First baseline data of the Klinefelter ItaliaN Group (KING) cohort: clinical features of adult with Klinefelter syndrome in Italy.

BACKGROUND: Klinefelter syndrome (KS) is frustratingly under-diagnosed. KS have a broad spectrum of clinical features, making it difficult to identify.  OBJECTIVE: We describe KS clinical presentation in a large Italian cohort. DESIGN: This is the first observational cohort study within a national network, the Klinefelter ItaliaN Group (KING). Primary outcomes were to describe the basic clinical features and the actual phenotype of KS in Italy. Secondary outcomes were to determine age at diagnosis and geographical distribution. METHODS: We performed a basic phenotyping and evaluation of the hormonal values of 609 adult KS patients. RESULTS: Mean age at diagnosis was 37.4 ± 13.4 years. The overall mean testicular size was 3 ml, and 2.5 ml in both testes in untreated KS group. BMI was 26.6 ± 5.8 kg/m2, and 25.5% of KS had metabolic syndrome (MetS). LH and FSH were increased, and mean total testosterone were 350 ± 9.1 ng/dl. A descriptive analysis showed that 329 KS patients were evaluated in Northern Italy, 76 in Central and 204 in Southern Italy. Analysis of variance demonstrated significant statistical differences (p < 0001) between the age at diagnosis of the three geographical groups. Compared with the expected number among male patients matched for age in Italy, only 16% of KS patients received a diagnosis. CONCLUSIONS: These data are the results of the only national database available that collects the clinical and hormonal data of the KS patients, currently referred at the KING centers. In Italy the typical KS patient is overweight, with small testes, and elevated LH and FSH. Only 25.5% of them are diagnosed with MetS. Early detection and timely treatment are mandatory.

Thyroid and COVID-19: a review on pathophysiological, clinical and organizational aspects.

BACKGROUND: Thyroid dysfunction has been observed in patients with COVID-19, and endocrinologists are requested to understand this clinical issue. Pandemic-related restrictions and reorganization of healthcare services may affect thyroid disease management. OBJECTIVE AND METHODS: To analyze and discuss the relationship between COVID-19 and thyroid diseases from several perspectives. PubMed/MEDLINE, Google Scholar, Scopus, ClinicalTrial.gov were searched for this purpose by using free text words and medical subject headings as follows: "sars cov 2", "covid 19", "subacute thyroiditis", "atypical thyroiditis", "chronic thyroiditis", "hashimoto's thyroiditis", "graves' disease", "thyroid nodule", "differentiated thyroid cancer", "medullary thyroid cancer", "methimazole", "levothyroxine", "multikinase inhibitor", "remdesivir", "tocilizumab". Data were collected, analyzed, and discussed to answer the following clinical questions: "What evidence suggests that COVID-19 may induce detrimental consequences on thyroid function?"; "Could previous or concomitant thyroid diseases deteriorate the prognosis of COVID-19 once the infection has occurred?"; "Could medical management of thyroid diseases influence the clinical course of COVID-19?"; "Does medical management of COVID-19 interfere with thyroid function?"; "Are there defined strategies to better manage endocrine diseases despite restrictive measures and in-hospital and ambulatory activities reorganizations?". RESULTS: SARS-CoV-2 may induce thyroid dysfunction that is usually reversible, including subclinical and atypical thyroiditis. Patients with baseline thyroid diseases are not at higher risk of contracting or transmitting SARS-CoV-2, and baseline thyroid dysfunction does not foster a worse progression of COVID-19. However, it is unclear whether low levels of free triiodothyronine, observed in seriously ill patients with COVID-19, may worsen the disease's clinical progression and, consequently, if triiodothyronine supplementation could be a tool for reducing this burden. Glucocorticoids and heparin may affect thyroid hormone secretion and measurement, respectively, leading to possible misdiagnosis of thyroid dysfunction in severe cases of COVID-19. High-risk thyroid nodules require a fine-needle aspiration without relevant delay, whereas other non-urgent diagnostic procedures and therapeutic interventions should be postponed. DISCUSSION: Currently, we know that SARS-CoV-2 could lead to short-term and reversible thyroid dysfunction, but thyroid diseases seem not to affect the progression of COVID-19. Adequate management of patients with thyroid diseases remains essential during the pandemic, but it could be compromised because of healthcare service restrictions. Endocrine care centers should continuously recognize and classify priority cases for in-person visits and therapeutic procedures. Telemedicine may be a useful tool for managing patients not requiring in-person visits.

Thyroid function in Klinefelter syndrome: a multicentre study from KING group.

PURPOSE: The prevalence and the etiopathogenesis of thyroid dysfunctions in Klinefelter syndrome (KS) are still unclear. The primary aim of this study was to evaluate the pathogenetic role of hypogonadism in the thyroid disorders described in KS, with the scope to distinguish between patients with KS and hypogonadism due to other causes (Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, iatrogenic hypogonadism and acquired hypogonadotropic hypogonadism after surgical removal of pituitary adenomas) called non-KS. Therefore, we evaluated thyroid function in KS and in non-KS hypogonadal patients. METHODS: This is a case-control multicentre study from KING group: Endocrinology clinics in university-affiliated medical centres. One hundred and seventy four KS, and sixty-two non-KS hypogonadal men were enrolled. The primary outcome was the prevalence of thyroid diseases in KS and in non-KS. Changes in hormonal parameters were evaluated. Exclusion criterion was secondary hypothyroidism. Analyses were performed using Student's t test. Mann-Whitney test and Chi-square test. RESULTS: FT4 was significantly lower in KS vs non-KS. KS and non-KS presented similar TSH and testosterone levels. Hashimoto's thyroiditis (HT) was diagnosed in 7% of KS. Five KS developed hypothyroidism. The ratio FT3/FT4 was similar in both groups. TSH index was 1.9 in KS and 2.3 in non-KS. Adjustment for differences in age, sample size and concomitant disease in multivariate models did not alter the results. CONCLUSIONS: We demonstrated in KS no etiopathogenic link to hypogonadism or change in the set point of thyrotrophic control in the altered FT4 production. The prevalence of HT in KS was similar to normal male population, showing absence of increased risk of HT associated with the XXY karyotype.

The basal to total insulin ratio in outpatients with diabetes on basal-bolus regimen.

OBJECTIVE: To evaluate the basal/total ratio of daily insulin dose (b/T) in outpatients with diabetes type 1 (DM1) and type 2 (DM2) on basal-bolus regimen, by investigating whether there is a relationship with HbA1c and episodes of hypoglycemia. METHODS: Multicentric, observational, cross-sectional study in Italy. Adult DM1 (n = 476) and DM2 (n = 541) outpatients, with eGFR >30 mL/min/1.73 m2, on a basal-bolus regimen for at least six months, were recruited from 31 Italian Diabetes services between March and September 2016. Clinicaltrials.govID: NCT03489031. RESULTS: Total daily insulin dose was significantly higher in DM2 patients (52.3 ± 22.5 vs. 46 ± 20.9 U/day), but this difference disappeared when insulin doses were normalized for body weight. The b/T ratio was lower than 0.50 in both groups: 0.46 ± 0.14 in DM1 and 0.43 ± 0.15 in DM2 patients (p = 0.0011). The b/T was significantly higher in the patients taking metformin in both groups, and significantly different according to the type of basal insulin (Degludec, 0.48 in DM1 and 0.44 in DM2; Glargine, 0.44 in DM1 and 0.43 in DM2; Detemir, 0.45 in DM1 and 0.39 in DM2). The b/T ratio was not correlated in either group to HbA1c or incidence of hypoglycemia (<40 mg/dL, or requiring caregiver intervention, in the last three months). In the multivariate analysis, metformin use and age were independent predictors of the b/T ratio in both DM1 and DM2 patients, while the type of basal insulin was an independent predictor only in DM1. CONCLUSION: The b/T ratio was independent of glycemic control and incidence of hypoglycemia.

Effectiveness of gonadotropin administration for spermatogenesis induction in hypogonadotropic hypogonadism: a possible role of androgen receptor CAG repeat polymorphism and therapeutic measures.

Prepuberal-onset (PRHH) and postpuberal-onset (PSHH) Hypogonadotropic Hypogondism (HH) refer to a heterogeneous group of patients, showing a broad spectrum of clinical signs and symptoms of androgen deficiency in consideration of the different possible aetiologies and the age at onset. These patients, though, required Gonadotropin treatment (GnTh) by means of administration of both the ß Human Chorionic Gonodadotropin (ß HCG) and the Follicle Stimulating Hormone (FSH) to obtain mature sperms in the ejaculate aiming to reach fertility levels. However, the response to GnTh is always unpredictable concerning either the effectiveness or the duration of the therapy. Consequently, different studies have been carried out to identify clinical (i.e. cryptorchidism, gynecomastia, testis size, etc) and biochemical markers [serum Testosterone (T) and Inhibin B (IB)] that can be useful to predict the effectiveness of GnTh. Given that the actions of T, even those directed at inducing and maintaining spermatogenesis, are mediated by its interaction with the Androgen Receptor (AR), we measured the AR CAG repeat polymorphism in men with HH, in order to examine whether the CAG polymorphism extensions could co-regulate the GnTh effectiveness. Twenty-three HH subjects were subdivided according to the age at onset (pre- and postpubertal) and treated with the same scheme and doses of GnTh, extending the period of treatment up to 30 months. Thirty-five healthy and fertile men served as a control group (CG). Twelve HH subjects (3 PRHH and 9 PSHH), who reached complete spermatogenesis within 12 months, showed the length of AR CAG repeat number [20 (19-23) = median (interquartile range 25th - 75th percentile)] not statistically different from our CG [20 (19-22)], while CAG repeat number [23 (20-25)] of 11 HH patients (9 PRHH and 2 PSHH) who obtained mature sperms in their ejaculate beyond a year to within 30 months, was significantly higher. Our results suggest that the length of AR CAG repeat polymorphism might affect the response to GnTh in men suffering from HH, in particular in those patients with prepubertal-onset hypogonadism.

Difference in growth hormone response to growth hormone-releasing hormone (GHRH) testing following GHRH subacute treatment in normal aging and growth hormone-deficient adults: possible perspectives for therapeutic use of GHRH or its analogs in elderly subjects?

The somatotroph axis function shows a decline in the elderly (somatopause). In particular growth hormone (GH) response to GH-releasing hormone (GHRH) is reduced in aged man but less than that observed in GH-deficient adults (GHDAs). Plasma GH response to GHRH (1 µg/kg BW) was significantly lower in four GHDAs than in seven healthy aged men 30, 60, and 90 min after acute GHRH administration. To verify whether a priming regimen might be able to increase the reduced GH response to GHRH, both healthy aged men and GHDA patients underwent repetitive administration of GHRH (100 µg GHRH intravenously as a single morning dose, every 2 days for 12 days). After the GHRH-priming regimen, plasma GH values 30, 60, and 90 min after the acute GHRH test were significantly higher than values at the corresponding time points before priming regimen in healthy aged men but not in GHDA patients. These findings confirmed that somatotroph cells become less sensitive to GHRH with normal aging and demonstrate that repetitive administration of GHRH restores the attenuated response only in healthy aged men but not in GHDA patients. This could support the possible use of GHRH or its analogs instead of recombinant human GH in elderly patients with the advantage of preserving the endogenous pulses of GH with the secretion of the different isoforms of GH. However, concerns arise about the possible role of these molecules in tumorigenesis and tumor growth promotion.

Hormonal control of inhibin B in men.

Serum inhibin B (IB) and testosterone (T) levels, secreted by Sertoli cells (SC) and Leydig cells (LC), respectively, are parameters of the functional state of these cells. Whereas LC activity and, consequently, T secretion are regulated by serum LH, factors regulating IB secretion by SC are still partially unknown. There is evidence that under certain conditions such as puberty, aging or some spermatogenesis defects, LH levels or Gn-independent factors might contribute to regulating SC activity and IB secretion. Among these factors, GH and IGF-I as well as PRL might have a role. Therefore, in order to explore the possible effects of either LH alone and FSH alone or a combination of both Gn, respectively, on SC function, IB plasma levels and spermatogenesis, we studied their effects in 6 patients with hypogonadotropic hypogonadism (HH), whereas the effects of GH on these parameters were studied in 6 men with panhypopituitarism (PH). Finally, the possible effects of PRL on SC function and spermatogenesis were studied in 6 patients with hyperprolactinemia (HPRL); 24 normal, fertile adults served as control group. In men with HH, neither human chorionic Gn (hCG) nor FSH, respectively, were able to increase serum IB after 3 months of therapy, whereas combined Gn therapy for 24 months increased IB plasma levels and stimulated spermatogenesis in 4 out of 6 hypogonadal men. In panhypopituitaric men, GH added to the classical Gn therapy did not have an additional effect on serum IB levels or spermatogenesis. Surprisingly, in our hyperprolactemic men, IB plasma levels were increased and positively correlated (p<0.01) with serum PRL levels, whereas normalization of the latter by cabergoline treatment caused a decrease of IB levels and a moderate increase in T, LH and FSH. In conclusion, the lack of SC response to FSH therapy alone, as opposed to the response to combined Gn therapy, might indicate that normalization of serum T by hCG is required to obtain IB secretion by SC. Addition of GH did not affect SC function, serum IB levels or spermatogenesis. Finally, our data suggest that PRL plasma levels might have a direct role on IB secretion, suggesting that the hypogonadism found in patients with HPRL might be a consequence of both central (inhibition of Gn secretion) and peripheral (stimulation of IB secretion) origin.

Influence of some biological indexes on sex hormone-binding globulin and androgen levels in aging or obese males.

Several aspects of the regulation of androgen secretion and plasma levels in males remain controversial. Among these, we cite the problem of whether the age-related decrease in testosterone (T) levels is an intrinsic aging phenomenon or is a sequel of previous illness, the mechanisms underlying the increase in sex hormone-binding globulin (SHBG)-binding capacity in aging men and the supranormal capacity observed immediately after a weight-reducing diet, and the role of insulin in the age-associated decrease in dehydroepiandrosterone (sulfate) [DHEA (DHEAS)] levels. To gain further insight into these issues, we investigated the influence of age, smoking, body mass index (BMI), serum albumin, insulin, GH, and insulin-like growth factor I (IGF-I) levels, respectively, on androgen levels and SHBG-binding capacity in a nonobese healthy population (n = 250) as well as in an obese population (n = 50) before and after weight loss. The influence of GH supplementation on SHBG, DHEAS, DHEA, and insulin levels was studied in a small group of men (n = 8) with isolated GH deficiency. In nonobese healthy men, age was inversely correlated with serum levels of all androgens studied (although total T levels stayed relatively stable until age 55 yr) as well as with albumin, GH, and IGF-I levels and positively correlated with BMI, insulin levels, and SHBG-binding capacity. Nevertheless, SHBG levels were significantly negatively correlated with insulin levels (P < 0.001) as well as with mean 24-h GH and IGF-I levels. Among possible confounding factors affecting (free) T [(FT)] levels in healthy men, smoking appeared to be accompanied by higher (F)T levels than those in nonsmokers. BMI increased with age, but although BMI was negatively correlated with T, FT, and SHBG, respectively, the age-dependent decrease in T levels persisted after correction for BMI. Data not corrected for BMI may, nevertheless, overestimate the age-associated decrease in T levels. The albumin concentration decreased with age, and if FT is the feedback regulator of plasma T levels, albumin concentration might be a codeterminant (although, evidently, less important than SHBG) of T levels and contribute to the age-associated decrease in T levels. In any case, albumin concentration is a codeterminant of DHEAS concentration. T, DHEA, and DHEAS levels were significantly correlated, but this correlation disappeared after controlling for age; hence, there is no evidence for an adrenal-gonadal interaction in men. In obese men, T, FT, and SHBG levels were significantly lower than those in the nonobese men and inversely correlated with BMI; DHEAS levels were slightly lower than those in the nonobese controls, but no significant correlation between DHEA or DHEAS, and insulin levels was observed. After a weight-reducing, protein-rich diet, resulting in a mean weight loss of +/- 15 kg, SHBG-binding capacity increased to normal values notwithstanding the fact that the subjects were still obese and that the insulin levels remained higher than those in the nonobese controls. Considering that after weight loss, GH and IGF-I levels remained lower than those in the nonobese controls, that adult men with isolated GH deficiency presented with higher SHBG levels than normal controls, which decreased to normal levels during GH substitution, and that elderly men have elevated SHBG levels notwithstanding high insulin levels, we suggest that the low GH and/or IGF-I levels might play a role in the elevated SHBG levels observed in both elderly males and obese men after a weight-reducing diet. As weight loss did not influence DHEAS levels notwithstanding an important decrease in insulin levels, our data do not support a role of insulin in the regulation of plasma DHEAS levels.

Is plasma 5 alpha-androstane 3 alpha, 17 beta-diol glucuronide a biochemical marker of hirsutism in women?

We investigated whether plasma androstanediol glucuronide (ADG) levels reflect the increased androgenicity in women with idiopathic hirsutism (n = 24) or hirsutism associated with polycystic ovary syndrome (n = 10). We also evaluated whether ADG levels parallel the clinical evolution of the hirsutism during a combined treatment, with cyproteroneacetate (2 mg) and ethinylestradiol (35 micrograms), of women with moderate idiopathic hirsutism. Finally, we investigated if there is evidence for increased conversion of precursors to ADG in hirsutism, by comparing the ADG levels, measured by RIA, to ADG levels obtained by applying the conversion rates of precursors obtained in non-hirsute women. ADG levels were increased in less than half of the patients with mild hirsutism. The clinical cure of hirsutism, which was obtained by the treatment in majority of patients, was accompanied by a significant decrease of plasma ADG levels, but a similar decrease was also observed in the 5 patients who did not respond to treatment. The data show that, although there is evidence for increased conversion of precursors to plasma ADG in mildly hirsute women, the latter is not a reliable parameter of androgenicity. Our data suggest, moreover, that treatment with cyproterone acetate and ethinylestradiol decreases 5 alpha-reductase activity, as indicated by the more important decrease in ADG levels than in the precursors.

Hormonal effects of a 5 alpha-reductase inhibitor (finasteride) on hormonal levels in normal men and in patients with benign prostatic hyperplasia.

Finasteride is a potent competitive 5 alpha-reductase inhibitor, active at a dose as low as 1 mg/day. After a single dose, the effects on 5 alpha-reductase last as long as 7 days. Both hepatic and target tissue 5 alpha-reductase are inhibited. Plasma testosterone and estradiol are unaffected and luteinizing hormone levels do not change. During chronic treatment with finasteride 5 mg/day, the effects on 5 alpha-reductase are maintained. Since the only significant effect of chronic finasteride therapy appears to be 5 alpha-reductase inhibition, and testosterone or estradiol levels are not affected, neither libido nor potency is lost. Testosterone is the active androgen at the muscular level; therefore, muscular catabolism is not expected.

Leydig cell function in infertile men with idiopathic oligospermic infertility.

To evaluate Leydig cell function in men with idiopathic oligospermic infertility and its eventual role in their infertility, plasma LH, testosterone (T), 17-hydroxyprogesterone (170HP), and estradiol levels as well as plasma T/LH and 170HP/T ratios were measured in 103 such men, subdivided into different groups according to their plasma FSH levels. The results were compared to results in normal young fertile men, the subgroup of men with idiopathic oligospermic infertility who within 12 months after consultation succeeded in impregnating their partner, infertile men with a history of undescended testes (excryptorchid men), and men with Klinefelter's syndrome. As a tentative parameter of androgen insensitivity, an androgen insensitivity index [LH (IU/L) X T (nMol/L)] was calculated. Although all men with idiopathic infertility had plasma T and LH levels within the normal range, LH levels increased and T/LH ratios decreased with increasing FSH levels, while the 170HP/T and estradiol/T ratios were independent of the FSH levels and T/LH ratios. The decreased T/LH ratios in the presence of normal T levels suggest compensated Leydig cell insufficiency, which possibly contributes to the infertility. Indeed, none of the men (n = 12) with normal FSH levels but a T/LH ratio lower than 1.50 achieved fatherhood within 12 months of follow-up, although all other hormonal parameters were within the normal range. During the same period 25 men with T/LH ratios greater than 1.50 succeeded in impregnating their partners (P less than 0.05). In infertile excryptorchid men and even more so in men with Klinefelter's syndrome, plasma T levels and T/LH ratios were significantly decreased, the decrease being greater than in patients with idiopathic azospermia with similar FSH levels. None of the excryptorchid men with normal FSH levels but T/LH ratios below 1.50 fathered a child during the follow-up study. We suggest that the T/LH ratio is an additional useful prognostic parameter of infertility. Plasma T levels were increased in 15% of patients with idiopathic infertility, but increased plasma LH together with increased T levels (increased androgen resistance index) were found in only 1 man. An increased index, however, was found in 6 azoospermic excryptorchid men and 4 of 28 men with Klinefelter's syndrome. Taken together these data suggest that this index is not a reliable parameter of androgen resistance.

Recovery of fertility in a hypogonadotropic man apparently resistant to gonadotrophin treatment.

Two subjects affected by panhypopituitarism, 17 and 19 years of age, were evaluated. One of the patients was able to ejaculate sperm (14 X 10(6)/ml) after 12 months of hMG-hCG therapy (75 IU 2 degrees IRP HMG + 850 IU hCG twice a week). In the other subject sperm production was not achieved until 6 1/2 years of uninterrupted therapy had been completed although the hCG doses were doubled and then quadrupled. In the patient who responded promptly to the therapy, blood levels of both FSH (2.5) and LH (1.7 (mUI/ml 2 degrees IRP hMG-RIA methods) were indeed detectable through very low. In the patient resistant to the therapy, FSH levels were still detectable (2.2 mUI/ml), but LH was undetectable at all. The seminiferous tubules of this patient contained few spermatogonia, and these would be attributed to the action of FSH by itself. However, the importance of endogenous LH in determining the maturation of the testes is stressed by the very long period of hCG therapy required to obtain in this patient ejaculations of sperm. Careful evaluation must be made of circulating FSH and LH levels, of FSH and LH pituitary stores, and of testicular biopsy scores when assessing prognosis of fertility and adequate treatment of hypogonadotropic subjects. In cases of severe LH deficiency a delayed response of the testis would be expected and recovery of fertility considered possible even when gonadotropin therapy is unsuccessful for many years.