The risk of developing mammary carcinoma may be increased relative to normal men but remains a rare occurrence and routine surveillance is not recommended (100; 101). In early puberty, LH and FSH increase while serum levels of testosterone plateaus at or just below the lower limit of the normal range. However, in some adult Klinefelter patients, foci of spermatogenesis up to the stage of mature testicular sperm can be detected ((97), and see below). To avoid symptoms of androgen deficiency, hormone replacement therapy should be initiated as early as needed. When testosterone serum levels are reduced, substitution with testosterone is necessary. However, Sciurano et al. nicely showed by fluorescence in situ hybridization (FISH) in testicular tissue of Klinefelter patients that all meiotic spermatocytes were euploid 46,XY(119). So far, over 170 babies were born using testicular sperm for ISCI, all showing normal karyotype, although aneuploidies can be occasionally found by preimplantation or prenatal diagnosis (117). Studies of the numerous mouse knock out models that display a spermatogenic phenotype, including sperm cell arrest, has contributed little of clinical relevance to the large number of men with idiopathic infertility. In some patients with predominant round spermatid maturation arrest, the expression of cAMP Responsive Element Modulator (CREM) is significantly reduced or undetectable (52). The BRDT protein is localized in the nuclei of spermatocytes, spermatids, and ejaculated spermatozoa, and transcription is almost zero in primary spermatocytes of testes showing meiotic arrest (51). Heat shock protein levels are low or absent, such as heat shock transcription factor, Y chromosome (HSFY) (39) or HSPA2 that is involved in DNA mismatch repair (MMR) (40). A major subgroup of patients lacks BOULE protein expression in primary spermatocytes, which is key factor of meiosis (38). Patients should be counseled on likelihood of successful treatment with TRT, particularly that the higher their systemic burden of disease, the less likely they are to have symptomatic improvement with therapy. Occasionally, patients may desire to continue therapy even without significant symptomatic improvement. Recently, a health phenotype score termed ACTIONS was developed, which was validated as an instrument that correlates comorbidity burden with urologic symptoms. Thus, TRT may lead to a non-response in certain hypogonadal men with symptoms primarily driven by their comorbidities rather than hypogonadism. Given that the symptoms in hypogonadal men are non-specific in nature, men with additional comorbidities may present with symptoms that are due to hypogonadism or their comorbid conditions or both. Low testosterone (male hypogonadism) is a condition in which your testicles don’t produce enough testosterone. The long arm of the Y chromosome contains three partially overlapping but discrete regions that are essential for normal spermatogenesis (136; 139). Translocations between the X chromosome and an autosome usually result in disturbed spermatogenesis, whereas inversions of the X chromosome do not substantially affect male fertility. For any carrier of a structural chromosome abnormality who considers fatherhood by any means, genetic counselling is strongly recommended, and it should be obligatory prior to any infertility treatment (133; 134). Infertile patients with structural chromosomal aberrations may conceive naturally while more severe cases may require 'symptomatic' treatment modalities such as intracytoplasmic sperm injection, however, success rates may be lower than in couples with normal karyotypes (131). Conversely, men with impaired spermatogenesis show an increased prevalence of structural chromosomal abnormalities (129; 91; 92).
