Reviews of reproduction最新文献

The gonadotrophic hormones, LH and FSH, are synthesized in and secreted from gonadotroph cells in the anterior pituitary and comprise a common alpha-subunit and a hormone-specific beta-subunit. Gonadotrophic gene expression is activated during embryogenesis, independent of GnRH stimulation and increases as GnRH output increases, reaching adult levels at puberty. The transcriptional regulation of pituitary gonadotrophin subunit gene expression is regulated by two types of transcription factor: those that restrict and direct gene expression to gonadotrophs and those that modulate GnRH-regulated gene expression. Synergism between these two types of factor ensures gonadotroph-specific GnRH-regulated gene expression. It is not known whether these two types of transcription factor are mutually exclusive or whether they have overlapping functions. GnRH-regulated gonadotrophin subunit gene expression is modulated by transcription factors controlled by a complex interaction of GnRH, steroids and gonadal peptides, all of which bind to receptors that activate disparate intracellular signalling pathways. It remains to be established how these signalling pathways interact to transduce specific transcriptional activation of common alpha-subunit and LH and FSH beta-subunit gene expression.

In the few years since leptin was identified as a satiety factor in rodents, it has been implicated in the regulation of various physiological processes. Leptin has been shown to promote sexual maturation in rodent species and a role in reproduction has been investigated at various sites within the hypothalamo-pituitary-gonadal axis. This review considers the evidence that leptin (or alteration in amount of body fat) can affect reproduction. There is evidence that leptin plays a permissive role in the onset of puberty, probably through action on the hypothalamus, where leptin receptors are found in cells that express appetite-regulating peptides. There is little evidence that leptin has a positive effect on the pituitary gonadotrophs and the gonads. There is also very little indication that leptin acts in an acute manner to regulate reproduction in the short term. It seems more likely that leptin is a 'barometer' of body condition that sends signals to the brain. Studies in vitro have shown negative effects on ovarian steroid production and there are no reports of effects on testicular function. Leptin concentrations in plasma increase in women during pregnancy, owing to production by the placenta but the functional significance of this is unknown. A number of factors that affect the production and action of leptin have yet to be studied in detail.

Recent genome analysis of the Y chromosome has increased the number of genes found on this chromosome markedly. Many of these genes in the part of the Y chromosome that does not undergo recombination with the X chromosome are members of gene families. Evolutionary considerations imply that genes on the Y chromosome will degenerate unless they have male advantageous or female deleterious functions. Spermatogenesis is an example of a male advantageous function and genes in three regions of the human Y chromosome have been promoted as candidate male fertility factors.

Communication between spermatozoa and egg before contact by chemotaxis appears to be prevalent throughout the animal kingdom. In non-mammalian species, sperm chemotaxis to factors secreted from the egg is well documented. In mammals, sperm chemotaxis to follicular factors in vitro has been established in humans and mice. The attractants of female origin in non-mammalian species are heat-stable peptides or proteins of various sizes, or other small molecules, depending on the species. Species specificity of the attractants in non-mammalian species may vary from high species specificity, through specificity to families with no specificity within a family, to absence of specificity. The mammalian sperm attractants have not been identified but they appear to be heat-stable peptides. The claim that progesterone is the attractant for human spermatozoa has failed to be substantiated, neither have claims for other mammalian sperm attractants been verified. The molecular mechanism of sperm chemotaxis is not known. Models involving modulation of the intracellular Ca2+ concentration have been proposed for both mammalian and non-mammalian sperm chemotaxis. The physiological role of sperm chemotaxis in non-mammalian species appears to differ from that in mammals. In non-mammalian species, sperm chemotaxis strives to bring as many spermatozoa as possible to the egg. However, in mammals, the role appears to be recruitment of a selective population of capacitated ('ripe') spermatozoa to fertilize the egg.

The HSP70 heat-shock proteins are molecular chaperones that assist other proteins in their folding, transport and assembly into complexes. Most of these proteins are either constitutively expressed or their expression is induced by heat shock and other stresses. However, two members of the Hsp70 family (HSP70-2 and HSC70T in mice) are regulated developmentally and expressed specifically in spermatogenic cells. The HSP70-2 protein is synthesized during the meiotic phase of spermatogenesis and is abundant in pachytene spermatocytes. The knockout approach was used to determine whether HSP70-2 is a chaperone for proteins involved in meiosis. Male mice lacking HSP70-2 were infertile while females lacking HSP70-2 were fertile. Spermatogenic cell development was arrested in prophase of meiosis I at the G2-M-phase transition and late pachytene spermatocytes were eliminated by apoptosis, resulting in an absence of spermatids. HSP70-2 is required for Cdc2 to form a heterodimer with cyclin B1, suggesting that it is a chaperone necessary for the progression of meiosis in the germ cells of male mice. HSP70-2 is also associated with the synaptonemal complex and desynapsis is disrupted in male mice lacking this protein. Homologues of HSP70-2 are present in the testes of many animals, suggesting that the role of this spermatogenic cell chaperone is conserved across phyla.

The molecular basis of many forms of male infertility is poorly defined. One area of research that has been studied intensely is the integrity of the DNA in the nucleus of mature ejaculated spermatozoa. It has been shown that, in men with abnormal sperm parameters, the DNA is more likely to possess strand breaks. However, how and why this DNA damage originates in certain males and how it may influence the genetic project of a mature spermatozoon is unknown. Two theories have been proposed to describe the origin of this DNA damage in mature spermatozoa. The first arises from studies performed in animal models and is linked to the unique manner in which mammalian sperm chromatin is packaged, while the second attributes the nuclear DNA damage in mature spermatozoa to apoptosis. One of the factors implicated in sperm apoptosis is the cell surface protein, Fas. In this review, we discuss the possible origins of DNA damage in ejaculated human spermatozoa, how these spermatozoa arrive in the ejaculate of some men, and what consequences they may have if they succeed in their genetic project.

Programmed cell death is an evolutionarily conserved cell death process that plays a major role during normal development and homeostasis. In many cases, the ordered execution of this internal death programme leads to typical morphological and biochemical changes that have been termed apoptosis. The crucial role of this mode of cell death in the pathogenesis of diverse human diseases including cancer, acquired immunodeficiency syndrome, neurodegeneratives disorders, atherosclerosis and cardiomyopathy is now supported by a wealth of data. In adult mammals, including humans, germ cell death is conspicuous during normal spermatogenesis and plays a pivotal role in sperm output. Withdrawal of gonadotrophins and testosterone further enhances the degeneration of germ cells in the testis. The availability of a quantitative method for analysing the testicular DNA fragmentation and in situ methods to localize specific germ cells undergoing apoptosis, either spontaneously or in response to a variety of death triggering signals, opens new avenues in the understanding of the significance of germ cell apoptosis during normal and abnormal states of spermatogenesis. A growing body of evidence demonstrates that both spontaneous (during normal spermatogenesis) and accelerated germ cell death triggered by deprivation of the gonadotrophic support or moderately increased scrotal temperature in adult rats occur almost exclusively via apoptosis. Although there has been spectacular progress in the understanding of the molecular mechanisms of apoptosis in various systems other than spermatogenesis, elucidation of the biochemical and molecular mechanisms by which germ cell apoptosis is regulated has only just begun. It is likely that germ cell apoptosis is controlled in a cell-type specific fashion, but the basic elements of the death machinery may be universal. In addition, there is increasing evidence that homozygous disruption of a number of genes in mice results in infertility through accelerated germ cell apoptosis. Manipulation of spermatogenesis by survival factor(s) deprivation or increases in extrinsic death signals in loss-of-function or gain-of-function mouse models provides a basis for further attempts to define the intrinsic regulation of various death-related genes by external death signals. Such information is crucial for effective management of male factor infertility as well as more targeted approaches to male contraception.

The abdominal gland in the male red-bellied newt, Cynops pyrrhogaster, is the source of a female-attracting pheromone. An attempt was made to isolate and characterize the female-attracting pheromone in the abdominal glands of male newts. The active substance, named sodefrin (from the Japanese 'sodefuri' which means 'soliciting') has been isolated and shown to be a novel decapeptide with the sequence, Ser-Ile-Pro-Ser-Lys-Asp-Ala-Leu-Leu-Lys. Its minimum effective concentration in water is 0.1-1.0 pmol 1-1. Synthetic sodefrin shows a female-attracting activity similar to that of the native peptide, and acts through the olfactory organ of female newts. Electrophysiological studies reveal that sodefrin evokes a marked electroolfactogram response in the vomeronasal epithelium in sexually mature females and in ovariectomized females treated with prolactin and oestrogen. The pheromonal activity of sodefrin appears to be species-specific since it does not attract females of a congeneric species, the sword-tailed newt C. ensicauda. However, C. ensicauda has a variant of sodefrin differing from that in C. pyrrhogaster by substitutions of Leu for Pro at position 3 and Gln for Leu at position 8. The C. ensicauda variant sodefrin does not attract C. pyrrhogaster females. Genes encoding the sodefrin precursor protein have been cloned in both C. pyrrhogaster and C. ensicauda. Immunostaining of the abdominal gland using the antiserum against sodefrin shows that sodefrin occurs in the epithelial cells, predominantly within the secretory granules. Sodefrin content, detected by immunoassay, in C. pyrrhogaster males decreases after castration and hypophysectomy and increases markedly in the castrated and hypophysectomized newts after treatment with androgen and prolactin. This combination of hormones also enhances sodefrin mRNA content in the abdominal gland as assessed by northern blot analysis using sodefrin cDNA.