[3 beta-hydroxysteroid dehydrogenase deficiency and 21-hydroxylase deficiency in hirsutism]. / 3 beta-Hydroxysteroiddehydrogenase-Mangel und 21-Hydroxylase-Mangel bei Hirsutismus.

Of 218 women with hirsutism 16 (7%) were found to have partial 21-hydroxylase deficiency, while 38 (17%) had partial 3 beta-hydroxysteroid dehydrogenase deficiency. Six women (3%) had a steroid constellation which resembled that of an augmented adrenarche. In the women with enzyme deficiency over-weight and abnormal menstruations were more frequent (50%) than in those without such deficiency (33%). The degree of hirsutism and age at diagnosis were similar in those with and those without partial enzyme deficiency. Furthermore, the diagnosis of partial enzyme deficiency could only be made with certainty by the ACTH stimulation test, because with sole measurement of basal levels (17-hydroxyprogesterone and 21-desoxycortisol in 21-hydroxylase deficiency, and 17-hydroxypregnenolone and dehydroepiandrosterone in 3 beta-hydroxysteroid dehydrogenase deficiency) the enzyme defects are in most instances not revealed.

[Clinical features and diagnosis of mild 3-beta-hydroxysteroid dehydrogenase deficiency in men]. / Klinik und Diagnostik bei Männern mit leichtem 3 beta-Hydroxysteroiddehydrogenase-Mangel.

3 beta-hydroxysteroid dehydrogenase (HSD) deficiency was demonstrated in six males, aged between 18 and 24 years, who had gynaecomastia, hypogonadism or infertility. The predominant laboratory finding was a striking elevation of dehydroepiandrosterone sulphate (DHEAS) levels. The diagnosis of HSD deficiency was confirmed by finding a marked rise in dehydroepiandrosterone (DHEA) and 17-hydroxypregnenolone levels. In contrast to these findings in late-onset enzyme deficiency, in four males with the classical form of 21-hydroxylase deficiency the only sign was a reduction in adult height. The prevalence of late-onset HSD deficiency in men is not known and may be more relevant in patients with gynaecomastia or abnormal gonadal function than has hitherto been realized.

Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency.

Specific 21-deoxycortisol (21-DF) antiserum was raised in New Zealand white rabbits using a 21-DF-3,20-oxime-bovine serum albumin complex. Plasma radioimmunoassay of 21-DF was developed and used together with a radioimmunoassay of 17-hydroxyprogesterone (17-OH-P) for diagnosis of patients with 21-hydroxylase deficiency of congenital and postpubertal forms. The assays were performed in plasma extracts after isolation by paper chromatography. The response of plasma 21-DF and 17-OH-P to i.v. ACTH (25 IU) was studied in 15 adult controls and compared to 8 women with the late onset form of 21-hydroxylase deficiency and 23 women with idiopathic hirsutism. Normal 21-DF values for women were 6.9 +/- 3.6 ng/dl and for men 9.71 +/- 2.73 ng/dl. Newborn children (age: 3-10 days) had a value of 8.3 +/- 4.8 ng/dl. These values are definitely lower than the lowest value ever published. This is possibly due to the specificity of the antibody. During the menstrual cycle the 21-DF values did not change. The baseline and post-stimulated concentrations of hormone were similar in controls and women with hirsutism but were significantly higher in women with the late onset form of 21-hydroxylase deficiency. In the congenital form of 21-hydroxylase deficiency the 21-DF values (baseline) were high. In general, the 21-DF and 17-OH-P values have shown parallel changes. However, one case of 21-hydroxylase deficiency with elevated 21-DF but normal 17-OH-P was observed. The use of 21-DF for the diagnosis of 21-hydroxylase deficiency is suggested.

Gynecomastia caused by estrogen containing hair lotion.

Two men at the age of 48 and 54 yr developed gynecomastia and lost their potency after the use of estrogen containing hair lotions. During exposure to the lotion the levels of 17-beta estradiol were increased, whereas the levels of testosterone and gonadotropins were depressed. Thus, a previous application of such hair lotions should be considered in the differential diagnosis of gynecomastia.

[Screening of newborn infants for hypothyroidism in Berlin (West) 1978-1982]. / Neugeborenen-Hypothyreose-Screening in Berlin (West) 1978-1982.

In July 1978 a neonatal screening program for congenital hypothyroidism was introduced in Berlin (West) covering more than 98% of the neonates born in the city area. Up to July 1982 TSH was determined on the fifth day of life in 74,350 newborns using a radioimmunoassay for TSH determination in dried blood spots. With a cut-off limit at 20 microU/ml, a control examination was necessary in 0.96% of the newborns. 32 infants with congenital hypothyroidism were detected and treated with 1-thyroxine, giving a total incidence of 1 in 2,323 newborns (permanent and transient cases). 63% of all newborns with elevated TSH levels (greater than 20 microU/ml) were born in the obstetric department of the Neukölln-Hospital, which uses PVP-Iodine for vaginal disinfection of the mothers during labor and delivery, especially after premature rupture of membranes. Those newborns had only transient TSH-elevations, which were normalized on the tenth day of life. The replacement therapy was started on the average on the ninth day of life. The symptoms present in the newborns with congenital hypothyroidism differed from patient to patient and from the "classical" signs of congenital hypothyroidism described in the literature. All infants detected by the screening program are followed in the outpatient department of the Children's Hospital of the Free University in Berlin and show a normal motor and mental development, except for two infants with other causes for retardation in psychomotor development.

Glucocorticosteroids and growth hormone secretion under physiological conditions and in states of steroid excess.

Cortisol and growth hormone (GH) secretion (spontaneous variations at night and the release induced by insulin hypoglycaemia) were investigated in 69 children and adolescents. Statistical analysis of approximately 600 pairs of cortisol and GH values in this study demonstrated that physiological fluctuations of cortisol do not alter GH secretion. A review of the literature shows that GH secretion is consistently depressed in Cushing's disease of central origin and in Cushing's syndrome due to adrenal carcinoma. When acutely administered, doses higher than 100 mg of cortisol (or equivalent amounts of other steroids) per adult are necessary to block GH secretion and the hormones have to be given several hours previously. In long-term steroid treatment, suppression of GH is observed in only 1 out of 3 patients. The effect apparently does not persist beyond elimination of the last dose, i.e. generally not longer than 12 to 24 h. These data can be taken as a rationale for intermittent or alternating dosage schedules, and for the use of short acting derivatives if long-term, high-dose steroid treatment is necessary in children. It remains to be established whether growth deficiency in exogenous hypercortisolism is due to suppression of GH secretion, decreased production of somatomedins, direct antagonism of the action of somatomedins on growing cartilage, or a combination of these mechanisms.

Prepubertal diagnosis of steroid 5 alpha-reductase deficiency.

The diagnosis of 5 alpha-reductase deficiency was proven in two prepubertal patients with male pseudohermaphroditism (MPH). Both had a 46-XY karyotype and were reared as females; one child had been castrated in infancy. Clitoromegaly, urogenital sinus, and short vaginal pouch were present in both; inguinal gonads were palpable in one. The diagnosis was made biochemically by observing characteristic changes in five parameters: 1) abnormally high testosterone to dihydrotestosterone (T:DHT) ratio after hCG stimulation (35 and 53 vs. normal, 11 +/- 3), 2) abnormally high 5 beta-T metabolites in urine (8.1 and 6.0 vs. normal, less than 1),3) deficient conversion of T to DHT during [3H] T infusion (0.3 and 0.4% vs. normal, 5.3 +/- 3), 4) deficient conversion of [14 C] T to 5 alpha-reduced metabolites by nongenital skin fibroblasts (2.2 and 1.9 pmol/microgram DNA/nmol substrate vs. 68.4+/- 7.8 Pmol/microgram DNA/nmol substrate in normal controls), and 5) deficient conversion of [14C]T to DHT in genital skin slices. The fact that this syndrome represents a defect in T metabolism rather in in T binding is demonstrated by the observation that binding of [3H]DHT to cytosol of skin fibroblasts was normal (4.2 dpm/micrograms DNA vs. normal male values of 3.7 +/- 0.64). Thus, the present report suggests that 5 alpha-reductase deficiency can be diagnosed during childhood and even after castration by metabolic studies of nongenital skin fibroblasts and determination of the conversion ratio of [3H]T to [3H]DHT in plasma.

Effect of testosterone on compensatory renal hypertrophy in the rat.

The effect of testosterone on compensatory renal hypertrophy (CRH) remains controversial. We therefore examined the effect of exogenous testosterone on CRH in adult male and female rats after unilateral nephrectomy. The influence of endogenous testosterone was studied by comparing the degree of CRH in normal male, castrated male, and in testosterone receptor deficient male pseudohermaphrodite rats. Furthermore, serial determinations of serum testosterone levels were performed after unilateral nephrectomy in male rats. Compensatory renal hypertrophy was comparable between male rats--with or without exogenous testosterone administration--and between normal male, castrated male, and psuedohermaphrodite male rats. In contrast, exogenous testosterone administration in female rats enhanced CRH. Serum testosterone levels fell markedly after unilateral nephrectomy or sham surgery, but increased to 183% and 234% of control values at 1 and 2 days after surgery in the unilaterally nephrectomized rats. At no time, however, did they exceed the range of normal values. The results indicate a different effect of testosterone on CRH in male and female rats.

Virilizing adrenal tumor in a child suppressed with dexamethasone for three years. Effect of o,p'-DDD on serum and urinary androgens.

Extensive hormonal evaluation was performed in a girl with adrenal carcinoma during the primary tumor stage, following adrenalectomy, during the period when metastases were evident and while on treatment with o,p'-DDD. At the age of 14 months a diagnosis of congenital adrenal hyperplasia was made and treatment with dexamethasone (0.125 to 0.25 mg/day) resulted in a fall-off in growth rate, normal advancement in bone age, decrease in virilization and suppression of 17- ketosteroid excretion which continued until 4 3/12 years of age when virilization increased. At five years of age elevated serum and urinary androgen levels unsuppressible with dexamethasone were noted. Following removal of a large right adrenal carcinoma, serum and urinary hormone levels returned to normal. There months following surgery, liver metastases were documented associated with elevated levels of serum androgens. With o,p'-DDD treatment, serum dehydroepiandrosterone sulfate (DS) and urinary 17-ketosteroid (17-KS) excretion fell rapidly while there was a delay in the fall of free androgens. The persistence of free steroid secretion with decreased formation of DS suggests that the o,p'-DDD may have altered sulfatase activity before causing tumor necrosis and total decrease in steroidogenesis.

Somatomedin and growth hormone in psychosocial dwarfism.

The diagnosis of psychosocial dwarfism (PSD) was made in a 7 year old boy upon admission to the hospital. In the period following admission, he grew at a slightly accelerated rate of 0.6 cm in 24 days (extrapolated growth rate--9.1 cm/yr); his caloric intake was 1663 calories/day (147 cal/kg/day), stimulable growth hormone was 5.9 ng/ml and somatomedin activity was in the hypopituitary range (0.24, 0.05 U/ml). In the following period of marked catch-up growth of 8.6 cm in 102 days (extrapolated growth rate 30.8 cm/yr), his caloric intake decreased significantly to 1514 cal/day (106 cal/kg/day, 0.005 less than p less than 0.01), stimulable growth hormone in this period was 13.6 ng/ml and somatomedin activity normalized (0.98 U/ml). While under continued observation, with separation from his favorite nurse, his growth velocity dropped significantly to the rate immediately following admission, but there was no change in his stimulable growth hormone or in somatomedin activity. With the return of his favorite nurse, he resumed his previous rapid catch-up growth with no change in caloric intake (p equals not significant), growth hormone level, or somatomedin activity. Upon transient return to his depriving home, his growth rate decreased to 1.4 cm in 70 days (extrapolated growth rate 7.2 cm/yr); growth hormone remained in the normal range. Somatomedin activity was in the low normal range (0.57 U/ml) and rose to high normal activity (1.31 U/ml) as rapid catch-up growth resumed after he had been readmitted. We conclude from these data that: 1. Serum somatomedin in longstanding untreated PSD may be in the hypopituitary range. 2. Markedly fluctuating growth rates during recovery in this patient with PSD were not due to changes in caloric nutrition, growth hormone release or somatomedin activity, but to an as yet unidentified factor affecting growth during emotional stress.

Presence of H-Y antigen and testis in 46, XX true hermaphroditism, evidence for Y-chromosomal function.

Endocrinologic and serologic studies of a 2-year-old child with the chromosomal complement 46,XX and ambiguous genitalia suggested the preoperative diagnosis of true hermaphroditism. Urinary and serum androgen production in response to human chorionic gonadotrophin was in the range expected for normal males, implying presence of cryptic testicular tissue. Moreover, detection of H-Y antigen, a cell surface component associated with testicular differentiation and coded or regulated by a Y-chromosomal gene, indicated presence of Y-chromosomal material. The diagnosis of true hermaphroditism was confirmed at surgery. Assuming a constant association of H-Y antigen and testicular differentiation is established, human H-Y serology may be an important adjunct to the endocrinologic evaluation of intersex patients. Our studies support the interpretation that a Y-chromosomal translocation too small for cytologic detection accounts for testicular differentiation in 46,XX true hermaphroditism. Expression of H-Y antigen remained positive after castration.

Evidence for the adrenal source of androgens in precocious adrenarche.

In order to determine the source of androgens in precocious adrenarche, serum androgens were determined in 8 girls with precocious adrenarche and 5 agonadal children in adrenarche under conditions of adrenal and gonadal stimulation and suppression. All androgens increased with ACTH stimulation in both groups. Stimulability of serum androgens in girls with precocious adrenarche with ACTH was more consistent than in 13 prepubertal children. Human chorionic gonadotrophin administration increased serum delta4-androstenedione, testosterone and dihydrotestosterone in the girls with precocious adrenarche but not in the agonadal children, demonstrating the failure of HCG to stimulate adrenals. Dexamethasone suppression decreased levels of all androgens in both groups, whereas Norlutin or Ovral produced variable changes. These studies support the adrenal origin of androgens in precocious adrenarche and the lack of ovarian contributions in this condition.

Dehydroepiandrosterone sulfate (DS) levels, a rapid test for abnormal adrenal androgen secretion.

Dehydroepiandrosterone sulfate (DS) concentration was measured in the sera of premature and full-term infants and in children throughout puberty. Panhypopituitary, Addisonian, and virilized children were also studied. DS decreased slowly during the first weeks of life from a high level in neonates to the low levels observed between one to five years. After five years of age, DS concentration started to rise. A steeper increase was observed with the onset of puberty, and adult DS concentrations were reached in late puberty. There was no sex difference in DS concentration at any pubertal stage or bone age. Day-to-day variations were small in childhood and during puberty, but were considerable in premature infants. DS concentrations measured at 0900 h were not significantly different from those at 1700 h. There was a positive correlation of serum DS concentrations with the excretion of urinary 17-ketosteroids in boys and girls (r=0.789). Premature infants had DS concentration in or above the late pubertal range. Five panhypopituitary patients and five Addisonian patients had DS concentrations below normal. DS was markedly elevated in patients with congenital adrenal hyperplasia and in one girl with adrenal carcinoma, and was suppressible with dexamethasone in the former. The ease of measurement and the small amount of blood required make serum DS determination a useful guide for adrenal androgen secretion.

Serum androgens in normal prepubertal and pubertal children and in children with precocious adrenarche.

Serum androgens testosterone (T), testosterone-like-substances (TLS), delta4-androstenedione (delta4), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA) were measured in 85 normal girls and 101 normal boys grouped according to pubic hair development in Tanner stages I to IV/V. The pattern of change with puberty differed for each androgen. In boys T and TLS rose with the onset of puberty but showed a more abrupt rise later in puberty. DHT also was higher in boys in late puberty but did not demonstrate a steep rise. The other androgens did not show a sex difference at any stage of puberty. While delta4 steroids did not show an increase in the years before onset of puberty, DHEA was significantly higher in prepubertal children over 7 years than in those under 7 years (mean +/- SD 166 +/- 110 vs. 31 +/- 25, P less than 0.005). The most rapid increase of DHEA concentrations was observed with the appearance of pubic hair (Stage II) in boys and girls. This contrasted with the more gradual rise of delta4 in both sexes. The oldest boys and girls (Tanner stages IV/V) had mean concentrations of all androgens in the adult range except for DHT. Twenty-two girls with precocious adrenarche (PA) aged 3-8 years had mean concentrations of T, DHT, delta4 and DHEA that were significantly higher (P less than 0.05) than in prepubertal children, but similar to those of girls in stage II and significantly lower (P less than 0.02) than in late pubertal girls (stage IV/V). Longitudinal studies in 12 of the girls indicated fluctuation of androgen concentrations, especially DHEA, but in general no increase during the years of followup. Precocious adrenarche appears to be a non-progressive disorder associated with an advanced maturation of adrenal androgen to an early pubertal stage. A rise in all androgens measured was correlated with the development of sexual hair.