Testicular Function in Klinefelter Syndrome

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. Copyright © 2008 S. Karger AG, Basel Received: November 29, 2006 Accepted: October 2, 2007 Published online: March 17, 2008 HORMONE RESEARCH Anne Wikström, MD, PhD HUCH, Hospital for Children and Adolescents University of Helsinki, PO Box 281 FI–00029 Helsinki (Finland) Tel. +358 9 471 75293, Fax +358 9 471 75888, E-Mail [email protected] © 2008 S. Karger AG, Basel 0301–0163/08/0696–0317$24.50/0 Accessible online at: www.karger.com/hre D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /5 /2 01 7 10 :0 3: 48 A M Wikström/Dunkel Horm Res 2008;69:317–326 318 boy often presents with language delay, learning disabilities or behavioral problems [6, 10] . Consequently, child neurologists or child psychiatrists, who perform chromosome analysis, along with fragile X screening, make the diagnosis. The tall stature typical of KS result from a notable increase in height velocity between ages 5 and 8 years owing to a greater leg growth, but otherwise identifying any differences between KS boys and normal boys in physical appearance is very difficult [11] . Furthermore, neither magnitude nor timing of the pubertal growth spurt differs from that of normal boys [11–13] . Only after puberty do small, firm testes and variable symptoms of androgen deficiency characterize the KS males most often detected among patients with azoospermia visiting at infertility clinics [6] . The aims of this article are to review present knowledge on longitudinal changes from fetal life to adulthood in hormone levels reflecting testicular function, and on morphological degeneration of the testis in KS. Reproductive Hormone Levels during Development Fetal Period When prenatal testosterone was investigated in amniotic fluid obtained at antenatal diagnosis between 16 and 20 weeks of gestation from 20 XXY fetuses and from XY and XX controls of the same age [14] , no significant difference was evident between the two male groups; both had significantly higher levels than the XX fetuses. Neonatal Period At birth there already may be some impairment of Leydig cell function. Cord blood testosterone was significantly lower in 2 47,XXY infants and in 1 46,XY/XXY than in 3 control infants [15] . However, in another study comparing testosterone levels of 6 KS infants to levels in a large cohort of normal infants, no significant difference appeared [8] . Lahlou et al. [16] compared reproductive hormone levels during minipuberty in 18 prenatally diagnosed 47,XXY boys to those in 215 healthy boys. The KS infants’ timing of peak serum testosterone was similar to healthy infants’, but levels in the KS boys were significantly lower from birth to 8 months. However, their serum LH, FSH, inhibin B and anti-müllerian hormone (AMH) levels were normal. Another study found, in 11 of 12 KS boys under age 6 months, lower than normal serum testosterone levels but normal gonadotropin levels [9] . In contrast, Aksglaede et al. [17] found in 10 KS infants aged 3.1 months, when compared to healthy controls, high normal concentrations of testosterone and elevated levels of LH and FSH. In summary, no indisputable hypoandrogenism appears in KS subjects during infancy. Table 1. Follow-up of 14 adolescent boys with KS