Crinecerfont: First Approval.

Disclosure: E. Silverstein: None. C. Eliazo: None. A. Diaz: None. Introduction: Classic congenital adrenal hyperplasia (CAH) is a rare condition affecting 1:16,000 newborns and is characterized by elevated testosterone levels from abnormal production of cortisol. Mutations of the CYP21A2 gene are the most common cause of CAH and can present as mild cases: non-classic/late onset CAH, or severe forms, as in classic CAH. Classic CAH can be simple virilizing or salt-wasting types, the latter, a life-threatening condition if not diagnosed soon after birth. In the U.S., screening for CAH is included on newborn screening; however, this evaluation is not often done in developing countries. Lack of early diagnosis and, in some cases surgical intervention, can be life threatening. Case report: We present the case of a 16-year-old girl born in rural Honduras and assigned as male at birth based on her male-appearing genitalia: a normal-sized and formed phallus with bilateral cryptorchidism. During infancy, this child had recurrent hospitalizations due to severe dehydration, hyponatremia, and hypotension. At 4-months of life, she was transferred to Tegucigalpa, the country's capital, and diagnosed with salt-wasting CAH. At that time, the family was asked to change her name and her gender to female, and she was started on hydrocortisone and fludrocortisone. The family moved to the U.S. when the child was 7 months old; and at that time, she was evaluated by endocrinology. A karyotype was reported as 46, XX and molecular analysis confirmed the diagnosis of CAH (Intron-2 deletions: homozygous in CYP21A2). Although legally the child appears as a male with a masculine name, the family raised her as a girl and socially changed her name. Due to non-typical gender behavior, a gender role evaluation was done by psychology at 8 years of age. However, due to learning difficulties, this evaluation was inconclusive; she identified as a girl, which matches her gender expression. Upon physical examination she has a Tanner V phallus with the urethral opening at the tip (Prader V) and bilateral cryptorchidism. She reached menarche at age 11 and has monthly bleeding through the urethra. She has been evaluated by urology and underwent cystourethroscopy and vaginogram, which showed bladder diverticula. She has had multiple urinary tract infections, some with septic shock, requiring PICU admissions. Due to lack of insurance, surgical repair is not possible. She receives prophylactic antibiotics with suboptimal compliance. Conclusion: Early CAH diagnosis is critical to prevent severe medical and social complications. While the timing of genital surgery in children with differences in sex development remains controversial, multidisciplinary evaluation is critical, especially for CAH patients, to minimize severe complications. Many adult patients report preferring genital surgery in early childhood. Unfortunately, lack of insurance coverage and surgical costs hinder access to care in the U.S. Presentation: Monday, July 14, 2025

Disclosure: O. Lekarev: Consultant for Neurocrine Biosciences and Eton Pharmaceuticals; medical and scientific advisory board for CARES Foundation. A. Erkin-Cakmak: None. M.G. Vogiatzi: Research support and consulting for Neurocrine, Spruce, Crinetics and Adrenas. E.A. Imel: Received clinical trial research funds and consulted for Neurocrine Biosciences; received clinical trial research funds from Spruce. M. Clemente: None. R. Coutant: None. G.B. Rosales: Full-time employee of Neurocrine Biosciences, Inc. E. Roberts: Full-time employee of Neurocrine Biosciences, Inc. G.S. Jeha: Full-time employee of Neurocrine Biosciences, Inc. R.H. Farber: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc..Background: Crinecerfont, a corticotropin releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to glucocorticoid (GC) replacement to control androgens in patients with classic congenital adrenal hyperplasia (CAH). In two phase 3 trials, crinecerfont significantly reduced excess adrenal androgens, enabling subsequent reductions in GC doses in pediatric and adult patients with CAH. Objective: To analyze changes in androstenedione (A4) levels and GC doses while maintaining or improving A4 in subgroups of participants from the CAHtalyst™ Pediatric study (NCT04806451) of crinecerfont. Methods: Children and adolescents with CAH were randomized 2:1 to double-blind treatment with crinecerfont (25, 50, or 100 mg BID based on weight) or placebo for 28 weeks. GC doses were kept stable for the first 4 weeks to evaluate the impact on androgens and then reduced to a target of 8-10 mg/m2/d in hydrocortisone equivalents (HCe) by Week 28 while maintaining or improving A4 relative to Day 1 baseline (BL). Least squares (LS) mean changes from BL in A4 (before morning GC dose) at Week 4 and in GC dose at Week 28 were analyzed in the overall population and in subgroups defined by: region (US, outside US); sex (male, female); race (white, non-white); age (<12, 12-17 years); weight at BL (<55, ≥55 kg); body mass index (BMI) at BL (<85th, ≥85th percentile); pubertal stage at BL (Tanner stages 1-2, stages 3-5); A4 at BL (≤ULN [upper limit of normal], >ULN); and GC dose at BL (<16, ≥16 mg/m2/d HCe, for GC change only). Results: The study included 103 participants (crinecerfont, n=69; placebo, n=34). The mean age (±SD) was 12.1±3.5 years and 51% (n=53) were male. Mean A4 at BL was 431±461 ng/dL; mean GC dose was 16.4±3.9 mg/m2/d HCe. At Week 4, A4 was significantly reduced with crinecerfont but increased with placebo (-197 vs. +71 ng/dL; LS mean difference [LSMD]: -268 ng/dL; P=0.0002 [primary endpoint]). LSMDs of the point estimates for A4 change at Week 4 favored crinecerfont over placebo in all subgroups. At Week 28, GC dose was significantly reduced with crinecerfont (while maintaining or improving A4) but increased with placebo (-18.0% vs. +5.6%; LSMD: -23.5%; P<0.0001 [key secondary endpoint]). LSMDs of the point estimates for percent change in GC dose at Week 28 favored crinecerfont over placebo in all subgroups. For both A4 and GC, subgroup analyses were consistent with the primary and key secondary endpoint results in the overall population. Conclusion: Crinecerfont was effective in enabling GC dose reductions while maintaining or improving A4 in pediatric patients with CAH across all subgroups analyzed. These results demonstrate that pediatric patients with CAH can derive the androgen-lowering and GC-lowering benefits of crinecerfont treatment regardless of region, sex, race, age, weight/BMI, pubertal stage, or pretreatment A4 level or GC dose.Presentation: Saturday, July 12, 2025

Disclosure: G. Johannsson: AstraZeneca, Novo Nordisk, Pharmanovia, Pfizer, Inc., Takeda, Shire. A. Velusamy: Immunovant, Novo Nordisk, Samsung/Philips/Canon. A. Prete: Diurnal, Spruce, Recordati, Lundbeck. H. Falhammar: None. M.M. Binderup: None. K.G. Larsen: None. M. Folden Flensburg: None. J. Luthman: None. U. Srirangalingam: Crinetics Pharmaceuticals Inc, Diurnal, Lundbeck.Introduction: Classic congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency is a rare autosomal recessive disorder. The defect in cortisol biosynthesis leads to impaired negative feedback on the hypothalamus-pituitary-adrenal axis, elevated adrenocorticotropic hormone (ACTH), and consequent hyperandrogenemia. Supraphysiologic glucocorticoid (GC) dosing, often required to manage hyperandrogenemia, is associated with adverse long-term health outcomes. Lu AG13909 is a novel, high-affinity, anti-ACTH monoclonal antibody that inhibits ACTH-induced signaling. Nonclinical studies demonstrated that Lu AG13909 induces a significant and durable reduction of corticosterone and aldosterone in rats, and of cortisol and aldosterone in cynomolgus monkeys. Here, we present the results of a first-in-human trial investigating the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of Lu AG13909 in adults with classic CAH. Methods: This was a phase 1, open-label, multiple-ascending-dose trial with intra-participant dose escalation (NCT05669950). Eligible participants were men and women, aged ≥18 to ≤70 years, with classic CAH and pre-GC morning 17-hydroxyprogesterone (17-OHP) concentrations >4 times the upper limit of normal. Each participant received up to 6 doses of Lu AG13909 every 28 to 35 days at increasing dose levels, with stable GC therapy and mineralocorticoid replacement if needed. The trial consisted of 2 parts: Part A had a 3+3 design, in which 3 participants were given a certain dose level, and escalation to the next dose level was based on a 28-day safety observation period. Part B explored the pharmacologically relevant Lu AG13909 doses identified in Part A in a larger number of participants. The primary endpoints included adverse events; clinical safety; maximum observed exposure and area under the Lu AG13909 concentration-time curve in a dosing interval; and the relative reductions in morning 17-OHP and androstenedione (A4) concentrations from baseline to the day after each Lu AG13909 dose. Results: In total, 11 participants were enrolled (4 men, 7 women), with a mean age of 37 years (range: 21-58 years). At the Baseline Visit the geometric means for the concentrations of morning 17-OHP and A4 were 274 nmol/L (range: 100-1033 nmol/L) and 11.0 nmol/L (range: 3.9-49.5 nmol/L), respectively. Preliminary data (N=11) demonstrated clear pharmacodynamic effects following up to 6 intravenous infusions of Lu AG13909 at increasing doses, with consistent reductions in morning 17-OHP and A4 concentrations observed at all dose levels. No safety concerns were raised. Conclusions: The preliminary results of this phase 1 study show that Lu AG13909 is well-tolerated and can reduce adrenal androgen production, reinforcing continued clinical development of Lu AG13909 as a novel anti-ACTH treatment strategy for classic CAH.Presentation: Monday, July 14, 2025

Disclosure: N. Reisch: Crinetics Pharmaceuticals, Diurnal, Lundbeck A/S, Neurocrine Biosciences, Recordati Rare Diseases, Spruce Biosciences. R.J. Auchus: Neurocrine Biosciences, Diurnal, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals, Adrenas, Spruce Biosciences, Quest Diagnostics, Xeris Pharmaceuticals, Novo Nordisk, H Lundbeck A/S, Sparrow Pharmaceuticals. U. Srirangalingam: Crinetics Pharmaceuticals, Diurnal, H Lundbeck A/S. T.A. Bachega: Crinetics Pharmaceuticals, Spruce Biosciences, Novo Nordisk. A. Ayala: Crinetics. Y. Wu: Crinetics Pharmaceuticals. E. De La Torre Ames: Crinetics Pharmaceuticals. A. Krasner: Crinetics Pharmaceuticals. L. Kjems: Crinetics Pharmaceuticals. D.P. Merke: Diurnal, Neurocrine Biosciences, Adrenas Therapeutics through the National Institutes of Health Cooperative Research and Development Agreements. In classic congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency (21-OHD), normal steroidogenesis pathways are disrupted, leading to a decrease in cortisol and aldosterone levels and virilization due to excess adrenal androgens. Traditional biomarkers of disease activity include 17-hydroxyprogesterone (17-OHP) and androstenedione (A4). The adrenals produce 11β-hydroxyandrostenedione (11-OHA4), which is metabolized to the potent androgen 11-ketotestosterone (11-KT); these 11-oxygenated androgens substantially contribute to the total androgen burden in patients with CAH. Atumelnant, a first-in-class competitive and selective melanocortin type 2 receptor (adrenocorticotropic hormone receptor) antagonist, was assessed in a Phase 2, open-label, dose-finding study. Adults age ≥18-75 years with classic CAH taking stable doses of glucocorticoid (GC) replacement therapy (≥15 mg daily dose hydrocortisone equivalent) for ≥6 months and morning serum A4 level ≥1.5 times the upper limit of normal were enrolled in 3 dose cohorts of oral atumelnant, 40 mg, 80 mg, 120 mg once daily for 12 weeks. A total of 28 patients (40 mg, n=11; 80 mg, n=11; 120 mg, n=6) completed treatment; 54% were women; mean (range) age 31.3 (20-47) years; and mean (range) GC dose 28.9 (20-40) mg/day hydrocortisone equivalent. Baseline 11-OHA4 was mean (range) 997 (142-3128) ng/dL, and baseline 11-KT was mean (range) 303 (54-1292) ng/dL. At week 2, the mean (SE) percent change from baseline (CFB) in morning 11-OHA4 for the 40-, 80-, and 120-mg cohorts was −49% (9.8), −74% (6.9), and −85% (4.6), respectively; at week 12, CFB was −60% (10.8), −68% (11.4), and −82% (3.5), respectively. The mean (SE) percent CFB in morning 11-KT for the 40-, 80-, and 120-mg cohorts at week 2 was −40% (11.1), −56% (13.0), and −79% (7.3), respectively; at week 12, CFB was −58% (10.0), −58% (13.2), and −77% (7.2), respectively. In conclusion, atumelnant results in rapid and substantial reductions of 11-oxygenated androgens and the traditional biomarkers A4 and 17-OHP in patients with classic CAH. The reduction in total androgen burden may explain previously reported improvements in clinical outcomes within the 12-week time frame of this study. Presentation: Sunday, July 13, 2025

The CYP21A2 gene, which encodes the 21-hydroxylase enzyme, plays a critical role in glucocorticoid (GC) and mineralocorticoid synthesis by the adrenal cortex. CYP21A2 pathogenic variants cause 21-hydroxylase deficiency (21OHD), the most common type of CAH, characterized by variable degrees of adrenal insufficiency and androgen excess. Standard treatment of classic 21OHD consists of daily doses of GC and mineralocorticoid. However, suppressive GC doses are often required to reduce androgen excess, and it is often not possible to dose exogenous GC in a manner that provides adequate disease control while avoiding overtreatment. Disease-related and treatment-related comorbidities are common and include life-threatening adrenal crises, impaired growth and development during childhood, adult short stature, virilization in females, subfertility in both sexes, obesity and cardiovascular risk factors, and decreased bone mineral density. Novel treatment approaches are needed to address these challenges and a treatment that restores the ability of the adrenals to produce cortisol and aldosterone in a physiologically-regulated manner would be particularly helpful. Here we present the design and rationale of a clinical trial using BBP-631, an AAV5 gene replacement therapy for adults with classic CAH due to 21-OHD. This treatment approach is based on the demonstration that a single intravenous administration of BBP-631 corrects the enzyme deficiency in the H2-aw18 CYP21-/- CAH mouse model of 21OHD, including response to stress. This correction was robust, dose-dependent and durable. BBP-631 treatment also resulted in robust and durable expression of the human CYP21A2 transgene in the non-human primate adrenal cortex. BBP-631 appears to be safe and well-tolerated in mice with 21-OHD, healthy mice and non-human primates. Taken together, these data support initiating clinical trials in adults with classic CAH due to 21-OHD. The trial will sequentially enroll individuals in up to 3 successive dose-escalation cohorts. Each subject will receive a single dose of BBP-631 and safety will be assessed prior to dose escalation. Endogenous production rates of adrenal steroids (cortisol, 17-hydroxyprogesterone, androstenedione) will be determined pre- and post- dose, and their concentrations assessed over a 1-year period after which subjects will roll over into an extension study for at least 4 years. The Phase 1 study will determine the tolerability of a single dose of BBP-631. The magnitude and durability of BBP-631 and effects on adrenal steroids, ACTH and, where relevant, aldosterone levels will be monitored. The ability of BBP-631 to allow tapering of GC doses will also be explored. This first in human study of gene therapy for CAH represents a milestone in the development of novel and improved treatment approaches for patients with classic CAH.

Disclosure: N. Nokoff: Consultant for Neurocrine Biosciences, Inc.; expert panel member for World Athletics. K.B. Krishna: None. L. Antonio: Sandoz, Merck, Advisory board member for Simple Pharma. R.H. Farber: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc. J. Sturgeon: Full-time employee of Neurocrine Biosciences, Inc. G.B. Rosales: Full-time employee of Neurocrine Biosciences, Inc. G.S. Jeha: Full-time employee of Neurocrine Biosciences, Inc. V.H. Lin: Full-time employee of Neurocrine Biosciences, Inc. A.N. Dauber: Consultant and grant recipient for BioMarin and Pfizer; consultant for Novo Nordisk and QED Therapeutics. Background: Crinecerfont, a corticotropin releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to glucocorticoid (GC) replacement to control androgens in patients with classic congenital adrenal hyperplasia (CAH). In two phase 3 trials, crinecerfont significantly reduced excess adrenal androgens, enabling reductions in GC doses in pediatric and adult patients with CAH. Objective: To evaluate changes in GC regimens in patients with CAH treated with crinecerfont. Methods: Individuals with CAH were randomized to crinecerfont (25, 50, or 100 mg BID in CAHtalyst™ Pediatric [NCT04806451]; 100 mg BID in CAHtalyst Adult [NCT04490915]) or placebo. In both studies, GC was kept stable for the first 4 weeks to measure the impact on androgens and then reduced to a target of 8-10 mg/m2/d in hydrocortisone (HC) equivalents at the end of double-blind treatment (Week 28 [pediatric]; Week 24 [adult]) while maintaining or improving androstenedione (A4) relative to baseline (BL). Long-acting, synthetic GCs (dexamethasone [DEX], (methyl)prednis(ol)one [PRED]) and timing (bedtime dose) were to be decreased first. Changes in dosing frequency and GC regimens (switching from with PRED or DEX to without PRED or DEX) were evaluated with nominal P-values. Fludrocortisone was continued as needed. Results: In CAHtalyst Pediatric (N=103), mean GC dose at BL was 16.4 mg/m2/d; 92.2% were taking only HC (no DEX or PRED). Percent changes in GC dose at Week 28 while maintaining/improving A4 showed a decrease with crinecerfont but not placebo (least squares mean difference [LSMD]: -23.5%; P&amp;lt;0.0001 [key secondary endpoint]). In participants taking only HC at BL, reduction in dosing frequency by ≥1 dose/d at Week 28 was more common with crinecerfont (16.1% vs 3.6%; P=0.1087). In CAHtalyst Adult (N=182), mean GC dose at BL was 17.6 mg/m2/d (32.3 mg/d) and 58.2% were taking only HC; 29.1% were taking PRED±HC and 12.6% were taking DEX (±another GC). At Week 24, the percent reduction in GC dose while maintaining/improving A4 was greater with crinecerfont than placebo (LSMD: -17.0%; P&amp;lt;0.0001 [primary endpoint]). In participants taking only HC at BL, reduction in dosing frequency was more common with crinecerfont than placebo (36.5% vs 12.5%; P=0.0253). Switching from a DEX-containing regimen at BL to a DEX-free regimen at Week 24 was more common with crinecerfont (87.5% vs 40.0%; P=0.0740), as was switching from PRED±HC to HC only (32.4% vs 10.5%; P=0.0418). Conclusion: Patients with CAH who received crinecerfont for ∼6 months had greater mean decreases in GC doses while maintaining or improving A4 compared to placebo. HC dosing frequency was more likely to decrease with crinecerfont, as was switching to DEX- and PRED-free regimens. These changes reduce the CAH treatment burden and may decrease the risk of adverse effects of chronic treatment with synthetic GCs. Presentation: Monday, July 14, 2025

Background: Debate still exist about the safety of long-term use of prednisone (PD) versus hydrocortisone (HC) for treating children with congenital adrenal hyperplasia -21OH D (CAH). Despite recent developments in congenital adrenal hyperplasia -21OH D (CAH), several issues related to patient growth and final height remain unsolved. Debate still exist about the safety of long-term use of PD versus HC for treating children with CAH. The mechanism by which glucocorticoid therapy interferes with growth is complex and multifactorial. Relatively slight supra-physiologic levels may be enough to blunt growth velocity. An increased risk of developing obesity is another possible consequence of hyper-cortisolism in children with CAH. Objectives of the study: To evaluate the anthropometric and biochemical effects of long-term PD versus HC treatment in children with CAH-21OHD. A brief review of the literature is also reported. Patients and Methods: This retrospective study evaluated linear growth and biochemical data of thirty children with classic CAH (19 females and 11 males), who were on PD (n=22) or HC (n=8) treatment, since their first diagnosis. Clinical data included age, gender, duration of therapy, dose of HC and or equivalent dose of HC in the PD group, blood pressure, height (Ht) and weight. Ht-SDS and BMI were also calculated. Biochemical data included measurement of 17- OH progesterone, cholesterol, triglycerides (TG), HDL, LDL, fasting glucose, and insulin concentrations. HOMA-IR was calculated. Carotid intima-media thickness (CIMT) was measured using high-resolution B-mode ultrasonography. Thirty normal age matched children were used as controls for the anthropometric and CIMT data. Results: The age of children and duration of treatment did not differ among the two treatment groups. After a mean of 6 years of treatment, the Ht-SDS and BMI did not differ between the three groups of children. The equivalent hydrocortisone dose of children on prednisone was significantly higher than the dose for the hydrocortisone group. Both systolic and diastolic blood pressures (BP) of children on PD was slightly higher compared to those on hydrocortisone group. However, the BP of the 2 treatment groups was not different compared to control children. Fasting blood glucose, homeostatic model assessment insulin resistance (HOMA-IR), plasma TG, HDL, and cholesterol did not differ among the two treatment groups. LDL levels were significantly higher in the PD group versus the HC group. The mean CIMT did not differ among the two treatment groups but was significantly higher in the treated groups versus controls. There was a significant linear correlation between BMI-SDS and CIMT (r=0.37, p=0.047). Conclusions: Children with CAH-21OHD who were kept on PD therapy for 6.4±2.7 years, since the beginning of diagnosis, have maintained normal linear growth. No difference in BMI, HOMA-IR, or CIMT was detected among the two treated groups. The efficiency, safety and convenience of a single daily dose of PD could be a good and relatively safe alternative to HC for the continuing medical treatment of patients with CAH-21OHD. However, more prospective studies across childhood and adolescence are necessary to draw definitive conclusions. (www.actabiomedica.it)

The effects of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency on final height and fertility were evaluated in 30 affected males, aged 17-43 yr. The mean adult height of these patients was 165.64 +/- 8.4 cm (mean +/- SD), with a mean SD score of -1.65 +/- 1.2 cm. The difference between the mean final height SD score and mean target height SD score was -1.67 +/- 1.0 cm. All patients had short stature and did not reach their estimated target heights. There was no difference in height SD score between the salt-wasting and simple virilizing CAH patients. No correlation between the final height and degree of hormonal control or bone age advancement was observed. Of the 30 subjects, 18 had testicular sonograms. Abnormal sonogram findings of testicular adrenal rests were present in 9 patients (group 1), whereas sonogram without adrenal rests comprised the remaining 9 patients (group 2). In group 1, 8 of 9 patients and in group 2, 4 of 9 patients were salt-wasters; the remainder were simple virilizers. In group 1, 7 of 9 patients had semen analysis, and all were judged infertile. Of the 6 patients in group 2 who had semen analysis, 1 was azoospermic, and the remainder were normal. During optimal adrenal hormone suppression, gonadotropins at baseline and after GnRH stimulation were significantly higher in group 1 than in group 2, reflecting the loss of Leydig cell function to secrete testosterone. In conclusion, adult males affected with CAH due to 21-hydroxylase deficiency do not achieve the height predicted from parental heights. The presence of adrenal rests within the testes of adult males with classic CAH are more frequent in the salt-wasting form and are associated with a higher risk for infertility.

Infant with classic congenital adrenal hyperplasia (CAH) born to a mother with classic CAH

Background: Despite treatment, the mean final height (FH) of patients with classic congenital adrenal hyperplasia (CAH) is below the mean height of a normal population. Aims:To show that CAH patients can achieve their target height (TH), 39 adult subjects, whose therapy had started in infancy, were studied in a retrospective analysis. All height SDS were corrected so that they related to TH SDS. Patients: Group 1: patients born before 1975 (n = 13) had received prednisolone, at doses equivalent to hydrocortisone 39.4 ± 15.6 mg/m² BSA daily, together with DOCA in the first 2 years of life. Group 2: patients born from 1975 to 1986 (n = 26) received at this age lower hydrocortisone doses (16.4 ± 6.9 mg/m² BSA daily, divided 8 hourly; p < 0.001) combined with fludrocortisone, had outpatient visits every 3 months and bone age (BA) estimation every 6 months. Results: Patients of group 1 (FH SDS –1.2 ± 1.0) had a poor outcome, whereas patients of group 2 (FH SDS 0.1 ± 0.9; p = 0.01) achieved their TH. Conclusion: Combined corticoid administration adjusted quarterly to keep height, BMI, blood pressure and BA within normal limits resulted in FH close to TH in patients with classic CAH.

M. Dolan: None. D. Marshall: None. J. Hawley: None. B.G. Keevil: None. Fludrocortisone (FC) is a fluorinated exogenous mineralocorticoid used to treat conditions associated with adrenal insufficiency including Addison’s disease and classic congenital adrenal hyperplasia (CAH). The mineralocorticoid action of FC allows the drug to compensate for aldosterone deficiency, thus helping to maintain blood pressure and other homeostatic mechanisms. Optimising FC replacement is vital as under-replacement can cause dizziness and hypotension, whereas over-replacement can lead to cardiometabolic disturbances. Treatment in classic CAH patients, who are typically diagnosed as new-borns, is even more complex as the requirement for mineralocorticoid replacement decreases with age. Endocrine Society guidelines recommend that FC monitoring should involve the clinical assessment of symptoms, which can be non-specific, and regular blood pressure measurements. Plasma renin activity (PRA) should be measured if clinical changes occur, aiming towards the upper end of the reference range. The utility of PRA is debated due to methodological issues and the inherent variability of the analyte itself, which may not always represent FC replacement status. Therefore, investigation into alternative biochemical markers of FC replacement is required. Here we aimed to facilitate this by developing an LC-MS/MS method for the measurement of salivary FC. Method: A salivary FC LC-MS/MS assay has been developed and validated for use according to FDA and EMA guidelines. Passive drool samples from 10 clinical trial patients with classic CAH were collected on two separate occasions at select time points throughout the day (0800, 1200, 1600, 2000 and 2300h). In most patients the 0800h sample was taken pre-FC dose. Once in the laboratory the patient samples were extracted and analysed using the FC method to produce a FC concentration day curve. Results: The method analysis time was 2.1 minutes, with a mean recovery of 102% and limit of quantification of 5 pmol/L (2.1 pg/mL). No analytical interference was identified. Analysis of patient samples using the method showed the presence of FC allowing the production of day curves. In most patients, the pre-dose sample contained no FC, with the subsequent samples showing a peak FC concentration corresponding to the Cmax. After this the FC concentration gradually tapered off throughout the remainder of the day. Conclusions: We have developed a novel assay for the measurement of salivary FC, which may allow the calculation of the area under the curve. As an optimal FC dose has yet to be determined this method may facilitate more in-depth pharmacokinetic studies into FC metabolism and blood pressure control. Thereby identifying patients that are fast metabolisers or poor absorbers of the medication, enabling a non-invasive strategy to optimise patient care. Saturday, June 1, 2024

Proinflammatory cytokines such as tumor necrosis factor (TNF) were demonstrated to inhibit adrenal steroidogenesis in patients with rheumatoid arthritis (RA), and this was particularly evident in the increase in adrenal androgen levels during anti-TNF therapy. This study investigated the influence on steroidogenesis of an interleukin-6 (IL-6)-neutralizing strategy using IL-6 receptor monoclonal antibodies (referred to as MRA). In a placebo-controlled, double-blind, randomized study over 12 weeks in 29 patients with RA being treated with prednisolone, 13 of whom received placebo and 16 of whom received 8 mg MRA/kg body weight, the effects of MRA on serum levels of adrenocorticotropic hormone (ACTH), cortisol, 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione (ASD), estrone, and 17beta-estradiol, as well as their respective molar ratios, were determined. MRA therapy markedly improved clinical signs of inflammation (the erythrocyte sedimentation rate, swollen joint score, and Disease Activity Score in 28 joints). Serum levels of ACTH and cortisol and the molar ratio of cortisol to ACTH did not change. Although serum levels of DHEA and DHEAS remained stable during therapy, the DHEAS:DHEA molar ratio significantly decreased in treated patients (P = 0.048). Serum levels of ASD as well as the ASD:cortisol and ASD:17OHP molar ratios increased in MRA-treated patients (minimum P < 0.004). Serum levels of estrone and 17beta-estradiol did not change. but the estrone:ASD molar ratio (an indicator of aromatization) decreased during 12 weeks of MRA treatment (P = 0.001). Neutralization of IL-6 increases secretion of biologically active adrenal androgens in relation to that of precursor hormones and estrogens. This is another important indication that proinflammatory cytokines interfere with adrenal androgen steroidogenesis in patients with RA.

Aims: To evaluate whether 7 year old VLBW (very low birth weight, <1500 g) survivors with and without bronchopulmonary dysplasia (BPD) evince similar growth status and higher adrenal androgen (AA)...

46,XX individuals with classical congenital adrenal hyperplasia (CAH) due to deficiency of the enzyme, 21-hydroxylase, show variable degrees of masculinization of body and behavior due to excess adrenal androgen production. Increased bisexuality and homosexuality have also been reported. This article provides a review of existing reports of the latter and presents a new study aimed at replicating the previous findings with detailed assessments of sexual orientation on relatively large samples, and at extending the investigation to the mildest form, non-classical (NC) CAH. Also, this is the first study to relate sexual orientation to the specific molecular genotypes of CAH. In the present study, 40 salt-wasters (SW), 21 SV (simple-virilizing), 82 NC, and 24 non-CAH control women (sisters and female cousins of CAH women) were blindly administered the Sexual Behavior Assessment Schedule (SEBAS-A, 1983 ed.; H. F. L. Meyer-Bahlburg & A. A. Ehrhardt, Privately printed). Most women were heterosexual, but the rates of bisexual and homosexual orientation were increased above controls not only in women with classical CAH, but also in NC women, and correlated with the degree of prenatal androgenization. Classifying women by molecular genotypes did not further increase the correlation. Diverse aspects of sexual orientation were highly intercorrelated, and principal components analysis yielded one general factor. Bisexual/homosexual orientation was (modestly) correlated with global measures of masculinization of non-sexual behavior and predicted independently by the degree of both prenatal androgenization and masculinization of childhood behavior. We conclude that the findings support a sexual-differentiation perspective involving prenatal androgens on the development of sexual orientation.

Background:CAH is caused by an enzyme deficiency involved in cortisol synthesis leading to an increase in ACTH. Increased ACTH causes elevated levels of steroid hormone precursors & chronic stimulation of the adrenal glands resulting in hyperplasia. The most common form of CAH is due to 21OH deficiency (21OHD) with the classic, salt-wasting form causing glucocorticoid & mineralocorticoid deficiency & androgen excess.Poorly controlled CAH causes increased production of androgens & progesterone & decreased fertility. Fertility in woman with 21OHD can be challenging due to decreased sexual interest & anatomical abnormalities. Despite these challenges, the pregnancy rate is not significantly lower in women with well controlled 21OHD. However, as these patients are uncommon recommendations for pregnancy can be challenging for endocrinologists.Clinical Case:A 27-year old G0P0 female with classic, salt losing CAH presented to discuss pregnancy. Her medications were hydrocortisone 10mg qAM & 5mg qHS & fludrocortisone 0.1mg daily. She denied symptoms of dehydration, nausea, vomiting, dizziness, or fatigue.She was diagnosed with CAH while in-utero & started on steroid therapy after birth. She did not require any surgical genital reconstruction. Menarche occurred at age 11 and she had regular menses every 35-40 days, with no evidence of excessive androgen exposure including excess body hair, deepening of her voice, or cliteromegaly.On physical exam she was normotensive & had no evidence of virilization or cushingoid features. She exhibited minor darkening of the palmar creases. Her labs were significant for free testosterone of 9.1 pg/ml (0.2-5.0 pg/ml), total testosterone of 115 ng/dl (2-45 ng/dl), ACTH of 780 pg/ml (6-50 pg/ml), androstenedione of 636 ng/dl (41-262 ng/dl), & 17 OHP of 1560 ng/dl (15-290 ng/dl).Her hydrocortisone dose was increased to 20 mg qAM & 10 mg qHS & fludrocortisone 0.1mg daily was continued. Our objectives were to normalize the androgen level & suppress serum progesterone to less than 2 nmol/L. If the objectives were not reached she would be converted to prednisone BID.Conclusion:Endocrine providers are the primary resource for fertility recommendations for 21OHD patients & must understand the challenges in this very rare group of patients. Collaboration with the perinatologist is crucial for success.The goals of preconception endocrine assessment in a patient with classic CAH are to adjust hormone therapy to ensure optimal endocrine milieu for conception & risk assessment of having a child affected with 21OHD. The patient will need a higher dose of fludrocortisone during the later part of pregnancy. Counseling that stress doses of glucocorticoids for intercurrent illness and during labor and delivery are required for both the patient and the obstetrician.