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Background: Subfertility is prevalent in men with classic 21-hydroxylase deficiency (21OHD). We sought to characterize the long-term evolution of their gonadal function., Methods: Retrospective longitudinal single-center study in 27 men (11 with testicular adrenal rest tissue [TART]), median observation period 12 years, testosterone (T), 11-oxygenated androgens, gonadotropins, and inhibin B measurement at each time point., Results: T concentrations were below the normal range (n.s.) in 43.2% (no TART) and 54.6% (TART) per patient. After accounting for body mass index, sex hormone-binding globulin, and age, men with TART exhibited higher T (14.0 ± 0.80 nmol/L) than those without (11.9 ± 0.71 nmol/L). During the observation period, T levels rose in both groups but more in men with TART (from 10.1 ± 1.1 to 17.3 ± 1.9 nmol/L vs 10.3 ± 1.0 to 12.8 ± 1.9 nmol/L); this was accompanied by rising luteinizing hormone and diminishing hydrocortisone equivalent dosages (TART: from 38.1 ± 3.2 to 35.1 ± 1.8 mg/d; vs no TART: 28.8 ± 2.7 to 28.1 ± 1.6 mg/d) without correlation with any markers of adrenal androgen control. Inhibin B declined in men with large TART over time while TART status remained stable., Conclusion: T levels below the normal range are frequent in men with 21OHD, regardless of TART, but change little over time. Besides adrenal androgen control gonadal axis suppression from supraphysiological glucocorticoid dosages needs to be considered. While our results do not endorse regular screening for alterations in TART status among adults, Sertoli cell function should be monitored in men with large TART., Competing Interests: Conflict of interest: All authors declare no conflict of interest. Co-author N.R. is on the editorial board of EJE. She was not involved in the review or editorial process for this paper, on which she is listed as author., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Context: Hypothalamus-pituitary-gonadal (HPG)-axis disturbances are a common phenomenon in patients with classic congenital adrenal hyperplasia (CAH). 11-oxygenated androgens have been suggested to play a role in this context., Design: Cross-sectional single center study including 89 patients (N = 42 men, N = 55 women) with classic CAH., Main Outcome Measures: Differences in steroid markers in men with hypogonadism and women with secondary amenorrhea with a special focus on 11-ketotestosterone (11KT) and 11β-hydroxyandrostenedione (11OHA4)., Results: Hypogonadotropic hypogonadism was present in 23 % of men and 61 % of those women currently not on contraceptives suffered from irregular menstrual cycles or amenorrhea. Testicular adrenal rest tumor (TART) was documented in 28 % of men. 11KT (3.5x) and 11OHA4 (5.7x) among other adrenal steroids were significantly elevated in men with hypogonadism and in women with amenorrhea in comparison to those with a regular cycle (11KT: 5.2x; 11OHA4: 3.7x). 11-oxygenated androgens were not higher in men with TART than in those without. There was a negative association of 11KT and 11OHA4 with FSH but not with LH in men. As expected, all steroids were strongly correlated with each other and cases of disproportionally elevated 11-oxygenated androgens that could explain for HPG-disturbances or TART in otherwise controlled patients were rare and also found in eugonadal individuals., Conclusions: In CAH, 11-oxygenated androgens are elevated in women with menstrual disturbances and in men with hypogonadotropic hypogonadism. Due to the close correlation of 11-oxygenated androgens with other adrenal steroids it remains to be shown if their measurement is superior to conventional markers of androgen control., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Context: Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly limited to single-center/country studies enrolling small patient numbers. Overall data indicate that gonadal function can be compromised in men with CAH., Objective: To determine gonadal function in men with CAH within the European 'dsd-LIFE' cohort., Design: Cross-sectional clinical outcome study, including retrospective data from medical records., Methods: Fourteen academic hospitals included 121 men with CAH aged 16-68 years. Main outcome measures were serum hormone concentrations, semen parameters and imaging data of the testes., Results: At the time of assessment, 14/69 patients had a serum testosterone concentration below the reference range; 7 of those were hypogonadotropic, 6 normogonadotropic and 1 hypergonadotropic. In contrast, among the patients with normal serum testosterone (55/69), 4 were hypogonadotropic, 44 normogonadotropic and 7 hypergonadotropic. The association of decreased testosterone with reduced gonadotropin concentrations (odds ratio (OR) = 12.8 (2.9-57.3)) was weaker than the association between serum androstenedione/testosterone ratio ≥1 and reduced gonadotropin concentrations (OR = 39.3 (2.1-732.4)). Evaluation of sperm quality revealed decreased sperm concentrations (15/39), motility (13/37) and abnormal morphology (4/28). Testicular adrenal rest tumor (TART)s were present in 39/80 patients, with a higher prevalence in patients with the most severe genotype (14/18) and in patients with increased current 17-hydroxyprogesterone 20/35) or androstenedione (12/18) serum concentrations. Forty-three children were fathered by 26/113 patients., Conclusions: Men with CAH have a high risk of developing hypothalamic-pituitary-gonadal disturbances and spermatogenic abnormalities. Regular assessment of endocrine gonadal function and imaging for TART development are recommended, in addition to measures for fertility protection., (© 2018 European Society of Endocrinology.)

Purpose of Review: The adrenal gland is considered a source of weak androgens, such as dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. Emerging evidence proposes a set of 11-oxygenated 19-carbon (11oxC19) adrenal-derived steroids as clinically important androgens. Such steroids include 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone. The present review will discuss the synthesis, androgenic activity, and clinical implications of the 11oxC19 steroids., Recent Findings: The clinical relevance of the 11oxC19 steroids resides in two key characteristics: the synthesis of all 11oxC19 originates predominantly in the adrenal cortex, and 11-ketotestosterone and its 5α-reduced metabolite, 11-ketodihydrotestosterone are potent agonists of the human androgen receptor, similar to the classic androgens testosterone and dihydrotestosterone, respectively. Recent studies have demonstrated higher than normal circulating levels of 11oxC19 steroids in patients with 21-hydroxylase deficiency and in polycystic ovary syndrome. The 11oxC19 steroids are also thought to contribute to castration-resistant prostate cancer progression. In addition, the 11oxC19 steroids might have clinical implications in adrenarche and postmenopausal women., Summary: Future prospective studies are needed to establish the clinical utility of the 11oxC19 steroids for individualized patient care. Preliminary data suggest that these biomarkers hold promise to improve the evaluation and management of androgen excess disorders.

Objective: Hyperandrogenism in congenital adrenal hyperplasia (CAH) provides an in vivo model for exploring the effect of androgens on erythropoiesis in women. We investigated the association of androgens with haemoglobin (Hb) and haematocrit (Hct) in women with CAH., Design: Cross-validation study., Patients: Women with CAH from Sheffield Teaching Hospitals, UK (cohort 1, the training set: n = 23) and National Institutes of Health, USA (cohort 2, the validation set: n = 53)., Measurements: Androgens, full blood count and basic biochemistry, all measured on the same day. Demographic and anthropometric data., Results: Significant age-adjusted correlations (P < 0·001) were observed for Ln testosterone with Hb and Hct in cohorts 1 and 2 (Hb r = 0·712 & 0·524 and Hct r = 0·705 & 0·466), which remained significant after adjustments for CAH status, glucocorticoid treatment dose and serum creatinine. In the combined cohorts, Hb correlated with androstenedione (P = 0·002) and 17-hydroxyprogesterone (P = 0·008). Hb and Hct were significantly higher in cohort 1 than those in cohort 2, while there were no group differences in androgen levels, glucocorticoid treatment dose or body mass index. In both cohorts, women with Hb and Hct in the highest tertile had significantly higher testosterone levels than women with Hb and Hct in the lowest tertile., Conclusions: In women with CAH, erythropoiesis may be driven by androgens and could be considered a biomarker for disease control., (© 2016 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.)

Objective: To comprehensively characterize androgens and androgen precursors in classic 21-hydroxylase deficiency (21OHD) and to gain insights into the mechanisms of their formation., Design: Serum samples were obtained from 38 patients (19 men) with classic 21OHD, aged 3-59, and 38 sex- and age-matched controls; 3 patients with 11β-hydroxylase deficiency; 4 patients with adrenal insufficiency; and 16 patients (8 men) undergoing adrenal vein sampling. Paraffin-embedded normal (n = 5) and 21OHD adrenal tissues (n = 3) were used for immunohistochemical studies., Methods: We measured 11 steroids in all sera by liquid chromatography-tandem mass spectrometry. Immunofluroescence localized 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) and cytochrome b5 (CYB5A) within the normal and 21OHD adrenals., Results: Four 11-oxygenated 19-carbon (11oxC19) steroids were significantly higher in male and female 21OHD patients than in controls: 11β-hydroxyandrostenedione, 11-ketoandrostenedione 11β-hydroxytestosterone, and 11-ketotestosterone (3-4-fold, P < 0.0001). For 21OHD patients, testosterone and 11-ketotestosterone were positively correlated in females, but inversely correlated in males. All 11oxC19 steroids were higher in the adrenal vein than in the inferior vena cava samples from men and women and rose with cosyntropin stimulation. Only trace amounts of 11oxC19 steroids were found in the sera of patients with 11β-hydroxylase deficiency and adrenal insufficiency, confirming their adrenal origin. HSD3B2 and CYB5A immunoreactivities were sharply segregated in the normal adrenal glands, whereas areas of overlapping expression were identified in the 21OHD adrenals., Conclusions: All four 11oxC19 steroids are elevated in both men and women with classic 21OHD. Our data suggest that 11oxC19 steroids are specific biomarkers of adrenal-derived androgen excess., (© 2016 European Society of Endocrinology.)

Introduction: Women with classic forms of congenital adrenal hyperplasia (CAH) or polycystic ovary syndrome have been found to have impaired sexual function., Aim: This study investigated sexual activity in young women with nonclassic CAH (NC-CAH)., Methods: The study included 24 untreated women with NC-CAH and 24 age-matched healthy women. Plasma levels of free and total testosterone, androstenedione, and dehydroepiandrosterone sulfate were measured. Hirsutism was evaluated according to the modified Ferriman-Gallwey score. Questionnaires assessing female sexual function (Female Sexual Function Index) and the presence and severity of depressive symptoms (Beck Depression Inventory, Second Edition) were completed by each participant., Main Outcome Measures: Sexual function and depressive symptoms in young women with NC-CAH., Results: Women with NC-CAH presented increased plasma levels of 17-hydroxyprogesterone, total and free testosterone, androstenedione, and dehydroepiandrosterone sulfate and higher hirsutism scores compared with healthy women. The study group also showed a lower total Female Sexual Function Index score and lower scores in four domains (sexual arousal, lubrication, sexual satisfaction, and dyspareunia). Scores for sexual desire and orgasm correlated with total hirsutism score and testosterone levels. The Beck Depression Inventory questionnaire showed that the total score was higher in women with NC-CAH than in healthy women, correlating with the hirsutism score and testosterone levels., Conclusion: The presence of NC-CAH in young women is associated with impaired sexual function and mild depressive symptoms., (Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Non-classic congenital adrenal hyperplasia (NC-CAH) is one of the most frequent genetic disorders and its presence often results in androgen excess. 4 females with coexisting symptomatic NC-CAH and isolated hypercholesterolemia and 11 sex- and weight-matched control subjects with elevated cholesterol but normal steroid levels, participating in our study, were treated with simvastatin (20 mg daily). Throughout the whole period of simvastatin treatment, plasma levels of 17-hydroxyprogesterone, testosterone, androstendione and dehydroepiandrosterone sulfate in patients with NC-CAH remained lower compared with baseline, but increased in 2 patients after withdrawal of this drug. No changes in plasma steroids were observed in simvastatin-treated control subjects. Our findings suggest that simvastatin treatment may bring some benefits to symptomatic female patients with NC-CAH., (© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.)

Prenatal exposure to excess testosterone induces reproductive disturbances in both female and male sheep. In females, it alters the hypothalamus-pituitary-ovarian axis. In males, prenatal testosterone excess reduces sperm count and motility. Focusing on males, this study tested whether pituitary LH responsiveness to GNRH is increased in prenatal testosterone-exposed males and whether testicular function is compromised in the testosterone-exposed males. Control males (n=6) and males born to ewes exposed to twice weekly injections of 30  mg testosterone propionate from days 30 to 90 and of 40  mg testosterone propionate from days 90 to 120 of gestation (n=6) were studied at 20 and 30 weeks of age. Pituitary and testicular responsiveness was tested by administering a GNRH analog (leuprolide acetate). To complement the analyses, the mRNA expression of LH receptor (LHR) and that of steroidogenic enzymes were determined in testicular tissue. Basal LH and testosterone concentrations were higher in the testosterone-exposed-males. While LH response to the GNRH analog was higher in the testosterone-exposed males than in the control males, testosterone responses did not differ between the treatment groups. The testosterone:LH ratio was higher in the control males than in the testosterone-exposed males of 30 weeks of age, suggestive of reduced Leydig cell sensitivity to LH in the testosterone-exposed males. The expression of LHR mRNA was lower in the testosterone-exposed males, but the mRNA expression of steroidogenic enzymes did not differ between the groups. These findings indicate that prenatal testosterone excess has opposing effects at the pituitary and testicular levels, namely increased pituitary sensitivity to GNRH at the level of pituitary and decreased sensitivity of the testes to LH.

In May 2011, more than a decade after the International Association of Athletics Federations (IAAF) and the International Olympic Committee (IOC) abandoned sex testing, they devised new policies in response to the IAAF's treatment of Caster Semenya, the South African runner whose sex was challenged because of her spectacular win and powerful physique that fueled an international frenzy questioning her sex and legitimacy to compete as female. These policies claim that atypically high levels of endogenous testosterone in women (caused by various medical conditions) create an unfair advantage and must be regulated. Against the backdrop of Semenya's case and the scientific and historical complexity of "gender verification" in elite sports, we question the new policies on three grounds: (1) the underlying scientific assumptions; (2) the policymaking process; and (3) the potential to achieve fairness for female athletes. We find the policies in each of these domains significantly flawed and therefore argue they should be withdrawn.

Objectives: To describe the presence of prostatic tissue in 46,XX patients with the classical form of congenital adrenal hyperplasia (CAH); to evaluate the sensitivity and specificity of prostatic specific antigen (PSA) measured in congenital adrenal hyperplasia patients with regard to the detection of prostatic tissue in pelvic MRI., Methods: We studied 52 children and adolescents, 32 with the classical form of congenital adrenal hyperplasia, 10 boys and 10 girls without CAH. Pelvic MRI was performed in all patients to detect prostatic tissue. Prostate specific antigen, testosterone and dihydrotestosterone were measured in all patients. We used Receiver Operating Characteristic Curve for PSA discrimination capacity., Results: Five girls with congenital adrenal hyperplasia showed image of prostatic tissue on pelvic MRI. Prostate specific antigen showed sensitivity and specificity of 100% and 88.9%, respectively, taking 0.1 ng/mL as the cutoff level., Conclusions: The incidence of prostatic tissue in 46,XX patients with the classical form of congenital adrenal hyperplasia was 15.6%. PSA demonstrated to be a good marker of prostatic tissue in these patients and should be used to screen patients to be submitted to image studies.

The androgen theory of autism proposes that autism spectrum conditions (ASC) are in part due to elevated fetal testosterone (FT) levels, which are positively correlated with a number of autistic traits and inversely correlated with social development and empathy. A medical questionnaire was completed by n=54 women with ASC, n=74 mothers of children with ASC, and n=183 mothers of typically developing children to test whether women with ASC have an increased rate of testosterone-related medical conditions, and to see whether mothers of children with ASC show similar abnormalities, as part of the 'broader autism phenotype'. Compared to controls, significantly more women with ASC reported (a) hirsutism, (b) bisexuality or asexuality, (c) irregular menstrual cycle, (d) dysmenorrhea, (e) polycystic ovary syndrome, (f) severe acne, (g) epilepsy, (h) tomboyism, and (i) family history of ovarian, uterine, and prostate cancers, tumors, or growths. Compared to controls, significantly more mothers of ASC children reported (a) severe acne, (b) breast and uterine cancers, tumors, or growths, and (c) family history of ovarian and uterine cancers, tumors, or growths. These results suggest current hormone abnormalities in women with ASC and their mothers. Direct investigations of serum testosterone levels and genetic susceptibility to high testosterone production or sensitivity in women with ASC would illuminate the origin of these conditions. The relationship between FT and current testosterone levels also needs to be clarified. The present results may be relevant to understanding the increased male risk to developing autism.

Objective: To present serum androgen levels during pregnancy in a twin gestation complicated by maternal late onset 21-hydroxylase deficiency., Design: Case report., Setting: University teaching hospital reproductive endocrinology and infertility practice., Patient(s): A 27-year-old with nonclassic 21-hydroxylase deficiency and infertility, twin female fetuses, and elevated androgens., Intervention(s): Steroid replacement., Main Outcome Measure(s): Serum T and 17-hydroxyprogesterone (17-OHP) levels., Result(s): Elevated androgen levels persisted throughout pregnancy in spite of aggressive steroid replacement. However, twin girls were born without any evidence of virilization., Conclusion(s): The changes associated with a twin gestation may result in excessive stimulation of androgens in mothers with nonclassic 21-hydroxylase deficiency. However, the increased placental aromatase provides protection.

Objective: To assess serum free testosterone (free T) concentrations in various groups of women by means of an ultrafiltration technique (UFT) or two RIAs and to investigate the influence of levonorgestrel (LNG) and norethisterone (NET) on free T., Design: Experimental study with serum samples from various groups of patients., Setting: Obstetrics and gynecology department of a university., Patient(s): Samples from 20 normal healthy women, 20 menopausal women, 21 pregnant women, 23 women using oral contraceptives (OC), 20 hyperandrogenemic women, 20 hirsute patients with normal total testosterone (total T), 18 patients with acne (normal total T), and 9 women with adrenogenital syndrome (AGS)., Intervention(s): Blood samples were taken by venipuncture., Main Outcome Measure(s): Serum concentrations of free T., Result(s): Mean free-T levels determined by UFT amounted to 5-6 pg/mL in most groups, except in patients with hyperandrogenemia (8.3 pg/mL) or AGS (10.7 pg/mL) and in women using OC (1.9 pg/mL). The values were twofold to fourfold and threefold to sevenfold higher than those determined with the RIAs. The proportion of free T as determined by UFT was 0.9-1.2% of total T and was 0.55% during OC treatment. The presence of 10 ng/mL of LNG or NET increased free-T levels by only 13%., Conclusion(s): Serum free-T levels determined with RIA are much lower than those measured with the UFT. The ratio between the UFT and RIA values may vary depending on the endocrine status. In women with normal or elevated sex hormone-binding globulin levels, nortestosterone derivatives increase free T levels only slightly.

A bloodspot assay for testosterone has been developed using an antiserum raised against testosterone-3-carboxymethyloxime-bovine serum albumin (T-3 CMO-BSA) conjugate and 125I-T-3CMO-histamine tracer. The method has a detection limit of 0.4 nmol/L with between-batch precision of less than 15% for testosterone values between 0.9 and 2.0 nmol/L and less than 10% for values greater than 2.0 nmol/L. Recovery of 4 nmol/L testosterone spiked into whole blood samples from 16 women (with unspiked bloodspot testosterone concentrations ranging from 0.4 to 3.7 nmol/L) was 100.9%. Bloodspot testosterone concentration was measured in thirty 6-9 day old infants (19 boys, 11 girls) with an absolute range in boys of < 0.4-2.3 nmol/L and in girls of < 0.4 nmol/L. In preterm infants (12 boys, 12 girls) of varying birth gestation and postnatal age, levels were higher than in term infants, with boys showing a rise with increasing postnatal age. Daytime bloodspot profiles in four children on replacement therapy for congenital adrenal hyperplasia demonstrated consistently low testosterone levels in the presence of moderately elevated early morning 17-hydroxyprogesterone concentrations, thus indicating adequate treatment. The bloodspot testosterone assay can be applied to the study of androgen physiology in preterm neonates as well as for monitoring treatment in disorders such as congenital adrenal hyperplasia.

Most hirsute women have polycystic ovaries. The few women who have a more sinister cause for their hirsutism can probably be identified by clinical symptoms and signs. Therefore, the purpose of investigation is to identify those women, and this can probably be best achieved by a first-line measurement of serum testosterone. If this is normal, subsequent investigations are only required to guide the choice and use of any systemic therapy. It is probably unnecessary to measure any endocrine parameters once therapy has been initiated, since there is no relationship between these variables and hair growth.

Following the incubation of plasma with a tracer amount of tritiated testosterone, the reaction mixture is separated into a sex hormone-binding globulin bound and an unbound fraction of radioligand using DEAE-cellulose columns placed in the incubator-separator module of the Centria radioimmunoassay centrifugal analyzer. Neural Tris-buffer elutes unbound steroid from the matrix, while acidic Tris-buffer can remove the protein-bound fraction in a subsequent step. Complementary and thus qualitatively equal results are obtained when counting either eluate. Comparison of this technique with an ammonium sulfate precipitation method showed high correlation. Free testosterone indices as determined by the Centria modification in a number of prepuberal children, normal men and women, as well as pregnant and hirsute women similar to those previously reported.

To determine maximal plasma levels of androstenedione (A) and testosterone (T) which still can be considered non virilizing in 21-hydroxylase deficiency, we investigated plasma levels of these steroids in unaffected children and in adults. For T we found an upper limit of the prepubertal normal range of 16 ng/dl in girls and of 20 ng/dl in boys, with the exception of boys in the first half-year of life in which T is elevated up to the low adult range with peak values in the 2nd and 3rd month. During puberty T values show a significant difference between pubic hair stage 1 and stage 2. T levels below 20 ng/dl can be considered to be non virilizing. For A we found a plasma concentration of 86 ng/dl to be the upper normal level in both sexes before the onset of puberty. A values below this limit are expected to be non virilizing. To evaluate the usefulness of 17-hydroxyprogesterone (OHP) for the prediction of A and T and to define "acceptable" OHP levels in CAH we performed simultaneous determinations of OHP, T, and A in prepubertal patients treated for CAH. From these values we calculated the 95% confidence interval for prediction of T and A on known OHP levels. On an OHP value of 1.000 ng/dl, T can be expected to be between 6 and 60 ng/dl and A between 25 and 320 ng/dl. Because of these wide ranges, OHP has to be considered an unreliable parameter for predicting androgen levels in CAH.

Plasma-borne testosterone was determined in 176 women with hirsutism, and in 47 patients sexual hormone binding globulin was determined as well. The highest average testostercne values were recorded from cases with congenital AGS. In cases of postnatal AGS values were much lower, but they were clearly in excess of those recordable from Stein-Leventhal syndrome. Plasmaborne testosterone in cases of hirustism came very close to testosterone levels established in the context of Stein-Leventhal syndrome. Testosterone levels dropped with significance, following AGS treatment, using cortisol derivatives, and following wedge-shaped ovariectomy. Sexual hormone binding globulin was found to be strongly reduced in almost all women with hirsutism. Such reduction seemed to suggest the presence of increased amounts of free active testosterone in the blood of those patients. Determination of plasma-borne testosterone in cases of hirsutism is considered to be essential to both diagnosis of the endocrinological syndromes and monitoring of therapy.

To determine whether a single morning plasma level of 17-hydroxyprogesterone (17OH-P), androstenedione, testosterone and progesterone reflected the degree of control of 21-hydroxylase congenital virilizing adrenal hyperplasia (CVAH) as indicated by 24-hour urinary 17-ketosteroid and pregnanetriol excretion, 142 simultaneous 24-hour urine and morning blood collections were made from 65 patients with CVAH. Patients were grouped into five categories on the basis of age, skeletal age, and sex. Paired blood and urinary data were analyzed. The results suggest that androstenedione is the most reliable indicator for all patient categories. Testosterone is an excellent indicator for children of both sexes and for adolescent and adult females. Levels of 17OH-P are difficult to interpret, as they can be several fold higher than the normal values when adrenal suppression appears adequate on the basis of urinary data. In general, progesterone is a poor indicator.

Twenty patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency have been followed during a mean period of 68.4 months (from 19 to 120 months). Plasma 17 alpha-hydroxyprogesterone, delta 4-androstenedione and testosterone have been measured at regular intervals and correlated to growth and bone maturation. Satisfactory growth was obtained through repeated changes in the daily dose of oral hydrocortisone which varied from 58.7 +/- 37 mg/m2/day in infants to respectively 19.3 +/- 7.0 and 25.3 +/- 7.2 mg/m2/day in prepuberty and puberty. Fludrocortisone was added in 15 cases because of evidence of salt loss. delta 4-androstenedione and 17 alpha-hydroxyprogesterone are the best markers of adequate suppression of the pituitary-adrenal axis in both sexes. Testosterone can be used in girls and prepubertal boys. In some cases with low levels of androgens suggesting oversuppression, a reduced velocity of bone maturation was observed, particularly in young subjects.

In 11 children aged between 2 and 17 years with (nonsalt-losing) congenital adrenal hyperplasia (21-hydroxylase deficiency) blood was drawn at 90-minute intervals during a 24-hour period and levels of 17-hydroxyprogesterone, testosterone, and cortisol were measured. Levels of 17-ketosteroids and pregnanetriol were measured too in 24-hour urine samples. These measurements were taken under different regimens of treatment and after interruption of treatment. Cortisol level rose and fell rapidly after administered corticosteroid, and reached unphysiologically high levels. Testosterone levels showed pronounced variations but stayed in the normal range for most of the time even in untreated patients; thus testosterone provides a poor control parameter. Levels of 17-hydroxyprogesterone showed extreme fluctuations and very high peak levels in untreated patients; standard treatment with two or three daily doses of corticosteroids did not prevent a pronounced rise in its level after midnight. After the first morning dose of hydrocortisone a very steep fall was observed. The 24-hour pregnanetriol excretion correlated well with the corresponding total integrated 17-hydroxyprogesterone area. It is concluded that single 17-hydroxyprogesterone values are unlikely to give adequate information about the quality of treatment.

The study of genealogy of the families with cases of congenital adrenocortical virilizing hyperplasia allowed one to suggest a possibility of the heterozygous bearing of a pathological gene. The investigation of the plasma testosterone level in the parents of children with the adrenogenital syndrome has shown that an increase in the blood circulating testosterone level 1.6 to 4 times compared with normal may serve as a marker of heterozygosis for this disease.

The blood plasma testosterone content was determined by radioimmunological method in patients with hirsutism, premature sexual maturation, false male hermaphroditism, true hermaphroditism, mixed gonad dysgenesis, adrenogenital syndrome, and also in some mothers of patients suffering from intersexualism and in healthy persons. The testosterone concentration proved to depend on clinical manifestations in boys with hyper- and hypogonadism and in girls with adrenogenital syndrome. In intersexual conditions in the presence of mixed gonad dysgenesis the testosterone level was found to be intermediate between the normal values in men and women of the same age. By the testosterone level patients with false male hermaphroditism were divided into two groups: with absolute androgen insufficiency and with disturbed receptor testosterone sensitivity.

Plasma 3 alpha-androstanediol levels are increased in a high percentage of hirsute women, including those with normal plasma levels of its precursors, repeatedly evaluated during the menstrual cycle. To better ascertain the origin of this form of hirsutism, so called "idiopathic", 17 hirsute women (aged 19.5 +/- 4.8 SD yr), with normal bw, showing an isolated increase in plasma 3 alpha-androstanediol (0.65 +/- 0.18 SD nmol/l) were studied in basal conditions (on day 6, 7, 17, 18 of the menstrual cycle). A hirsute female (aged 14 yr) with congenital adrenal hyperplasia due to 21-hydroxylase deficiency was also included in the protocol. Sex hormone binding globulin was evaluated using a saturation method (dihydrotestosterone- 3H 0.5-25 nM) with and without 200x cold dihydrotestosterone. Maximum number of binding sites and Ka were calculated in all cases with Scatchard analysis. Free testosterone was evaluated by the equilibrium dialysis technique. The results obtained showed a significant increase in Ka values in 10 out of the 17 cases; low plasma levels of sex hormone binding globulin in 13 cases and normal levels in 4 cases; high levels of free testosterone fraction in 5 cases and in the upper limits of the normal range or normal in the remaining 12. These findings demonstrate that some cases of "idiopathic" hirsutism may present an alteration in the binding affinity of the sex hormone binding globulin which may be genetically transmitted, being found to be increased in two sisters and in their brother.

The paper treats of the data on the use of radioimmunoassays for the measurement of steroid hormone content (17-hydroxyprogesterone, testosterone) in blood serum and saliva of children with congenital adrenocortical dysfunction. It is confirmed that these hormones can be detected in saliva only with the aid of highly sensitive and highly specific RIA systems. A positive correlation has been established between hormonal levels in both biological fluids.