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Open access

Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia

Alessandro Prete, Richard J Auchus, and Richard J Ross

Background

Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid.

Methods

Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia.

Summary

Therapies in clinical development target different levels of the hypothalamo–pituitary–adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients.

Conclusions

CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

Free access

Abiraterone acetate treatment lowers 11-oxygenated androgens

Connor Wright, Patrick O’Day, Mohammed Alyamani, Nima Sharifi, and Richard J Auchus

Context

The human adrenal is the dominant source of androgens in castration-resistant prostate cancer (CRPC) and classic 21-hydroxylase deficiency (21OHD). Abiraterone, derived from the prodrug abiraterone acetate (AA), inhibits the activity of cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1), the enzyme required for all androgen biosynthesis. AA treatment effectively lowers testosterone and androstenedione in 21OHD and CRPC patients. The 11-oxygenated androgens are major adrenal-derived androgens, yet little is known regarding the effects of AA administration on 11-oxygenated androgens.

Objective

To test the hypothesis that AA therapy decreases 11-oxygenated androgens.

Design

Samples were obtained from 21OHD or CRPC participants in AA or AA plus prednisone (AAP)-treatment studies, respectively.

Methods

We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the 11-oxygenated androgens, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone, in plasma or serum samples from six 21OHD and six CRPC patients before and after treatment with AA or AAP, respectively.

Results

In CRPC patients, administration of AAP (1000 mg/day AA with prednisone and medical castration) lowered all four 11-oxygenated androgens to below the lower limits of quantitation (<0.1–0.3 nmol/L), equivalent to 64–94% reductions from baseline. In 21OHD patients, administration of AA (100–250 mg/day for 6 days) reduced all 11-oxygenated androgens by on average 56–77% from baseline.

Conclusions

We conclude that AA and AAP therapies markedly reduce the production of the adrenal-derived 11-oxygenated androgens, both in patients with high (21OHD) or normal (CRPC) 11-oxygenated androgens at baseline, respectively. Reduction of 11-oxygenated androgens is an important aspect of AA and AAP pharmacology.

Free access

Puberty in a case with novel 17-hydroxylase mutation and the putative role of estrogen in development of pubic hair

Serap Turan, Abdullah Bereket, Tulay Guran, Teoman Akcay, Mahboubeh Papari-Zareei, and Richard J Auchus

Objective

17-Hydroxylase/17,20-lyase deficiency (17OHD) results from mutations in the CYP17A1 gene, leading to failure to synthesize cortisol, adrenal androgens, and gonadal steroids. Adrenarche is a consequence of the increased production of adrenal androgens. Here, we report a case carrying novel R239Q mutation causing complete functional loss of CYP17A1, and thus absence of adrenal and gonadal sex hormone production. The patient has had unexpected pubic hair development and insufficient breast development with estrogen replacement therapy. Possible mechanisms leading to pubic hair development and breast underdevelopment are discussed.

Patient and methods

A 15-year-old female born to consanguineous parents presented with the lack of full breast development and irregular menses after the age of 14 years. She had Tanner III breast development on one side, Tanner I on the other side and Tanner I pubic hair and, no axillary hair development. The serum levels of FSH, LH, and progesterone were high and, estradiol was low. The measurement of basal and ACTH-stimulated steroids was consistent with the diagnosis of 17OHD. Genetic analysis revealed novel homozygous mutation R239Q in CYP17A1 gene. Therapy with hydrocortisone was initiated and followed by the addition of conjugated estrogen. Her breast development did not improve considerably, however, pubic hair development started after estrogen treatment in spite of undetectable serum levels of androgens.

Conclusion

This case study suggests that estrogen exerts a permissive effect on pubic hair development in girls, even in the presence of very low-circulating androgens, and impaired breast development might be due to estrogen/progesterone imbalance in breast tissue.

Free access

Gene expression profiles in aldosterone-producing adenomas and adjacent adrenal glands

Tao Wang, Fumitoshi Satoh, Ryo Morimoto, Yasuhiro Nakamura, Hironobu Sasano, Richard J Auchus, Michael A Edwards, and William E Rainey

Background

Primary aldosteronism (PA) is the most common form of endocrine hypertension affecting ∼8–10% of hypertensive subjects. Aldosterone production in PA occurs under low-renin conditions, and the mechanisms that maintain the production of aldosterone in PA remain unknown.

Objective

This study was designed to compare the transcript profiles between aldosterone-producing adenoma (APA) and their adjacent adrenal gland (AAG) from the same adrenal.

Methods

Total RNA was extracted from ten APA and ten AAG; and subsequently analyzed by microarray and real-time quantitative RT-PCR (qPCR). The microarray data were paired for each APA–AAG, and analyzed by GeneSpring GX 11 with paired t-test and fold change calculations for each transcript. Changes identified by microarray analysis were confirmed by qPCR.

Results

Microarray analysis indicated that 14 genes had significantly up-regulated expression in APA compared to AAG. Among the elevated genes were aldosterone synthase (CYP11B2) as well as novel transcription factors, calmodulin-binding proteins, and other genes that have not been previously studied in APA. Selective analysis of 11 steroidogenic enzymes using microarray demonstrated that only CYP11B2 showed a significantly higher transcript level in APA compared to AAG (P<0.001). In contrast, AKR1C3 (17β-hydroxysteroid dehydrogenase type 5), CYP17 (17α-hydroxylase/17,20 lyase), and CYB5 (cytochrome b5) showed significantly lower transcript level in APA (P<0.05).

Conclusion

The transcriptome analysis of APA compared with AAG showed several novel genes that are associated with APA phenotype. This gene list provides new candidates for the elucidation of the molecular mechanisms leading to PA.

Free access

Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men

Adina F Turcu, Lili Zhao, Xuan Chen, Rebecca Yang, Juilee Rege, William E Rainey, Johannes D Veldhuis, and Richard J Auchus

Background

Many hormones display distinct circadian rhythms, driven by central regulators, hormonal bioavailability, and half-life. A set of 11-oxygenated C19 steroids (11-oxyandrogens) and pregnenolone sulfate (PregS) are elevated in congenital adrenal hyperplasia and other disorders, but their circadian patterns have not been characterized.

Participants and methods

Peripheral blood was collected every 2 h over 24 h from healthy volunteer men (10 young, 18–30 years, and 10 older, 60–80 years). We used mass spectrometry to quantify 15 steroids, including androstenedione (A4), testosterone (T), 11β-hydroxy- and 11-ketotestosterone (11OHT, 11KT),11β-hydroxy- and 11-ketoandrostenedione (11OHA4, 11KA4), and 4 ∆5-steroid sulfates. Diurnal models including mesor (rhythm adjusted median), peak, and nadir concentrations, acrophase, and amplitude were computed.

Results

11OHA4 followed a rhythm similar to cortisol: acrophase 8:00 h, nadir 21:00 h and were similar in young and old men. 11KT had similar diurnal patterns, but the peak was lower in older than in young men, as was the case for A4. All four steroid sulfates were higher in young vs older men. PregS and 17-hydroxypregnenolone sulfate (17OHPregS) showed sustained elevations between 8:00 and 18:00 h, and nadirs around midnight, while DHEAS and AdiolS displayed minimal diurnal variations. All 4 11-oxyandrogens correlated tightly with cortisol (r from 0.54 for 11OHT to 0.81 for 11OHA4, P  < 0.0001 for all), but very weakly with T, supporting their adrenal origin and ACTH governance.

Conclusions

11-Oxyandrogens, PregS, and 17OHPregS display distinct circadian and age variations, which should be accounted for when used as clinical biomarkers.

Free access

Androgen excess and diagnostic steroid biomarkers for nonclassic 21-hydroxylase deficiency without cosyntropin stimulation

Adina F Turcu, Diala El-Maouche, Lili Zhao, Aya T Nanba, Alison Gaynor, Padma Veeraraghavan, Richard J Auchus, and Deborah P Merke

Free access

Androgen excess and diagnostic steroid biomarkers for nonclassic 21-hydroxylase deficiency without cosyntropin stimulation

Adina F Turcu, Diala El-Maouche, Lili Zhao, Aya T Nanba, Alison Gaynor, Padma Veeraraghavan, Richard J Auchus, and Deborah P Merke

Objectives

The clinical presentation of patients with nonclassic 21-hydroxylase deficiency (N21OHD) is similar with that for other disorders of androgen excess. The diagnosis of N21OHD typically requires cosyntropin stimulation. Additionally, the management of such patients is limited by the lack of reliable biomarkers of androgen excess. Herein, we aimed to: (1.) compare the relative contribution of traditional and 11-oxyandrogens in N21OHD patients and (2.) identify steroids that accurately diagnose N21OHD with a single baseline blood draw.

Design

We prospectively enrolled patients who underwent a cosyntropin stimulation test for suspected N21OHD in two tertiary referral centers between January 2016 and August 2019.

Methods

Baseline sera were used to quantify 15 steroids by liquid chromatography-tandem mass spectrometry. Logistic regression modeling was implemented to select steroids that best discriminate N21OHD from controls.

Results

Of 86 participants (72 females), median age 26, 32 patients (25 females) had N21OHD. Age, sex distribution, and BMI were similar between patients with N21OHD and controls. Both testosterone and androstenedione were similar in patients with N21OHD and controls, while four 11-oxyandrogens were significantly higher in patients with N21OHD (ratios between medians: 1.7 to 2.2, P < 0.01 for all). 17α-Hydroxyprogesterone (6.5-fold), 16α-hydroxyprogesterone (4.1-fold), and 21-deoxycortisol (undetectable in 80% of the controls) were higher, while corticosterone was 3.6-fold lower in patients with N21OHD than in controls (P < 0.001). Together, baseline 17α-hydroxyprogesterone, 21-deoxycortisol, and corticosterone showed perfect discrimination between N21OHD and controls.

Conclusions

Adrenal 11-oxyandrogens are disproportionately elevated compared to conventional androgens in N21OHD. Steroid panels can accurately diagnose N21OHD in unstimulated blood tests.

Free access

Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency

Adina F Turcu, Aya T Nanba, Robert Chomic, Sunil K Upadhyay, Thomas J Giordano, James J Shields, Deborah P Merke, William E Rainey, and Richard J Auchus

Abstract

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.

Open access

Long-term outcomes of osilodrostat in Cushing’s disease: LINC 3 study extension

Maria Fleseriu, John Newell-Price, Rosario Pivonello, Akira Shimatsu, Richard J Auchus, Carla Scaroni, Zhanna Belaya, Richard A Feelders, Greisa Vila, Ghislaine Houde, Rama Walia, Miguel Izquierdo, Michael Roughton, Alberto M Pedroncelli, and Beverly M K Biller

Objective

To investigate the long-term efficacy and tolerability of osilodrostat, a potent oral 11β-hydroxylase inhibitor, for treating Cushing’s disease (CD).

Design/methods

A total of 137 adults with CD and mean 24-h urinary free cortisol (mUFC) > 1.5 × upper limit of normal (ULN) received osilodrostat (starting dose 2 mg bid; maximum 30 mg bid) during the prospective, Phase III, 48-week LINC 3 (NCT02180217) core study. Patients benefiting from osilodrostat at week 48 could enter the optional extension (ending when all patients had received ≥ 72 weeks of treatment or discontinued). Efficacy and safety were assessed for all enrolled patients from the core study baseline.

Results

Median osilodrostat exposure from the core study baseline to study end was 130 weeks (range 1–245) and median average dose was 7.4 mg/day (range 0.8–46.6). The reduction in mean mUFC achieved during the core was maintained during the extension and remained ≤ ULN. Of 106 patients, 86 (81%) patients who entered the extension had mUFC ≤ ULN at week 72. Improvements in cardiovascular/metabolic-related parameters, physical manifestations of hypercortisolism (fat pads, central obesity, rubor, striae, and hirsutism in females), and quality of life in the core study were also maintained or improved further during the extension. No new safety signals were reported; 15/137 (10.9%) and 12/106 (11.3%) patients discontinued for adverse events during the core and extension, respectively. Mean testosterone in females decreased towards baseline levels during the extension.

Conclusions

Data from this large, multicentre trial show that long-term treatment with osilodrostat sustains cortisol normalisation alongside clinical benefits in most patients with CD and is well tolerated.

Open access

Levoketoconazole treatment in endogenous Cushing’s syndrome: extended evaluation of clinical, biochemical, and radiologic outcomes

Maria Fleseriu, Richard J Auchus, Yona Greenman, Sabina Zacharieva, Eliza B Geer, Roberto Salvatori, Rosario Pivonello, Ulla Feldt-Rasmussen, Laurence Kennedy, Michael Buchfelder, Beverly MK Biller, Fredric Cohen, and Anthony P Heaney

Objective

This extended evaluation (EE) of the SONICS study assessed the effects of levoketoconazole for an additional 6 months following open-label, 6-month maintenance treatment in endogenous Cushing’s syndrome.

Design/Methods

SONICS included dose-titration (150–600 mg BID), 6-month maintenance, and 6-month EE phases. Exploratory efficacy assessments were performed at months 9 and 12 (relative to the start of maintenance). For pituitary MRI in patients with Cushing’s disease, a threshold of ≥2 mm denoted change from baseline in the largest tumor diameter.

Results

Sixty patients entered EE at month 6; 61% (33/54 with data) exhibited normal mean urinary free cortisol (mUFC). At months 9 and 12, respectively, 55% (27/49) and 41% (18/44) of patients with data had normal mUFC. Mean fasting glucose, total and LDL-cholesterol, body weight, BMI, abdominal girth, hirsutism, CushingQoL, and Beck Depression Inventory-II scores improved from the study baseline at months 9 and 12. Forty-six patients completed month 12; four (6.7%) discontinued during EE due to adverse events. The most common adverse events in EE were arthralgia, headache, hypokalemia, and QT prolongation (6.7% each). No patient experienced alanine aminotransferase or aspartate aminotransferase >3× upper limit of normal, Fridericia-corrected QT interval >460 ms, or adrenal insufficiency during EE. Of 31 patients with tumor measurements at baseline and month 12 or follow-up, the largest tumor diameter was stable in 27 (87%) patients, decreased in one, and increased in three (largest increase 4 mm).

Conclusion

In the first long-term levoketoconazole study, continued treatment through a 12-month maintenance period sustained the early clinical and biochemical benefits in most patients completing EE, without new adverse effects.