The roles of activin A and its binding protein, follistatin, in inflammation and tissue repair

Activin A, a member of the transforming growth factor-β superfamily of cytokines, is a critical controller of inflammation, immunity and fibrosis. It is rapidly released into the blood following a lipopolysaccharide challenge in experimental animals, through activation of the Toll-like receptor 4 signalling pathway. Blocking activin action by pre-treatment with its binding protein, follistatin, modifies the inflammatory cytokine cascade, and reduces the severity of the subsequent inflammatory response and mortality. Likewise, high serum levels of activin A are predictive of death in patients with septicaemia. However, activin A has complex immunomodulatory actions. It is produced by inflammatory macrophages, but can regulate either pro- or anti-inflammatory responses in these cells, depending on their prior activation status. Activin A is also produced by Th2 cells, and stimulates antibody production by B cells and the development of regulatory T cells. Production of activin A during inflammatory responses stimulates fibrosis and tissue remodelling, and follistatin inhibits these actions of activin A. The modulation of activin by follistatin may represent an important therapeutic target for the modulation and amelioration of inflammatory and fibrotic disorders.     

Stimulation of serum inhibin concentrations by gonadotropin-releasing hormone in men with idiopathic hypogonadotropic hypogonadism

Inhibin is a gonadal hormone thought to be important in FSH regulation. We investigated the effects of the hypogonadotropic state and subsequent GnRH-induced increases in gonadotropin levels on inhibin secretion. Serum levels of inhibin, LH, FSH, and testosterone (T) as well as sperm concentrations were measured in 5 men with idiopathic hypogonadotropic hypogonadism (IHH) before (baseline) and during 8 weeks of GnRH therapy (5 micrograms, sc, every 2 h). Baseline and peak inhibin levels were compared to those in a group of 19 normal men. Before GnRH administration, the mean serum inhibin level was significantly lower in the IHH men than in the normal men [166 +/- 56 (+/- SE) vs. 588 +/- 30 U/L; P less than 0.001]. Serum inhibin levels rose after 1 week of GnRH therapy (P less than 0.05) and remained higher than the baseline level thereafter. The mean peak inhibin level during GnRH administration was lower than the mean value in normal men (485 +/- 166 vs. 588 +/- 30 U/L; P less than 0.05). Serum LH and FSH levels rose promptly to the midnormal range or slightly above it. Serum T levels did not significantly increase until 4-5 weeks of GnRH administration and remained in the low normal range. All IHH men were azoospermic throughout the study. These data are consistent with the hypothesis that inhibin is produced by the testis under gonadotropin control. They also suggest the possibility of defective Sertoli and Leydig cell function in men with IHH, since the men's serum inhibin and T levels did not rise to the same extent as did their normalized serum gonadotropin levels during GnRH administration.     

Inhibin and estradiol responses to ovarian hyperstimulation: effects of age and predictive value for in vitro fertilization outcome

We have compared the time courses of serum inhibin and estradiol responses to ovarian hyperstimulation in patients undergoing in vitro fertilization and embryo transfer as well as their predictive value for outcome of intermediate variables and pregnancy in in vitro fertilization and embryo transfer. Blood samples (n = 749) were collected for up to 6 days before hCG administration in 100 consecutive treatment cycles, of which 44 resulted in pregnancy, as defined by elevated luteal phase serum hCG beta levels. Inhibin and estradiol levels increased markedly in parallel during hyperstimulation and were highly correlated (r = 0.89; P less than 0.001). Inhibin responses were significantly lower in women 35 yr of age or older (P less than 0.001), although estradiol responses were not influenced by age. Gravidity and tubal disease also had marginal effects on the time course of inhibin responses, but not on overall mean inhibin levels or estradiol responses. The time course of hormonal responses to hyperstimulation was not influenced by any other demographic or etiological factors. Peak values of both hormones correlated with the total number of follicles (inhibin, r = 0.70; estradiol, r = 0.65; P less than 0.001) and oocytes retrieved per cycle (inhibin, r = 0.49; estradiol, r = 0.39; P less than 0.001). The time course and peak values of inhibin and estradiol responses to hyperstimulation did not differ significantly between conception or nonconception cycles whether judged by biochemical (luteal hCG beta) or clinical (viable ongoing pregnancy) criteria. Luteal phase serum inhibin, estradiol, progesterone, and hCG levels were significantly higher in conception than in nonconception cycles (P less than 0.001). These data suggest that the rises in serum inhibin and estradiol levels during hyperstimulation have similar predictive properties for IVF-ET outcomes and could, therefore, be used interchangeably to monitor hyperstimulation regimens. The age-related reduction in inhibin, but not estradiol, responses suggests that these two hormones reflect different granulosa cell functions and that serum inhibin responses to maximal ovarian stimulation may be a sensitive and early index of declining ovarian function with advancing age.     

Analysis of the testicular phenotype of the follicle-stimulating hormone beta-subunit knockout and the activin type II receptor knockout mice by stereological analysis.

This study evaluated the role of FSH and activin A on testicular function using quantitative stereological analysis of testicular cell types in mice with targeted disruption of genes encoding the FSH beta-subunit and the activin type IIA receptor (ActRIIA). Using the optical dissector technique, the numbers of Sertoli cells and germ cells per testis were determined. Testis weights in homozygous males lacking the FSHbeta gene or the ActRIIA gene were decreased approximately 60% compared with wild-type or respective heterozygotes. Sertoli cell numbers decreased in both homozygous mice by 30-39%, and there was a comparable decline in germ cell numbers in both models. The degree of germ cell attrition increased in the later stages of spermatogenesis from a 46% reduction of spermatogonia to a 60% decrease in round spermatids. As the FSH levels are decreased in both models, the cellular lesion in both is most likely due to the FSH deficiency. Although the decrease in the Sertoli cell complement represents one cause of lower germ cell numbers, the ability of Sertoli cells to nurture germ cells is compromised by the lower FSH levels, as shown by a decrease in the round spermatid to Sertoli cell ratios in both homozygous models. We conclude that the defects in FSH beta-subunit gene knockout and ActRIIA knockout mice are related to diminished FSH action on both Sertoli cell proliferation and the capacity of Sertoli cells to nurture germ cells.     

Quantitative cytological studies of spermatogenesis in intact and hypophysectomized rats: identification of androgen-dependent stages

A stereological study of the numbers of germ cells in various stages of spermatogenesis was undertaken in testosterone-treated intact and hypophysectomized (HPX) rats. Adult Sprague-Dawley rats were given testosterone by Silastic implants, which either inhibited (3-cm length) or partially maintained (10 cm) spermatogenesis over a 13-week period. The numbers of nuclei of the various germ cell categories (spermatogonia, spermatocytes, and round spermatids) in the testes were estimated by profile counting and measurement of nuclear diameter. The numbers of elongated spermatids were determined separately in testicular homogenates. Testis weight, seminiferous tubule volume, and tubule diameter were significantly decreased in intact rats with 3- and 10-cm testosterone implants and in HPX rats, although they were partially maintained in groups with 10-cm implants compared to those in groups with 3-cm implants (P less than 0.05). The effect of 3-cm testosterone implants in the intact group was to suppress the number of spermatogonia to 57%, reduce the conversion of spermatogonia to spermatocytes to 85%, and reduce the conversion of round to elongated spermatids to 19% of the control value. This latter effect was largely overcome with 10-cm testosterone implants. In HPX rats, only 10-cm implants were effective in maintaining the conversion of round spermatids to elongated spermatids. However, testosterone alone was less effective in maintaining the conversion of spermatocytes to round spermatids, suggesting that a pituitary factor, probably FSH, was involved. It is concluded that testosterone has a major effect on the conversion of round to elongated spermatids. The conversion of spermatogonia to spermatocytes and the conversion of spermatocytes to round spermatids depend on the synergistic action of both FSH and testosterone. However, the effect of FSH is greatest on the conversion of spermatocytes to spermatids, i.e. meiosis.     

Effects of hypophysectomy and subsequent FSH and testosterone treatment on inhibin production by adult rat testes

The hormonal control of inhibin production by adult rat testes was investigated using an in-vitro inhibin bioassay validated for the measurement of inhibin activity in charcoal-treated rat testicular extracts. The effect of hypophysectomy examined at 16 h, 3, 7 and 42 days after surgery showed a decrease in testicular inhibin content and seminiferous tubule fluid production by 7 days and a decrease in inhibin production by 42 days. Serum FSH and LH were suppressed 3 days after surgery. In 30-day chronically hypophysectomized adult rats treated for 3 days with twice daily s.c. injections of (a) human FSH (hFSH, 22 i.u./rat per day), (b) testosterone (5 mg/rat per day), (c) hFSH + testosterone (same doses as a and b), or (d) human chorionic gonadotrophin (hCG, 12 i.u./rat per day), hFSH or hFSH and testosterone stimulated an increase in testicular inhibin content but not in inhibin production or tubule fluid production. Testosterone and hCG had no effect on these parameters. It is concluded that in vivo, FSH alone stimulates an increase in testicular inhibin content. The failure to observe an increase in inhibin production in vivo is attributed to the suppression of seminiferous tubule fluid production under the same experimental conditions.     

男性健康的决定因素：生物及社会因素的相互影响

本文讨论了影响男性从受孕到成年的整个发育过程,同时诱发诸多男性健康问题的社会学和生物学因素。这方面的探讨有助于决策者制定与男性健康相关的政策。男性根本的生物学特征是由遗传白父母的基因组决定的,本文着重探讨了基于这些生物特征的有同样决定性意义的社会因素;还强调了男性特有的生殖疾病的重要性,这同时也会通过睾丸分泌的雄激素来影响整个机体结构。此外,心血管及神经系统的功能可明显影响生殖,例如引起勃起功能障碍。     

Increased maternal serum activin A but not follistatin levels in pregnant women with hypertensive disorders

Activin A levels are elevated in maternal serum of pregnant women with hypertensive disturbances. Because follistatin is a circulating binding protein for activin A, the present study was designed to evaluate whether serum follistatin and activin A levels also change in patients with hypertensive disorders in the last gestational trimester. The study design was a controlled survey performed in the setting of an academic prenatal care unit. Healthy pregnant women (controls, n=38) were compared with patients suffering from pregnancy-induced hypertension (PIH, n=18) or pre-eclampsia (n=16). In addition, the study included a subset of patients with pre-eclampsia associated with intrauterine growth restriction (IUGR, n=5). Maternal blood samples were withdrawn at the time of diagnosis (patients) or in a random prenatal visit (controls), and serum was assayed for follistatin and activin A levels using specific enzyme immunoassays. Hormone concentrations were corrected for gestational age by conversion to multiples of median (MoM) of the healthy controls of the same gestational age. Follistatin levels were not different between controls and patients, while activin A levels were significantly increased in patients with PIH (1.8 MoM), pre-eclampsia (4.6 MoM), and pre-eclampsia+IUGR (3.2 MoM, P<0.01, ANOVA). The ratio between activin A and follistatin was significantly increased in patients with PIH (1.5 MoM) and was further increased in patients with pre-eclampsia (4.5 MoM) and in the group with pre-eclampsia+IUGR (2.6 MoM). Follistatin levels were positively correlated with gestational age in control subjects (r=0. 36, P<0.05) and in patients with PIH (r=0.46, P<0.05) or pre-eclampsia (r=0.61, P<0.01), while activin A correlated with gestational age only in the healthy control group (r=0.69, P<0.0001). The finding of apparently normal follistatin and high activin A levels in patients with PIH and pre-eclampsia suggests that unbound, biologically active, activin A is increased in women with these gestational diseases.