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One and the same androgen for all? towards designer androgens

Louis J G Gooren1, Nhu Thanh Nguyen2

1Division of Andrology, Department of Endocrinology, Hospital of the Vrije Universiteit, Amsterdam, The Netherlands
2Department of Urology, Binh Dan Hospital, Ho Chi Minh City, Vietnam

Asian J Androl  1999 Jun; 1: 21-28

Keywords: androgens; synthetic androgens; designer drugs
The introduction of designer oestrogens as a treatment modality in hormone replacement in women has invited to consider the concept of compounds with selective androgenic effects for male hormone replacement therapy. The full spectrum of the actions of testosterone may not be necessary of even undesired for certain indications for testosterone treatment. To define for what indications certain androgenic properties are desired and undesired more insight in basic androgen (patho)physiology is required. There is convincing evidence that aromatization of androgenic compounds to oestrogens might be an advantage for maintenance of bone mass and it might also mitigate negative effects of androgens on biochemical parameters of cardiovascular risks; the potentially negative effects of oestrogens on prostate pathology in ageing men needs further elucidation. While the role of dihydro-testosterone (DHT) for the male sexual differentiation and for pubertal sexual maturation is evident, its role in mature and ageing males seems less significant or may even be harmful. It is, however, of note that a negative effect of DHT on prostate pathophysiology is certainly not proven. For male contraception a progestational agent with strong androgenic properties might be an asset. For most of the androgenic actions the critical levels of androgens are not well established. The latter is relevant since the large amount of androgen molecules required for its biological actions(as compared to oestrogens)is an impediment in androgen replacement modalities. There may be room for more biopotent androgens since delivery of large amounts of androgen molecules to the circulation poses problems for treatment modalities.

1 Introduction

In cases of hormone deficiencies traditional endocrinology aims to replace the missing hormone with a substitute. To afford the full biological action of the hormone, this substitute ideally mimics the natural hormone in molecular structure as closely as possible; and plasma levels to be achieved over the day must come close to average levels, and ideally follow the normal diurnal pattern. Increasing insight how hormones exert their biological effects, has paved the way for rethinking of this traditional aim.

In this contribution ideas are presented for clinical applications of androgens intentionally designed not to render the full spectrum of androgenic actions which the normal testosterone molecule has. There may be clinical situations where the full spectrum is redundant or may be even harmful by carrying a (long-term) health risk.

In fact, this idea is not completely novel. Examples are the so-called anabolic steroids designed to exert the anabolic effects of androgens but without the typical androgenic effects so that they also could be used in women or in children. Critical examination shows that this goal was not (fully) achieved, hence the justified suggestion to use the new term androgenic-anabolic steroids[1].

In order to escape hepatic inactivation and allow oral administration modifications of the testosterone molecule have been devised, such as 17-alkylation, or modifications of the ring structure(5-reduction, oxidations at positions 1 or 2; removal of the methyl group at position 19; substitutions at positions 2,3, 4, 6, 9, or 11; and substitution of the A ring). 17-Alkylation renders the molecule potentially hepatotoxic and ring modifications reduce androgenic potency. So the present modifications of testosterone molecule are less than ideal. Of late 7-methyl-19-nortestosterone (MENT) has been introduced. It has a high biopotency and it does not undergo 5 reduction which may or may not be an advantage for its effects on the prostate. It retains, however, its capacity to be aromatized to oestradiol[2].

1.1 New approaches

Hormone replacement therapy (HRT) in postmenopausal women has set the stage for new developments. While HRT with traditional oestrogens has been demonstrated to be beneficial with regard to preservation of bone mass and protection against the higher incidence of cardiovascular disease associated with the postmenopausal state, oestrogens also increase the risk of endometrial and breast cancer which limits the acceptablity of HRT by women themselves and their physicians[3].

The observation that the non-steroidal oestrogen receptor antagonist tamoxifen preserved bone mass in postmenopausal women with breast cancer[4] invited to rethink the concept of biological action of both oestrogens and oestrogen receptor blockers and their potential clinical use. A compound closely related to tamoxifen, but with less potency to stimulate the endometrium, raloxifene has been developed. A study by Yang et al has elucidated the mechanism(s) of action of oestrogens and anti-oestrogens[5]. The mechanism is interpreted as follows[6]. Oestrogens bind to the oestrogen receptor, inducing a conformational change that leads to activation of gene transcription through specific oestrogen response elements of target genes. Transcriptional activation of this genes is thought to occur through two distinct domains of the oestrogen receptor, TAF-1 and TAF-2. Different activation of these two domains by oestrogens and anti-oestrogens explains the tissue selectivity of the latter. The existence of cell-specific co-activators and co-repressors which interact with oestrogen receptors and the presence of antagonist-specific binding sites within the oestrogen receptor further increases the complexity of oestrogen signalling pathways(for review Compston[7]). Thus a paradigm is created how `designer' oestrogenic compounds are able to modulate the oestrogen receptor selectively. Hence the term `selective estrogen receptor modulator'(SERM) has been introduced. The therapeutical potential of SERM in women may set the stage for the development of selective androgen receptor modulators (SARM).

1.2 Medical and pharmaceutical interest in androgens versus oestrogens

In sharp contrast to oestrogenic compounds, the clinical use of androgens has not received due attention over the past decades. Most physicians, or even endocrinologists, have little understanding of androgen (patho) physiology. It is often assumed that androgen-related problems are rare in clinical medicine. This is not the case. Androgen deficiencies are more frequent than, for instance, insulin-dependent diabetes mellitus and it is estimated that 1:200 men is androgen-deficient, though 50% of these men go undiagnosed and untreated. Unlike adrenal, thyroid and pituitary endocrine pathology, sex steroid deficiency is not perceived as a serious threat to health. Moreover, use of androgens is thought to be associated with serious risks, such as induction of prostate carcinomas and increasing cardiovascular risks. In view of the little medical interest and the resulting limited marketing opportunities pharmaceutical companies have only been marginally interested in further developing androgen treatment modalities.

Fortunately, the medical and pharmaceutical interest in androgens is growing. The acceptance of HRT with oestrogens in menopausal women has raised the issue whether androgen replacement in ageing men is appropriate. The almost immediate reflex is to dismiss this idea in view of the preconceived harmful effects on the prostate and the cardiovascular system. Several preconceptions of the dangers of androgen administration to ageing men may be wrong as the first results of androgen administration to ageing men indicate. But it certainly worthwhile to investigate whether the full spectrum of effects of normal testosterone are needed in old age or whether certain effects are potentially harmful.

Another area is male contraception. Female emancipation brings up the question whether the burden of contraception should not be fairly shared between the two spouses. Hormonal contraception in men involves either high doses of androgens or the combination of an antigonadotropic compound+testosterone. It would be desirable if, for instance, androgens with increased antigonadotropic action could be devised.

There is increasing attention in medicine for quality of life issues, to which androgens may make an important contribution. Several of the above indications do not require the full spectrum of biological actions of testosterone itself. Modifications of androgenic compounds specifically designed to achieve the specified goals may be progress, particularly when (some) side effects of androgens can be minimized.

2 Requirements for an androgen to exert its physiological functions

2.1 Induction of virilization

Testosterone may be regarded as a prohormone. It is converted to DHT and 17-oestradiol. It is incompletely known what the biological relevance of these conversions are. The receptors for testosterone and DHT are identical but the binding of DHT is considerably stonger and therewith this conversion is a biological mechanism to amplify testosterone action. Prenatally conversion of testosterone to DHT is a requirement for the formation of the prostate and male external genitalia as evidenced by the syndrome of 5-reductase deficiency characterized by genital malformations. Beyond this stage of development this conversion is still a necessity. In subjects with 5-reductase deficiency development and function of the prostate are subnormal. But approximately normal growth of the phallus, rugation and pigmentation of the scrotum and deepening of the voice are observed. It cannot be excluded that these actions are more efficacious when testosterone is converted to DHT. There is now a vast experience with clinical use of the 5-reductase type 2 inhibitor finasteride. In less than 5% of the patients complaints of decreased libido, impotence, and decreased volume of the ejaculate are noted. No effects on lipids and erythropoiesis were observed. So it seems that limitation of the reduction of testosterone to DHT produces no major effects in adulthood[8]. Rather mute is whether the aromatization of testosterone to oestradiol fulfils a significant biological role. In contrast to findings in some animal species, it could not be shown in adult men that aromatization of testosterone to oestradiol is needed for the effects of testosterone on male sexual functioning[9,10]. The men described in the literature with disruptions in the biological action of oestradiol seemed, at face value, not to have gender identity problems and their sexual orientation was heterosexual.

Maintenance of sexual functioning in adult men could be achieved with 40-60% of normal adult male testosterone levels[11]. Whether aromatization is relevant for other psychotropic effects of testosterone (spatial abilities and mood elevating effects) is unknown. There are convincing data that aromatization of testosterone is essential for closure of the epiphyses and bone mass formation and maintenance of bone mass in adulthood. Aromatization may limit some of the negative effects that androgens may have on cardiovascular risk factors. These issues will be addressed below.

Apart from a lack of information on the biological relevance of the conversion products of testosterone, also little is known of their quantitative aspects. Direct testicular secretion of oestradiol and DHT accounts for only 20-25% of the production rates found in the general circulation (50 g and 300 g, respectively). The remaining 75-80% arises from peripheral conversion of secreted testosterone. A major question is whether the circulating levels of oestradiol and DHT represent total peripheral production. The plasma concentration of a hormone may not be an accurate marker of the amount per unit time that reaches target organs. The formation of oestrogens takes predominantly place via aromatase locally in fat, muscle, kidney and liver. The non-testicular production of DHT occurs in liver, kidney, muscle, prostate and skin, either via 5-reductase type 1 (liver and non-genital skin) or type 2 (genital and male accessory gland tissues). So more information is needed about the qualitative and quantitative aspects of the conversion products of testosterone, DHT and oestradiol.

2.2 Muscles

There is little 5-reductase activity in muscle and indeed, subjects with a 5-reductase deficiency develop normal male muscle mass in puberty. Significant aromatase concentrations are present in muscle but non-aromatizable anabolic steroids are effective in animal models. Men with a disruption in the biological action of oestradiol had normal male muscle contours. So it would seem that testosterone itself is capable of its anabolic effects on muscle.

2.3 Bones

Sex steroid deficiencies in both men and women are associated with loss of bone mineral density (BMD) and increases in bone fractures. The evidences that oestrogens protect women from osteoporosis is very convincing. Also androgen replacement in men increases BMD[12,13]. In a recent study it could be shown in men that both androgen deficiency and hypovitaminosis D are associated with age-related femoral neck fractures[14]. Two cases of men with an impairment of the biological effects of oestrogens presenting with delayed epiphyseal closure and osteopenia have stirred up attention for the role of oestrogens in acquiring and maintaining BMD in men. It could be shown in another man with aromatase deficiency that oestrogen administration had a significant beneficial effect on skeletal growth and bone maturation[15]. In male-to-female transsexuals, orchiectomized in adulthood, estrogen administration is capable of maintaining BMD[16]. It is very likely though that in men androgens play a predominant physiological role. Plasma oestrogens in men are below levels that are capable of maintaining BMD in women. In a rat model with testicular feminization (Tfm) it could be shown that in spite of higher plasma oestrogen concentrations than in nonaffected male rats (as a result of aromatization of elevated testosterone levels in the Tfm rat) the size of bone mass was smaller and the turnover of bone was lower than in male rats[17]. Androgen receptors are present at low densities in osteoblast, which express 5-reductase activity. (Non)aromatizable androgens probably induce proliferation and differentiation of osteoblasts. Androgen action may be direct or through interaction with growth hormone-IGF-I axis. Androgen excess in women is associated with an increased BMD. (for review on the relation of androgens and bone[18]). So there is convincing evidence that androgens exert effects on (peak) bone mass in men in their own right but part of the effects may be ascribed to aromatization to oestrogens which may occur locally in bone and may therefore not be evident from plasma levels of estrogens. The presently available evidence for a role of oestrogens in the bone loss of ageing men was recently reviewed[19]. So with the present state of knowledge it would therefore seem desirable that induction and maintenance of bone mass androgens are aromatizable.

2.4 Quantitative aspects of androgen action

One of the pharmaceutical problems of androgen therapy is the vast amount of androgen molecules to be administered for replacement. The daily testosterone production in the eugonadal adult man lies in the range of 5-7 mg, as opposed to daily production of oestradiol which lies at its peak in the late follicular phase of the menstrual cycle and amounts to 0.5-1.0 mg/day. The challenge in androgen replacement treatment has been to deliver a sufficiently large amount of androgen molecules to the circulation. This difficulty can be demonstrated by comparing transdermal delivery of testosterone with that of 17-oestradiol. The latter has been relatively easy (two patches per week containing 50-100 g 17-oestradiol), while with transdermal testosterone treatment this is relatively difficult (daily scrotal or large nonscrotal patch containing 8-14 mg of testosterone). There may be a parallel with another hormone that is produced in abundance: progesterone. The large quantities of testosterone and progesterone needed for their biological actions as compared to oestradiol, may be explained by the properties of the androgen and the progesterone receptor. They share some aspects. It is conceivable that an androgen can be designed that retains (most of) its properties, but which has a hormone-receptor interaction in a way comparable to oestrogen action where relatively few oestrogen molecules achieve powerful biological effects. MENT is claimed to be 10 times more biopotent than normal testosterone[2] and MENT or similar compounds would maybe offer advantages in this regard.

Androgens exert a spectrum of biological actions: effects on muscle/bone, libido, spatial cognition and mood, erythropoiesis. It is largely unknown what the critical plasma levels for the single targets are. In other words: must testosterone substitution aim to replace the full normal daily production of androgens? Or would a lower-than-normal plasma levels suffice to exert all androgen effects. It could be shown that around 50% of normal testosterone levels is enough to sustain androgen effects on libido and sexual functions[10,11]. For other biological actions of testosterone the critical plasma levels are less well established. Tentatively the following observations may be presented. We found that male-to-female transsexuals lose on average about 4 kg of lean body mass following total androgen deprivation. About the same amount is gained by female to male transsexuals receiving parenteral testosterone esters in a dose of 250 mg/2 weeks. This does not allow to define a critical testosterone level, but it demonstrates that testosterone concentrations achieved with this mode of treatment probably maintain muscle mass[20]. Less reassuring are our findings with regard to preservation of bone mass in female-to-male transsexuals on long-term androgen treatment with conventional replacement doses for hypogonadal men (testosterone esters 250 mg per 2-3 weeks). In a number of them a loss of BMD was observed[16]. The best predictor of loss of BMD was plasma LH; a high plasma LH predicted loss of BMD, so there might have been an undersubstitution or a noncompliance with these conventional androgen replacement regimens.

2.5 Non-genomic actions of androgens

It is of note that gonadal steroids have almost exclusively been investigated for their slow and prolonged action involving their passage through the cell membrane to cytosolic or nuclear receptors, where they produce effects on DNA-related protein synthesis. In recent years it has become clear that (some) steroid hormones may also have a direct rapid action (seconds to minutes) that do not involve gene expression and therefore are termed non-genomic action. Among the non-genomic actions of steroids that have been described are the interactions with a variety of membrane receptors, ion channels, and transporters. Steroids may change the biophysical properties of membranes[21]. Therefore designer androgens have not only to be tested for their receptor modulation but also for their non-genomic actions on membranes.

3 Requirements for the various androgen treatment indications

3.1 Induction of virilization

For this indication one would like to administer an androgenic compound that preserves most androgen properties. Normal pubertal development of the prostate and induction of a normal male hair pattern require sufficient concentrations of DHT and aromatization of androgens is probably significant for epiphyseal closure and bone mass. It would be advantageous if the induction of acne could be avoided. In our recent review of side effects of androgen administration to female-to-male transsexuals acne was observed in 80 of 293 subjects (37%)[22]. Actions of androgens on the skin are mediated by 5-reductase type 1; selective inhibition of 5-reductase type 1 would probably prevent acne but would also interfere with the development of sexual hair.

3.2 Maintenance of virilization

Once complete virilization has been induced or when hypogonadism occurs past pubertal development, the requirements for androgen replacement may be different. Our large experience with removal of sexual hair in (Caucasian) male-to-female transsexuals shows convincingly that only minimal androgen stimulation is required for maintaining sexual hair growth. The relatively little effects of finasteride on prostate function and on sexual interest/functions of ageing men provide an indication that in adulthood, low levels of DHT suffice to maintain sexual functioning. So it would seem that a high degree of conversion of androgens to DHT is not a requirement. In view of the long-term use of androgens in substitution treatment aromatization may be an advantage thus limiting negative cardiovascular side effects and possibly preserving bone mass more efficaciously.

3.3 Male contraception

Effective suppression of spermatogenesis requires a profound suppression of both gonadotropic hormones and of intratesticular testosterone concentrations. Administration of testosterone enanthate 200 mg/week parenterally induced azoospermia in about 60% of white men and severe oligospermia in almost all the remaining men. Pregnancies did not occur in the couples in which the man became azoospermic, but pregnancies were reported in the men with oligozoospermia. These doses of androgens lower levels of HDL-cholesterol and the regimen requires weekly injections. The combination of a progestin with androgen could achieve probably more effectively the endocrine requirements for a total suppression of spermatogenesis[23]. Even more ideal would be a progestin with androgenic properties. Some of these compounds have been devised by pharmaceutical companies in search of new progestional compounds for female oral contraceptives. Virilizing progestagens are undesirable for use in women but might be suited for male contraception. In view of the probably long-term use, this drug or its combination with androgens should be safe with regard to cardiovascular risk factors and the prostate and maintain bone mineral density.

3.4 Ageing male

Only partial androgen deficiency occurs in a subset of ageing men. So only partial supplementation of androgens is needed. One aspect is the increased negative feedback sensitivity to androgens with ageing, so the androgen molecule must be preferably little antigonadotropic so as to preserve the own residual testosterone production of the ageing male.  Anabolic effects on muscle and bone are desirable. For the actions on bone aromatization may be relevant which may also limit negative cardiovascular side effects though this may be less favourable for effects on the prostate. A limited conversion to DHT might be an advantage.

4 Modifications to limit potentially negative effects of androgens

4.1 Cardiovascular aspects

The higher frequency of cardiovascular disease in men than in premenopausal women is usually related to the atherogenic effects of androgens. It has become clear that both endogenous and exogenous testosterone account for the lower HDL-cholesterol levels in men compared to women. This view turns out to be too narrow; both androgens and oestrogens exert a wide range of favourable and unfavourable effects on laboratory variables related to cardiovascular disease, such as plasma endothelin, clotting factors, insulin sensitivity, homocysteine and lipolysis (for review[24]). In cross-sectional studies of men relatively low levels of testosterone appear to be associated coronary disease and myocardial infarction[25]. A recent longitudinal study confirmed this observation. In a follow-up study over 13 years of 66 men, aged 41-61 years, the decline in endogenous testosterone was associated with an increase in plasma triglycerides and a decrease in HDL-cholesterol in multivariate analysis controlling for obesity and other lifestyle covariates[26]. There is some evidence that administration of androgens to middle-aged obese men improves their cardiovascular risk profile[27]. Whether aromatization of androgens mitigates the negative effects that androgens have on some (but certainly not on all!) biochemical cardiovascular risk factors remains to be established. Two studies suggest that the aromatization of testosterone prevents largely the negative effects of androgens on HDL-cholesterol[28,29]. Further, in a man with a disruptive mutation in the oestrogen receptor gene, flow-mediated endothelium-dependent peripheral vasodilation was impaired[30]. So with the present limited knowledge it would seem that aromatizable androgens are to be preferred in regard of cardiovascular risk factors.

4.2 Prostate

Available evidence indicates that prostate carcinomas do not occur in men who are deprived of androgen action from early age on. It is further well established that androgen ablation prolongs survival of men with prostate carcinomas. As a result it runs contrary to belief that there is no serious evidence that androgens initiate prostate carcinoma[31]. The same applies to the induction of benign prostate hyperplasia (BPH), though pharmacological inhibition of androgen action (with LHRH agonists and antagonists, 5-reductase inhibitors) improves clinical signs of BPH. Substitution of hypogonadal men with conventional androgen preparations induce prostate volumes and PSA levels similar to age-matched controls[32]. Twin studies have shown that elevated testosterone and DHT levels do not predispose to prostate enlargement or symptoms of BPH[33]. A designer androgen that cannot be converted to DHT would at face value be a step forward with regard to safety but whether that is really true remains to be established. MENT is such a compound. Large scale long term studies of men taking the 5-reductase inhibitor type 2 finasteride are underway and may provide some answers. But a recent report indicated that finasteride is not very effective as a chemopreventive agent for prostate cancer in men with elevated levels of PSA[34].

There are indications that oestrogens may be implicated in the pathophysiology of BPH and prostate cancer. It is believed that oestrogens stimulate stromal proliferation and conditions, through IGF-I, the response of epithelium to androgens[35]. Recent studies show that sex hormone-binding globulin (SHBG) binds to a receptor on prostatic cell membranes generating intracellular cAMP and hence growth in these cells. This event is activated by estradiol and produces a degree of PSA secretion similar to following administration of DHT[36]. If this information can be substantiated nonaromatizable androgens may be an advantage for the prostate in ageing men, though they are probably a disadvantage for maintaining bone mass and for limiting the negative effects on cardiovascular disease.

5 Conclusion

Designer oestrogens as a treatment modality in hormone replacement in women has initiated the consideration of the concept of compounds with selective androgenic effects for male hormone replacement therapy. So far little attention has been paid to the definition of desired and undesired androgenic properties of synthetic androgenic compounds. This requires insight in basic androgen (patho) physiology. There is convincing evidence that aromatization of androgenic compounds to oestrogens might be an advantage for maintenance of bone mass and it might also mitigate negative effects of androgens on biochemical parameters of cardiovascular risks. There are theoretical considerations that oestrogens may have negative effects on prostate pathology in ageing men. While the role of DHT for the male sexual differentiation and for pubertal sexual maturation is evident, its role in mature and ageing males seems less significant. At first sight androgens that are not reduced to DHT would be an advantage for ageing men. It is, however, of note that a negative effect of DHT in prostate pathophysiology is not proven. And, indeed, a recent report indicated that finasteride is not very effective as a chemopreventive agent for prostate cancer in men with elevated levels of PSA[34]. Male contaception is another area that might benefit from designer androgens. It is mandatory for successful hormonal male contaception that FSH levels are well suppressed. Therefore, for male contraception a progestational agent with strong antigonadotropic action and, at the same time, strong androgenic properties might be an asset. For most of the androgenic actions the critical levels of androgens are not well established. The latter is relevant since a large amount of androgen molecules is required for its biological actions (as compared to oestrogens); this is an impediment in androgen replacement modalities. Androgen patches, for instance, are large and must be replaced every day as compared to oestrogen patches which are small and are applied twice weekly. There may be room for more biopotent androgenic compounds.


[1] Wilson JD. Androgen abuse by athletes. Endocr Rev 1988; 9: 181-9.
[2]  Sundaram K, Kumar N, Bardin CW. 7-methyl-19-nortestosterone (MENT): an ideal androgen for replacement therapy. In: Bhasin S, Gabelnick HL, Spieler JM,  Wang C, editors. Pharmacology, Biology, and Clinical Applications of Androgens. New York: Wiley-Liss, 1996. p 493-502.
[3] Salamone LM, Pressman AR, Seely DG, Cauley JA. Estrogen replacement therapy: a survey of older women's attitudes. Arch Intern Med 1996; 156: 1293-7.
[4] Love RR, Mazzess RB, Newcomb HS. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992; 326: 852-6. 
[5] Yang NN, Venugopalan M, Hardikar S, Glasebrook A. Identification of an estrogen response element activated by metabolites of 17-estradiol and raloxifene published erratum appears in Science 1997; 275: 249. Science 1996; 273: 1222-5.
[6] El-Hajj Fuleihan G. Tissue-specific estrogens-the promise for the future (editorial). N Engl J Med 1997; 337: 1686-7.
[7] Compston JE. Selective oestrogen receptor modulators: potential therapeutic applications. Clin Endocrinol 1998; 48: 389-91.
[8] Gormley GJ, Stoner E, Bruskewitz RC, Imperato-McGinley J, Walsh PC, McConnell JD, et al. The effect of finasteride in men with benign prostate hyperplasia. N Engl J Med 1992; 327: 1185-91.
[9] Gooren LJG. Human male sexual functions do not require aromatization of testosterone: a study using tamoxifen, testolactone and dihydrotestosterone. Arch Sex Bebav 1985; 14: 539-48.
[10] Bagatell CJ, Heiman JR, Rivier JE, Bremner WJ. Effects of endogenous testosterone and estradiol on sexual behavior in normal young men. J Clin Endocrinol Metab 1994; 78: 711-6. 
[11] Gooren LJG. Androgen levels and sex functions in testosterone-treated hypogonadal men. Arch Sex Behav 1987; 16: 463-73.
[12] Katznelson L, Finkelstein JS, Schoenfield DA, Rosenthal DI, Anderson EJ, Klibanski A. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab 1996; 81: 4358-65.
[13] Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E. Long-term effects of testosterone on bone mineral density in hypogonadal men. J Clin Endocrinol Metab 1997; 82: 2386-90.
[14] Boonen S, Vanderschueren D, Cheng XG, Verbeke G, Dequeker J, Geusens P, et al. Age-related (type II) femoral neck osteoporosis in men: biochemical evidence for both hypovitaminosis D- and androgen deficiency-induced bone resorption. J Bone Mineral Res 1997; 12: 2119-26.
[15] Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997; 337: 91-5.
[16] Van Kesteren P, Lips P, Gooren LJG, Asscheman H, Megens J. Long term follow-up of bone mineral density in transsexuals treated with cross-sex hormones. Clin Endocrinol 1998; 48: 347-54.
[17] Vanderschueren D. Androgens and their role in skeltal homeostasis. Horm Res 1996; 46: 95-8.
[18] Vanderschueren D, Bouillon R. Androgens and bone. Calcif Tissue Int 1995; 56: 341-6.
[19] Riggs BL, Koshla S, Melton LJ III. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in ageing men. J Bone Miner Res 1998; 13: 763-73.
[20] Elbers JMH, Asscheman H, Seidell JC, Gooren LJG. Effects of sex steroid hormones on regional fat depots as assessed by magnetic resonance imaging in transsexuals. Am J Physiol 1999; 276: E317-E325.
[21] Schwarz S, Pohl P. Steroids and opioid receptors. J Steroid Biochem Molec Biol 1994; 48: 391-402.
[22] Van Kesteren P, Megens JAJ, Asscheman H, Gooren LJG. Side effects of cross-sex hormone administration in transsexuals. Clin Endocrinol 1997; 47: 337-42.
[23] Meriggiola MC, Bremner WJ. Progestin-androgen combination regimens for male contraception. J Androl 1997; 18: 240-4.
[24] Vermeulen A, Kaufman JM. Androgens and cardiovascular disease in men and women. The Aging Male 1998; 1: 35-50.
[25] Phillips GB, Pinkernell BH, Jing T-Y. The association between hypotestosteronemia and coronary disease in men. Arterioscl Thromb 1994; 14: 701-6.
[26] Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13 year follow-up of former Multiple Risk Factor Invention Trial participants. Am J Epidemiol 1997; 146: 609-17.
[27] Marin P, Krotkiewski M, Bjorntorp P. Androgen treatment of middle-aged obese men: effects on metabolism, muscle and adipose tissue. Eur J Int Med 1992; 1: 329-36.
[28] Friedl KE, Hannan CJ, Jones RE, Kettler T-M. High density lipoprotein is not decreased if an aromatizable androgen is administered. Metabolism 1990; 39: 69-77.
[29] Bagatell CJ, Knopp RH, Rivier JE, Bremner WJ. Physiological levels of estradiol stimulate plasma high density lipoprotein cholesterol levels in normal men. J Clin Endocrinol Metab 1994; 78: 855-61.
[30] Sudhir K, Chou T-M, Messina LM, St Hutchison J, Korach KS, Chatterjee K, et al. Endothelial dysfunction in a man with disruptive mutation in oestrogen receptor gene. Lancet 1997; 349: 1146-7.
[31] Frick J, Jungwirth A, Rovan E. Androgens and the prostate. In: Nieschlag E, Behre HM, editors. Testosterone, Action, Deficiency, Substitution. 2nd ed. Berlin: Springer; 1998. p 259-91.
[32] Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched controls. Clin Endocrinol 1994; 40: 341-9.
[33] Meikle AW, Stephenson RA, Lewis CM, Middleton RG. Effects of afe and sex hormones on transition and peripheral zone volumes of prostate and benign prostate hyperplasia in twins. J Clin Endocrinol Metab 1997; 82: 571-5.
[34] Cole RJ, Skinner EC, Salem CE, Mertes SJ, Stanczyk FZ, Henderson BE, et al. The effect of finasteride on the prostate gland in men with elevated serum prostate-specific antigen levels. Br J Cancer 1998; 78: 413-8.
[35] Farnsworth WE. Roles of estrogen and SHBG in prostate physiology. The Prostate 1996; 28: 17-23.

[36] Nakhla AT, Romas NA, Rossner W. Estradiol activates the prostate
 androgen receptor and prostate specific antigen secretion through the intermediacy of sex hormone-binding globulin. J Biol Chem 1997; 272: 6838-41.


Correspondence to Prof LJG Gooren, Endocrinology/AZVUPO Box 7057, 1007 MB Amsterdam, The Netherlands.
Tel: +31-20-444 4444 pager 199. Fax: +31-20-444 0502.
E-mail: ljg.gooren@azvu.nl 
Dr Nhu Thanh Nguyen is a visitor to the Hospital of the Vrije Universiteit,
Amsterdam, The Netherlands.
Received 1999-03-01     Accepted 1999-04-30