Excess Production Of Adrenal Androgens Research Articles

PSAT028 Congenital Adrenal Hyperplasia with Adrenal Myelolipoma: Gender Identity and Choice of Therapy

Abstract Background Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder characterized by impaired glucocorticoid and mineralocorticoid synthesis with excessive adrenal androgen production. In affected females, most forms of CAH lead to virilization. Persons with CAH have a higher prevalence of adrenal myelolipomas compared with the general population. Clinical case A 38-year-old Spanish speaking individual who identified as male presented with headache and chest pain. Imaging revealed diffuse nodular thickening and enlargement of the right adrenal gland consistent with hyperplasia as well as 11 cm multilobulated left adrenal lesion containing macroscopic fat and soft tissue consistent with myelolipoma. A small uterus posterior to the bladder and presumed ovaries were also visualized with no visualization of prostate, spermatic cord or testicles. He reported a brother with a childhood hormone condition leading to an attempt to raise as female, resulting in subjective distress and unhappiness. Our patient never had breast development, menstrual cycles, or recurrent abdominal pain. There was no history of adrenal crisis, lightheadedness, or syncope and no hyperpigmentation on exam. He recalled salt craving as a child. Genital exam was refused by the patient. Labs demonstrated plasma cortisol 4.5 mcg/dl (6-18.4), ACTH 123 pg/ml (7-63), serum aldosterone 30 ng/dl (<=21), plasma renin activity 3.0 ng/ml/h (<=0.6-4.3), sodium 139 mEq/l (135-145) and potassium 4.2 mEq/l (3.5-5). The 17-hydroxyprogesterone concentration was 16,713 ng/dl (<=138), androstenedione was 36.52 ng/ml (0.33-1.34), and total testosterone was 621 ng/dl (male reference range 249-836). Based on the above findings and clinical history, his biologic sex was strongly felt to be female. A decision had to made regarding the need for glucocorticoid therapy and for possible adrenalectomy for the large myelolipoma. Because he had no symptoms of adrenal insufficiency and quite content with his gender identity, neither hormone therapy nor surgical intervention were performed. As of 8 months after presentation, he reported on going health and well-being. We recommended follow-up adrenal imaging and discussed glucocorticoid coverage for possible future stress conditions and educated him for this potential need. Discussion This case is unusual in that he was asymptomatic for adrenal insufficiency yet maintained male gender identity into adulthood. His adrenal myelolipoma likely developed from untreated CAH. We felt that treating with steroids and/or resecting his adrenal gland might well suppress ACTH and adrenal androgen production which would be detrimental to his gender identity and quality of life. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Increased Prevalence of Elevated DHEAS in PCOS Women with Non-Classic (B or C) Phenotypes: A Retrospective Analysis in Patients Aged 20 to 29 Years.

It is well known that a subgroup of women with PCOS present an excessive adrenal androgen production, generally associated with ovarian hyperandrogenism. In the past, it has been impossible to correlate adrenal hyperandrogenism to any clinical or hormonal pattern of PCOS. However, adrenal androgens are strictly dependent on age and their blood values reduce by 40% in patients moving from their twenties to thirties. Due to this, serum DHEAS values are strongly influenced by the age distribution of studied populations. To avoid this bias, in this study we retrospectively analyzed the clinical and hormonal data of PCOS women in their twenties (age between 20 and 29 years). Data of 648 young hyperandrogenic women with PCOS were evaluated. Serum DHEAS was increased in a third (33%) of studied patients and was associated with higher values of testosterone (T) and androstenedione (A). In each phenotype, patients with high DHEAS had higher values of T and A than patients with normal DHEAS of the same phenotype. Therefore, a DHEAS increase is generally part of a generalized higher androgen production in a subgroup of PCOS patients, independently of the finding of anovulatory or ovulatory cycles or of polycystic or normal ovaries. However, our study showed some important differences between PCOS phenotypes. A lower prevalence of increased DHEAS in A phenotype PCOS patients who generally have the highest androgen levels, versus non-classic (B or C) PCOS phenotypes, was observed. It was also found that patients with A phenotype PCOS present significantly lower BMI and serum insulin than patients with normal DHEAS of the same phenotype while, in patients with the B or C phenotype, the opposite occurs. We conclude that adrenal hyperandrogenism is more common in patients with non-classic (B and C) phenotypes of PCOS and is generally part of a generalized higher production of androgens in a subgroup of PCOS patients. However, other factors may increase the adrenal androgen production and influence the clinical expression of the syndrome. More studies in large, selected for age, populations of PCOS women with different phenotypes are needed.

MON-183 Adrenal Androgen Control and Steroidal Side Effects in Adolescents and Adults with Congenital Adrenal Hyperplasia Treated with Glucocorticoids

Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a rare autosomal recessive disorder that results in little or no cortisol biosynthesis, increased production of precursor steroids, and excess production of adrenal androgens. Glucocorticoid (GC) treatment, the current standard of care for CAH, is used to correct cortisol deficiency and reduce excessive androgens. Elevated 17-hydroxyprogesterone (17OHP) is used for diagnosis and management. GC titration to achieve 17OHP <1000 ng/dL may be targeted for adrenal androgen control; however, patients with 17OHP <1000 ng/dL might be at risk for complications of long-term GC excess. This real-world study evaluated adrenal androgen levels and potential GC complications in adolescents and adults with CAH. Methods: TriNetX, a research network that includes electronic medical records from >37 million U.S. patients, was searched on 30Aug2019 for patients who met the following criteria: diagnosis code of E25.0 (ICD-10) or 255.2 (ICD-9); history of GC use; available 17OHP laboratory result; and ≥15 years of age (“grown”) at the most recent 17OHP assessment. Patients were categorized as “adequately controlled” (17OHP <1000 ng/dL) or “poorly controlled” (17OHP ≥1000 ng/dL). Assessments included: demographics; laboratory results for 17OHP, adrenocorticotropic hormone (ACTH), and androstenedione (A4); and low-density lipoprotein (LDL). Adequately vs. poorly controlled groups were compared using Chi-square tests and t-tests. Results: Of 511 grown CAH patients, 352 were adequately controlled and 159 were poorly controlled. Mean concentrations for 17OHP were 244 and 5939 ng/dL in the adequately and poorly controlled cohorts, respectively (p<0.01). Adequately controlled patients also had lower ACTH and A4 than poorly controlled patients: ACTH (72 vs 389 pg/mL, p<0.01); A4 (82 vs 256 ng/dL, p<0.01). Compared to poorly controlled patients, adequately controlled patients were more likely to be female (81% vs 57%, p<0.01) and older (mean birth year: 1981 vs 1986, p<0.01). Adequately controlled patients also had evidence of more metabolic and infection complications, including higher mean LDL (105 vs 94.3 mg/dL, p=0.02), more type 2 diabetes mellitus (9% vs 4%, p=0.08), and more respiratory tract infections (21% vs 11%, p=0.01). Conclusions: In this retrospective analysis, patients with adequately controlled CAH (17OHP <1000 ng/dL) had better adrenal androgen control (lower A4) but also higher rates of complications potentially related to excessive GC exposure. These findings highlight the current challenges of managing CAH with GC regimens alone.

Polycystic Ovary Syndrome: An Apparently Simple yet Challenging Diagnosis.

Polycystic Ovary Syndrome: An Apparently Simple yet Challenging Diagnosis.

Hormonal hypertension in children: 11beta-hydroxylase deficiency and apparent mineralocorticoid excess.

Blood pressure is determined by the product of cardiac output, intravascular volume, and peripheral resistance. Because hormones are involved in blood pressure regulation and affect these parameters, hypertension is a prominent feature of certain adrenal enzymatic abnormalities. In this report, two steroid-dependent forms of genetic low-renin hypertension are examined: 11beta-hydroxylase deficiency and apparent mineralocorticoid excess. 11beta-Hydroxylation is an enzymatic function necessary for the biosynthesis of cortisol by the zona fasciculata (ZF) of the adrenal cortex. Defects in this step lead to the abnormally increased production by the ZF of the steroid 11-deoxycorticosterone (DOC), a moderately potent mineralocorticoid, which causes sodium retention and volume expansion that result in hypertension. Further, the excess production of adrenal androgens leads to virilization, prenatally in the genetic female, and postnatally in both sexes. The disorder of 11beta-hydroxylase deficiency is due to an autosomal recessive defect of the enzyme protein-encoding gene CYP11B1. Numerous mutations in CYP11B1 causing 11beta-hydroxylase deficiency have been characterized. Apparent mineralocorticoid excess is a potentially fatal genetic disorder causing severe juvenile hypertension, pre- and postnatal growth failure, and low to undetectable levels of potassium, renin, and aldosterone. It is caused by autosomal recessive mutations in the HSD11B2 gene, which result in a deficiency of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2).

11β-hydroxyandrostenedione and δ 5-androstenediol as markers of adrenal androgen production in patients with 21-hydroxylase–deficient nonclassic adrenal hyperplasia

Objective: To determine the sensitivity of 11β-hydroxyandrostenedione (11-OHA4) and Δ 5-androstenediol (ADIOL) as markers of excessive adrenal androgen production. Design: Prospective study. Setting: Academic medical centers. Patient(s): Thirteen women with untreated 21-hydroxylase–deficient nonclassic adrenal hyperplasia (NCAH) and 18 healthy, eumenorrheic, nonhirsute controls matched for age and body mass index. Intervention(s): All subjects were studied before and after acute adrenal stimulation with 0.25 mg of IV ACTH-(1–24). Main Outcome Measure(s): Basal levels of total testosterone, sex hormone-binding globulin, DHEAS, and free testosterone were measured. Levels of androstenedione (A4), DHEA, 11-OHA4, and ADIOL were determined before (Steroid 0) and 60 minutes after (Steroid 60) acute ACTH-(1–24) stimulation. Result(s): Patients with NCAH had higher median basal levels of DHEAS and total and free testosterone than controls. Patients with NCAH had higher median A4 0, A4 60, DHEA 0, DHEA 60, 11-OHA4 0, ADIOL 0, and ADIOL 60 levels but similar 11-OHA4 60 levels compared with controls. Among patients with NCAH, 30%, 54%, 15%, and 85% had 11-OHA4 0, ADIOL 0, 11-OHA4 60, and ADIOL 60 levels, respectively, above the 95th percentile of controls. Conclusion(s): Overall, serum levels of 11-OHA4 did not appear to be a very sensitive marker of excessive adrenal androgen production, at least in patients with NCAH. Although ACTH-stimulated ADIOL levels were elevated in 85% of the patients studied, they did not appear to have any advantage over the measurement of A4 or DHEA levels.

Congenital Adrenal Hyperplasia: Is there an Effect on Penile Growth?

Purpose Experimental evidence in rodents suggests that prepubertal exposure to excess androgens may prematurely down regulate the penile androgen receptor and cause micropenis in adulthood. To evaluate the effect of prepubertal androgens on human penile growth we reviewed phallic development in male patients with congenital adrenal hyperplasia. Materials and Methods We retrospectively reviewed the records of 12 patients with hydroxylase deficiency. Stretched penile length was recorded at diagnosis and at last followup. Bone age, height and weight were recorded at each visit. Results At diagnosis mean z-score for stretched penile length (z-score equals the number of standard deviations above or below the mean, that is z-score for micropenis equals -2.5) was 2.95 (1.23 to 4.88). Final mean z-score for stretched penile length in adulthood was -1.70 (-2.96 to 1.87). Mean decrease in z-score from diagnosis until the last followup was -4.68 (-1.08 to -6.82). Only 2 of the 12 patients (17 percent) had micropenis in adulthood. Notably excessive adrenal androgen production resulted in diminutive stature with median height in adulthood in the 10th percentile. Conclusions These findings suggest that excessive prepubertal androgen exposure due to congenital adrenal hyperplasia is associated with a reduction in adult somatic height but it does not routinely result in micropenis.

Adrenal androgen production in polycystic ovary syndrome

Secondary PCOS may occur in association with disorders characterized by adrenal androgen excess, e.g. congenital adrenal hyperplasia. Primary PCOS is associated frequently with more subtle abnormalities in adrenal androgen status. However, it has not been established that the mild adrenal androgen occurring in PCOS is causally involved in the development of PCOS, although adrenal hyperresponsiveness to stimulation appears to be characteristic of PCOS. It remains to be clarified whether this is due to excess stimulation of the adrenal by the putative CASH, which with ACTH probably coordinates adrenal androgen steroidogenesis, or whether adrenal hyperresponsiveness occurs as a consequence of increased cortisol clearance with compensatory hypersecretion of ACTH, which is associated with excessive adrenal androgen production. The possibility also exists that the enzyme system responsible for 17-hydroxyprogesterone production and its conversion to androgens is excessively active and may occur as a common defect in the adrenal and ovaries as a consequence of a congenital disorder. For at least some patients, treatment with a nocturnal low-dose glucocorticoid is an effective form of treatment. Indeed, this is the only hormonal form of treatment for hirsutism that also facilitates fertility and pregnancy. It is possible that PCOS may occur as a consequence of any disorder in which anovulation is associated with normal or elevated oestrogen levels. For some patients with PCOS, mild adrenal androgen excess is probably primary to development of the disorder. Thus, a trial of treatment with low-dose glucocorticoid at night appears to be a reasonable option in susceptible patients who can probably be recognized by demonstration of an excessive androgen response to ACTH or metyrapone.

Isolated dehydroepiandrosterone sulphate hypersecretion: A case report

The case of a 17-year-old male with isolated hypersecretion of dehydroepiandrosterone sulphate (DHEAS) is described. Cushing syndrome, congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency, an androgen producing adrenal tumour, and elevated plasma DHEAS due to an increased renal threshold were excluded. Selective renal vein catheterization confirmed bilateral, isolated adrenal DHEAS hypersecretion. The dexamethasone suppression suggests a functional nature of this alteration. This condition has to be considered in the differential diagnosis of excessive adrenal androgen production in males, or of hirsutism in females.

Adrenal abnormalities in idiopathic hirsutism.

The possibility that abnormal adrenal androgen production may be present in patients with idiopathic hirsutism was examined. Plasma testosterone, dihydrotestosterone and androstenedione levels were elevated in hirsute patients. In response to exogenous alpha 1-24 ACTH the increments in plasma androstenedione, dehydroepiandrosterone (DHA) and cortisol were significantly greater in hirsute patients than in normal subjects. The testosterone response was exaggerated following endogenous stimulation induced by metyrapone. Treatment with dexamethasone, 0.5 mg each night for 3 months, corrected both the androgen excess and the exaggerated androgen responses but not the excessive cortisol response to stimulation. These observations indicate adrenal abnormalities in idiopathic hirsutism. The dissociation of cortisol and adrenal androgen responsiveness following dexamethasone suggests that the abnormalities observed may be due to excessive adrenal androgen production stimulated by a dexamethasone-suppressible factor other than ACTH. Excess adrenal androgen production may be the primary disorder leading to the development of idiopathic hirsutism.

Circulating levels of plasma adrenocorticotropin in polycystic ovary disease.

Excessive adrenal androgen production contributes to hyperandrogenism in polycystic ovarian disease (PCO). This study was performed to determine the concentration of basal plasma ACTH in PCO patients and normal women and correlate its level with that of circulating adrenal androgen. In PCO patients, significant increases in serum testosterone, androstenedione, and dehydroepiandrosterone sulfate were noted compared to levels in normal women. The mean circulating plasma ACTH in PCO patients (22 +/- 2 pg/ml) was not different from that in normal controls (20 +/- 2 pg/ml). The mean ratio of dehydroepiandrosterone sulfate to ACTH in individual PCO patients was significantly greater than that in normal subjects, whereas the cortisol to ACTH ratio was similar in both groups. These results suggest that increased adrenal androgen production in PCO patients is not due to abnormal ACTH secretion but arises from either altered adrenal responsiveness to ACTH or abnormal adrenal stimulation by a factor(s) other than ACTH.

ROENTGENOLOGY OF THE CONGENITAL ADRENOGENITAL SYNDROME.

The congenital adrenogenital syndrome is a hereditary form of hyperadrenal corticism present at birth. The basic abnormality is an enzymatic defect in cortisol synthesis, resulting in adrenal hyperplasia and excessive adrenal androgen production. The three basic clinical types are: (1) simple virilism, (2) virilism and adrenal insufficiency, and (3) virilism and hypertension.Although there are no pathognomonic roentgen findings several features are present which characterize patients with this disease. Six of a series of 43 cases are briefly reported to show some of these roentgen features.Approximately 6o per cent of patients are of the type with simple virilism. Accelerated maturation is reflected roentgenographically in the skeleton, teeth, and muscular tissue. Five patterns of genital malformations in the female are listed, some of which can be best defined by roentgen analysis.One-third of the cases have virilism and adrenal insufficiency. These patients present in early infancy with roentgen signs o...

The adrenogenital syndrome in children.

Although the adrenogenital syndrome has been known for about 150 years, it was not until 1950 when Wilkins et al. succeeded in suppressing the excessive adrenal androgen production with cortisone, that a better understanding of the abnormal adrenal function and its treatment was obtained.

ADRENOGENITAL SYNDROME WITH ASSOCIATED EPISODES OF HYPOGLYCEMIA

THE adrenogenital syndrome is a type of hyperadrenocorticism characterized by excess production of adrenal androgens. When it occurs congenitally it is due to hyperplasia of the adrenal glands, and is manifested as pseudohermaphrodism in females and macrogenitosomia praecox in males. Wilkins (1) has recently described the syndrome and collected 99 such cases from the literature and his own observations. A postnatal variety of adrenogenital syndrome also occurs, and is caused usually by adrenal tumors. Forty-one cases are mentioned by Wilkins (1). Wilkins, Fleischmann, and Howard (2) and Butler, Ross and Talbot (3) in 1939 first described cases of adrenogenital syndrome in which Addisonian symptoms of acute adrenal insufficiency occurred. Zuelzer and Blum (4) recently collected 17 such cases from the literature and added 4 of their own. Since their review, 2 cases have been reported by DeJong and Schaberg (5), 1 case by Chenoweth (6), and 1 case by the New York Hospital group (7). At least 3 and possibly m...