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      Managing congenital hypogonadotrophic hypogonadism: a contemporary approach directed at optimizing fertility and long-term outcomes in males

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          Abstract

          Hormonal induction of spermatogenesis offers men with azoospermia due to hypogonadotrophic hypogonadism (HH) the promising prospect of fertility restoration. However, an important exception is the subset of individuals affected by congenital hypogonadotrophic hypogonadism (CHH), also known as Kallmann syndrome if associated with anosmia, who often display dismal responses to fertility induction, despite prolonged therapy. This primarily stems from the loss of minipuberty, which is a crucial phase of testicular maturation in early life that has a far-reaching impact on eventual spermatogenic capacity. Further exacerbating the compromised reproductive health is the failure to initiate timely pubertal induction in many CHH patients, resulting in suboptimal genital and psychosexual development. In this paper, the clinical implications and management of male HH across the lifespan is comprehensively reviewed, with a special focus on novel strategies that have the potential to modify disease severity and maximize fertility potential in CHH by addressing the inadequacies of conventional approaches.

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          Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline

          To update the "Testosterone Therapy in Men With Androgen Deficiency Syndromes" guideline published in 2010.
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            Clinical practice. Delayed puberty.

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              Oligogenic basis of isolated gonadotropin-releasing hormone deficiency.

              Between the genetic extremes of rare monogenic and common polygenic diseases lie diverse oligogenic disorders involving mutations in more than one locus in each affected individual. Elucidating the principles of oligogenic inheritance and mechanisms of genetic interactions could help unravel the newly appreciated role of rare sequence variants in polygenic disorders. With few exceptions, however, the precise genetic architecture of oligogenic diseases remains unknown. Isolated gonadotropin-releasing hormone (GnRH) deficiency caused by defective secretion or action of hypothalamic GnRH is a rare genetic disease that manifests as sexual immaturity and infertility. Recent reports of patients who harbor pathogenic rare variants in more than one gene have challenged the long-held view that the disorder is strictly monogenic, yet the frequency and extent of oligogenicity in isolated GnRH deficiency have not been investigated. By systematically defining genetic variants in large cohorts of well-phenotyped patients (n = 397), family members, and unaffected subjects (n = 179) for the majority of known disease genes, this study suggests a significant role of oligogenicity in this disease. Remarkably, oligogenicity in isolated GnRH deficiency was as frequent as homozygosity/compound heterozygosity at a single locus (2.5%). Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%. No oligogenicity was detected among controls (P < 0.05), even though deleterious variants were present. Viewing isolated GnRH deficiency as an oligogenic condition has implications for understanding the pathogenesis of its reproductive and nonreproductive phenotypes; deciphering the etiology of common GnRH-related disorders; and modeling the genetic architecture of other oligogenic and multifactorial diseases.
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                Author and article information

                Contributors
                Journal
                Ther Adv Endocrinol Metab
                Ther Adv Endocrinol Metab
                TAE
                sptae
                Therapeutic Advances in Endocrinology and Metabolism
                SAGE Publications (Sage UK: London, England )
                2042-0188
                2042-0196
                10 February 2019
                2019
                : 10
                : 2042018819826889
                Affiliations
                [1-2042018819826889]Department of Endocrinology, Royal Victoria Infirmary, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, NE1 4LP, UK Institute of Genetic Medicine, University of Newcastle-upon-Tyne, NE1 3BZ, UK
                [2-2042018819826889]Royal Victoria Infirmary, Newcastle-upon-Tyne, UK
                Author notes
                Author information
                https://orcid.org/0000-0001-8162-6600
                Article
                10.1177_2042018819826889
                10.1177/2042018819826889
                6378644
                30800268
                dee73b27-3f84-4b68-8285-a5e37a578713
                © The Author(s), 2019

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 26 October 2018
                : 7 January 2019
                Categories
                Review
                Custom metadata
                January-December 2019

                hypogonadotrophic hypogonadism,kallmann syndrome,minipuberty,delayed puberty,infertility,spermatogenesis,gonadotrophin therapy

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