The hypothalamus–pituitary–gonadal axis (HPG) during mini-puberty in boys with KS has been evaluated by several investigative groups and “all” possible results recorded: above normal, below normal or indistinguishable from normal (Aksglaede, Petersen, Main, Skakkebæk, & Juul, 2007; Lahlou, Fennoy, Ross, Bouvatier, & Roger, 2011; Ross et al., 2005). None of these studies has enough boys evaluated at various times over the course of mini-puberty and very few studied longitudinally. That has led to variable prescription of T for infant boys with KS. Davis et al. have noted that T secretion during mini-puberty leads to sexually dimorphic changes in linear growth, genital growth, and anabolic changes in body composition. Her group has further studied those with KS by administering 3 monthly doses of T, 25 mg each. The results compared to boys with KS who did not receive T indicate lesser increase in fat mass and greater increase in fat free mass and linear growth (Davis, Reynolds, Dabelea, Zeitler, & Tartaglia, 2019). One cannot determine from these data whether one is replacing subnormal amounts of T or using T as a pharmacological agent
Rogol, A. D. (2020). Human sex chromosome aneuploidies: The hypothalamic–pituitary–gonadal axis. American Journal of Medical Genetics Part C: Seminars in Medical Genetics
Klinefelter syndrome (XXY), first described by Harry Klinefelter in 1942, is the most common sex-chromosomal variation, with a prevalence of 1:660 in the general population. It is caused by the presence of an extra X chromosome (80% karyotype 47, XXY; 20% 46, XY/47, XXY mosaicism or structural X chromosome variations). It is also one of the most frequent causes of infertility, affecting 11% of azoospermic and 3.1% of all infertile males
The prevalence of diagnosed XXY has risen in recent decades, but its true prevalence is still thought to be underestimated, probably due to the extreme variability of its clinical presentation and a lack of awareness among general practitioners. Abramsky and Chapple showed that up to 64% of KS patients are never diagnosed, with 10% diagnosed prenatally and only 26% in prepuberty or adulthood.
47, XXY males may present with a variety of subtle, age related clinical signs. Hypospadias, small phallus, cryptorchidism, developmental delay, behavioral problems, incomplete pubertal development with eunuchoid body habitus, gynecomastia, and small testes are its most frequent features in infancy and childhood. Adults are often evaluated for infertility and sexual disorders, but metabolic syndrome, osteoporosis, thyroid dysfunctions, humoral immunoreactivity and the presence of specific personality traits and personality disorders are also described. As regards fertility aspects, it has been recently stated that Y chromosome micro-deletions do not represent a further negative genetic factor in KS.
The function of the hypothalamus–pituitary–gonadal (HPG) axis in KS subjects has already been investigated, especially in relation to mini-puberty and puberty. Mini-puberty has been investigated extensively, as it is an important temporal window lasting from the first to about the sixth-to-ninth month of life, in which the first significant HPG axis activation takes place. There is literature evidence of prenatal tubular damage, but these results were not confirmed in childhood biopsies of boys with non-mosaic KS. In 2011, Aksglaede reported that testicular damage begins at the age of 4–9 years with a gradual degeneration of germ cells and reaches its peak from mid-puberty to adulthood, by which time the testes have undergone extensive seminiferous tubule hyalinization and Leydig and Sertoli cell hyperplasia. Literature studies agree that mini-puberty in KS boys is similar to that in healthy boys. However, there is no consensus on the hormonal and clinical profile of young KS patients, nor on when testicular damage occurs.
The aim of this study was therefore to accurately establish the testicular function and the main auxological features over a longer time period, from mini-puberty to the onset of puberty, in order to find any auxological and/or hormonal changes that might be used as an early indicator of KS. This broader clinical and hormonal follow-up might also clarify the specific timing of the onset of puberty, given that while most KS patients present a normal puberty, in some it is delayed and in even more it is precocious