Showing papers on "Testosterone published in 1982"

Tumor growth inhibition in patients with prostatic carcinoma treated with luteinizing hormone-releasing hormone agonists

Abstract: Ten patients with prostatic carcinoma--six with stage C and four with stage D disease--were treated for 6 weeks to 12 months with agonistic analogues of luteinizing hormone-releasing hormone (LH-RH). [D-Trp6]LH-RH was given subcutaneously once daily at a dose of 100 microgram and [D-Ser(But)6]des-GlyNH2(10)-LH-RH ethylamide (HOE 766) was given subcutaneously (50 microgram once daily) or intranasally (500 microgram twice daily). In all patients, mean plasma testosterone levels showed a 75% suppression by the third week of treatment and remained low thereafter. This was followed by a decrease or normalization of plasma acid phosphatase levels by the second month of treatment and a 47% decrease in serum alkaline phosphatase by the 10th week of treatment in all but one patient. In patients with stage C disease presenting with prostatism or urinary outflow obstruction, there was a noticeable clinical improvement. In two such patients, a decrease in the size of the prostate was confirmed by ultrasonography. In patients with stage D disease manifested by diffuse bone metastases, there was relief of bone pain, and in one patient treated for greater than 12 months the improvement was documented by radioisotope bone imaging. It is concluded that superactive agonistic LH-RH analogues hold promise as therapeutic agents in patients with androgen-sensitive prostatic adenocarcinoma. Furthermore, the analogous of LH-RH may be used to assess the responsiveness of patients to surgical castration. Long-term administration of LH-RH analogues could become an alternative to surgical castration and estrogen therapy for the treatment of hormone-dependent prostatic carcinoma.

The 5alpha-reduction of testosterone in the neuroendocrine structures. Biochemical and physiological implications.

Abstract: Introduction It is now well established that the prostate and other androgen-sensitive peripheral structures (seminal vesicles, sebaceous gland, kidney, etc.) metabolize testosterone into 5α-androstane-17β-ol-3-one (dihydrotestosterone, DHT) and subsequently into 5α-androstane-3α, 17β diol (3α-diol) (1–6). In the peripheral androgen-responding tissues little amounts of 5α-androstane-3β,17β-diol (3β-diol) are also formed from DHT (7–9). These conversions occur under the influence of an enzymatic complex that includes a 5α-reductase, and two (3α- and 3β-) hydroxysteroid dehydrogenases. According to a theory which is now generally accepted, these 5α-reduced metabolites act as the intracellular mediators for many of the multiple actions testosterone exerts on its target structures (1–3, 10). A large group of in vivo and in vitro studies indicate that, in adult male mammals, the anterior pituitary (11–25) and several central nervous structures (in descending order: the hypothalamus, the midbrain, the amygdala,...

"Medical oophorectomy" using a long-acting GNRH agonist--a possible new approach to the treatment of endometriosis.

Abstract: Five women with endometriosis were given a daily dose of a potent long-acting GnRH agonist, D-Trp6-Pro9-Net-LHRH (GnRH-A) for 28 days in an attempt to suppress ovarian estrogen secretion. The mean level of estradiol (E2) during sampling over 24 hours decreased (P less than 0.01) from 62 +/- 11 to 10 +/- 1 pg/ml at the end of treatment. Mean concentrations of androstenedione, testosterone, estrone and E2 on day 28 of therapy were similar to those measured in oophorectomized women. The level of FSH was decreased (P less than 0.001) during GnRH-a, whereas that of LH was significantly (P less than 0.001) increased, suggesting differing intracellular control mechanisms for release of the two gonadotropins. Desensitization of the pituitary was demonstrated at the end of treatment by a complete lack of acute response of FSH or LH to the daily dose of GnRH-a. "Medical oophorectomy" provides a new approach to the treatment of endometriosis.

Male Rats Secrete Luteinizing Hormone and Testosterone Episodically

Abstract: We studied the temporal aspects of endocrine signaling between the pituitary gland and testes by measuring moment to moment changes in blood LH and testosterone levels in individual male rats. Each rat was fitted with an indwelling vascular cannula, and blood was withdrawn every 5 min for 8–12 h. Rats were maintained throughout the intensive blood-sampling period with an isotonic blood replacement mixture containing rat red blood cells and a human plasma protein preparation. LH and testosterone measurements were made in plasma volumes of 50 and 60 μl. Most rats released LH in well defined pulses, characterized by a rapid increase in plasma LH within 5–10 min and a gradual decline lasting for the next 50–70 min. LH pulses occurred singly or in trains of two to four. Episodes of testosterone secretion spanned 3–6 h and were marked by a slowly graded rise and fall of plasma testosterone. In several instances, testosterone episodes were preceded (1–2 h) by a train of closely coupled LH pulses. Within a partic...

3 alpha, 17 beta-androstanediol glucuronide in plasma. A marker of androgen action in idiopathic hirsutism.

Abstract: Biologically active androgens and peripheral androgen metabolites in plasma were measured in 25 women with idiopathic hirsutism (IH). Plasma testosterone was not significantly elevated. Free testosterone however was increased although the elevation was not impressive (10.9 +/- 6.6 SD vs. 3.3 +/- 1.5 ng/dl) and one-fourth of the cases had normal unbound testosterone. Dihydrotestosterone (DHT) values were elevated (23.5 +/- 14 vs. 12.5 +/- 3.59) but again over half of the values were within the normal range. In our series of mild to moderate cases, 3 alpha-diol was not at all discriminatory. However, plasma 3 alpha-diol glucuronide was markedly increased (604 +/- 376 vs. 40 +/- 10 ng/dl), and elevated in all but one mild case. Previous studies document that DHT is the important androgen in skin and formation of DHT and 3 alpha-diol is markedly increased in vitro in IH. Since 3 alpha-diol glucuronide is derived largely from extrasplanchnic events, beta-glucuronidase is present in skin, and androgen stimulates formation of the enzyme in extrasplanchnic tissue, we conclude that 3 alpha-diol glucuronide is a marker of peripheral androgen action and markedly elevated in IH.

Association between Plasma Level of Growth Hormone and Sex Differentiation of Hepatic Steroid Metabolism in the Rat

Abstract: The hypothesis that the plasma pattern of growth hormone (GH) regulates hepatic steroid metabolism in the rat was studied in two different animal models: 1) different plasma patterns of GH were achieved by the administration of human GH at different frequencies or by infusing the hormone continuously by means of Alzet osmotic minipumps to hypophysectomized female rats and 2) the plasma pattern of GH in animals with an intact pituitary gland was investigated under conditions which lead to feminization of hepatic steroid metabolism. The pattern of GH was determined by studying minimum and maximum plasma GH levels in blood samples taken from the tip of the tail at various times. After continuous administration of human GH to hypophysectomized female rats, the liver microsomal metabolism of 4-[4-14C]androstene-3,17-dione was feminized, e.g. the ratio between 5α-reductase and 16α-hydroxylase activities (5α/16α ratio) increased from 2.45 ± 0.21 to 31.2 ± 1.76. Similar results were observed when the animals were...

Mild Hypogonadotropic hypogonadism in obese men.

Abstract: 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.

Luteinizing hormone and testosterone secretion in young and old male mice

Abstract: This study documents, for the first time, the temporal pattern of luteinizing hormone (LH) release and the relationship between plasma LH concentrations and testicular androgenic responses in young and aged male mice. Both LH and testosterone were measured in the same samples of blood plasma withdrawn at frequent intervals over 9 h from awake, mobile mice through intra-atrial cannulae. The results demonstrate unequivocally that LH and testosterone are discharged into the circulation in discontinuous pulses in this important animal model. Robust episodes of LH release occur at infrequent intervals and increments of circulating LH occasion time-delayed elevations of plasma testosterone. Thus, the frequency of LH release is the major factor determining peripheral concentrations of this gonadotropins. The obvious one-to-one coupling between intermittent LH discharges and testosterone secretion has significant functional and investigative implications. The reduction in circulating testosterone concentrations observed in old male mice is a consequence of fewer LH discharges, which is due most likely to the slowing of a neural GnRH pulse generator. However, age-related declines in copulatory behavior were not associated with altered patterns of hormone secretion. Hence, we suggest that deficits in sexual behavior and episodic LH release in old males result from neural senescence rather than diminished testicular support of reproduction.

Significance of Aromatase Activity in Human Breast Cancer

Abstract: The significance of in vitro aromatization of [7 alpha-3H]testosterone to estradiol by human breast cancer has been investigated by correlation with (a) estrogen receptor activity and (b) clinical response to endocrine therapy. Evidence for estradiol synthesis was obtained in 66 and estrogen receptor activity in 81 of 110 tumors. Whereas most estrogen receptor-positive tumors synthesized estradiol, the majority of the receptor-negative tumors did not. This tendency for aromatization to be associated with estrogen receptor-positive tumors was statistically significant (p less than 0.005). Mean level of receptor was also significantly higher in tumors with aromatization than in tumors without estradiol synthesis (p less than 0.001). Forty patients with advanced breast cancer have been treated by endocrine therapy. There was a significant trend for tumors with aromatization to be associated with response to treatment (p less than 0.05), but the correlation was not absolute and may simply reflect the association between aromatase activity and estrogen receptors. Within the small subgroup of patients treated with aminoglutethimide or adrenalectomy, tumors with high aromatase activity responded whereas those without aromatization did not. Tumor estrogen biosynthesis may therefore be of clinical significance in selecting patients for treatments which remove sources of precursor for aromatization of inhibit aromatase activity itself.

Mechanism of glucocorticoid-induced suppression of testicular androgen biosynthesis in vitro.

Abstract: The mechanism whereby glucocorticoids directly inhibit gonadotropin-stimulated testosterone production was studied by using primary cultures of testicular cells from adult hypophysectomized rats. Testicular cells were maintained in serum-free media with hormone treatments administered on Day 8 and media collected 48 h later for steroid and cAMP measurement. Highly purified human chorionic gonadotropin (hCG) increased testosterone production relative to controls. Concomitant administration of either natural (cortisone greater than deoxycorticosterone = aldosterone) or synthetic (dexamethasone greater than or equal to prednisolone) corticosteroids inhibited hCG-stimulated testosterone production in a dose-dependent manner. Dexamethasone at 10(-7) M decreased testosterone production by approximately 50-60% and this inhibitory effect was reversible upon removal of the glucocorticoid. In the presence or absence of a phosphodiesterase inhibitor, dexamethasone decreased hCG-stimulated cAMP production by approximately 60%. Dexamethasone also decreased testosterone production induced by cholera toxin and (Bu)2 cAMP by 43 and 63%, respectively. The dexamethasone suppression of testosterone production was accompanied by marked decreases in androstenedione (80% decrease) and 17 alpha-hydroxyprogesterone (57%) production, with a lesser effect on progesterone production (28% decrease) and no effect on pregnenolone production. Exogenous progesterone and 17 alpha-hydroxyprogesterone augmented hCG-stimulated testosterone production. Dexamethasone reduced the conversion of exogenous progesterone to testosterone by 33% but did not affect the conversion of 17 alpha-hydroxyprogesterone to androstenedione and testosterone, suggesting a specific inhibition of 17 alpha-hydroxylase. These results suggest that glucocorticoids directly suppress Leydig cell steroidogenesis by decreasing gonadotropin stimulation of cAMP production and the activity of 17 alpha-hydroxylase.

Insulin Resistance Associated with Androgen Excess in Women with Autoantibodies to the Insulin Receptor

Abstract: Hirsutism, polycystic ovaries, and elevated levels of plasma testosterone are characteristic clinical features in women with extreme insulin resistance and acanthosis nigricans. Extreme in...

Age variation of the 24-hour mean plasma concentrations of androgens, estrogens, and gonadotropins in normal adult men.

Abstract: 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 mean, 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 informa...

The frequency of androgen receptor deficiency in infertile men

Abstract: To ascertain the frequency of androgen resistance as the cause of male infertility and to determine whether endocrine abnormalities are a universal feature of the disorder, we measured the androgen receptor in fibroblasts cultured from the genital skin of 28 unrelated phenotypically normal men with idiopathic azoospermia or oligospermia. The amounts of androgen receptor were compared with those in genital skin fibroblasts from a variety of other subjects, including 10 men with azoospermia of known cause, 5 normal men, 28 subjects with disorders of androgen formation of metabolism of known cause, and 28 persons with documented disorders of the androgen receptor (testicular feminization and Reifenstein syndrome). The mean androgen receptor Bmax (amount of high affinity binding) was 12 fmol/mg protein or greater in 10 infertile men with azoospermia of known cause and in 6 infertile men with mild oligospermia. In fibroblasts from 1 to 4 individuals with severe oligospermia of unknown cause (less than 1 million/ml) and 8 of 18 subjects with idiopathic azoospermia, the androgen receptor Bmax was less than 12 fmol/mg protein. The mean value in these 9 men was not significantly different from that in subjects with testicular feminization or Reifenstein syndrome. Serum concentrations of testosterone and LH were normal in 6 of these 9 infertile men, and plasma production rates of testosterone were elevated in only 2 of the 6 men studied in whom the Bmax values in genital skin fibroblasts were less than 12 fmol/mg protein. We conclude that androgen resistance may be the cause of a significant fraction (40% or more) or idiopathic male infertility due to azoospermia or severe oligospermia, and that this disorder may not be manifested by a functional defect in the pituitary-testicular axis.

Obesity, Androgens, Estrogens, and Cancer Risk

Abstract: Obesity is associated with increased incidence of cancers arising from tissues responsive to estrogenic stimulation, including endometrium, breast, and prostate. We thus wished to explore estrogen production and its origin in obesity in an attempt to provide a possible hormonal link to explain increased cancer risk. Studies of the hormonal milieu of obese men and women revealed several abnormalities of sex hormone production and metabolism. (a) Androstenedione production rates are elevated and serve as proehormones of both testosterone and estrogens. (b) Extragonadal aromatization of androgens to form estrogens (androstenedione to estrone and testosterone to estradiol) is elevated, resulting in (c) increased production rates of estrogens. The obese person is thus chronically exposed to hyperestrogenemia. In addition, obesity is associated with other alterations of sex hormone metabolism such as decreased levels of sex hormone-binding globulin and increased metabolic clearance rates of several hormones. After weight loss to ideal body weight, there appears to be normalization of androgen and estrogen production rates, as well as circulating hormone levels; however, metabolic abnormalities such as increased aromatization of androgens to estrogens and accelerated metabolic clearance rates of androstenedione remain abnormal.

Hormonal Evaluation of a Large Kindred with Complete Androgen Insensitivity: Evidence for Secondary 5α-Reductase Deficiency*

Abstract: Seventeen individuals from a pedigree with complete androgen insensitivity, [testicular feminization (TF)] are presented. Their hormonal evaluation was compared with those of normal males and male pseudohermaphrodites with primary 5a-reductase deficiency. The mean plasma testosterone to di-hydrotestosterone ratio was 12 ± 3 in normals, 24 ± 8 in TF subjects (P < 0.001), and 41 ± 14 (P < 0.001) in 5α-reductase-deficient subjects. In 4 TF subjects the MCRs for testosterone and dihydrotestosterone were normal. The dihydrotestosterone blood production rate averaged 383 μg/day in normals, 162 μg/ day in TF subjects, and 86 μg/day in 5α-reductase-deficient subjects. The conversion ratio of testosterone to dihydrotestos-terone averaged 2.53 in normals, 1.8 in TF subjects, and 0.63 in 5α-reductase-deficient subjects. The mean plasma estradiol level was 2.8 ± 1.0 ng/100 ml in normal males, 4.8 ± 1.3 ng/100 ml (P < 0.001) in TF subjects, and 3.1 ± 1.3 ng/100 ml (P < 0.5) in 5a-reductase-deficient subjects. The frac...

Induction of androgen receptor formation by epithelium-mesenchyme interaction in embryonic mouse mammary gland

Abstract: The role of tissue interaction in the development of hormone responsiveness was studied in the embryonic mammary gland of the mouse, which becomes sensitive to testosterone on day 14. Previously, the mesenchyme had been identified as the sole target tissue for the hormone, although it was also demonstrated that its response to testosterone required the presence of mammary epithelium. Using autoradiography, we now show that [3H]testosterone or [3H]5 alpha-dihydrotestosterone is bound only by those mesenchymal cells closest to the epithelial mammary bud. When mammary epithelia were experimentally associated with mesenchyme of the mammary region and cultured together for 3 days in vitro, they also became surrounded by several layers of [3H]testosterone-binding mesenchymal cells. Correspondingly, this tissue association was accompanied by a substantial increase of androgen-binding sites in the explants. No hormone-building mesenchymal cells were seen in combinations with epidermis or pancreas epithelium; only salivary epithelium showed a weak positive effect. From these results we conclude that mammary epithelium induces the formation of androgen receptors in adjacent mesenchyme and thereby controls the development of androgen responsiveness in this tissue.

Acquisition of Regulatory Mechanisms for Gonadotropin Receptors and Steroidogenesis in the Maturing Rat Testis

Abstract: Testicular LH, lactogen, and estrogen receptors and in vitro steroidogenic and cAMP responses were measured in rats between the ages of 1 and 60 days. Testicular LH and lactogen receptors increased gradually with advancing age, although there was no direct correlation between the concentrations of the two receptors. Cytosolic estrogen receptors were present in the testis at 6 days of age, but α-fetoprotein represented the major estrogen-binding component until 20 days of age. The basal and maximally stimulated in vitro production rates of testosterone, pregnenolone, and cAMP per unit weight were more than 10-fold higher in neonatal rats than in 60-dayold animals. These production rates decreased rapidly to a nadir at 15 days and increased again between 15 and 60 days of age. Treatment of 1-day-old rats with a low dose of hCG (10 IU/kg daily) for 3 days caused an increase of 91% (P < 0.01) -in LH receptors per testis. This effect of hCG diminished gradually with advancing age and became insignificant in an...

Patterns of breeding behaviour and plasma levels of hormones in a free‐living population of Pied flycatchers, Ficedula hypoleuca

Abstract: Plasma levels of luteinizing hormone (LH) and steroid hormones were measured by radioimmunoassay in a series of plasma samples collected from a free-living population of Pied flycatchers, Ficedula hypoleuca. Both males and females have similar circulating levels of LH and testosterone when they arrive in the breeding area. However, as territories and pair bonds are established, and as courtship and nest-building ensue, the plasma levels of testosterone in males become elevated over those of females, although a lesser peak also occurs in females. As the egg laying phase and incubation begin, plasma levels of LH and testosterone decline sharply in both sexes. On the other hand polyterritorial males, that establish secondary territories, maintain higher levels of LH and testosterone than males remaining in the home-territory, at least until they return to the home-territory, usually at the middle part of the incubation period. By this time polyterritorial males also have basal levels of these hormones. Curiously, females on home-territories show a small, but significant, rise of circulating LH and testosterone at the time the males return. In males, plasma levels of corticosterone are elevated from the time of arrival on the breeding grounds until the end of the nest-building period. Thereafter corticosterone levels decline in males staying on the home-territory but remain elevated in polyterritorial males until the latter return to the home-territory. In contrast, circulating levels of corticosterone in females are only elevated for brief period during egg laying.

Biochemistry of Aromatase: Significance to Female Reproductive Physiology

Abstract: The formation of estrogens in mammals via aromatase involves the relatively unique capacity to form an aromatic ring de novo in contrast to most other aromatic substances (essential amino acids) which are obtained only in the diet. The reaction is the only example of a cytochrome P-450 system which resides in both the mitochondrial and microsomal fractions of the cell. It occurs widely throughout the body in diverse tissues and functions via both de novo synthesis and transformation of prehormones (androstenedione and testosterone). It is found widely in animal species in both the brain and gonads even in phylogenetically primitive species. Placental aromatase appears to be associated with the evolution of viviparity and an extended gestational period in utero. Follicular aromatase which is dependent upon follicle-stimulating hormone stimulation appears to be essential for oogenesis, ovulation, and normal luteal functions while central nervous system aromatase serves to determine sexual behavior and the neurohormonal link to the hypothalamus and pituitary for ovarian cyclicity. While estrogens are the key to pituitary, breast, and endometrial growth and development, this hormone is one of the few examples of an endogenous steroid that has been implicated as a carcinogen or a stimulant for carcinogenesis.

Development and cellular localization of rat testicular aromatase activity

Abstract: Summary. Oestradiol secretion by isolated Leydig cells, Sertoli cells, myoid cells, germinal cells and liver cells from rats of different ages was measured by a validated radioimmunoassay technique. All cells, except germinal cells and liver cells, produced oestradiol when incubated in the presence of testosterone. Sertoli cells from 7- and 10-day-old rats and from prenatally irradiated adult rats were 7 times more active than cell preparations from 15\p=n-\50-day-oldrats. The oestradiol production in Sertoli cells prepared from 7\p=n-\25-day-oldrats could be stimulated with FSH. Oestradiol production by isolated Leydig cells from mature animals was 3\p=n-\4times greater than that with preparations from immature animals. LH had no effect on oestradiol production, but testosterone production was stimulated more than 5-fold. The oestradiol production by the isolated cells was affected by culture time, the presence of fetal calf serum in the culture medium and incubation temperature. During a culture period of 6 days oestradiol production by immature Sertoli cells increased more than 5-fold and that by Leydig cells decreased to about 10%. Oestradiol levels in testes from 10\p=n-\50-day-oldrats were approximately 20% of those in testes from 7-day-old animals.

The relation of plasma androgen levels to sexual behaviors and attitudes of women.

Abstract: Four androgens: dehydroepiandrosterone (DHEA), androstenedione (A), testosterone (T), and dihydrotestosterone (DHT), a variety of sexual behaviors and attitudes, and several moods were determined regularly in two groups of healthy, married women who differed by three decades in age. The younger women exhibited significantly higher levels of each androgen, the differences being almost entirely attributable to ovarian failure in the older group. Although the older women reported the same levels of sexual desire and sexual arousal as the younger women, their intercourse frequencies and self-rated sexual gratification scores were significantly lower than the values obtained for the younger wives. One or more of the androgen levels related significantly and in the expected direction to each stage of the four-stage sexual response process. Global measures of so-called "sexual adjustment" and estimates of anxiety, depression, and hostility feelings experienced by these women did not relate significantly to any of the four androgen levels.