Fertility And Sexual Function In CAH: CALLIOPE

Official title

Channelling Fertility And Sexual Function In Congenital Adrenal Hyperplasia. CALLIOPE: An Observational, Longitudinal Pilot Study

Overview

This is a multicenter study designed to assess the effects of groundbreaking CAH therapies on a spectrum of clinical and biochemical outcomes, with a special emphasis on reproductive and sexual health. Fertility is a profound concern for individuals with CAH, given the high prevalence of gonadal dysfunction that arises from the hormonal derangements that characterize this complex disease. At our endo-ERN accredited center for rare diseases at Policlinico Umberto I, addressing these fertility issues in CAH patients represents a daily commitment. The revolution of the pharmacological management of CAH is one of the most debated topics to date. Data on the effects of novel management options for CAH on fertility are scarce, but the anecdotal improvements in sperm count and menstrual regularity reported in the latest clinical trials have significantly motivated us to design the CALLIOPE study. Thus, we aim to delve deeper into the fertility and sexual function of CAH patients, employing advanced seminal parameter evaluations, multiparametric gonadal ultrasound, and sophisticated hormonal analyses in both females and males performed by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Beyond fertility, the CALLIOPE trial aspires to provide further understanding of therapy's effects on body composition, metabolism, immune function, coagulation, and quality of life, among other factors. We will explore the immunological impact of novel CAH therapies by quantifying Peripheral Blood Mononuclear Cells (PBMCs) and analyzing transcriptomic profiles to unveil gene expression patterns and identify biomarkers that could signal therapeutic targets or disease management strategies in CAH. Moreover, seminal plasma will be used to assess the expression of adrenal miRNAs regulating steroidogenesis and metabolism. The research will be conducted at our rare disease referral center (Policlinico Umberto I, Sapienza University of Rome) in collaboration with leading centers across Italy: Modena (Università degli Studi di Modena e Reggio Emilia), Naples (Università Federico II), Rome (Ospedale Sant'Andrea) and Bologna (Alma Mater Studiorum - Università di Bologna). https://isidorilab.com/home

Detailed description

Classic Congenital Adrenal Hyperplasia (CAH) is the most common rare disease affecting the adrenal glands. It is characterized by primary adrenal insufficiency due to congenital enzymatic defects, which impair glucocorticoid synthesis. As a result, patients require lifelong glucocorticoid replacement therapy, often combined with mineralocorticoid supplementation in the salt-wasting form of the disease. Standard treatment involves short-acting, immediate-release glucocorticoids (such as hydrocortisone or cortisone acetate) administered two or three times daily. Although lifesaving, chronic glucocorticoid therapy is associated with increased cardiometabolic risk, altered glucose and lipid metabolism, weight gain, osteoporosis, higher infection susceptibility, and reduced life expectancy, even at replacement-level doses.

In CAH, supraphysiologic doses and reverse circadian timing of glucocorticoid administration are often employed to suppress androgen excess. This approach, however, may exacerbate side effects related to glucocorticoid overexposure. A dose-dependent impact of glucocorticoid therapy has been observed on cardiovascular risk, bone mineral density, body composition, and immune function. Despite these known effects, reproductive and sexual health outcomes remain under-investigated, representing a significant unmet need in the comprehensive management of CAH.

In male patients, reproductive dysfunction is frequently observed and is often attributed to the development of testicular adrenal rest tumors (TARTs), which can impair fertility. Current medical approaches to TARTs include high-dose, long-acting glucocorticoid therapy, with variable effects on tumor regression and semen quality. However, this strategy is associated with additional metabolic and cardiovascular risks. Furthermore, uncontrolled androgen excess may be converted to estrogens and, together with elevated progestogen levels, suppress the hypothalamic-pituitary-gonadal axis, contributing to hypogonadotropic hypogonadism.

Female patients with CAH may present with menstrual disturbances, anovulation, biochemical and clinical hyperandrogenism, and infertility. Additionally, non-hormonal factors such as anatomical variations and psychological distress may impact sexual health and reproductive intentions.

Recent advances in CAH therapy include the development of novel glucocorticoid formulations that aim to better replicate the circadian rhythm of cortisol secretion. Dual-release hydrocortisone and non-glucocorticoid therapeutic options have shown promise in improving metabolic, immunological, and hormonal parameters, and may allow a decoupling of glucocorticoid replacement from androgen suppression. However, real-world data on the long-term cardiometabolic outcomes of these newer treatments remain limited, and reproductive parameters-such as semen quality, pregnancy rates, and menstrual cycle normalization-require further clinical investigation.

The aim of this observational prospective study is to evaluate the impact of hormonal alterations and treatment strategies on reproductive and sexual health in individuals with CAH. The study will adopt a multidimensional clinical-translational approach, integrating clinical assessments with advanced profiling techniques such as steroidomics, microRNA analysis, and gene expression profiling. These precision medicine tools are expected to identify novel biomarkers and mechanistic pathways involved in reproductive dysfunction, ultimately supporting the development of targeted therapeutic strategies.

Following screening based on inclusion and exclusion criteria, eligible participants will provide informed consent and undergo baseline evaluations. Follow-up assessments will be conducted after significant modifications in therapy or lifestyle interventions, typically within 3 to 6 months. In the absence of changes, at least one follow-up evaluation will be scheduled within a 3- to 12-month timeframe, as appropriate for each participant. Study evaluations will be integrated into routine clinical care without altering standard management protocols.

Primary outcome measures

• Change in sperm concentration (total count per ejaculate) at semen analysis (male subjects) [Time frame: At baseline and during follow-up (up to 5 years)]
• Change in sperm concentration (concentration per mL) at semen analysis (male subjects) [Time frame: At baseline and during follow-up (up to 5 years)]
• Change in Serum Testosterone:LH ratio (female subjects) [Time frame: At baseline and during follow-up (up to 5 years)]
• Change in serum Estradiol:FSH ratio (female subjects) [Time frame: At baseline and during follow-up (up to 5 years)]

Secondary outcome measures (12)

• Number of pregnancies and childbirths from baseline [Time frame: From baseline until the end of the study (up to 5 years)]
• Change in bilateral testicular volume and TARTs volume (scrotal ultrasound, male subjects) [Time frame: At baseline and during follow-up (up to 5 years)]
• Change in fructose levels in seminal plasma (male subjects) [Time frame: At baseline and during follow-up (up to 5 years)]
• Change in Circadian, multi-matrix, serum, urinary and salivary LC-MS/MS steroid profiles [Time frame: At baseline and during follow-up (up to 5 years)]
• Change in Circadian quantification of Peripheral Blood Mononuclear Cells (PBMCs) subpopulations by flow cytometry [Time frame: At baseline and during follow-up (up to 5 years)]
• Change in total and regional fat and lean mass measured by DXA [Time frame: At baseline and during follow-up (up to 5 years)]
• Change in Bone mineral density (BMD) of femur and lumbar spine assessed by DXA [Time frame: Baseline and follow-up scans every 18-24 months, until the end of the study (up to 5 years)]
• Change in International Index of Erectile Function (IIEF-15) questionnaire score (male sexual dysfunction) [Time frame: At baseline and during follow-up (up to 5 years)]
• Change in Structural cardiac parameters assessed by transthoracic echocardiography [Time frame: At baseline and during follow-up (up to 5 years)]
• Change in Lipid metabolism parameters [Time frame: At baseline and during follow-up (up to 5 years)]
• Change in CAHQoL questionnaire scores (Health-related Quality fo Life) [Time frame: At baseline and during follow-up (up to 5 years)]
• Change in Serum liver enzymes (AST, ALT, gamma-GT, alkaline phosphatase) [Time frame: At baseline and during follow-up (up to 5 years)]

Eligibility criteria

Inclusion criteria

• Adult patients, males in the age range 18-65 years and pre-menopausal females in the age range 18-55 years;
• a known/new diagnosis of CAH.

Exclusion criteria

• BMI > 40 Kg/m2;
• Any other concomitant condition requiring steroid treatment;
• Severe liver and/or kidney disease;
• Thyroid dysfunctions (overt hyperthyroidism and hypothyroidism);
• Malignant neoplasms;
• Drug and alcohol abuse;
• Use of drugs acting on hormonal levels (e.g. antiandrogens);
• Psychiatric diseases;
• Postmenopausal women;
• Women taking combined oral contraceptive pill (women) or other contraceptives will require stability for at least 6 months.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Case-only

Study locations

Italy · 1 center

• Department of Experimental Medicine, Sapienza University of Rome — Rome

Publications

• Sytkowski PA, Kannel WB, D'Agostino RB. Changes in risk factors and the decline in mortality from cardiovascular disease. The Framingham Heart Study. N Engl J Med. 1990 Jun 7;322(23):1635-41. doi: 10.1056/NEJM199006073222304. PMID 2288563
• Cantisani V, Bertolotto M, Weskott HP, Romanini L, Grazhdani H, Passamonti M, Drudi FM, Malpassini F, Isidori A, Meloni FM, Calliada F, D'Ambrosio F. Growing indications for CEUS: The kidney, testis, lymph nodes, thyroid, prostate, and small bowel. Eur J Radiol. 2015 Sep;84(9):1675-84. doi: 10.1016/j.ejrad.2015.05.008. Epub 2015 May 14. PMID 26014102
• Pozza C, Gianfrilli D, Fattorini G, Giannetta E, Barbagallo F, Nicolai E, Cristini C, Di Pierro GB, Franco G, Lenzi A, Sidhu PS, Cantisani V, Isidori AM. Diagnostic value of qualitative and strain ratio elastography in the differential diagnosis of non-palpable testicular lesions. Andrology. 2016 Nov;4(6):1193-1203. doi: 10.1111/andr.12260. Epub 2016 Aug 27. PMID 27565451
• Auchus RJ, Hamidi O, Pivonello R, Bancos I, Russo G, Witchel SF, Isidori AM, Rodien P, Srirangalingam U, Kiefer FW, Falhammar H, Merke DP, Reisch N, Sarafoglou K, Cutler GB Jr, Sturgeon J, Roberts E, Lin VH, Chan JL, Farber RH; CAHtalyst Adult Trial Investigators. Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia. N Engl J Med. 2024 Aug 8;391(6):504-514. doi: 10.1056/NEJMoa2404 PMID 38828955
• Whitaker MJ, Huatan H, Ross RJ. Chronotherapy based on modified-release hydrocortisone to restore the physiological cortisol diurnal rhythm. Drug Deliv Transl Res. 2023 Jan;13(1):1-8. doi: 10.1007/s13346-022-01183-w. Epub 2022 May 26. PMID 35618893
• Schroder MAM, Claahsen-van der Grinten HL. Novel treatments for congenital adrenal hyperplasia. Rev Endocr Metab Disord. 2022 Jun;23(3):631-645. doi: 10.1007/s11154-022-09717-w. Epub 2022 Feb 23. PMID 35199280
• Merke DP, Mallappa A, Arlt W, Brac de la Perriere A, Linden Hirschberg A, Juul A, Newell-Price J, Perry CG, Prete A, Rees DA, Reisch N, Stikkelbroeck N, Touraine P, Maltby K, Treasure FP, Porter J, Ross RJ. Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2021 Apr 23;106(5):e2063-e2077. doi: 10.1210/clinem/dgab051. PMID 33527139
• Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BM, Colao A. Complications of Cushing's syndrome: state of the art. Lancet Diabetes Endocrinol. 2016 Jul;4(7):611-29. doi: 10.1016/S2213-8587(16)00086-3. Epub 2016 May 10. PMID 27177728

Identifiers

NCT: NCT07099456 · CALLIOPE

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗