:: Asian Journal of Andrology ::

Oestrogen-androgen crosstalk in the pathophysiology of erectile dysfunction

B Srilatha, PG Adaikan

Department of Obstetrics & Gynaecology, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074

Asian J Androl 2003 Dec; 5: 307-313

Keywords: oestrogen; environmental oestrogens; oestrogen receptor; testosterone; functional crosstalk; erectile dysfunction

Abstract

Ageing in man is associated with a decline in testosterone following changes in the hypothalamo-pituitary-testicular axis. This may offset the physiologic equilibrium between oestrogen and androgen and at some point when the ratio of free testosterone to oestradiol reaches a critical level, the oestrogenic gonadotropin suppressive effect predominates with decreased release of FSH and LH. Adding to this endocrinal complexity is the continued peripheral conversion to oestradiol through aromatisation. Although the androgen deficiency is not the sole cause for impotence in the elderly, there is a gradual decrease in nocturnal penile tumescence (NPT) and spontaneous morning erections with ageing. Despite the age related increase in oestrogen levels, the information on the pathophysiological role of the "female hormone" in erectile dysfunction has been scanty. Together with our identification of oestrogen receptors within the penile cavernosum, we have delineated dysfunctional changes on male erection mediated by oestradiol. These findings parallel the recent concerns over environmental oestrogens on fertility declines in young men. Oestrogenic activity is also present in plants and thereby in human diet. These phytoestrogens are structurally and functionally similar to oestradiol and more potent than the environmental oestrogenic chemicals such as organochlorine and phenolic compounds. Thus in the light of growing concerns of possible compromising effects on sexuality by endogenous and environmental oestrogens, we are faced with the scientific need to delineate their role on the mechanism of male erectile pathway in health and disease for clinical correlates and prognostics.

1 Introduction

Erectile dysfunction (ED) is progressively more prevalent in older men, because ageing is associated with many of the risk factors for ED [1, 2]. With the prospect of global doubling of men over 65 years by 2025 [3], this reciprocal influence of aging with ED entails special consideration. Most importantly, the aging process in man is accompanied by a number of endocrine changes [4]. These hormone modulations gained in interest as several studies such as the Massachusetts Male Aging [5, 6] convincingly demonstrated age-related changes in serum levels of total testosterone, free testosterone and sex hormone binding globulin (SHBG). Consequently a number of symptoms including ED, frequently seen in aging and collectively referred as the partial androgen deficiency state of aging male (PADAM) may have been associated with such age-related hormone changes. Doubtless, steroid hormone secretions are correlated with men's health status and understanding the dynamics of endocrine changes in man is important because of their role in sexual and reproductive function. Normal male reproductive function depends on the secretion of luteinizing and follicle stimulating hormones (LH and FSH) by the pituitary gland under the influence of hypothalamic gonadotropin releasing hormone (GnRH). LH stimulates the testicular Leydig cells to secrete testosterone (T); men produce moderate oestrogen along this steroidogenesis [7] and 75 % ~ 90 % of this "female" hormone in the male is from a simple enzymatic conversion (aromatization) of testosterone [8]. Aging changes at all three components of the hypothalamo-pituitary-testicular axis lead to decline in circulating T levels [9], however, oestradiol (E₂) does not follow this pattern [8]. Considering that oestrogen possesses opposing functional role [10], the decline in T level will therefore affect its "ying yang" physiological balance with oestrogen in man. This phenomenon will be compounded by the significantly higher E₂ level in the aging male [8], whose strong gonadotropin suppressive effect may lead to secondary hypogonadism from LH and FSH decrease [9].

2 Implications of functional crosstalk

Low testosterone level is implicated in decrease of NPT and loss of libido [11]. However, despite the concomitant elevation of oestrogen during this stage, available scientific information on the physiological role of E₂ on erectile function is too limited to correlate it with the aetiology for ED in these cases. The existing knowledge is that therapeutically oestrogen was as effective as antiandrogens or GnRH analogues in countering the hypersexuality of paraphilias [12] and oestrogen supplementation prior to gender reassignment reportedly feminized male transsexuals [13]. Indeed, months of oestrogen therapy is the mainstay for the development of breast and other female traits in these patients. In the process of such preoperative treatment, prospective male-female transsexuals have observed a gradual reduction in erectile and ejaculatory capacity and loss of NPT and morning erections (personal observation).

E₂ seems to play a distinct physiological role in male reproductive function. Together with the identification of oestrogen receptors alpha and beta (ER and ER) at some sites of the male reproductive tract [14], several reports have clarified the essentiality of oestrogen receptor activation in sperm production and fertility [7, 10, 15]. Underlying these reports is the awareness for oestrogenic activity in males; it could be that some of the physiological functions considered androgenic (e.g. effects on bones, cardiovascular and central nervous systems) might be mediated after aromatization of androgen to oestrogen [16]. Thus the pathophysiological consequences of endogenous oestrogen excess is more pertinent and critical in the male. Besides its occurrence in physiological aging, clinical conditions of such hyperestrogenism include non-insulin dependent diabetes mellitus [8], obesity, hypercholesterolemia and chronic liver diseases [17], idiopathic haemochromatosis [18], Klinefelter's disease [19] and tumours of male breast [17,19], Leydig cells [20] and adrenal cortex [21]; some of these clinical states are known to be associated with ED.

Similar oestrogenic challenge of great health concern which is scientifically yet to be qualified is the hormonal activity of compounds of environmental and plant origin, structurally related to endogenous oestrogen [22]. These oestrogen mimics are hazardous to human reproductive health as they are also anti-androgens [23]; early foetal exposure during sexual development affects differentiation and growth of the male reproductive tract[24] and is implicated in cryptorchidism, low sperm counts, and increased risk for testicular cancer later in life [25]. Recent studies have indicated that these environmental agents (xenoestrogens) [26] and plant oestrogens (phytoestrogen) [27] could also be antierectile, similar to oestradiol [28, 29]. Thus, an excessive intake/exposure to these chemical substances on a daily basis are likely to affect not only the fertility but also the sexual profile in male population. Hormone-like potency of these exogenous substances is further supported by their affinity for oestrogen receptors and extracellular proteins such as SHBG, a fetoprotein and albumin fractions [24,30], hence such actions arising from modulations on the endogenous hormone levels may be complex. Thus in the light of these reports, a rational understanding of the testosterone pathophysiology and the effects of oestrogen on endogenous androgen milieu and erectile function will bridge the scientific void in this area.

3 Testosterone in sexual function

Over 95 % of the testosterone in the male is secreted by the testicular Leydig cells. It is the precursor (prohormone) for the formation of other two hormones (dihydrotestosterone/DHT and E₂) that may mediate many of the physiologic processes of androgen action. About 5 % of systemic testosterone is reduced to DHT by 5a-reductase and oestrogen(s) is formed by aromatase enzyme complex in the extraglandular tissues including fat, muscle, kidney and liver. All steroid hormones exist either in a free (unbound) state or in combination with serum proteins with approximately 38 % of testosterone bound to albumin and 60 % to SHBG [31]. Circulating oestradiol on the other hand is loosely bound to albumin and a lesser extent to SHBG because of its low affinity compared to testosterone [32].

It has been suggested that the role of circulating androgens with regard to erectile physiology and sexual behaviour remains somewhat unclear [33] since in men with normal gonadal function, there is minimal correlation between testosterone levels and erectile function [34]. In lower animals, certain well-defined changes in sexual activity are precipitated following castration. Among the different parameters of the copulatory pattern, the ability to ejaculate disappears early, followed by intromission and mounting. Hormonal replacement restores all aspects of mating in these animals [35] and it is interesting to note that the amount of testosterone required to reinstate such behaviour is much less than the normal range [36, 37]. Central functional effect of testosterone is demonstrated by the fact that exogenous T restores apomorphine induced erections in castrated rats [38, 39]. Peripherally, it contributes to mediation of nitrergic neurotransmission, accentuates nitric oxide synthase activity and nitric oxide release [40-42] and increases intracavernous pressure [43]; it is possible that T also acts directly on the motoneurons supplying the striated muscles of the penis [44].

The positive actions observed for testosterone in animals are related to improvement of parameters of libido and ejaculation relating to frequency and not ED per se. Similarly, it is observed that the level of testosterone in man is a dominant determinant of frequency of coitus, indicating its role on improvement of libido [45]. Hence, as in animals, testosterone may play a similar contributory physiological role on erectile physiology through NO-cGMP axis as well as improvement of frequency of coitus, ejaculatory capacity and libido. The effect of castration on sexual function in humans has been shown to range widely from complete loss of libido to continued normal sexual activity[46]. In the clinical scenario of some hypogonadal men, a simple restoration of T level to 50 % ~ 60 % of the physiological range was adequate for normal sexual functioning [47, 48] whereas in others, there was limited effectiveness to androgen supplement[49] although the frequency of sexual thoughts and erections per week showed some dose-response relationship [31, 50].

4 Benign hypogonadism of the aging male

While developed countries all over the world now enjoy a life expectancy well into the eighth decade, a review of literature indicates that a possible male equivalent of menopause is existent and is denoted by terms such as the male climacteric, viropause, andropause, andropenia, low testosterone syndrome or more commonly the partial androgen deficiency of the aging male, PADAM. There is no clear consensus about the physiology of the rather moderate but age related decline of the androgen levels with aging. Many factors from the external and internal milieu may affect the highly sensitive hormonal balance; aging is one of them with changes at all three levels of the hypothalamo-pituitary-testicular axis [9] and probably more so in the aging testes [51]. This secondary hypogonadism is identified in elderly males seeking help for their ED. As mentioned earlier, the second mechanism involves continued peripheral formation of oestradiol from testosterone and its inhibitory effect on gonadotropin release leading to low androgen. Understandably, these changes lead to endocrine imbalance in T-E₂ levels.

5 Oestrogen in the male

Since estrogens have multiple effects in males, this hormone class is no longer referred to as female sex hormones; indeed some so-called androgen effects are dependent on its peripheral aromatization to 17 oestradiol and oestrone [7, 8, 16] in addition to testicular oestrogen secretion which is stimulated by LH [52]. Oestrogen synthetase or aromatase is an enzyme complex (P450arom and NADPH-cytochrome P₄₅₀ reductase) located in the cellular endoplasmic reticulum; it catalyses the formation of C18 oestrogens from C19 androgens. Three consecutive oxidative reactions convert the A ring of androgens to the phenolic A ring of oestrogens [53]. As males and females synthesise oestrogens, it is not surprising that oestrogen receptors (ER) exist in both sexes in many parts of the body [14]; this includes the penile cavernosum [54]. Subsequent to initial cloning of two unique ER subtypes (a, b) in humans [55, 56], the structural domains of both these receptors have been described; ER is also shown to have two isoforms, 1 and 2 [57]. Furthermore, ER and ER show an overlapping tissue distribution and occur together with androgen receptors [53]. Adding to this complexity is another mode of action for oestrogens i.e. the non-genomic mechanism which operates on the cell surface influencing ionic channels in tissue response [58]. These insights have opened newer perspectives on the effects of oestrogens in areas not previously recognized to be sensitive to the hormone.

6 Clinical pictures for the studies of oestrogen function in males

The importance of oestrogen in normal female physiology is well known but uncertainty still lingers in males regarding its different mechanisms and sites of action in health and disease. Two clinical conditions are likely models in males to study effects of congenital oestrogen deficiency. These include oestrogen resistance caused by ER gene mutation and aromatase deficiency due to mutation of aromatase cytochrome P450. In these cases, the physiological responses by oestrogens were lacking; these subjects had elevated serum FSH and LH levels and normal or elevated T levels confirming that oestrogen has an important role in the regulation of gonadotropin secretion [53] in males.

Feminizing tumors of the adrenal cortex are associated with features of oestrogen excess and androgen deficiency such as gynaecomastia, diminished libido and impotence and testicular and prostatic atrophy [21]. As discussed earlier, this sustained oestrogen excess could induce hypogonadism in men by dual effects on the gonadal axis - by suppressing the secretion of LH and Leydig cell steroidogenesis. Similarly, a case of testicular dysfunction also contributed to a clinical picture of hypo-gonadotropic hypogonadism and azoospermia associated with excessive oestrogen production. In this case report, the patient responded by increased T release to clomiphene citrate and GnRH; this indicates that the testicular abnormality was overcome by competitive inhibition of oestrogenic action [59].

Action of oestradiol (produced by aromatase activity in the testis) has not been fully characterized on spermatogenesis in human. In oligospermia, with high E₂/T ratio, it is considered that the role of E₂ is suppressive to spermatogenesis [60]. In such infertile patients, sperm counts (and serum free T) were significantly increased by treatment with testolactone, an aromatase inhibitor [61]. On the contrary, animal studies indicate that oestrogen has a positive effect on sperm count through fluid reabsorption in the rete testis and efferent ductules [15]. To accomplish this function, its concentration in the testicular fluid is high and comparable to the serum 17 oestradiol level in females of reproductive age. Another complimentary finding is oestrogen synthesis within the sperm. Developing spermatids in several species contain aromatase and the intrinsic E₂ plays a role in the regulation of number of sperms transported [62]. Therefore, further research is necessary to delineate the possible oestrogen dysfunction in evaluations of male infertility.

On the other hand, the role of oestrogen in the human male sexual behaviour is still unknown. Since the initial clinical report of impotence with hyperoestrogenism [63] and the immediate refutes [64, 65], few studies have looked at the effect of oestrogens on human male sexual behaviour with conflicting results [8, 66]. Similarly in animal studies, the sexual behaviour is impaired in ERKO mice [67] but not in ERKO mice [68]. In normal adult male rats, E₂ produced dose related inhibitory effects on sexual function [29] and improvement of fecundity on oestradiol withdrawal, administration of testosterone propionate or tamoxifen citrate [69]. This indicates the possible existence of a functional crosstalk between androgen and oestrogen. Thus it appears that despite these recent discoveries, we are still largely in the dark about the precise physiological importance and sexual health implications of oestrogens in man. Comparable studies in men will prove more difficult to design and interpret because of the absence of a woman-equivalent dramatic hormonal menopause. However, it seems plausible that the exact functional roles for oestrogen as well as the androgen-oestrogen balance in the male will eventually be clarified to characterize the changes in male fertility and erectile physiology.

7 Oestrogens from the external source

Great concern belies the threat posed to male reproductive health and sperm count by chemical and physical hormonal mimics present in the environment. However until recently, less attention was paid to the possible effect of these agents on male sexual function. Going by the review so far, industrial chemicals with oestrogenic and antiandrogenic potentials [30] are likely to interfere directly or indirectly with sexual health parameters; workers contacting synthetic oestrogen diethylstil-boesterol and its byproduct diaminostilbene presented with decreased libido and impotence [26]. This observation supports our hypothesis that active environmental oestrogenic substances may precipitate ED [28]. While considerable attention has been focused on the potential effects of a variety of environmental contaminants on male reproductive function, it is imperative that sexual function/dysfunction is given due scientific consideration because of the possible extension of these deleterious effects from changes in the sex hormones milieu. Despite being weak analogues, their ability to interact with more than one steroid-sensitive pathway [23] makes it all the more imperative to do so.

Existing scientific evidence indicates the identity of four major classes of environmental hormone substances; these include environmental oestrogens, antioestrogens, antiprogestins and antiandrogens [25]. Among the environmental oestrogens, both phyto and xenoestrogens actively bind to oestrogen receptor in vivo and in vitro [24]. Xenoestrogens are components of organochlorine pesticides, polychlorinated biphenyls, phenolic compounds and phthalate esters and commonly used antiperspirants, deodorants, lotions, shampoos etc [70]. These chemicals are 103~104 folds less potent than oestradiol although this factor is independent of their lipophilicity and bioaccumulation and the effects of individual compounds in man will depend on the extent of exposure. Hence, it may be perceived that exposure to such chemicals is of minor significance compared to naturally derived plant oestrogens, which are consumed on a daily basis. Hence, an inadvertent exposure of the male population to these oestrogenic substances can disrupt the critical quantitative balance of the two endogenous hormones with untoward implications on their sexuality, besides the reported effects on fertility.

8 Phytoestrogen pathophysiology

Phytoestrogen is the blanket term for non-steroidal oestrogen mimics and precursors from several plants; they are phenylpropanoids or simple phenols [71]. The chemical derivatives of scientific interest are isoflavones (present in peas, beans, lentils and soy), lignans (found in berries, cereals, most vegetables, fruits and nuts) and coumestans occurring in alfalfa, bean sprouts and red clover [72, 73]. These phytoestrogens are phenolic ring mimics of oestradiol; this structure is an important prerequisite for affinity to endogenous ER [70]. Thus, they can act as oestrogen agonists or antagonists; their actions being dependent on their concentration, availability of endogenous receptor and oestrogen status. Despite weak affinity (10-2 to 10-3) when compared to E₂ or oestrone, the preferential binding of these compounds to ER than ER [74] suggests that they may exert their actions more selectively than the endogenous oestrogens, conforming to their new identity as natural selective oestrogen receptor modulators (SERMs) [73].

At the ER, these compounds may be agonistic (activate transcription) or antagonistic (inhibit endogenous oestrogenic effect by mechanical presence at the receptor and preventing activation of DNA response elements). They may act as antioestrogens also by competing for the oestrogen biosynthesizing and metabolizing enzymes such as aromatase and 17 beta-hydroxy steroid oxidoreductase type1 [75]. Additionally, lignan and isofla-vone phytoestrogens are also antiandrogenic as they inhibit conversion of T to DHT [30] and induce synthesis of SHBG [22] with further hormonal disruption. With less affinity for extracellular binding proteins such as SHBG and a fetoprotein compared to endogenous E2, phytoestrogens may mediate greater receptoral effects because of higher free levels [25]. All soybean proteins and foods commonly consumed in Asia contain significant amounts of the isoflavones daidzein and genistein, either as the aglycone (unconjugated form) or as different types of glycoside conjugate [76, 77]. They are enzymatically converted to the active heterocyclic phenols in the gastrointestinal tract [78]; the pharmacokinetics therefore varies widely in individuals consuming the same quantity [72]. The precursors and metabolites exert oestrogenic activity, enter the portal circulation and get eliminated by kidneys similar to endogenous oestrogens[74].

9 Conclusion

While high levels of isoflavones in blood and urine after soy food consumption and the lesser prevalence of hot flushes in menopausal women of Japan compared to Europe or North America [74] explain the therapeutic benefits of these SERMs, the possibility that there may be toxic hormonal effects in males cannot be ignored. Although this issue is currently recognised, there has been little progress towards a realistic assessment of whether environmental oestrogens per se pose serious sexual health threat in them. Besides the lack of known physiological role for oestrogen in males, the reason for the limited progress is the wide number of oestrogenic chemicals to be evaluated. However, the current knowledge that there is inadvertent exposure to a number of oestrogenic substances is a matter of great scientific concern. The mechanism by which these factors may affect male sexual health needs to be identified. Active research studying the epidemiological corollaries in animal models will address the paucity of scientific evidence on these changes and lead to a greater understanding of the management measures to achieve satisfying sexuality in men.

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Correspondence to: Prof PG Adaikan, Department of Obstetrics & Gynaecology, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074.
Tel: +65-6772 4128, Fax: +65-6779 4753
Email: obgadaik@nus.edu.sg
Received 2003-09-12 Accepted 2003-09-15

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