Klinefelter syndrome (KS) is the most common genetic form of male hypogonadism, but the phenotype becomes evident only after puberty. During childhood, and even during early puberty, pituitary-gonadal function in 47,XXY subjects is relatively normal, but from midpuberty onwards, FSH and LH levels increase to hypergonadotropic levels, inhibin B decreases to undetectable levels, and testosterone after an initial increase levels off at a low or low-normal level. Hence, most adult KS males display a clear hypergonadotropism with a varying degree of androgen deficiency; subsequently, testosterone substitution therapy is widely used to prevent symptoms and sequels of androgen deficiency. Testicular biopsies of prepubertal KS boys have shown preservation of seminiferous tubules with reduced numbers of germ cells, but Sertoli and Leydig cells have appeared normal. The testes in the adult KS male are, however, characterized by extensive fibrosis and hyalinization of the seminiferous tubules, and hyperplasia of the interstitium, but the tubules may show residual foci of spermatogenesis. Introduction of testicular sperm extraction in combination with intracytoplasmic sperm injection techniques has allowed non-mosaic KS males to father children.

Natural history of seminiferous tubule degeneration in Klinefelter syndrome.Hum Reprod Update. 2006 Jan-Feb;12(1):39-48. Epub 2005 Sep 19.

Klinefelter syndrome (47,XXY) is characterized by small, firm testis, gynaecomastia, azoospermia and hypergonadotropic hypogonadism. Degeneration of the seminiferous tubules in 47,XXY males is a well-described phenomenon. It begins in the fetus, progresses through infancy and accelerates dramatically at the time of puberty with complete hyalinization of the seminiferous tubules, although a few tubules with spermatogenesis may be present in adult life. Activation of the pituitary-gonadal axis at 3 months of age is seen in Klinefelter boys similar to healthy boys. However, the level of testosterone in Klinefelter boys is significantly lower than in controls. After this 'minipuberty', the hormone levels decline to normal prepubertal levels until puberty. In puberty, an initial rise in testosterone, inhibin B, LH and FSH occurs in Klinefelter boys. However, the rise in testosterone levels off and ends at a low-normal level in young adults. Likewise, serum concentration of inhibin B exhibits a dramatic decline to a low, often undetectable level, concomitantly with a rise in FSH, reflecting the degeneration of the seminiferous tubules. Many hypotheses about the underlying mechanism of the depletion of the germ cells in Klinefelter males have been reported and include insufficient supranumerary X-chromosome inactivation, Leydig cell insufficiency and disturbed regulation of apoptosis of Sertoli and Leydig cells. However, at present, the exact mechanism remains unclear. In this article, we summarize current knowledge on the development of the classical endocrinological and histological features of 47,XXY males from fetus to adulthood and review the literature concerning the degeneration of the seminiferous tubules in this syndrome.

Immunoexpression of androgen receptors and aromatase in testes of patient with Klinefelter's syndrome.Folia Histochem Cytobiol. 2004;42(4):215-20.

Klinefelter's syndrome (47, XXY) is the most common chromosome aneuploidy in men and is usually characterized by underdeveloped testes and sterility. The aim of the present study was to detect cellular distribution of androgen receptors (AR) and aromatase in testes of patient with KS. The tissue sections were processed for morphological and immunohistochemical staining. Additionally, levels of FSH, LH, PRL, estradiol, and testosterone were measured in the plasma. Morphological analysis revealed a complete absence of spermatogenesis. No germ cells were present in seminiferous tubules. In some tubules, nests of apparently degenerating Sertoli cells were found. In the interstitium, Leydig cell hyperplasia was observed. Using immunohistochemistry, nuclear AR staining was detected in Sertoli cells and peritubular cells, whereas in Leydig cells the staining was exclusively cytoplasmic. The immunostaining of aromatase was detected in the cytoplasm of Sertoli cells and Leydig cells. Increased levels of gonadotropins and decreased level of testosterone concomitantly with the cytoplasmic localization of AR in Leydig cells might contribute to the impaired testicular function in patient with KS.

Klinefelter syndrome in adolescence: onset of puberty is associated with accelerated germ cell depletion. J Clin Endocrinol Metab. 2004 May;89(5):2263-70.

The process of germ cell depletion in patients with Klinefelter syndrome (KS) is incompletely characterized. In the current work, we evaluated the presence of germ cells in adolescent boys with KS for possible future use in assisted reproduction techniques. Fourteen nonmosaic 47,XXY boys (aged 10-14 yr) were enrolled. Every fourth month their puberty was staged, and serum was obtained for hormone analyses. Each boy underwent a single testicular biopsy. Biopsy specimens of seven peripubertal boys (testicular volume < 2.0 ml) had spermatogonia of adult type, whereas older boys with larger testes (> 2.0 ml) exhibited no germ cells. No meiotic germ cells were detectable in any of these subjects. Depletion of germ cells was associated with an increase in testicular volume but was not immediately reflected in levels of serum gonadotropin, inhibin B, or anti-Müllerian hormone. In contrast, hypergonadotropism and suppression of serum inhibin B and anti-Müllerian hormone developed later, during midpuberty, after an unequivocal increase in serum testosterone (>2.5 nmol/liter) levels and degeneration of Sertoli cells. In conclusion, these prepubertal and early pubertal boys with KS had diploid germ cells that vanished in early puberty when testicular volume increased, whereas serum gonadotropin and inhibin B levels displayed pathological changes later during midpuberty.

Immunohistochemical and quantitative study of interstitial and intratubular Leydig cells in normal men, cryptorchidism, and Klinefelter's syndrome.J Pathol. 1991 Aug;164(4):299-306.

Testicular specimens from normal men and men with cryptorchidism (CR) or Klinefelter's syndrome (KS) were taken, processed for light microscopy, and stained with the avidin-biotin peroxidase complex method for immunohistochemical detection of testosterone. The Leydig cells were classified by their morphology (normal, multivacuolated, and pleomorphic Leydig cells) and by their staining affinity for anti-testosterone antibodies (T-, T+, and T++ cells), and the average numbers of each cell type for each group of testes were calculated. Normal testes showed morphologically normal interstitial Leydig cells (96.0 +/- 10 per cent) and multivacuolated Leydig cells (4.0 +/- 1 per cent). Cryptorchid testes showed normal Leydig cells (85.8 +/- 11 per cent) and multivacuolated Leydig cells (14.2 +/- 2.3 per cent). Men with KS showed normal Leydig cells (78.9 +/- 9.1 per cent), multivacuolated Leydig cells (9.2 +/- 1.2 per cent), and pleomorphic Leydig cells (11.0 +/- 1.8 per cent). The percentage of T++ cells was higher in normal testes (29.4 +/- 2.1 per cent) than in CR (11.4 +/- 2.2 per cent) and KS testes (6.3 +/- 0.7 per cent). This suggests reduced functional Leydig cell activity in CR and KS. Multivacuolated Leydig cells showed weaker immunostaining than did normal Leydig cells in all the testicular groups. No immunostaining was shown by pleomorphic Leydig cells. Intratubular Leydig cells were only found in CR and KS. Immunostaining was weaker in intratubular Leydig cells than in interstitial Leydig cells. This suggests that intratubular location reduces functional activity of Leydig cells.

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