Mild hypogonadotropic hypogonadism in obese men

To evaluate the pituitary-gonadal axis of obese men, we compared the 24-hour mean plasma concentrations of total and free testosterone and of dihydrotestosterone, FSH, and LH in 21 healthy obese men, aged 18–50, and 24 age-matched healthy nonobese men. In the obese men, we also measured the volume of ejaculate and the number and motility of sperm, and investigated libido by psychiatric interview, and potency by history and by measurement of nocturnal penile tumescence. As a group, the obese men had less than two-thirds the normal mean plasma levels of total testosterone, free testosterone, and FSH; the difference from normal was highly significant for all three. 24 hr LH levels were normal, which is inappropriately low in view of the subnormal testosterone levels. 24 hr mean levels of dihydrotestosterone and spermatogenesis, libido, and potency were essentially normal. Taken together, the findings represent a state of mild hypogonadotropic hypogonadism, which thus appears to be characteristic of obese men. This abnormality probably results from partial suppression of the pituitary by the elevated plasma estrogen levels we and others find in these men.     

The gonadotropin-suppressive activity of androgen is increased in elderly men

The influence of aging on the responsiveness to sex steroid hormones in men was studied by comparing circulating gonadotropin concentrations, pulsatile LH release, and sex hormone-binding globulin (TeBG) levels. This was done before and during a four-day continuous infusion of testosterone (T) (7.5 mg/d), dihydrotestosterone (DHT) (7.0 mg/d), or estradiol (E2) (45 micrograms/d) in young adult men, ages 18 to 32, and healthy elderly men, ages 65 to 80. DHT reduced mean serum LH and FSH levels as well as the frequency of spontaneous LH secretory episodes to a greater extent (p less than 0.05) in old men than in young men. T administration also reduced serum LH levels more in aged than in young men (P less than 0.05); however, this difference was less pronounced than for DHT. During T infusion, the decrease in serum FSH levels was similar in the two groups. Spontaneous LH pulse amplitude also declined during both T and DHT infusion in aged, but not in young men. By contrast, infusion of E2 reduced both serum LH and FSH levels comparably in aged and young men. DHT infusion also reduced serum TeBG levels equally in old and young men. Finally, each steroid infusion produced comparable mean circulating levels of T, DHT, and E2 in both groups. These data indicate that elderly men are more responsive than are young men to the gonadotropin-suppressive effects of androgen, but not to DHT effects on circulating TeBG levels. The more pronounced deceleration of spontaneous LH secretory episodes during DHT infusion in aged men provides evidence for an alteration in hypothalamic function in male senescence.     

Increased estrogen production in obese men.

Serum estrone (E1) and 17beta-estradiol (E2) were noted to be 2-fold elevated in a group of morbidly obese men. Urinary E1 and E2 production rates were elevated in proportion to the degree of obesity, with values as high as 127 and 157 micrograms/day, respectively. Although serum testosterone (T) concentrations were reduced in obese men, averaging 348 +/- 35 vs. 519 +/- 42 ng/dl in lean controls, the dialyzable T fractions were elevated and, hence, the calculated free T concentrations were normal in obese men. Further, the obese men exhibited normal serum LH, FSH, and T responses to clomiphene citrate, indicating intact hypothalamic-pituitary-Leydig cell axes. MCRs of T and peripheral conversion of T to E2 and androstenedione (delta) to E1 were all increased in obese men in proportion to the percentage above ideal weight. Although the obese mean exhibited increased blood levels and production rates of estrogens, there were no signs of feminization, increased T-estrogen-binding, globulin levels, or suppressed basal gonadotropin levels, suggesting a lack of biological effect. We postulate that obese men exhibit defective estrogen receptors, leading to decreased T-estrogen-binding globulin, increased clearance of androgenic hormones, and elevated estrogen production rates.     

Evidence for Leydig cell dysfunction in infertile men with a selective increase in plasma follicle-stimulating hormone

Recent studies in acutely castrated males of several species have demonstrated that testosterone (T) alone, given in doses that produce normal plasma T levels, can maintain normal plasma FSH and LH levels. This suggests that a nonsteroidal factor from the seminiferous tubule is not required to regulate FSH release, and raises the possibility that Leydig cell function may not be fully normal in oligo- or azoospermic men with increased plasma FSH levels. To clarify this, we studied T production rates in 11 sexually mature, infertile, but otherwise healthy men who had increased plasma FSH and normal plasma LH, T, and estradiol levels and in 9 normal men. Although individual plasma T and LH levels in the infertile men were within the normal ranges, the mean plasma T level of the infertile men was significantly lower (P less than 0.002), and the mean plasma LH level was significantly higher (P less than 0.002) than values in the normal men. The infertile men also had significantly lower plasma free T concentrations (P less than 0.005), while sex hormone-binding globulin and estradiol levels were similar to those of the normal men. The production rate of T in the infertile men was half that in the normal men (P less than 0.001). We conclude that T production is significantly reduced in infertile men who have a selective increase in plasma FSH. Because of the known role of Leydig cell sex steroids in the negative feedback control of FSH, this finding may explain the elevated plasma FSH concentrations characteristic of men with germ cell loss without the need to postulate a deficiency of a separate seminiferous tubule factor.     

Low free testosterone is an independent risk factor for Alzheimer's disease

The purpose of this study was to assess pituitary gonadotropins and free testosterone levels in a larger cohort of men with Alzheimer's disease (AD, n=112) and age-matched controls (n=98) from the Oxford Project to Investigate Memory and Ageing (OPTIMA). We measured gonadotropins (follicle stimulating hormone, FSH, and luteinizing hormone, LH), sex hormone binding globulin (SHBG, which determines the amount of free testosterone) and total testosterone (TT) using enzyme immunoassays. AD cases had significantly higher LH and FSH and lower free testosterone levels. LH, FSH and SHBG all increased with age, while free testosterone decreased. Low free testosterone was an independent predictor for AD. Its variance was overall explained by high SHBG, low TT, high LH, an older age and low body mass index (BMI). In controls, low thyroid stimulating hormone levels were also associated with low free testosterone. Elderly AD cases had raised levels of gonadotropins. This response may be an attempt to normalize low free testosterone levels. In non-demented participants, subclinical hyperthyroid disease (a risk factor for AD) which can result in higher SHBG levels, was associated with low free testosterone. Lowering SHBG and/or screening for subclinical thyroid disease may prevent cognitive decline and/or wasting in men at risk for AD.     

Gonadotropin determinations and thyrotropin-releasing hormone and luteinizing hormone-releasing hormone testing in critically ill postmenopausal women with hypothyroxinemia

Critically ill patients often have altered serum levels of thyroid hormones. The present study was undertaken to further define hormonal changes in such patients. Since postmenopausal women have normally elevated gonadotropin levels, this group was chosen as the study population. Thirteen critically ill patients with serum T4 concentrations below 5 micrograms/dl (group I), 16 critically ill patients with T4 concentrations of 5 micrograms/dl or greater (group II), and 19 normal subjects (group III) were studied. Basal gonadotropin levels (FSH and LH) were significantly lower (P less than 0.01) in both critically ill groups. The LH level in group I was 36.5 +/- 39.3 (+/- SD) mIU/ml, in group II it was 45.3 +/- 30.4, and in group III it was 75.3 +/- 24.4. The FSH level in group I was 43.0 +/- 39.7 (+/- SD) mIU/ml, in group II it was 78.0 +/- 37.9, and in group III it was 133.0 +/- 38.2. Most group I patients had LH and FSH concentrations far below the normal postmenopausal range. The response to dynamic testing with TRH and LRH revealed a significantly lower incremental TSH response to TRH in group I (8.0 +/- 5.6 mIU/ml) compared to that in group III (13.7 +/- 2.8; P less than 0.05). However, the maximal responses of FSH and LH to LRH were not different between groups I and III, despite the fact that 2 of 10 group I patients had no response. These data indicate that a subset of patients with the low T4 syndrome have hypogonadotropism, inappropriate to their menopausal state. This suggests that acute critical illness may cause hypothalamic or pituitary dysfunction, only part of which is recognized as the low T4 syndrome. The mechanism for this dysfunction and its importance in contributing to the overall mortality in this group is unknown.     

LHRH pulse frequency in normal and infertile men

The aim of this study was to examine the hypothesis that decreased LHRH pulse frequency may be responsible for the preferential rise in FSH in infertile men. The LH pulse pattern was determined as an index of hypothalamic LHRH secretion in 21 infertile patients with idiopathic azoospermia or oligoasthenozoospermia and 14 fertile age-matched controls by frequent blood sampling at 10-min intervals for 24 h. The infertile patients were further divided into three groups according to their relative concentrations of FSH and LH: (1) normal FSH and LH, (2) raised FSH but normal LH, and (3) raised FSH and LH. LH pulses were detected by a computerized algorithm (Munro) validated against a threshold method. Concentrations of FSH, testosterone, sex hormone-binding globulin and oestradiol were measured in pooled plasma. Luteinizing hormone pulse frequencies in normal men were not significantly different from the infertile group as a whole. Similarly, mean LH pulse frequencies in infertile subgroups 1, 2 and 3 were not significantly lower than normal. Pulse interval, however, was increased in subgroup 1 compared with normal. Mean 24 h LH in group 2 was significantly higher than normal, but still within the normal range. The total testosterone, but not the free testosterone index was significantly decreased in the infertile group compared with normal. There was no correlation between mean FSH and LH pulse frequency or interval. In conclusion, our results show that in patients with seminiferous tubular dysfunction, the typical pattern of raised plasma FSH, increased LH pulse amplitude, raised FSH: LH ratio and normal or marginally low testosterone was not associated with any significant deviations in LHRH pulse frequency from the range observed in normal fertile men. This is not compatible with the hypothesis that decreased LHRH pulse frequency is associated with or the cause of the preferential rise in FSH in men with idiopathic infertility. Thus unlike anovulatory infertility in females, functional defects of hypothalamic LHRH secretion remain an uncommon finding in male infertility. Attempts to treat idiopathic oligozoospermia by altering LHRH pulse frequency is therefore unlikely to yield any clinical benefit.     

Daytime titers of testosterone, LH, estrone, estradiol, and testosterone-binding protein: acute effects of LH and LH-releasing hormone in men.

Four normal 18-20 yr-old men were studied on 3 occasions, from 0830 h to 1500 h. The baseline for each study consisted of 3 or 4 measurements of the respective hormone obtained between 0830 and 0900 h. In the control studies mean testosterone (T) fell by 43% (P less than 0.01) during the final 30 min. The fall was gradual throughout the day and was significant by 1100 h (P less than 0.05). Administration of LH and LH-releasing hormone (LHRH) at 0900 h resulted in 9-fold (5 min) and 3-fold (30 min) higher concentrations of LH respectively. LH declined more slowly after LHRH. Titers of T rose to the 0830-0900 h mean 130 min after LH but were never significantly elevated; the occurrence of a significant drop in mean T was delayed for 70 min. After LHRH there was a nonsignificant 24% increase of the mean T followed by a slow decline; however, T did not fall significantly below the mean baseline level. In contrast, in 2 of the 4 subjects LHRH resulted in rises in T levels (P less than 0.05) above the basal titers. Testosterone-binding globulin (TeBG) mean titers showed no diurnal rhythm in the control studies. There were statistically significant elevations of mean TeBG 150 min after LH and 340 to 370 min after LHRH, as well as sustained increases during the final 30 to 210 min of 1 or 2 individuals in each group. The reason for these increases in TeBG is not presently known. Estrogen analyses performed in all studies on 2 of the subjects revealed: 1) afternoon titers of estrone were lower than baseline in all 6 studies, 2) there was no diurnal rhythm for estradiol in control studies, and 3) estradiol increased during the final 2.5 to 3 h after LHRH (P less than 0.01), but after LH it was not altered in 1 man and was lower in the other.     

Evidence for decreased luteinizing hormone-releasing hormone pulse frequency in men with selective elevations of follicle-stimulating hormone

To examine the hypothesis that the frequency of endogenous pulsatile LHRH stimulation controls the relative secretion of FSH and LH from the pituitary, we studied men with elevated FSH levels and normal LH levels to determine whether they have an altered frequency of pulsatile LHRH secretion compared to normal men. Because peripheral blood measurements of LHRH do not reflect the pulsatile characteristics of hypothalamic LHRH secretion, and it is generally accepted that the pulse frequency of LH secretion is an index of the frequency of endogenous LHRH pulsation, we used LH pulse frequency as the indicator of LHRH pulse frequency. Frequent blood sampling was performed to characterize LH pulse patterns in five men with selective elevations of FSH and seven age-matched normal men. Beginning at 0800-0930 h, blood samples were obtained every 10 min for 24 h through an indwelling iv catheter. Serum LH and FSH levels were measured by RIA in each sample, and the pattern of LH secretion was determined. Testosterone (T), estradiol, sex hormone-binding globulin, and free T were measured in a pooled serum sample from each man. Men with selective elevations of FSH had fewer LH pulses per 24 h (mean +/- SEM, 10.6 +/- 0.5) than the control group (12.9 +/- 0.6; P less than 0.01). There was no statistically significant difference in LH pulse amplitude (23 +/- 4 vs. 17 +/- 3 ng/ml). There were no statistically significant differences in T (4.9 +/- 0.5 vs. 6.1 +/- 0.5 ng/ml), estradiol (23 +/- 7 vs. 31 +/- 5 pg/ml), sex hormone-binding globulin (7.7 +/- 1.4 vs. 7.7 +/- 1.2 ng bound dihydrotestosterone/ml), or free T (0.16 +/- 0.02 vs. 0.23 +/- 0.04 ng/ml) in these men vs. normal subjects. We conclude that 1) compared to normal men, men with selectively elevated FSH levels have decreased LH pulse frequency, which suggests decreased LHRH pulse frequency; and 2) the relative secretion rates of LH and FSH by the pituitary may be regulated by the frequency of pulsatile LHRH secretion from the hypothalamus.     

Relative binding of testosterone and estradiol to testosterone-estradiol-binding globulin

The binding of estradiol (E2) and testosterone (T) to testosterone-estradiol-binding globulin (TeBG) was studied in vivo at 37 C by three independent methods: equilibrium dialysis, steady state polyacrylamide gel electrophoresis, and TeBG-ligand dissociation kinetics. Equilibrium dialysis was performed at 37 C with the dialysate containing human serum albumin in amounts equivalent to that of the plasma dialysand. Scatchard analysis indicated that under these conditions E2 does not measurably bind to TeBG, while T has a Kd of 3.7 X 10(-10) M. Similarly, Scatchard-type analysis of E2 binding to TeBG in steady state polyacryalmide gel electrophoresis at 37 C revealed no high affinity saturable binding, while dihydrotestosterone was bound with a Kd of 2.7 X 10(-10) M. Examination of the dissociation kinetics of T and E2 ffrom TeBG revealed that the mean (+/-SD) T1/2 of dissociation of T from plasma at 37 C (10.8 +/- 2.4 min) was significantly shortened to 3.5 +/- 0.4 min by saturation of plasma with dihydrotestosterone (P less than 0.01), whereas that of E2 (8.9 +/- 1.4 min) was not changed (9.6 +/- 3.0 min). These data suggest that TeBG is not an important binder of plasma E2 at physiological temperatures and explain the observation that in diseases characterized by high TeBG levels, such as hyperthyroidism and liver disease, the MCR and free E2 levels have generally been normal.     

Effects of chronic testosterone administration in normal men: safety and efficacy of high dosage testosterone and parallel dose-dependent suppression of luteinizing hormone, follicle-stimulating hormone, and sperm production

In normal men, chronic testosterone (T) administration results in negative feedback suppression of gonadotropin and sperm production. However, azoospermia is achieved in only 50-70% of men treated with high dosages of T. Furthermore, the relative sensitivity of LH and FSH secretion to chronic administration of more physiological dosages of T is unclear. We determined whether a T dosage higher than those previously given would be more or less effective in suppressing spermatogenesis and whether, within the physiological range, T would exert a more selective effect on LH than on FSH secretion. After a 4- to 6-month control period, 51 normal men were randomly assigned to treatment groups (n = 9-12/group) receiving either sesame oil (1 mL) or T enanthate (25, 50, 100, or 300 mg, im) weekly for 6 months. Monthly LH and FSH levels by RIA and twice monthly sperm counts were determined. During treatment, T levels were measured daily between two weekly injections. Chronic T administration in physiological to moderately supraphysiological dosages resulted in parallel dose-dependent suppression of LH, FSH, and sperm production. T enanthate (50 mg/week) suppressed LH and FSH levels and sperm counts to 50% of those in placebo-treated men (ED50). T enanthate (300 mg/week), was no more effective than 100 mg/week in suppressing LH, FSH, and sperm production. Serum T levels in men who received 100 and 300 mg/week T enanthate were 1.5- and 3-fold higher than those in placebo-treated men, respectively. Except for mild truncal acne, weight gain, and increases in hematocrit, we detected no significant adverse health effects of chronic high dosage T administration. We conclude that 1) LH and FSH secretion are equally sensitive to the long term negative feedback effects of T administration; 2) sperm production is suppressed in parallel with the LH and FSH reductions induced by chronic T administration; and 3) even at the clearly supraphysiological dosage of 300 mg/week, T enanthate does not reliably induce azoospermia in normal men. However, there was also no evidence of a stimulatory effect of this T dosage on spermatogenesis. Furthermore, we found no evidence of major adverse health effects of T administered chronically even at the highest dosage.     

Obesity and its role in polycystic ovary syndrome

To examine the mechanism by which obesity influences ovulation, 55 patients with oligo- or anovulation were studied. Parameters measured in serum were sex steroid-binding globulin (SSBG), testosterone (T), PRL, LH, FSH, and estradiol (E2). The women were divided into 2 groups: an obese group (group 1), greater than 145% of ideal body weight, and a normal weight group, less than 120% ideal body weight. SSBG was measured by saturation analysis T, LH, FSH, PRL, and E2 were measured by RIA. SSBG group 1 levels were 7.14 ng dihydrotestosterone bound/ml compared to 14.7 ng dihydrotestosterone bound/ml in group 2 (P less than 0.05). There were no significant differences in FSH, T, or E2. The correlation of body weight vs. SSBG in all patients was r = -0.62. In these 2 groups, the SSBG was significantly lower in the obese patients compared to that in the normal weight patients, independent of T or E2 levels. SSBG correlated negatively with body weight, suggesting that obesity has an influence on SSBG levels independent of hormonal status. When SSBG is lowered, there may be an increase in free T which, by inhibiting follicular maturation, may begin the sequence of events seen in polycystic ovary syndrome.     

Effects of testosterone plus medroxyprogesterone acetate on semen quality, reproductive hormones, and germ cell populations in normal young men

Testosterone (T) treatment suppresses gonadotropin levels and sperm counts in normal men, but the addition of a progestin may improve the efficacy of hormonal contraception. This study aimed to investigate the speed and extent of suppression of testicular germ cell number induced by T plus or minus progestin treatment and correlate these changes with serum gonadotropins and inhibin B levels, testicular androgens, and sperm output. Thirty normal fertile men (31-46 yr) received either testosterone enanthate (TE, 200 mg im weekly) alone or TE plus depot medroxyprogesterone acetate (DMPA, 300 mg im once) for 2, 6, or 12 wk (n = 5 per group) before vasectomy and testis biopsy. Five men (controls) proceeded directly to surgery. The inclusion of DMPA led to a more rapid fall in serum FSH/LH levels (time to 10% baseline: FSH; 12.6 +/- 2.6 vs. 7.9 +/- 1.4 d; LH, 9.9 +/- 3.4 vs. 3.4 +/- 1.7 d, TE vs. TE+DMPA, respectively, mean +/- SD, both P < 0.0001), yet the mean time to reach a sperm count 10% of baseline was not different (23.7 +/- 7.3 vs. 25.3 +/- 13.9 d, NS). The maximum extent of FSH/LH suppression was identical at 12 wk (mean serum FSH 1.2 and 1.6%, and mean LH 0.3 and 0.2% of baseline: TE vs. TE+ DMPA, respectively) as was sperm count suppression (5 of 5 and 4 of 5 men, respectively, with sperm counts < or =0.1 x 10(6)/ml). Serum inhibin decreased to 55% control at 12 wk in the TE+DMPA group (P < 0.05) but was unchanged by TE treatment (86% control, NS). Testicular T levels declined to approximately 2% of control levels, but testicular dihydrotestosterone and 5alpha-androstane-3alpha,17beta-diol (Adiol) levels were not different to control. Germ cell numbers as determined by stereological methods did not differ between TE and TE+DMPA except at 2 wk when type B spermatogonia and early spermatocytes were significantly lower in the TE+DMPA group (P < 0.05). In all groups, a marked inhibition of Apale-->B spermatogonial maturation was seen along with a striking inhibition of spermiation. We conclude that: 1) the addition of DMPA hastens the onset of FSH/LH suppression, correlating with a more rapid impairment of spermatogonial development, but in the longer term, neither germ cell number nor sperm count differed; 2) testicular dihydrotestosterone and Adiol levels are maintained during FSH/LH suppression despite markedly reduced T levels suggesting up-regulation of testicular 5alpha-reductase activity; and 3) spermatogonial inhibition is a consistent feature, but spermiation inhibition is also striking and is an important determinant of sperm output.     

The hypothalamus–pituitary–gonad axis and testicular function in male patients after treatment for haematological malignancies

Abstract. Kauppila M, Viikari J, Irjala K, Koskinen P, Remes K (Turku University Central Hospital, Turku, Finland). The hypothalamus–pituitary–gonad axis and testicular function in male patients after treatment for haematological malignancies. J Intern Med 1998; 244 : 411–6.

Objective

The effect of aggressive chemotherapy on the hypothalamus–pituitary–gonad axis and on testicular function was assessed in nine male patients who had received chemotherapy only (CT, group I) and in 10 males after allogeneic bone marrow transplantation (BMT, group II). The mean time from CT or BMT to the assessment was 3.7 (range, 1.0–11.7) years.

Design

The responses of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were assessed by the gonadotropin-releasing hormone (GnRH) test and, in addition, serum basal values for testosterone and sex hormone binding globulin (SHBG) were measured and the free androgen index (FAI) was calculated. In 13/19 patients the human chorionic gonadotropin (hCG) test was performed.

Results

In group I, only one patient had an abnormal basal FSH value, but all (100%) had pathologically poor responses to the GnRH test. In contrast, all baseline FSH values were raised in group II (mean, 18; range, 11–30 U L^?1), indicating toxic injury to the seminiferous tubules. Also in group II the responses to GnRH were low throughout the test (90%) and there were no clear peak values. In group II, the basal FSH and its maximum response to GnRH were significantly more affected than in group I (P < 0.001). The difference may be due to the effect of the conditioning regimen. Serum basal LH was raised in three of the patients in group I and they also had abnormal releasing test responses. In group II, baseline LH was abnormal in four patients, but the responses to GnRH were normal. However, the maximum response to the releasing test was significantly more affected in group II (P = 0.024). Serum testosterone levels were normal in all test subjects in both study groups. However, in two patients in both groups, the serum free androgen index was below the low reference limit, and an impaired response of serum testosterone to hCG stimulation was common (60%).

Conclusions

A toxic injury in the testis is common in haematological patients, especially after high-dose chemoradiotherapy. Serum basal testosterone usually remains normal, but even then subnormal serum free androgen index, impaired testosterone response to hCG injection and abnormal response in LH may indicate a deficient androgen status. It may well be that testosterone replacement therapy should be considered in these cases.

     

Hormone blood levels and their inter-relationships in normal men and men with benign prostatic hyperplasia (BPH).

In 128 non-hospitalized men (age range 36-65 years) rectal palpation revealed in 54 cases an enlargement of the prostate (group II), which was very distinct in 20 cases (group III). The measurement of testosterone (T), 5alpha-dihydrotestosterone (DHT), 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) oestradiol (Oe2), sex-hormone-binding-globulin binding capacity (SHBG), luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (Prl) in the blood of normal men (group I) and those with BPH (group II or III) demonstrated no significant differences between the three groups when respective age ranges were compared. A significant increase of FSH and decrease of 3alpha-diol with age was seen in the normal group (I), which was similar but less pronounced in BPH (groups II and III). A distinct increase of DHT with age was found in BPH (group II), which was not so dominant in normal men (group I). From these data it is concluded that the conversion of DHT to 3alpha-diol might be reduced in older males independent from the occurrence of BPH and that the hyperplastic prostate possibly secretes significant amounts of DHT into the circulation. These results are discussed with respect to their possible role in the pathogenesis of BPH.     

Effect of carbohydrate supplementation on reproductive hormones during fasting in men

We previously demonstrated that during a 10-day fast in mildly obese men, urinary gonadotropin excretion significantly increased, and serum testosterone concentrations significantly decreased. The mechanisms by which these changes occur are unknown. We postulated that the mechanism of the gonadotropinuria might involve decreased proximal renal tubular reabsorption of gonadotropins during fasting and might be related to renal tubular reabsorption of ketones during fasting, a process that is enhanced by carbohydrate (CHO) administration. We studied the effects of CHO supplementation on ketosis, ketonuria, and reproductive hormone secretion and excretion in 14 mildly obese men, 24-54 yr old, who were 14-69% above ideal body weight. Group I (n = 6) received no CHO supplementation, group II (n = 4) received 15 g CHO, and group III (n = 4) received 45 g CHO daily during the 10-day fast (F). During the control (C) and refeeding (R) periods, all subjects received a 1500-cal diet. Daily 24-h urine collections were made for the measurement of total ketones (millimolar concentrations) and LH and FSH (expressed as international units of the Second International Reference Preparation of human menopausal gonadotropin). Values (mean +/- SE) for 3 representative days (control day 3, fasting day 8, and refeeding day 3) for all subjects are shown below: (table; see text) We also studied the effects of CHO supplementation on serum levels of pituitary gonadotropins, LH and FSH responses to exogenous LHRH stimulation, biological activity of LH, and circulating total and free testosterone levels. Neither dose of CHO prevented the decline in total and free testosterone levels. Serum LH concentrations, as measured by both the RIA and in vitro bioassay did not change significantly with fasting. Serum FSH concentrations in daily samples did not change significantly. The previously reported decline in the FSH response to LHRH stimulation with fasting was not prevented by CHO. We conclude that CHO supplementation prevents the gonadotropinuria of fasting in men. The effect appears to occur in the kidney. The mechanisms may be related to that by which CHO promotes the renal tubular reabsorption of ketones. The reduced serum testosterone level cannot be explained by a lack of biologically active LH. It appears that fasting has a direct effect on the testis, possibly by reducing its responsiveness to gonadotropic stimulation or by inhibiting steroidogenesis.     

Androgen plasma levels in male diabetics

Plasma level of androgens were studied in 47 normal male controls (20-50 yr-old; mean age 38 yr) and in a group of forty-one male diabetics (23-55 yr-old; mean age: 37.5 yr). Of these 36 showed type II and 5 type I diabetes. The results showed that while the mean basal plasma LH was unchanged, there was a decrease in testosterone levels in the diabetics. Moreover, testosterone binding globulin (TeBG) capacity appeared to be augmented and, as a consequence, the apparent free testosterone concentration (AFTC) was markedly decreased. It is interesting to note that the anomalies in androgen secretion observed are rather similar to those found in elderly man and could play some role (with other factors) in the onset of the frequent sexual disturbances in male diabetics.     

Leydig cell function in infertile men with idiopathic oligospermic infertility

To evaluate Leydig cell function in men with idiopathic oligospermic infertility and its eventual role in their infertility, plasma LH, testosterone (T), 17-hydroxyprogesterone (170HP), and estradiol levels as well as plasma T/LH and 170HP/T ratios were measured in 103 such men, subdivided into different groups according to their plasma FSH levels. The results were compared to results in normal young fertile men, the subgroup of men with idiopathic oligospermic infertility who within 12 months after consultation succeeded in impregnating their partner, infertile men with a history of undescended testes (excryptorchid men), and men with Klinefelter's syndrome. As a tentative parameter of androgen insensitivity, an androgen insensitivity index [LH (IU/L) X T (nMol/L)] was calculated. Although all men with idiopathic infertility had plasma T and LH levels within the normal range, LH levels increased and T/LH ratios decreased with increasing FSH levels, while the 170HP/T and estradiol/T ratios were independent of the FSH levels and T/LH ratios. The decreased T/LH ratios in the presence of normal T levels suggest compensated Leydig cell insufficiency, which possibly contributes to the infertility. Indeed, none of the men (n = 12) with normal FSH levels but a T/LH ratio lower than 1.50 achieved fatherhood within 12 months of follow-up, although all other hormonal parameters were within the normal range. During the same period 25 men with T/LH ratios greater than 1.50 succeeded in impregnating their partners (P less than 0.05). In infertile excryptorchid men and even more so in men with Klinefelter's syndrome, plasma T levels and T/LH ratios were significantly decreased, the decrease being greater than in patients with idiopathic azospermia with similar FSH levels. None of the excryptorchid men with normal FSH levels but T/LH ratios below 1.50 fathered a child during the follow-up study. We suggest that the T/LH ratio is an additional useful prognostic parameter of infertility. Plasma T levels were increased in 15% of patients with idiopathic infertility, but increased plasma LH together with increased T levels (increased androgen resistance index) were found in only 1 man. An increased index, however, was found in 6 azoospermic excryptorchid men and 4 of 28 men with Klinefelter's syndrome. Taken together these data suggest that this index is not a reliable parameter of androgen resistance.     

Free testosterone index: comparison with plasma free testosterone

Blood-free testosterone indices were measured among 28 normal men (age; 24-48 yrs.), 20 normal women (20-36 yrs.), 18 pregnant women (22-31 yrs.), 17 males with hypogonadism (23-56 yrs.), 17 males with chronic hepatitis (20-42 yrs.), 24 males with liver cirrhosis (29-68 yrs.), 34 males with hyperthyroidism (20-42 yrs.) and 7 hirsute women (18-31 yrs.), and these were compared with the plasma concentrations of free testosterone. The testosterone index was obtained by multiplying the plasma concentration of testosterone by the percent of sex hormone-binding globulin (SHBG), non-bound testosterone precipitated by dextran-coated charcoal. A significant increase of plasma testosterone was observed in patients with chronic hepatitis (p less than 0.001) and hyperthyroidism (p less than 0.001) as compared with normal men and was also observed in pregnant (p less than 0.01) and hirsute women (p less than 0.01) as compared with normal women. The close negative correlation between plasma levels of testosterone and the percent of SHBG non-bound testosterone (r = -0.87, n = 79, p less than 0.001) was observed among normal men, male patients with chronic hepatitis and hyperthyroidism. The sex hormone binding capacity was increased from two to three fold in patients with chronic hepatitis and hyperthyroidism. The patients with compensated liver cirrhosis had increased plasma testosterone and a decreased percent of SHBG non-bound testosterone, and those with decompensated liver cirrhosis had decreased plasma testosterone and a normal percent of SHBG non-bound testosterone. The plasma concentration of free testosterone was normal in patients with chronic hepatitis and hyperthyroidism. It decreased in pregnancy (p less than 0.01) and increased in hirsute women (p less than 0.01). The blood free testosterone index was slightly high in one third of the patients with chronic hepatitis and hyperthyroidism as compared with that in normal men. However, a close correlation of the percent of SHBG non-bound testosterone and fractional free testosterone (%) measured by equilibrium dialysis (gamma = 0.82, p less than 0.001) was obtained in all subjects (n = 170). These data suggest that the blood free testosterone index parallels the plasma concentration of free testosterone and is useful to evaluate the status of androgenicity.     

Inhibin B in men with severe obesity and after weight reduction following gastroplasty

Although the effect of obesity on some gonadal functions in men is known, its effect on Sertoli cell function has not been reported. We tested the hypothesis that the serum inhibin B level is decreased in men with severe obesity, and that this change persists after significant weight loss. We measured gonadal hormones in 17 obese men before (baseline) and after weight reduction following silastic ring vertical gastroplasty (SRVG). Their baseline body mass index (BMI) was 44.3 +/- 1.7 kg/ m2, mean +/- standard error of the mean (SEM). Seven of 16 obese men (44%), compared to 8 of 69 reference men (12%), had a baseline inhibin B level below 100 pg/ml (p < 0.01). A weak inverse association was found between inhibin B and BMI before weight reduction (r = -0.494, p = 0.072). Furthermore, FSH levels, which were weakly inversely associated with inhibin B levels (r = -0.482, p = 0.059), were inappropriately unelevated in 5 of the 7 obese men with low (below 100 pg/ml) inhibin B. After a weight reduction of 40 +/- 2.6 kg, mean +/- SEM, following surgery, the obese men's BMI was 31.6 +/- 1.5 kg/m2, mean +/- SEM, and inhibin B normalized in 3 of the 7 patients with low inhibin B. Despite weight reduction, FSH remained inappropriately unelevated in 2 of the 4 patients whose inhibin B remained low. This study also confirmed previously published findings that obese men have low serum total and free testosterone and relative hypogonadotropic (low LH) hypogonadism that may persist after weight reduction. In conclusion, Serum inhibin B levels in obese men may be low. This may be due to relative hypogonadotropic (also low FSH) hypogonadism.