Channelling Fertility And Sexual Function In Congenital Adrenal Hyperplasia. CALLIOPE: An Observational, Longitudinal Pilot Study
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Change in sperm concentration (total count per ejaculate) at semen analysis (male subjects)
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Only
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
结局指标
主要结局
Change in sperm concentration (total count per ejaculate) at semen analysis (male subjects)
时间窗: At baseline and during follow-up (up to 5 years)
Sperm concentration will be evaluated through standard semen analysis in male participants, according to WHO guidelines. Measurements will be used to assess changes over time in relation to disease control and treatment modifications. Semen analyses will be repeated at follow-up visits if clinically indicated or in case of significant therapeutic changes. Unit of Measure: millions per ejaculate (10⁶/ejaculate)
Change in sperm concentration (concentration per mL) at semen analysis (male subjects)
时间窗: At baseline and during follow-up (up to 5 years)
Sperm concentration will be evaluated through standard semen analysis in male participants, according to WHO guidelines. Measurements will be used to assess changes over time in relation to disease control and treatment modifications. Semen analyses will be repeated at follow-up visits if clinically indicated or in case of significant therapeutic changes. Unit of Measure: millions per mL (10⁶/mL)
Change in Serum Testosterone:LH ratio (female subjects)
时间窗: At baseline and during follow-up (up to 5 years)
Assessment of changes in the ratio between serum total testosterone and luteinizing hormone (LH) concentrations in female participants. Blood samples will be collected in the early follicular phase or as appropriate based on menstrual status. The ratio will be calculated at each time point, and changes will be expressed as percent change from baseline or through paired comparison. The aim is to evaluate this ratio as a potential biomarker of hyperandrogenism severity and treatment response. Unit of Measure: Ratio (ng/dL per IU/L)
Change in serum Estradiol:FSH ratio (female subjects)
时间窗: At baseline and during follow-up (up to 5 years)
Evaluation of changes in the ratio between serum estradiol (E2) and follicle-stimulating hormone (FSH) concentrations in female participants. Blood samples will be collected in the early follicular phase when possible or based on clinical context. The E2:FSH ratio will be calculated at each visit and used to assess hypothalamic-pituitary-ovarian axis function and treatment effects over time. Changes will be analyzed using paired comparisons or percentage variation from baseline. This outcome is part of a broader hormonal assessment that includes additional ratios such as Testosterone:LH. Unit of Measure: Ratio (pg/mL per mIU/mL)
次要结局
- Number of pregnancies and childbirths from baseline(From baseline until the end of the study (up to 5 years))
- Change in bilateral testicular volume and TARTs volume (scrotal ultrasound, male subjects)(At baseline and during follow-up (up to 5 years))
- Change in fructose levels in seminal plasma (male subjects)(At baseline and during follow-up (up to 5 years))
- Change in Circadian, multi-matrix, serum, urinary and salivary LC-MS/MS steroid profiles(At baseline and during follow-up (up to 5 years))
- Change in Circadian quantification of Peripheral Blood Mononuclear Cells (PBMCs) subpopulations by flow cytometry(At baseline and during follow-up (up to 5 years))
- Change in total and regional fat and lean mass measured by DXA(At baseline and during follow-up (up to 5 years))
- Change in Bone mineral density (BMD) of femur and lumbar spine assessed by DXA(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)(At baseline and during follow-up (up to 5 years))
- Change in Structural cardiac parameters assessed by transthoracic echocardiography(At baseline and during follow-up (up to 5 years))
- Change in Lipid metabolism parameters(At baseline and during follow-up (up to 5 years))
- Change in CAHQoL questionnaire scores (Health-related Quality fo Life)(At baseline and during follow-up (up to 5 years))
- Change in Serum liver enzymes (AST, ALT, gamma-GT, alkaline phosphatase)(At baseline and during follow-up (up to 5 years))
- Change in total sperm motility (& motile spermatozoa) at semen analysis (male subjects)(At baseline and during follow-up (up to 5 years))
- Change in the percentage of spermatozoa with typical morphology at semen analysis (male subjects)(At baseline and during follow-up (up to 5 years))
- Change from Baseline in Number of Regular Menses (female subjects)(during follow-up (up to 5 years))
- Change in Testicles and TARTs vascularity (Testicular Ultrasound, male subjects)(At baseline and during follow-up (up to 5 years))
- Change in Testicles and TARTs parenchymal homogeneity (Testicular Ultrasound, male subjects)(At baseline and during follow-up (up to 5 years))
- Change in TARTs number (Testicular Ultrasound, male subjects)(At baseline and during follow-up (up to 5 years))
- Change in Radiomic features of testicular adrenal rest tumors (TARTs) and normal testicular parenchyma on ultrasound imaging(At baseline and during follow-up (up to 5 years))
- Change in CEUS perfusion patterns (time parameters) of testicular adrenal rest tumors (TARTs, male participants) and other testicular inhomogeneities(At baseline and during follow-up (up to 5 years))
- Change in Anthropometric Parameters(At baseline and during follow-up (up to 5 years))
- Change in CEUS perfusion patterns (intensityparameters) of testicular adrenal rest tumors (TARTs, male participants) and other testicular inhomogeneities(At baseline and during follow-up (up to 5 years))
- Change in ovarian volume (pelvic ultrasound, female subjects)(Baseline and follow-up visits (up to 5 years))
- Change in number of ovarian follicular cysts (pelvic ultrasound, female subjects)(At baseline and during follow-up (up to 5 years))
- Change in size of ovarian follicular cysts (pelvic ultrasound, female subjects)(At baseline and during follow-up (up to 5 years))
- Change in Ultrasonographic signs of ovulation (pelvic ultrasound, female subjects)(At baseline and during follow-up (up to 5 years))
- Presence of ovarian adrenal rest tumors (OARTs) on pelvic ultrasound(At baseline and during follow-up (up to 5 years))
- Change in seminal acid phosphatase levels (male subjects)(At baseline and during follow-up (up to 5 years))
- Change in Expression levels of microRNAs in serum and seminal plasma (male subjects)(At baseline and during follow-up (up to 5 years))
- Change in Circadian transcriptomic profile of PBMCs using targeted gene expression analysis(At baseline and during follow-up (up to 5 years))
- Prevalence and incidence of asymptomatic vertebral fractures (lateral spine imaging, DXA)(Baseline and follow-up assessments every 18-24 months, until the end of the study (up to 5 years))
- Change in Trabecular Bone Score (TBS) calculated from lumbar spine DXA(Baseline and follow-up assessments every 18-24 months, until the end of the study (up to 5 years))
- Change in body composition indices and fat distribution ratios measured by DXA(At baseline and during follow-up (up to 5 years))
- Change in Left ventricular mass index (LVMI) assessed by echocardiography(At baseline and during follow-up (up to 5 years))
- Change in Left atrial volume index (LAVI) assessed by echocardiography(At baseline and during follow-up (up to 5 years))
- Change in Left ventricular ejection fraction (EF) assessed by echocardiography(At baseline and during follow-up (up to 5 years))
- Change in Doppler-derived diastolic function parameters (E/A and E/e' ratios)(At baseline and during follow-up (up to 5 years))
- Change in Fasting glucose and C-peptide levels (mg/dL)(At baseline and during follow-up (up to 5 years))
- Change in Fasting insulin levels (µU/mL)(At baseline and during follow-up (up to 5 years))
- Change in Glycated hemoglobin (HbA1c)(At baseline and during follow-up (up to 5 years))
- Change in Insulin resistance index (HOMA-IR)(At baseline and during follow-up (up to 5 years))
- Change in Prothrombin time and activated partial thromboplastin time (seconds)(At baseline and during follow-up (up to 5 years))
- Change in International Normalized Ratio (INR)(At baseline and during follow-up (up to 5 years))
- Change in Fibrinogen levels and coagulation factors (mg/dL)(At baseline and during follow-up (up to 5 years))
- Change in Coagulation factor activity (functional %)(At baseline and during follow-up (up to 5 years))
- Change in FSFI-19 questionnaire score (female sexual dysfunction)(At baseline and during follow-up (up to 5 years))
- Change in body weight(At baseline and during follow-up (up to 5 years))
- Change in Body Mass Index(At baseline and during follow-up (up to 5 years))
- Change in waist-to-hip ratio and waist-to-height ratio(At baseline and during follow-up (up to 5 years))
- Change in blood pressure(At baseline and during follow-up (up to 5 years))
- Change in Handgrip strength test(At baseline and during follow-up (up to 5 years))
- Change in Ferriman-Gallwey score (female subjects)(At baseline and during follow-up (up to 5 years))
- Change in Chair stand test (5-times sit-to-stand) and Balance test(At baseline and during follow-up (up to 5 years))
- Change in Gait speed test(At baseline and during follow-up (up to 5 years))
- Change in Short Physical Performance Battery (SPPB) total score(At baseline and during follow-up (up to 5 years))
- Change in AddiQoL questionnaire score (Health-related quality of life)(At baseline and during follow-up (up to 5 years))
- Change in Short Form 36 questionnaire score (General health-related quality of life)(At baseline and during follow-up (up to 5 years))
- Change in Pittsburgh Sleep Quality Index scores (PSQI) (Sleep quality)(At baseline and during follow-up (up to 5 years))
- Change in Serum bilirubin levels(At baseline and during follow-up (up to 5 years))
- Change in Serum creatinine(At baseline and during follow-up (up to 5 years))
- Change in Urinary creatinine and electrolytes (24-hour collection)(At baseline and during follow-up (up to 5 years))
- Change in Serum levels of Inhibin B and SHBG(At baseline and during follow-up (up to 5 years))
- Change in Serum C Reactive Protein(At baseline and during follow-up (up to 5 years))
- Change in erythrocyte sedimentation rate (ESR)(At baseline and during follow-up (up to 5 years))
- Change in Serum albumin(At baseline and during follow-up (up to 5 years))
- Change in Plasma levels of POMC-derived peptides(At baseline and during follow-up (up to 5 years))
- Change in Serum TSH levels(At baseline and during follow-up (up to 5 years))
- Change in Serum free T3 (fT3) levels(At baseline and during follow-up (up to 5 years))
- Change in Serum free thyroxine (fT4) levels(At baseline and during follow-up (up to 5 years))
- Change in Timed Up and Go (TUG) test(At baseline and during follow-up (up to 5 years))
- Change in sperm vitality (Eosin-nigrosin test, male patients)(At baseline and during follow-up (up to 5 years))
- Serum levels of pro-inflammatory and anti-inflammatory cytokines(At baseline and during follow-up (up to 5 years))
- Serum levels of adipokines and other adiposity-related biomarkers(At baseline and during follow-up (up to 5 years))
- Gene expression of markers of HPA axis activity and glucocorticoid sensitivity(At baseline and during follow-up (up to 5 years))
研究者
Andrea M. Isidori
Full Professor of Endocrinology and Metabolism
University of Roma La Sapienza