Clinics in Endocrinology and Metabolism最新文献

The pathophysiology of glandular androgen hypersecretion must be regarded as a continuous process without sharp borderlines from normal to non-tumorous conditions, such as polycystic ovaries and hyperthecosis, to neoplastic disease. Hirsutism and related symptoms are most often caused by excess androgens of ovarian and/or adrenal origin, i.e. testosterone, dihydrotestosterone, Δ⁴-androstenedione, dehydroepiandrosterone and its sulphate. As demonstrated by selective catheterization of glandular effluents, combined hypersecretion occurs more frequently than either purely gonadal or adrenal overproduction. No correlation can be found between the type, frequency and extent of hormonal changes and the clinical, laparoscopic, angiographic, or histological findings. Dynamic function tests do not reliably discriminate between the various aetiological subgroups due to extremely variable and even non-specific individual responsiveness. Selective catheterization is presently the most sensitive method for the preoperative identification and localization of androgensecreting neoplasms.

We have provided a brief historical review of developments in our understanding of the endocrine mechanisms underlying the expression of androgen action in women. An alternative to the free hormone concept is considered which proposes that, at least in some target cells, androgens bound to SHBG are the biologically relevant molecules. In nearly every instance, the changes in blood levels of SHBG that have been observed are consistent with this idea. At present there are only bits of direct evidence to support the hypothetical mechanism proposed. As already mentioned, control of androgen action at the level of cellular uptake would provide obvious advantages as well as a potential mechanism to explain the antagonism between androgens and oestrogens which is still a mystery. It is important to note that the proposed mechanism is not obligatory for androgen or other steroid hormone action. Synthetic steroids which do not bind to SHBG or CBG clearly can gain access to target cells by simple diffusion and bind to intracellular receptors. Compounds such as methyltestosterone and dexamethasone are metabolized much more slowly than their natural counterparts and therefore are cleared slowly from the circulation. It is possible that the well-known difficulties in selecting appropriate therapeutic regimens with such compounds is related to the fact that they bypass an important regulatory step in steroid hormone action—modulated entry into target cells. Hopefully, the recent development of powerful new tools of molecular endocrinology will hasten the answer to the question: What is the active androgen in blood?

This chapter has reviewed the factors underlying the transport of testosterone and oestradiol into tissues in vivo. The following points have been emphasized. (1) Albumin-bound testosterone is nearly freely available for transport into brain and liver and is partially available for transport into salivary gland and lymph node; testosterone transport into hair follicles has not been measured thus far.

(2) SHBG-bound testosterone is not available for transport into tissues; SHBG-bound oestradiol is available for transport into liver, salivary gland, and lymph node, but not into brain under normal conditions.

(3) The transport of hormone from the circulating plasma protein-bound pool involves tissue-mediated enhanced dissociation of the hormone from the protein without significant exodus of the plasma protein from the microcirculation compartment. The tissue-mediated enhanced dissociation mechanism varies in activity between different organs and is a much more important factor than organ differences in capillary transit times in regulating the amplification of hormone delivery to different tissues.

(4) The concentration of free testosterone inside cells in the absence of significant cellular metabolism of the hormone is nearly ten times greater than the concentration of free testosterone in vitro, but is nearly equal to the concentration of free plus albumin-bound hormone.

(5) In the presence of active tissue metabolism of hormone, the concentration of cellular free testosterone may be much less than the albumin-bound hormone and may fortuitously approximate the concentration of free testosterone in vitro. This is the situation in salivary gland; the low concentration of testosterone in saliva appears to be due to active salivary metabolism of the hormone, since both free and albumin-bound testosterone are available for transport into salivary gland.

Both the adrenal and the ovary contain the biosynthetic pathways necessary for androgen synthesis and secretion. The fetal ovary is not very active but the fetal adrenal is an important source of DHAS. However the secretion of DHAS declines markedly after birth and until puberty there is little androgen secretion by either the adrenal or the ovary.

Post-pubertally, the adrenal secretes DHAS, DHA, Δ⁴-A and T from the reticularis and probably the fasciculata. This secretion is under ACTH control, at least in part, but apparently also under control of another pituitary polypeptide tentatively called ‘adrenal androgen secretory hormone’. The adrenal secretion rates are in the range of 7–14 mg/day for DHAS, 3–4 mg/day for DHA, 1–1.5 mg/day for Δ⁴-A and 50 μg/day for T.

Androgen secretion from the ovary arises in part from the theca cells of the follicle, the corpus luteum and the stromal cells, under LH control, and will vary somewhat during the normal menstrual cycle. The ovarian secretion rate in the follicular phase is 1–2 mg/day for DHA, 1–1.5 mg/day for Δ⁴-A and about 50 μg/day for T. In the peri-ovulatory period the secretion rate of Δ⁴-A can rise to 3–3.5 mg/day but there appears to be little change in the secretion of DHA and T. The normal ovary does not secrete significant amounts of DHAS.

In about 50% of post-menopausal women the ovaries continue to secrete some T but little Δ⁴-A or DHA.

The discovery of compounds possessing antiandrogenic activities has led to their utilization in the treatment of hirsutism of various aetiologies. Spironolactone generally lowers the plasma testosterone by altering its formation and metabolism as well as by decreasing its blood production rate; the medication also contributes to increase the peripheral conversion of testosterone to oestradiol. A major action is that spironolactone inhibits androgen binding to receptor molecules in the cytosol or the nucleus of target tissues such as the skin. During the last five years, we have studied over 450 cases of hirsutism. Approximately 80% of these women were treated with spironolactone alone or in association with dexamethasone (2.5%) or an oral contraceptive (15%). Hirsutism was classified according to Lorenzo (1970). Good to very good clinical results were observed in 80% of the patients who were under study for a minimum of 3 to 4 years. Adverse side-effects were recorded in less than 5% of our group of patients. On the basis of our data and our clinical experience, we conclude that spironolactone is an effective drug in the treatment of female hirsutism.

The hormonal activity of androgens is mediated in target cells, particularly in human skin, by two kinds of proteins: the androgen receptor and the enzyme 5α-reductase. In well differentiated androgen target cells, 5α-reductase achieves the transformation of testosterone (T) into dihydrotestosterone (DHT), a more active androgen than T, because of its higher affinity for the receptor. In other words, 5α-reductase acts as an amplifier of the androgen signal but is not absolutely required for androgen action. Regarding the regulation of the androgen receptor, minimal information is available. However, in genital skin, the receptor seems to be predominantly localized in the cytosolic compartment before puberty in males and in the nuclear compartment after puberty. In hirsute patients, recent data on genital skin fibroblasts do not show significant differences between the binding capacity of fibroblasts from normal and hirsute women whereas there is no difference between normal men and women.

5α-Reductase activity seems to be a very important step in the processes involved in androgen action. While 5α-reductase activity present in the skin of external genitalia does not seem to be androgen dependent, this is not the case for the enzyme located in pubic skin. In this area, a sex difference between males and females may be observed both in skin homogenates and in cultured fibroblasts. In addition DHT added to a medium of pubic skin fibroblasts is capable of increasing 5α-reductase activity. This increase is not observed when cyproterone acetate is added to the medium and in patients with testicular feminization syndrome without receptors. Pubic 5α-reductase activity is an androgen receptor mediated phenomenon. In patients with hirsutism, and particularly idiopathic hirsutism, 5α-reductase activity is high without an increase in circulating androgens. This may be observed both in pubic skin homogenates and in cultured fibroblasts. Thus, an excess of skin 5α-reductase activity may be considered as a cause of hirsutism but both the exact level of the abnormality in the regulation of the enzyme and its genetic control remain to be elucidated.

Much of the evidence gathered from studies of 5α-reductase activity levels and androgen metabolism in the skin of hirsute women and the excretion of androgen metabolites by hirsute women indicates that 5α-reduced androgens are probably of primary importance in hirsutism. Unfortunately, until very recently, the lack of a suitable 5α-reductase inhibitor made it very difficult to adequately test the hypothesis that such an inhibitor might be useful in the treatment of hirsutism and certain other androgen-related diseases. No substance was available which had good, unambiguous activity in vivo as a 5α-reductase inhibitor.

A number of 4-azasteroids have now been found to possess excellent 5α-reductase inhibitory activity both in vitro and in vivo. Among other properties, several of these compounds show little or no affinity for the androgen receptor of rat prostate cytosol, they attenuate the growth promoting effect of T, but not DHT, on the ventral prostate of castrated male rats, they cause a marked reduction in prostatic DHT concentration in acutely treated rats and dogs and they bring about a significant decline in prostate size in chronically treated rats and dogs. It is expected that, in the near future, one or more of these highly active 5α-reductase inhibitors will be tested in the clinic as a treatment for hirsutism. The results of those studies will be awaited with a great deal of interest since they should considerably advance our understanding of this disease and possibly contribute to its control.

The topographical affinity between certain cell types in rat anterior pituitary as well as the presence of biogenic amines, neuropeptides, growth and tissue factors in specific cell types suggest participation of paracrine control mechanisms in the regulation of anterior pituitary hormone secretion. Due to the recent advances in the separation of pituitary cell types and the development of three-dimensional cell cultures, direct experimental evidence for control by intercellular messengers has become available. The stimulation of PRL release from superfused pituitary cell aggregates by LHRH has been shown to be mediated by gonadotrophs. Gonadotrophs appear to secrete a factor with PRL-releasing activity. Gonadotrophs also modulate the stimulation of PRL release by angiotensin II. Interaction of somatotrophs with an unknown small-sized cell type strongly amplifies the GH response to adrenaline, GRF and VIP. The latter phenomenon requires the permissive action of glucocorticoids. Some of these in vitro observations can be correlated with recently reported in vivo actions of LHRH, PRL and angiotensin II and with pathophysiological changes in the pituitary.