Androgen Therapy
0021-972X/01/$03.00/0 Vol. 86, No. 6
Printed in U.S.A. The Journal of Clinical Endocrinology & Metabolism
Copyright © 2001 by The Endocrine Society
COMMENTARY
Androgen Replacement Therapy in the Aging Male—A Critical Evaluation
A. VERMEULEN
Department of Internal Medicine, Section of Endocrinology, University Hospital, 9000 Gent, Belgium
Recent years have seen an increasing interest in the study of the aging male, with a particular interest in the problem of whether so-called rejuvenating hormones and, more specifically, androgens can improve quality of life, counteract progressive skeletal muscle loss and strength, prevent falls
and fractures, prolong independent living, and reduce the dependence on medical care.
Almost a decade has elapsed since the first studies on androgen supplementation in elderly men were published (1,2) and, in the view of the persisting controversies concerning this problem as well as the increasing public interest for rejuvenating hormones, it may be indicated to evaluate critically the clinical relevance of the relative androgen deficiency in elderly males, the diagnostic criteria of androgen deficiency, as well as the risks and benefits of androgen supplementation in elderly men.
Male hormone replacement therapy implies, of course, that elderly men have a significant deficit in male hormone. Therefore, the first question to be answered is whether the common occurrence of the age-associated decline of testosterone levels is inherent to the aging process and occurs also in healthy men or whether the observed decline is the consequence of intercurrent disease, obesity, stress, relative physical inactivity or medications, etc.
After years of controversy, due to differences in the characteristics of the population studied and variation in the timing of blood sampling (morning or afternoon) or the frequently small number of elderly subjects studied, authors now agree that in healthy men also there is a clear, slow but continuous, age-dependent decline of testosterone (T) levels, which is more pronounced for free T (FT) than for total T, a consequence of the age-associated increase of the levels of sex hormone binding globulin (SHBG); at 75 yr of age mean total T level in the morning is about two thirds of the mean level at 20 -30 yr of age, whereas the mean FT and bioactive T (FT plus albumin bound T) level are only 40% of the mean levels in younger males. Moreover, the circadian rhythm of plasma T levels, with higher levels in the morning than in the evening, is generally lost in elderly men (3). However, wide interindividual variations exist due to genetic factors, body mass index, diet, social habits (alcohol, tobacco), and stress, and about 20% of males over 70 yr old have T levels in the upper third of males 20-40 yr of age (4). This is in clear distinction to the situation in postmenopausal women who all have clearly decreased estradiol levels. It is important to mention that this decrease, observed in cross-sectional studies, has now been confirmed by longitudinal studies (5-9). However, the androgen deficiency in elderly men is generally moderate; therefore, some authors have suggested the term partial androgen deficiency in the aging male (PADAM). Others, in analogy with the term menopause in women, use the term andropause, although distinct from women in menopause, elderly men retain their reproductive capacity.
Although the decrease in (F)T levels occurs in healthy elderly men, it is evident that sequelae of intercurrent disease (10), medication, environmental, psychosocial, and socioeconomic factors accelerate this age-associated decrease. Recently, the important role of abdominal obesity in the age-associated decrease of T levels has been stressed (10-12).
Clinical Significance of theAge-Associated Decline in Androgen Levels in Elderly Men.
Androgens have many physiologic actions, but does the age-associated decrease in (F)T levels have clinical significance, and does it indicate hypogonadism? Evidence for the clinical significance could be provided by the eventual similarity between signs and symptoms of aging and androgen deficiency, respectively, in young men, the existence of a significant correlation between symptoms and (F)T levels, and the eventual beneficial effect of androgen supplementation in elderly men with low T levels.
Similarity of Signs an Symptoms of Aging and Androgen Deficiency, Respectively, in Young Men.
The age-associated decrease in muscle mass and strength, energy and work capacity, body hair, and hematopoiesis; the decrease in sexual drive and activity, bone mass, and cognitive function; the decline of memory and of the sense of general well being; the difficulties in concentration; and the increase in abdominal fat mass are reminiscent of the symptomatology of androgen deficiency. However, these symptoms are multifactorial in origin; aging is accompanied by a decrease of almost all physiological functions and, as far as the endocrine system is concerned, by a decrease not only of gonadal and adrenal androgen secretion but also of GH secretion. Moreover, the age-associated decrease in physical activity is partly responsible for the decrease in muscle mass and bone mineral density (BMD) (13). Hence, it is not surprising that the correlation between aging symptoms and T levels is often rather poor.
Correlation Between Aging Symptoms and (F)T Levels.
Whereas the age-associated decrease of BMD with an exponential increase in bone fracture rate with age (14, 15) is well established, the role of the partial androgen deficiency in aging males in this decrease remains to be established (16). Indeed, available data are equivocal, some studies showing a significant, albeit weak, association between FT levels and BMD at some but not all bone sites (13,17,18), whereas others did not find any correlation (19-21). Recently, several large-scale studies, involving several hundreds of elderly men (22-24), found bio-T to be significantly associated with bone density at radius, spine and hip; however, the correlation with bioavailable estradiol, the levels of which decline in elderly males, was even stronger, suggesting that part of the androgen effects on bone are at least partially indirect, mediated via their aromatization (25). Nevertheless bio-T also was correlated with all regions of proximal femur BMD and total body BMD after adjustment for age (24). Barrett-Connor et al. (26) observed a significant negative graded association between levels of total and bioavailable estradiol but not bio-T and fracture prevalence in males (median age 67 yr, range 56-87 yr) independently of age, body mass index, or exercise.
On the basis of these recent large-scale studies it seems reasonable to accept a role of the decreased T levels in the age-associated osteopenia. Aging is also accompanied by a increase in abdominal fat mass and a decrease of muscle mass. We (27) as well as Seidell et al. (28) and Tchernof et al. (29) observed abdominal fat mass to be inversely correlated with FT, independently of age. Visceral fat accumulation is highly significantly associated with increased risk of cardiovascular disease, impaired glucose tolerance, and non-insulindependent diabetes mellitus (syndrome X) (30, 31). Whether the abdominal obesity is the consequence of the low T levels or vice versa is not clear. Indeed, obesity induces a decrease of T levels via a decrease in SHBG levels, and morbid obesity (BMI >35) also induces a decrease of FT (11).
The age-associated decline in muscle mass (12 kg between 20 and 70 yr of age), which is most pronounced for the fast twitch type II fibers (32), is a major contributor to the ageassociated decline in muscle strength and early onset of fatigue (33) and a strong predictor of falls, fractures, and loss of independent living. In fact, maximal muscle strength correlates with muscle mass independently of age (34).
Whereas van den Beld et al. (24) observed that in men 73-97 yr of age, serum T levels were, independently of age,positively related to isometric grip strength and leg extension strength, and Abassi et al. (35) observed a correlation between T levels and severity of loss of muscle function in
institutionalized men who have lower T concentrations than healthy elderly men, Baumgartner et al. (36) observed in elderly men (65-97 yr old) a significant correlation between FT and muscle mass, but not grip strength. Verhaar et al.(37), similarly, did not find any association between T levels and muscle strength.
It should be stressed that although a correlation exists between the lower T concentration and reduced muscle function in older men, T is not the only factor responsible for the age-associated muscle loss.
The prevalence of atherosclerosis in men increases spectacularly with aging. In the view of the higher prevalence in men than in women, the decrease of high density lipoprotein cholesterol (HDL-C) levels at puberty in boys (38), the atherogenic lipid profile in hirsute women, and the sporadic reports of premature cardiovascular disease in athletes abusing anabolic/ androgenic steroids, this difference is generally considered to be related to the higher androgen levels in men. Nevertheless, the vast majority of crosssectional studies show a positive correlation between FT levels and HDL-C (39-41) and a negative correlation with fibrinogen, plasminogen activator inhibitor-1 (42), and insulin levels as well as with coronary heart disease (43, 44), but not with cardiovascular mortality (45-47). However, the correlation between T levels and HDL-C and insulin sensitivity is only observed within the physiologic male concentration range of T (48, 49). Androgen blockade by GnRH leads to an increase of HDL-C and, to a lesser extent, of total cholesterol, the effect of which is neutralized when T enanthate was injected in parallel, to maintain physiological T concentrations (48), whereas supraphysiological T levels induce an increase in low density lipoprotein cholesterol (LDL-C) and a decrease of HDL-C (40) Moreover, it should be realized that, beside the effects on lipids, T has direct
effects on several vasoactive factors such as endothelin (50), prostacyclin, and thromboxane A2 (51).
The inverse correlation between T levels and the severity of coronary artery disease as reported by Phillips et al. (43), may be related to the fact that low androgen levels are accompanied by an accumulation of abdominal visceral fat (28, 29), which is known to be associated with increased cardiovascular risk factors (52), and Tchernof et al. (29) observed that upon multivariate analysis, adjusting for visceral obesity, the correlation between androgen levels and lipid parameters lost its significance.
As to the role of the age-associated decline in T levels in the highly negative correlation between sexual desire, arousal, activity, and age, Schiavi (53) reported that men desiring intercourse with a greater frequency than once a week, had higher T levels than men with lower frequency. Moreover they observed (54) that men with the primary diagnosis of hypoactive sexual desire had significantly lower T levels than controls. Similarly, Pfeilschifter et al. (55) reported that men with greater sexual activity had higher bio-T levels than men with a lower frequency and they conclude that androgen deficiency may contribute to the age-related decline in male sexuality. Nilsson et al. (56) finally, in an epidemiological study of 500 51-yr-old men, observed that low levels of bio T were associated with low sexual activity.
However, other authors (57, 58) did not observe any correlation between plasma T levels within the normal range and sexual activity. Moreover, it is known that healthy males have much higher T levels than required to maintain sexual function, although Schiavi (53) as well as Bancroft (59) suggested that circulating androgen levels in elderly men might be insufficient to sustain nocturnal penile tumescence and adequate sexual function.
As to erectile dysfunction, which increases dramatically with age, whereas androgens, acting both centrally and peripherally (60) are essential for normal penile erection and T-stimulating nitric oxide synthesis in the corpora cavernosa (60, 61), androgen deficiency is rarely the major cause of
impotence in elderly males, although it may play a subsidiary role. There is good evidence that, whereas nocturnal penile tumescence is androgen dependent, erection in response to visual erotic stimuli is androgen independent (62). Davidson et al. (63) suggested that the effects of T may be mediated via changes in genital sensitivity.
Finally there is good evidence for a strong correlation between T levels and cognitive performance such as spatial abilities or mathematical reasoning (64, 65), findings which were confirmed in Western and non-Western groups of healthy males (64). Studies addressing correlations between T levels and cognitive functions specifically in elderly man are not available.
As to the role of T in the depressed mood frequently observed in elderly men, whereas data in the literature are rather divergent [for review see Christiansen (66)], a recent large study by Barrett-Connor et al. (67) involving 856 men age 50-89 yr showed a significant inverse correlation between bioavailable T and a depression score, independent of age and weight.
In summary, many aging symptoms in men are suggestive of androgen deficiency and, in fact, there frequently exists a weak correlation of these signs with plasma T levels; many, but not all, studies show the persistence of these correlations after correction for age.
Nevertheless, it should be kept in mind that most of the aging symptoms are multifactorial in origin and that the age-associated decrease in GH levels might play an important role in the symptomatology (68), because symptoms of GH deficiency in young men and the symptoms of aging again show a striking similarity; decrease in muscle mass, increase in abdominal fat, thinning of the skin, asthenia, and adynamia.
Aging and Adrenal Androgens
Aside from a decrease in the secretion and plasma levels of T, aging is accompanied by a decrease of the plasma levels of the major adrenal androgen, dehydroepiandrosterone sulfate (DHEAS). The age-associated decrease is the most important decrease of all hormones; at 75 yr of age, mean DHEAS levels are only 20% of levels in young adults and, whereas rather important interindividual variations exist, all men and women show an important age-dependent decrease (69-71).
Does this decrease have clinical significance? Although it has been reported that in animals that do not secrete DHEAS, administration of DHEAS generally in pharmacological doses, has antiatherogenic, immunostimulatory, and anticarcinogenic effects, the effects of DHEAS in man remain questionable. Functional parameters of daily living in the oldest males were reported to be lowest in men with the lowest DHEAS levels (72), whereas data of Abassi et al. (73) show that men with higher DHEAS levels appear to be more fit and leaner than men with lower DHEAS levels. This, of course, does not indicate a causal role of DHEAS in physical fitness or general well-being. Moreover, it has been reported that men with low DHEAS levels would be at higher risk of cardiovascular mortality within the next 2 yr (74,75), but this has not been confirmed (76,77). Finally, the increase in physical well-being after DHEAS administration reported by some authors (78) was not confirmed by others (79), but there is some evidence that DHEAS administration to men with Addison’s disease improves general well-being (80, 81).
References
1. Tenover JS. 1992 Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab. 75:1092-1098.
2. Morley JE, Perry HM, Kaiser FE, et al. 1993 Effect of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc. 41:149-152.
3. Bremner WJ, Vitiello WV, Prinz PN. 1983 Loss of circadian rhythmicity in blood testosterone levels with aging. J Clin Endocrinol Metab. 51:1278-1281.
4. Kaufman JM, Vermeulen A. 1998 Androgens in male senescence. In: Nieschlag E, Behre HM, eds. Testosterone, Action, Deficiency, Substitution. Springer; 437-471.
5. Morley JE, Kaiser FE, Perry HM, et al. 1997 Longitudinal changes in testosterone, luteinizing hormone and follicle stimulating hormone in healthy old men. Metabolism. 46:410-413.
6. Pearson UJD, Blackman MR, Metter EJ, Waclawiw Z, Carter HB, Herman JM, Effect of age and cigarette smoking on longitudinal changes in androgens and SHBG in healthy males. Proc 77th Meeting of The Endocrine Soc., Washington, DC, 1995, p 322 (Abstract).
7. Krithivas K, Yurgalevitch SM, Mohr BA, et al. 1999 Evidence that the CAG repeat in the androgen receptor is associated with age related decline in serum androgens levels in men. J Endocrinol. 162:137-142.
8. Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH. 1997 Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle age men: a 13 year follow-up of former Multiple
Risk Factors Intervention Trial participants. Am J Epidemiol. 46:609-617.
9. Harman ME, Metter J, Toben JD, Pearson J, Blackman MR. 2000 Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab. 86:724-731.
10. Turner HE, Wass JAH. 1997 Gonadal function in men with chronic illness. Clin Endocrinology. 47:379-403.
11. Vermeulen A, Kaufman JM, Giagulli VA. 1996 Influence of some biological indices on the sex hormone binding globulin and androgens in aging and obese men. J Clin Endocrinol Metab. 81:1821-1827.
12. Couillard C, Gagnon J, Bergeron F, et al. 2000 Contribution of body fatness and adipose tissue distribution to the age variation in plasma steroid hormone concentration in men. The HERITAGE study. J Clin Endocrinol Metab.
85:1026-1031.
13. Rudman D, Drinka PJ, Wilson CR, et al. 1994 Relations of endogenous anabolic hormones and physical activity to bone mineral density and lean body mass in elderly men. Clin Endocrinol. 40:653-661.
14. Orwoll ES, Klein RF. 1995 Osteoporosis in men. Endocr Rev. 16:87-116.
15. Foresta G, Ruzza G, Mioni R, et al. 1984 Osteoporosis and decline of gonadal function in the elderly male. Horm Res. 19:18-22.
16. Center JR, Nguyen TV, Sambrook PN, Eisman JA. 1999 Hormonal and biochemical parameters in the determination of Osteoporosis in elderly men. J Clin Endocrinol Metab. 84:3626-3635.
17. Murphy S, Khaw KT, Cassidy A, Compston E. 1993 Sex hormones and bone mineral density in elderly men. Bone Miner. 20:133-140.
18. Kaufman JM. 1996 Androgens, bone metabolism and Osteoporosis. In: Oddens B, Vermeulen A, eds. Androgens and the Aging Male. New York, London: Parthenon Publishing Group; 39-60.
19. Drinka PJ, Olson J, Bauwens S, Voeks SK, Carlson I, Wilson M. 1993 Lack of association between free testosterone and bone density separate from age in elderly males. Calcif Tissue Int. 52:67-69.
20. Meier DE, Orwoll ES, Keenan EJ, Fagerstrom RM. 1987 Marked decline of trabecular bone mineral content in healthy men with age: lack of association with sex steroid levels. J Am Geriatr Soc. 35:198-197.
21. Clarke BL, Ebeling PR, Jones JD, et al. 1996 Changes in quantitative bone histometry in aging healthy men. J Clin Endocrinol Metab. 81:2264-2270.
22. Greendale G, Edelstein S, Barrett-Connor E. 1997 Endogenous sex steroids and bone mineral density in older women and men. The Rancho Bernardo Study. J Bone Miner Res’ 12:1833-1841.
23. Khosla S, Melton LJ, Atkinson EJ, O’Fallon WM, Klee GG, Riggs BL. 1998 Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men: a key role for bio-available estrogen. J Clin Endocrinol Metab. 83:2266-2275.
24. van den Beld AW, de Jong FH, Grobbee DE, Pols HAP, Lamberts S WJ. 2000 Measures of bio-available serum testosterone and estradiol and their relationship with muscle strength, bone density and body composition in elderly
men. J Clin Endocrinol Metab. 85:3276-3282.
25. Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J. 1997 Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med. 337:91-95.
26. Barrett-Connor E, Mueller JE, von Miihlen DG, Laughlin GA, Schneider DL, Sartoris DJ. 2000 Low levels of estradiol are associated with vertebral fractures in older men but not in women. The Rancho Bernardo Study. J Clin Endocrinol Metab. 85:219-223.
27. Vermeulen A, Goemaere S, Kaufman JM. 1999 Sex hormones, body composition and aging. The Aging Male. 2:8-15.
28. Seidell JC, Bjorntorp P, Sjostrom L, Kvist H, Sannerstedt R. 1990 Visceral fat accumulation in men is positively associated with insulin, glucose and Cpeptide levels, but negatively with testosterone levels. Metabolism. 39:897-
901.
29. Tchernof A, Labrie F, Belanger A, et al. 1997 Relationships between endogenous sex steroid hormones, sex hormone binding globulin and lipoprotein levels in men: contribution of visceral obesity, insulin levels and other metabolic variables. Atherosclerosis. 133:235-244.
30. Kennell WB, Cupples LA, Ramaswani R, Stokes III J, Kreger BE, Higgins M. 1991 Regional obesity and risk of coronary disease. The Framingham Study. J Clin Epidemiol. 44:183-190. COMMENTARY 2387
31. Bjorntorp P. 1993 Visceral obesity: a civilization syndrome. Obes Res. 1:206- 222.
32. Larsson L. 1983 Histochemical characteristics of human skeletal muscle during aging. Act Physiol Scand. 117:469-471.
33. Frontera WR, Hughes VV, Fiatarone MA, Fielding RA. 2000 Aging and skeletal muscle: a 12 year longitudinal study. J Appl Physiol. 88:1321-1326.
34. Reed RL, Pearlmutter E, Jochum K, Meredith KE, Mooradian AD. 1991 The relationship between muscle mass and muscle strength in the elderly. J Am
Geriatr Soc. 39:555-591.
35. Abassi A, Drinka PJ, Mattson DE, Rudman D. 1993 Low circulating levels of insulin-like growth factors and testosterone in chronically institutionalized
elderly men. J Am Geriatr Soc. 48:975-981.
36. Baumgartner RN, Waters DE, Gallagher D, Morley JE, Carry PJ. 1999 Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev. 107:123-136.
37. Verhaar HJJ, Samson MM, Aleman A, de Vries WR, de Vreede PE, Koppeschaar HPF. 2000 The relationship between indices of muscle function and circulating anabolic hormones in healthy. The Aging Male. 3:75-80.
38. Kirkland RT, Keenan BS, Probstfield JE, Patsch W, Tsai-Eien E, Clayton WJ, Insull Jr W. 1987 Decrease in plasma high density lipoprotein cholesterol at puberty in boys with delayed adolescence. Correlation with plasma testosterone
levels. JAMA. 27:502-507.
39. Barrett-Connor E, Khaw RT, Yen SS. 1995 Testosterone and risk factors for cardiovascular disease in men. Diabetes Metab. 21:156-161.
40. Bagatell CS, Bremner WJ. 1995 Androgen and progestogen effects on plasma lipids. Prog Cardiovasc Dis. 38:255-271.
41. Haffner JM. 1996 Androgens in relation to cardiovascular disease and insulin resistance in aging men. In: Oddens B, Vermeulen A, eds. Androgens and the Aging Male. New York, London: Parthenon Publishing Group; 65-84.
42. Caron P, Bennet A, Camare E, Eouvet JP, Boneu S, Sie P. 1989 Plasminogen activator inhibitor in plasma is related to testosterone in man. Metabolism. 38:1010-1013.
43. Phillips G, Pinkernell BH, Jing TY. 1994 The association between hypotestosteronemia and coronary heart disease in men. Arterioscler Thromb. 14:701- 706.
44. Swartz CA, Young MA. 1987 Low serum testosterone and myocardial infarction in geriatric male inpatients. J Am Geriatr Soc. 35:39-44.
45. Haffner JE, Moss SE, Klein BEK, Klein R. 1996 Sex hormones and DHE ASO4 in relation to ischemic heart disease in diabetic subjects. The WESDR Study
Diabetes Care. 19:1045-1050.
46. Barrett-Connor E, Khaw KS. 1988 Endogenous sex hormone levels and cardiovascular disease in men: a prospective population based study. Circulation.
788:539-543.
47. Cauley JA, Gutai JP, Kuller EH, Dai WS. 1987 Usefulness of sex steroid hormone levels in predicting coronary artery disease in men. Am J Cardiol. 60:771-777.
48. Goldberg RB, Rabin AN, Alexander AN, Doelle GC, Getz GS. 1985 Suppression of plasma testosterone leads to an increase in serum total and high density lipoprotein cholesterol and Apo A and B. J Clin Endocrinol Metab.
60:203-207.
49. Moorjani S, Dupont A, Eabrie F, et al. 1987 Increase in plasma high density lipoprotein concentration following complete androgen blockade in men with prostatic carcinoma. Metabolism. 36:244-250.
50. Polderman KH, Stehouwer CD A, van de Kamp GJ, Dekker GH, Verheugt FWA, Gooren EJG. 1993 Influence of sex hormones on plasma endothelin levels. Ann Intern Med. 118:429-431.
51. Ajayi AA. 1995 Testosterone increases platelet thromboxane A2 receptor density. Circulation. 91:2740-2747.
52. Kannell WB, Cupples EA, Ramaswami R, Stokes Jr J, Kreger BE, Higgings M. 1991 Regional obesity and the risk of coronary disease: The Framingham Study. J Clin Epidemiol. 44:183-190.
53. Schiavi RC. 1996 Androgens and sexual function in men. In: Oddens B, Vermeulen A, eds. Androgens and the Aging Male. New York, London: Parthenon Publishing Group; 111-128.
54. Schiavi RC, Schreiner-Engel P, White D, Mandeli J. 1988 Pituitary-gonadal function during sleep in men with hypoactive sexual desire and in normal controls. Psychosomat Med. 50:304-318.
55. Pfeilschifter J, Scheidt-Nave C, Eeidig-Bruckner G, et al. 1996 Relationship between circulating insulin-like growth factor components and sex hormones in population based sample of 50-80 year old men and women. J Clin
Endocrinol Metab. 81:2534-2540.
56. Nilsson P, Moller E, Solkad K. 1995 Adverse effects of psychosocial stress on gonadal function and insulin levels in middle aged males. J Intern Med. 237:479-486.
57. Buena F, Swerdloff RS, Steiner BC, et al. 1993 Sexual function does not change when serum testosterone levels are varied pharmacologically within the normal male range. Fertil Steril. 59:1118-1123.
58. Kraemer HC, Becker HB, Brodie HH, Doering CH, Moos RH, Hamburg DA. 1976 Orgasmic frequency and testosterone levels in normal human males. Arch Sex Behav. 5:125-128.
59. Bancroft J. 1984 Androgens, sexuality and the aging male. In: Labrie F, Proulx L, eds. Endocrinology. Amsterdam: Elsevier; 913-916.
60. Mills TM, Reilly CM, Lewis RW. 1996 Androgens and penile erection. A review. J Andrology. 17:633-638.
61. Eugg J, Raf jer J, Gonzale active androgen in the maintenance of nitric-oxide mediated penile erection in
the rat. Endocrinology. 136:1495-1501.
62. Carani C, Scuberi A, Marrama P, Bancroft J. 1990 Effect of testosterone administration and visual erotic stimuli on nocturnal penile tumescence. Horm Behav. 24:435-441.
63. Davidson JM, Kwan M, Greenleaf WJ. 1982 Hormonal replacement therapy and sexuality. Clin Endocrinol Metab. 11:599-623.
64. Christiansen K, Kussmann R. 1987 Sex hormones and cognitive functions in men. Neuropsychobiology. 18:27-36.
65. McKeever WF, Deyo A. 1990 Testosterone, dihydrotestosterone and spatial task performance of males. Bull Psychonomic Soc. 28:305-308.
66. Christiansen K. 1998 Behavioural correlates of testosterone. In: Nieschlag E, Behre HM, eds. Testosterone, Action, Deficiency, Substitution. Springer; 107- 142.
67. Barrett-Connor E, von Miihlen DG, Kritz-Silverstein D. 1999 Bio-available testosterone and depressive mood in older men. The Rancho-Bernardo Study. J Clin Endocrinol Metab. 84:573-577.
68. Martin FC, Ye men: aging and the somatopause. Bailiere’s Clin Endocrinol Metab. 11:213- 220.
69. Orentreich N, Brind JE, Rizer RE, Vogelmang JM. 1984 Age changes and sex difference in serum dihydroepiandrosterone sulfate concentration during
adulthood. ] Clin Endocrinol Metab. 59:551-555.
70. Zumoff B, Rosenfeld RS, Strain W, Eevin J, Fukushima DK. 1980 Sex differences in the twenty four hour plasma concentration of dehydroisoandrosterone
(DHA) and dehydroisoandrosterone sulfate (DHAS) in normal
adults. J Clin Endocrinol Metab. 51:330-333.
71. Eaughlin CA, Barrett-Connor E. 2000 Sexual dimorphism in the influence of advancing age on adrenal hormone levels: The Rancho Bernardo Study. J Clin Endocrinol Metab. 85:3561-3568.
72. Ravaglia G, Forti P, Maioli F, et al. 1996 The relationship of dehydroepiandrosterone sulfate (DHEAS) to endocrine metabolic parameters and functional status in the oldest old. Results from an Italian study on healthy free living over ninety years old. J Clin Endocrinol Metab. 81:1373-1178.
73. Abassi A, Duthie Jr EH, Sheldahl E, et al. 1998 Association of dehydroepiandrosterone sulfate, body composition and physical fitness in independent community dwelling older men. J Am Geriatr Soc. 46;263-273.
74. Barrett-Connor E, Khaw KT, Yen SCC. 1986 A prospective study of dehydroepiandrosteronesulfate: morbidity and cardiovascular disease. N Engl ] Med. 315:1519-1524.
75. Berr C, Eafont S, Debuire B, Dartigues JF, Baulieu EE. 1996 Relationship of dehydroepiandrosterone sulfate in the elderly with functional, psychological and mental status and short term mortality. A French community based study.
Proc Nat Acad Sc USA. 93:13410-13415.
76. Barrett-Connor E, Goodman-Gruen D. 1995 The epidemiology of DHEAS and cardiovascular disease. Ann NY Acad Sci. 774:259-270.
77. Eacroix AZ, Katzuhiko Y, Reed DM. 1992 Dehydroepiandrosterone sulfate, incidence of myocardial infarction and extend of atherosclerosis in men.
Circulation. 86:1929-1935.
78. Morales AJ, Haubicht RH, Hwang JY, Asakura H, Yen SS. 1998 The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age advanced men and women. Clin Endocrinol. 49:421-432.
79. Flynn AMA, Weaver-Osterholz D, Sharpe-Timms KE, Krause G. 1999 Dehydroepiandrosterone in aging humans. J Clin Endocrinol Metab. 84:1527-
1533.
80. Arlt W, Callies F, van Vlijmen JC, et al. 1999 Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med. 341:1013- 1020.
81. Hunt PJ, Gurnell EM, Huppert FA, et al. 2000 Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison’s disease in a randomized, double blind trial. J Clin Endocrinol Metab. 85:4650-4656.
82. Vermeulen A, Kaufman JM. 1995 Aging and the hypothalamo-pituitary testicular axis in men. Horm Res. 43:25-28.
83. Winters J, Sherins RJ, Troen P. 1984 The gonadotropin repressive activity of androgens is increased in elderly men. Metabolism. 33:1052-1059.
84. Deslypere JP, Kaufman JM, Vermeulen T, Vogelaers D, Vandalem JE, Vermeulen A. 1987 Influence of age on pulsatile luteinizing hormone release and responsiveness of the gonadotrophs to sex hormone feed-back. J Clin Endocrinol Metab. 64:68-73.
85. Winters SJ, Atkinson E, for the Testoderm Study Group. 1997 Serum LH concentration in hypogonadal men during transdermal testosterone replacement through scrotal skin: further evidence that aging enhances testosterone