Isurugi K, Kanazawa M, Yanaihara T, Kambegawa A
Prostate Suppl 1981;1:19-26

Serum levels of testosterone (T), dihydrotestosterone (DHT), androsterone (A), 5 alpha-androstane-3 alpha, 17 beta-diol (5 alpha-diol) and estradiol-17 beta (E2) were measured by radioimmunoassay in the sera of 9 patients with untreated prostatic cancer and in 11 with benign prostatic hypertrophy (BPH). Basal levels and responses to hCG stimulation were investigated. Although no specific changes in steroid hormone levels in either disease group were found, response patterns of serum T, DHT, and E2 were shown to be those characteristic of male senescence, suggesting a relative predominance of estrogens over androgens. Neither 5 alpha-diol nor A exhibited appreciable responses to hCG stimulation in our study.

Vatten LJ, Ursin G, Ross RK, Stanczyk FZ, Lobo RA, Harvei S, Jellum E
Department of Community Medicine and General Practice, University Medical Center, Trondheim, Norway.
lars.vatten@medisin.ntnu.no
Cancer Epidemiol Biomarkers Prev 1997 Nov;6(11):967-9

We tested the hypothesis that serum levels of testosterone (T), dihydrotestosterone (DHT), and the DHT metabolite 3 alpha,17 beta-androstanediol glucuronide are positively associated with the risk of prostate cancer. This nested case-control study was based on the cohort of men who donated blood to the Janus serum bank at Oslo University Hospital (Oslo, Norway) between 1973 and 1994. Cancer incidence was ascertained through linkage with the Norwegian Cancer Registry. The study included sera from 59 men who developed prostate cancer (cases) subsequent to blood donation and 180 men who were free of any diagnosed cancer (controls) in 1994 and were of similar age (+/- 1 year) and had similar blood storage time (+/- 6 months) to the cases. Neither T, DHT, nor the ratio T:DHT was associated with risk of developing prostate cancer. Compared to the bottom quartile, the odds ratio (OR) associated with the top quartile of T was 0.83 [95% confidence interval (CI), 0.36-1.93]; the OR for the top (compared to the bottom) quartile of DHT was 0.83 (95% CI, 0.36-1.94), and the equivalent OR for T:DHT was 1.31 (95% CI, 0.58-2.97). Similarly, 3 alpha,17 beta-androstanediol glucuronide showed no association with prostate cancer risk; the OR for the top (compared to the bottom) quartile was 1.10 (95% CI, 0.41-2.90). These results showed no association, positive or negative, between androgens measured in serum and the subsequent risk of developing prostate cancer.

Nomura AM, Stemmermann GN, Chyou PH, Henderson BE, Stanczyk FZ
Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu 96817, USA.
Cancer Epidemiol Biomarkers Prev 1996 Aug;5(8):621-5

It is suspected that male hormones are associated with the risk of prostate cancer. To test this hypothesis, we conducted a nested case-control study in a cohort of 6860 Japanese-American men examined from 1971 to 1975. At the time of examination, a single blood specimen was obtained, and the serum was frozen. After a surveillance period of more than 20 years, 141 tissue-confirmed incident cases of prostate cancer were identified, and their stored sera and those of 141 matched controls were assayed for total testosterone, free testosterone, dihydrotestosterone, 3-alpha-androstanediol glucuronide, androsterone glucuronide, and androstenedione. Odds ratios for prostate cancer, based on quartiles of serum hormone levels, were determined using conditional logistic regression methods. The odds ratios for the highest quartiles were 1.37 (95% confidence interval, 0.73-2.55) for 3-alpha-androstanediol glucuronide and 1.24 (95% confidence interval, 0.62-2.47) for androstenedione, but none of the differences was statistically significant. The results were unremarkable for the other four hormonal measurements. In addition, the patients and controls were compared by hormonal ratios (i.e., total testosterone:dihydrotestosterone), but the results were also unremarkable. The findings of this study indicate that none of these androgens is strongly associated with prostate cancer risk.

Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
J Natl Cancer Inst 1996 Aug 21;88(16):1118-26

BACKGROUND: Sex steroids, particularly androgens, have been implicated in the pathogenesis of prostate cancer. Data from previous studies comparing circulating hormone levels in men with and without prostate cancer are difficult to interpret, since the studies were limited in size, hormone levels were analyzed in blood drawn after the diagnosis of cancer, nonrepresentative control subjects were used, and hormone and hormone-binding protein levels were not simultaneously adjusted.

PURPOSE: We conducted a prospective, nested case-control study to investigate whether plasma hormone and sex hormone-binding globulin (SHBG) levels in healthy men were related to the subsequent development of prostate cancer.

METHODS: Among participants in the Physicians' Health Study who provided plasma samples in 1982, we identified 222 men who developed prostate cancer by March 1992. Three hundred ninety control subjects, matched to the case patients on the bases of age, smoking status, and length of follow-up, were also identified. Immunoassays were used to measure the levels of total testosterone, dihydrotestosterone (DHT), 3 alpha-androstanediol glucuronide (AAG), estradiol, SHBG, and prolactin in the stored (at -82 degrees C) plasma samples. Correlations between individual hormone levels and between hormone levels and SHBG in the plasma of control subjects were assessed by use of Spearman correlation coefficients (r). Odds ratios (ORs) and 95% confidence intervals (CIs) specifying the prostate cancer risk associated with quartile levels of individual hormones, before and after adjustment for other hormones and SHBG, were calculated by use of conditional logistic regression modeling. Reported P values are two-sided.

RESULTS: No clear associations were found between the unadjusted levels of individual hormones or SHBG and the risk of prostate cancer. However, a strong correlation was observed between the levels of testosterone and SHBG (r = .55), and weaker correlations were detected between the levels of testosterone and the levels of both estradiol (r = .28) and DHT (r = .32) (all P < .001). When hormone and SHBG levels were adjusted simultaneously, a strong trend of increasing prostate cancer risk was observed with increasing levels of plasma testosterone (ORs by quartile = 1.00, 1.41, 1.98, and 2.60 [95% CI = 1.34-5.02]; P for trend = .004), an inverse trend in risk was seen with increasing levels of SHBG (ORs by quartile = 1.00, 0.93, 0.61, and 0.46 [95% CI = 0.24-0.89]; P for trend = .01), and a non-linear inverse association was found with increasing levels of estradiol (ORs by quartile = 1.00, 0.53, 0.40, and 0.56 [95% CI = 0.32-0.98]; P for trend = .03). No associations were detected between the levels of DHT or prolactin and prostate cancer risk; for AAG, a marker of 5 alpha-reductase activity, only suggestive evidence of a positive association was found. The results were essentially unchanged when case patients diagnosed within 4 years of plasma collection, case patients diagnosed with localized (i.e., nonaggressive) disease, or control subjects with elevated prostate serum antigen levels (> 2.5 ng/mL) were excluded from the analyses.

CONCLUSIONS: High levels of circulating testosterone and low levels of SHBG-both within normal endogenous ranges-are associated with increased risks of prostate cancer. Low levels of circulating estradiol may represent an additional risk factor. Circulating levels of DHT and AAG do not appear to be strongly related to prostate cancer risk.

Meikle AW, Smith JA, Stringham JD
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City 84132.
J Steroid Biochem 1989 Jul;33(1):19-24

We recently observed a familial influence on the plasma concentration of sex-steroids and the metabolic clearance in men with prostatic cancer. We have now determined, by isotope dilution techniques, the blood estradiol and testosterone production and clearance rates in men with prostatic cancer and in unrelated controls. Thirty-eight men had a diagnosis of prostatic cancer before the age of 63, and 22 controls matched for age were randomly selected from the general population. None of the patients or controls had received endocrine therapy. The plasma content of testosterone, dihydrotestosterone, estrone, estradiol, 3 alpha-androstanediol glucuronide, dehydroepiandrosterone sulfate, sex-hormone binding globulin, apparent free testosterone concentration, follicle stimulating hormone and luteinizing hormone were not significantly different between the groups. The metabolic clearance and production rates of testosterone were significantly (P = 0.008 and P = 0.013, respectively) higher in patients [447 +/- 26 L/day/body surface area(m2) and 2.21 +/- 0.17 mg/day/m2, n = 38] than in controls [346 +/- 20 L/day/m2 and 1.70 +/- 0.11 mg/day/m2, n = 22]. The PR and MCR of estradiol were not significantly different between patients with prostatic cancer (n = 19) and controls (n = 12). These results indicate that men with prostatic cancer have elevated clearance and production rates of testosterone without an alteration of estradiol production or clearance.

Demark-Wahnefried W, Lesko SM, Conaway MR, Robertson CN, Clark RV, Lobaugh B, Mathias BJ, Strigo TS, Paulson DF
Division of Urology, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Androl 1997 Sep-Oct;18(5):495-500

Cancer of the prostate is the leading cancer among American men, yet few risk factors have been established. Hair growth and development are influenced by androgens, and it has long been suspected that prostate cancer also is responsive to these hormones. A blinded, case-control study was undertaken to determine if hair patterning is associated with risk of prostate cancer, as well as specific hormonal profiles. The study accrued 315 male subjects who were stratified with regard to age, race, and case-control status (159 prostate cancer cases/156 controls). Hair-patterning classification and serum levels of total and free testosterone (T), sex hormone binding globulin, and dihydrotestosterone (DHT) were performed. Data indicate that hair patterning did not differ between prostate cancer cases and controls; however, significant hormonal differences were detected between the two groups. Free T was greater among cases than in controls (16.4 +/- 6.1 vs. 14.9 +/- 4.8 pg/ml, P = 0.02). Conversely, DHT-related ratios were greater among controls (P = 0.03 for DHT/T and P = 0.01 for DHT/free T). Several strong associations also were found between hormone levels and hair patterning. Men with vertex and frontal baldness had higher levels of free T (16.5 +/- 5.5 and 16.2 +/- 8.0 pg/ml, respectively) when compared to men with either little or no hair loss (14.8 +/- 4.7 pg/ml) (P = 0.01). Data suggest that increased levels of free T may be a risk factor for prostatic carcinoma. In addition, although no differences in hair patterning were detected between cases and controls within this older population, further research (i.e., prospective trials or case-control studies among younger men) may be necessary to determine if hair patterning serves as a viable biomarker for this disease, especially given the strong association between free T levels and baldness.

Curran MJ, Bihrle W 3rd
Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts 01805, USA.
Urology 1999 Feb;53(2):423-4

We present the case of a hypogonadal patient in whom a 20-fold increase in prostate-specific antigen and a palpable prostatic nodule developed 6 months into the administration of intramuscular testosterone.

Smith Kline Beecham

U.S. Prescribing Information 1997

Alexander GM, Swerdloff RS, Wang C, Davidson T, McDonald V, Steiner B, Hines M
Department of Psychology, University of New Orleans, Louisiana 70148, USA.
gmaps@uno.edu
Horm Behav 1998 Apr;33(2):85-94

Sex-typed cognitive abilities were assessed in 33 hypogonadal men receiving testosterone replacement therapy, 10 eugonadal men receiving testosterone in a male contraceptive clinical trial, and 19 eugonadal men not administered testosterone. Prior to and following hormone administration, men completed four tests measuring visuospatial ability, three tests measuring verbal fluency, two tests measuring perceptual speed, and a measure of verbal memory. Group differences in testosterone levels were unrelated to performance on most cognitive measures, including visuospatial ability. Relative to other men, hypogonadal men were impaired in their verbal fluency and showed improved verbal fluency following treatment with testosterone. These data suggest that testosterone may enhance verbal fluency in hypogonadal men and support the general hypothesis that current levels of testosterone may influence some aspects of cognitive function.

Jeppesen LL; Jorgensen HS; Nakayama H; Raaschou HO; Olsen TS; Winther K
Department of Clinical Chemistry, Glostrup Hospital, Copenhagen, Denmark.
Arterioscler Thromb Vasc Biol (United States) Jun 1996, 16 (6) p749-54

Serum levels of total and free testosterone and 17 beta-estradiol were determined in 144 men with acute ischemic stroke and 47 healthy male control subjects. Blood samples from patients were drawn a mean of 3 days after stroke onset and also 6 months after admission in a subgroup of 45 patients. Initial stroke severity was assessed on the Scandinavian Stroke Scale and infarct size by computed tomographic scan. Mean total serum testosterone was 13.8 +/- 0.5 nmol/L in stroke patients and 16.5 +/- 0.7 nmol/L in control subjects (P = .002); the respective values for free serum testosterone were 40.8 +/- 1.3 and 51.0 +/- 2.2 pmol/L (P = .0001). Both total and free testosterone were significantly inversely associated with stroke severity and 6-month mortality, and total testosterone was significantly inversely associated with infarct size. The differences in total and free testosterone levels between patients and control subjects could not be explained by 10 putative risk factors for stroke , including age, blood pressure, diabetes, ischemic heart disease, smoking, and atrial fibrillation. Total and free testosterone levels tended to normalize 6 months after the stroke . There was no difference between patients and control subjects in serum 17 beta-estradiol levels. These results support the idea that testosterone affects the pathogenesis of ischemic stroke in men.

Abbasi A; Mattson DE; Cuisinier M; Schultz S; Rudman I; Drinka P; Rudman D
Department of Medicine, Medical College of Wisconsin, Milwaukee.
Arch Phys Med Rehabil (United States) May 1994, 75 (5) p594-9

The purpose of this study was to determine the prevalence of low serum insulin-like growth factor-I (IGF-I) and testosterone in men with poststroke hemiplegia. Serum concentrations of IGF-I, total testosterone , and free testosterone were compared in healthy young men, healthy old men, and old men with poststroke hemiplegia. A low IGF-I level, below the lower 2.5 percentile of the healthy young men, occurred in 85% of the healthy old men, and in 88% of the poststroke hemiplegic patients. When a low IGF-I was defined as a value below the lower 2.5 percentile of the healthy old men, the prevalence in the hemiplegic men was 5%. For total testosterone , a value below the lower 2.5 percentile in the healthy young men occurred in 78% of the healthy old men and in 79% of the stroke survivors. Low total testosterone , defined as a value below the lower 2.5 percentile of the healthy old men, occurred in 17% of the hemiplegic men. The results with free testosterone were similar. Compared with healthy young men, most healthy old men have low serum IGF-I and testosterone levels. Old hemiplegic men resemble healthy old men in their IGF-I levels, but they have more cases of severe hypogonadism (total tostosterone < 193ng/dL). Because correction of IGF-I and testosterone deficiencies in younger adults improves muscle strength, work capacity, and quality of life, treatment with human growth hormone and testosterone may be a useful adjunct to physical measures in the rehabilitation of selected hemiplegic stroke survivors.

Elwan O; Abdallah M; Issa I; Taher Y; el-Tamawy M
Neurology Department, Cairo University, Egypt.
J Neurol Sci (Netherlands) Sep 1990, 98 (2-3) p235-43

Fifty-one patients with CCT verified cerebral infarction were submitted to serum and CSF radioimmunoassay of FSH, LH, estradiol (E2), progesterone, testosterone , cortisol and T4. The results were compared to those of 82 matched controls. Our findings suggest that (1) high serum E2 is a risk factor of stroke in males; (2) low serum T4 is a risk factor in males; (3) serum testosterone is reduced in acute stroke in males confirming that it is stress sensitive; (4) serum LH was higher in hypertensive thrombotic males when compared to normotensive ones, and (5) FSH, LH, E2 and T4 are undetectable in CSF of patients and controls.

Dash RJ; Sethi BK; Nalini K; Singh S
Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Funct Neurol (Italy) Jan-Mar 1991, 6 (1) p29-34

Serum LH, FSH and testosterone were quantitated in 9 patients with pure motor stroke within 24-48 h of its reported onset. High circulating LH with normal or low testosterone was noted in 8 of them. In response to an intravenous bolus of GnRH, the LH responses were exaggerated in all, but the FSH responses in 7 of them were comparable to those in eugonadal age matched controls. The rise in testosterone following 2000U hCG daily for 3 consecutive days was insignificant in the patients group compared to the controls. The data suggest normally operative pituitary testicular feed-back but decreased Leydig cell response in pure motor stroke .

Ishikawa S, Soloway MS, Van der Zwaag R, Todd B
Department of Urology, University of Tennessee, Memphis.
J Urol 1989 May;141(5):1139-42

We analyzed 110 patients with metastatic prostate cancer (stage D2) to determine the associations between interval until progression and the pretreatment testosterone level, extent of bone metastases, performance status, race, age and pretreatment level of prostatic acid phosphatase. The median followup was 21 months (4 to 89 months). All patients received androgen deprivation therapy when metastases were identified. This multivariate analysis demonstrated that the pretreatment serum testosterone was the most significant variable (p less than 0.01) associated with interval until progression and the extent of bone metastases observed on the bone scan was the second most important variable (p less than 0.05). Age, race and prostatic acid phosphatase were not significantly correlated with the interval free of progression. Performance status was significantly correlated but it was nonsignificant in the multivariate analysis if the model already included testosterone level and extent of metastasis. Patients with a pretreatment testosterone level of less than 300 ng. per 100 ml. and more than 6 areas of increased uptake on the bone scan had the most rapid progression. We conclude that serum testosterone and extent of bone metastases are the most important of the analyzed factors in terms of interval to progression in patients with protate cancer following androgen deprivation.

Ribeiro M, Ruff P, Falkson G
Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa.
Am J Clin Oncol 1997 Dec;20(6):605-8

Carcinoma of the prostate gland is one of the most common malignancies in males. This study was undertaken to determine which factors predict the course and outcome of patients treated with first line hormonal manipulation. A total of 144 patients with Stage D2 prostate cancer who received androgen deprivation therapy were studied. Pretreatment parameters analyzed were age, performance status, analgesia usage, concurrent disease, histologic differentiation, hemoglobin, leukocyte and platelet count, serum creatinine, alkaline phosphatase, lactate dehydrogenase, prostate specific antigen, total and prostatic acid phosphatase, serum testosterone, follicle stimulating and luteinizing hormone levels, number of metastatic sites and bone scan grade. Only initial serum testosterone (> 10 nmol/l) had a positive impact on response (p = 0.0304), whereas age older than 60 years had a positive impact on time to progression (16 vs. 11 months, p = 0.0414). Both serum testosterone (26 vs. 20 months, p = 0.003), and age (28 vs. 17 months, p = 0.036) had a significant influence on overall survival. Low testosterone, indicating androgen independence, and a younger age, seem to result in a more aggressive disease and a poorer prognosis in advanced prostate cancer.

Soloway MS, Ishikawa S, van der Zwaag R, Todd B
Department of Urology, University of Tennessee, Memphis.
Urology 1989 May;33(5 Suppl):53-6

One hundred ten patients with metastatic prostate cancer (Stage D2) were analyzed to determine the associations among time until progression and the pretreatment testosterone level, extent of bone metastases as indicated by a semiquantitative grading scale for extent of disease, performance status, race, age, and the pretreatment level of prostatic acid phosphatase (PAP). The median follow-up period was twenty-one months, with a range of four to eighty-nine months. All patients received androgen deprivation at the time metastases were identified. A multivariate analysis demonstrated that pretreatment serum testosterone was the most significant variable associated with time until progression (P less than 0.01) and that the extent of bone metastases observed on the bone scan was the second most important variable (P less than 0.05). The following factors did not significantly correlate with progression-free intervals: age, race, and PAP. The performance status was significantly correlated, but was nonsignificant in the multivariate analysis when the model already included the testosterone level and the extent of bone metastases. Patients with a pretreatment testosterone level of less than 300 ng/dL and with more than six areas of increased uptake on the bone scan progressed more rapidly.

Iversen P, Rasmussen F, Christensen IJ
Department of Urology, Rigshospitalet, University of Copenhagen, Denmark.
Scand J Urol Nephrol Suppl 1994;157:41-7

In 245 patients with previously untreated advanced carcinoma of the prostate, serum concentrations of testosterone have been measured before androgen deprivation therapy, and patients were divided in quartiles according to their serum concentration. Pretreatment level of serum testosterone was confirmed as having significant prognostic value on progression-free, overall, and cancer-specific survival, and the hazard ratios of lower quartiles compared to the upper quartile for these endpoints were 2.3, 2.1, and 2.0, respectively. However, correlations with symptomatology and other pretreatment parameters suggest that low serum testosterone merely is a consequence of the advanced malignancy rather than a causative factor in the pathogenesis of prostatic cancer.

Wilson DW, Harper ME, Jensen HM, Ikeda RM, Richards G, Peeling WB, Pierrepoint CG, Griffiths K
Prostate 1985;7(2):131-41

Patients with histologically proven carcinoma of the prostate (n = 186) were initially assessed and followed up according to the standardized protocol of the British Prostate Study Group, urologists from which contributed patients to this investigation. These patients were given either endocrine therapy or orchidectomy as first line treatment; the ratio of the number of patients receiving these two treatments was similar in each group of subjects compared for survival. Prognostic indices were derived for all patients and for those classified according to the presence (M1) or absence (M0) of metastases. The prognostic indices were derived from clinical and hormone data obtained at initial presentation. Whereas the degree of tumor differentiation and plasma testosterone concentrations were significant prognostic factors in both M0 and M1 disease, growth hormone was only significant in M1 patients, where age was also of borderline significance; elevated growth hormone, higher Gleason grade, younger age, and lower testosterone indicated a poorer prognosis in M1 patients. These findings indicated the feasibility of selecting a poor prognostic group of patients that may derive benefit from a more aggressive therapy.

Soloway MS
Department of Urology, University of Tennessee, Memphis.
Cancer 1990 Sep 1;66(5 Suppl):1017-21

Three factors were identified in a multivariate analysis of prognostic factors in men with metastatic prostate cancer as significantly associated with their progression-free survival: 1) extent of disease on the bone scan, 2) pretreatment serum testosterone, and 3) performance status. Men with less than six bone metastases, a pretreatment testosterone greater than 300 ng/100 ml, and an excellent performance status will have a progression-free survival much longer than a man with more extensive bone metastases, a low testosterone prior to androgen deprivation, and a poor performance status. This information should be used to ensure proper stratification in randomized trials. It may also be helpful in identifying the patient unlikely to be helped by our current treatment. Such patients should be considered for alternative approaches with the aim of improving survival.

Haffner SM
Horm Res 1996;45(3-5):233-7

Possible data complicating sex hormones, especially testosterone, in the etiology of cardiovascular disease and noninsulin-dependent diabetes mellitus (NIDDM) comes from the much higher rates of cardiovascular disease in men than in women. Pharmacological administration of anabolic steroids to both men and women increases glucose and insulin concentrations and also insulin resistance. In vivo assessment of sex hormones and binding proteins in both premenopausal and postmenopausal women has suggested that increased free testosterone and decreased sex hormone-binding globulin (SHBG) is associated with higher glucose and insulin concentrations. In a few studies, increased insulin resistance has been associated with decreased SHBG levels. Some data suggests that visceral fat mediated the associates of sex hormones with insulin in women. Little prospective data is available on the association of sex hormones to the development of NIDDM in women but in two studies, low SHBG concentrations predicted NIDDM in Gothenburg and San Antonio. Recently, attention has focused on the role of sex hormones in relation to insulin in men. Surprisingly, higher levels of testosterone have been associated with improved cardiovascular risk factors (such as high-density lipoprotein cholesterol) and lower glucose and insulin levels. Total testosterone and SHBG have been associated with defects in nonoxidative glucose disposal and upper body adiposity in normoglycemic Finnish men. The latter observation is of interest since specific defects in nonoxidative glucose disposal are observed in normoglycemic relatives of subjects with NIDDM. The temporal relationship between sex hormones and insulin has been controversial. The traditional view of sex hormones increasing insulin resistance has been challenged in women by studies showing that insulin stimulates androgen production in the ovary. Recent data [JCEM 1995;80:654-658] suggests that insulin stimulates testosterone production and suppresses SHBG production in normal and obese men. On the other hand, administration of testosterone to centrally obese hypogonadal middle-aged men has improved insulin sensitivity.

Sewdarsen M, Jialal I, Vythilingum S, Desai R
Arteriosclerosis 1986 Jul-Aug;6(4):418-21

The finding of abnormal levels of sex hormones in men with coronary artery disease has led to the hypothesis that alterations in sex hormones may represent an important risk factor for myocardial infarction. In this study, the sex hormone profile of 28 young men (aged less than 40 years) with myocardial infarction was compared with 28 age- and weight-matched normal men. Although the mean total serum estradiol levels and the free estradiol index of the patients and controls were similar, the mean serum total testosterone level and the free testosterone index were significantly lowered in the patients with myocardial infarction (p less than 0.01). The ratio of serum estradiol to testosterone was significantly increased in the patients (p = 0.0005) and correlated with serum cholesterol, triglycerides, and plasma glucose. A significant inverse correlation was also demonstrated between total testosterone and serum cholesterol and triglycerides. Hence, the results of this study support the hypothesis that low plasma testosterone and an increased estradiol-to-testosterone ratio may be important risk factors for myocardial infarction.

Marsh JD; Lehmann MH; Ritchie RH; Gwathmey JK; Green GE; Schiebinger RJ
Department of Medicine, Harper Hospital, Detroit, Mich, USA.
marsh@cardiology.harper.wayne.edu.
Circulation 1998 Jul 21;98(3):256-61

BACKGROUND: The role of androgens in producing cardiac hypertrophy by direct action on cardiac myocytes is uncertain. Accordingly, we tested the hypothesis that cardiac myocytes in adult men and women express an androgen receptor gene and that myocytes respond to androgens by a hypertrophic response.

METHODS AND RESULTS: We used reverse transcription-polymerase chain reaction methods to demonstrate androgen receptor transcripts in multiple tissues and [3H]phenylalanine incorporation and atrial natriuretic peptide secretion as markers of hypertrophy in cultured rat myocytes. Messenger RNA encoding androgen receptors was detected in myocytes of male and female adult rats, neonatal rat myocytes, rat heart, dog heart, and infant and adult human heart. Both testosterone and dihydrotestosterone produced a robust receptor-specific hypertrophic response in myocytes, determined by indices of protein synthesis and atrial natriuretic peptide secretion.

CONCLUSIONS: Androgen receptors are present in cardiac myocytes from multiple species, including normal men and women, in a context that permits androgens to modulate the cardiac phenotype and produce hypertrophy by direct, receptor-specific mechanisms. There are clinical implications for therapeutic or illicit use of androgens in humans.

Alexandersen P; Haarbo J; Christiansen C
Center for Clinical and Basic Research, Ballerup, Denmark.
Atherosclerosis (Ireland) Aug 23 1996 , 125 (1) p1-13

Published studies dealing with the relationship between circulating levels of testosterone and dehydroepiandrosterone (sulfate) (DHEA(S)) and coronary heart disease (CHD) in males, as well as corresponding experimental animal studies are reviewed. One randomized intervention study, eight prospective and 30 cross-sectional studies have evaluated this relationship. In the intervention study, testosterone undecanoate given orally significantly improved angina pectoris in 62 patients with CHD as compared to placebo. No significant association between serum testosterone and CHD was reported in the prospective studies, whereas those studies concerning DHEAS found either no or an inverse association with CHD. Of 30 cross-sectional studies, 18 reported reduced concentrations of testosterone (primarily), and/or DHEA(S) in CHD patients as compared to normals, 11 found similar circulating levels of these androgens in controls and patients with CHD, and one study found elevated levels of DHEA(S) in patients. Animal studies (six male rabbits and one in male chicks) suggest an anti-atherogenic effect of testosterone and DHEA. In conclusion, one intervention, eight cohort and several cross-sectional studies suggest either a neutral or a favourable effect of testosterone and DHEA(S) on CHD in males.

Lumineau S; Guyomarc'h C; Boswell T; Richard JP; Leray D
U.M.R. 6552, Ethologie Evolution Ecologie, Universite de Rennes 1-C.N.R.S., Rennes, France.
J Biol Rhythms (United States) Aug 1998, 13 (4) p278-87

Studies in vertebrates have shown that hormones can influence circadian rhythms of behavior. We investigated whether testosterone could induce rhythmicity in arrhythmic Japanese quail, kept in DD. The animals used were 3 1/2-week-old castrated males from a line of quail selected for the lack of the circadian rhythm of feeding activity. After 3 weeks in DD, 8 birds were implanted with an empty implant and 16 others with a testosterone implant. Two weeks later, the operation was repeated. After implantation, we noticed that 15 out of 16 testosterone -treated birds showed a circadian rhythm of feeding activity, in contrast to the control birds, which remained arrhythmic. The clarity of this rhythm increased significantly after each implantation. A positive correlation was found between the indexes of clarity of the rhythm (autocorrelation coefficient ratio and area of the peak of spectrum) and the plasma testosterone level. The period of the induced free-running rhythm was identical to the specific value of the endogenous circadian rhythm in immature quail. The circadian period showed a significant lengthening with the second implantation. This lengthening looks like the variation previously observed in maturing rhythmic or implanted quail. So, it would appear that testosterone can act on rhythmicity on at least two levels: by inducing the circadian rhythm and increasing its clarity and by modulating its period. To explain these results, several hypotheses can be considered. First, the observed arrhythmy may be the consequence of an internal desynchronization of oscillators, responsible for generating the circadian rhythm of feeding activity, and testosterone could play a role in the coupling of these oscillators. Alternatively, we suggest that testosterone could act on the transcription of genes implicated in the control of the rhythmicity or may regulate by rapid signals the cellular rhythmic activity. The possible functional values of the enhancing of circadian rhythmicity by testosterone at different stages of the bird's life were discussed.

Izbicki J.R.; Wambach G.; Hamilton S.R.; et al.
II Department of Surgery, University of Cologne, D-5000 Koln 91 Germany
Journal of Cancer Research and Clinical Oncology (Germany) 1986, 112/1 (39-46)

Sex hormones may play a role in colonic carcinogenesis, as evidenced by epidemiologic and experimental data showing different tumor rates in males and females. We investigated the effects of hormonal manipulation on tumor development and on androgen receptor binding in both colonic wall and experimentally induced tumors in male rats. Five of six groups, each with 40 animals, were given 10 weekly s.c. injections of azoxymethane (AOM), 7.5 mg/kg body weight. Group-I served as normal controls. Group-II received AOM only. Group-III was castrated 2 weeks prior to carcinogen treatment. Group-IV was castrated similarly and then hormone substituted with testosterone propionate. Group-V was chemically castrated with the anti androgen cyproterone acetate. Group-VI was castrated and given hormone vehicle. Scatchard analysis for androgen receptors in cytosol from normal colonic wall and tumor was performed with sup 3H-methyltrienolone as the ligand. Androgens were found to have an inhibitory effect on carcinogenesis: chemical castration increased colonic tumor development (P < 0.05 for multiplicity), and testosterone administration produced a borderline statistically significant reduction in tumor incidence in surgically castrated rats (P < 0.053), particularly in the right colon. Specific binding sites for androgen with high affinity and low capacity were found in the colonic wall of all groups. Receptor density was not altered by AOM administration, but increased after surgical castration. Receptor density was markedly lower in tumors than in normal colonic wall. Receptor binding sites in tumors were not altered by the various hormonal manipulations. Our study demonstrated that although cytoplasmic androgen receptors are present in colonic wall and in experimental tumors, AOM-induced colonic carcinogenesis appears to be only mildly affected by manipulation of androgens.

Izbicki JR, Hamilton SR, Wambach G, Harnisch E, Wilker DK, Dornschneider G, Eibl-Eibesfeldt B, Schweiberer L
Dept of Surgery, University of Munich, FR Germany.
Circulation 1998 Jul 21;98(3):256-61

Epidemiological and experimental studies suggest that androgens influence colonic carcinogenesis. We investigated the effects of hormonal manipulations (surgical and chemical castration, hormone substitution) on colonic tumour development, tumour and mucosal histopathology, and epithelial proliferation in macroscopically normal colonic mucosa in male rats, after induction of chemical colon carcinogenesis by subcutaneous injections of azoxymethane (AOM). Chemical castration with cyproterone acetate, but not surgical castration, resulted in increased colonic tumorigenesis, which was accompanied by decreased crypt length, decreased number of cells per crypt, and increased crypt epithelial mitotic index in the right colon. Chemically castrated rats also had crypt hyperplasia and increased numbers of dysplastic foci in the left colon which were not seen with surgical castration. By contrast, rats given testosterone after surgical castration showed decreased colonic tumorigenesis with an increased proportion of tumours in the left colon and lower percentage of tumours with invasion. The grossly normal mucosa of the testosterone-substituted castrated rats showed decreased crypt length in the right colon similar to the other groups of castrated rats, but no significant increase in mitotic index. Our results suggest that the anti-androgenic progestin cyproterone is a potent enhancer of colonic tumorigenesis and epithelial proliferative abnormalities after AOM administration. Exogenous testosterone after castration alters tumour distribution and characteristics and suppresses epithelial proliferative abnormalities. Finally, androgen effects on the colonic mucosa are more prominent in the right than in the left colon, suggesting different influences of hormones on the epithelium of these anatomical sites.

Marin P, Arver S
Department of Heart and Lung Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden.
Baillieres Clin Endocrinol Metab 1998 Oct;12(3):441-51

Central or visceral obesity is recognized as a main risk factor for cardiovascular disease and type 2 diabetes mellitus. The co-existence of visceral obesity, increased blood lipid levels, hypertension and impaired glucose tolerance defines the metabolic syndrome that today is widely recognized as one of the prime factors behind cardiovascular morbidity and mortality. Endocrine disorders such as insulinoma, hypothyroidism and hypercortisolism are known to cause obesity. However, it is only hypercortisolism that is associated with increased abdominal fat accumulation. Recently, new findings have shed light on subtle endocrinopathies that are prevalent in individuals presenting with the metabolic syndrome. Such derangements are of borderline character and often fall within the normal reference range. Intervention studies demonstrate that correction of relative hypogonadism in men with visceral obesity and other manifestations of the metabolic syndrome seem to decrease the abdominal fat mass and reverse the glucose intolerance, as well as lipoprotein abnormalities in the serum. Further analysis of the underlying mechanism has also disclosed a regulatory role for testosterone in counteracting visceral fat accumulation. Longitudinal epidemiological data demonstrates that relatively low testosterone levels are a risk factor for development of visceral obesity. The primary event that triggers the initial development of visceral obesity is not known, but it seems plausible that increased activity in the hypothalamus-pituitary-adrenal axis can be of major importance.

Schneider G; Kirschner M A; Berkowitz R; Ertel N H
Veterans Adm. Hosp., East Orange, N.J. 07019, USA.
J Clin Endocrinol Metab 48 (4). 1979. 633-638.

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

Khaw KT; Barrett-Connor E
Department of Clinical Gerontology, University of Cambridge, School of Clinical Medicine, United Kingdom.
Ann Epidemiol (United States) Sep 1992, 2 (5) p675-82,

Central adiposity, sometimes described as male pattern fat distribution, is adversely related to cardiovascular risk and mortality independent of other measures of obesity. In a cohort of 511 men aged 30 to 79 years in 1972 to 1974, levels of androstenedione, testosterone , and sex hormone-binding globulin measured at baseline were inversely related to subsequent central adiposity, estimated 12 years later using the waist-hip circumference ratio. The observed differences in waist-hip ratio between top and bottom tertiles of these hormones and sex hormone-binding globulin were similar to mean waist-hip ratio differences between men with stroke or ischemic heart disease and those without in another prospective study. These findings, consistent with studies suggesting that testosterone seems to mobilize the abdominal depot on males, suggest that "male pattern" fat distribution may be a misleading description for central adiposity, at least, in men. Degree of maleness as indicated by total androgen levels is, in fact, negatively associated with central adiposity. However, the role of sex hormone-binding globulin in regulating androgenic activity warrants further investigation.

Kley HK, Deselaers T, Peerenboom H, Kruskemper HL
J Clin Endocrinol Metab 1980 Nov;51(5):1128-32

In normal and obese young males [90--120% and > 160% of ideal body weight (IBW); IBW = 100%], plasma concentrations of testosterone, androstenedione, estrone, and estradiol were measured. Metabolic clearance and production rates of androstenedione and the conversion ratios of androstenedione to testosterone, estrone, and estradiol were determined using the constant infusion technique. In the obese subjects, IBW was inversely correlated (P < 0.001) with plasma concentrations of androstenedione (r = 0.81) and testosterone (r = 0.87), while the levels of estrone (r = 0.92) and estradiol (r = 0.95) increased with IBW (P < 0.001). Thus, when normal and obese subjects were compared as groups, plasma androstenedione decreased form 1.24 +/- 0.13 to 0.93 +/- 0.15 ng/ml (mean +/- SD) and plasma testosterone decreased from 5.89 +/- 0.82 to 3.29 +/- 0.92 ng/ml (P < 0.001), while estrone increased from 28.2 +/- 3.4 to 60.0 +/- 9.4 pg/ml, and estradiol increased from 21.7 +/- 3.5 to 43.9 +/- 5.3 pg/ml. The testosterone to androstenedione and the estradiol to estrone ratios were not different in obesity, but changes in IBW were positively correlated (P < 0.001) with differences in the estrone to androstenedione (r = 0.93) and estradiol to testosterone ratios (r = 0.93), indicating that fat tissue may aromatize androgens, whereas reduction of 17-oxo-steroid appears to be of minor importance. As the MCR of androstenedione increased with IBW (from 2156 to 2636 liters/day P < 0.05) while plasma levels decreased, the apparent production rate of androstenedione was not influenced by the degree of obesity. The conversion of androstenedione to estrone (r = 0.89) and of androstenedione to estradiol (r = 0.82) was enhanced in obese subjects (P < 0.001). We suggest that enhanced aromatization of androstenedione due to an increased adipose tissue mass may account for the high plasma estrogen levels observed in obese men.

Continued on the next page...