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MALE HORMONE MODULATION
ABSTRACTS
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31. Endogenous testosterone, fibrinolysis, and coronary heart disease risk in hyperlipidemic men.
Glueck CJ, Glueck HI, Stroop D, Speirs J, Hamer T, Tracy T
Department of Pathology, University of Cincinnati College of Medicine.
J Lab Clin Med 1993 Oct;122(4):412-20

To assess relationships of endogenous testosterone with fibrinolysis and coronary heart disease risk factors in 55 newly referred hyperlipidemic men, we studied the relationships of testosterone to basal fibrinolytic activity, lipids, lipoproteins, and apolipoproteins. Testosterone correlated positively with the major stimulator of fibrinolysis, tissue plasminogen activator activity (r = 0.30; p = 0.02) and correlated inversely with two independent coronary heart disease risk factors, plasminogen activator inhibitor activity, the major fibrinolysis inhibitor (r = -0.33; p = 0.01), and fibrinogen (r = -0.39; p = 0.004). Testosterone correlated inversely with plasma triglycerides (r = -0.33; p = 0.01). Stepwise multiple regression was done with fibrinolytic activities as the dependent variables, and age, Quetelet Index (relative ponderosity), apolipoprotein A-I, apolipoprotein B, triglyceride, testosterone, time of blood sampling, and lipoprotein (a) as explanatory variables. Testosterone was an inverse, independent predictor of fibrinogen (p = 0.002); 53% of the variance of fibrinogen could be accounted for by age and triglyceride level (positive; p = 0.001, p = 0.01), and by apolipoprotein A-I and testosterone (negative; p = 0.02, p = 0.002). Testosterone was an independent inverse predictor of tissue plasminogen activator antigen (p = 0.0008), with tissue plasminogen activator antigen correlating inversely with tissue plasminogen activator activity. Quetelet index and apolipoprotein B wereindependent negative predictors of tissue plasminogen activator activity (p =0.02, p = 0.03); Quetelet index and triglycerides were independent positive predictors of plasminogen activator inhibitor activity (p = .0001, p = .0001) and alpha 2-antiplasmin (p = 0.0003, p = 0.009).

32. Effects of androgens on haemostasis.
Winkler UH
Zentrum fur Frauenheilkunde, Universitatsklinikum Essen, Germany.
Maturitas 1996 Jul;24(3):147-55

Androgen deficiency is associated with an increased incidence of cardiovascular disease. There is evidence that thromboembolic disease as well as myocardial ifarction in hypogonadic males are mediated by low baseline fibrinolytic activity. Hypogonadism in males is associated with an enhancement of fibrinolytic inhibition via increased synthesis of the plasminogen activator inhibitor PAI 1. On the other hand, stanozolol and danazol reduce PAI 1 and are associated with increased fibrinolytic activity. However, in male abusers of anabolic steroids the net effect on the haemostatic system may change from anti- to prothrombotic; there appears to be an individual threshold dose above which thrombogenic effects on platelets and vasomotion may overcome the profibrinolytic effects on PAI 1. There are numerous reports on weight-lifters dying of atherothrombotic ischemic heart disease while abusing anabolic steroids. Androgens are known to have profound effects on carbohydrate and lipid metabolism. In fact, much of the individual inconsistency of the effects of androgens on fibrinolytic and haemostatic activity appears to be based on the close interrelationship of these metabolic systems. Androgens may have unfavourable effects on the HDL/LDL cholesterol ratio, on triglyceride levels and on the insulin/insulin-like growth factor 1 (IGF 1) system. Hypertriglyceridemia as well as insulin resistance are both associated with low fibrinolytic activity and increased PAI 1 levels. On the other hand, lipoprotein(a), a recently acknowledged independent risk factor of CVD was shown to respond favourable to androgen treatment, in men as well as in women. In women, agonistic as well as antagonistic effects of estrogens and progestins need to be taken into account. In fact, estradiol may modulate testosterone effects on haemostasis. Androgen medication in premenopausal women, such asdanazol, was found to reduce PAI 1 suggesting an improvement of the fibrinolytic activity. Also, in hormone replacement therapy (HRT) androgenic progestins or complex compounds with androgenic effects are associated with a marked reduction of PAI 1 and an improvement of fibrinolytic activity. Further improvement of fibrinolytic activity may be associated with the marked decrease of lipoprotein (a) (Lp(a)) in women on androgenic HRT. However, little is known on the interrelationship of estrogens, 19-nortestosterone or progesterone derivatives and testosterone. an interrelationship that may have substantial impact on the metabolic and particularly haemostatic net effects of a preparation. In summary, information on the effects of androgens on haemostasis is limited and may be particularly incomplete due to the fact that interaction with other sex steroids appears to be an important confounder. In any case, there are numerous effects of synthetic androgens on the synthesis and release of haemostatic factors, namely an increase of the inhibitors of coagulation and a decrease of the inhibitor of the fibrinolytic system. However, the use of androgens in patients with congenital deficiencies of these coagulation factors or previous events of cardiovascular disease has yielded disappointing results. On the other hand, particularly the reduction of fibrinolytic inhibition (PAI 1) and Lp(a) were considered favourable effects of androgens with regard to the risk of cardiovascular disease. Differences between preparations withpronounced androgenic versus antiandrogenic effects and the effect of combined preparations need to be studied in much more detail. The profibrinolytic effects of androgens may be of particular interest with regard to favourable effects of HRT on cardiovascular disease.

33. Plasminogen activator inhibitor in plasma is related to testosterone in men.
Caron P, Bennet A, Camare R, Louvet JP, Boneu B, Sie P
Service d'Endocrinologie, Hopital Purpan, Toulouse, France.
Metabolism 1989 Oct;38(10):1010-5

Low plasma testosterone and high levels of the rapid inhibitor of plasminogen activator (PA-I) have been proposed as risk factors for myocardial infarction. In this study, the relationship between testosterone and PA-I activity levels in middle-aged men without thrombotic antecedent was investigated. In 54 normogonadic men (testosterone, 7.3 to 29.1 nmol/L), PA-I was related positively to body mass index (BMI) and triglycerides and negatively to testosterone. When these variables were controlled, the relation between PA-I and testosterone remained significant (P less than .01). In the 41 normogonadic men with BMI less than 25, testosterone was the only variable to influence PA-I. Fibrinolytic activity was evaluated by the euglobulin lysis plate method and the specific measurement of functional tissue plasminogen activator. The basal fibrinolytic activity and the response to venous occlusion were essentially controlled by PA-I but were not significantly related to testosterone. In 17 men with severe hypogonadotrophinic hypogonadism (testosterone less than 3 nmol/L), PA-I was significantly increased (18.5 +/- 1.8 AU/mL, mean +/- SE) compared with 9.5 +/- 0.8 AU/mL in 41 normogonadic men of normal weight (P less than .001). However, 14 hypogonadic men had a hypertriglyceridemia or a BMI greater than 25, which could explain high PA-I levels. This study shows that the level of the inhibitor of plasminogen activator is partly dependent on hormonal status in men and provides a link between independently established epidemiologic data.

34. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses
Ajayi AA; Mathur R; Halushka PV
Department of Pharmacology, Medical University of South Carolina, Charleston 29425-2251, USA.
Circulation (United States) Jun 1 1995, 91 (11) p2742-7

BACKGROUND: The incidence of thrombotic cardiovascular disease is greater in men than in premenopausal women. Testosterone has been implicated as a significant risk factor for cardiovascular disease and for acutemyocardial infarctions and strokes in young male athletes who abuse anabolic steroids. Thromboxane A2 (TXA2) is a vasoconstrictor and platelet proaggregatory agent that has been implicated in the pathogenesis of cardiovascular disease. We therefore tested the hypothesis that testosterone regulates the expression of human platelet TXA2 receptors.

METHODS AND RESULTS: In a double-blind, placebo-controlled, randomized, parallel-group study, we determined the effects of testosterone cypionate 200 mg IM given twice, 2 weeks apart, or saline placebo in 16 healthy men. Platelet TXA2 receptor density (Bmax) and dissociation constant (Kd) were measured by use of the TXA2 mimetic 125I-BOP. Platelet aggregation responses to I-BOP and to thrombin and plasma testosterone concentrations were measured before treatment (pretreatment phase), at 2 and 4 weeks (active phase), and again at 8 weeks (recovery phase). Treatment with testosterone was associated with an increase in the Bmax value from 0.95 +/- 0.13 to 2.10 +/- 0.4 pmol/mg protein (n = 9), with a peak effect at 4 weeks (P = .001), returning to baseline by 8 weeks. There was no significant change in Bmax values in the saline-treated group. The Kd values were unchanged. Testosterone treatment was associated with a significant increase in the maximum platelet aggregation response to I-BOP (P < .001) at 4 weeks and returned to baseline at 8 weeks. The EC50 values were not significantly changed. Platelet TXA2 receptor density was positively correlated (r = .56, P < .001, n = 32 measurements) with pretreatment (endogenous) plasma testosterone levels (range, 215 to 883 ng/dL) but not Kd.

CONCLUSIONS: Testosterone regulates the expression of platelet TXA2 receptors in humans. This may contribute to the thrombogenicity of androgenic steroids.

35. Endocrine environment of benign prostatic hyperplasia: prostate size and volume are correlated with serum estrogen concentration.
Suzuki K, Ito K, Ichinose Y, Kurokawa K, Suzuki T, Imai K, Yamanaka H, Honma S
Department of Urology, School of Medicine, Gunma University, Japan.
Scand J Urol Nephrol 1995 Mar;29(1):65-8

Estrogen plays an important role in the development of benign prostatic hyperplasia (BPH), as has been shown in both experimental and clinical studies. T determine the endocrine environment of BPH, serum total testosterone (Total-T), free testosterone (Free-T), and estradiol (E2) conceptions were measured, and the relationship between these levels and prostate size and volume was analyzed. Blood samples were collected from subjects who attended the mass screening for prostate disease performed by our institute. No significant correlations were found between Total-T levels, Free-T levels, and prostate size, as determined by digital rectal examination. However, E2 levels and the ratios for E2 levels and the ratios for E2/Total-T and E2/Free-T were significantly correlated with prostate size. To confirm these relationships, prostate volume was calculated from transrectal ultrasonographic images. E2 levels and these two ratios were, indeed, highly correlated with prostate volume. These results suggest that an estrogen-dominant environment plays an important role in the development of BPH.

36. A prospective study of plasma hormone levels, nonhormonal factors, and development of benign prostatic hyperplasia.
Gann PH, Hennekens CH, Longcope C, Verhoek-Oftedahl W, Grodstein F, Stampfer MJ
Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Prostate 1995 Jan;26(1):40-9

We assessed the relation of plasma hormone levels and nonhormonal factors with subsequent occurrence of surgical treatment for benign prostatic hyperplasia (BPH) among participants in the Physicians' Health Study. Frozen plasma samples, collected at the study onset, were available for 320 men who developed surgically treated BPH up to 9 years later and for 320 age-matched controls. Plasma testosterone (T), dihydrotestosterone (DHT), androstenedione, estradiol (E2), and estrone (E1) were measured for each case-control pair. In unadjusted analyses, none of the hormones or hormone ratios were associated with BPH; for example, for T and E2 the odds ratios (OR) comparing the highest quintile (Q5) with the lowest (Q1) were 0.74 (95% CI = 0.42, 1.30) and 1.07 (95% CI = 0.51, 2.22), respectively. However, in multivariate analyses controlling diastolic blood pressure, exercise, alcohol, E1, and DHT:T ratio, we observed a strong trend for increasing risk across quintiles for E2 (Q5 vs. Q1 OR = 3.56, P trend = 0.009), and a weak inverse trend for E1 (Q5 vs Q1 OR = 0.51, P trend = 0.07). The excess risk associated with E2 was confined to men with relatively low androgen levels. Three nonhormonal factors previously suspected as risk factors were independently associated with surgical BPH in these data. The OR for a 1-mm Hg difference in diastolic blood pressure was 1.04 (95% CI = 1.01, 1.07). Alcohol use and infrequent exercise were inversely associated with risk of BPH surgery; however, risk estimates were not consistent across categories of exercise and alcohol frequency. Our results indicate that normal variation in circulating androgen levels does not influence development of BPH, but that variation in estrogen levels might be important.

37. Estrogen formation in human prostatic tissue from patients with and without benign prostatic hyperplasia.
Stone NN, Fair WR, Fishman J
Prostate 1986;9(4):311-8

Prostatic tissue removed at the time of cystoprostatectomy was separated into periurethral and peripheral zones. Homogenized tissue was incubated with [1,2,6,7(3)H] androstenedione in the presence or absence of an aromatase inhibitor, 4-hydroxyandrostenedione (4-OHAD) and a 5 alpha-reductase inhibitor 4-MA (N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane 17 beta-carboxamide). Estrogen formation was determined by reverse isotope dilution of [3H] estrone and [3H] estradiol and crystallization to constant specific activity. Control incubations were carried out in parallel utilizing heated prostatic tissue. Total estrogens produced in the periurethral zone in patients with benign prostatic hyperplasia (BPH) was 223 fmol/mg protein/hr (SE +/- 57) compared to 102 fmol (SE +/- 17) in patients without BPH. Estrogen formation in the peripheral zone was 175 fmol (SE +/- 69) and 105 fmol (SE +/- 26) in patients with and without BPH, respectively. The prostatic aromatase exhibits Michaelis-Menton kinetics with an apparent Km of 90 nM. 4-OHAD inhibited aromatization in the prostatic tissue by 57-93%. Aromatization was also strongly inhibited by 4-MA, indicating that 4-MA is a potent aromatase as well as a 5 alpha-reductase inhibitor in this tissue. These results suggest that aromatization of androgens to estrogens in the human prostate proceeds at a substantial rate and that local estrogen formation could preexist and be a factor in the etiology of BPH and prostatic cancer.

38. Expression of estrogen receptor in diseased human prostate assessed by non-radioactive in situ hybridization and immunohistochemistry.
Ehara H; Koji T; Deguchi T; Yoshii A; Nakano M; Nakane PK; Kawada Y
Department of Urology, Gifu University School of Medicine, Japan.
Prostate 1995 Dec;27(6):304-13

To understand the role of estrogen in the pathogenesis of benign prostatic hyperplasia, expressions of estrogen receptor (ER) mRNA and ER protein by in situ hybridization and by immunohistochemistry, respectively, were investigated in human prostatic tissues. In non-malignant region, ER mRNA and ER protein were found in cytoplasm and nucleus, respectively, of stromal cells, but not in glandular epithelial and basal cells. In benign regions, ER mRNA/ER protein positive cells were found in fibromyoadenomatous and myoadenomatous hyperplasia, but not in adenomatous hyperplasia. A striking feature was periacinar arrangement of ER mRNA/ER protein positive stromal cells in all prostate carcinoma treated with androgen withdrawal. The ER mRNA/ER protein positive cells were immunohistochemically identified as fibroblasts, myoblasts, and smooth muscle cells. These results indicate that stromal cells are the primary target of estrogen in prostate, and that androgen withdrawal upregulates the expression of ER gene.

39. Roles of estrogen and SHBG in prostate physiology.
Farnsworth WE
Department of Urology, Northwestern University Medical School, Chicago, Illinois, USA.
Prostate 1996 Jan;28(1):17-23

Heretofore, the function of estrogen in the prostate, other than as an antiandrogen, has been unclear. In this review of a growing fund of knowledge about both estrogen and the plasma protein, sex hormone-binding globulin (SHBG), or testosterone-estradiol binding globulin (TeBG), the hypothesis is proposed that estrogen, mediated by SHBG, participates with androgen in setting the pace of prostatic growth and function. It is suggested that the estrogen not only directs stromal proliferation and secretion, but also, through IGF-I, conditions the response of the epithelium to androgen.

40. [The role of tissue steroids in benign hyperplasia and prostate cancer].
[Article in German]
Voigt KD, Bartsch W
Universitatskrankenhaus Eppendorf, Abteilung fur klinische Chemie, Hamburg.
Urologe [A] 1987 Nov;26(6):349-57

This paper presents a large body of data relating to benign prostatic hyperplasia, which have been derived from fundamental endocrinological research. For the urologist, the data open up interesting aspects of the pathomorphology of prostatic hyperplasia. The most interesting findings can be summed up as follows: 1. Testosterone is the circulating androgenic prohormone that mediates the intracellular message leading to androgen secretion, though by way of its metabolite dihydrotestosterone, which is really the active substance. 2. This metabolic conversion is catalyzed by 5 alpha-reductase, which is predominantly a stromal enzyme. 3. The estrogen metabolism in the stromal cells of the prostate may be associated with the abnormal growth of the prostate. 4. In the presence of benign prostatic hyperplasia dihydrotestosterone and 17 beta-estradiol accumulate in the nuclei of the stromal cells. 5. Adrenal androgens are also metabolized in the human prostate, yielding some substances with androgenic and some with estrogenic potency. 6. Changes in sex hormone binding globulins (SHBG) are found with age whether benign prostatic hyperplasia is present or not. It is therefore questionable whether it has any influence on the development of prostatic hyperplasia. 7. Although in some cases it is not yet possible to determine whether the findings presented in this paper have any causal significance, the data can be used as a rational basis for hormonal treatment of prostatic disease.

41. Estradiol causes the rapid accumulation of cAMP in human prostate.
Nakhla AM; Khan MS; Romas NP; Rosner W
Department of Medicine, St. Luke's/Roosevelt Hospital Center, New York, NY 10019.
Proc Natl Acad Sci U S A 1994 Jun 7;91(12):5402-5

Androgens are widely acknowledged to be central to the pathogenesis of benign prostatic hypertrophy (BPH). However, BPH increases in prevalence as men age, at precisely the stage of life when plasma androgens are decreasing. The decrease in total plasma androgens is amplified by an age-related increase in plasma sex hormone-binding globulin (SHBG) that results in a relatively greater decrease in free androgens than in total androgens. In addition, estrogens have long been suspected to be important in BPH, but a direct effect on the human prostate has never been demonstrated. We present data that are consistent with a role for estradiol, and for a decrease in androgens and an increase in SHBG, in the pathogenesis of BPH. We show that estradiol, but not dihydrotestosterone, acts in concert with SHBG to produce an 8-fold increase in intracellular cAMP in human BPH tissue. This increase is not blocked by an antiestrogen and is not provoked by an estrogen (diethylstilbestrol) that does not bind to SHBG, thus excluding the classic estrogen receptor as being operative in these events. Conversely, dihydrotestosterone, which blocks the binding of estradiol to SHBG, completely negates the effect of estradiol. Finally, we demonstrate that the SHBG-steroid-responsive second-messenger system is primarily localized to the prostatic stromal cells and not to the prostatic epithelial cells. Thus, we have shown a cell-specific, powerful, nontranscriptional effect of estradiol on the human prostate.

42. The effect of extracts of the roots of the stinging nettle (Urtica dioica) on the interaction of SHBG with its receptor on human prostatic membranes.
Hryb DJ, Khan MS, Romas NA, Rosner W
Department of Medicine, St. Luke's/Roosevelt Hospital Center, New York, N.Y. 10019.
Planta Med 1995 Feb;61(1):31-2

Extracts from the roots of the stinging nettle (Urtica dioica) are used in the treatment of benign prostatic hyperplasia. The mechanisms underlying this treatment have not been elucidated. We set out to determine whether specific extracts from U. dioica had the ability to modulate the binding of sex hormone-binding globulin to its receptor on human prostatic membranes. Four substances contained in U. dioica were examined: an aqueous extract; an alcoholic extract; U. dioica agglutinin, and stigmasta-4-en-3-one. Of these, only the aqueous extract was active. It inhibited the binding of 125I-SHBG to its receptor. The inhibition was dose related, starting at about 0.6 mg/ml and completely inhibited binding at 10 mg/ml.

43. Effects of stinging nettle root extracts and their steroidal components on the Na+,K(+)-ATPase of the benign prostatic hyperplasia.
Hirano T, Homma M, Oka K
Department of Clinical Pharmacology, Tokyo College of Pharmacy, Japan.
Planta Med 1994 Feb;60(1):30-3

The effects of organic-solvent extracts of Urtica dioica (Urticaceae) on the Na+,K(+)-ATPase of the tissue of benign prostatic hyperplasia (BPH) were investigated. The membrane Na+,K(+)-ATPase fraction was prepared from a patient with BPH by a differential centrifugation of the tissue homogenate. The enzyme activity was inhibited by 10(-4)-10(-5) M of ouabain. The hexane extract, the ether extract, the ethyl acetate extract, and the butanol extract of the roots caused 27.6-81.5% inhibition of the enzyme activity at 0.1 mg/ml. In addition, a column extraction of stinging nettle roots using benzene as an eluent afforded efficient enzyme inhibiting activity. Steroidal components in stinging nettle roots, such as stigmast-4-en-3-one, stigmasterol, and campesterol inhibited the enzyme activity by 23.0-67.0% at concentrations ranging from 10(-3)-10(-6) M. These results suggest that some hydrophobic constituents such as steroids in the stinging nettle roots inhibited the membrane Na+,K(+)-ATPase activity of the prostate, which may subsequently suppress prostate-cell metabolism and growth.

44. The inhibiting effects of Urtica dioica root extracts on experimentally induced prostatic hyperplasia in the mouse.
Lichius JJ, Muth C
Institut fur Pharmazeutische Biologie, Philipps-Universitat, Marburg, Germany.
Planta Med 1997 Aug;63(4):307-10

Extracts of stinging nettle roots (Urtica dioica L. Urticaceae) are used in the treatment of benign prostatic hyperplasia (BPH). We established a BPH-model by directly implanting an urogenital sinus (UGS) into the ventral prostate gland of an adult mouse. Five differently prepared stinging nettle root extracts were tested in this model. The 20% methanolic extract was the most effective with a 51.4% inhibition of induced growth.

45. Severe sexual impairment produced by morbid obesity. Report of a case.
Blum I; Marilus R; Barasch E; Sztern M; Bruhis S; Kaufman H
Department of Medicine C, Rokach (Hadassah) Hospital, Tel-Aviv, Israel.
Int J Obes (ENGLAND) 1988, 12 (3) p185-9

A 45-year-old man, was admitted for investigation of severe sexual impairment. During 20 years of marriage, he had had no normal sexual intercourse and the couple was childless. Physical examination disclosed a severely obese man (weight 300 kg, height 1.75 m), with a relatively small and invaginated penis and small (5 ml) soft testes. Laboratory examinations disclosed the following: low serum testosterone (1 ng/ml), with a reduced response to HCG (3.8 ng/ml). Sex hormone binding globulin was at the lower limit of normal (0.38 microgram/dl), serum free testosterone was low (0.98% of total testosterone) as well as non-SHBG bound testosterone (22% of total testosterone). Daily total urinary estrogen excretion was increased (107 micrograms), the plasma estrone (78 pg/ml) and estradiol (74 pg/ml) were elevated. The gonadotropins were normal and responded adequately to LRH. Plasma growth hormone was decreased, prolactin, T4 and adrenal steroids were normal and responded normally to stimuli and inhibitors. Chromosomal constitution was 46XY. Thus, in this man the marked obesity produced a significant increase in estrogens which subsequently induced a severe decrease in testosterone and its free counterpart in excessive impairment of sexual function.

46. The Testosterone Syndrome
Shippen and Fryer
1998 M. Evans and Company New York, NY

No abstract.

47. Endocrine aspects of ageing in the male.
Gooren LJ
Department of Endocrinology, Hospital of the Vrije Universiteit, Amsterdam, The Netherlands.
lgooren@inter.nl.net
Mol Cell Endocrinol 1998 Oct 25;145(1-2):153-9

There is a statistical decline of testosterone levels in ageing men, most manifest in free testosterone. While this fall is only moderate, ageing men show clinical signs of hypogonadism (loss of muscle mass/strength, reduction in bone mass and an increase in visceral fat). This might represent not only a fall but (also) an impairment of the biological action of androgens in target organs. The first small scale studies of androgen supplement administration in ageing men were not disappointing. Anticipated risks lie with the prostate and the cardiovascular system. The risks with regard to prostate disease are often over-rated. The question remains how the segment of the ageing male population possibly benefiting from androgen supplements, can be identified. For the treatment of postmenopausal women 'designer oestrogens' are being developed; similarly, designer androgens retaining beneficial anabolic effects with elimination of harmful effects on the prostate and cardiovascular system, could be devised.

48. [Sexual hormones in ageing males (author's transl)]
Kley HK; Nieschlag E; Wiegelmann W; Kruskemper HL
Aktuelle Gerontol (Germany, West) Feb 1976, 6 (2) p61-7

Alterations of sexual hormones in plasma of ageing males occur between the 50th and 60th year of life with individual variations: 1. Decreased values of testosterone in plasma and a poor response to gonadotrophins demonstrate a diminished synthesizing capacity of the testes in old men. 2. The decreased testosterone plasma values are followed by an increase in LH. The response of the anterior pituitary gland to LH-RH stimulation in old men is normal. 3. Under basal conditions estrone as well as estradiol plasma concentrations increase significantly with age because of increased conversion from androgens. 4. Parallel to estrogen plasma values an increased concentration of the sexual hormone binding globulin (SHBG) is found, resulting in a steep decrease of the free (= active) testosterone fraction. 5. Decreased testosterone, which is more strongly bound to SHBG and increased estrone and estradiol plasma values result in an androgen/estrogen imbalance in old men. (25 Refs.)

49. Direct effects of estrogens on the endocrine function of the mammalian testis.
Moger WH
Can J Physiol Pharmacol 1980 Sep;58(9):1011-22

This article reviews literature relevant to the view that estradiol (E2) synthesized in the testis acts locally to modify testosterone secretion. Despite a lack of convincing evidence from in vitro experiments, in vivo experiments with intact and hypophysectomized animals have demonstrated that estrogens can inhibit testosterone secretion by acting directly on the testis. Reduced testosterone production in estrogen-treated animals probably results from reduced 17 alpha-hydroxylase and (or) C17-C20 lyase activity. Estrogen-inhibited steroidogenesis may result from estrogen binding to high affinity--low capacity estrogen receptors. Besides being an estrogen target tissue, the testis produces E2; the cellular site of testicular E2 synthesis remains controversial. Recent studies indicate that E2 is synthesized primarily in the Sertoli cells of neonatal rats and in the Leydig cells of older rats. Follicle-stimulating hormone and human chorionic gonadotropin (hCG) increase testicular aromatase activity and E2 concentrations in neonatal and older rats, respectively. An increase in testicular E2 concentrations, following hCG administration, may be one mechanism by which testosterone synthesis becomes desensitized to subsequent hCG stimulation. However, whether gonadotropin-stimulated testicular E2 synthesis is part of a physiologically relevant "short" feedback loop that participates in the regulation of testosterone synthesis remains to be determined.

50. Direct inhibitory effect of estrogen on the human testis in vitro.
Namiki M, Kitamura M, Nonomura N, Sugao H, Nakamura M, Okuyama A, Utsunomiya M, Itatani H, Matsumoto K, Sonoda T
Department of Urology, Osaka University Medical School, Japan.
Arch Androl 1988;20(2):131-5

The direct inhibitory effects of estrogens on human testicular functions were investigated with a testicular organ culture technique. 125I-labeled human chorionic gonadotropin (125I-hCG) bindings in testes cultured in media containing diethylstilbestrol diphosphate (DESDP) began to dose-relatedly decrease a day after the start of the culture, and this decrease remained relatively constant during the 5-day culture. On the other hand, testosterone produced by the cultured testes time-relatedly decreased during the 5-day culture. From the above results it may be concluded that the direct inhibitory effect of estrogens on human testicular androgen production consists of not only the loss of testicular hCG receptors but also of other mechanisms at a distal step from hCG receptor activation.

51. The acute effect of estrogens on testosterone production appears not to be mediated by testicular estrogen receptors
Damber JE; Bergh A, Daehlin L, Ekholm C, Selstam G, Sodergard R
Department of Physiology, University of Umea, 90187, Umea.
Mol Cell Endocr 31 (1). 1983. 105-116.

Scatchard binding analysis was performed to measure the cytoplasmic estrogen receptor in the testis of rats. After treatment of rats with the antiestrogen tamoxifen no estrogen receptor binding was found in testicular low speed supernatant between 12 and 96 h after treatment. Such tamoxifen-treated rats were used to study the acute effect of estrogens on testosterone secretion, both in vivo and in vitro. Injection of estradiol benzoate (50 .mu.g, 24 h prior to experiment) resulted in a significant depression of basal and LH[lutropin]-stimulated plasma testosterone levels in control rats and this effect was unchanged in tamoxifen-pretreated rats. In vitro, estradiol-17.beta. also inhibited the LH-induced rise in testosterone secretion by isolated testicular interstitial cells. This inhibition was not affected if the rats had been pretreated with tamoxifen. The inhibitory effects of exogenous estrogens on testicular testosterone production are probably not mediated by the estrogen receptor.

52. The effect of testosterone aromatization on high-density lipoprotein cholesterol level and postheparin lipolytic activity.
Zmuda JM; Fahrenbach MC; Younkin BT; Bausserman LL; Terry RB; Catlin DH; Thompson PD
Department of Medicine, Miriam Hospital, Providence, RI.
Metabolism (United States) Apr 1993, 42 (4) p446-50,

Stanozolol, an oral 17 alpha-alkylated androgen, increases hepatic triglyceride lipase activity (HTGLA) and decreases high-density lipoprotein cholesterol (HDL-C) levels, whereas intramuscular testosterone has comparatively little effect. In the present study, we tested the hypothesis that aromatization of androgen to estrogen blunts the lipid and lipase effects of exogenous testosterone. Fourteen male weightlifters received testosterone enanthate (200 mg/wk intramuscularly), the aromatase inhibitor testolactone (250 mg four times per day), or both drugs together in a randomized cross-over design. Serum testosterone level increased during all three drug treatments, whereas estradiol level increased only with testosterone alone (+47%, P < .05), demonstrating that testolactone effectively inhibited testosterone aromatization. Testosterone decreased HDL-C(-16%, P < .05), HDL2-C(-23%, NS), and apoprotein (apo) A-I (-12%, P < .05) levels, effects that were consistently but not significantly greater with simultaneous testosterone and testolactone administration (HDL-C, -20%; HDL2-C, -30%; apo A-I, -15%; P < .05 for all). In contrast, both testosterone regimens decreased HDL3-C levels by 13% (P < .05 for both). HTGLA increased 21% during testosterone treatment and 38% during combined testosterone and testolactone treatment (P < .01 for both). Lipoprotein lipase activity (LPLA) increased only during combined testosterone and testolactone treatment (+31%, P < .01), suggesting that estrogen production may counteract the effects of testosterone on LPLA. Testolactone alone had little effect on any lipid, lipoprotein, apoprotein, or lipase concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

53. Effects of estradiol administration in vivo on testosterone production in two populations of rat Leydig cells
Keel B.A.; Abney T.O.
Dep. Endocrinol., Med. Coll. Georgia, Augusta, GA 30912 United States
Biochemical and Biophysical Research Communications (United States) 1982, 107/4 (1340-1348)

The effects of in vivo administration of estradiol on isolated rat testicular Leydig cells were investigated. Adult intact rats were injected s.c. with 50 mug/100 g B.W. of 17beta-estradiol or vehicle twice daily for 2 days. Twelve hours after the last injection, collagenase dispersed interstitial cells were obtained and Leydig cells were subsequently isolated on metrizamide gradients. Two distinct peaks of specific sup 1sup 2sup 5I-hCG binding corresponding to population I and II Leydig cells were observed. The hCG binding profile was unaltered as a result of estradiol treatment. Although twice as much testosterone was produced in population II, the responsiveness of the two populations to hCG or dbcAMP in vitro was identical (11- to 13-fold increase). Estradiol administration in vivo resulted in a 33-48% decrease in basal and stimulated testosterone production in both populations. These data indicate for the first time that both population I and II Leydig cells are sensitive to the direct inhibitory effects of estrogens on testosterone production. This inhibitory effect was not associated with an alternation in hCG binding capacity in either population. Therefore, we conclude that no functional difference exists between the two populations of Leydig cells with respect to the action of estrogens.

54. Tetrahydroisoquinoline alkaloids mimic direct but not receptor-mediated inhibitory effects of estrogens and phytoestrogens on testicular endocrine function. Possible significance for Leydig cell insufficiency in alcohol addiction.
Stammel W, Thomas H, Staib W, Kuhn-Velten WN
Abteilung Physiologische Chemie, Universitat Ulm, F.R. Germany.
Life Sci 1991;49(18):1319-29

Possible effects of various tetrahydroisoquinolines (TIQs) on rat testicular endocrine function were tested in vitro in order to prove whether these compounds, some of which have been claimed to accumulate in alcoholics, may be mediators of the development of Leydig cell insufficiency, a well-known side-effect of ethanol ingestion. TIQ effects on different levels of regulation of testis function were compared in vitro with estrogen effects, since both classes of compounds have structural similarities. Gonadotropin-stimulated testosterone production by testicular Leydig cells was inhibited by tetrahydropapaveroline and isosalsoline, the IC50 values (30 microM) being comparable to those of estradiol (3 microM), 2-hydroxyestradiol (10 microM), and the phytoestrogens, coumestrol (15 microM) and genistein (7 microM); salsolinol (85 microM) and salsoline (240 microM) were less effective, and salsolidine was ineffective. None of these TIQs interacted significantly with testicular estrogen receptor as analyzed by estradiol displacement. However, tetrahydropapaveroline, isosalsoline and salsolinol competitively inhibited (Ki 130-150 microM) substrate binding to cytochrome P450XVII, one key enzyme of androgen biosynthesis, with similar efficiency as the estrogens did (Ki 50-110 microM); salsoline and salsolidine were again much less effective. Since the efficient TIQ concentrations in this system are identical with those reported to generate central-nervous effects, it is concluded that certain TIQs may amplify peripheral inhibitory effects of ethanol on testicular endocrine function by their interaction with at least one enzyme of the androgen biosynthetic pathway.

55. Levels of sex hormone-binding globulin and corticosteroid-binding globulin mRNAs in corpus luteum of human subjects: correlation with serum steroid hormone levels.
Misao R, Nakanishi Y, Fujimoto J, Iwagaki S, Tamaya T
Department of Obstetrics and Gynecology, Gifu University School of Medicine, Japan.
[Medline record in process]
Gynecol Endocrinol 1999 Apr;13(2):82-8

To understand regulation of the function of human ovarian corpus luteum by sex steroid-binding proteins, the levels of luteal intracellular sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) mRNAs and serum steroid hormones were simultaneously determined. The expression of SHBG and CBG mRNAs was detected in all samples analyzed. SHBG mRNA level was positively correlated with serum estradiol-17 beta level (p < 0.05), but not with serum progesterone level. There was a positive correlation between SHBG mRNA level and serum estradiol-17 beta/progesterone ratio (p < 0.01). On the other hand, CBG mRNA level was positively correlated with serum estradiol-17 beta and progesterone level (p < 0.01 and p < 0.01, respectively). There was no correlation between CBG mRNA level and serum estradiol-17 beta/progesterone ratio. SHBG and CBG mRNA levels were not correlated with the levels of serum testosterone, free testosterone or cortisol. These findings suggest that the synthesis of luteal SHBG and CBG is complexly regulated by estrogen and progesterone, and that SHBG and CBG interact with estrogen and progesterone, respectively, for luteal steroidal activity.

56. Effects of ethinyloestradiol on plasma levels of pituitary gonadotrophins, testicular steroids and sex hormone binding globulin in normal men.
Van Look PF, Frolich M
Clin Endocrinol (Oxf) 1981 Mar;14(3):237-43

Daily measurements of plasma FSH, LH, prolactin, testosterone, 17 beta-oestradiol and sex hormone binding globulin (SHBG) activity were made in eight healthy, normal men during treatment with oral ethinyloestradiol (EE2) in a dose of 30 micrograms/day for 5 days following a 5-day control period. No significant changes in plasma levels of FSH and prolactin during oestrogen treatment occurred. In contrast, plasma concentrations of both LH and testosterone showed a biphasic pattern. Following an initial suppression during the first 3 days of oestrogen treatment both LH and testosterone increased again to baseline values despite continuation of oestrogen administration. The secondary rise of both hormones was associated with (and probably resulted from) a nearly 100% increase in the plasma concentration of SHBG binding activity, and hence reduction of free testosterone index (FTI). Unlike testosterone, plasma 17 beta-oestradiol during EE2 administration did not show a biphasic pattern, but a progressive decline that was positively correlated with the fall in FTI. The rapidity of onset and magnitude of the observed rise in SHBG levels emphasizes the need for measurement of this binding protein (or the free testosterone fraction) in studies on feedback regulation of gonadotrophins employing exogenous EE2 in human males. The observed increase of SHBG to supraphysiological values suggests that currently employed EE2 doses in such studies may be less 'physiologic' than is often assumed.

57. Changes in testosterone muscle receptors: effects of an androgen treatment on physically trained rats.
Bricout VA; Germain PS; Serrurier BD; Guezennec CY
IMASSA-CERMA, Departement de Physiologie Systemique, Bretigny sur Orge, France.
Cell Mol Biol (Noisy-le-grand) 1994 May;40(3):291-4

From results obtained in physiological investigations carried out on various tissues sensitive to androgens, it seems that the hormonal receptivity can reflect changes in the endocrine status and specific response of a tissue. The purpose of the present investigation was to test whether an androgen treatment could modify the receptivity to testosterone of the skeletal muscle and myocardium of endurance trained rats. The experiment extended over 8 weeks, and animals received injections of delayed testosterone heptylate every seven days. The myocardium and two skeletal muscles with opposed functions and typology were examined: the extensorum digitorum longus (EDL), and the soleus (SOL). Results obtained using techniques based upon the radio-competition principles provided information on the testosterone-receptor binding. The binding curves were plotted up to the saturating concentration of tritiated mibolerone, a synthetic androgen specific of androgen receptors. The quantity of receptors, calculated at the specific saturation plateau is expressed in fmol/mg protein. Results show that contractile muscular activity always increased the quantity of receptors whereas the steroid treatment decreased it. Thus for EDL and SOL of control trained rats the quantity of receptors was 0.78 and 0.82 fmol/mg protein, respectively, compared to 0.23 and 0.43 fmol/mg protein for sedentary testosterone-treated rats. The same "contractile activity" effect was observed on the myocardium but enhanced with values of 1.63 fmol/mg protein for control trained rats versus 0.30 fmol/mg protein for sedentary testosterone-treated rats. The receptivity to testosterone of the skeletal muscle and myocardium changes under the effect of an androgen treatment.

58. Steroid hormones and neurotrophism: relationship to nerve injury.
Jones KJ
Department of Biological Chemistry and Structure, University of Health Sciences, Chicago Medical School, Illinois 60064.
Metab Brain Dis (United States) Mar 1988, 3 (1) p1-18

Current data on the neurotrophic effects of steroid hormones suggest that, in brain and spinal cord regions containing receptor systems, steroids act at the level of RNA and protein synthesis to effect metabolic changes associated with nerve-cell survival, elaboration/maintenance of dendritic and axonal processes, synaptogenesis, and neurotransmission. While many of these effects appear to be associated with the neuroanatomical systems involved in the endocrine and behavioral aspects of reproduction, evidence does exist for similar neurotrophic effects outside the reproductive sphere. Both estrogens and androgens appear to exert this stimulatory, growthlike effect on target neurons. The effects of progesterone are not discussed in this review because relatively little information is available regarding the independent effects of progesterone on the brain . We have just completed a study (Jones et al., 1987b) which suggests that progesterone may act independently in the brain to affect protein synthesis. A number of conclusions concerning the mechanism of steroid action in producing trophic effects on neurons can be drawn. First, the time course of hormone action is similar to that found in nonneural target tissue, such as the uterus. Second, steroid hormones act on neurons through receptor-mediated genomic activation. Third, this effect on the genome appears to be at the level of both transcription and translation. Fourth, there is brain -region specificity in the gene products resulting from steroid hormone administration. Finally, short-term exposure to estrogens or androgens generally results in an anabolic response within target neurons. The brain and spinal cord, injured either by disease or by experimentally induced trauma , is responsive in a reparative manner to exogenous and/or endogenous gonadal steroid hormones. The mechanism underlying this therapeutic role of steroids on damaged neurons is not known but has been postulated to involve direct action of steroid hormones or target neurons. It has been hypothesized that two diseases, Alzheimer's and ALS, may be related to steroid hormone/receptor deficiencies. In this regard, Appel (1981) has suggested that putative "neurotrophic hormones" acting at the synapse may be critical in maintaining the neural networks affected in ALS, Alzheimer's disease, and parkinsonism. Extending that hypothesis to include direct action of such putative hormones within the cell body and at the level of the genome, the evidence presented in this discussion would argue that possible candidates could be gonadal steroids.

59. Androgen deficiency and aging in men.
Swerdloff RS, Wang C
Department of Medicine, University of California, Los Angeles, School of Medicine.
West J Med 1993 Nov;159(5):579-85

Androgen levels decrease with age in men. Androgen deficiency in men older than 65 years leads to asthenia, a decrease in muscle mass, osteoporosis, and a decrease in sexual activity. Androgen deficiency has been reported to cause changes in mood and cognitive function. The combination of these factors results in impaired quality of life in older men. Androgen replacement therapy in hypogonadal men increases bone and muscle mass, enhances muscle and cardiovascular function, and improves sexual function and general well-being; whether elderly men experience benefits of androgen replacement is not known. These benefits have to be weighed against the possible adverse effects of prostate and cardiovascular diseases. Careful long-term studies are needed to assess the risk-to-reward ratios of androgen or other hormone replacement therapy before treatment strategies similar to estrogen therapy for postmenopausal women are implemented.

60. Androgens and aging in men.
Swerdloff RS, Wang C
Division of Endocrinology, Harbor-UCLA Medical Center, Torrance 90509.
Exp Gerontol 1993 Jul-Oct;28(4-5):435-46

Androgen levels decrease with aging in men. Androgen deficiency in elderly men may lead to asthenia, decrease in muscle mass, osteoporosis, decrease in sexual activity, and, in some cases, changes in mood and cognitive function. Combination of these factors may result in impaired quality of life in the elderly male. Androgen replacement therapy may increase bone and muscle mass, enhance muscle and cardiovascular function, and improve sexual function and general well-being. These potential benefits of androgens have to be weighed against the possible adverse effects on prostate and cardiovascular diseases. Careful long-term studies will be required to assess the risk-to-reward ratios of androgen or other hormone replacement therapy before the development of treatment strategies similar to estrogen and progestagen substitution therapy for the postmenopausal female.


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