Basal 17-OHP Research Articles

17-Hydroxyprogesterone response to ACTH in bilateral and monolateral adrenal incidentalomas.

The aim of our study was to assess the frequency of 21-hydroxylase deficiency, a cause of congenital adrenal hyperplasia (CAH), in incidentally discovered asymptomatic adrenal masses (incidentalomas) and to compare the prevalence of this enzymatic disorder in monolateral (M) and bilateral (B) forms. Twenty-seven patients with incidentalomas (12 M and 15 B) and 16 sex and age-matched controls (C) received synthetic adrenocorticotropin (ACTH, 250 micrograms i.v.). Plasma 17-OHprogesterone (17-OHP) and cortisol were collected in basal conditions and after 30, 60, 90 minutes. Basal plasma 17-OHP in C [1.25 +/- 0.15 (0.61) ng/ml, mean +/- SE (SD)] was not significantly different from that in patients with M [0.85 +/- 0.13 (0.44) ng/ml] or B [0.94 +/- 0.23 (0.90) ng/ml] incidentalomas. After ACTH, 17-OHP levels significantly (p < 0.05) increased in C, in M and B incidentalomas. However, the rise in plasma 17-OHP in C both in terms of peak [2.5 +/- 0.28 (1.1) ng/ml] and of AUC values [174 +/- 16 (64) ng/ml/min] was significantly lower than that observed in M [peak 6.32 +/- 1.66 (5.7) ng/ml, p < 0.01; AUC 410 +/- 111 (385.5) ng/ml/min, p < 0.01] and in B [peak 8.84 +/- 1.98 (7.65) ng/ml, p < 0.001; AUC 613 +/- 149 (579.3), ng/ml/min, p < 0.001] incidentalomas. Individual data indicated that while 17-OHP response to ACTH in C never reached 5 ng/ml (cut-off for normal response), 16 out of 27 patients with incidentalomas (59.2%) exceeded this value. Moreover, the abnormal response was more frequently observed in B (66.6%) than in M (50%) incidentalomas. Basal and stimulated plasma cortisol did not differ among the three groups. In conclusion, our data indicate that in adrenal incidentalomas the endocrine pattern of 21-hydroxylase deficiency is very common and that this enzymatic defect is more frequent in bilateral than in monolateral lesions.

11 3 α ANDROSTANEDIOL GLUCURONIDE AS A HARKER OF ANDROGENIC ACTIVITY IN GIRLS WITH PREMATURE PUBARCHE

Previous reports have postulated that 3 androstanediol glucuronide(3α AG)constitutes a marker of the 5 reductase activity in peripheral tissues. We studied the serum levels of androgens and their metabolites in 20 girls with premature pubarche (PP). EC X: 6.6±2.3 years, and in a control group of 12 girls, 5 of them prepubertal and the other 7 pubertal. 17 hidroxiprogesterone (17OHP), Androstenedione (Δ 4A), dehidroepiandrosterone sulfate (DS), testosterone (T)and 3 AG were determined by RIA. All patients showed pubic hair Tanner grade II-III. Besides pubic hair, 13 girls had one or more associated androgenic signs like acne: or face. trunk or limbs hair. Serum T and 17OHP levels were in prepubertal range in girls with PP except in one that showed basal 17OHP of 2 ng/ml and a response to ACTH stimulation of 20, which lead to a diagnosis of non classical 21OHlase deficiency. The elevated 3α AG levels found in PP agree with the pubertal levels of its precursors Δ4A and DS. The high 3α AG/4A ratio found in PP associated with other androgenic signs suggests and enhanced peripheral 5 reductase activity in those patients.

EVIDENCES OF OVARIAN HYPERFUNCTION IN ADDLESCENT GIRLS WITH INSULIN DEPENDENT DIABETES MELLITUS (IDDM) AND MENSTRUAL DISORDERS

Diabetic women present an elevated incidence of mestrual disorders often associated with partial gonadotropic insufficiency with reduced LH, E2 and ovarian androgen production. Among our adolescent IDDM population 8 over 36 postmenarcheal girls (22%) complained of oligo- or amenorrhea and 4 of hirsutism also. To verify therir pituitary and ovarian functions we assessed the gonadotropine and ovarian steroid response to the administration of 500 ng s.c. of GnRHa Leuprolide acetate in 7 patients with IDDM (age 17.8±1.7 yrs) and 12 age-matched normal girls. Basal and stimulated LH, FSH, E2, DEAS, 1 and basal 17OHP and 04-A levels were similar in the two groups, regardless of elevated baseline androgens levels in few girls. 24hr-stimulated 17OHP levels were significantly higher in patients than in controls (7.8±2.2 vs. 2.8±0.3 nMol/L, P 0.0001). D4-A responses were also higher than in control although the difference was not statistically significant (9.8±1.4 vs. 6.1±0.7 nMol/L n.s.). This behaviour was similar to that of a previously studied group of 35 adolescents with hirsuitism and ovarian hyperfunction (17OHP 7.0±0.4 nMol/L, D4-A 11.2±0.9 nMol/L). These data demonstrate the presence of a high incidence of ovarian hyperfunction in adolescent diabetic girls which can underline the menstrual disorders. We need a follow-up of these patients to clarify whether they will develop a clear hyperandrogenism, as suggested by our results, or a partial gonadotropin insufficiency as other observed in older diabetic patients.

Incidental adrenal nodules: association with exaggerated 17-hydroxyprogesterone response to adrenocorticotropic hormone.

The etiology of incidentally discovered, nonfunctional adrenal nodules was evaluated by using the 17-hydroxyprogesterone (17-OHP) response to synthetic adrenocorticotrophin (cosyntropin) (ACTH) administration. Patients who were discovered to have adrenal nodules and age-matched volunteers were studied. A total of 12 patients with adrenal nodules and 10 control subjects were studied. None of the patients with adrenal nodules had any evidence of hormonal hypersecretion consistent with pheochromocytoma, Cushing's syndrome or hyperaldosteronism. All subjects had serum 17-OHP and cortisol responses measured at baseline and at 30 and 60 min following the intravenous administration of 250 micrograms of ACTH. Baseline 17-OHP levels in patients with adrenal nodules were not significantly different from those of the normal controls (adrenal nodules 17-OHP: 75 +/- 13 vs control 68 +/- 11 ng/dl). After stimulation with ACTH, both 30 min and 60 min 17-OHP levels in patients with adrenal nodules (322 +/- 47 and 361 +/- 54 ng/dl, respectively) were significantly elevated over the responses seen with the controls (169 +/- 29 ng/dl at 30 min, p < 0.015, and 158 +/- 20 ng/dl at 60 min, p < 0.004). Baseline and post-ACTH serum cortisol levels were similar in both groups. Out of these twelve patients with adrenal nodules, nine were reevaluated twelve months later. In this group the basal 17-OHP remained comparable to normal levels (72 +/- 8.4 ng/dl) whereas the post-ACTH levels still remained exaggerated (30 and 60 min values 327 +/- 37 and 373 +/- 39 ng/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence of nonclassical congenital adrenal hyperplasia among women self‐referred for electrolytic treatment of hirsutism

Nonclassical congenital adrenal hyperplasia (NCCAH) is well recognized among women who seek medical attention for hirsutism. However, the prevalence of this disorder among women self-referred for electrolytic treatment of hirsutism is unknown. We hypothesized that the prevalence of NCCAH among women attending an electrolysis clinic might be high. By measuring the morning salivary 17-hydroxyprogesterone (17-OHP) as a screening test for NCCAH in 46 women in the follicular phase of their menstrual cycle, we identified 12 subjects with a high basal salivary 17-OHP. Eleven agreed to have a 60-minute Cosyntropin-stimulation test, as did an additional 6 of 9 women with normal basal salivary 17-OHP, but with a particularly high hirsutism score. One of the women with high basal salivary 17-OHP had a 60-minute Cosyntropin response, which was diagnostic of NCCAH. She was of the Ashkenazi Jewish decent, a group previously reported to have a high prevalence of NCCAH. A second woman with high salivary 17-OPH had a Cosyntropin-stimulation response consistent with heterozygosity for 21-hydroxylase deficiency. None of the Cosyntropin-stimulation responses in those chosen for a high hirsutism score were diagnostic. Thus, 1 of 46 (2.2%) of the women who entered our study had unrecognized NCCAH, a prevalence only about 2-fold greater than that reported in the general population. Therefore, we recommend that electrolysis clinics advise clients from ethnic groups known to have a high frequency of NCCAH of the advisability of having a formal medical evaluation for NCCAH.

Late-onset congenital adrenal hyperplasia in a group of hyperandrogenic women.

The aim of this study was to determine the prevalence of late-onset congenital adrenal hyperplasia (LOCAH) in a group of hyperandrogenic women presenting with menstrual disturbances and/or infertility. Thirty-five women were evaluated by basal hormonal profiles and underwent ACTH stimulation testing. In this study, 17.1% of women showed evidence of partial 21-OH deficiency (21-OHD), and 5.7% 3 beta-HSD deficiency. Neither basal hormonal levels nor clinical characteristics distinguished women with LOCAH from other hyperandrogenic women. And although the mean basal 17-OH progesterone (17-OHP) level in women with 21-OHD (152 +/- 66 ng/dl) was significantly higher than levels in other hirsute women, 4 of 6 (67%) women with 21-OHD had normal 17-OHP levels. Thus, to identify all affected individuals with partial 21-OHD, our data suggest that hyperandrogenic women with basal unsuppressed 17-OHP levels greater than 100 ng/dl should undergo dynamic testing. With regard to partial 3 beta-HSD deficiency, basal DHEA-S levels greater than the 95th percentile of other hirsute women may be used to screen for this deficiency. In conclusion, LOCAH due to partial steroid enzyme deficiencies are a frequent occurrence in women who present with symptoms of hyperandrogenism and ACTH stimulation remains an important tool in making the diagnosis of enzyme deficiencies.

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

Recent studies have described mild adrenal enzymatic defects in patients presenting with precocious pubarche. In order to identify these defects we have evaluated basal and ACTH- (25 IU iv) stimulated serum adrenal steroid levels in 19 girls, 2- to 8.3-year-old, with precocius pubarche (pubic hair Tanner II-III). Two patients had clitorial enlargement. Bone age was moderatly advanced in 10 patients and 2 to 3.7 yr in four others. Four patients had high basal serum levels of 17-hydroxyprogesterone (17OHP) (525 + 202 ng/dl, mean +SD), compatible with the diagnosis of nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCCAH-21OH), which was confirmed by an increased response of 17OHP to ACTH (3425 +/- 953 ng/dl). Fifteen patients had moderately elevated basal 17OHP levels (56 + 38 ng/dl) but a normal 170HP response (191 +/- 71 ng/dl) to ACTH, compatible with the diagnosis of idiopathic precocious pubarche (IPP). The cortisol response to ACTH was normal in both groups. Basal values of DHEA-S were 651 +/- 256 and 506 + 462 ng/ml and of DHEA 380 +/- 24 ng/dl and 205 +/- 102 ng/dl, in NCCAH-210H and IPP, respectively. We conclude that: i) clinical findings and baseline levels of DHEA-S and DHEA in IPP can be indistinguishable from the late onset 21 hydroxylase deficiency; ii) baseline levels of 17OHP are sufficient for the diagnosis of NCCAH-21OH; iii) the ACTH stimulation test is indicated only when baseline levels of 17OHP are moderately elevated (100-300 ng/dl).

Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway

Plasma 21-deoxycorticosterone (21-DB) concentrations were measured before (basal) and 1 h after ACTH stimulation in a population of 34 normal subjects, 18 patients with the late-onset form of congenital adrenal hyperplasia (LO-CAH) due to 21-hydroxylase deficiency, and 19 LOCAH heterozygotes. For comparison, plasma 21-deoxycortisol (21-DOF) and 17-hydroxyprogesterone (17-OHP) were determined simultaneously in the same subjects. Plasma 21-DB concentrations as well as those of 21-DOF did not vary significantly as a function of age, sex, or phase of the menstrual cycle, in contrast to plasma 17-OHP. The mean plasma 21-DB concentrations in normal subjects (adult men, follicular and luteal phase women, and children) were 19.0 +/- 9.5 (+/- SD) pmol/L before and 73.2 +/- 31.0 after ACTH stimulation. In the LOCAH patient group, the mean post-ACTH plasma 21-DB concentration was 1736.0 +/- 1243.0 pmol/L, and all values were above the highest post-ACTH value (148.2 pmol/L) in the normal subjects. Similarly, in the LOCAH patients the post-ACTH plasma 21-DOF concentration was 33.7 +/- 20.3 nmol/L, and the post-ACTH plasma 17-OHP value was 134.0 +/- 70.6 nmol/L; all LOCAH patients had supranormal responses to ACTH. However, 38.9%, 11.2% and 16.7% of the basal plasma 21-DB, 21-DOF, and 17-OHP values in the LOCAH patients overlapped those in the normal subjects. There was a rather large overlap (63.2%) in post-ACTH plasma 21-DB levels between the LOCAH heterozygotes and the normal subjects; it was less than the overlap in plasma 17-OHP (74%) and more than the overlap in plasma 21-DOF values (5.2%) in these same 2 groups. There was moderate overlap (21%) in the post-ACTH plasma 21-DB levels between the LOCAH heterozygotes and LOCAH patients, but no overlap between these 2 groups for either 21-DOF or 17-OHP. The abnormally elevated post-ACTH plasma 21-DB levels found in all the LOCAH patients as well as in some LOCAH heterozygotes suggest the existence of minor 21-hydroxylase deficiency in the mineralocorticoid synthetic pathway in these patients in addition to the well known impairment in the glucocorticoid pathway demonstrated by the elevated post-ACTH 21-DOF and 17-OHP levels.

Prevalence of late-onset adrenal hyperplasia in postmenarchal hirsutism.

The response of plasma 17-hydroxyprogesterone (17-OHP) to exogenous ACTH was investigated in 85 consecutive women referred for postmenarchal hirsutism, in order to assess the prevalence of late-onset adrenal hyperplasia due to 21-hydroxylase deficiency and its relevance to the clinical practice. An exaggerated response of plasma 17-OHP to ACTH, indicating 21-hydroxylase deficiency, was found in only one patient with a prevalence of 1.1%. The patient with late-onset adrenal hyperplasia presented signs of virilism and had high basal levels of 17-OHP. On the basis of our results, late-onset adrenal hyperplasia accounts for a very small proportion of cases of hirsutism; moreover, from this and previous studies it is apparent that the determination of basal plasma 17-OHP may be sufficient to discover late-onset 21-hydroxylase deficiency. Therefore, we do not consider ACTH testing an advisable step in the routine screening for hirsutism.

INCOMPLETE TESTICULAR FEMINIZATION WITH INCOMPLETE MULLERIAN REGRESSION

A 12 years old girl with clitoral hypertrophy, palpable testes in labia majora and prepubertal aspect of breast, pubic and axillary hair was evaluated. Her karyotype was 46 XY. Bone age was 9 years. Basal and peak FSH (34 and 104 mU/ml) and LH (10 and 49 mU/ml) were evaluated during a GnRH test. Testosterone levels (T), before and after HCG test (1000 U. I. every other day foi 5 days), were 27 and 208 ng/dl, respectively; basal Estradiol, 17OHP and Cortisol during ACTH test and TSH, T3 and T4 during TRH test were in the normal range. Genitography revealed the presence of rudimentary uterus with a right tube. Histologic examination of removed testes showed bilaterally normal prepubertal testes. Neither ovarian nor dysplastic tissue was found. Two months after surgery, basal and peak FSH (37 and 103 mU/ml) and LH (11 and 62 mU/ml) levels persisted elevated during GnRH test; T (<15 ng/dl) did not rise after HCG. This is the first report of incomplete testicular feminization with persistance of Mullerian structures probably due to a defective synthesis of MIF or some impairment of its action. Elevated FSH values, already reported in some cases of prepubertal TF, could be due to a decreased production of Inhibin.

Detection of late-onset adrenal hyperplasia in girls with peripubertal virilization

We investigated the value of serum levels of adrenal steroids (dehydroepiandrosterone sulphate, testosterone, 17-hydroxyprogesterone, cortisol) in the identification in peripubertal females with late-onset congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Among 68 females (age 3-18 years) with virilization in childhood, peripubertally or postpubertally, we selected 21 girls for an ACTH test by measurement of basal blood-spot or serum 17-hydroxyprogesterone (17-OHP) levels. Eight of 21 patients had supranormal post-ACTH serum 17-OHP concentration (57-153 nmol/l) with low normal cortisol concentration. All of them had supranormal basal and post-ACTH 17-OHP to cortisol ratios. These data show a relatively high incidence (about 12%) of mild 21-hydroxylase deficiency among prepubertal and adolescent girls with virilization. It is concluded that the first step in the investigation of peripubertally virilized girls should be the determination of serum 17-OHP and cortisol. Patients with basal morning 17-OHP concentration and 17-OHP to cortisol ratio above reference range should be given an ACTH test.

Adrenocorticotropic hormone testing in idiopathic hirsutism and polycystic ovarian disease: a test of limited usefulness

The plasma 17 alpha-hydroxyprogesterone (17-OHP) concentration was determined in the basal state and 60 minutes after cosyntropin, 0.25 mg, in 139 patients with idiopathic hirsutism (IH) and polycystic ovarian disease (PCOD). Although there was an increased response of 17-OHP in subjects with PCOD when compared with IH subjects, in no instance was stimulated 17-OHP abnormal in the presence of normal basal 17-OHP. Two subjects with 21-hydroxylase (21-OH) deficiency were discovered; both demonstrated elevated basal levels of 17-OHP. We therefore conclude that routine adrenocorticotropic hormone testing is not a useful tool in detecting 21-OH deficiency in hyperandrogenic women.

861 THE MOST FREQUENT HUMAN AUTOSOMAL RECESSIVE DISEASE

Nonclassical steroid 21-hydroxylase deficiency (nc21OHD) is an autosomal recessive disease which results in a phenotypically variable syndrome of postnatal hyperandrogenism. Its prevalence is unknown because basal serum 17-OHP levels are not sufficiently elevated for detection with the microfilter paper technique used in screening for classical 21-OHD. We therefore ascertained the frequency of the nc21OHD gene using ethnic group-specific HLA-B-nc21OHD associations in conjunction with ACTH testing in obligate heterozygote parents. Confirmation of this approach was obtained by the affected sib pair method of Thomson and Bodmer. The gene frequency for nc21OHD was highest in Ashkenazi Jews (19.1%) and was also high in Hispanics (13.6%), Yugoslavs (12.5%), and Italians (5.8%). In other Caucasians studied it was 0.1%. Disease frequencies were 1/27 for Ashkenazi Jews, 1/53 for Hispanics, 1/63 for Yugoslavs, 1/333 for Italians, and 1/1000 for other Caucasians. Carriers of the HLA-B14 marker had a 32-fold increased risk of nc21OHD compared to controls. Linkage disequilibrium betweeen HLA-B14 and nc21OHD was significant in Ashkenazi Jewish, Hispanic, and Italian patients, but not in Yugoslavs or other Caucasians.Conclusion: It appears that nc21OHD is the most frequent autosomal recessive genetic disorder in man.

Basal and adrenocorticotropic hormone-stimulated serum 17α-hydroxyprogesterone in men with idiopathic infertility

Basal serum 17 alpha-hydroxyprogesterone (17-OHP) concentrations and the 17-OHP response to acute adrenocorticotropic hormone administration were studied in infertile men with idiopathic oligospermia to determine the prevalence of attenuated 21-hydroxylase deficiency. Mean (+/- standard error of the mean) basal serum 17-OHP levels in 50 infertile men (1.17 +/- 0.06 ng/ml) and 25 normal volunteers (1.09 +/- 0.08 ng/ml) were indistinguishable (not significant). However, two infertile men had 17-OHP levels which were above the normal range. Following the intravenous administration of 0.25 mg of synthetic adrenocorticotropic hormone (cosyntropin) to these two men and to eight additional infertile men, the mean increase in 17-OHP concentrations was 0.84 +/- 0.15 ng/ml, a response which was similar to that of normal men (0.94 +/- 0.26 ng/ml). No patient demonstrated the minimum fourfold rise in 17-OHP previously reported in men with attenuated 21-hydroxylase deficiency, suggesting the absence of this disorder among these subjects. This study suggests that subtle 21-hydroxylase deficiency is rare among infertile men with idiopathic infertility.

Attenuated Forms of Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

A variety of mild forms of congenital adrenal hyperplasia (CAH) due to partial 21-hydroxylase deficiency have recently been described. We report two families in whom members presented with CAH with various degrees of enzyme deficiency. In family A, two children had the classical salt-losing CAH. Their male sibling and mother presented a very mild asymptomatic form of CAH, characterized by elevated basal plasma levels of 17-hydroxyprogesterone (17-OHP) and exaggerated responses of progesterone and 17-OHP to ACTH stimulation. The Hormonal profile and HLA types of these two individuals suggested allelic compounds, having one mutant gene for classical CAH and another for a mild form. In family B, the proband presented an attenuated form of CAH, manifested by amenorrhea and hirsutism, elevated basal levels of plasma 17-OHP and androgens, as well as markedly increased ACTH response. Two of her four siblings had the same ad HLA type, elevated basal plasma 17-OHP levels, and increased ACTH response. Their father, their paternal aunt, and their paternal uncle had the ab HLA type and normal basal plasma 17-OHP but markedly increased ACTH response. The haplotypes a, b, and d were considered to be linked to a mutation resulting in mild 21-hydroxylase deficiency, the homozygotes with ab HLA type having a milder form of CAH than the homozygotes with the ad HLA type. The wide spectrum of clinical and hormonal characteristics among homozygotes for the 21-hydroxylase deficiency trait suggests that their is a continuum of degree of enzyme deficiency. Furthermore, it suggests that most nonclassical subjects are allelic compounds for variable degrees of severity in the mutation at the 21-hydroxylase locus. More specifically, the study of families A and B shows that the so-called cryptic and attenuated forms of CAH have the same pathophysiological basis.

The age-related changes in serum 17-hydroxyprogesterone secretion in men

In order to clarify the age-related changes in serum 17-hydroxyprogesterone (17-OHP) secretion in men, serum basal 17-OHP levels were determined in 203 healthy male subjects from 10 months to 116 years of age, and serum 17-OHP responses to dexamethasone (Dex), fluoxymesterone (FM), HCG and ACTH were compared between the young and elderly groups. The mean basal 17-OHP level remarkably increased from pubescence to the third decade and gradually decreased with advance in age after fifty. Basal serum 17-OHP level was correlated more closely with serum testosterone (T) than cortisol (F), and was suppressed more remarkably after the administration of FM than Dex in both groups. Serum 17-OHP increased with 2 peaks at 6 and 24 hours after HCG injection, and serum 17-OHP response to HCG was significantly greater in the young than in the elderly group. Furthermore, in the aged subjects with low serum T levels, serum 17-OHP response to HCG was remarkably decreased. Within 3 hours after ACTH injection, serum 17-OHP response to ACTH was significantly lower in the elderly than in the young group. On the other hand, 12 hours after ACTH administration, serum 17-OHP response was remarkably greater in the elderly group, and the F/17-OHP ratio was significantly lower than in the young. These data indicate a decline of Leydig cell function in the testis of the elderly male and also suggest the occurrence of enzyme deficiencies, especially impaired C17, 20 lyase activity, in adrenal steroid hormone synthesis with aging.

Attenuated forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

A variety of mild forms of congenital adrenal hyperplasia (CAH) due to partial 21-hydroxylase deficiency have recently been described. We report two families in whom members presented with CAH with various degrees of enzyme deficiency. In family A, two children had the classical salt-losing CAH. Their male sibling and mother presented a very mild asymptomatic form of CAH, characterized by elevated basal plasma levels of 17-hydroxyprogesterone (17-OHP) and exaggerated responses of progesterone and 17-OHP to ACTH stimulation. The Hormonal profile and HLA types of these two individuals suggested allelic compounds, having one mutant gene for classical CAH and another for a mild form. In family B, the proband presented an attenuated form of CAH, manifested by amenorrhea and hirsutism, elevated basal levels of plasma 17-OHP and androgens, as well as markedly increased ACTH response. Two of her four siblings had the same ad HLA type, elevated basal plasma 17-OHP levels, and increased ACTH response. Their father, their paternal aunt, and their paternal uncle had the ab HLA type and normal basal plasma 17-OHP but markedly increased ACTH response. The haplotypes a, b, and d were considered to be linked to a mutation resulting in mild 21-hydroxylase deficiency, the homozygotes with ab HLA type having a milder form of CAH than the homozygotes with the ad HLA type. The wide spectrum of clinical and hormonal characteristics among homozygotes for the 21-hydroxylase deficiency trait suggests that their is a continuum of degree of enzyme deficiency. Furthermore, it suggests that most nonclassical subjects are allelic compounds for variable degrees of severity in the mutation at the 21-hydroxylase locus. More specifically, the study of families A and B shows that the so-called cryptic and attenuated forms of CAH have the same pathophysiological basis.

Testicular reserve of testosterone precursors in primary testicular failure

To explore the abnormal steroidogenesis in subjects with primary testicular failure, we measured serum levels of testosterone (T) and its precursors androstenedione (delta 4A) and 17-hydroxyprogesterone (17-OHP) in the basal state and after stimulation by human chorionic gonadotropin (hCG) for 4 hours (acute reserve) or 72 hours (chronic reserve). Subjects with primary testicular failure had decreased mean basal serum T, decreased mean chronic T reserve, and absent mean acute T reserve. In contrast, these subjects had normal mean basal serum 17-OHP and delta 4A, normal chronic 17-OHP reserve, and non-zero mean acute 17-OHP and delta 4A reserve, although mean chronic delta 4A reserve was reduced. Heterogeneity of biochemical abnormalities depending on the etiology of testicular failure was apparent. In primary testicular failure, the testicular reserves of the T precursors 17-OHP and delta 4A are better maintained than is the reserve of T itself, raising the possibility that this disorder might be associated with biochemical blocks in conversion of T precursors to T.

Enhancement of gonadotrophin induced 17,20-lyase suppression one week after human chorionic gonadotrophin priming.

A single injection of 1500 IU of human chorionic gonadotrophin (hCG) in normal men, induced a block in the conversion of 17-hydroxyprogesterone (17-OHP) to testosterone (T) which reached its maximum 24 h after hCG loading. One week after hCG administration both basal 17-OHP (3.8 +/- 0.6 vs 5.1 +/- 0.5 nmol/l, P less than 0.02) and T levels (15.1 +/- 1.7 vs 18.5 +/- 2.3 nmol/l, P less than 0.05) were about 20% lower than before hCG exposure. The ratio 17-OHP to T (0.29 +/- 0.04 vs 0.31 +/- 0.04, P greater than 0.10) was however similar, suggesting recovery from the prior 17,20-lyase suppression at a lower overall capacity of T synthesis. hCG administration one week after the priming dose elicited an increase in the ratio 17-OHP to T, which was about twice as high as after the first hCG injection. Together the data suggest: 1) suppression of testicular steroidogenesis proximal to 17-OHP one week after hCG priming, 2) enhanced hCG induced 17,20-lyase suppression one week after hCG exposure.

Basal and Human Chorionic Gonadotropin-Stimulated 17α-Hydroxyprogesterone and Testosterone Levels in Klinefelter's Syndrome

In nine patients with Klinefelter's syndrome, mean basal plasma levels of testosterone (302 +/- 145 ng/100 ml) and its major precursor, 17 alpha-hydroxyprogesterone (17-OHP; 86 +/- 46 ng/100 ml), were significantly lower (P less than 0.01 to less 0.05) than in eight eugonadal men (605 +/- 180 and 136 +/- 39 ng/100 ml, respectively). The ratio of 17-OHP to testosterone, however, was comparable in both groups (0.29 +/- 0.09 vs. 0.24 +/- 0.08; P less than 0.10). In the Klinefelter patients, basal plasma testosterone and 17-OHP levels were positively correlated (rs = 0.87). Administration of hCG for 3 days raised plasma testosterone and 17-OHP levels in both groups. In the Klinefelter patients, the plasma 17-OHP rise exceeded the testosterone increment, leading to a statistically significant increase (0.48 +/- 0.19) of the 17-OHP to testosterone ratio, whereas this ratio remained virtually unchanged in the control subjects (0.20 +/- 0.06). Together, these findings indicate that in the basal state testicular steroidogenesis is globally attenuated, whereas short term hCG stimulation shows that the later steps in the biosynthesis of testosterone may be rate limiting in Klinefelter's syndrome.