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The hypothalamic–pituitary–thyroid hormone axis might be affected in COVID-19, but existing studies have shown varying results. It has been hypothesized that hyperinflammation, as reflected by the secretion of cytokines, might induce thyroid dysfunction among patients with COVID-19. We explored thyroid hormone involvement in the acute phase of symptomatic COVID-19 and its possible associations with cytokine levels and mortality risk. This was a single-center study of 116 consecutive patients hospitalized for moderate-to-severe COVID-19 disease. Serum concentrations of thyroid-stimulating hormone (TSH), free thyroxine (T4), and 45 cytokines/chemokines were measured in all patients within 3 days of admission. Data were extracted retrospectively through a manual review of health records. At admission, 95 (81.9%) were euthyroid; while 21 (18.1%) had biochemically thyroid dysfunction including subclinical thyrotoxicosis (n= 11), overt thyrotoxicosis (n= 2), hypothyroidism (n= 1), non-thyroidal illness (n= 2), and normal TSH but high free T4(n= 5). TSH levels were inversely correlated with IL-8 (rs= –0.248), IL-10 (rs= –0.253), IL-15 (rs= –0.213), IP-10 (rs= –0.334), and GM-CSF (rs= –0.254). Moreover, IL-8 levels, IP-10, and GM-CSF were significantly higher in patients with serum TSH < 0.4 mIU/L. Lastly, a two-fold increment of IL-8 and IL-10 was associated with significantly higher odds of having TSH < 0.4 mIU/L (odds ratio 1.86 (1.11–3.10) and 1.78 (1.03–3.06)). Serum TSH was not associated with 30- or 90-day mortality. In conclusion, this study suggests that fluctuations of TSH levels in patients with COVID-19 may be influenced by circulating IL-8, IL-10, IL-15, IP-10, and GM-CSF as previously described in autoimmune thyroid diseases.

Purpose: Insulin-like factor 3 (INSL3) is an emerging testicular marker, yet larger studies elucidating the clinical role of INSL3 in patients with hypogonadism are lacking. The aim was to describe serum INSL3 concentrations analyzed by LC–MS/MS methodology in males with hypogonadotropic hypogonadism (HH) and Klinefelter syndrome (KS). Methods: This was a combined study from two tertiary centers in Denmark and France analyzing INSL3 concentrations by LC–MS/MS. In total, 103 patients with HH and 82 patients with KS were grouped into treated (HH: n= 96; KS: n= 71) or untreated (HH: n= 7; KS: n= 11). Treatment modalities included testosterone and hCG. Serum concentrations and standard deviation (SD) scores of INSL3, total testosterone, and LH according to age and treatment were evaluated. Results: In both HH and KS, INSL3 concentrations were low. In HH, INSL3 was low regardless of treatment, except for some hCG-treated patients with normal concentrations. In untreated HH, testosterone was low, while normal to high in most testosterone- and hCG-treated patients. In untreated KS, INSL3 and testosterone concentrations were low to normal, while in testosterone-treated KS, serum INSL3 was low in most patients. INSL3 SD scores were significantly lower in untreated HH than in untreated KS (p= 0.01). Conclusions: The dichotomy between lower INSL3 and higher testosterone concentrations, particularly observed in hCG-treated patients with HH, confirms that INSL3 is a different marker of Leydig cell function than testosterone. However, the clinical application of INSL3 in males with hypogonadism remains unclear.

In a large group of healthy infants, we defined sex-specific cutoff values and applied these in infants with disorders of sex development.

Context:Puberty is initiated by a complex interaction of suppressing and stimulating factors. Genetic studies of familial central precocious puberty have suggested makorin ring finger protein 3 (MKRN3) as a major inhibitor of GnRH secretion during childhood. Furthermore, genetic variation near MKRN3(rs12148769) affects age at menarche in healthy girls.Objective:The purpose of this study was to evaluate whether serum levels of MKRN3 declined before pubertal onset in healthy girls.Design:This was a population-based longitudinal study of healthy Danish girls and a cohort study of early maturing girls.Setting:The study was performed in the general community and in a tertiary referral center for pediatric endocrinology.Patients or Other Participants:Healthy girls (n = 38) aged 9.3 years (range, 5.9–11.3 years) at baseline and followed for 6.0 years (2.7–7.6 years) (2006–2014) with blood sampling every 6 months and early maturing girls (n = 13) with breast development ay <8.3 years of age were included.Main Outcome Measures:Serum levels of MKRN3 were measured in 354 samples (median, 9 per girl; range, 2–14 per girl), and genotyping of variants near MKRN3(rs12148769 and rs12439354) was performed.Results:MKRN3 concentrations declined preceding pubertal onset; the geometric mean (95% confidence interval) 3 years before pubertal onset vs the last visit before pubertal onset was 304 pg/mL (264–350 pg/mL) vs 257 pg/mL (243–273 pg/mL), corresponding to a reduction of 15% (1–27%) (P= .033). In prepubertal girls, circulating MKRN3 correlated negatively with gonadotropin levels: for FSH, r= −0.262 (P= .015) and for LH, r= −0.226 (P= .037). After adjustment, MKRN3 levels were lower in early maturing girls than in age-matched prepubertal girls: 171 pg/mL (<25–333 pg/mL) vs 262 pg/mL (94–624 pg/mL) (P= .051). Genetic variants near MKRN3did not correlate with serum levels of MKRN3.Conclusions:Declining levels of circulating MKRN3 preceded pubertal onset. The negative correlation between MKRN3 and gonadotropins further supports MKRN3 as a major regulator of hypothalamic GnRH secretion during childhood. Undetectable or low MKRN3 levels were observed in a subgroup of patients with early onset of puberty.