Functional role of progestin and the progesterone receptor in the suppression of spermatogenesis in rodents

Abstract

SUMMARYSynthetic progestins such as levonorgestrel (LNG) are used in combination with testosterone (T) in male contraceptive clinical trials to suppress gonadotropins secretion, but whether progestins have additional direct effects on the testis are not known. This study aimed to examine the effect of a potent progestin, (LNG), alone or in combination with testosterone (T) on spermatogenesis in adult rats, and to evaluate the functional role of the progesterone receptors (PRs) in the testis. In comparison with a low dose of LNG treatment in adult rats for 4 weeks, T and T + LNG treatment decreased testicular sperm count to 64.1 and 40.2% of control levels respectively. LNG induced germ cell apoptosis at stages I-IV and XII-XIV; T increased apoptosis at stages VII-VIII; LNG + T treatment induced greater germ cell apoptosis at a wider range of seminiferous epithelial stages. RT-PCR and Western Blots showed that PR was present in testes and up-regulated during suppression of spermatogenesis induced by testicular hormonal deprivation. PR knockout (PRKO) mice had larger testes, greater sperm production, increased numbers of Sertoli and Leydig cells. Suppression of gonadotropin and intratesticular T by GnRH-antagonist treatment induced PR promoter driven LacZ expression in Leydig cells of PRKO mice. This suggests that GnRH-antagonist treatment while inducing germ cell apoptosis also up-regulates PR. We conclude that (i) LNG + T induced greater suppression of spermatogenesis through increase in germ cell apoptosis involving a wider range of seminiferous epithelial stages than either treatment alone, (ii) up-regulation of PR was associated with inhibition of spermatogenesis, (iii) PR knockout mice showed increased sperm production suggesting that testicular PR activated events play a physiological and pharmacological inhibitory role in the testis. These data support the hypothesis that in addition to its known suppressive effects on gonadotropins, progestins may have direct inhibitory actions on the testis.

Exposure to Hypoxia at High Altitude (5380 m) for 1 Year Induces Reversible Effects on Semen Quality and Serum Reproductive Hormone Levels in Young Male Adults

“…FSH promotes spermatogenesis (Kumar et al, 2003). The imbalance of reproductive hormones could lead to a series of target organ responses (Lue et al, 2013;Rey et al, 2013;Ribeiro et al, 2013;Szafarowska et al, 2013).…”

TAp73 is required for spermatogenesis and the maintenance of male fertility

“…S4B). The PR knockout mice show increased sperm production (23), suggesting that the up-regulation of PR in the TAp73 KO testes could be associated with defective spermatogenesis. , and p53 Saos-2 tet-on cells were exposed to 2 μM doxycycline for 16 h, followed by qPCR determinations of the indicated mRNAs.…”

Association of progesterone receptor gene polymorphism with male infertility and clinical outcome of ICSI

“…We and others have previously demonstrated that PR is expressed in the mammalian testis and the expression is downregulated in testis of infertile men [2,17,20,25,37,38]. In the present study, we tested if loss of PR was due to any sequence alterations in the PR gene and may be a cause of oligo or azoospermia.…”

“…PRs are also detected in testis of other mammals [17,20,25] suggesting that progesterone may regulate spermatogenesis. While PR knockout mice (PRKO) have larger testes, greater sperm production, increased numbers of Sertoli and Leydig cells [25]; in humans, PR mRNA and protein are reduced in testis of azoospermic men with maturation arrest and hypospermatogenesis [2,16] and also in spermatozoa of oligoasthenoteratozoospermic infertile men [12]. These observations are definitive evidence to suggest that PR has a role in regulation of spermatogenesis and reduced PR expression is associated with defective spermatogenesis.…”

“…Indeed, we reported the presence of progesterone receptors (PR) in the germ cells of human testis and its differential expression during various stages of spermatogenesis [37,38]. PRs are also detected in testis of other mammals [17,20,25] suggesting that progesterone may regulate spermatogenesis. While PR knockout mice (PRKO) have larger testes, greater sperm production, increased numbers of Sertoli and Leydig cells [25]; in humans, PR mRNA and protein are reduced in testis of azoospermic men with maturation arrest and hypospermatogenesis [2,16] and also in spermatozoa of oligoasthenoteratozoospermic infertile men [12].…”