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.     

Testicular dysfunction in untreated Hodgkin's disease

Gonadal function was examined in 19 young men with Hodgkin's disease before therapy and compared with that of 11 men with other malignancies, 13 men with primary testicular failure, and 19 normal men of similar age. Total (p less than 0.01) and free (p less than 0.05) testosterone levels were decreased in Hodgkin's disease. In those with advanced (stage III + IV) and symptomatic (B), Hodgkin's disease serum testosterone levels were indistinguishable from those in primary testicular failure, yet serum levels of luteinizing hormone were normal. Moreover, the acute response of serum testosterone to exogenous human chorionic gonadotropin (HCG) was significantly greater in Hodgkin's disease than in primary testicular failure (p less than 0.03). These data and the finding that basal serum follicle-stimulating hormone levels are significantly lower than normal in Hodgkin's disease (p less than 0.05) suggest that the cause of pretreatment hypogonadism in Hodgkin's disease is not simple primary testicular failure. Total sperm count was decreased in 40 percent of men with Hodgkin's disease but in none of the men with other malignancies (p less than 0.05), suggesting specific seminiferous tubular dysfunction in Hodgkin's disease. However, motility was abnormal in 69 percent of men with Hodgkin's disease and 60 percent of those with other malignancies, suggesting that this is a nonspecific effect of cancer. Serum prolactin levels were significantly higher than normal in Hodgkin's disease (p less than 0.05) but not in other malignancies. Our findings suggests that the cause of testicular dysfunction that is present before treatment of Hodgkin's disease is complex, perhaps involving both pituitary and gonadal abnormalities.     

Androgen receptor abnormalities in identical twins with oligospermia. Clinical and biochemical studies

Identical twin brothers presented with oligospermia, small testes, normal male phenotypes, elevated serum luteinizing hormone levels, and normal or elevated serum testosterone levels. Both men had low to low-normal cytosol androgen receptor binding capacity in cultured fibroblasts from pubic skin biopsy specimens. Qualitative abnormalities of cellular androgen receptors were suggested by low-normal or low nuclear androgen uptake in fibroblasts from both brothers as well as abnormal thermolability and subnormal molybdate stabilization of androgen receptors from one brother. In vivo androgen sensitivity was assessed in one twin following administration of testosterone or the non-aromatizable androgen fluoxymesterone. Fluoxymesterone suppressed serum luteinizing hormone and serum testosterone/estradiol-binding globulin, and although testosterone suppressed both serum luteinizing hormone and serum follicle-stimulating hormone, the suppression of serum luteinizing hormone by testosterone was subnormal. Both subjects showed marked exaggeration of the serum 17-hydroxyprogesterone increase after administration of human chorionic gonadotropin, despite normal serum testosterone increases, suggesting a block in testicular 17,20-desmolase, which converts 17-hydroxyprogesterone to testosterone. These studies suggest that oligospermia and block of the enzyme 17,20-desmolase may be the earliest manifestations of androgen resistance, and the finding of the syndrome of oligospermia, normal male phenotype, and androgen receptor abnormalities in identical twins indicates a genetic etiology of this disorder.     

In men older than 70 years, total testosterone remains stable while free testosterone declines with age. The Health in Men Study

OBJECTIVE: An age-related decline in serum total and free testosterone concentration may contribute to ill health in men, but limited data are available for men > 70 years of age. We sought to determine the distribution and associations of reduced testosterone concentrations in older men. DESIGN: The Health in Men Study is a community-representative prospective cohort investigation of 4263 men aged > or = 70 years. Cross-sectional hormone data from 3645 men were analysed. METHODS: Early morning sera were assayed for total testosterone, sex hormone binding globulin (SHBG) and LH. Free testosterone was calculated using the Vermeulen method. RESULTS: Mean (+/- s.d.) serum total testosterone was 15.4 +/- 5.6 nmol/l (444 +/- 162 ng/dl), SHBG 42.4 +/- 16.7 nmol/l and free testosterone 278 +/- 96 pmol/l (8.01 +/- 2.78 ng/dl). Total testosterone correlated with SHBG (Spearman's r = 0.6, P < 0.0001). LH and SHBG increased with age (r = 0.2, P < 0.0001 for both). Instead of declining, total testosterone increased marginally (r = 0.04, P = 0.007) whilst free testosterone declined with age (r = -0.1, P < 0.0001). Free testosterone was inversely correlated with LH (r = -0.1, P < 0.0001). In multivariate analyses, increasing age, body mass index (BMI) and LH were associated with lower free testosterone. CONCLUSIONS: In men aged 70-89 years, modulation of androgen action may occur via an age-related increase in SHBG and reduction in free testosterone without a decline in total testosterone concentration. Increasing age, BMI and LH are independently associated with lower free testosterone. Further investigation would be required to assess the clinical consequences of low serum free testosterone, particularly in older men in whom total testosterone may be preserved.     

The prevalence of low sex steroid hormone concentrations in men in the Third National Health and Nutrition Examination Survey (NHANES III)

Background Physiologic processes during ageing leading to multi‐morbidity and diseases that increase risk of premature death may be influenced by ageing‐associated changes in endogenous hormone production. Objective To evaluate the decline in sex steroid hormone levels across age and estimate the number of US men 40+ years old who may have low hormone levels. Design We measured serum testosterone, oestradiol and sex hormone binding globulin by immunoassay in 1351 men 20+ years old in Third National Health and Nutrition Examination Survey. We estimated free hormones by mass action. Results Free testosterone declined most rapidly with age (a 2% decline in geometric mean concentration occurred after ageing 1·3 years), followed by total testosterone (2·4 years), free oestradiol (4·1 years) and total oestradiol (8·1 years). These hormone changes with age translated into 25·0% and 30·2% of men 70+ years old having low total (which we defined as <10·4 nm ) and free (<0·17 nm ) testosterone, respectively, and 8·3% and 23·9% having low total (<73·4 pm ) and free (<2·2 pm ) oestradiol. Using population size projections between the 2000 and 2010 Censuses, we estimated that 8·4 (95% CI 4·7–12·2), 6·2 (3·1–9·2) and 6·0 (3·1–9·0) million men 40+ years old may have low total testosterone, free testosterone and free oestradiol, respectively. The prevalences were only modestly lower in men without prevalent chronic diseases. Conclusion Although no consensus exists for defining low hormone levels in ageing men, a substantial number of US men may have low sex steroid hormone levels, possibly putting them at risk for adverse health consequences and premature death.     

Reproductive hormones in aging men. II. Basal pituitary gonadotropins and gonadotropin responses to luteinizing hormone-releasing hormone

Although basal serum LH and FSH levels have been shown to increase with age in men, there is evidence that aging may impair pituitary gonadotropin secretion to some extent. We have measured serum LH and FSH before and after the iv injection of 100 micrograms LRH in 69 healthy men, divided into 3 age groups: A (25-49 yr; n = 24), B (50-69 yr; n = 23), and C (70-89 yr; n = 22). We have previously demonstrated these men to have unaltered serum androgens and estrogens over the entire age range. Only log-transformed measures were analyzed in order to equalize variance among groups. Because we found increasing age to be associated with significant rises in basal levels of LH and FSH, and because the basal level affects the magnitude of response, we used repeated measures analysis of variance to compare LRH peak responses with basal gonadotropin levels. The presence of a significant interaction term would indicate an effect of age on response beyond that expected from the effect of basal level alone. The mean LRH responses (log peak--log basal) decreased, with significant interaction terms for both LH (P = 0.001) and FSH (P less than 0.0001) responses. This means that the function relating basal to peak gonadotropin concentrations changed significantly with age. Peak LH responses in the youngest group (A) occurred equally as often 15 and 30 min after LRH injection, but in the oldest group (C) there were no 15 min peaks, and 40% of the peak values occurred at 60 min (P less than 0.01). FSH peaks were equally distributed at 30, 60, and 120 min in all 3 groups. Total testicular volumes did not decrease significantly with age. We conclude that there is a small but statistically significant tendency for LH and FSH responses to LRH to be both diminished and delayed in healthy aging men. The mechanisms responsible for this apparent pituitary gonadotropic hypofunction remain to be clarified.     

Sex hormone status of male patients with rheumatoid arthritis: evidence of low serum concentrations of testosterone at baseline and after human chorionic gonadotropin stimulation

Serum concentrations of luteinizing hormone, follicle-stimulating hormone, prolactin, 17 beta-estradiol, testosterone, androstenedione, dehydrotestosterone, dehydroepiandrosterone sulfate, and cortisol were examined in 14 men with rheumatoid arthritis (RA) and in age-matched osteoarthritis controls. Hypophyseal, adrenal, and testicular responses to stimulation with luteinizing hormone-releasing hormone, adrenocorticotropin, and human chorionic gonadotropin, respectively, were evaluated in 8 RA patients and in 8 age-matched healthy volunteers. Basal serum testosterone concentrations were significantly lower in male RA patients than in the osteoarthritis control subjects (P less than 0.01). After human chorionic gonadotropin stimulation, serum concentrations of testosterone were also lower in the RA patients than in normal healthy controls (P less than 0.05). These findings suggest that diminished testicular steroid biosynthesis might contribute to the serum testosterone deficiency observed in male RA patients.     

Stimulation of testosterone production in vivo and in vitro in the male rhesus monkey fetus in late gestation.

To assess intrauterine fetal testicular function, the carotid or femoral vessels of rhesus monkey fetuses, 129-145 days gestational age, were catheterized following hysterotomy of the mother. The fetus was returned to the uterus, the catheters were exteriorized through the mother's vagina and the pregnancy was allowed to continue. In this chronic preparation, basal levels of testosterone (measured with an RIA with 65% cross-reactivity with 5 alpha-dihydrotestosterone) in male fetal serum were 0.85 +/- 0.29 (SD) ng/ml. Administration of a 10 or 100 IU intra-arterial bolus of hCG into the fetal circulation stimulated in increase in fetal serum testosterone levels of 70 and 630%, respectively. Other fetuses were challenged with bolus infusions of 10 and 50 micrograms of synthetic gonadotropin releasing hormone (GnRH). The lower dose caused an increase in serum testosterone concentrations in only one of four fetuses, while the higher dose resulted in a positive response in all three experiments performed. With this dose, the mean increase in circulating testosterone concentration after 1 h was 105%. In vitro, specific binding of iodinated hCG was demonstrated in testicular homogenates from rhesus fetuses near term and hCG stimulated testosterone biosynthesis in testicular minces. Maximal stimulation was achieved at hCG concentrations between 5 and 50 ng/ml. The data indicate that the testes of fetal rhesus monkeys during late gestation are capable of androgen biosynthesis and can bind and respond to gonadotropin stimulation. Furthermore, the pituitary-gonadal axis in the fetal male monkey is capable of responding to GnRH stimulation at this stage of gestation.     

Feminizing testicular Leydig cell tumor: hormonal profile before and after unilateral orchidectomy

The effect of chronic hyperestrogenism on gonadal function was studied in three men who had estrogen-secreting Leydig cell tumors before unilateral orchidectomy and for 11-43 months after surgery. All three men had low plasma gonadotropin and testosterone levels and increased estradiol levels. Impairment of testicular steroidogenesis was also suggested by increased progesterone to 17-hydroxyprogesterone and 17-hydroxyprogesterone to androstenedione ratios in both spermatic venous plasma and the medium of Leydig tumor cells from one patient incubated in vitro. Before surgery, spermatogenesis was abnormal in two men. Testicular endocrine function and spermatogenesis did not return to normal after surgery. During the follow-up period, plasma gonadotropin levels were high in all three men, and testosterone was low normal. Estradiol levels decreased to normal immediately after surgery and then returned to the upper normal limit. The response to hCG stimulation in one man was subnormal. We conclude that chronic hyperestrogenism produced hypothalamo-pituitary inhibition as well as direct steroidogenic blockade at the testicular level. Long term impairment of both endocrine and exocrine testicular functions may be secondary to slowly reversible (or irreversible) estrogen-induced damage to tubular and Leydig cells.     

Regulation of gonadal function in uremia

Gonadal function and its neuroendocrine control were studied in seven uremic men on chronic hemodialysis. Testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in plasma or serum by established radioimmunoassay techniques. The metabolic clearance rate (MCR) of testosterone was also determined by constant infusion of ³H testosterone, and blood production rates were then estimated from the AM plasma level and the metabolic clearance rates. Predialysis, plasma testosterone in these uremic men were subnormal, measuring only $\text{289 ng}\text{100 ml ± 60 SE}$ (normal male values are 660 ± 70). The blood production rate of testosterone was also subnormal, averaging 2.7 mg/day in the two individuals studied, since the metabolic clearance rates were normal. However, after dialysis testosterone levels rose to $\text{408 ± 49 ng}\text{100 ml}$ (p < 0.01), the MCR to 1570 liters/day, and the calculated mean production rate increased to a normal level of 6.9 mg/day. Base-line serum LH was increased in the uremic state to 22.7 ± 1.8 mlU/ml (normal 5.9 ± 2), while FSH levels were normal at 7.7 mlU/ml ± 1.2 SE. Dialysis did not significantly alter serum immunoassayable gonadotropin levels. Gonadal stimulation by chorionic gonadotropin (4000 IU/day) initially did not increase testosterone levels, but continued stimulation-caused a two- to threefold rise by the fourth day. Clomiphene citrate (200 mg daily for 7 days) produced variable changes in testosterone and LH; two subjects did not respond, while two had a rise in both testosterone and gonadotropin. Luteinizing releasing hormone (LRH-Guillemin 150 μg intravenously) caused a two- to threefold rise in serum LH in both subjects studied. This work indicates that uremic men have subnormal testosterone production which is rapidly reversible with hemodialysis. The subnormal testosterone production appears to be primarily that of Leydig cell dysfunction, since there is elevated serum immunoassayable LH and a blunted initial response to exogenous gonadotropin.     

The effects of gonadotropin suppression and selective replacement on insulin-like factor 3 secretion in normal adult men

CONTEXT: Gonadotropic regulation of the testicular Leydig cell hormone insulin-like factor 3 (INSL3) is incompletely characterized. OBJECTIVE: The objective of this study was to assess the effects of gonadotropin suppression and induced or spontaneous recovery on serum INSL3. DESIGN AND PARTICIPANTS: Serum samples from 15 men enrolled in a short-term study of gonadotropin stimulation, suppression, and recovery and 11 men in a long-term study of gonadotropin suppression and spontaneous recovery were analyzed for INSL3. Intervention: Gonadotropins were suppressed by exogenous testosterone and progestin. Recovery was spontaneous or induced with exogenous gonadotropins. OUTCOME MEASURE: The outcome measure was serum INSL3 in relation to other reproductive hormones. RESULTS: Serum INSL3 was not acutely sensitive to gonadotropins. In both studies, INSL3 declined markedly with gonadotropin suppression (6-13.5% of baseline; P < 0.05). In the short-term study, human chorionic gonadotropin partially restored suppressed serum INSL3 within 4 d of administration (from 7.5 to 38.3% baseline; P < 0.05); the increase correlated with the corresponding increase in serum pro-alphaC (r = 0.82; P < 0.01). FSH did not stimulate the suppressed INSL3. In the long-term study, serum testosterone recovered significantly better (80% baseline) compared with serum INSL3 (38.9% baseline; P < 0.01) in the presence of fully recovered serum LH. CONCLUSIONS: INSL3 is not sensitive to gonadotropin stimulation in normal men, but declines markedly in response to gonadotropin deprivation. After suppression, INSL3 was responsive to hCG 4 d after administration. After long-term suppression, INSL3 did not recover to the same degree as testosterone, suggesting that INSL3 is more sensitive to Leydig cell impairment than testosterone.     

Hypogonadotropic hypogonadism in nephrotic rats: increased sensitivity to negative feedback effects of testosterone

Pituitary-testicular function was examined in adult male rats with aminonucleoside-induced nephrotic syndrome as a model for similar disease in humans. Nephrotic rats developed androgen deficiency, as manifested by decreased prostate and seminal vesicle weights, lower serum total and free testosterone levels, and reduced testosterone release from testes incubated in vitro. Despite hypoandrogenism, the weight and histologic appearance of the testes (light microscopy) were not affected in nephrotic rats. This androgen deficiency seemed to be a consequence of decreased gonadotropin output rather than primary testicular failure, since both pituitary gonadotropin content and serum gonadotropin levels (basally and after luteinizing hormone releasing factor; LHRH) were reduced in nephrotic rats. In addition, the percentage increase in testosterone release by testes incubated in vitro after addition of exogenous gonadotropin was similar in nephrotic and control groups. However, gonadotropin output in nephrotic rats was not impaired in the absence of testis, since no reduction was seen in either post-castration serum gonadotropin levels in vivo or gonadotropin release from pituitaries incubated in vitro. This presumed inhibitory effect of the testis on gonadotropin output in nephrotic rats was confirmed directly by demonstrating an increased sensitivity to testosterone-mediated suppression of gonadotropins in castrate animals in vivo. The presence or absence of albumin also seemed to modulate the suppressive effect of testosterone on gonadotropin output from normal pituitaries incubated in vitro. We conclude that nephrotic male rats develop hypogonadotropic hypogonadism secondary to an increase in sensitivity of the pituitary to the negative feedback effects of testosterone.     

Hypogonadism in hemochromatosis: reversal with iron depletion

Gonadal function was evaluated in 64 persons homozygous for the HLA-linked hemochromatosis allele. Of 41 men, 10 had reduced libido or impotence and 6 had testicular atrophy. Before treatment, 5 men had below normal testosterone concentrations, 4 of whom also had low gonadotrophin levels. Four hypogonadal men were reevaluated after iron depletion treatment. In 2, 1 with primary and another with secondary hypogonadism, testosterone levels returned to normal after phlebotomy and were accompanied by a return of normal sexual function. None of 23 women with hemochromatosis had loss of libido or had a natural menopause before age 45. Our findings indicate that in some men with hereditary hemochromatosis and hypogonadism of either testicular or central origin, sexual function and sex hormone concentrations can be restored to normal after iron depletion therapy.     

Effect of renal transplantation on pituitary gonadal function.

Twelve adult male patients who had undergone successful renal transplantation were investigated. The gonadotropin responses to 100 microgram luteinizing hormone-releasing hormone (LRH) were studied, and basal serum testosterone and prolactin assayed. Significantly elevated mean basal levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were found, associated with a correspondingly excessive LH and FSH response to LRH. Mean basal serum testosterone levels in the posttransplant patients were significantly lower than in normal controls, while the mean basal prolactin levels were similar in the two groups. The results were not influenced by the varying degrees of renal function found in the posttransplant patients.     

Plasma testosterone stimulation-suppression dynamics in hirsute women. correlation with long-term therapy

Clinical response and changes in plasma testosterone were measured in 22 hirsute women during the administration of dexamethasone, ethinyl estradiol-medroxyprogesterone, or both. The response of plasma testosterone to the administration of adrenocorticotropic hormone (ACTH), human chorionic gonadotropin (HCG) and dexamethasone was measured before treatment in 16 patients, and six additional patients were treated without initial testing. Patients were treated with three month courses of each therapy, regardless of their test results. Results of short-term testing did not correlate with those of long-term treatment. Previously elevated testosterone levels were suppressed in 80 per cent of the patients treated with dexamethasone and in all the patients treated with ethinyl estradiol-medroxyprogesterone (EE-MP).Hirsutism diminished in a third of the patients treated with dexamethasone and in half of the patients treated with EE-MP. Acne diminished in half of the patients with either therapy. There was good correlation between normalization of plasma testosterone levels and clinical improvement.Normal plasma testosterone levels were maintained for several months after dexamethasone treatment was discontinued.Recommendations are given for the approach to diagnosis and treatment of the female patient with hirsutism.     

Fertility decline in aging roosters is related to increased testicular and plasma levels of estradiol.

The relationships between testicular and plasma hormone levels and the decline in fertility in aging roosters were examined. Body mass, testicular mass, and fertility were measured in roosters from 20 to 72 weeks of age. Plasma was assayed for LH and testosterone, and estradiol and testicular extracts were assayed for testosterone and estradiol contents. Fertility increased rapidly in young roosters to a peak of 96.2 +/- 3.9% at 37 weeks of age. Thereafter, fertility declined and by 72 weeks of age was significantly lower than at 37 weeks. Plasma LH reached 16.8 +/- 2.5 ng/ml at 27 weeks and remained high until 60 weeks of age, when it decreased significantly. Plasma and testicular testosterone levels increased from low levels in young birds to a peak that coincided with highest fertility and declined thereafter. Plasma and testicular estradiol showed a striking inverse relationship with testosterone. Plasma estradiol was 29.4 +/- 4.0 pg/ml in 20-week-old birds, decreased rapidly as testosterone increased, and increased again in older birds as testosterone decreased. Thus, the decline in fertility in aging roosters was associated with a decrease in plasma LH and testosterone and an increase in plasma and testicular estradiol. It is suggested that plasma levels of LH and testosterone in roosters are regulated by a negative feedback mechanism involving estradiol that is produced not only by the aromatization of testosterone in the brain but also by peripheral estradiol originating in the testes and that estradiol has a major role in the decline in fertility in aging roosters.     

The low gonadotropin-independent constitutive production of testicular testosterone is sufficient to maintain spermatogenesis

Spermatogenesis is thought to critically depend on the high intratesticular testosterone (T) levels induced by gonadotropic hormones. Strategies for hormonal male contraception are based on disruption of this regulatory mechanism through blockage of gonadotropin secretion. Although exogenous T or T plus progestin treatments efficiently block gonadotropin secretion and suppress testicular T production, only approximately 60% of treated Caucasian men reach contraceptive azoospermia. We now report that in luteinizing hormone receptor knockout mice, qualitatively full spermatogenesis, up to elongated spermatids of late stages 13-16, is achieved at the age of 12 months, despite absent luteinizing hormone action and very low intratesticular T (2% of control level). However, postmeiotic spermiogenesis was blocked by the antiandrogen flutamide, indicating a crucial role of the residual low testicular T level in this process. The persistent follicle-stimulating hormone action in luteinizing hormone receptor knockout mice apparently stimulates spermatogenesis up to postmeiotic round spermatids, as observed in gonadotropin-deficient rodent models on follicle-stimulating hormone supplementation. The finding that spermatogenesis is possible without a luteinizing hormone-stimulated high level of intratesticular T contradicts the current dogma. Extrapolated to humans, it may indicate that only total abolition of testicular androgen action will result in consistent azoospermia, which is necessary for effective male contraception.     

Overweight and anthropometric changes in adulthood: a prospective study of 17,000 Finns

Changes in weight, body mass index (BMI), and thickness of triceps and subscapular skinfolds were studied in 17,294 adult Finns who, as part of a health survey, were examined twice after an interval of 4 to 7 (average 5.7) years. During the follow-up, the mean weight and BMI rose in men and women below the age of 50 at entry, changed little in men aged 50-70 and in women aged 50-60, and rapidly declined at later ages. Individual weight changes were generally small; about two-thirds of the participants maintained their weight within 5 kg from the initial weight. About 9 per cent of the men and 4 per cent of the women gained 10 kg or more, and 2 per cent of the men and 4 per cent of the women lost 10 kg or more in 5 years. Weight loss was associated with old age and high initial BMI, whereas weight gain was most common in the young, even in those with a high initial BMI. Young overweight subjects need most attention in prevention and treatment programmes for obesity.