Are all males equal? Anatomic and functional basis for sexual orientation in males.

In non-human primates anterior hypothalamic nuclei are closely involved in heterosexual activity in males. In humans, hypothalamic nuclei which correspond to these nuclei in non-human primates have been shown to have a neuronal density in homosexual men that is approximately half of that seen in heterosexual men. In addition, homosexual men exhibit a positive luteinizing hormone response to acutely administered estrogen that is intermediate between women (flat response) and heterosexual men (exaggerated response). Furthermore, on the basis of serum testosterone concentrations in similarly feminized transsexual males on estrogen/progestogen treatment 3 distinct groups can be identified. It is postulated that anatomic differences in the anterior hypothalamic nuclei that regulate sexual orientation in males may lead to alteration in the gonadotropin releasing hormone (GnRH) pulse/frequency leading to a more female-type pattern of gonadotropin secretion in homosexual males. Based on data in transsexual males this pattern may be more or less of the female-type in subsets of male homosexuals.

Hormone pattern in pharmacologically feminized male transsexuals in the California State prison system.

The hormonal profile of 40 transsexual inmates from a pool of 86 inmates in the California State prison system was studied before and after therapy with feminizing hormones. Clinical and social data were obtained on all 86 inmates; the incidence of human immunodeficiency virus (HIV) seropositivity was examined in 76 of the 86 individuals. Despite similar degrees of feminization in all 40 individuals in whom hormonal studies were performed, variable suppression of serum testosterone concentrations was present. Based on their testosterone concentrations while on feminizing hormone therapy, the transsexual inmates could be divided into three groups. In Group I (the "suppressed" group), the serum testosterone concentrations were markedly depressed (less than 10 ng/dL); in Group II (the "non-suppressed" group), the values of testosterone were normal (446 to 1072 ng/dL); and in Group III (the "intermediate" group), the testosterone values were between those of the suppressed group and the nonsuppressed group. We speculate that feminizing hormone therapy may induce the development of a state of target hormone resistance to testosterone that results in similar degrees of feminization independent of the circulating concentrations of testosterone. The incidence of HIV seropositivity (3/76) was considerably less than anticipated based on previous studies in populations at high risk for developing the acquired immunodeficiency syndrome.

Male hypogonadism due to nontumorous hyperestrogenism.

Male hypogonadism due to the nontumorous production of estrogen was studied in a patient with gynecomastia and bilateral small testicles. Both the gynecomastia and the decrease in testicular size developed in the 5-year period before presentation. Peripheral serum concentrations of testosterone were in the low to low-normal range, while those of 17 beta-estradiol (E2) were significantly elevated, as were the urinary concentrations of total estrogen. Steroid hormone concentrations were measured in the left and right spermatic veins and the left and right adrenal veins in the basal state, and after stimulation with GnRH and ACTH. Spermatic vein concentrations of E2 were 3 to 20 times higher than concentrations previously reported in normal males. Spermatic vein concentrations of testosterone were normal. The spermatic vein concentrations of androstenedione were approximately three times higher than the mean concentration of androstenedione previously reported in the spermatic vein of normal males. The concentrations of E2 and androstenedione in the adrenal veins were also significantly elevated when compared to the concentrations previously reported in normal subjects. The authors postulate that the hyperestrogenism in this patient was due to increased aromatization of the precursor substrates, testosterone in the testes, and androstenedione in the adrenals to E2 and E1 in the testes and adrenals, respectively. Alternatively, an increased abundance or activity of the 17 beta-hydroxysteroid dehydrogenase isoenzyme which converts estrone (E1) to E2 or a relative deficiency of the 17 beta-hydroxysteroid dehydrogenase isoenzyme, which converts androstenedione to testosterone, could theoretically account for the reported abnormalities.

Correlation between macrovascular disease as assessed by bioimpedance plethysmography and various parameters used to assess diabetic "control".

Blood flow in a segment of the leg was determined by bioimpedance plethysmography in 47 diabetic patients and in 19 normal volunteers. The blood flow through the limb, expressed as stroke volume/m2 (SV/m2), was not significantly different in the two populations. SV/m2 showed significant negative correlation with the presence of peripheral vascular disease, fasting serum cholesterol concentration, glycosylated hemoglobin (HbA1c) concentration, and the duration of diabetes. The presence or absence of retinopathy (27.7% of cases) or nephropathy (4.3% of cases) did not show strong association with the SV/m2. Neither the duration of the hypertension nor the systolic or diastolic blood pressure correlated significantly with blood flow in the extremity. These data suggest that only some of the parameters used to assess "control" of diabetic patients can be useful predictors of macrovascular as well as microvascular disease in diabetic patients.

Immunomodulatory effect of bovine PTH extract on lymphocyte response to plant mitogens.

Human peripheral blood lymphocytes were incubated in the presence of various concentrations of bovine parathyroid hormone extract (PTH) or with PTH plus different concentrations of plant mitogens (PHA, Con-A and PWM) to determine whether PTH can modulate lymphocyte proliferation. Lymphocyte proliferation was assessed by 3H-thymidine incorporation into the lymphocytes after a 72-96 h incubation period. After initial inhibition, PTH stimulated lymphocyte proliferation at concentrations of 0.25-0.5 micrograms/0.2 ml and inhibited 3H-thymidine uptake at concentrations of greater than 1 microgram/0.2 ml. Similar responses were seen when the lymphocytes were incubated with PTH plus PHA. In contrast, PTH inhibited 3H-thymidine uptake by the lymphocytes when the cells were stimulated with Con-A (0.25-2 micrograms/0.2 ml) and PWM (0.25-2 micrograms/0.2 ml). The suppressive effects of PTH were not due to loss of lymphocyte viability as determined by trypan blue exclusion. It is speculated that the PTH mediated immunomodulatory effect on peripheral blood lymphocytes may be due to PTH itself or to some other factor(s) in the extract. In view of the common embryonic origin of the parathyroid glands and the thymus, the possibility that thymic-like hormones may be involved in the immunomodulatory process cannot be excluded.

A combined anterior pituitary stimulation test: experience with 285 individuals.

A pituitary reserve test was performed in 285 individuals. Eighteen were healthy volunteers without any endocrine disease, 25 suffered from a presumed hypothalamic abnormality, 22 from hypopituitarism, 10 from acromegaly, 65 from the amenorrhea-galactorrhea syndrome, 2 from Nelson's syndrome, 32 from borderline primary hypothyroidism, 15 from borderline hyperthyroidism, 20 were on chronic levothyroxine therapy for primary hypothyroidism, and 15 had severe uncorrected primary hypothyroidism. Sixteen postmenopausal women were also included, as well as 15 patients with idiopathic ovarian failure and six with ovarian dysgenesis. Twelve male patients with hypergonadotropic and 12 with hypogonadotropic hypogonadism were also examined.The pituitary reserve test consisted of intravenous administration of a mixture of the thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (GnRH), and regular insulin. The following tests were obtained prior to the injection only (time 0): serum thyroxine (T(4)), tri-iodothyronine (T(3)), T(3) resin uptake or thyroxine-binding globulin, total and free testosterone in men, estradiol and progesterone in women, and sex hormone binding globulin. At times 0, 20, 30, and 60 minutes, serum concentrations of the following compounds were obtained: glucose, adrenocorticotropic hormone, cortisol, growth hormone, prolactin, thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone.Normal responses were established in a large number of cases. More or less typical patterns were demonstrated in the above-listed disease categories. Poor correlations between basal and stimulated values were observed, which emphasizes the diagnostic importance of the stimulation test. Maximum data were obtained using a combined test that has negligible morbidity, may be performed within an hour in an outpatient setting, and which examines the anterior pituitary function in a comprehensive fashion.

Clinical acromegaly with undetectable growth hormone and hyperprolactinemia.

A patient with clinical acromegaly was shown to have hyperprolactinemia, a pituitary macroadenoma, and undetectable levels of immunoreactive growth hormone.

Pluripotent steroidogenesis and ultrastructure in adrenocortical adenomas causing Cushing's syndrome.

Adrenal vein catheterization data from 2 patients with adrenocortical adenomas causing Cushing's syndrome are presented and the electron-microscopic features of one of the tumors are described. Based on the catheterization data both tumors produced all three classes of adrenal steroids (mineralocorticoids, glucocorticoids and sex steroids). Electron-microscopic examination of the tumor cells suggested an origin from the zona fasciculata. If one accepts the theory of a common cellular origin of adrenal tumors, then the pattern of steroidogenesis would indicate that the postulated original 'stem' cell retains the potential of secreting all classes of adrenocortical steroids. The clinical presentation of such tumors would thus reflect the hypersecretion of one of the steroid classes relative to the others.

Steroid hormones in the adrenal venous effluents in idiopathic hirsutism under basal and stimulated conditions.

Steroid hormone concentrations in the peripheral blood and the adrenal veins were measured in the basal state and after ACTH stimulation in 5 patients with idiopathic hirsutism. The basal concentrations of the steroids in the adrenal veins of the patients with idiopathic hirsutism were not significantly different from a control group of 5 patients catheterized for investigation of pheochromocytoma. Following ACTH stimulation, the concentrations of the steroids in the adrenal veins were also not significantly different in the hirsute and the control groups except for the concentrations of DHA and DHAS which were higher in the patients with idiopathic hirsutism. 17-hydroxyprogesterone (17-OHP) concentrations after ACTH stimulation were lower in the hirsute group compared to the control population. It is concluded that patients with idiopathic hirsutism have a defect in the biosynthesis of cortisol proximal to the action of the 11 beta- and 21-hydroxylase enzymes, deficiencies of which have been previously considered to be the usual causes of hirsutism due to an adrenocortical abnormality. The lower 17-OHP concentrations in the hirsute group can be explained on the basis of deficiency of substrate for the action of the 17-hydroxylating enzyme, consequent to the postulated deficiency of 3 beta-hydroxysteroid dehydrogenase.

The renin-angiotensin system in hypothyroidism of short duration.

In six hypothyroid patients (2 male, 4 females, ages 22 through 59 years), plasma renin activity (PRA) and aldosterone (Aldo) were measured when the patients were euthyroid on levothyroxine therapy and one month after the therapy was stopped. Colonic mucosal potential differences were measured during the hypothyroid and euthyroid stages, and catecholamine sensitivity was determined by the blood pressure response to infused norepinephrine. Significant differences were observed in the PRA and aldosterone concentrations which were 4.1 +/- 2.5 ng/ml/h and 9.4 +/- 5.9 ng/dl, respectively in the hypothyroid stage and 6.9 +/- 2.3 ng/ml/h and 15.2 +/- 7.3 ng/dl, respectively when the patients were made euthyroid. The colonic mucosal potential differences (which reflect increased endogenous mineralocorticoid activity), became more electronegative after correction of hypothyroidism (-16.8 +/- 7.5 mV vs -32 +/- 18.2 mV; P less than 0.04) concentrations. Statistically significant decreases in norepinephrine pressor effects were observed in hypothyroid patients when compared to the euthyroid state (7.4 +/- 2.3 vs 10.9 +/- 1.9 micrograms/ng/min; P less than 0.01). It is concluded that patients with hypothyroidism have a hormonal pattern reminiscent of "low renin hypertension", and exhibit decreased sensitivity to catecholamines. Such changes are corrected when the patients become euthyroid on levothyroxine therapy.

Modified fasting in treatment of obesity. Effects on serum lipids, electrolytes, liver enzymes, and blood pressure.

We studied 71 patients who followed a supplemental fasting regimen (Optifast) for up to six weeks. Serum triglyceride levels were lowered significantly. The mean serum cholesterol concentration fell to less than 200 mg/dl after four weeks on the diet, and the high-density lipoprotein/cholesterol ratio increased. Serum glucose and uric acid concentrations, which changed initially, returned to baseline after the third week. Minimal elevation of SGPT concentration was the only change revealed by liver function tests. In general, the patients were hypertensive, and their blood pressure levels were significantly lower after fasting. Our data suggest that supplemental fasting deserves further study as a method of weight loss in obese persons. A majority of the problems that can accompany total starvation and surgical approaches are avoided. Combined with behavior modification techniques and medical supervision, supplemental fasting is an effective initial approach to managing obese patients.

ACTH stimulation of adrenal epinephrine and norepinephrine release.

Epinephrine (E) and norepinephrine (NE) levels were measured simultaneously in the adrenal veins of 6 patients before and after stimulation with 0.25 mg beta 1-24 ACTH. In 1 patient with Cushing's syndrome, E and NE were also measured before and 30 min after dexamethasone. There was a significant increase in NE and E secretion (p less than 0.002) from both adrenal glands after ACTH stimulation. In the patient with Cushing's syndrome, there was also a slight increase in plasma E levels after dexamethasone. It is postulated that ACTH stimulated NE and E secretion by augmenting blood flow through the adrenals and by induction of tyrosine hydroxylase and dopamine beta-hydroxylase, although a direct effect of ACTH on NE and E secretion cannot be excluded. It is also possible that the increase in adrenal catecholamine secretion after ACTH may be due to ACTH augmentation of catecholamine secretion by endogenous opioids such as beta-endorphin.

Effect of bromocriptine on serum PTH, calcium and phosphate levels in azotemic rats.

The dopamine agonist, bromocriptine, was studied with respect to its effects on PTH secretion and calcium homeostasis in Sprague-Dawley rats made azotemic by either total or subtotal nephrectomy. The oral or intraperitoneal administration of 0.25 mg of bromocriptine resulted in a significant increase in the serum calcium concentration when compared to animals given placebo. Bromocriptine produced no significant change in the BUN or the serum concentrations of creatinine, inorganic phosphate or PTH. The mechanism of the hypercalcemic effect of bromocriptine in azotemic rats is unknown. The hypercalcemia may, however, be due to stimulation of PTH secretion, since PTH levels in the serum were inappropriately high for the corresponding levels of calcium.