Apoptosis and Proliferation of Human Testicular Somatic and Germ Cells during Prepuberty: High Rate of Testicular Growth in Newborns Mediated by Decreased Apoptosis

Abstract

Programmed cell death and proliferation are evolutionary conserved processes that play a major role during normal development and homeostasis. In the testis, during the fetal and newborn periods, they might determine final adult size and fertility potential. In the present study, we have measured the relative number of testicular cells in apoptosis and in active proliferation in the seminiferous cords and in the interstitium, at different age periods of prepubertal testicular development in humans. Testes from 44 prepubertal subjects without endocrine and metabolic abnormalities were collected at necropsy. They were divided in three age groups (Gr): Gr 1, newborn (1- to 21-d-old neonates), n = 18, mean (+/-SD) age 0.3 +/- 0.23 months; Gr 2, post natal activation (1- to 6-month-old infants), n = 13, mean age 3.93 +/- 1.90 months; and Gr 3, early childhood period (1- to <6-yr-old boys), n = 13, mean age 31.5 +/- 18.9 months. Apoptosis was detected in 5- microm tissue sections using a modified terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay and cell proliferation was assessed by Ki-67 immunohistochemistry. Evaluation of apoptosis was confirmed by estimation of active caspase-3. Mean (+/-SD) testicular weight was 0.38 +/- 0.20, 0.54 +/- 0.35, and 0.51 +/- 0.11 g in Gr 1, Gr 2, and Gr 3, respectively. In Gr 1, there was a significant positive correlation between age and testis weight (P = 0.02). Mean (+/-SD) germ cell apoptotic index, AI, (% of apoptotic cells out of total cell number) was 15.0 +/- 6.60, 27.0 +/- 8.80 and 33.4 +/- 11.4 in Gr 1, Gr 2, and Gr 3, respectively. In Sertoli cells, it was 6.60 +/- 4.07, 22.0 +/- 14.0 and 27.5 +/- 19.8, respectively. In interstitial cells, it was 10.2 +/- 6.38, 18.0 +/- 6.70 and 25.7 +/- 15.5, respectively. In the three types of cells, AI in Gr 1 was significantly lower than in Gr 2 or Gr 3 (P < 0.05). Mean (+/-SD) germ cell proliferation index, PI, was 18.6 +/- 13.0, 10.0 +/- 6.50 and 10.9 +/- 6.24% in Gr 1, Gr 2, and Gr 3, respectively. In Sertoli cells and in interstitial cells PI was similar in the three age groups. The PI/AI ratio was used to compare relative differences among age groups. The PI/AI ratio of germ cells, Sertoli cells and interstitial cells in Gr 1 was significantly higher than in Gr 2 or Gr 3 (P < 0.05). It is concluded that, in normal subjects, there is a vigorous growth of the testis during the newborn period with subsequent stabilization during the first years of prepuberty. This cell growth seems to be mainly mediated by decreased apoptosis. The factors that modulate apoptosis of testicular cells are not known, but it is remarkable that this change takes place before the testosterone peak of the post natal gonadal activation of the first trimester of life. These changes taking place during the newborn period might be important to define testicular function in adults.

Expression of FGFR3 during human testis development and in germ cell-derived tumours of young adults

“…However, these observations are uncertain due to the small number and variable technical quality of these hardto-get human samples. Nevertheless, such a pattern of FGFR3 expression mimics roughly the proliferation profile of germ cells throughout development (Berensztein et al, 2002;Honecker et al, …”

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

“…Another difference resides in the fact that rodent gonocyte undergoes two phases of proliferation in the fetal and neonatal periods, respectively, separated by a proportionally long period of quiescence, whereas humans and marmosets lack this quiescent phase, and instead, one can find proliferative gonocytes in all periods surveyed, from gestation weeks (GWs) 12-14 until 2.5-4 months after birth in human, albeit at various levels (Hilscher & Engemann 1992, Berensztein et al 2002, Honecker et al 2004, Ewen et al 2013. Overall, these studies reported the highest rates of proliferation between the third and fifth gestation months, followed by decreased proliferation in late gestation and a small increase in proliferation in 2.5-to 6-month-old infants.…”

Mini puberty and its interpretation

“…After the 6th month after delivery, the spermatogonia decrease in number in parallel to decreased gonadotropins. Activity in the GnRH pulse generator which lasts from the neonatal period to the middle infancy (mini puberty) is important for criptorchidism and the spermatogenic function and fertility in advanced years (20,(23)(24)(25)(26)(27). In addition, it is thought that increased level of testosterone provides masculinization of the brain an determines cognitive functions, sexual behavior and sexual orientation in relation (4,28).…”