Clinics in Endocrinology and Metabolism最新文献

The mammalian testis is under the overall control of pituitary gonadotropins but the utilization of these signals to achieve normal testicular function involves complex local interactions between the Sertoli and germ cells, the Sertoli and peritubular cells, and the Sertoli and Leydig cells as well as local control of the testicular vasculature. These interactions serve two purposes: (1) to coordinate the functions of the three testicular compartments (seminiferous tubules, interstitium and the vasculature); and (2) to control the complex but orderly sequence of events that constitutes the spermatogenic cycle. This process, which involves multiplication, differentiation and translocation of the germ cells is organized into a sequence of stages, each of which is composed of a constant association of germ cells at four or five different stages of development. At each stage of the spermatogenic cycle, different events occur and the function of the Sertoli cells alters, probably in accordance with the changing requirements of the associated germ cells. As yet, our understanding of these many local events is extremely limited, particularly with respect to the identity of the hormones/factors involved in controlling the various processes.

Our knowledge of paracrine control mechanisms in the testis is derived mainly from studies of the rat, but as the process of spermatogenesis is essentially the same in most mammals and involves the same sequence of events, then findings in the rat can probably be applied in general, if not in detail, to the human testis; the limited direct information available on the human testis supports this view. As most cases of infertility in men occur despite normal or raised serum gonadotropin levels and are characterized by the production of reduced or normal numbers of sperm, then it seems likely that malfunction of one or more of the intricate paracrine processes within the testis may be involved in the aetiology of idiopathic oligospermia. It is therefore argued that advances in our knowledge of the paracrine control of the testis should have major repercussions on our ability to understand, and eventually treat, idiopathic infertility in men, and also to induce infertility for contraceptive purposes.

The preovulatory surge of gonadotropins induces within the mature Graafian follicle a series of changes culminating in the release of a fertilizable ovum. These include resumption of the meiotic division, a process held in abeyance from a short time after birth and the progression of the oocyte from the dictyate stage to the metaphase of the second meiotic division. Here the role of a follicular factor, oocyte maturation inhibitor (OMI), in preventing resumption of meiosis by ova of antral follicles prior to the surge of gonadotropins has been reviewed.

The suggested involvement of OMI in regulation of meiosis is based on the following observations: (1) fully grown mammalian oocytes explanted from their follicles undergo meiotic maturation spontaneously, whereas follicle-enclosed ova remain immature until stimulated; (2) co-culture of oocytes isolated from their follicles with follicular granulosa cells, granulosa cell extract and follicular fluid inhibits the spontaneous maturation; (3) the inhibition of oocyte maturation by OMI is reversible and in several of the models employed can be removed by the addition of the physiological trigger of meiosis, luteinizing hormone (LH). The current state of OMI characterization and purification has been described and the involvement of additional factors, such as cyclic AMP, in the regulation of meiosis discussed.

The mechanisms controlling luteal function may involve factors that are produced both within the corpus luteum and outside the ovary. The process of luteal control appears to involve a series of molecular species, proteins, peptides, steroids and prostaglandins. Each of these factors may act independently or in concert modifying the actions of one another. The effect of GnRH on luteal function has not been completely examined and thus its significance is unclear. The neurohypophyseal peptides, oxytocin and arginine vasopressin, in combination with LH, prolactin, oestrogens and prostaglandins may play an important regulatory role on the corpus luteum.

The growth and differentiation of the mammary gland is a complex process involving the interactions of various steroid and polypeptide hormones. The mammary growth occurs in a discontinued way during five distinct phases, i.e. fetal, prepubertal, postpubertal, pregnancy, and early lactation periods. The gland expresses its differentiated function by producing milk during the period of lactation. Although the mammary gland has been regarded as one of the well-known target tissues for various types of hormones, evidence has been accumulating in recent years indicating the involvement of other factors and substances in the process of mammary growth and differentiation. In this chapter the importance of the mesenchymal component in mammary epithelial cell growth has been documented. This component, including embryonic mesenchyme and adipocytes in adult tissue, play an essential role by not only serving as a structural entity of the gland but also by producing extracellular matrix substances and various factors that promote the growth, morphologic development and differentiation of mammary epithelium in a paracrine fashion. Other possible paracrine peptide factors for mammary cell growth have been isolated from several other sources including mammary tumours and milk. Thus, it is possible that paracrine growth factors play a role in mammary tumorigenesis. Since most of these factors are present in minute amounts, it is difficult to obtain pure forms of these factors in sufficient amounts for detailed physicochemical characterization. Moreover, further studies are needed to assess the physiological importance of these growth factors, their mode of action, and the mechanism of regulation relating to their production. It is conceivable that some mammary paracrine agents interact with each other or with endocrine agents in promoting the normal and neoplastic growth of mammary cells. Furthermore, the possibility exists that the production and release of paracrine factors are under the endocrine control.

In view of the rapid progress and great interest in this area, these questions may be answered before long, along with the discovery of some other new growth regulating agents in this system. Clearly such information is important for understanding the complex process of normal and neoplastic growth of the mammary gland.

Since the heterogeneous development of individual follicles in a given ovary cannot be accounted for by changes in circulating gonadotropin levels, local modulatory factors play an important role in the paracrine control of follicular development. The important paracrine role of ovarian steroids has been well established. Oestrogen is important in the augmentation of gonadotropin action. High local concentration of oestrogens enhances the gonadotropin stimulation of aromatase activity, resulting in further increases in oestrogen production. The elevated local oestrogens in the follicular fluid are also capable of enhancing the FSH induction of LH receptors. Similar to oestrogens, local high concentrations of progesterone may enhance the gonadotropin stimulation of progesterone biosynthesis in granulosa and luteal cells. This positive autofeedback mechanism is believed to be important for the autonomy of luteal cell steroidogenesis. Ovarian actions of androgens are diverse. In the absence of FSH, androgens exert mainly negative effects at the follicular level by causing atresia and granulosa cell death, whereas in the presence of FSH, androgens augment FSH stimulation of progesterone and oestrogen biosynthesis. Since androgen and oestrogen appear to antagonize each other's actions, the ratio of these two steroids is important in determining the fate of an individual follicle.

In contrast to ovarian steroids, the role of ovarian peptides as paracrine signals is less clear. In vitro studies clearly demonstrated that GnRH exerts both stimulatory and inhibitory actions on follicular functions, while IGF-I and VIP stimulate ovarian steroidogenesis. The actions of these peptides are presumably mediated through specific granulosa cell receptors that have been tentatively identified. It is presumed that GnRH and IGF-I may be produced by ovarian cells, while VIP may be derived from ovarian nerves. It is anticipated that new methodologies will be developed to study individual follicles as independent units, capable of synthesizing hormones, releasing them, and exerting local paracrine functions.