and the same androgen for all? towards designer androgens
J G Gooren1, Nhu Thanh Nguyen2
of Andrology, Department of Endocrinology, Hospital of the Vrije Universiteit, Amsterdam, The Netherlands
Asian J Androl 1999 Jun; 1: 21-28
Keywords: androgens; synthetic androgens; designer drugs
AbstractThe 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.
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.
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
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.
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.
observation that the non-steroidal oestrogen receptor antagonist tamoxifen
preserved bone mass in postmenopausal women with breast cancer
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. The mechanism is interpreted as follows.
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). 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).
Medical and pharmaceutical interest in androgens versus oestrogens
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.
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
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. 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.
of sexual functioning in adult men could be achieved with 40-60% of normal adult male testosterone
levels. 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.
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
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.
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.
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. 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. In male-to-female transsexuals, orchiectomized in adulthood, estrogen administration is capable of maintaining BMD. 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. 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). 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. So with the present state of knowledge it would therefore seem desirable that induction and maintenance of bone mass androgens are aromatizable.
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 and MENT or similar compounds would maybe offer advantages in this regard.
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:
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. 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. 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.
Non-genomic actions of androgens
3 Requirements for the various androgen treatment indications
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%). 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.
Maintenance of virilization
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.
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.
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.
4 Modifications to limit potentially negative effects of androgens
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).
In cross-sectional studies of men relatively low levels of testosterone
appear to be associated coronary disease and myocardial infarction.
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. There is some evidence
that administration of androgens to middle-aged obese men improves their
cardiovascular risk profile. 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. So with the present
limited knowledge it would seem that aromatizable androgens are to be
preferred in regard of cardiovascular risk factors.
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. 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. Twin studies have shown that elevated testosterone
and DHT levels do not predispose to prostate enlargement or symptoms of
BPH. 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.
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. 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. 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
Wilson JD. Androgen abuse by athletes. Endocr Rev 1988; 9: 181-9.
to Prof LJG Gooren, Endocrinology/AZVUPO Box 7057, 1007 MB Amsterdam,