Advances in sex hormone research最新文献

The neuroendocrine control of prolactin secretion is very complex. Even though the hypothalamus exerts a profound inhibitory influence upon the secretion of this hormone, the mechanism(s) involved is poorly understood. The cerebrospinal fluid seems to be becoming increasingly important as regards neuroendocrine regulatory mechanisms involving prolactin. Pharmacological agents such as apomorphine and many of the ergot alkaloids are very effective inhibitors of the secretion of prolactin. Still other pharmacological agents such as DMPEA, alpha-methyldopa, reserpine, and certain of the phenothiazines are very effective in causing a stimulation of prolactin secretion.

Many antiandrogens, mainly steroidal and some nonsteroidal agents, have been synthesized and tested in several available biological assays. Unfortunately, many of these compounds have other biological activities which make it difficult to ascertain the precise mechanism of antiandrogenic action. The blocking of androgen action can be accomplished by a number of ways: (1) the inhibition of gonadotropin release and/or synthesis, (2) the interference with testosterone and/or dihydrotestosterone biosynthesis, (3) the blocking of protein synthesis, and (4) the competition with androgens at receptor sites. Although the major reason for the development of antiandrogens is to utilize them in certain clinical situations, some have become important tools in studying androgen action, particularly on the molecular level. The clinical effectiveness of some antiandrogens in prostatic hyperplasias, hirsutism, and acne represents an important advance in therapeutics, but the search for more potent antiandrogens with minimal side effects should continue.

The mammalian pineal gland has become firmly established as a neuroendocrine structure possessing the ability to influence the functions of the sex glands. There is substantial evidence in the literature that pineal factors also affect the activities of other endocrine systems. The pineal gland is thus conceivably far-reaching in its regulatory actions on physiological function, involving actions on the adrenal cortex, the thyroid, and parathyroid glands as well as the gonads of both sexes. The pineal gland of the hamster and the rat responds to environmental influences, particularly changes in length of the daily photoperiod, and in turn exerts regulatory effects on the activity of the testis. This relation is much more sensitive in the hamster where lack of adequate illumination stimulates pineal antigonadal activity to produce inhibition of both testicular gametogenesis and androgenesis. Involvement of the pineal in these responses to darkness or blinding has been clearly demonstrated by the negating effects of its removal. The physiological role of the pineal in regulating seasonal changes in testicular activity and reproductive capacity of the hamster has now been formulated (Reiter, 1973a, 1973b). The laboratory rat, a continuous breeder, is far less sensitive to lack of photic input. Surgical and environmental manipulations involving altered pineal activity invariably lead to less dramatic changes in various parameters of male reproductive function. The evidence would seem to indicate that pineal function in the rat is primarily related to the regulation of testicular endocrine function. Consequently, its physiological role may be associated with seasonal changes in libido in relation to environmental influences, by virtue of the action of pineal factors on androgen status. Spermatogenesis, on the other hand, was unaffected for periods as long as 1 year after the blinding of rats at the time of puberty (Kinson and Liu, 1974). There is evidence that the pineal gland has a part to play in the timing of puberty in the rat and in circadian variations in testosterone levels in the adult animal. Two groups of compounds have been identified as pineal agents and possibly pineal hormones. While the indoles have been more widely investigated as pineal antigonadal factors, the involvement of polypeptides in pineal actions was indicated a decade ago and these compounds are now receiving vigorous attention. Pineal factors influence testicular function by interaction with the neuroendocrine system to affect pituitary gonadotropin secretion. The higher neural centers appear to be responsive to indoles and via the releasing factors give rise to changes in pituitary content and circulating levels of FSH and LH. Prolactin also has been shown to respond to change in ambient lighting and to pinealectomy. Partially purified polypeptide fractions are now claimed to be considerably more potent antigonadotropically than melatonin, the indole most favored as

Methodologies for the extraction of both pituitary and urinary gonadotropins are described. The chemical composition of some of the gonadotropins is discussed, and the significance of the subunit structures is reviewed. Immunological properties of the gonadotropins are discussed from the standpoint of antisera and procedures involving radioimmunoassay. Finally, certain clinical conditions which are characterized by fluctuations in gonadotropin levels are discussed.

Growth of a normal androgen-responsive organ appears to be ordered by the function of three constraint mechanisms which are sensitive to the intranuclear concentration of androgens. For the complete expression of these constraint mechanisms, several properties underlying hormonal responsiveness must be manifest by the cell, including the presence of cytoplasmic receptor, the ability to transfer androgens into the nucleus, the competence to form nuclear receptor, and the fidelity of the interaction between androgens and chromatin. Cytoplasmic receptor alone is not an exclusive indication of hormonal dependence in vivo, but its presence is associated with enhanced ability of the cell to incoropate androgens into the nucleus. Androgens are required for the initiation of DNA synthesis and cell proliferation, and nuclear receptor may not be required for these responses. On the other hand, it is possible that the function of the latter molecule is concerned with negative feedback or cellular autolysis.

The present status and perspectives in the control of fertility in the male have been reviewed. There are two potential sites in the male reproductive processes that can be used as targets for regulation of fertility in the male: (1) inhibition of spermatogenesis, and (2) interference with sperm maturation in the epididymis. A variety of compounds tested for their antispermatogenic action in laboratory animals have no future for the control of fertility in the human male because of a number of undesirable side effects (cf. Prasad, 1973). Progestational compounds inhibit spermatogenesis by affecting the hypothalamo-hypophysial system and result in impairment of libido. The possibility of adjustment of the minimal dose of progestational compounds required to induce suppression of spermatogenesis and reduction of plasma testosterone to a level compatible with the maintenance of normalcy of libido and potency needs to be studied. A new approach to contraception in the male involves the use of a combination of progestational compounds for suppression of spermatogenesis along with testosterone (administered through silastic capsule implants or as intramuscular injections) for maintenance of libido and accessory sex gland function. A number of such combinations have been tested clinically with some success. However, the limitations of side effects, such as weight gain, gynecomastia, and psychological complications preclude their long-term use for contraception in man. Short-term use of these combination regimens by the male for 1 year followed by use of a contraceptive method by the female may be desirable to encourage partnership in family planning. Although testosterone and other androgens suppress spermatogenesis in man, the feasibility of their use for contraception depends on the establishment of a dosage and mode of adminstration that provide antispermatogenic action without causing more general metabolic alterations. Inhibition of spermatogenesis by selective interference with the action of FSH on the Sertoli cells by active or passive immunization or by selective suppression of synthesis and release of FSH by administration of "Inhibin" offers exciting possibilities in the control of fertility in the male. Studies on the physiology of the rete testis highlight its importance as a post-tubular site of action of antifertility agents in conveying (to the epididymis) compounds interfering with epididymal functions and/or viability of spermatozoa. A new approach to the induction of functional sterility in the male by selective alteration of epididymal function by a local androgen deprivation effect has been successfully tested in clinical trials. Small doses of cyproterone acetate, administered orally, result in maintenance of libido and accessory sex gland function accompanied by a decrease in the motility of ejaculated spermatozoa and incomplete inhibition of spermatogenesis...

The hormones of the pituitary gland are capable of directly influencing the function of male accessory sex organs. Among these hormones, prolactin in particular has been observed to enhance consistently the effects of androgens in the prostate gland and/or the seminal vesicles of rats, mice, and guinea pigs as well as in the accessory sex organs of other species. Prolactin-mediated augmentation of testosterone's effects upon these tissues is related primarily to the growth-promoting influences of this steroid. However, under certain experimental conditions, the androgen-dependent production of secretions by these organs has also been enhanced by prolactin treatment. Studies in the mouse have indicated that prolactin primarily enhances the proliferative phase of androgen action in male accessory sex tissues. Testosterone stimulation of RNA synthesis was unaffected by simultaneous administration of prolactin. The mechanism by which prolactin causes enhanced androgen responses in the prostate gland and seminal vesicles is not well understood. It would appear, however, that prolactin neither stimulates increased accumulation of androgen into the accessory sex organs, nor does it enhance the conversion of testosterone to the more "active" androgen, dihydrotestosterone. The effects of prolactin on these tissues are, however, dependent upon the presence of dihydrotestosterone. Uncertain, at present, are the possible effects of prolactin on the binding or retention of androgens (dihydrotestosterone?) in the prostate gland or in the seminal vesicles. There is evidence that hypophysectomy reduces the nuclear binding of dihydrotestosterone in the cells of the prostate gland. Perhaps prolactin is a pituitary factor(s) which is important in regulating nuclear binding of dihydrotestosterone in male accessory sex organs. The direct influences of prolactin upon androgen action in the cells of the accessory sex organs may involve several sites of action (Figure 2). For example, it is currently understood that when testosterone enters the cell cytoplasm it is subsequently converted to the more "active" androgen, dihydrotestosterone (DHT), by reduction at the 5alpha position. Dihydrotestosterone is then either bound to a cytoplasmic "receptor" protein (Rc) or is further metabolized to either 5alpha-androstane-3alpha,17beta-diol or 5alpha-androstane-3beta,17beta-diol (DIOL). The binding of DHT to its cytoplasmic receptor protein results in translocation of the steroid-receptor complex into the nucleus where presumably the complex dissociates and DHT exerts its androgenic effects. The transport of DHT to the nucleus can also result from the conversion of testosterone to DHT by nuclear membrane-bound 5alpha-reductase. Prolactin augmentation of DHT effects is envisioned as resulting from interaction of prolactin with its receptor, which due to the large size of the prolactin molecule is probably located in or on the plasma membrane...