Stephen B. Strum
Culver City, & Whittier, California

Over 75% of patients with prostate cancer receiving combination hormonal blockade (CHB) with an LHRH agonist + Eulexin develop a moderate anemia with hematocrits ranging from 30-36%. In patients with underlying heart disease, in physically active patients or in those travelling to areas of high altitude, this anemia may become clinically significant. Hematologic findings in these patients are those of a normochromic and normocytic anemia that are not related to bone metastases nor to renal insufficiency. The anemia is temporally related to the administration of CHB and is apparent 3 months after the start of CHB and disappears within 2 to 3 months after the termination of CHB. In a pilot study, Epogen was administered at a dose of 4000 units sq 3 times per week. Within 2 months hematocrits returned to normal. Most patients were titrated down to doses of 2000 units sq twice each week while maintaining hematocrits slightly lower, in the 38-40% range. In those patients in whom the Epogen was stopped, the hematocrits dropped to pretreatment values(30-36%) within 2 months. No patients had evidence of phlebitis or thrombosis after starting Epogen. We conclude that the anemia of androgen deprivation is: 1] a common finding in patients receiving CHB & 2] highly responsive to low dose erythropoietin. Studies have begun to evaluate erythropoietin levels obtained prior to CHB, during CHB and during CHB + exogenous erythropoietin.

Strum SB; McDermed JE; Scholz MC; Johnson H; Tisman G
Daniel Freeman Marina Medical Centre, Marina del Rey, California, USA.
Br J Urol (ENGLAND) Jun 1997 , 79 (6) p933-41

OBJECTIVE: To describe the incidence, time to onset and extent of anaemia occurring in patients with prostate cancer receiving combined hormone blockade (CHB) and the timing and extent of recovery from anaemia in those patients where CHB was discontinued.

PATIENTS AND METHODS: Patients with prostate cancer were evaluated prospectively by physical examination and laboratory tests at baseline and at routine intervals while receiving CHB. Of 142 patients who received CHB, 133 were evaluable for the assessment of anaemia; CHB was discontinued in 76 patients, of whom 64 were assessable for recovery from their anaemia.

RESULTS: Haemoglobin levels declined significantly in all patients from a mean baseline of 149 g/L to means of 139 g/L, 132 g/L and 131 g/L at 1, 2 and 3 months, respectively. Haemoglobin levels continued to decline during CHB to a mean nadir of 123 g/L at a mean of 5.6 months of CHB, representing a mean absolute haemoglobin decline at nadir of 25.4 g/L. In 120 of the 133 (90%) patients, the relative decline in haemoglobin at nadir was > or = 10% and was > or = 25% in 17 (13%) others, representing a mean absolute haemoglobin decline in this subset of 42.7 g/L. Significant symptoms related to anaemia occurred in 17 patients (13%). Anaemia and symptoms in these patients were easily corrected with the subcutaneous administration of recombinant human erythropoietin.

CONCLUSIONS: The anaemia associated with androgen deprivation is significant and occurs routinely in men receiving CHB. It is normochromic, normocytic, temporally-related to the initiation of androgen blockade and usually resolves after CHB is discontinued. We suggest that patients receiving CHB undergo haematological testing at baseline, 1-2 months after initiating CHB and periodically thereafter. Patients developing anaemia should be questioned about symptoms reflecting physiological compromise (e.g. angina , dyspnoea on exertion). In the absence of other causes, CHB should be suspected in the development of anaemia in patients receiving this treatment.

[Article in Polish]
Rabijewski M, Adamkiewicz M, Zgliczynski S
Klinika Endokrynologii Centrum Medycznego Ksztalcenia Podyplomowego, Szpital Bielanski.
Pol Arch Med Wewn 1998 Sep;100(3):212-21

The aim of this study was to determine the influence of testosterone replacement therapy in elderly men on mood, bone mineral density, and lipids. We investigated thirty men (mean +/- SD; age 61.1 +/- 5.6 yr) with testosterone concentrations (mean +/- SEM) 2.1 +/- 0.2 ng/ml. Testosterone deficiency was replacement by intramuscular injections of testosterone enanthate 200 mg every second week from 1.5 to 6 yr. (mean +/- SD; 3.35 +/- 1.6 yr.). During the treatment serum testosterone increased reaching normal levels (mean +/- SEM; 6.6 +/- 0.2 ng/ml). This was associated with significant increase in positive mood parameters and a decrease in negative mood parameters. Also self assessment of libido, potence and dream were improved. Bone mineral density (BMD) of lumbar spine increased. We noticed significant decrease in total cholesterol, and LDL-cholesterol. Hematocrit was increased. Prostate-specific antigen concentration statistically increased from 0.65 +/- 0.1 to 1.35 +/- 0.1 ng/ml (mean +/- SEM), but in the cases of its levels were in normal range. Patients with coronary heart disease demonstrated decreasing symptoms of angina pectoris and nitrate requirement. In summary, long-term testosterone replacement therapy in elderly men may have beneficial effects on well-being, libido, potence, dream, bone mineral density, lipids, blood cell count and body mass (BMI). This therapy appears to be safe and there is no adverse effection on prostate.

Seidman SN, Walsh BT
Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Am J Geriatr Psychiatry 1999 Winter;7(1):18-33

In men, testosterone secretion affects neurobehavioral functions such as sexual arousal, aggression, emotional tone, and cognition. Beginning at approximately age 50, men secrete progressively lower amounts of testosterone; about 20% of men over age 60 have lower-than-normal levels. The psychiatric sequelae are poorly understood, yet there is evidence of an association with depressive symptoms. The authors reviewed 1) the physiology of the hypothalamic-pituitary-gonadal axis and its changes with age in men; and 2) the evidence linking testosterone level and major depression in men. Data on this relationship are derived from two types of studies: observational studies comparing testosterone levels and secretory patterns in depressed and non-depressed men, and treatment studies using exogenous androgens for male depression. The data suggest that some depressed older men may have state-dependent low testosterone levels and that some depressed men may improve with androgen treatment.

Barrett-Connor E, Von Muhlen DG, Kritz-Silverstein D
Department of Family and Preventive Medicine, School of Medicine, University of California, San Diego, La Jolla 92093-0607, USA.
J Clin Endocrinol Metab 1999 Feb;84(2):573-7

A cross-sectional population-based study examined the association between endogenous sex hormones and depressed mood in community-dwelling older men. Participants included 856 men, ages 50-89 yr, who attended a clinic visit between 1984-87. Total and bioavailable testosterone, total and bioavailable estradiol, and dihydrotestosterone levels were measured by radioimmunoassay in an endocrinology research laboratory. Depressed mood was assessed with the Beck Depression Inventory (BDI). Levels of bioavailable testosterone and bioavailable estradiol decreased with age, but total testosterone, dihydrotestosterone, and total estradiol did not. BDI scores increased with age. Low bioavailable testosterone levels and high BDI scores were associated with weight loss and lack of physical activity, but not with cigarette smoking or alcohol intake. By linear regression or quartile analysis the BDI score was significantly and inversely associated with bioavailable testosterone (both Ps = 0.007), independent of age, weight change, and physical activity; similar associations were seen for dihydrotestosterone (P = 0.048 and P = 0.09, respectively). Bioavailable testosterone levels were 17% lower for the 25 men with categorically defined depression than levels observed in all other men (P = 0.01). Neither total nor bioavailable estradiol was associated with depressed mood. These results suggest that testosterone treatment might improve depressed mood in older men who have low levels of bioavailable testosterone. A clinical trial is necessary to test this hypothesis.

Schweiger U, Deuschle M, Weber B, Korner A, Lammers CH, Schmider J, Gotthardt U, Heuser I
Max-Planck-Institute of Psychiatry, Clinical Institute, Munich, Germany.
schweiger.u@psychiatry.mu-Luebeck.de
Psychosom Med 1999 May-Jun;61(3):292-6

OBJECTIVE: Previous studies of sex hormone concentrations in depression yielded inconsistent results. However, the activation of the hypothalamic-pituitary-adrenal system seen in depression may negatively affect gonadal function at every level of regulation. The objective of this study was to explore whether major depressive episodes are indeed associated with an alteration of gonadal function. METHODS: Testosterone, pulsatile LH secretion, FSH, and cortisol were assessed using frequent sampling during a 24-hour period in 15 male inpatients with major depression of moderate to high severity and in 22 healthy comparison subjects (age range 22-85 years).

RESULTS: An analysis of covariance model showed that after adjustment for age only, daytime testosterone (p < .01), nighttime testosterone (p < .05), and 24-hour mean testosterone secretion (p < .01) were significantly lower in the depressed male inpatients. There was also a trend for a decreased LH pulse frequency in the depressed patients (p < .08).

CONCLUSIONS: Gonadal function may be disturbed in men with a depressive episode of moderate to high severity.

Rabkin JG; Wagner GJ; Rabkin R
New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York 10032, USA.
jgr1@columbia.edu
J Clin Psychopharmacol (UNITED STATES) Feb 1999, 19 (1) p19-27

This study was designed to evaluate the safety and effectiveness of testosterone therapy for clinical symptoms of hypogonadism (low libido, low mood, low energy, loss of appetite/weight) in human immunodeficiency virus-positive men with CD4 cell counts less than 400 cells/mm3 and deficient or low normal serum testosterone levels. The trial consisted of 8 weeks of open treatment with 400 mg of intramuscular testosterone cypionate biweekly. Responders were maintained at this dosage for another 4 weeks and then were randomized in a double-blind, placebo-controlled, 6-week discontinuation trial. Of the 112 men who completed at least 8 weeks of treatment, 102 (91%) were rated as responders on a global assessment of sexual desire/function. Of the 34 study completers with major depressive disorder and/or dysthymia, 79% reported significant improvement in mood at week 8. Average weight change was a gain of 3.7 pounds, with 45% gaining more than 5 pounds. Eighty-four men entered and 77 completed the double-blind phase; of these, 78% of completers randomized to testosterone and 13% randomized to placebo maintained their response. No significant medical or immunologic adverse effects were identified. Testosterone therapy was well tolerated and effective in ameliorating symptoms of clinical hypogonadism, and equally so for men with and without testosterone deficiency. For patients with major depression and/or dysthymia, improvement was equal to that achieved with standard antidepressants.

Mooradian AD, Morley JE, Korenman SG
Endocr Rev 1987 Feb;8(1):1-28

Though unnecessary for life itself, androgens are essential for the propagation of the species and for establishment and maintenance of the quality of life of males through their support of sexual behavior and function, muscle strength, and sense of well-being. In carrying out its many functions, T acts both as hormone and prohormone. It is an outstanding example of the diverse evolutionary utilization of a primitive informational molecule both among and within species. Not only does T act through the androgen receptor both unchanged and via 5 alpha-reduction, but it acts in tissues with a high aromatase level as an estrogen via the estrogen receptor. Furthermore, DHT, binding to the estrogen receptor, can act as an inhibitor of estrogen action. The products of androgen metabolism may also play active regulatory roles in hematopoiesis and in the regulation of certain hepatic enzymes. Table 3 summarizes the actions of secreted T in males indicating the probable effector hormone. While gross hypogonadism is uncommon, mild androgen insufficiency may be much more frequent, especially in older men, and in those receiving treatment for chronic medical conditions. It is quite possible that such individuals would benefit from appropriate androgen therapy were it available, but the current forms of replacement therapy are not very satisfactory. Better approaches are required. With the exception of a small number of secreted proteins, the products of transcription induced by androgens are not, as yet, known. When the androgen receptor gene is cloned it will be possible to identify androgen-regulated genes and their products. It will then be possible to design agents selectively producing specific desired androgenic effects.

Anderson RA, Bancroft J, Wu FC
Medical Research Council Reproductive Biology Unit, Centre for Reproductive Biology, Edinburgh, Scotland.
J Clin Endocrinol Metab 1992 Dec;75(6):1503-7

The effects of supraphysiological levels of testosterone, used for male contraception, on sexual behavior and mood were studied in a single-blind, placebo-controlled manner in a group of 31 normal men. After 4 weeks of baseline observations, the men were randomized into two groups: one group received 200 mg testosterone enanthate (TE) weekly by im injection for 8 weeks (Testosterone Only group), the other received placebo injections once weekly for the first 4 weeks followed by TE 200 mg weekly for the following 4 weeks (Placebo/Testosterone group). The testosterone administration increased trough plasma testosterone levels by 80%, compatible with peak testosterone levels 400-500% above baseline. Various aspects of sexuality were assessed using sexuality experience scales (SES) questionnaires at the end of each 4-week period while sexual activity and mood states were recorded by daily dairies and self-rating scales. In both groups there was a significant increase in scores in the Psychosexual Stimulation Scale of the SES (i.e. SES 2) following testosterone administration, but not with placebo. There were no changes in SES 3, which measures aspects of sexual interaction with the partner. In both groups there were no changes in frequency of sexual intercourse, masturbation, or penile erection on waking nor in any of the moods reported. The Placebo/Testosterone group showed an increase in self-reported interest in sex during testosterone treatment but not with placebo. The SES 2 results suggest that sexual awareness and arousability can be increased by supraphysiological levels of testosterone. However, these changes are not reflected in modifications of overt sexual behavior, which in eugonadal men may be more determined by sexual relationship factors. This contrasts with hypogonadal men, in whom testosterone replacement clearly stimulates sexual behavior. There was no evidence to suggest an alteration in any of the mood states studied, in particular those associated with increased aggression. We conclude that supraphysiological levels of testosterone maintained for up to 2 months can promote some aspects of sexual arousability without stimulating sexual activity in eugonadal men within stable heterosexual relationships. Raising testosterone does not increase self-reported ratings of aggressive feelings.

Davidson JM, Kwan M, Greenleaf WJ
Clin Endocrinol Metab 1982 Nov;11(3):599-623

Only in the last few years has the scientific study of hormonal replacement therapy for hyposexuality begun in earnest with the advent of appropriately controlled experiment studies. Dose-response relationships can be demonstrated between testosterone (T) and sexual measures, but these have not yet been investigated in detail. Some aspects of sexual function are maintained in the presence of androgen levels well below the normal range, but preliminary evidence suggests that within a normal population high levels of T are correlated with more vigorous responses to visual erotic stimuli. Though T (and to a greater extent free T) declines with aging in parallel with the decline of sexual function, these hormonal changes contribute only to a minor extent to the behavioural change. Some non-aromatizable androgens may be less effective in stimulating sexual behaviour than T, but initial data on effects of dihydrotestosterone suggests that the capacity of an androgen to be aromatized (converted to oestrogen) is not a requirement for its sexual action. While T apparently increases the incidence of all types of male sexual activity, recent data contradict the belief that it directly facilitates the erectile mechanism in men, even though erection frequency is greatly reduced in untreated hypogonadal men. At the present juncture, it appears that the initial action of T may be on libido factors which lead in turn to the stimulation of other aspects of sexuality. Specifically, we propose that androgen acts through stimulating genital sensations and/or other pleasurable awareness of sexual response rather than directly through cognitive processes such as sexual imagery.

Tenover J.L.
Dr. J.L. Tenover, Wesley Woods Geriatric Hospital, 1821 Clifton Road NE, Atlanta, GA 30329-5102 United States
Endocrinology and Metabolism Clinics of North America (United States) 1998, 27/4 (969-987)

Adult onset male hypogonadism and the testosterone deficiency of the aging male often are under-recognized entities. The etiologies, presentation, and diagnosis of hypogonadism and andropause in the adult male are presented. The expected therapeutic goals, potential treatment risks, and management of androgen replacement therapy for the adult man are reviewed. The advantages and disadvantages of the various androgen delivery systems currently available and under investigation are discussed.

Ahmed SR, Boucher AE, Manni A, Santen RJ, Bartholomew M, Demers LM
Department of Medicine, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033.
J Clin Endocrinol Metab 1988 Mar;66(3):546-51

Five hypogonadal men were treated with transdermal testosterone therapy, using a testosterone patch applied to the scrotal skin. Daily application of the patch, which contained 10 mg testosterone, produced an increase in serum testosterone concentrations from a pretreatment value of 45 +/- 12 (+/- SE; 1.5 +/- 0.4) to 436 +/- 80 ng/dL (15.1 +/- 2.8 nmol/L; P less than 0.001) after 4 weeks of treatment. Normal serum testosterone concentrations were achieved in all men after 6-8 weeks of therapy and were maintained during continued long term therapy for 9-12 months with a patch containing 15 mg testosterone. All men reported a subjective increase in libido and sexual function during therapy, and three men preferred it to testosterone injections. The serum testosterone and estradiol levels did not rise above the normal adult male range at any time during therapy. However, elevated serum dihydrotestosterone (DHT) concentrations occurred during treatment; the pretreatment DHT concentration was 95 +/- 3 ng/dL (3.3 +/- 0.1 nmol/L), and it increased to 228 +/- 40 ng/dL (7.8 +/- 1.4 nmol/L) after 4 weeks of treatment and remained elevated thereafter. The individual mean DHT to testosterone ratio increased from a pretreatment value of 0.2 (range, 0.1-0.3) to 0.6 (range, 0.4-0.7) after 2 weeks of therapy and remained high thereafter. Comparison of the serum DHT levels in patients during therapy with those in normal men who had similar testosterone concentrations [531 +/- 62 vs. 566 +/- 72 ng/dL (18.4 +/- 2.1 vs. 19.6 +/- 2.5 nmol/L); P greater than 0.05] revealed that the mean serum DHT concentration was significantly higher in the patients [315 +/- 69 vs. 87 +/- 6 ng/dL (10.8 +/- 2.4 vs. 2.9 +/- 0.2 nmol/L); P less than 0.001], as was the mean DHT to testosterone ratio [0.6 (range, 0.25- 1.1) vs. 0.16 (range, 0.09- 0.24); P less than 0.001]. The high serum DHT levels presumably were due to increased metabolism of testosterone to DHT by the 5 alpha-reductase in the scrotal skin. Serum 3 alpha-androstanediol glucuronide levels were not elevated in the patients. We conclude that transdermal testosterone therapy is an effective long term treatment for hypogonadism in men. It is, however, associated with high serum DHT levels, whose potential long term effects on the prostate and other tissues need to be investigated.

Phillips GB
Am J Med 1984 Jun;76(6):1041-8

The previous findings of hyperestrogenemia in men with myocardial infarction and of a correlation between the ratio of serum estradiol to testosterone and the glucose-insulin-lipid defect have led to the hypothesis that hyperestrogenemia may be responsible for the increased incidence of atherosclerosis and its complications in patients with diabetes. The hypothesis predicts that the mean serum level of estradiol and the ratio of serum estradiol to testosterone are elevated in patients with diabetes. To test this hypothesis, the serum levels of estradiol and testosterone were measured in 21 nonobese men with diabetes and in 19 apparently healthy men of similar age and weight. A higher mean serum estradiol level (p less than 0.001) and estradiol-to-testosterone ratio (p less than 0.005) were observed in the patients with diabetes, whereas the mean serum testosterone level was not significantly different. The findings are consistent with the hypothesis.

Sewdarsen M, Vythilingum S, Jialal I, Desai RK, Becker P
Department of Medicine, R.K. Khan Hospital, Durban, South Africa.
Atherosclerosis 1990 Aug;83(2-3):111-7

The relation between sex hormone levels and myocardial infarction was studied in a case-control study among 117 Indian men with myocardial infarction aged 30-60 years and in 107 healthy Indian male controls. The patients and controls were further divided into subsets defined by age in decades. In the total patient population, testosterone concentration was significantly lower than in the controls (P less than 0.01), whilst oestradiol (P less than 0.0005) and the oestradiol to testosterone ratio (P less than 0.0005) were significantly higher. Multivariate stepwise logistic regression analyses demonstrated that free testosterone index, the free oestradiol index, and the oestradiol to testosterone ratio were significantly associated with myocardial infarction, and that this association was independent of age, body mass index, smoking and serum lipids. Further analyses according to age subsets revealed that compared to respective control groups, patients in the 4th decade had both significant hypotestosteronaemia and hyperoestrogenaemia, whereas in patients of the 5th decade significant differences in total and in the calculated free oestradiol index were noted, and in the 6th decade a significant difference was detected only in the free oestradiol index. Hence, we conclude that aberrations in endogenous sex hormones are significantly associated with myocardial infarction, and that this association appears to be strongest in young men and diminishes with age, suggesting that these disturbances in sex hormones may be associated with premature manifestation of coronary artery disease.

Phillips GB
Proc Natl Acad Sci U S A 1977 Apr;74(4):1729-33

Fifteen patients who had had a myocardial infarction before the age of 43 were compared with thirteen age-matched normal subjects. Twelve of the patients and three of the controls had a delayed glucose and insulin peak in the glucose and insulin areas than normal curves. When the measurements of the four patients with the largest areas under the glucose tolerance curve were separated, significant correlations were observed in the remaining patients and controls. The ratio in serum of the concentrations of estradiol-17beta to testosterone (E/T) correlated with serum glucose area (r equals + 0.69, P is less than 0.001), insulin area (r equals + 0.80, P is less than 0.001), and the ratio of insulin area to glucose area (I/G) (r equals + 0.64, P is less than 0.005) in the glucose tolerance test. Serum cholesterol concentration correlated with E/T, insulin area, and I/G, and serum triglyceride concentration correlated with glucose area, I/G, and serum cholesterol concentration. The hypothesis is presented (i) that in men who have had a myocardial infarction, an abnormality in glucose tolerance and insulin response and elevation in serum cholesterol and triglyceride concentrations are all part of the same defect (glucose-insulin-lipid defect), (ii) that this glucose-insulin-lipid defect when glucose intolerance is present is the "mild diabetes" commonly associated with myocardial infarction but is based on a mechanism different from that of classical diabetes, (iii) that this glucose-insulin-lipid defect is secondary to an elevation in E/T, and (iv) that an alteration in the sex hormone milieu is the major predisposing factor for myocardial infarction.

Luria MH, Johnson MW, Pego R, Seuc CA, Manubens SJ, Wieland MR, Wieland RG
Arch Intern Med 1982 Jan;142(1):42-4

An alteration in sex hormones has been considered a risk factor for myocardial infarction. In this study, estradiol (E2) and testosterone (T) levels were evaluated in healthy firefighters, patients with myocardial infarction acutely and during their convalescence, patients with no evidence of occlusive coronary artery disease on arteriography, and patients with chronic angina pectoris in whom there was at least one vessel that indicated 50% occlusive coronary artery disease. Although T levels were similar in all groups, E2 levels were substantially higher in patients with myocardial infarction and in patients with chronic angina pectoris. These results support the hypothesis that elevated estrogen levels may be a risk factor for myocardial infarction and coronary artery disease, possibly by promoting clotting or coronary spasm.

Mendoza SG, Zerpa A, Carrasco H, Colmenares O, Rangel A, Gartside PS, Kashyap ML
Artery 1983;12(1):1-23

A series of thirty-three Venezuelan men with premature myocardial infarction (mean age (M +/- SEM) 45 +/- 1.5 yrs) and with greater than 50% occlusion of at least 2 coronary arteries, and 19 weight matched control men (age 44 +/- 2 yrs) with normal coronary arteries on coronary angiography were studied. The percentages of significantly abnormal (greater than +/- 2 S.D. of controls) serum or plasma concentrations of various measurements (in decreasing order) were: estradiol (33%), total apolipoprotein (apo)B (24%), estradiol/testosterone ratio (21%), low density lipoprotein (LDL) apo B (19%), apo AI (17%), apo AI/total plasma apo B ratio (17%), total cholesterol (17%), and LDL-cholesterol (LDL-C) (11%). In addition, a multivariate discriminant function analysis showed that only estradiol, apo AI, LDL-C, estradiol/testosterone ratio and total cholesterol were statistically significant independent markers of myocardial infarction with occlusive coronary disease in these patients. Both serum estradiol and estradiol/testosterone ratio correlated positively with plasma apo B and LDL apo B, and inversely with apo AI; serum testosterone correlated inversely with plasma apo B (p less than 0.05). The data suggest that circulating sex hormones (estrogens, testosterone) are not only independent markers of coronary disease but may be pathogenetically linked to apo B and apo AI metabolism.

Phillips GB, Pinkernell BH, Jing TY
Department of Medicine, Columbia University College of Physicians and Surgeons, St. Luke's-Roosevelt Hospital Center, New York, NY.
Arterioscler Thromb 1994 May;14(5):701-6

Hyperestrogenemia and hypotestosteronemia have been observed in association with myocardial infarction (MI) and its risk factors. To determine whether these abnormalities may be prospective for MI, estradiol and testosterone, as well as risk factors for MI, were measured in 55 men undergoing angiography who had not previously had an MI. Testosterone (r = -.36, P = .008) and free testosterone (r = -.49, P < .001) correlated negatively with the degree of coronary artery disease after controlling for age and body mass index. When the patient group was successively reduced to a final study group of 34 men by excluding the patients with other major disorders, the testosterone and free testosterone correlations persisted (r = -.43, P < .02 and r = -.62, P < .001, respectively). Neither estradiol nor the risk factors, except for high-density lipoprotein cholesterol, correlated with the degree of coronary artery disease in the final group. Testosterone correlated negatively with the risk factors fibrinogen, plasminogen activator inhibitor-1, and insulin and positively with high-density lipoprotein cholesterol. The correlations found in this study between testosterone and the degree of coronary artery disease and between testosterone and other risk factors for MI raise the possibility that in men hypotestosteronemia may be a risk factor for coronary atherosclerosis.

Chou TM, Sudhir K, Hutchison SJ, Ko E, Amidon TM, Collins P, Chatterjee K
Cardiovascular Research Institute, University of California at San Francisco 94143-0124, USA.
chou@cardio.ucsf.edu
Circulation 1996 Nov 15;94(10):2614-9

BACKGROUND: Although estrogens have been shown to be vasoactive hormones, the vascular effects of testosterone are not well defined. Like estrogen, testosterone causes relaxation of isolated rabbit coronary arterial segments. We examined the vasodilator effects of testosterone in vivo in the coronary circulation and the potential mechanisms of its actions.

METHODS AND RESULTS: Using simultaneous intravascular two-dimensional and Doppler ultrasound, we examined the effect of intracoronary testosterone in coronary conductance and resistance arteries in 10 anesthetized dogs (5 male, 5 female). We also assessed the contribution of NO, prostaglandins, ATP-sensitive K+ channels, and classic estrogen receptors to testosterone-induced vasodilation. Testosterone induced a significant increase in cross-sectional area, average coronary peak flow velocity, and calculated volumetric coronary blood flow at the 0.1 and 1 mumol/L concentrations. This effect was independent of sex. Pretreatment with N omega-nitro-L-arginine methyl ester to block NO synthesis decreased testosterone-induced increase in cross-sectional area, average coronary peak flow velocity, and coronary blood flow. Pretreatment with glybenclamide to assess the role of ATP-sensitive K+ channels did not influence testosterone-induced dilation in epicardial arteries but did attenuate its effect in the microcirculation. Pretreatment with indomethacin or the classic estrogen-receptor antagonist ICI 182,780 did not alter testosterone-induced changes.

CONCLUSIONS: Short-term administration of testosterone induces a sex-independent vasodilation in coronary conductance and resistance arteries in vivo. Acute testosterone-induced coronary vasodilation of epicardial and resistance vessels is mediated in part by endothelium-derived NO. ATP-sensitive K+ channels appear to play a role in the vasodilatory effect of testosterone in resistance arteries.

Costarella CE, Stallone JN, Rutecki GW, Whittier FC
Department of Physiology, Northeastern Ohio Universities College of Medicine, Rootstown, USA.
J Pharmacol Exp Ther 1996 Apr;277(1):34-9

Several recent studies have provided evidence that gonadal steroid hormones can exert acute (nongenomic) effects on both neural and vascular tissues. This study examines the acute effects of testosterone (T) on vascular reactivity of the rat thoracic aorta. Aortic rings from male Sprague-Dawley (SD) rats with (+ENDO) and without (-ENDO) endothelium were prepared for isometric tension recording. In (+ENDO) male aortae precontracted with phenylephrine (PE), T produced dose-dependent relaxation from 25 microM (30.3 +/- 7.1%) to 300 microM (99.4 +/- 0.4%), whereas T vehicle (< or = 0.5% ethanol) had no effect. Pretreatment of (+ENDO) aortae with T (50 microM; 10 min) attenuated subsequent contractile responses to PE. Both maximal contraction and sensitivity to PE were reduced by T. Pretreatment of (+ENDO) aortae with both T and N omega-nitro-L-arginine methyl ester (250 microM) reversed in part the attenuating effects of T alone; however, both maximal response and sensitivity to PE were still reduced compared to control rings (without T or N omega-nitro-L-arginine methyl ester). Pretreatment of (-ENDO) aortae with T reduced sensitivity to PE, but had no effect on maximal contraction. T pretreatment (50 microM; 10 min) of both (+ENDO) female SD aortae and (+ENDO) male testicular-feminized rat aortae reduced maximal contraction and sensitivity to PE in both groups to a similar extent as in (+ENDO) male SD aortae. These data suggest that T has a direct vasodilating effect on the rat aorta, which involves endothelium-dependent (enhanced NO release) and Bindependent mechanisms and is gender- and intracellular androgen receptor-independent.

Yue P, Chatterjee K, Beale C, Poole-Wilson PA, Collins P
Department of Cardiac Medicine, National Heart and Lung Institute, London, UK.
Circulation 1995 Feb 15;91(4):1154-60

BACKGROUND: Until menopause, women appear to be protected from coronary heart disease. Evidence suggests that estrogen may play a role in the protection of the cardiovascular system by exerting a beneficial effect on risk factors such as cholesterol metabolism and by a direct effect on the coronary arteries. To date there has been no evidence linking testosterone with the occurrence of coronary heart disease. Testosterone may affect the cardiovascular system directly, thus partially explaining the difference in the incidence of coronary artery disease in men and premenopausal women. The purpose of this study was to assess the direct effect of testosterone and a number of testosterone analogues on rabbit coronary arteries and aorta in vitro. METHODS AND RESULTS: Rings of coronary artery and aorta of adult male or nonpregnant female New Zealand White rabbits were suspended in organ baths containing Krebs solution; isometric tension then was measured. The response to testosterone was investigated in prostaglandin F2 alpha (PGF 2 alpha)- and KCl-contracted rings. The effects of endothelium and nitric oxide synthase, prostaglandin synthetase, and guanylate cyclase inhibition on testosterone-induced relaxation were investigated. The effects of ATP-sensitive potassium channels and potassium conductance were also assessed. Relaxing responses in the presence of aromatase inhibition and testosterone receptor blockade were performed. The relaxing responses to the testosterone analogues etiocholan-3 beta-ol-17-one, epiandrosterone, 17 beta-hydroxy-5 alpha-androst-1-en-3-one, androst-16-en-3-ol, and testosterone enanthanate were measured. Testosterone relaxed rabbit coronary arteries and aorta. There was no significant difference between the relaxation effect of testosterone with or without endothelium. Similar results were obtained from male and nonpregnant female rabbits. The relaxing response of testosterone in the coronary artery was significantly greater than in the aorta. The relaxing response of testosterone in the coronary artery was significantly reduced by the potassium channel inhibitor barium chloride but not by the ATP-sensitive potassium channel inhibitor glibenclamide. The relaxing response to testosterone was greater in PGF 2 alpha-contracted rings compared with KCl-contracted rings. Inhibitors of nitric oxide synthase, prostaglandin synthetase, and guanylate cyclase did not affect relaxation induced by testosterone. Inhibition of aromatase and testosterone receptors did not affect relaxation. Testosterone did not shift the rabbit coronary arterial calcium concentration-dependent contraction curves, whereas verapamil did. There were, however, significant differences in the relaxing response to testosterone compared with testosterone analogues. Testosterone was the most potent relaxing agent, suggesting that there may be a structure-function relation in the relaxing response. CONCLUSIONS: Testosterone induces endothelium-independent relaxation in isolated rabbit coronary artery and aorta, which is neither mediated by prostaglandin I2 or cyclic GMP. Potassium conductance and potassium channels but not ATP-sensitive potassium channels may be involved partially in the mechanism of testosterone-induced relaxation. The in vitro relaxation is independent of sex and of a classic receptor. The coronary artery is significantly more sensitive to relaxation by testosterone than the aorta. Testosterone is a more potent relaxing agent of rabbit coronary artery than other testosterone analogues.

Webb CM, Adamson DL, de Zeigler D, Collins P
Cardiac Medicine, National Heart & Lung Institute, Imperial College School of Medicine, and Royal Brompton Hospital, London, United Kingdom.
Am J Cardiol 1999 Feb 1;83(3):437-9, A9

The effect of acute testosterone administration on exercise-induced myocardial ischemia was assessed in 14 men with coronary artery disease and low plasma testosterone concentrations in a study of randomized, double-blind, crossover design. Testosterone increased time to 1-mm ST-segment depression compared with placebo by 66 (15 to 117) seconds (p = 0.016), suggesting a beneficial effect of testosterone on myocardial ischemia in these patients.

Rosano GM, Leonardo F, Pagnotta P, Pelliccia F, Panina G, Cerquetani E, della Monica PL, Bonfigli B, Volpe M, Chierchia SL
Department of Cardiology, Istituto H. San Raffaele, Roma and Milano, Italy.
rosanog@roma.hsr.it
Circulation 1999 Apr 6;99(13):1666-70

BACKGROUND: The role of testosterone on the development of coronary artery disease in men is controversial. The evidence that men have a greater incidence of coronary artery disease than women of a similar age suggests a possible causal role of testosterone. Conversely, recent studies have shown that the hormone improves endothelium-dependent relaxation of coronary arteries in men. Accordingly, the aim of the present study was to evaluate the effect of acute administration of testosterone on exercise-induced myocardial ischemia in men.

METHODS AND RESULTS: After withdrawal of antianginal therapy, 14 men (mean age, 58+/-4 years) with coronary artery disease underwent 3 exercise tests according to the modified Bruce protocol on 3 different days (baseline and either testosterone or placebo given in a random order). The exercise tests were performed 30 minutes after administration of testosterone (2.5 mg IV in 5 minutes) or placebo. All patients showed at least 1-mm ST-segment depression during the baseline exercise test and after placebo, whereas only 10 patients had a positive exercise test after testosterone. Chest pain during exercise was reported by 12 patients during baseline and placebo exercise tests and by 8 patients after testosterone. Compared with placebo, testosterone increased time to 1-mm ST-segment depression (579+/-204 versus 471+/-210 seconds; P<0. 01) and total exercise time (631+/-180 versus 541+/-204 seconds; P<0. 01). Testosterone significantly increased heart rate at the onset of 1-mm ST-segment depression (135+/-12 versus 123+/-14 bpm; P<0.01) and at peak exercise (140+/-12 versus 132+/-12 bpm; P<0.01) and the rate-pressure product at the onset of 1-mm ST-segment depression (24 213+/-3750 versus 21 619+/-3542 mm Hgxbpm; P<0.05) and at peak exercise (26 746+/-3109 versus 22 527+/-5443 mm Hgxbpm; P<0.05).

CONCLUSIONS: Short-term administration of testosterone induces a beneficial effect on exercise-induced myocardial ischemia in men with coronary artery disease. This effect may be related to a direct coronary-relaxing effect.

Zgliczynski S, Ossowski M, Slowinska-Srzednicka J, Brzezinska A, Zgliczynski W, Soszynski P, Chotkowska E, Srzednicki M, Sadowski Z
Department of Endocrinology, Bielanski Hospital, Warszawa, Poland.
Atherosclerosis 1996 Mar;121(1):35-43

We investigated the effects of long-term testosterone replacement in hypogonadal and elderly men on lipids and lipoproteins. Twenty-two men with initial serum testosterone concentrations below 3.5 ng/ml took part in the study: 11 with hypopituitarism (1st group) and 11 otherwise healthy elderly men with low testosterone levels (2nd group). Testosterone deficiency was replaced by intramuscular injections of testosterone enanthate 200 mg every second week. Plasma levels of sex hormones, gonadotropins, SHBG, lipids and lipoproteins were determined before the treatment and after 3, 6 and 12 months of treatment. During the treatment serum testosterone and estradiol increased significantly, reaching normal levels. This was associated with a decrease in total cholesterol (from 225 +/- 16.9 mg/dl to 202 +/- 13.6 mg/dl after 6 months and 198 +/- 12.8 mg/dl after 1 year of testosterone administration, P < 0.0001 in men with hypoandrogenism associated with aging and from 255 +/- 12.1 mg/dl to 214 +/- 10.6 mg/dl after 6 months and 206 +/- 9 mg/dl after 1 year of treatment, P < 0.0001 in men with hypopituitarism) and LDL-cholesterol concentrations (from 139 +/- 12.5 mg/dl to 126 +/- 10.7 mg/dl after 6 months and 118 +/- 9.8 mg/dl after 1 year of testosterone administration, P < 0.0001 in men with hypoandrogenism associated with aging and from 178 +/- 10.3 mg/dl to 149 +/- 10.2 mg/dl after 6 months and 140 +/- 7.3 mg/dl after 1 year of treatment, P < 0.001 in men with hypopituitarism). However, no significant decrease in HDL-cholesterol levels or HDL2- and HDL3-cholesterol subfractions was observed. The effects of testosterone replacement therapy on lipids and lipoproteins were similar in both groups with different aetiology of hypogonadism. No side effects on the prostate were observed. The results of this study indicate that testosterone replacement therapy in hypogonadal and elderly men may have a beneficial effect on lipid metabolism through decreasing total cholesterol and atherogenic fraction of LDL-cholesterol without significant alterations in HDL-cholesterol levels or its subfractions HDL2-C and HDL3-C.

Wu S, Weng X
Beijing Red Cross Chaoyang Hospital.
Chin Med Sci J 1993 Dec;8(4):207-9

Several recent observations suggest that atrial natriuretic peptides (ANP) can modulate steroidogenesis in isolated rat Leydig cells and in young men. Other observations suggest that catechol estrogen can inhibit prostaglandin (PGI2) release in the endothelium, and we had found that androgen can relieve angina pectoris and improve myocardial ischemia in elderly men with coronary heart disease (CHD), possibly through relieving coronary artery smooth muscle spasm. Because ANP and PGI2 are vasoactive peptides which regulate vasomotion, there must be an interaction between steroidogenesis hormones and vasoactive peptides. We evaluated the effects of androgen (Sustanon 250) administration on plasma ANP, PGI2 and thromboxane (TXA2) levels in elderly men with CHD. Thirty 60-75-year-old men with CHD received 250 mg (1 ml) Sustanon 250 injection, and 30 age- and sex-matched CHD patients received 1 ml saline. Plasma ANP, PGI2, TXA2, estradiol (E2) and testosterone (T) were determined before injection and 3 weeks thereafter. The results showed that Sustanon 250 administration increased plasma ANP levels, decreased TXA2 and increased PGI2 levels significantly, and thereby improved the TXA2/PGI2 imbalance in CHD patients (all P < 0.01). Meanwhile, serum T levels rose (P < 0.01), but E2 levels remained unchanged, and thus the E2/T ratio decreased (P < 0.05). Our findings demonstrate that androgen exerts its regulatory role by altering plasma ANP levels and the TXA2/PGI2 ratio.

[Article in Chinese]
Wu SZ, Weng XZ, Yao XX
Department of Internal Medicine, Beijing Red-Cross Chaoyang Hospital.
Chung Hua Nei Ko Tsa Chih 1993 Mar;32(4):235-8

Sixty-two elderly men with coronary heart disease (CHD), 54 of them also suffering from hyperlipidemia, were treated with a new oral androgenic preparation (Andriol) through crossover study. The results showed that after oral Andriol administration for one month, serum estradiol/testosterone (E2/T) ratio was reduced, (P < 0.05) symptom of angina pectoris was relieved (total effective rate, 77.4%), signs of myocardial ischemia in ECG and Holter monitoring were improved (total effective rate, 68.8% and 75% respectively), serum total cholesterol (TC) and triglyceride (TG) levels were reduced dramatically (both P < 0.001) and the serum level of high density lipoprotein cholesterol (HDL-ch) was increased (P < 0.05), but the blood levels of apolipoprotein-AI (APO-AI) and B (APO-B) remained unchanged. No significant side effect of Andriol was observed.

Stone NN, Laudone VP, Fair WR, Fishman J
Urol Res 1987;15(3):165-7

Human prostatic tissue and expressed prostatic secretions (EPS) from patients with benign prostatic hyperplasia (BPH) and prostate cancer were incubated with (1 beta 3H) androstenedione. The extent of aromatization was determined by measuring the transfer of 3H from the 1 beta position into water. The amount of 3H2O recovered corresponds to the estrogens formed. Tissue from 5 patients with BPH yielded 2.13 (+/- 1.05) pmol/mg protein/h while the EPS from the same patients yielded 727 fmol/mg protein/h. In patients with prostate cancer the mean formation of estrogens was 388 fmol/mg protein/h (+/- 75). 4-hydroxy-androstenedione, an aromatase inhibitor, successfully inhibited aromatization in BPH and prostate cancer 53-98%.

Ekman P
Department of Urology, Karolinska Hospital, Stockholm, Sweden.
J Urol (Paris) 1995;101(1):22-5

Endocrine therapy by means of castration for benign prostatic hyperplasia was introduced already in the middle of the 19th century. The technique was never popularized and was abandoned following the introduction of safe surgical techniques. In the second half of this century, small series of various endocrine treatments have been reported, mainly using progestational agents. The hormone dependency of the prostate is unique, since testosterone itself is not very active on the prostate cells but has to be converted to 5 alpha-dihydrotestosterone, which is almost ten times as effective an androgen in the prostate cell. By blocking this conversion, highly specific antiandrogenic effect will be obtained in the prostate but not in other organs of the body. The first 5 alpha-reductase inhibitor, finasteride, has proven effective in reducing prostate DHT. In large clinical trials, it has shown to reduce prostate size, improve urinary flow and reduce symptom score, statistically significantly better than placebo. The effect is sustained over at least 3 years. In a double-blind, randomized, placebo-controlled study over 2 years, patients were similarly improved in the finasteride group, whereas they deteriorated in the placebo group. This indicates that finasteride is able to halt the progression of the natural course of benign prostatic hyperplasia. Benign prostatic hyperplasia, generally believed to be a stromal disease, is potentially dependent on estrogens for its development. By blocking aromatization of testosterone to estrogen in the prostate cells, a hypothetical beneficial effect on the disease process should be gained. Results from phase II-studies have been promising. However, in placebo-controlled studies, aromatase inhibitors did not perform better than placebo.

[Article in French]
Sole-Balcells F
Instituto de Urologia, Nefrologia y Andrologia, Fundacion Puigvert Escuela de Post-Graduados, Universidad Autonoma de Barcelona, Espagne.
J Urol (Paris) 1993;99(6):303-6

The hypothesis of the etiopathogenesis of Benign Prostatic Hypertrophy (BPH) on the basis of stroma-epithelium interaction is presented. The fetal prostate has its origin in the urogenital sinus depending on the dehydrotestosterone stimulating the stromal cells having androgenic receptors. This stroma hyperplasia is considered to be the initial factor in the BPH formation. The inequality in growth factors is also relevant for its formation. Stimulating factors, especially the epidermal growth factor (EGF) prevail on involution factors. The stromal cell has estrogenic receptors. The estrogens from the testosterone aromatization are the first stimulus on the prostatic stroma on the transitional and periurethral area stimulating the glandular epithelium causing BPH. The knowledge of BPH etiopathogenesis will make its rational medical treatment possible, and eventually slow or stop its growth when therapy in its early evolutive stages is prescribed.

Chang WY, Prins GS
Department of Urology, University of Illinois College of Medicine, Chicago 60612, USA.
Prostate 1999 Jul 1;40(2):115-24

Estrogens can have profound effects on prostate growth and differentiation. These effects were thought to be mediated by the classical estrogen receptor; however, the discovery of a second estrogen receptor has redefined the estrogen signaling pathway and may have broad implications on estrogen-responsive tissues, including the prostate. The new estrogen receptor, named estrogen receptor-beta (ERbeta), is preferentially expressed in the prostate and maintains some characteristics that are different from ERalpha. Establishing the distribution and function of ERbeta in the various estrogen-responsive tissues is critical to defining its pharmacological and physiological impact. Differential expression of ERbeta may facilitate development of tissue-specific estrogen agonists and antagonists, a goal in the treatment of diseases in estrogen-sensitive tissues such as breast cancer. This article reviews the current knowledge on ERbeta and its potential impact on the prostate.

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