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Because we had observed that smoking has a pronounced effect on serum progesterone levels, we reinvestigated in healthy nonsmokers the relative progesterone levels of men and follicular-phase women. Each of eight women had multiple measurements of serum progesterone during the follicular phase of a menstrual cycle (10 days through 3 days prior to the luteinizing hormone peak of that cycle), and the average of those values was taken to represent the basal progesterone level for that woman. Seven men had blood samples drawn at 20-minute intervals between 6:00 and 9:00 am, through an indwelling venous catheter, and the average of those values was taken. The mean follicular-phase serum progesterone level in the women was 21.4 ± 5.4 ng/dl and the mean level in the men was 18.1 ± 3.1 ng/dl. The difference was not statistically significant. In view of this finding, we conclude that there is essentially no ovarian secretion of progesterone during the follicular phase of the menstrual cycle. (Steroids 55: 557–559, 1990)

Since smoking has been shown to affect serum progesterone and estradiol levels in postmenopausal women, we evaluated the levels of these hormones and luteinizing hormone (LH) over an entire menstrual cycle (17 points) in eight healthy nonsmokers and eight healthy smokers. The total length of the cycle and the lengths of the follicular and luteal phases did not differ between the groups. There was no difference in estradiol, progesterone, or LH levels during the periovulatory and luteal phases. Follicular-phase serum progesterone, which had a level 37% higher in smokers, showed a plateau in both groups (28.3 +/- 5.7 ng/dl versus 20.7 +/- 5.7; P less than 0.0001). Follicular-phase serum estradiol showed a rising curve in both groups. The mean value in smokers was slightly higher than that in nonsmokers (107 pg/ml versus 95; P approximately 0.05); during the early part of the follicular phase, prior to the rapid preovulatory increase, the difference was greater (23%) and of higher statistical significance (80 pg/ml versus 65; P less than 0.001). The follicular-phase LH levels of smokers were skewed downward from the levels in nonsmokers, presumably by negative feedback from the elevated estradiol and progesterone levels; the difference was significant (P less than 0.001). The elevations of serum progesterone and estradiol in smokers probably represent activation of adrenocortical secretion by smoking. The greater and more clear-cut rise of progesterone than of estradiol is probably due to the fact that essentially all of the follicular-phase serum progesterone is secreted by the adrenal, while only part of the follicular-phase serum estradiol comes from the adrenal (via androstenedione and estrone).

It is known that plasma total testosterone (T) is decreased in obese men in proportion to the degree of obesity, but similar information is not available for plasma free T and non-sex-hormone-binding globulin (SHBG)-bound T. We measured the 24-h mean plasma total T in 48 healthy (non-weight-stable men, aged 18-55 yr, with body mass indexes (BMI) ranging from 21-95 kg/m2. Free T and non-SHBG-bound T were calculated using the measured total T, the concentrations of albumin and SHBG, and the association constants of T to albumin and SHBG. Total body fat content was measured by deuterium-water isotope dilution. Findings were as follows. 1) BMI was very highly correlated with total body fat content (r = 0.96; P less than 0.001); thus, the degree of obesity can be calculated just as appropriately from simple height and weight measurements as from measurements of total body fat content. 2) Total, non-SHBG-bound, and free T were all highly correlated inversely with BMI; for total T, r = -0.727, P less than 0.01; for non-SHBG-bound T, r = 0.677, P less than 0.01; and for free T, r = -0.653, P less than 0.01. Thus, free T and non-SHBG-bound T are decreased in obese men in proportion to the degree of obesity, just as is the case for total T; percentage-wise, the decrease was the same for all 3 parameters.

[24,25- 3 H]Cholesteryl ester-labeled rat high-density and low-density lipoproteins were administered to recipient rats. Following death of the rats, a major portion of the radioactivity in administered [ 3 H]cholesteryl ester-high-density lipoprotein rapidly appeared in less dense [ 3 H]cholesteryl esterlipoproteins and was isolated with the low-density lipoprotein fraction. The specific activity of the esterified cholesterol in the product lipoproteins found with the low-density lipoproteins exceeded that of the precursor high-density lipoproteins. In vitro, the addition of [ 3 H]cholesteryl ester-high-density lipoprotein to plasma resulted in a five- to six-fold increase in radioactivity recovered in the low-density lipoprotein. These results demonstrate that, under a variety of experimental conditions, isolated high-density lipoprotein particles (both in vitro and in vivo) tend to become larger and less dense. Rapid changes in the density of lipoproteins labeled with [ 3 H]cholesteryl ester must be considered when interpreting physiologic studies using this label.

To study the ability of weight loss to reverse the hyperestrogenemia-induced hypogonadotropic hypogonadism that occurs in obese men, we measured the 24-h mean plasma free and total estradiol (E2), total estrone, FSH, LH, and free and total testosterone concentrations in 11 healthy obese men (100-305% above desirable body weight) and again 5-39 months later after weight loss of 26-129 kg and restabilization at the new weight. Weight loss produced significant increases in mean plasma total testosterone [240 +/- 116 (+/- SD, 8.5 +/- 4.0) to 377 +/- 113 ng/dL (13.0 +/- 4.0 nmol/L); P less than 0.01], free testosterone [9.5 +/- 5.0 (329 +/- 173) to 13.4 +/- 4.3 ng/dL (464 +/- 149 pmol/L); P less than 0.025], and FSH (6.5 +/- 4.7 to 10.9 +/- 8.5 IU/L; P less than 0.025). Plasma LH was lower than levels in normal men before and after weight loss and did not change significantly (10.3 +/- 4.8 and 10.8 +/- 6.8 IU/L, respectively). There was no change in plasma total E2 [54 +/- 26 (196 +/- 94) to 50 +/- 13 pg/mL (180 +/- 50 pmol/L)], free E2 [1.48 +/- 0.7 (5.37 +/- 2.54) to 1.33 +/- 0.42 pg/mL (4.83 +/- 1.45 pmol/L)], or total estrone [75 +/- 38 (280 +/- 140) to 82 +/- 24 (300 +/- 90) pmol/L], and sex hormone-binding globulin rose from 9.2 +/- 3.2 to 12.9 +/- 5.4 nmol/L (P less than 0.005). The increases in plasma free and total testosterone and sex hormone-binding globulin were proportional to the degree of weight loss. Thus, the hypogonadotropic hypogonadism was largely reversed by the weight loss without any decrease in hyperestrogenemia, its presumed cause. We postulate a change in hypothalamic-pituitary function with weight loss, such that GnRH-gonadotropin secretion becomes less sensitive to suppression by a given amount of estrogen.

The 24-h mean plasma concentrations of androgens (dihydrotestosterone and total and free testosterone), estrogens (estrone and estradiol), and gonadotropins (LH and FSH) were measured in 35 healthy men, aged 21-85 yr, who were rigorously screened to exclude factors known or suspected to alter endocrine function. The plasma total testosterone concentration showed a slow continuous decline with age, decreasing about 35% between 21 and 85 yr of age; the free testosterone level was closely correlated with that of total testosterone over the entire observed concentration range. The concentrations of dihydrotestosterone, estrone, estradiol, and LH were age invariant. The concentration of FSH showed a continuous linear increase with age; the level at age 85 was about 2.5 times the level at age 21. The following conclusions were drawn. 1) Testosterone secretion appears to decline slowly and continuously throughout adult life in men. 2) Measurement of the plasma free testosterone level adds no independent information in healthy men, since its level is closely correlated with that of total testosterone at all concentrations. 3) The continuous rise with age in FSH concentration while LH is age invariant cannot be explained by changes in testosterone or estrogen production, but might be due to a decline of inhibin production with age.

The purpose of the study was to test the hypothesis that high density lipoprotein (HDL) cholesterol would be more easily oxidized in vivo than low density lipoprotein (LDL) cholesterol. Homologous plasma was incubated with [24,25-3H]cholesterol and fractionated by ultracentrifugation to obtain HDL and LDL each labeled with [3H] free sterol. HDL and LDL labeled with [24,25-3H]cholesteryl esters were prepared by ultracentrifugation of plasma from donor rats injected 24 hr previously with [24,25-3H]cholesterol in propylene glycol. These four labeled lipoproteins were administered to recipient rats. It was found that more tritium oxide (3H2O) was produced after the HDL doses than after the corresponding LDL doses, from 2--3-fold more when lipoprotein free cholesterol was labeled and from 2--6-fold more when lipoprotein cholesteryl esters were labeled. More 3H2O was produced from free cholesterol-labeled lipoproteins than from cholesteryl ester-labeled lipoproteins. Since oxidation of cholesterol is a measure of bile acid formation, it is concluded that under the conditions of the study HDL-cholesterol is a better precursor of bile acids than LDL-cholesterol.

The 24-hr mean plasma concentrations of 13 hormones or hormone metabolites (cortisol, testosterone, dihydrotestosterone, dehydroisoandrosterone, dehydroisoandrosterone sulfate, androsterone, androsterone sulfate, estrone, thyroxine, triiodothyronine, LH, FSH, and prolactin) were measured in 16 rigorously screened patients (aged 55-80) with stage C or D prostate cancer and 36 normal men. Nine of the hormones showed no abnormalities in the patients but four (testosterone, dihydrotestosterone, cortisol, and estrone) showed abnormalities. Testosterone and dihydrotestosterone, which, respectively, decreased with age and showed no change with age in the normal men, rose sharply with age in the patients. The patients' curves crossed the normal curves at about age 65; patients 65 or above showed normal values while patients under age 65 showed significantly subnormal levels of both hormones: testosterone averaged 282 ng/dl in patients vs 434 ng/dl in controls (P less than 0.0001) and dihydrotestosterone averaged 70 ng/dl in patients vs 99 ng/dl in controls (P less than 0.01). Cortisol, which was age invariant in the normal men, fell sharply with age in the patients; patients under 65 had significantly elevated levels (10.1 vs 6.9 micrograms/dl; P less than 0.0001), while patients 65 or older had normal levels. Estrone levels were age invariant in both patients and controls, but the mean level in patients was markedly elevated (81 vs 47 pg/ml in controls; P less than 0.001). The cortisol/testosterone ratio almost completely separated prostate cancer patients under 65 from normal men, but did not discriminate patients 65 or older from normal. The findings indicate that prostate cancer patients under 65 differ markedly in their endogenous hormonal pattern from patients 65 or older. This leads us to propose a "two-disease" theory of prostate cancer, with possible differences in genetic factors and prognosis.

On the basis of clinical observations suggesting interactive effects of biliary obstruction and estrogen therapy on plasma cholesterol levels, a prospective study of the effect of ethinyl estradiol on plasma lipid levels was carried out in a patient with total biliary obstruction. A daily dose of 50 micrograms of ethinyl estradiol raised the plasma free cholesterol concentration from 265 mg/dl to 550 mg/dl over a period o 3 weeks; there was no change in plasma ester cholesterol concentration. Withdrawal of the estrogen was followed by a fall to baseline of the free cholesterol concentration over a 45-day period; once again there was no change in ester cholesterol. Plasma phospholipid concentration rose and fell in direct proportion to the changes in free cholesterol; plasma triglyceride concentration was unaffected by the estrogen. To account for the results of this study, it is suggested that the already elevated plasma levels of lipoprotein-X in biliary obstruction are further elevated by estrogen administration.

Twenty-four-hour mean plasma concentrations of cortisol, dehydroisoandrosterone (DHA), and dehydroisoandrosterone sulfate (DHAS) were measured in 14 young women (aged 19–29 yr) with anorexia nervosa (AN) in relapse and 10 age-matched healthy control women. Six of the AN patients were restudied after 5–35 months, when they were in partial remission. The AN patients in relapse showed significantly elevated plasma cortisol levels (11.3 vs. 7.3 μg/dl; P < 0.0001), as previously reported, but had subnormal adrenal androgen levels; DHA averaged 375 ng/dl (vs. 540 ng/dl in controls; P < 0.05), and DHAS averaged 64 μg/dl (vs.86 μg/dl in controls; P = NS). The DHA to cortisol ratio, which reflects the relative activities of the 17-hydroxypregnenolone → DHA and 17-hydroxypregnenolone → cortisol pathways, averaged less than half of normal (32 vs. 74;P < 0.001). Each of the 6 patients restudied while in partial remission showed an increase in the DHA to cortisol ratio, and the group as a whole showed a significant in...

Plasma luteinizing hormone (LH) and testosterone (T) were measured by radioimmunoassay in 9 pubertal boys and 9 sexually mature adult men at 20 min intervals for 24 h. Polygraphic monitoring of sleep was also carried out to precisely identify sleep onset, wakefulness and specific sleep stages. In all 9 pubertal boys, plasma LH showed the characteristic augmentation of secretion synchronous with sleep. This increased LH secretory activity was effective in stimulating increased T secretion during sleep that resulted in uniformly higher mean T concentrations during sleep compared with waking. Plasma LH and T were also measured in 3 of these pubertal boys during acute inversion of the sleep wake cycle. The results showed that plasma LH and T were now augmented during the reversed daytime sleep period; the mean LH and T concentrations were significantly higher than during nocturnal waking. Measurement of LH and T in the 9 adult men showed episodic secretion of both hormones during waking and sleep periods with no consistent augmentation of either hormone during sleep.

Synthetic [7α-3H]cholesterol [1-14C]palmitate was administered intravenously to two subjects in order to study the fate of cholesterol ester injected into the peripheral circulation. By 3 min over 80% of the injected cholesterol palmitate had disappeared from the plasma and by 10 h, the specific activity (3H) of free cholesterol was 3 to 5 times greater than the specific activity of cholesterol from the ester fraction. During this interval, the 14C:3H ratio rapidly declined and then leveled off at about 6% of the initial ratio in the injected cholesterol palmitate. These observations demonstrate the rapid removal of the injected ester followed by hydrolysis and reappearance of the cholesterol moiety in plasma both in free and esterified form. The efficiency of removal and hydrolysis of newly absorbed dietary sterol which enters the circulation largely as cholesterol ester may be of pertinence to the process of atherogenesis.

Δ5-Pregnene-3α,16α,20α-triol was the principal metabolite isolated from the urine following administration of 3β, 16α-dihydroxy-Δ5-pregnen-20-one to two men. Δ5-Pregnene-3β,16α,20α-triol and 5β-pregnane-3α,16α,20α-triol were present in small amounts. The results suggest that the 16α-hydroxy group of the administered steroid alter the normal course of transformation of 3β-hydroxy-Δ5-steroids in man. Isolation of Δ5-pregnene-3α,16α,20α-triol (II) from urine of a patient with adrenocortical carcinoma was described in 1961, and was the first report of a Δ5-3α-hydroxysteroid from natural sources (1). At that time it was postulated that the probable precursor of the metabolite was 3β,16α-dihydroxy-Δ5-pregnen-20-one (I), and that the 16α-hydroxyl group interfered with the isomerization of the Δ5-3-ketosteroid sufficiently to permit reduction to the unsaturated alcohol in the favored 3α orientation. In order to explore this postulate further the in vivo transformation of 3β,16α-dihydroxy-Δ5-pregnen —20-one (I) was studied. In agreement with expectation Δ5-pregnene-3α,16α,20α-triol (II) was obtained in larger amount than the 5β-saturated trihydroxy analog (III) (2,3). It is concluded that the 16α-hydroxyl group of this substrate does in fact alter its reaction with a Δ5-3-ketosteroid isomerase.

Urinary excretion of testosterone glucuronide was compared in 13 men with typical Type A behavior pattern (as determined by structured interviews) and 10 age-matched men with typical Type B behavior pattern. Twenty-four hour urine collections were divided into three periods: 9AM - 6PM , 6PM to bedtime, and bedtime to 9AM . Type A men showed a significantly higher excretion than Type B men in the daytime ( 9AM - 6PM ); the geometric mean value was 24 micrograms in Type A and 15 micrograms in Type B (P less than 0.05). There were no significant differences between Type A and Type B men for the other two time periods. Indicating an elevated daytime testosterone secretion in Type A men, this finding is consistent with a recent report that exposure to laboratory tests of reaction time causes an increase in plasma testosterone levels in Type A but not Type B men. Since a role for testosterone in the genesis of coronary heart disease (CHD) is suggested by the much higher incidence of CHD in men and the acceleration of murine atherogenesis by testosterone, the findings of this and the previous report may represent a mechanism for the elevated incidence of CHD in Type A men.

The 24-h mean plasma concentrations of 8 hormones were measured in 11 men with chronic uremia and 32 normal men. Our findings confirm previous reports of subnormal levels of testosterone, T3, and T4 and elevated levels of LH, PRL, and cortisol. In addition, we observed a new finding: markedly subnormal levels of the adrenal androgens dehydroisoandrosterone (DHA) and DHA sulfate. The mean DHA level in the patients was 164 +/- 46 (SD) ng/dl, compared with 320 +/- 124 in age-matched controls (P0.0001); the geometric mean DHA sulfate level was 40 micrograms/dl (95% confidence limits, 11-113) in the patients and 76 micrograms/dl (95% confidence limits, 26-214) in age-matched controls (P = 0.005). The depression of adrenal androgen levels in the face of elevated cortisol levels suggests a biosynthetic block in the adrenal cortex at the step where the C-19 and C-21 pathways diverge, namely the removal of the 2-carbon side chain by C-17, 20-lyase. If a similar defect were present in the testes, it could account for the diminished synthesis of testosterone, which is a further metabolite of DHA in the testes.

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 24-h mean plasma concentrations of dehydroisoandrosterone (DHA) and dehydroisoandrosterone sulfate (DHAS) and the DHA to DHAS ratio were determined in 37 normal women, aged 21-75 yr, and 32 normal men, aged 21-72 yr. As predicted from our study of sex differences in the metabolism of DHAS, women showed a markely higher DHA to DHAS ratio than men at all ages; the geometric mean for women was 7.5 x 10(-3) and that for men was 3.9 x 10(-3) (P less than 0.0001); and the mean for premenopausal women (6.7 x 10(-3) did not differ significantly from that for postmenopausal women (8.6 x 10(-3)). The two steroids showed a clear-cut linear inverse correlation between concentration and age in both sexes, and menopause was "nonevent" in the age progression for both steroids in the women. The slopes of the concentration vs. age curves were considerably greater in the women, as a reuslt of which the sex differences in concentrations of these steroids changed with age. Under age 50 yr, the plasma DHA concentration of women was considerably higher than that of men [462 +/- 187 (mean +/- SD) vs. 336 +/- 103; P less than 0.025], while the concentrations of DHAS showed no significant sex difference ((77 +/- 38 vs. 101 +/- 67; P greater than 0.1). In persons 50 yr of age or over, plasma DHA concentrations were about the same in women and men (238 +/- 119 vs. 287 +/- 121; P greater than 0.1), but plasma DHAS concentrations were very much lower in women (31 +/- 21 vs. 83 +/- 49; P less than 0.0001).

Plasma concentrations of 14 hormones or hormone metabolites and urinary excretion of 15 hormones or hormone metabolites were studied in four rigorously selected groups: 13 men who had recovered well from prior myocardial infarction (at least 6 months earlier), 35 clinically normal men, 25 men with severe coronary artery disease diagnosed by coronary arteriograms but no history or signs of myocardial infarction, and 44 men with normal coronary arteriograms. Aside from a minor finding that a subset of the post-infarction patients (3 out of 12) showed subnormal plasma T3 levels (? the non-specific low-T3 syndrome), there were four major findings: post-infarction patients had significantly higher 24-hour mean plasma concentrations of estrone (80 vs 49 pg/ml, P 0.0001), dehydroisoandrosterone (444 vs 298 ng/dl, P 0.025), and dehydroisoandrosterone sulfate (112 vs 72 micro g/dl, P = 0.05) than clinically normal men, while men with positive coronary arteriograms but no infarction had the same levels as men with negative arteriograms; men with positive arteriograms but no infarction had significantly lower urinary excretion of androsterone glucuronide (2.6 vs 3.2 mg/g creatinine, P 0.05) than men with negative arteriograms, while post-infarction patients excreted normal amounts of this steroid. In the case of all three differing plasma steroids, nearly all the post-infarction patients had values at or below the upper 95% confidence limit of the normal range; the significant elevation of the post-infarction patients' mean value was due in each case to clustering of the patients' values in the upper half of the normal range.

Plasma luteinizing hormone (LH) and testosterone (T) were measured by radioimmunoassay in 9 pubertal boys and 9 sexually mature adult men at 20 min intervals for 24 h. Polygraphic monitoring of sleep was also carried out to precisely identify sleep onset, wakefulness and specific sleep stages. In all 9 pubertal boys, plasma LH showed the characteristic augmentation of secretion synchronous with sleep. This increased LH secretory activity was effective in stimulating increased T secretion during sleep that resulted in uniformly higher mean T concentrations during sleep compared with waking. Plasma LH and T were also measured in 3 of these pubertal boys during acute inversion of the sleep wake cycle. The results showed that plasma LH and T were now augmented during the reversed daytime sleep period; the mean LH and T concentrations were significantly higher than during nocturnal waking. Measurement of LH and T in the 9 adult men showed episodic secretion of both hormones during waking and sleep periods with no consistent augmentation of either hormone during sleep.

Excerpt Thorp and Waring (1) studied a series of aryloxyisobutyric acids in rats for their ability to lower the level of cholesterol and lipids in serum and liver and found the compounds with maxim...