Jan Frystyk

Context: Children born small for gestational age (SGA) without spontaneous catch-up growth may require GH treatment; however, daily injections are burdensome. Somapacitan is a once-weekly long-acting GH. Objective: To assess efficacy and safety of once-weekly somapacitan in children born SGA, including outcomes after switching from daily GH. Design: REAL8 is a randomized, multinational, open-label, active-controlled phase 3 study with a 52-week main period and 104-week extension (NCT05330325). REAL9 (NCT05723835) is a multinational, open-label, uncontrolled phase 3 study. Setting: Clinics across Europe, Asia, and the Americas. Participants: REAL8 randomized 142 GH-treatment-naïve, prepubertal children born SGA; 141 received treatment and 139 completed 104 weeks. REAL9 enrolled 12 children/adolescents born SGA (GH-naïve or previously treated). Interventions: In REAL8, participants were randomized (2:1:1) to somapacitan 0.24 mg/kg/week or daily GH (0.035 or 0.067 mg/kg/day) for 52 weeks; all received 0.24 mg/kg/week somapacitan in weeks 52–104. In REAL9, participants received 0.24 mg/kg/week somapacitan for 26 weeks. Main Outcome Measures: Annualized height velocity (HV); secondary outcomes included height SD score (HSDS). Results: In REAL8, mean HV during weeks 52–104 remained above baseline across groups (8.5–8.8 cm/year), including after switching from daily GH; HSDS increased through week 104, and IGF-I SDS were similar between groups. In REAL9, HV increased in GH-naïve participants and was maintained in previously treated participants. Somapacitan was well-tolerated; adverse events were mostly mild and injection-site reactions were infrequent. Most participants switching from daily GH preferred somapacitan. Conclusions: In children born SGA, once-weekly somapacitan maintained efficacy through 2 years, with safety comparable to daily GH, and was preferred after switching.

Objective: Cardiovascular disease (CVD) risk is elevated in transgender individuals during gender‐affirming hormone therapy (GAHT) with expected different mechanisms between T‐ and E2‐based GAHT. We investigated prospective changes in cardiometabolic proteins relating to complement, inflammation, and transport during GAHT. Design: Prospective clinical study with assessment at baseline and after 1 year of GAHT. Patients: The main study population comprised 55 GAHT‐naïve individuals (34 TM, 21 TF). An additional 35 GAHT‐ongoing individuals (26 TM, 9 TF) were included as a cross‐sectional comparison group at baseline. Measurements: 19 cardiometabolic proteins relating to atherosclerotic and thrombotic processes were analysed using targeted proteomics. Body composition was assessed by dual‐energy X‐ray absorptiometry. Results: In GAHT‐naïve TM individuals, the mean age at baseline was 27 years and median BMI was 26.5 (22.3–28.9) kg/m ² . Following T‐based GAHT, complement factor H and B, 3, 4b, and transport proteins (sex hormone‐binding globulin, ceruloplasmin, corticosteroid‐binding globulin, vitamin D ‐binding protein, vitronectin, and afamin) decreased, and transthyretin increased. In GAHT‐naïve TF individuals, the mean age at baseline was 27 years and median BMI was 21.5 (20.3–23.6) kg/m ² . Following E2‐based GAHT, complement factor H and B, 3, 4b, 9, C‐reactive protein, immunoglobulin heavy constant alpha 1 (IGHA1), and transport proteins increased. In cross‐sectional analyses, complement factor H and B, 3, 4b, 9, C‐reactive protein, IGHA1, and afamin were higher in GAHT‐ongoing TF individuals at baseline compared to GAHT‐naïve TF individuals at 1 year. Conclusion: T‐ and E2‐based GAHT were associated with opposite directional changes in cardiometabolic protein profiles. Trial Registration: ClinicalTrials. gov (Identifier: NCT04254354, NCT05169762).

Objective: Anabolic androgenic steroids (AAS) may exert effects through the insulin-like growth factor (IGF) system. We compared the IGF system in male and female recreational athletes who were current or former AAS users and non-users. Methods: The cross-sectional study included 80 active AAS users (19 women), 26 former users (8 women), and 58 age- and sex-matched non-users (16 women). Participants underwent clinical examination, echocardiography, and measurement of circulating IGF-1, IGF-2, IGF bioactivity, IGF-binding proteins (IGFBPs), pregnancy-associated plasma protein-A (PAPP-A) and -A2 (PAPP-A2), and stanniocalcin-1 (STC1) and −2 (STC2). Results: In active AAS users, IGF-2 levels were reduced by 36.1% vs. former users and 38.4% vs. non-users (P < .001), and IGFBP-3 levels were 13.6% and 35.8% lower (P < .001). STC2 was increased in AAS-using men only, being 24.5% higher than former users (P = .029) and 45.7% higher than non-users (P < .001). PAPP-A was higher in non-using men than women, whereas levels were similar in active users. Differences remained after adjustment for age, sex, body fat, exercise and strength training, family history of coronary disease, smoking, alcohol, and drug use. No group differences were observed for IGF-1, bioactive IGF, IGFBP-2, or PAPP-A2. Cumulative lifetime AAS exposure was associated with IGF-2, IGFBP-3, and STC2 in multivariable models. Higher IGF-2 and IGFBP-3 associated with lower left ventricular mass, higher left ventricular ejection fraction, and better diastolic function, whereas higher STC2 associated with adverse outcomes (all P < .05). Conclusions: Illicit AAS use is associated with persistent, sex-specific alterations in the IGF–PAPP-A–STC2 axis, potentially contributing to cardiovascular risk in recreational athletes.

Individuals with schizophrenia suffer from reduced life expectancy, primarily due to obesity-related metabolic disorders and cardiovascular disease (CVD).

Background: The Itabaianinha cohort in Brazil carries a homozygous growth hormone-releasing hormone (GHRH) receptor (GHRH-R) gene mutation, causing congenital isolated GH deficiency (GHD). Affected individuals present with severe short stature, central obesity, hypercholesterolemia, and marked reductions in serum GH, IGF-I, and IGFBP 3 concentrations yet show no premature atherosclerosis and maintain a normal lifespan. IGF-I mostly circulates bound to IGFBPs and requires proteolytic cleavage for IGF-I receptor activation. Pregnancy-associated plasma protein A (PAPP-A) is an important IGF-dependent cleavage enzyme, binding to IGFBP 4 and releasing IGF-I. PAPP-A activity is inhibited by stanniocalcin-2 (STC2). The IGFBP 4-STC2-PAPP-A axis (ISPa) has emerged as a key regulator of IGF-I bioactivity. Methods: We evaluated the ISPa in: (1) GHD subjects with homozygous GHRH-R c.57 + 1G→A mutation, (2) heterozygotes (HTZ), and (3) homozygous wild-type controls (HMZ). Parameters from the ISPa were measured at LMU Klinikum, Munich. Additional biochemical parameters were analyzed at the Federal University of Sergipe, Brazil. Results: As expected, GHD subjects had markedly low GH, IGF-I, IGF-II, free IGF-I, and IGFBP 3 (P < .001), while HTZ resembled HMZ subjects. STC2, PAPP-A, and PAPP-A-STC2 complex concentrations did not differ between groups. However, PAPP-A2 and intact IGFBP 4 were higher in the GHD subjects (P < .05 and P < .01). Notably, IGF-I and IGFBP 3 positively correlated with IGF-II, whereas intact IGFBP 4 and PAPP-A2 showed inverse correlations with IGF-I and IGF-II. Conclusion: Our findings suggest altered IGF-I bioavailability regulation via the ISPa in congenital lifetime GHD, leading to increased PAPP-A2 proteolytic activity, reduced PAPP-A enzymatic activity, and reduced sequestration of PAPP-A2 by STC2.

Background: Monitoring IGF-I concentration is recommended during GH therapy in children. Supranormal levels of total IGF-I have raised concerns of long-term risks. Aim: To evaluate bioactive and total IGF-I in healthy and in GH-treated children and adolescents. Materials and methods: A reference population of 570 children (59% girls) from the Copenhagen Puberty Study III and 126 short children (36% girls) with GH deficiency (GHD) and other non-GHD conditions. We established pediatric, sex-specific reference ranges of serum concentrations of bioactive IGF-I (KIRA) and compared with total IGF-I and IGF-I/IGFBP-3 molar ratio (iSYS) and total IGF-I, -II, IGFBP-3, and acid labile subunit (liquid chromatography-tandem mass spectrometry) in a subgroup. Further, we compared IGF-I bioactivity with total IGF-I, IGFBP-3 (iSYS) and IGF-I/IGFBP-3 molar ratio during GH therapy. Results: Bioactive IGF-I increased with age in healthy children and correlated positively with total IGF-I and IGF-I/IGFBP-3 in healthy males (r = 0.61 and r = 0.57; P < .001) and females (r = 0.58 and r = 0.59; P < .001) and with IGF-I, BP-3, and acid labile subunit (liquid chromatography-tandem mass spectrometry) (r = 0.56, r = 0.29, and r = 0.38; P < .001). Bioactive IGF-I and IGF-II (r = -0.29; P < .001) correlated negatively. In 13% (17/126) of the patients, bioactive IGF-I was above +2SD, whereas total IGF-I was above +2SD in 25% (32/126) patients. Nine patients had both total and bioactive IGF-I above +2SD. In the non-GHD groups, bioactive IGF-I SDS were lower than IGF-I SDS (P = .015). Conclusion: Bioactive IGF-I was within reference ranges in the majority of GH-treated children. Monitoring bioactive IGF-I may help optimize GH dosing in specific patient subgroups.

Importance: The illicit use of anabolic androgenic steroids (AAS) is common among recreational athletes, yet studies on adverse cardiovascular outcomes, especially in female AAS users, are sparse.Objective: To assess cardiovascular status in Danish male and female recreational athletes using AAS compared with not using AAS.Design, Setting, and Participants: This cross-sectional study in a single center in Denmark included recreational athletes aged 18 years or older who were active AAS users, previous users (defined as those who discontinued AAS use at least 3 months prior to the study), or nonusers, all recruited from fitness centers between March and December 2022.Exposure: Cumulative lifetime use of AAS.Main Outcomes and Measures: Presence of atherosclerosis (carotid, femoral, and coronary artery plaques) and cardiac function assessed by echocardiography. Linear regression was used to estimate regression coefficients for echocardiographic characteristics and logistic regression to estimate odds ratios (ORs) for carotid and femoral plaques, coronary artery calcium (CAC) scores, and coronary noncalcified plaques (NCPs).Results: Of 164 participants, 80 (48.8%) were active AAS users (median age, 35 [IQR, 30-43] years; 61 men [76.2%]), 26 (15.9%) were previous users (median age, 36 [IQR, 28-51] years; 18 men [69.2%]), and 58 (35.4%) were nonusers (median age, 40 [IQR, 31-46] years; 42 men [72.4%]). Median cumulative lifetime AAS use was 2.2 (IQR, 1.2-7.2) years for active and 2.2 (IQR, 1.0-5.5) years for previous users. No group differences were observed when comparing the number of participants with femoral (active users, 15 [19.7%]; previous users, 5 [19.2%]; nonusers, 11 [20.8%]; P = .89) or carotid (active users, 24 [31.2%]; previous users, 12 [46.2%]; nonusers, 13 [24.1%]; P = .47) artery plaques or CAC scores (median score was 0 across all groups with range of 0-228 for active users, 0-800 for previous users, and 0-163 for nonusers; P = .36), whereas a statistically significant difference in the prevalence of coronary NCPs was found between active users (19 [23.8%]) and nonusers (6 [10.3%]) (P = .03). However, in confounder-adjusted logistic regression, longer cumulative lifetime AAS use was associated with higher odds of a positive CAC score (OR, 1.23; 95% CI, 1.09-1.39; P = .001) and presence of coronary NCPs (OR, 1.17; 95% CI, 1.05-1.30; P = .004). AAS use exceeding 5 years was associated with greater severity of calcifications (n = 94; χ² = 9.78; P = .04). Echocardiography showed that cumulative AAS use was associated with worse left ventricular (regression coefficient: 0.08; 95% CI, 0.03-0.12; P = .002) and right ventricular (0.08; 95% CI, 0.03-0.13; P = .001) global longitudinal strain. Nearly all athletes (35 of 36) with more than 5 years of cumulative AAS use had ventricular mass greater than and left ventricular ejection fraction below the median of the normal range.Conclusions and Relevance: In this cross-sectional study, cumulative lifetime AAS exposure was associated with adverse cardiovascular findings and impaired ventricular function in both sexes, and athletes with AAS exposure exceeding 5 years showed more severe calcification. The findings support measures to prevent AAS use by both men and women in recreational sports.

Objective: Somapacitan is a long-acting GH approved for once-weekly treatment of GH deficiency (GHD). This study aims to evaluate the efficacy and tolerability of somapacitan after 3 years of treatment and 2 years after switch from daily GH in children with GHD. Design: Randomized, multi-national, open-labelled, active-controlled parallel-group phase 3 trial, with a 52-week main phase and 3-year safety extension (NCT03811535). Methods: Treatment-naïve children with GHD were randomized (2:1) to continuous somapacitan (0.16 mg/kg/week; “soma/soma” group) or daily GH (Norditropin®; 0.034 mg/kg/day) followed by somapacitan (0.16 mg/kg/week; “switch” group). Results: Of 200 participants, 188 completed 3 years of treatment. Sustained growth was observed in both groups. At week 156, mean (SD) height velocity (HV) between weeks 104 and 156 was 7.4 (1.5) cm/year in the soma/soma group and 7.8 (1.4) cm/year in the switch group. At week 156, the soma/soma and switch groups had reached a mean (SD) height SD score (HSDS) of −0.95 (0.98) and −1.08 (0.93), respectively, and were approaching the mean mid-parental HSDS of −0.74 (for both groups). Mean total insulin-like growth factor I (IGF-I) SDS during year 3 was similar between groups and within normal range (−2.0 to +2.0). Bioactive IGF-I and bioactive IGF-I to IGF-I ratio were similar between groups. Somapacitan was well tolerated, with low proportions reporting injection-site reactions. Conclusions: Sustained efficacy and tolerability were observed for continuous somapacitan treatment for 3 years, and for 2 years after the switching from daily GH treatment. HSDS in both groups was approaching mean mid-parental HSDS. Clinical trial registration: NCT03811535

Background and Objectives: A few studies have explored the impairment of pituitary gonadotroph and Leydig cell function in men who recently ceased illicit androgen use, as assessed by stimulation tests. However, the capacity of the pituitary-testis axis in previous users who discontinued androgen use years ago remains unclear. This study evaluated the pituitary-testis-axis capacity in previous illicit androgen users and nonusers. Methods: We conducted a cross-sectional study of recreational strength training men with (n = 30) and without (n = 26) a history of illicit androgen use. Previous users were subdivided into 2 subgroups based on detectable (group 1, n = 17) and undetectable (group 2, n = 13) performance-enhancing drugs in the urine. We performed gonadotropin-releasing hormone and human chorionic gonadotropin (hCG) stimulation tests. Serum LH was measured with immunoassay, total testosterone, and insulin-like factor 3 with liquid chromatography-tandem mass spectrometry. Sexual function was assessed using the 15-question International Index of Erectile Function questionnaire. Results: Elapsed duration since androgen cessation, geometric mean (95% confidence interval), was 1.9 (1.2; 3.0) years in previous androgen users. The mean (SD) age of all participants was 33 (8) years. Testosterone secretion after hCG injection was lower in previous users than nonusers: group 1 difference, −6.4 (−11.3; −1.5) nmol/L, (P = .031); group 2 difference, −14.2 (−19.5; −8.8) nmol/L, (P < .001). LH secretion did not differ between the groups. Multivariate linear regressions using erectile function as a dependent variable revealed that higher testosterone secretion during the hCG test (P = .046) was independently associated with better erectile function, whereas baseline serum testosterone (P = .780) and estradiol (P = .405) were not. Conclusion: Previous illicit androgen users exhibited decreased Leydig cell capacity 2 years after androgen cessation, which potentially influences erectile function.