from which lipids, histones, and chromatin have been extracted. In intact cultured normal human genital skin fibroblasts incubated for 1 h at 37 C with a saturating concentration (2 nM) of [3H]dihydrotestosterone [( 3H]DHT), approximately 50% of the total intracellular androgen receptor-steroid complexes were found in the nucleus. Within isolated nuclei from such cells, 28-49% of the specific androgen receptor binding was associated with the nuclear matrix. The antiandrogen cyproterone acetate inhibited DHT binding within the nuclear matrix. Cultured genital skin fibroblasts from two unrelated patients with receptor-positive complete androgen insensitivity (CAIS, AR+), had normal (approximately 50%) nuclear binding of DHT, and 35% and 45% of it was localized to the nuclear matrix. Genital skin fibroblasts from a patient with receptor-negative complete androgen insensitivity (CAIS, AR-) had no specific DHT binding in isolated nuclei or nuclear matrix. Scatchard analysis of specific DHT binding in the nuclear matrix isolated from cells of normal subjects after an in vitro exchange assay (0 C; 24 h) revealed the presence of saturable (maximum binding, approximately equal to 200 fmol/mg nuclear DNA), high affinity (Kd approximately equal to 1.0 nM) binding sites. By contrast, in the nuclear matrix isolated from cells of a patient with CAIS, AR+, the binding affinity for DHT was 3-fold lower (Kd approximately equal to 3.0 nM). When cytosolic androgen receptor-DHT complexes prepared from cells preincubated at 37 C for 1 h with [3H]DHT were incubated at 0 C for 1 h with isolated nuclei and nuclear matrix in the presence of 0.15 M KCl, 40-60% of specific nuclear binding was associated with the nuclear matrix. In these cell-free in vitro experiments, radiolabeled DHT-receptor complexes prepared from normal or mutant cells were mixed with isolated nuclei and nuclear matrix prepared from cells of normal subjects or patients with CAIS, AR+ or CAIS, AR-. Under these conditions, specific DHT binding in nuclei and nuclear matrix was quantitatively similar in the presence of a mutant (CAIS, AR+) receptor-steroid complex or in the presence of nuclei or nuclear matrix from the mutant cells (CAIS, AR- or AR+) when compared simultaneously with the same subcellular fractions prepared from the cells of normal subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1986

Gene conversion in salt-losing congenital adrenal hyperplasia with absent complement C4B protein.

Two of four siblings expressed the salt-losing form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) and had identical human lymphocyte antigen (HLA) and complement C4 (fourth component of complement) types (HLA-A3,C4,B35,C4A3,C4BQO,DR1/A2,C-,B18,C4A3, C4BQO,DR6). The father and one unaffected sibling were heterozygous carriers of CAH, as determined by a 30-min iv ACTH stimulation test and HLA typing. In addition, the iv ACTH stimulation test revealed that the mother and the other unaffected sibling also carried an allele for an attenuated form of CAH. Restriction endonuclease digests of genomic DNA obtained from members of this family and from normal unrelated subjects were hybridized with cDNA probes encoding human 21-hydroxylase and C4. With the 21-hydroxylase probe, Southern blots prepared from control DNA samples revealed two major restriction fragments in each of four restriction endonuclease digests; TaqI produced major bands at 3.7 and 3.2 kilobases (kb), KpnI at 4.0 and 2.9 kb, EcoRI at 18 and 13 kb, and BglII at 15 and 12.5 kb. Southern blots prepared from DNA of the two patients lacked the 3.7-kb TaqI and 2.9-kb KpnI fragments, but had increased hybridization intensity (relative to control DNA samples) in the 3.2-kb TaqI and 4.0-kb KpnI fragments. By contrast, blots with EcoRI or BglII had two large hybridization fragments not different from control DNA samples. These data indicate the presence of two different 21-hydroxylase genes. Additional mapping studies revealed that the two genes had the restriction pattern of the inactive 21-hydroxylase gene. When genomic DNA that had been isolated from all members of this family and from normal subjects was hybridized with the human C4 cDNA probe, the restriction fragment hybridization patterns for all four endonuclease digests were similar in the two groups. Hence, our results suggest that the 21-hydroxylase deficiency of our patients is due to conversion of the active 21-hydroxylase gene to the inactive gene. This gene conversion was associated with absence of functional C4B protein, without any detectable alterations in the restriction fragment pattern of the C4 genes.

Adrenal Hyperplasia, Congenital↗
PubMed1986

Time-dependent biphasic response of aromatase to dexamethasone in cultured human skin fibroblasts.

Human genital skin fibroblasts grown in cell culture possess aromatase activity and, therefore, provide a model to investigate the molecular mechanisms that control aromatase in extraglandular tissues. Following the observation by other investigators that glucocorticoids stimulated aromatase activity in cultured stromal-vascular cells from adipose tissue, we examined the influence of dexamethasone (DEX) on aromatase in cultured skin fibroblasts. Preincubation of skin fibroblasts with DEX stimulated aromatase expression in all cell strains. In time-course studies, aromatase activity showed a biphasic curve, with peak levels at 12 h and a return to baseline levels by 72 h. When DEX was removed after 12 h, aromatase activity could be completely restimulated by DEX only after a period of 60-72 h. The DEX stimulation appeared to involve glucocorticoid receptor function, since the concentration of DEX required for half-maximal stimulation of aromatase activity (4.2 nM) was similar to the dissociation constant (Kd, 4.3 nM) of the receptor (for DEX). Actinomycin D and cycloheximide (CHX) inhibited DEX stimulation of aromatase when they were present in the preincubation and assay media. When cells were preincubated with DEX and CHX and then washed free of CHX and DEX before the assay, superinduction of aromatase activity occurred. Our data concerning the time course and superinduction of aromatase activity by DEX are in contrast to the findings reported by others for adipose tissue stromal-vascular cells and suggest that the mechanisms for the control of aromatase in extraglandular tissue may vary significantly in different tissues.

Adult↗
PubMed1986

Congenital adrenal hyperplasia: molecular mechanisms resulting in 21-hydroxylase deficiency.

21-Hydroxylase deficiency resulting in congenital adrenal hyperplasia (CAH) is a HLA-linked autosomal recessive disorder that has a wide range of phenotypic expression. Two homologous 21-hydroxylase genes (21-OHA and 21-OHB) occur within the Class III region of the major histocompatibility complex, but only one (21-OHB) appears to function in adrenal steroidogenesis. Our restriction maps, and initial sequence data from White et al. (Pediatr Res 20:274A (1986)) for the two human 21-OH genes reveal a high degree of homology between these genes and a reading frame shift mutation in the 21-OHA gene respectively. Among fourteen control subjects, the intragenic restriction patterns of the 21-OHA and 21-OHB genes are invariant. The few restriction fragment length polymorphisms (RFLPs) found in some controls result from polymorphic restriction sites outside the 21-OH genes. In patients with CAH, several different mechanisms for mutation of the 21-OHB gene have been described: deletion of the unique sequences of the 21-OHB gene, conversion of the unique sequences of the 21-OHB gene to those of 21-OHA, and mutations of 21-OHB which do not result in a detectable alteration of restriction pattern (e.g., point mutations). Duplication of the 21-OHA gene has been found in some patients with attenuated CAH; however, the significance of this finding remains unclear.

Adrenal Hyperplasia, Congenital↗
PubMed1985

Familial gynecomastia with increased extraglandular aromatization of plasma carbon19-steroids.

We evaluated a family in which gynecomastia occurred in five males in two generations. In each affected subject, gynecomastia and male sexual maturation began at an early age. The ratio of the concentration of plasma estradiol-17 beta to that of plasma testosterone was elevated in each affected subject. In the three siblings with gynecomastia, the transfer constant of conversion of androstenedione to estrone (i.e., the fraction of plasma androstenedione that was converted to estrone as measured in the urine) was 10 times that of normal persons. The transfer constant of conversion of testosterone to estradiol-17 beta in the one subject studied also was 8-10 times that of normal men, whereas the transfer constants of conversion of estrone to estradiol-17 beta and of estradiol-17 beta to estrone were normal. Despite the elevation in extraglandular aromatase activity, there was a normal response of the hypothalamic-pituitary axis to provocative stimuli. This is the second documentation of gynecomastia that is associated with increased extraglandular aromatase activity, and the first time that the defect was found to be familial with a probable X-linked (or autosomal dominant, sex limited) mode of inheritance.

Adolescent↗
PubMed1985

Ascertainment of 21-hydroxylase deficiency in individuals with HLA-B14 haplotype.

21-Hydroxylase activity was measured in North American caucasian individuals with the HLA-B14 antigen to estimate the frequency of heterozygosity for the attenuated congenital adrenal hyperplasia trait. A 30-min iv ACTH stimulation test was administered to 9 normal HLA-B14-positive subjects and to a comparable HLA-B14-negative control group. Changes in plasma progesterone and 17-hydroxyprogesterone over 30 min were summed and expressed as a combined rate of rise. Six of 9 HLA-B14-positive individuals had a rate of rise greater than 2 SD above the mean control value. On this basis, about two thirds of B-14-positive individuals are heterozygote carriers for 21-hydroxylase deficiency. Thus, the frequency of the attenuated form of congenital adrenal hyperplasia linked to the HLA-B14 locus in women is approximately 1 in 6000 if there is only 1 B14, and 1 in 2000 if there are 2 B14s in the HLA type.

17-alpha-Hydroxyprogesterone↗
PubMed1985

Androgen receptor in cultured human testicular fibroblasts.

Androgen receptors and 5 alpha-reductase activity were studied previously in genital skin fibroblasts cultured from normal subjects and patients with abnormalities of sex differentiation. We have now identified and characterized the androgen receptor in cultured human testis fibroblasts (HTF). HTF possess specific receptor proteins for androgens and translocate the receptor-steroid complex to nuclei. Approximately 50% of total cell binding was within nuclei, and 60-70% of nuclear binding was extracted by 0.5 M KCl (1 h; 0 C). Specific binding of dihydrotestosterone (DHT) was absent in HTF cultured from three patients with receptor-negative complete androgen insensitivity. 5 alpha-Reductase activity was very low (less than 100 pg 5 alpha-reduced products/micrograms DNA X h) in HTF after incubation with 200 nM [3H] testosterone (T). Based on this finding, androgen receptor binding of T was studied and resulted in a maximum binding capacity similar to that for DHT, but with a slightly lesser binding affinity (Kd). Binding to the receptor in HTF was specific for androgens (DHT, T, and R1881). [3H]DHT (2 nM) binding in the presence of 100 nM radioinert steroid was decreased by DHT (87%), R1881 (82%), and T (72%), but less with estradiol (53%), progesterone (31%), androstanediol (23%), and dexamethasone (10%). The androgen receptor in HTF was characterized as a macromolecule which sedimented at 4-5S on 0.4 M KCl sucrose density gradients and eluted as three high mol wt peaks on Sephacryl S-300 chromatography. Low but detectable aromatase activity was present in HTF and had the characteristics of being induced by glucocorticoid and having a Km similar to that of aromatase activity for genital skin fibroblasts. In summary, specific androgen receptors are present in HTF, and their characteristics are similar to those previously described for genital skin fibroblasts.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1984

Etiologic evaluation of male pseudohermaphroditism in infancy and childhood.

We outlined a diagnostic scheme for use with prepubertal patients with male pseudohermaphroditism (MPH) that included karyotyping, a genitourethrogram, a human chorionic gonadotropin stimulation test with plasma hormone level determinations, and determination of 5 alpha-reductase activity and androgen receptor binding in genital skin fibroblasts. A thorough evaluation is warranted in all patients since the correct diagnosis may assist in determining gender assignment and providing appropriate genetic counseling. We studied 25 patients by the prescribed diagnostic scheme: seven of them had a partial gonadal dysgenesis, two were deficient in 5 alpha-reductase activity, two showed partial androgen insensitivity, four had multiple congenital malformations, one had a Wilms' tumor, and nine were considered as having an idiopathic form of MPH.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1984

Isolated growth hormone deficiency type 1A in a Japanese family.

A Japanese family is described in which a 7-year-old child had isolated growth hormone deficiency type 1A, as described by Illig et al. He was shown to be homozygous for a deletion of the structural gene for hGH (hGH-N gene). Initially his growth rate responded well to hGH administration, but rapidly he developed high titers of hGH antibodies, and growth ceased. At that time, a somatomedin-C generation test gave negative results, suggesting that the growth arrest was related to the inability of hGH to generate somatomedin. Both parents were heterozygous for the hGH-N gene deletion and had a low hGH response to arginine and L-dopa tolerance tests, but had normal basal somatomedin-C levels and normal somatomedin-C generation tests. This family is the fourth to be reported with IGHD type 1A caused by deletion of the hGH-N gene. This cause of growth hormone deficiency can be distinguished from other severe autosomal recessive types of hGH deficiency by the demonstration of the deletion of hGH-N gene using restriction endonuclease analysis.

Adult↗
PubMed1984

Gonadal function in two siblings with Fanconi's anemia.

2 siblings with Fanconi's anemia, 1 male and 1 female, aged 22 and 24 years, respectively, were evaluated at the Johns Hopkins Hospital because of short stature and hypogonadism. Plasma levels of somatomedin-C were normal in both patients, suggesting that the production of biologically active growth hormone was normal in these subjects. In addition, measurements of serum gonadotropins and plasma androgens in our patients, along with data accumulated from previous studies in the literature, show that abnormal sexual development in patients with Fanconi's anemia is due to hypergonadotropic hypogonadism.

Adult↗
PubMed1984

Phenotypic heterogeneity in familial isolated growth hormone deficiency type I-A.

We studied an Argentinian family of Spanish ancestry in which the parents are of normal height and three of their four children have isolated GH deficiency type I-A. Restriction endonuclease analysis of DNA isolated from leukocytes was done using 32P-labeled human GH (hGH) cDNA sequences as a probe. The three siblings were homozygous, while their parents and the remaining sibling were heterozygous for a deletion of about 7.5 kilobases DNA, which included the normal hGH gene. The phenotype of the affected subjects differed in several respects. There was variation between the homozygotes in birth length and height before hGH treatment and growth responses during long term hGH treatment. Furthermore, heterozygotes in this family had normal height despite their diminished hGH responses to provocative tests.

Adolescent↗
PubMed1984

Aromatase activity in cultured human genital skin fibroblasts.

Aromatase activity of human genital skin fibroblasts grown in cell culture was studied using both [1,2,6,7-3H] androstenedione (A) and [1-3H]A as substrates. With the former substrate the generation of [3H]estrogens was determined, whereas with the latter substrate, the formation of [3H]H2O was measured. Our results showed that the release of [3H]H2O from [1-3H]A provides an accurate and sensitive method for determining aromatase activity in cultured human skin fibroblasts. Because genital skin fibroblasts also possess marked 5 alpha-reductase activity, we found that addition of an alternate substrate for 5 alpha-reductase was necessary to prevent shunting of A from the aromatase pathway. Hence, all aromatase assays were carried out in the presence of 5 microM progesterone. Under these experimental conditions, no correlation was found between levels of 5 alpha-reductase and aromatase activities. The Michaelis-Menten constant (Km) of the aromatase in cultured genital skin fibroblasts measured in the presence of A and added progesterone ranged between 10 and 39 nM, and the maximum velocity (Vmax) ranged between 0.14 and 1.46 pmol product/mg protein/h. These values are in good agreement with those previously described for adipose tissue stromal-vascular cells, suggesting that the aromatase complexes are similar in skin and adipose tissue. We conclude that skin may be an important site for aromatization of androgens to estrogens in men.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1984

A clinical syndrome of mild androgen insensitivity.

We studied four patients from three kindreds who had normal male body habitus and external genitalia except for short penile length and gynecomastia. Prostate size was small in all patients and spermatogenesis was decreased markedly in one and absent in three. Testicular biopsies in two patients revealed normal histology but evidence of spermatogenic arrest at the spermatocyte stage. Circulating levels of testosterone and LH were increased and the testosterone-dihydrotestosterone ratios were normal. Plasma estradiol was elevated in three of the four patients. Serum FSH levels were significantly elevated in only one patient. The response of LH and FSH to LHRH stimulation was normal in the two patients who were tested. Despite the normal male phenotype, the laboratory studies suggested the diagnosis of androgen insensitivity. This was confirmed in two patients by finding decreased dihydrotestosterone-binding capacity in genital skin fibroblasts. Two of the patients had normal levels of androgen receptor binding, suggesting that their defect represented a mild form of androgen insensitivity with normal receptor activity. These results demonstrated that mild forms of androgen insensitivity exist in which the only obvious clinical manifestations may be the presence of reduced penile length, gynecomastia, and/or infertility. The incidence of androgen insensitivity among men with these subtle phenotypic abnormalities, including infertility, remains to be determined.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗