Fertility And Sexual Function In CAH: CALLIOPE

NCT ID: NCT07099456

Last Updated: 2025-08-01

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 50 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2024-11-01
• Study Completion Date: 2030-11-01

Brief Summary

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.

Conditions

Congenital Adrenal Hyperplasia (CAH)

Study Design

• Observational Model Type: CASE_ONLY
• Study Time Perspective: PROSPECTIVE

Study Groups

Patients with Congenital Adrenal Hyperplasia (CAH)

Adult patients with a known/new diagnosis of CAH requiring chronic glucocorticoid replacement therapy

No interventions assigned to this group

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Modena and Reggio Emilia

OTHER

Sponsor Role: collaborator

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

OTHER

Sponsor Role: collaborator

Federico II University

OTHER

Sponsor Role: collaborator

S. Andrea Hospital

OTHER

Sponsor Role: collaborator

University of Roma La Sapienza

OTHER

Sponsor Role: lead

Responsible Party

Andrea M. Isidori

Full Professor of Endocrinology and Metabolism

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Department of Experimental Medicine, Sapienza University of Rome

Rome, Italy, Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Andrea M Isidori, MD, PhD, FRCP

Role: CONTACT

andrea.isidori@uniroma1.it

+39 0649970540

Davide Ferrari, MD

Role: CONTACT

davide.ferrari@uniroma1.it

+39 3403843502

Facility Contacts

Andrea M Isidori, MD, PhD, FRCP

Role: primary

andrea.isidori@uniroma1.it

+39 0649970540

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Other Identifiers

CALLIOPE

Identifier Type: -

Identifier Source: org_study_id