CHANGES IN THE PITUITARY-TESTICULAR SYSTEM WITH AGE

In order to provide a comprehensive account of pituitary-testicular function in man, 466 subjects, ranging in age from 2 to 101 years, were studied to examine blood levels of the pituitary gonadotrophins (LH and FSH), the sex steroids testosterone and oestradiol, the binding capacity of the sex hormone binding globulin (SHBG), the free testosterone and oestradiol fractions, and the transfer constant for the peripheral conversion of testosterone to oestradiol. The results were compared with clinical indices of testicular size, sexual function and secondary sex hair distribution. Serum LH and FSH were low before puberty, increased in pubertal adolescents to levels somewhat above those of adults and subsequently increased progressively over the age of 40 years. Testosterone levels fell slowly after the age of 40, while there was a slight rise in plasma oestradiol with increasing age. FSH and testosterone showed small seasonal variations in young adult men, the lowest values being seen in winter. SHBG binding capacity was high in two prepubertal boys, fell in adult men, but increased in old age. Free testosterone and oestradiol levels fell in old age. The metabolic clearance rates (MCR) of testosterone and oestradiol also fell in old age, while the conversion of testosterone to oestradiol was increased. Many correlations were observed between various hormonal and clinical measurements. The evidence is consistent with a primary decrease in testicular function over the age of 40 years.     

PLASMA INHIBIN LEVELS IN MEN WITH CHEMOTHERAPY-INDUCED SEVERE DAMAGE TO THE SEMINIFEROUS EPITHELIUM

Immunoreactive plasma inhibin levels and free testosterone index (FTI) were estimated in 17 patients who had previously received combination chemotherapy for Hodgkin's disease and in 16 age-matched controls. In the same patients we had previously found significantly raised FSH and LH levels in the presence of normal basal and HCG-stimulated total testosterone levels. Mean plasma inhibin levels were not different between the patients (601 +/- 321 U/l) and controls (530 +/- 174 U/l) nor were FTI values (81.5 +/- 35 vs 91 +/- 47 respectively). There was a positive correlation (r = 0.53, P less than 0.05) between FSH and inhibin levels and a negative correlation between FSH and FTI (r = -0.51, P less than 0.05) in the patients but not in the controls. No such correlations with inhibin or FTI existed for LH but there was a positive correlation between LH and FSH levels in the patients. In four patients inhibin levels were pathologically raised and in this group mean FSH values (21.7 +/- 4.7 IU/l) were higher (P less than 0.001) and mean FTI (59.1 +/- 22.6) lower (P less than 0.001) than respective values (13.6 +/- 5.3 IU/l and 88.4 +/- 35) for the remainder of the patients. These data are not compatible with the hypothesis that inhibin is the major negative feedback signal for the control of FSH secretion.     

EFFECTS OF SYNTHETIC ORAL OESTROGENS IN NORMAL MEN AND PATIENTS WITH PROSTATIC CARCINOMA: LACK OF GONADOTROPHIN SUPPRESSION BY CHLOROTRIANISENE

The effects of the oral synthetic oestrogens, diethylstiboestrol and chlorotrianisene, have been studied in healthy male volunteers and in patients with prostatic carcinoma. The plasma levels of follicle stimulating hormone, luteinizing hormone and testosterone decreased significantly during treatment with diethylstilboestrol. Although plasma levels of testosterone decreased during treatment with chlorotrianisene, levels of follicle stimulating and luteinizing hormones were not significantly suppressed. This pattern of response was observed both in healthy males and in patients with prostatic carcinoma, regardless of whether chlorotrianisene was used as the primary therapy in the latter group or following therapy with diethylstilboestrol or orchidectomy. The capacity of the sex steroid binding globulin for testosterone was increased following prolonged administration of both agents. It is concluded that suppression of plasma testosterone levels observed during chlorotrianisene therapy is the result of a direct effect on the testis and that this agent may be of value in studies of gonadotrophin physiology. Although the palliative effect of treating prostatic carcinoma with synthetic oestrogens such as diethylstilboestrol (DES) and chlorotrianisene (CTA) has been known for many years, the mechanism of this action is obscure. It is generally believed that reduction of circulating androgens secondary to suppression of pituitary gonadotrophin secretion is the main effect, but it is possible such drugs have direct effects both on the testis and the carcinoma. During investigations designed to evaluate the mode of action of these two drugs, an interesting difference emerged between their effects on serum levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH). An earlier study had demonstrated that when a patient who had been previously treated with DES was given CTA, plasma levels of testosterone remained low despite rising levels of FSH and LH (Burger et al., 1972). This paper reports the results of more detailed investigations of the effects of DES and CTA in healthy volunteers and in patients with carcinoma of the prostate.     

INCREASES IN SERUM CONCENTRATIONS OF FOLLICLE-STIMULATING HORMONE (FSH) DURING THYROTROPHIN-RELEASING HORMONE (TRH) INFUSIONS IN NORMAL MEN

Increases in serum FSH values to approximately 50% above basal concentrations were found during TRH infusions of 2.0 microgram/min into normal men (n = 10). These increases could not be explained by cross-reactivity of thyrotrophin (TSH) in the FSH assay. No significant change was found in serum concentrations of FSH during saline infusions (n = 4) nor in LH concentrations during either TRH or saline infusions. Many previous studies using single injections of TRH have failed to demonstrate changes in serum FSH concentrations. It is possible that prolonged infusions of TRH, as used in this study, are more likely to lead to non-specificity of the effects of this tripeptide on pituitary hormone secretion.     

THE CLINICAL USES OF HUMAN GONADOTROPHINS

With the recent preparation of hormones from human pituitaries and human postmenopausal urine, a wider range of pituitary gonadotrophin activity has become available for clinical use. To the luteinizing and interstitial cell stimulating effects of gonadotrophin prepared from human placentas can now be added the follicle stimulating activity of pituitary and urinary gonadotrophin. The clinical applications of these hormones lie in both the diagnostic and therapeutic fields. Their administration as gonadal stimulants followed by measurement of gonadal response allows an assessment of function and the determination of the level of gonadal failure. The range of biological gonadotrophic activity of these hormones allows their use as effective replacement therapy in gonadotrophin deficiency states in both sexes and for the infertile female, even in the absence of obvious hypogonadotrophinism.     

Inhibin secretion is influenced by Ley dig cells: evidence from studies using the cytotoxin ethane dimethane sulphonate (EDS)

Adult male rats given a single intraperitoneal injection of the Leydig cell cytotoxin ethane dimethane sulphonate (EDS) show a significant decrease in testosterone from 7 to 14 days, and elevation of serum FSH and LH levels commencing 7 days after treatment, returning to normal at 28 days for LH and 49 days for FSH. A significant rise in serum inhibin levels was seen at day 14 after EDS treatment with levels returning to normal at day 49. In a second series of experiments, silastic implants of testosterone, either 2.5 cm or 22.5 cm in length, were introduced subcutaneously into adult male rats which were treated with EDS 10 days later. Both doses of testosterone suppressed basal LH levels but did not significantly change FSH levels. The rise in FSH and LH levels seen in normal rats after EDS treatment did not occur in either group of testosterone-implanted rats. However, serum inhibin levels rose significantly in both groups after EDS treatment, suggesting that the rise in serum inhibin levels was not due to stimulation arising from the increase in FSH levels after EDS treatment. The data suggest that the rise in serum inhibin levels after EDS treatment is linked to destruction of the Leydig cells through mechanisms that require further investigation.     

HORMONAL STUDIES IN KLINEFELTER''S SYNDROME

Some aspects of the hormonal abnormalities of Klinefelter's syndrome have been studied in nineteen patients. As a group the plasma production rate, the total and free levels of testosterone, and the metabolic clearance rates of testosterone and oestradiol were low. Plasma oestradiol, LH and FSH levels were elevated and there was increased peripheral conversion of testosterone to oestradiol. The production rates of oestradiol and the binding capacities of the sex steroid binding globulin were normal. There were fluctuations in the blood levels of LH, FSH, testosterone and oestradiol, but these appeared to be less marked than in healthy men. Both LH and FSH levels were suppressed by acute or prolonged testosterone administration and there was no evidence for a differential effect on LH. It is suggested that the threshold for suppression of LH and FSH is increased in hypergonadotrophic states. Although no statistically significant relationships were found between the hormonal and clinical abnormalities of the syndrome it is probable that the hyperoestrogenism and androgen deficiency are linked to the development of the signs of feminization and hypogonadism.     

Determination of Sertoli cell numbers in the developing rat testis by stereological methods

Stereological studies were performed to determine the number of Sertoli cells present during the postnatal development of the rat testes. Sprague-Dawley rats aged from 1 to 70 days were used in two experiments, and in each were fixed by vascular perfusion and embedded in Epon-Araldite, subsequent to which 1 micron sections stained with Toluidine blue were prepared. In the first experiment, rats aged from 1 to 20 days were used in groups of three, and number estimates were made using a direct counting method. In the second, which used groups of four rats aged from 20 to 70 days, a point sampled intercept was used to estimate nuclear volume and thence number. The results of the experiments indicate that the newborn rat testis contains 1.3 +/- 0.2 x 10(6) Sertoli cells and that this number increases to 38.4 +/- 2.7 x 10(6) at day 15. No further increase in Sertoli cell number occurred thereafter up to day 70 of age.