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Disorders of Puberty: The Causes and the Endocrine Medical Treatment

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Endocrinology & Metabolism".

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 64111

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Prof. Dr. Sandro La Vignera

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Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
Interests: male infertility; female infertility; osteoporosis; transitional age; diabetes; thyroid gland; male and female sexual disorders; neuroendocrine tumors
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Prof. Dr. Aldo E. Calogero

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Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
Interests: endocrinology of reproduction and sexuality
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Male idiopathic infertility is highly spread world-wide. Meta-regression studies provide evidence for a major decrease of conventional sperm parameters with age. The reasons for this decline are not well-understood, and therefore research into its causes is urgently needed. Since pubertal disorders may hide abnormal Sertoli cell (SC) function, the early detection of these abnormalities might help to prevent male idiopathic infertility. Therefore, the aim of the present Special Issue is to deeply examine the physiology of gonadal and sexual differentiation, minipuberty, GnRH neuron and SC function, as well as the physiopathology of disorders of sex development (DSD), and to provide an updated overview of the etiology and treatments that are currently available for delayed and precocious puberty. Diagnostic strategies for the early diagnosis of pubertal disorders and the assessment of testicular function in childhood and transitional age will also be discussed. In summary, andrological counseling should take place early in life. This practice might help to slow down the temporal decline in sperm concentration and count.

Prof. Dr. Sandro La Vignera
Prof. Dr. A.E. Calogero
Guest Editors

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Keywords

gonadal differentiation
sex development
Sertoli cells
IGF1
AMH
pubertal disorders
delayed puberty
precocious puberty

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Published Papers (11 papers)

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Editorial

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3 pages, 301 KiB

Open AccessEditorial

Disorders of Puberty: Endocrinology of the Pre-Pubertal Testis

by Sandro La Vignera, Rossella Cannarella, Rosita A. Condorelli and Aldo E. Calogero

J. Clin. Med. 2020, 9(3), 780; https://doi.org/10.3390/jcm9030780 - 13 Mar 2020

Cited by 4 | Viewed by 3886

Abstract

Male infertility is a widespread condition among western countries. Meta-regression data show that sperm concentration and total sperm count have halved in the last decades. The reasons of this decline are still unclear. The evaluation of testicular function in pre-pubertal children may be effective in the timely detection of Sertoli cell (SC) disfunction, which anticipates the diagnosis of male infertility. The aim of this Special Issue is to gather together in vitro evidence on SC physiology, causes of SC dysfunction, and to suggest a practical approach to be adopted in children. Full article

(This article belongs to the Special Issue Disorders of Puberty: The Causes and the Endocrine Medical Treatment)

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Research

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12 pages, 1401 KiB

Open AccessArticle

Testicular Function of Childhood Cancer Survivors: Who Is Worse?

by Ylenia Duca, Andrea Di Cataldo, Giovanna Russo, Emanuela Cannata, Giovanni Burgio, Michele Compagnone, Angela Alamo, Rosita A. Condorelli, Sandro La Vignera and Aldo E. Calogero

J. Clin. Med. 2019, 8(12), 2204; https://doi.org/10.3390/jcm8122204 - 13 Dec 2019

Cited by 14 | Viewed by 3293

Abstract

Background: A multi-disciplinary approach has led to an improvement in prognosis of childhood cancers. However, in parallel with the increase in survival rate, there is a greater occurrence of long-term toxicity related to antineoplastic treatment. Hypogonadism and infertility are among the most frequent endocrinological sequelae in young adult childhood cancer survivors. The aim of this study was to identify which category of patients, grouped according to diagnosis, therapy, and age at treatment, shows the worst reproductive function in adulthood. Methods: We evaluated morpho-volumetric development of the testis, endocrine function of the hypothalamic–pituitary–gonadal axis, and sperm parameters in 102 young adult childhood cancer survivors. Results: Overall, about one-third of patients showed low total testicular volume, total testosterone (TT) <3.5 ng/mL, and altered sperm count. Hodgkin’s disease, hematopoietic stem cell transplantation, and non-cranial irradiation associated to chemotherapy were risk factors for poor gonadal function. Patients treated in pubertal age showed lower total testicular volume; however, the difference was due to more gonadotoxic treatment performed in older age. Testicular volume was more predictive of spermatogenesis than follicle-stimulating hormone (FSH), while anti-Müllerian hormone (AMH) was not useful in the evaluation of testicular function of male childhood cancer survivors. Conclusions: Pre-pubertal subjects at high risk of future infertility should be candidates for testicular tissue cryopreservation. Full article

(This article belongs to the Special Issue Disorders of Puberty: The Causes and the Endocrine Medical Treatment)

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10 pages, 1226 KiB

Open AccessArticle

The Risky Health Behaviours of Male Adolescents in the Southern Italian Region: Implications for Sexual and Reproductive Disease

by Anna Perri, Danilo Lofaro, Giulia Izzo, Benedetta Aquino, Massimo Bitonti, Giuseppe Ciambrone, Sandro La Vignera, Carlotta Pozza, Daniele Gianfrilli and Antonio Aversa

J. Clin. Med. 2019, 8(9), 1414; https://doi.org/10.3390/jcm8091414 - 8 Sep 2019

Cited by 6 | Viewed by 2762

Abstract

Recent epidemiological studies suggest an increase of sexual and reproductive chronic diseases caused by problematic behaviours acquired during peri-pubertal age. The aims of our study were: (i) to investigate awareness of sexual transmitted infections (STIs) among adolescents; (ii) to describe the close relationship between possibly incorrect lifestyles during adolescence and reproductive and sexual disturbances during adulthood. The “Amico-Andrologo” survey is a permanent nationwide surveillance program supported by the Italian Ministry of Health. We administered a validated structured interview to investigate the lifestyle of adolescents and their knowledge of STIs. We selected a cohort of 360 male high-school students aged ≥18 years old. In this cohort, 150 (41.5%) were smokers while 59 (19.7%) smoked more than 10 cigarettes/day; 25 (9.3%) declared a consumption ≥6 drinks/weekend; and 65 (19.7%) were habitual cannabis consumers (at least twice/week). Among the sample of students selected, the main sources of sexual disease information were the internet and friends. The perceived level of knowledge on STIs was the same between students that used contraceptive methods and students that did not. The present results demonstrate that adolescents in Calabria do not receive appropriate information about risky health behaviours. Therefore, there is a necessity for specific educational programs to increase awareness of dangerous behaviours during the transitional age that is relevant for a safe sexual and reproductive adult life. Full article

(This article belongs to the Special Issue Disorders of Puberty: The Causes and the Endocrine Medical Treatment)

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9 pages, 1249 KiB

Open AccessArticle

Effects of GH and IGF1 on Basal and FSH-Modulated Porcine Sertoli Cells In-Vitro

by Rossella Cannarella, Francesca Mancuso, Rosita A. Condorelli, Iva Arato, Laura M. Mongioì, Filippo Giacone, Cinzia Lilli, Catia Bellucci, Sandro La Vignera, Riccardo Calafiore, Giovanni Luca and Aldo E. Calogero

J. Clin. Med. 2019, 8(6), 811; https://doi.org/10.3390/jcm8060811 - 6 Jun 2019

Cited by 20 | Viewed by 3182

Abstract

Several lines of evidence suggest that insulin-like growth factor 1 (IGF1) is involved in Sertoli cell (SC) proliferation and that its receptor (IGF1R) could mediate follicle-stimulating hormone (FSH) effects. To examine the role of the growth hormone (GH)-IGF1 axis on SC function, we evaluated the effects of GH and IGF1 on basal and FSH-modulated SC proliferation, as well as on anti-Müllerian hormone (AMH) and inhibin B expression and secretion in-vitro. SCs from neonatal pigs were incubated with (1) placebo, (2) 100 nM highly purified urofollitropin (hpFSH), (3) 100 nM recombinant GH (rGH), (4) 100 nM recombinant IGF1 (rIGF1), (5) 100 nM hpFSH plus 100 nM rGH, (6) 100 nM hpFSH plus 100 nM rIGF1, for 48 h. We found that IGF1, but not FSH nor GH, stimulated SC proliferation. Furthermore, an inhibitory effect of FSH, GH and IGF1 on AMH secretion, and a stimulatory role of FSH and IGF1, but not GH, on inhibin B secretion were found. These results suggest that the GH-IGF1 axis influences basal and FSH-modulated SC proliferation and function. We speculate that SC proliferation occurring in childhood might be supported by the increased serum IGF1 levels observed during this period of life. Full article

(This article belongs to the Special Issue Disorders of Puberty: The Causes and the Endocrine Medical Treatment)

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11 pages, 1926 KiB

Open AccessArticle

Effects of Insulin on Porcine Neonatal Sertoli Cell Responsiveness to FSH In Vitro

by Rossella Cannarella, Iva Arato, Rosita A. Condorelli, Laura M. Mongioì, Cinzia Lilli, Catia Bellucci, Sandro La Vignera, Giovanni Luca, Francesca Mancuso and Aldo E. Calogero

J. Clin. Med. 2019, 8(6), 809; https://doi.org/10.3390/jcm8060809 - 6 Jun 2019

Cited by 16 | Viewed by 3028

Abstract

There is ongoing debate as to whether the decline of sperm production in recent times may be related to a parallel increase in the rate of obesity and diabetes. Lower anti-Müllerian hormone (AMH) and inhibin B secretion have been observed in young hyperinsulinemic patients compared to healthy controls, suggesting a Sertoli cell (SC) dysfunction. The pathophysiological mechanisms underlying SC dysfunction in these patients are poorly understood. To the best of our knowledge, no evidence is available on the effects of insulin on SC function. Therefore, this study was undertaken to assess the effects of insulin on basal and follicle-stimulating hormone (FSH)-stimulated SC function in vitro. To accomplish this, we evaluated the expression of AMH, inhibin B and FSHR genes, the secretion of AMH and inhibin B and the phosphorylation of AKT473 and SC proliferation on neonatal porcine SC after incubation with FSH and/or insulin. We found that similar to FSH, the expression and secretion of AMH is suppressed by insulin. Co-incubation with FSH and insulin decreased AMH secretion significantly more than with FSH alone. Insulin had no effect on the expression and secretion of the inhibin B gene, but co-incubation with FSH and insulin had a lower effect on inhibin B secretion than that found with FSH alone. FSH and/or insulin increased AKT473 phosphorylation and SC proliferation. In conclusion, the results of this study showed that insulin modulates SC function. We hypothesize that hyperinsulinemia may therefore influence testicular function even before puberty begins. Therefore, particular care should be taken to avoid the onset of hyperinsulinemia in children to prevent a future deleterious effect on fertility. Full article

(This article belongs to the Special Issue Disorders of Puberty: The Causes and the Endocrine Medical Treatment)

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8 pages, 1076 KiB

Open AccessArticle

Thyroid Hormones and Spermatozoa: In Vitro Effects on Sperm Mitochondria, Viability and DNA Integrity

by Rosita A. Condorelli, Sandro La Vignera, Laura M. Mongioì, Angela Alamo, Filippo Giacone, Rossella Cannarella and Aldo E. Calogero

J. Clin. Med. 2019, 8(5), 756; https://doi.org/10.3390/jcm8050756 - 27 May 2019

Cited by 18 | Viewed by 3787

Abstract

The aim of this study wasto assess the in vitro effects of levothyroxine (LT4) on conventional and bio-functional sperm parameters and its implications on fertility. Patients with male idiopathic infertility were enrolled and subjected to examination of the seminal fluid and capacitation according to the WHO 2010 criteria and flow cytometric sperm analysis for the evaluation of bio-functional sperm parameters. LT4 significantly increased the percentage of spermatozoa with high mitochondrial membrane potential (MMP), decreased the percentage of spermatozoa with low MMP and increased sperm motility already at a concentration of 0.9 pmol L⁻¹. Therefore, LT4 significantly reduced sperm necrosis and lipid peroxidation ameliorating chromatin compactness. These effects of LT4 were evident at a concentration of 2.9 pmol L⁻¹, close to the physiological free-thyroxine (FT4) concentrations in the seminal fluid of euthyroid subjects. We showed a beneficial role of thyroid hormones on sperm mitochondrial function, oxidative stress and DNA integrity. The results of this in vitro study could have a clinical application in patients with idiopathic infertility, clarifying the role of thyroid function on male fertility. Full article

(This article belongs to the Special Issue Disorders of Puberty: The Causes and the Endocrine Medical Treatment)

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8 pages, 1011 KiB

Open AccessArticle

Poor Efficacy of L-Acetylcarnitine in the Treatment of Asthenozoospermia in Patients with Type 1 Diabetes

by Rosita A. Condorelli, Aldo E. Calogero, Rossella Cannarella, Filippo Giacone, Laura M. Mongioi’, Laura Cimino, Antonio Aversa and Sandro La Vignera

J. Clin. Med. 2019, 8(5), 585; https://doi.org/10.3390/jcm8050585 - 28 Apr 2019

Cited by 3 | Viewed by 2892

Abstract

Introduction. In recent years, research has focused on the impact that diabetes mellitus (DM) has on male reproductive function. The available evidence has mainly considered type 2 DM (DM2). However, we have previously shown that type 1 DM (DM1) also affects male reproductive health. Given the efficacy of carnitine in the treatment of male infertility, a topic that merits further investigation is its role in the treatment of infertile patients with DM1. Aim. To investigate the efficacy of carnitines for the treatment of asthenozoospermia in DM1 patients. Methods. This was a two-arm single-blind, randomized control trial. The patients enrolled in this study were assigned to the group receiving L-acetylcarnitine (LAC) (1.5 g daily for 4 months) or to the group receiving LAC (same dosage) plus L-carnitine (LC) (2 g daily for 4 months). Serum-glycated hemoglobin levels did not differ significantly after either of the two treatments given. Administration of LAC plus LC showed greater efficacy on progressive sperm motility than single therapy (increase 14% vs. 1% after treatment, respectively). Discussion. The results of this study showed that the administration of LAC plus LC is more effective than the administration of LAC alone. The lower efficacy of LAC alone could be due to the lower overall administered dosage. Alternatively, a selective defect of carnitine transporters at an epididymal level could be hypothesized in patients with DM1. Further studies are needed to clarify this point. Full article

(This article belongs to the Special Issue Disorders of Puberty: The Causes and the Endocrine Medical Treatment)

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9 pages, 2128 KiB

Open AccessArticle

The IGF1 Receptor Is Involved in Follicle-Stimulating Hormone Signaling in Porcine Neonatal Sertoli Cells

by Rossella Cannarella, Iva Arato, Rosita A. Condorelli, Giovanni Luca, Federica Barbagallo, Angela Alamo, Catia Bellucci, Cinzia Lilli, Sandro La Vignera, Riccardo Calafiore, Francesca Mancuso and Aldo E. Calogero

J. Clin. Med. 2019, 8(5), 577; https://doi.org/10.3390/jcm8050577 - 27 Apr 2019

Cited by 18 | Viewed by 3495

Abstract

Experimental evidence has shown that the IGF1 receptor (IGF1R) is involved in testicular development during embryogenesis. More recently, data gathered from mice granulosa cells and zebrafish spermatogonia suggest that IGF1R has a role in Follicle-stimulating hormone (FSH) signaling. No evidence has been reported on this matter in Sertoli cells (SCs) so far. The aim of the study was to evaluate the role, if any, of the IGF1R in FSH signaling in SCs. The effects of FSH exposure on myosin-phosphatase 1 (MYPT1), ERK 1/2, AKT³⁰⁸, AKT⁴⁷³, c-Jun N-terminal kinase (JNK) phosphorylation and on anti-Müllerian hormone (AMH), inhibin B and FSH receptor (FSHR) mRNA levels were assessed with and without the IGF1R inhibitor NVP-AEW541 in purified and functional porcine neonatal SCs. Pre-treatment with NVP-AEW541 inhibited the FSH-induced MYPT1 and ERK 1/2 phosphorylation, decreased the FSH-dependent Protein kinase B (AKT)³⁰⁸ phosphorylation, but did not affect the FSH-induced AKT⁴⁷³ and JNK phosphorylation rate. It also interfered with the FSH-induced AMH and FSHR down-regulation. No influence was observed on the FSH-stimulated Inhibin B gene expression. Conclusion. These findings support the role of theIGF1R in FSH signaling in porcine SCs. The possible influence of IGF1 stimulation on the FSH-mediated effects on SCs should be further explored. Full article

(This article belongs to the Special Issue Disorders of Puberty: The Causes and the Endocrine Medical Treatment)

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Review

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11 pages, 410 KiB

Open AccessReview

Management and Treatment of Varicocele in Children and Adolescents: An Endocrinologic Perspective

by Rossella Cannarella, Aldo E. Calogero, Rosita A. Condorelli, Filippo Giacone, Antonio Aversa and Sandro La Vignera

J. Clin. Med. 2019, 8(9), 1410; https://doi.org/10.3390/jcm8091410 - 8 Sep 2019

Cited by 15 | Viewed by 9266

Abstract

Pediatric varicocele has an overall prevalence of 15%, being more frequent as puberty begins. It can damage testicular function, interfering with Sertoli cell proliferation and hormone secretion, testicular growth and spermatogenesis. Proper management has a pivotal role for future fertility preservation. The aim of this review was to discuss the diagnosis, management and treatment of childhood and adolescent varicocele from an endocrinologic perspective, illustrating the current evidence of the European Society of Pediatric Urology (ESPU), the European Association of Urology (EAU), the American Urological Association (AUA) and the American Society for Reproductive Medicine (ASRM) scientific societies. According to the ASRM/ESPU/AUA practice committee, the treatment of adolescent varicocele is indicated in the case of decreased testicular volume or sperm abnormalities, while it is contraindicated in subclinical varicocele. The recent EAS/ESPU meta-analysis reports that moderate evidence exists on the benefits of varicocele treatment in children and adolescents in terms of testicular volume and sperm concentration increase. No specific phenotype in terms of testicular volume cut-off or peak retrograde flow (PRF) is indicated. Based on current evidence, we suggest that conservative management may be suggested in patients with PRF < 30 cm/s, testicular asymmetry < 10% and no evidence of sperm and hormonal abnormalities. In patients with 10–20% testicular volume asymmetry or 30 < PRF ≤ 38 cm/s or sperm abnormalities, careful follow-up may ensue. In the case of absent catch-up growth or sperm recovery, varicocele repair should be suggested. Finally, treatment can be proposed at the initial consultation in painful varicocele, testicular volume asymmetry ≥ 20%, PRF > 38 cm/s, infertility and failure of testicular development. Full article

(This article belongs to the Special Issue Disorders of Puberty: The Causes and the Endocrine Medical Treatment)

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26 pages, 806 KiB

Open AccessReview

Substance Abuse and Male Hypogonadism

by Ylenia Duca, Antonio Aversa, Rosita Angela Condorelli, Aldo Eugenio Calogero and Sandro La Vignera

J. Clin. Med. 2019, 8(5), 732; https://doi.org/10.3390/jcm8050732 - 22 May 2019

Cited by 45 | Viewed by 24694

Abstract

Progressive deterioration of male reproductive function is occurring in Western countries. Environmental factors and unhealthy lifestyles have been implicated in the decline of testosterone levels and sperm production observed in the last fifty years. Among unhealthy lifestyles, substance and drug abuse is a recognized cause of possible alterations of steroidogenesis and spermatogenesis. Alcohol, opioids and anabolic-androgenic steroids are capable to reduce testosterone production in male interfering with testicular and/or hypothalamic-pituitary function. Other substances such as nicotine, cannabis, and amphetamines alter spermatogenesis inducing oxidative stress and subsequent apoptosis in testicular tissue. Substance and drug abuse is a potentially reversible cause of hypogonadism, defined as the failure of the testis to produce physiological concentrations of testosterone and/or a normal number of spermatozoa. The identification of the abuse is important because the withdrawal of substance intake can reverse the clinical syndrome. This review summarizes the most important clinical and experimental evidence on the effect of substance abuse on testosterone and sperm production. Full article

(This article belongs to the Special Issue Disorders of Puberty: The Causes and the Endocrine Medical Treatment)

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Other

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7 pages, 647 KiB

Open AccessOpinion

Early Identification of Isolated Sertoli Cell Dysfunction in Prepubertal and Transition Age: Is It Time?

by Sandro La Vignera, Rosita A. Condorelli, Laura Cimino, Rossella Cannarella, Filippo Giacone and Aldo E. Calogero

J. Clin. Med. 2019, 8(5), 636; https://doi.org/10.3390/jcm8050636 - 9 May 2019

Cited by 5 | Viewed by 2774

Abstract

The male transitional phase is of fundamental importance for future fertility. This aspect is largely neglected in clinical practice. This opinion aims to shed light on these issues. The children frequently complete the transition phase with a slight reduction of testicular volume. The system of detecting testicular volume is often inadequate. These patients evidently complete puberty in an incomplete way because they do not reach an adequate testicular volume, albeit in the presence of adequate height and regular secondary sexual characteristics. Full article

(This article belongs to the Special Issue Disorders of Puberty: The Causes and the Endocrine Medical Treatment)

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