Partial 21-hydroxylase Deficiency Research Articles

An unusual cause of adrenal insufficiency with elevation of 17-hydroxyprogesterone: case report

BackgroundWe present an intriguing case of primary adrenal lymphoma, with associated primary adrenal insufficiency (PAI), in a patient presenting a transitory partial 21-hydroxylase deficiency during the active phase of the adrenal disease.Case presentationAn 85-years old woman was referred because of worsening asthenia, lumbar pain, generalized myalgia and arthralgia. During investigations a computed tomography (CT) scan evidenced two large bilateral adrenal masses, highly suspicious for primary adrenal tumor. The hormonal assessment revealed very low levels of morning plasma cortisol and 24-h urinary cortisol, elevated ACTH levels with low plasma concentration of aldosterone, pointing to the diagnosis of PAI. After diagnosis of PAI our patient started glucocorticoid and mineralcorticoid replacement therapy with clinical benefit. In order to further characterize the adrenal lesions, adrenal biopsy, was performed. The histology revealed a high grade non-Hodgkin lymphoma with an immunophenotype consistent with intermediate aspects between diffuse large B-cell and Burkitt lymphoma, with a high proliferation index (KI-67 > 90%). The patient received chemotherapy with epirubicin, vincristine, cyclophosphamide, and rituximab, associated with methylprednisolone that resulted in a complete clinical and radiological remission within one year. After 2 years from the diagnosis and a total of 6 cycles of rituximab, the patient was in good clinical condition and was taking only the replacement therapy for PAI. The patient initially presented also a slight increase of 17-hydroxyprogesterone (17-OHP) for age that normalize after resolution of lymphoproliferative disease.ConclusionsIn the presence of bilateral adrenal disease and/or in the presence of signs and symptoms of PAI clinicians must exclude the presence of PAL. The evidence of elevated ACTH-stimulated 17-OHP levels also in patients with other adrenal masses, together with the detection of elevated basal 17-OHP levels in our patient make it more plausible, in our view, an effect of the lesion on the “healthy” adrenal tissue residue than a direct secretory activity by the adrenal tumor.

MON-362 Undiagnosed Non-classic Congenital Adrenal Hyperplasia as a Driving Force for Persistent Hyperandrogenemia in Prostate Cancer

Background Non-classic congenital adrenal hyperplasia (CAH) is a common condition and can lead to adrenal hyperandrogenemia. Clinical case We present a case of an 82-year-old man with prostate adenocarcinoma (Gleason 4+3=7) diagnosed 5 years prior to presentation. During surveillance, he was found to have lymphadenopathy, extra-capsular extension, and rising prostate specific antigen (PSA) (from 4.5 to 14.2 ng/ml, n< 4). Stereotactic radiation therapy and androgen deprivation therapy (ADT) with Gonadotropin-releasing hormone (GnRH) analog leuprolide (22.5 mg every 3 months) were initiated. Post-treatment labs showed inadequate testosterone suppression (total testosterone [TT], 87 ng/dl; target,<5.0). Therefore, bicalutamide (50 mg daily), an androgen receptor inhibitor, was added. Subsequently, PSA declined to 0.29 ng/ml and TT remained at 88.4 ng/dl. Prostate cancer remained stable and Leuprolide was discontinued. Three months prior to presentation, F18-Fluciclovine PET/CT revealed skeletal metastases and incidental bilateral adrenal enlargement. PSA increased to 10.86 ng/dl and TT to 218 ng/dl. ADT was resumed with the GnRH analog degarelix (240 mg monthly). Subsequently, PSA remained elevated (10.6 ng/dl) with TT only partly suppressed (90 ng/dl). Further work-up revealed 17-hydroxyprogesterone 4910 ng/dl (n<220), DHEAS 312 mcg/dl (n<166), corticotropic hormone 39 pg/mL (n,7.2-63), cortisol 5.6 mcg/dl (n,5-23), plasma normetanephrine 1.1 nmol/l (n<0.9), plasma metanephrine 0.39 nmol/l (n<0.5), aldosterone 4.0 ng/dl (n<21), and TT 119 ng/dl. An adrenal CT showed diffuse bilateral adrenal hyperplasia, with a 5.6-cm right adrenal gland and 6.7-cm left adrenal gland. The patient shared that he underwent precocious puberty, was shorter than predicted based on the sex adjusted mid-parental height, and never fathered children. In light of his history, he was diagnosed with non-classic CAH due to partial 21-hydroxylase deficiency (21-OHD), causing inadequate testosterone suppression and progression of prostate cancer despite ADT and androgen receptor blocker. Following the diagnosis, the patient was treated with abiraterone (1000 mg daily), a CYP17A1 inhibitor, and prednisone (2.5 mg twice daily), to suppress adrenal androgen production. TT became undetectable (< 5 ng/dl) and PSA declined from 12.93 to 1.27 ng/ml. Conclusion: Non-classic CAH is a common autosomal recessive disorder and presents in late childhood as premature pubarche and accelerated bone age. The prevalence of non-classic CAH is 0.1%-1% among Caucasians and even higher among Ashkenazi Jews and Hispanics. Treatment in men is generally not required unless there is oligospermia in those desiring fertility. Adrenal hyperandrogenemia can be treated with systemic steroids. Non-classic 21-OHD CAH should be considered in men with prostate cancer with inadequate testosterone suppression after ADT.

Clinical and Molecular Characterization of a Cohort of 161 Unrelated Women with Nonclassical Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency and 330 Family Members

Nonclassical congenital adrenal hyperplasia (NC-CAH) due to partial 21-hydroxylase deficiency is one of the most frequent autosomal recessive diseases. The aim of this study was to determine the genotype/phenotype relationship in probands and family members. A total of 161 NC-CAH unrelated women diagnosed on late-onset symptoms, mainly hirsutism, and post-ACTH 17-hydroxyprogesterone more than 10 ng/ml, and 330 of their relatives was explored. CYP21A2 was genotyped in 124 probands. The most frequent mutation was V281L. One severe mutation was found in 63.7% of probands, and surprisingly two severe mutations in four probands. Contrasting with the absence of clinical differences, basal testosterone, and androstenedione, basal and post-ACTH 17-hydroxyprogesterone were significantly higher in probands carrying at least one severe mutation than in those with two mild mutations (P < 0.01). Among the 330 family members, 51 were homozygotes or compound heterozygotes, and 42 were clinically asymptomatic; 242 were heterozygotes and 37 unaffected. Post-ACTH 21-deoxycortisol (21dF) was significantly higher in heterozygotes than in unaffected, however, an overlap existed. In 12 heterozygotes, post-ACTH 21dF was below 0.55 ng/ml, the cutoff value usually accepted for suggesting heterozygosity. The study of family members underlines the variable expression of NC-CAH even within a family, suggesting that modifier factors may modulate phenotype expression. Post-ACTH 21dF cannot reliably detect heterozygous subjects. Considering the high frequency of heterozygotes in the general population, it is essential to genotype the partner(s) of the patients with one severe mutation to offer genetic counseling.

3 beta-hydroxysteroid dehydrogenase deficiency and 21-hydroxylase deficiency in hirsutism

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.

Hormonal status and clinical relevance of hirsutism in elderly women

Hirsutism is a common condition of elderly women, but its aethiopathogeny and its clinical implications remain unclear. We therefore studied circulating androgen concentrations in elderly women. In addition, this study aims to define a possible relationship between hirsutism and anthropometric determinations, bone mass and serum lipids. Androgen levels were determined at basal state, after adrenocorticotrophin (ACTH) stimulation and after dexamethasone administration in 10 hirsute elderly women and compared to 10 age-matched non-hirsute women. Anthropometric determinations included measurements of skinfold thickness and body mass index. Spinal bone mass density was assessed using dual photon absorptiometry. Hirsute women presented significantly higher levels of testosterone than controls (1.49 +/- 0.38 vs 0.59 +/- 0.05 nmol/l, mean +/- SEM; p < 0.05) and dihydrotestosterone (0.54 +/- 0.07 vs 0.32 +/- 0.03; p < 0.02). 17-hydroxyprogesterone levels after ACTH stimulation tended to be higher in hirsute women than in controls. No differences were observed between the two groups in serum oestrogen concentrations, plasma lipid pattern or bone mineral density. Hirsute women had a lower body mass index and lower calculated percentage body fat than the control group. We conclude that: (i) hirsutism of elderly women is associated with increased androgen levels, probably from adrenal origin; (ii) in some cases, enhanced response in 17-hydroxyprogesterone after ACTH stimulation suggests a partial adrenal 21-hydroxylase deficiency; (iii) hirsute women present anthropometric characteristics compatible with the known anabolic effect of androgens on fat-free mass.

3α-Androstanediol Glucuronide in Premature and Normal Pubarche*

To investigate the role of adrenal androgens in 3 alpha-androstanediol glucuronide (3AG) production in childhood, we compared serum 3AG and androgen levels [dehydroepiandrosterone (DHEA), DHEA sulfate (DS), androstenedione (delta 4-A), and testosterone (T)] in 32 children with premature pubarche due to idiopathic premature adrenarche (IPA; n = 26), partial 21-hydroxylase deficiency (n = 2), or 3 beta-hydroxysteroid dehydrogenase deficiency (n = 4) with those in 36 normal prepubertal (18 males and 18 females) and 22 normal pubertal Tanner II-III subjects (10 males and 12 females). Serum 3AG (2.7 +/- 2.0 nmol/L) and all androgen concentrations in children with IPA were significantly higher (P less than 0.05-0.001) than those in normal prepubertal children (3AG, 0.8 +/- 0.5 nmol/L). Serum 3AG and androgen levels, except T, in all children with premature pubarche due to 21-hydroxylase deficiency or 3 beta-hydroxysteroid dehydrogenase deficiency were higher than those in the normal prepubertal children. Serum 3AG and all androgen levels in normal Tanner II-III male (3AG, 3.8 +/- 1.7 nmol/L) or female (3AG, 1.74 +/- 0.52 nmol/L) subjects were also significantly higher (P less than 0.05-0.001) than those in prepubertal children. Serum 3AG, DHEA, DS, and delta 4-A levels in children with IPA were similar to those in normal Tanner II-III females or males, but serum T in children with IPA (0.37 +/- 0.2 nmol/L) was significantly lower (P less than 0.05-0.001) than that in normal pubertal females (0.71 +/- 0.37 nmol/L) or males (4.5 +/- 2.6 nmol/L). In the combined group (n = 88), 3AG levels correlated better with serum DS (r = 0.7), DHEA (r = 0.6), and delta 4-A (r = 0.52), than with T (r = 0.31) levels. These data suggest that the weak adrenal androgens DS, DHEA, and delta 4-A contribute substantially to 3AG production in premature and normal pubarche.

Assessment of the one hour adrenocorticotrophic hormone test in the diagnosis of attenuated 21-hydroxylase deficiency.

Attenuated or partial 21-hydroxylase deficiency is one of several biochemical defects in steroid metabolism that can lead to hirsutism in young women after puberty. The diagnosis is made through the exaggerated response of 17 alpha-hydroxyprogesterone (17-OH) to adrenocorticotrophic hormone (ACTH). To provide reference data 72 mild to moderately hirsute patients aged 18 to 35 were studied (over two years) with the ACTH test. Four patients with an exaggerated response were found. The mean (+/- 1SD) for zero time was 2.4 (0.96) nmol/l and for the 60 minute time was 7.2 (2.04) nmol/l. A subpopulation was found with a significantly higher baseline at 6.2 (1.3) nmol/l but a blunted 60 minute response at 8.7 (2.5) nmol/l. This is important because of the potential confusion arising from the known variability in baseline values in previously reported patients with partial 21-hydroxylase deficiency. Extending the test to 90 minutes did not show further increase in the 17-OH response to ACTH, thus confirming the validity of the 60 minutes ACTH test. The cortisol response to ACTH was also studied. One patient with presumptive partial 21-hydroxylase deficiency overlapped in cortisol response with eight of the reference population. Theoretically, a blunted cortisol response would be expected because of the postulated enzyme block, and these results suggest that other steroid enzyme defects should also be considered when an exaggerated 17-OH response to ACTH is seen.

LATE ONSET ADRENAL HYPERPLASIA IN A GROUP OF IRISH FEMALES WHO PRESENTED WITH HIRSUTISM, IRREGULAR MENSES AND/OR CYSTIC ACNE

The aims of this study were to determine the frequency of late-onset adrenal hyperplasia due specifically to 21-hydroxylase deficiency in a group of Irish women who presented at a Dublin Clinic with symptoms of hyperandrogenism, including hirsutism, menstrual irregularities and/or cystic acne, and to determine if those with 21-hydroxylase deficiency showed particular HLA associations. 119 women had blood samples taken basally and 1 h after an injection of 0.25 mg synacthen with the following hormones profiled: 17-hydroxyprogesterone, 11-deoxycortisol, androstenedione, testosterone, DHEAS and cortisol. Blood sampling was carried out between 0900 and 1000 h during the early follicular phase of the menstrual cycle (when applicable). Ninety-six subjects were new referrals to the Clinic for investigation of hyperandrogenism and 23 were acting as controls. In this study, 6% of patients showed evidence of partial 21-hydroxylase deficiency. In addition, 3 of the 6 with partial 21-hydroxylase deficiency had normal baseline levels of 17-hydroxyprogesterone, with the biochemical abnormality becoming manifest only on synacthen stimulation. Late-onset adrenal hyperplasia due to partial deficiency of this enzyme should always be considered as a possible diagnosis in women who present with symptoms of hyperandrogenism. Synacthen stimulation is an important diagnostic tool in elucidating partial enzyme deficiency as baseline 17-hydroxyprogesterone may be normal in such patients.

ADAPTATION OF THE HYPOTHALAMIC-P ITU ITARY-ADRLNAL AXIS IN LATE-ONSET CONGENITAL ADRENAL HYPERPLASIA

Patients with late-onset congenital adrenal hyperplasia(LOCAH)due to partial 21-hydroxylase deficiency have no clinical evidence of hypocortisolism, unlike patients with classical forms of CAR, who have elevated plasma ACTH and low serum cortisol levels. In order to study the interactions of the various components of the hypothalamic-pituitary-adrenal axis in LOCAH. we administered ovine corticotropin releasing hormone(oCRH), 1 ug/kg, at 20:00h to 10 untreated patients with LOCAH (8 females, 2 males, ages 7-35y). Baseline(basal, B) and oCRH-stimulated(peak, P) ACTH and cortisol responses did not differ from normal and the integrated ACTH:cortisol response ratio was also normal. Stimulated serum 17-hydroxyprogesterone responses were significantly greater than normal (p<0.005). Stimulated serum Δ 4-androstenedione responses in 5 postpubertal female patients moderately exceeded those of 5 age-matched control females(p=NS). [Data shown as mean + SBM] We conclude that patients with LOCAH compensate for the cortisol biosynthetic defect at the expense of a moderate increase in adrenal androgen secretion. The normal ACTH and cortisol responses to oCRH suggest that a new equilibium has been established between the pituitary and the adrenal gland.

Infertility caused by bilateral testicular masses secondary to congenital adrenal hyperplasia (21-hydroxylase deficiency)

Two male cousins with partial 21-hydroxylase deficiency presented with bilateral testicular masses and infertility. In both cases, the testicular masses, consisting of adrenocorticotropic hormone-dependent pluripotential cells, were thought to play a major etiologic role in infertility. The administration of very small doses of dexamethasone, given at 11:00 P.M., led to the disappearance of the masses and a subsequent return of fertility. Although 21-hydroxylase deficiency is not by itself an uncommon condition, the presentation of testicular masses with subsequent reversible infertility in two family members with this condition has not previously been described.

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.

Effect of adrenocorticotropic hormone and human chorionic gonadotropin before and after bilateral oophorectomy in a patient with acquired adult-onset adrenal hyperplasia: A case report

A 29-year-old woman presented with hirsutism, obesity, oligomenorrhea, and infertility caused by oligoovulation and tubal occlusion. Partial 21-hydroxylase deficiency of the adrenal was suggested by an abnormal adrenocorticotropic hormone (ACTH) stimulation test. The patient subsequently developed bilateral tuboovarian abscesses and underwent abdominal hysterectomy and bilateral salpingo-oophorectomy. Thus, an opportunity was presented to study the adrenal endocrine disorder in the absence of ovaries and to investigate the effect of human chorionic gonadotropin (hCG) on the adrenals. There was no change in the adrenal response to ACTH stimulation after oophorectomy. hCG stimulation resulted in an increase in dehydroepiandrosterone sulfate and 17β-estradiol levels, suggesting that hCG had a stimulatory effect on the adrenal. The ovarian-adrenal relationship and effects of adrenal stimulation in the absence of ovaries are discussed.

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.

Evaluation of the gonadotropic responsiveness of the pituitary to acute and prolonged administration of [formula omitted] hormone (LHRH) in untreated patients with congenital adrenal hyperplasia

The pituitary gonadotropic responsiveness to acute and prolonged administration of LH FSH-releasing hormone (LHRH) were assessed in 6 patients with untreated congenital virilizing adrenal hyperplasia (partial 21-hydroxylase deficiency). The oldest subjects had normal response in comparison to females at the midfollicular phase, to the acute infusion of 25 ug LHRH regarding both gonadotropins whereas LH secretory area was decreased during the prolonged (100 ug LHRH in 8 hours) infusion with normal FSH secretion. The two youngest subjects, with higher steroid levels in our series, were either unresponsive on both ways of testing or presented pre-pubertal response.

Congenital adrenal hyperplasia due to partial 21-hydroxylase deficiency. A study of five cases.

Abstract. Five women with post pubertal hirsutism due to a partial 21-hydroxylase deficiency were studied. These patients had no abnormalities of the external genitalia. They were compared to 3 adult women with a complete defect in 21-hydroxylase. The diagnosis of 21-hydroxylase deficiency was substantiated by the dramatic increase in 17-hydroxyprogesterone (17-OHP) after im injection of 250 μg synthetic ACTH (22 ± 12 nmol/l to 349 ± 153 nmol/l). However, in adult women with 21-hydroxylase deficiency recognized at birth and presenting abnormalities of the external genitalia, plasma 17-OHP was elevated in basal conditions (512 ± 106 nmol/l) and only slightly increased after ACTH administration (657 ± 133 nmol/l). Plasma cortisol levels determinated at 08.00 h were lower than normal in both groups but only slightly in groups with partial 21-hydroxylase deficiency. After ACTH stimulation, plasma cortisol levels remained lower than normal in all patients but with a noticeable increase in patients with partial defect. The differences noted between precocious and delayed onset virilization gave an indication of the importance of the enzyme defect. Plasma testosterone (T) and androstenedione (Δ4) levels were elevated both in basal conditions and after ACTH administration. However, in patients with delayed onset of hirsutism most circulating T seems to originate from peripheral conversion of Δ4 to T. Plasma ACTH values were strongly elevated in patients with a complete defect in 21-hydroxylase (260 ± 50 pg/ml) but normal in patients with partial deficiency (&lt; 40 pg/ml). In vitro testosterone 5α-reductase activity was determined in pubic skin homogenates from 4 patients with partial 21-hydroxylase deficiency. The amount of dihydrotestosterone + androstanediols formed from incubated [3H]testosterone was in the normal range for women. Virilization of patients with partial 21-hydroxylase deficiency therefore seems to be essentially due to an increase in active androgen production and not to exaggerated skin 'utilization' of pre-androgens as observed in idiopathic hirsutism.

An XX male with 21-hydroxylase deficiency

The patient is the second child of healthy unrelated parents,his older brother is normal. At birth the genitalia were ambiguous; the phallus was adequate in size but there was chordee and perineal hypospadias. The labio-scrotal folds were fused. Gonads were palpable in both groins. The karyotype (blood and skin) was normal female XX. Biopsy of both gonads showed immature testes with no ovarian elements; the XX genotype was confirmed in gonadal tissue. Laparotomy showed normal male and absent female internal genitalia. Hypospadias repair was undertaken and the child was reared in the male sex. At 6 years he was noted to be virilising.He had shown rapid growth and weight gain and development of pubic and axillary hair. Plasma steroids by RIA and urinary steroids by GLC/MS indicated partial 21-hydroxylase deficiency. There was normal suppression with exogenous steroids and a selenocholesterol scan showed bilateral adrenal hyperplasia.He is maintained on hydro-cortisone and continues to make a good progress at the age of 9.This patient has an apparently unique combination of genetic endocrine defects unlikely to be due to chance.It is possible that translocation of part of a Y chromosome has influenced the expression of the 21-hydroxylase locus on chromosome 6.

Oestrogen dynamics in adrenal venous effluents in congenital virilizing adrenal hyperplasia.

Four patients with untreated congenital virilizing adrenal hyperplasia (partial 21-hydroxylase deficiency) were studied by bilateral adrenal vein catheterization. Simultaneous right and left adrenal and peripheral blood samples were collected for determination of oestrone (E1) and oestradiol (E2). The concentrations of both were higher in the adrenal effluents than in the peripheral blood samples, indicating their secretion by the adrenals. All patients were also studied during a sequential test of suppression (0.5 h after i.v. administration of 4 mg dexamethasone) and stimulation (5 min after i.v. administration of 250 microgram ACTH 1-24; Synacthen). Mean peripheral E2 concentrations did not change significantly whereas E1 increased above control levels after stimulation. In contrast, suppression of adrenal venous blood concentrations with dexamethasone, and stimulation with ACTH, was demonstrated for every patient. The results indicate that in congenital adrenal hyperplasia the adrenal glands secrete significant amounts of E1 and E2.

Adrenal Steroid Dynamics in Congenital Adrenal Hyperplasia: Evaluation by Simultaneous Bilateral Adrenal Venous Catheterization

Ten patients with untreated congenital virilizing adrenal hyperplasia (partial 21-hydroxylase deficiency) were studied by bilateral adrenal vein catheterization. Simultaneous right and left adrenal and peripheral venous blood samples were collected for determination of cortisol, progesterone (P), 17- hydroxyprogesterone (17-OHP), androstenedione, dehydroepiandrosterone, testosterone, and dihydrotestosterone. The concentrations of the above steroids were always higher in the adrenal effluents than in the peripheral blood samples, indicating their secretion by the adrenals. Five of the patients had their steroid dynamics studied during a sequential test of suppression (0.5 h after iv administration of 4 mg dexamethasone) and stimulation [5 min after iv administration of 250 μg β ACTH-(1- 24)]. Peripheral steroid concentrations did not change significantly during these dynamics studies, except for P and 17-OHP which decreased significantly during suppression and increased above control after stimulation. In ...

Virilizing syndrome associated with an adrenal cortical adenoma secreting predominantly testosterone

A 22 year old woman had virilization and mild Cushing's syndrome. Serum testosterone levels were high (3.2 ng/ml), urinary 17-ketosteroid levels slightly elevated (17.5 mg/d) and plasma cortisol at 16:00 hours normal (7.2 μg/dl). Basal level of cortisol secretion was normal but with evidence of autonomy. An abnormal adrenal scan led to an adrenal venogram showing a tumor image in the left adrenal gland. Selective adrenal venous catheterization indicated that the tumor was secreting testosterone and cortisol; left/right adrenal venous values were 53.5 3.7 ng/ml for testosterone and 92.8 13.6 μg/dl for cortisol. Testosterone levels did not rise with human chorionic gonadotropin (hCG). The basal serum level of Δ 4 androstenedione was at the upper limit of normal and of 17 α-hydroxyprogesterone high. The patient underwent surgical removal of a well circumscribed, 19 g left adrenal adenoma. Values for serum testosterone, DHEA-S and 17β-estradiol (E 2) decreased markedly postoperatively. The in vivo biochemical findings were corroborated in vitro by incubation of tumor tissue slices and nontumorous adrenal cortex. The tumor was capable of secreting testosterone, cortisol, DHEA and E 2, but the capacity was greatest for testosterone, DHEA and E 2. Analysis of tissue homogenates also revealed the presence of testosterone, cortisol, DHEA and E 2. The pattern of steroid production suggests partial 21-hydroxylase deficiency and enhanced 17β-reductase activity.

17-HYDROXYPROGESTERONE IN THE COSYNTROPIN TEST: RESULTS IN NORMAL AND HIRSUTE WOMEN AND IN MILD CONGENITAL ADRENAL HYPERPLASIA

The variations in plasma cortisol, testosterone and 17-hydroxyprogesterone (17-OHP) induced by an im injection of 0.25 mg cosyntrophin were studied in three groups of subjects: 16 healthy women, 16 hirsute women (HW) and 10 mild cases of congenital adrenal hyperplasia (CAH). The basal values of cortisol and testosterone were comparable between the three groups. In the patients with mild CAH, the mean 17-OHP concentration was increased: 483.9 ng/100 ml (113-1200 ng), but it should be noted that the individual values could overlap with the normal concentrations found in the controls and the HW during the luteal phase of the cycle. One hour after the injection of cosyntropin, a massive response of 17-OHP was observed in the mild cases of CAH, the mean basal concentration was multiplied by ten: 4843 ng/100 ml. The minimum concentration reached was 1740 ng/100 ml which is still 3-fold the highest level seen either in normal women (400 ng/ml) or in hirsute women (550 ng/100 ml). Determination of 17-OHP following a short-term ACTH stimulation, therefore provides evidence of partial 21-hydroxylase deficiency.