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Differences in reproductive endocrinology between Asian men and Caucasian mena literature review

M.E. van Houten, Louis J.G. Gooren

Andrology Unit of the Department of Endocrinology, Hospital of the Vrije Universiteit, Amsterdam, the Netherlands

Asian J Androl  2000 Mar; 2: 13-20


Keywords: ethnology; Asian men; Caucasian men; prostatic neoplasms; endocrinology; male contraceptive agents; androgen
Abstract
This review provides an overview of the literature on aspects of reproductive endocrinology wherein Asian men may differ from Caucasian, notably, prostatic nioplasm and the sensivity to pharmacological regimens of male contraception. Both genetic and environmental factors, such as nutrition, might be relevant. Asian men residing in Asia seem to be relatively protected from clinical prostatic nioplasm while the prevalence of preclinical prostatic nioplasm is not different. Migration to an area with a higher prevalence reduces this difference but does not undo it. With regard to prostatic nioplasm the following factors have been considered as relevant in Asian men: 1) a reduction in 5-reductase level, 2) decreased levels of androgenic ketosteroid precursors of 5-reduced androgen metabolites, 3) the decreased presence of a P53 mutation, 4) a higher CAG-repeat length of the androgen receptor, 5) a possible higher level of physical activity, 6) differences in sexual activity. Furthermore, Asian men respond to a higher degree with azoospermia in response to contraceptive steroids. Possible explanations offered for the more pronounced response to contraceptive steroids are: 1) differences in testicular structure and decreased spermatogenic potential, 2) an earlier and more marked suppression in LH secretion by exogenous androgens. The differences may be due to genetical and/or environmental factors influencing the peripheral testosterone metabolism. Dietary factors such as the higher intake of phytoestrogens in Asians might exert effects on 5-reductase activity and/or on sex hormone binding globulin (SHBG) levels, thus having an impact on the biological efficay of circulating androgens.

1 Introduction

In the biomedical sciences it is widely assumed that (patho)physiological mechanisms  reliably established in a certain group of subjects, carry a general validity for other subjects, regardless of their ethnic background. In its generality this is a workable principle. Though Asian men are  identical to Caucasian men in most aspects of reproductive endocrinology, certain research findings over the last twenty to thirty years invite the idea that there are some features that distinguish them from Caucasians. For instance, Asian men, with the same dosages of contraceptive drugs, have a higher percentage of azoospermia than Caucasian men[1-3]. Another finding has been that Asian men residing in Asia are relatively protected from the clinical manifestations of prostatic carcinoma while the occurence of preclinical carcinomas is not different from that of Caucasians. Migration to an area with a more Western lifestyle narrows this difference but does not neutralize it[4-6]. The latter might imply that certain differences found between Asian and Caucasian men might not be based on ethnicity per se but on environmental factors such as nutrition, for instance, with differences in intake of phytoestrogens.

This review attempts to provide an overview of the literature addressing aspects of reproductive endocrinology with a certain specificity for Asian men.

2 Clinical findings

2.1 Prostatic cancer

Prostate cancer is the most common malignancy in men, and one of the most common causes of death from cancer. The incidence rate of clinical prostatic neoplasm varies substantially among countries throughout the world[7]. There is a considerable evidence for a racial variation in morbidity and mortality from prostatic neoplasm. African-American men have the highest rate of prostatic nioplasm in the world, whereas Japanese and Chinese men native to those countries have the lowest; there is a 30-50 fold difference in risk between these groups[8,9]. Clinical prostatic neoplasm appears not to be a different disease in Japan and the United States, but the probability of progression from histological to clinical prostatic neoplasm has been found to be much lower in Japanese than in American men[10]. Furthermore, when Asian men migrate to a Western country, the prevalence of prostatic neoplasm increases but still remains low, even in their second and third generations after migration[11]. So, some environmental factors may delay tumour progression, while others promote it[7]. Possible explanations offered for the the difference in prevalance of prostatic neoplasm between Asian men and Caucasian men include genetic factors, environmental factors and differences in peripheral androgen metabolism. Genetic factors that could play an important role are the p53 tumor suppressor gene (a p53 mutation associated with progression of latent prostatic neoplasm); this was found to be more rare in Japanese men than in Caucasian men [12,13]. Another genetic factor might be the CAG repeat length of the androgen receptor (variations in these repeats are associated with polymorphism of the androgen receptor, and thus may be associated with growth regulation of prostatic cells). Difference in CAG repeat length is reportedly associated with a difference in risk of prostatic neoplasm[14]. Environmental factors thought to be of importance are possible differences in levels of exercise, levels of sexual activity and nutritional differences between various ethnic groups[15-17] Hypothesized differences in peripheral androgen metabolism are the diminished activity of the enzyme 5-reductase reported in several studies in Asian men versus Caucasian men[18,5]. This enzyme is involved in conversion of testosterone to the major effector hormone dihydrotestosterone. A lower level of 5-dihydrotestosterone could theoretically slow down the progression of latent prostatic neoplasm to clinical cancer.

2.2 Contraceptive studies

Spermatogenesis is a complex process whereby spermatogonia (the primitive stem cells) undergo a complex development to become mature spermatozoa[19]. Luteinizing hormone (LH) affects spermatogenesis by stimulating the Leydig cells to secrete testosterone. FSH primarly acts on the Sertoli cells to secrete inhibinand activin. Thus FSH together with testosterone initiates and stimulates spermatogenesis. FSH and LH secretion is controlled by pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Lately, male contraception has been an important research topic. Azoospermia and oligozoospermia could be reached in the majority of men with a combination of GnRH antagonists and replacement doses of testosterone[19]. Steroid hormones suppress gonadotropin output[20] and secondarily suppress testicular functions including the production of spermatozoa. Multiple trials have shown the efficacy of testosterone enanthate administration in suppressing spermatogenesis[3,21,22]. Recent clinical trials, to determine the efficacy of different male contraceptive regimens, disclosed ethnic differences in response to contraceptive steroids[1]. Testosterone-induced suppression of spermatogenesis to azoospermia occurred in about 90% of Asian subjects, but only in 60-70% of Caucasian subjects[2,3]. It is unclear whether ethnigenetic differences in steroid metabolism, or gonadotropin susceptibility to suppression by the androgen on quantitative aspects of spermatogenesis, are accountable for the differences seen between Caucasian and Asian populations[19].

3 Differences in reproductive physiology

3.1 Hypothalamus-pituitary-testis axis

To explain the observed differences in male contraceptive efficacy between Asian men and Caucasian men, a clinical study tested whether there are ethnic differences in the sensitivity of gonadotropin secretion to suppression by testosterone[2]. In the human male, the major circulating serum androgen is testosterone. More than 95% testosterone is from testicular origin. Testicular testosterone secretion is controlled by pituitary LH secretion, which stimulates Leydig cell steroidogenesis. Testosterone  exerts a negative feedback action through inhibition of hypothalamic GnRH and also pituitary gonadotropin. In this study ramped increases in infused testosterone doses were monitored in normal Asian and Caucasian men living in the United States. Compared to Caucasian men, Asian men responded earlier and with more marked suppression of pulsatile LH secretion to ramped testosterone infusions. But, with increasing testosterone doses no differences in suppression were observed. In contrast to pulsatile LH secretion, the responsiveness of pulsatile FSH secretion to exogenous testosterone infusion was not significantly different between the two ethnic groups. Still the regularity of FSH release in the Asian subjects, compared to Caucasians, seemed to be reduced. At baseline, the mean serum FSH concentration was lower in the Caucasian versus the Asian men. This may suggest a possible decrease in spermatogenic reserve and/or gonadal negative feedback action in Asian men. This is in agreement with other studies[23,24] that conclude the presence of smaller testes in Asian men. One study reported the presence of smaller testes coupled with reduced Sertoli cell number and function and reduced daily sperm production in Asian men[24].

Possible explanations for these observed differences in Asian men versus Caucasian men may be due to differences in peripheral androgen metabolism, spermatogenetic potential, genetic differences and environmental factors.

3.2 Peripheral Androgen Metabolism

Testosterone has to enter the prostatic from the circulation to exert its effects. Only 4 % of testosterone is unbound to sex hormone binding protein (SHBG) and albumin and is able to enter the prostatic cell through diffusion. Over 95% of testosterone that enters the prostatic cell is converted to 5-dihydrotestosterone DHT. DHT is considered to be the major effector hormone in certain androgen dependent tissues, particularly the pilosebaceous unit of the skin and prostatic gland. In these tissues DHT is formed from testosterone via the enzyme 5-reductase. In the human there are two isozymes of 5-reductase, type I and II. Type I is expressed mainly in the skin and hair tissues, and type II in the prostatic gland. After conversion of testosterone to DHT, DHT binds to androgen receptors to control the growth of facial and body hair and the development of the prostatic gland[18].

One potential explanation for the observed reduction in cancer risk and the observed difference in response to exogenous testosterone administration in contraceptive studies in Asian men, might be a lower activity of 5-reductase in Asian men. DHT is important for the prostatic and its size[25] and DHT and other 5-reduced androgen metabolites play an important role in the regulation of spermatogenesis under conditions of intratesticular testosterone deficiency[3]. Several studies have addressed the possible differences in the activity of 5-reductase between Asian and Caucasian men. Some studies have found that Chinese men may have less 5-reductase activity than Caucasian men[5,18]. This conclusion was based on the lower amount of  5-reduced androgen metabolites found in Asian men versus Caucasian men, such as 3,17-androstanediol and androsteronglucuronide. These metabolites were assumed to reflect the rate of tissue 5-reduction of androgens[18]. In a clinical trial[3], the role of the extent of 5-reductase activity in an individual was observed to determine whether an azoospermic or oligozoospermic response was obtained on exogenous administration of testosterone resulting in gonadotropin and presumably testicular steroidogeneses suppression, regardless of his ethnic group. After exogenous testosterone administration to a group of Caucasian men, an increase in 5-reductase activity was observed in men remaining oligozoospermic (non-suppressors), but not in those becoming azoospermic (suppressors). The higher the increase in 5-reductase activity, the less suppression of spermatogenesis.

A later study[26], however, demonstrated that the decreased levels of 5-reduced androgen metabolites in Asian men was not explained by a genetically determined low 5-reductase activity. Instead, reduced levels of the androgenic ketosteroid precursors of these plasma metabolites are a more likely reason. They found a significant reduction in the production of testosterone and plasma testosterone in Chinese residents compared to Chinese migrants in Pennsylvania. No difference was found between Chinese residents and Caucasians living in Pennsylvania. No information was provided in the study regarding the amount of years for which the Chinese migrants had already resided in Pennsylvania. The study of Lookingbill DP et al, 1991[18] showed no obvious difference in serum total and free testosterone levels between Asian and Caucasian men. Yet concentrations of the precursor androgens, DHEA sulfate and androstenedione were significantly elevated in the Caucasian men compared to the Chinese men.

Apart from the effect of DHT on spermatogenesis and development of prostatic carcinoma, DHT may also be of importance in regulating LH-secretion. In the presence of decreased production of DHT, one expects an increase in LH secretion. Such an effect of DHT has been demonstrated in several studies[27,28], but not all[29,30]. Though very high concentrations of DHT are capable of decreasing serum LH, DHT is, however, unlikely to play an important role in the physiological regulation of LH[29].

Other factors which possibly influence peripheral androgen metabolism are dietary and/or other environmental factors. Especially the high phytoestrogen contents of Asian diets appears to influence peripheral androgen metabolism (see paragraph on environmental factors)[31]. The level of plasma sex hormone binding globulins (SHBG) could also be of significance. The relation of SHBG levels to prostatic disease is still unclear, but SHBG may potentially protect against progression of latent to clinical prostatic neoplasm by modulating free testosterone levels and therewith its androgenic action[32]. The contrary has also been suggested i.e., SHBG-binding may be required for steroid hormones to bind to their tissue receptors[33]. Contradictory results about the levels of SHBG in Asian men have been reported[5,26].

3.3 Genetic factors

3.3.1 Testicular structure and spermatogenic potential

The elevated basal serum FSH concentrations in Asian men found in contraceptive studies, may suggest an inherent relative reduction in inhibin production by the Sertoli cells, subsequent reduced gonadal feedback of FSH release and/or lower spermatogenic capacity in Asian versus Caucasian men[2]. One study found mean testicular size in Chinese men to be lower than that of Caucasian men[23]. In another study the testes from 12 Chinese men were compared to those from 8 Hispanic men and 12 nonHispanic Caucasian men of ages 293, 302, and 293 years, respectively[24]. Asian men were found to have smaller testes volumes, reduced Sertoli cell number and function, reduced daily sperm production and increased apoptotic germ cell rate, which together with elevated serum FSH levels suggest a decreased spermatogenic potential in Asian men in comparison to Caucasian men. Furthermore the volume density of Leydig cell cytoplasma was highest in Asian men, potentially a mechanism to preserve a relatively normal spermatogenesis. In view of this, Asian men may be more susceptible to exogenous testosterone administration and this mechanism might subject them to a heightened negative feedback response to administration of exogenous testosterone[24]. Possible explanations offered for the observed difference in testicular structure, volume and spermatogenic potential are genetic[34] or dietary differences between Asian and Caucasian men[31].

3.3.2 p53 tumorsuppressor gene

Several molecular techniques have attempted to discover whether mutational profiles of oncogenes or tumor suppressor genes may provide clues to etiological factors for the observed difference in age specific prevalence rate of clinical prostatic neoplasm in Asian men versus Caucasian men[10,13]. Analyses of the tumor suppressor gene p53, located on chromosome 17p, in various tissues suggested that p53 gene mutations are more closely associated with the subset of advanced and/or highly malignant carcinomas, including those of the prostatic[12,35]. Two studies have concluded that p53 mutations play a role in progression of latent prostatic neoplasm in Japanese man, as well in European and American men[13,35] The p53 mutational spectrum (at CpG site) appears to be rare in Japanese men than in American men.

3.3.3 CAG repeats

Androgens play a direct role in normal and malignant growth of cells via androgen receptor (AR) mechanisms. After binding of androgens to the AR, the transcription of androgen-responsive genes is stimulated. The AR is thus involved in the growth regulation of prostatic cells[36]. A lot of research has been directed to study possible differences at the AR receptor level, which can explain the observed differences in prostatic neoplasm incidence between Asian men and Caucasian men. Among known polymorphisms regarding the AR, only one has so far been associated with functional variation in androgen action, namely, the CAG repeat polymorphism. The length and number of CAG repeats have been associated with the risk of development of prostatic neoplasm; a shorter CAG repeat length compared to longer CAG repeat length might be associated with an increased risk of prostatic neoplasm[14,37,38]. The distribution of the number of repeats was highest in Asians compared to African-Americans and non-Hispanic whites thus offering a relative protection to Asian men as compared to non-Asian men[39].

3.4 Environmental factors

3.4.1 Dietary factors

Diets differ between Asians and Caucasians. A modern Western diet is high in fat and protein, whereas a traditional Asian diet is low in fat and protein but high in carbohydrates. An important part of the Asian diet consists of soy and vegetarian foods with high amounts of isoflavonoids, flavonoids and lignans. These are metabolized by the gut microflora to produce phytoestrogens such as enterolactone, daidzein and genistein[40]. Phytoestrogens are plant chemicals that resemble steroidal oestrogens in structure or function. Most phytoestrogens are isoflavonoids or lignans. A wide range of biochemical actions of phytoestrogens has been reported. These actions include their capacity to bind to oestrogen receptors, elucidate a variety of non-receptor-mediated actions, act as anti-oxidants, have an inhibitory action of enzymes involved in the biosynthesis of oestradiol and other steroids, such as 17-hydroxysteroid dehydrogenase, 5-reductase or aromatase. Both coumestrol and genistein appear to have higher affinity for the newly discovered oestrogen receptor variant ER (present in the prostatic) than for the classical oestrogen receptor (ER)[31].

Only a few, non-clinical, studies have examined the effects of phytoestrogen on testicular function, and results are somewhat contradictory[31]. In a study in prepubertal mice fed with 900-3 600 mg/kg of genistein glycoside (genistin) during six weeks, testicular weight and spermatogenesis was suppressed[41]. But an oral dose of 300-1 000 mg/kg genistein or genistin fed to adult male rats over a period of four weeks had no effect on the testicular weight[42]. A recent study[43] explored the effects of an Asian diet (fat 15%, protein 15%, carbohydrate 70%) compared to an Western diet (fat 35%, protein 25%, carbohydrate 40%) on sperm numbers and quality in cynomolgus monkeys. The monkeys were administered testosterone enanthate and medroxyprogesterone for a certain period to suppress spermatogenesis. A lower level of free testosterone and higher LH level was found in the group of monkeys that received a Western diet versus the group receiving an Asian diet. When, after termination of the drug administration, spermatozoa became detectable again it was noticed that the quality of spermatozoa during and after treatment was better in the group which had received the Western diet than in the group which had received the Asian diet. Phytoestrogens may also have an important effect on 5-reductase activity. It has been found that isoflavonoiden and lignans inhibit 5-reductase activity[44].

Another effect of phytoestrogens on testosterone metabolism has been noted. Vegetarians and Asian men seem to have higher plasma levels of SHBG and lower levels of free and total testosterone than do men on a Western diet[40].This is in agreement with a recent study[45] which reports that diets low on protein, especially if consumed by elder men, may lead to elevated SHBG levels and decreased testosterone bioactivity. Total caloric intake, carbohydrate and fat did not have a significant influence. An increase in SHBG levels has been reported[46] when a diet low in fat and high in fibres is consumed plus a daily exercise regimen is followed. These effects on SHBG might result from the action of phytoestrogens, which as weak oestrogens may stimulate the synthesis of sex hormone binding globulin in the liver[40,47]. SHBG may protect against progression of latent to clinically apparent prostatic neoplasm by modulating the androgen action[32]. The latter study observed a higher level of SHBG in Chinese men living in China compared to Chinese migrants to Australia. However, the findings are not consistent as low levels of SHBG in Chinese residents compared to Chinese migrants have also been found[5,26], whereas no difference in SHBG levels was observed between Caucasian men in Pennsylvania as compared to Asian migrants[26]. The same discrepancies have been found on comparison of testosterone levels between Asian and Caucasian men. One study showed no difference in serum total and free testosterone levels between Asian and Caucasian men[18], while another found low levels of total plasma testosterone in Chinese residents compared to Chinese migrants[26].

Finally, experimental studies provide evidence for the effects of phytoestrogen on gonadotrophin secretion through the presence of an ER-receptor in pituitary gonadotrophs. Zearolone, a fungal oestrogen, was able to suppress LH secretion in rhesus macaques. Genistein and zearalenone inhibited GnRH-stimulated LH release in ovariectomized rats[31]. But these experiments were done in female animal species. The previously mentioned study[43] in male monkeys fed with either an Asian diet or a Western diet showed that the serum levels of LH were significantly higher in animals fed an Western diet than those fed an Asian diet. FSH levels were also found to be higher in the group receiving the Western diet. The high levels of FSH found in monkeys receiving a Western diet is in contradiction with the results reported in humans where FSH levels were found to be higher in Asian men as compared to Caucasian men[2]. Finally, an interesting study that investigated the influence of ethnic differences on concentrations of lignans and isoflavonoids in plasma and prostatic fluid[48] reports that higher concentrations of the isoflavonoid phyto-estrogens, daidzein and equol, were found in the plasma and prostatic fluid of men from Hong Kong as compared to those from Britain and Portugal.

In conclusion, isoflavonoids and lignans have many interesting properties, and may in part be responsible for lower incidences of prostatic neoplasm in men from Asia. The isoflavonoiden from soya, present in high concentrations in the prostatic fluid of Asian men, may be protective against prosate disease[48].

3.4.2 Physical exercise

Experimental studies in animals and epidemiological studies in human populations show some evidence for an inverse relationship between exercise and development of cancer. Physical activity has been suggested to be protective against the development of breast and colon cancer, and also prostatic neoplasm[15,46,49,50]. This is, however, not confirmed by other studies[51-53]. Long-term physical activity may decrease tumor risk by its effect on natural immunity, antioxidant defenses, improved energy balance, hormonal changes, or by other unknown mechanisms[46,49]. Especially the influence of physical activity on levels of hormones is interesting. A diet low in fat and high in fibre combined with daily exercise might decrease insulin level[46]. A decreased insulin level might decrease mitogenic activity in the prostatic. Short term exercise produces transient elevations in serum testosterone levels in elderly men, which is partly due to an increase in SHBG concentrations[54].This was not confirmed in another study[55], which showed no consistent relationship of androgens and SHBG to physical activity. Though no study has reported effects of different levels of physical activity in Asian men compared to Caucasian men but it is not unreasonable to assume that until recently levels of physical activity were higher in Asians living in Asia than in the Western world.

3.4.3 Sexual activity

Several investigators have studied the history of men with prostatic neoplasm to determine if sexual behavior and/or fertility are related to the development of prostatic neoplasm[16]. Risk factors found in epidemiological study of prostatic neoplasm are marriage, increased fertility, a larger number sexual partners or just the opposite, more experience with prostitutes, STD among patients or partner and more frequent coitus. The conclusions from these investigations were that a highly active sex life was a risk factor for prostatic neoplasm, partly because of the higher risk to be exposed to STD and thus possible oncogenic factors and partly because increased sexual activity might also be a reflection of a higher androgenic stimulus[16]. However, prostatic neoplasm patients reportedly have delayed sexual drive and sexual frustration[56]. On investigating sexual risk factors for prostatic neoplasm in Japanese men living in China, marital status and level of fertility (measured by number of siblings) were not found to be linked to prostatic neoplasm[16]. This was not in agreement with other studies which found a higher risk of prostatic neoplasm in married men compared to single men[57,58]. Furthermore the study concluded that Japanese prostatic neoplasm patients had delayed onset of sexual activity, more frequent sexual intercourse during their 20s and 30s, poor quality of sexual life and less frequent episodes of STD. Marital status might be influenced by the amount of circulating androgens acting as a sexual stimulus as well as by social customs or culture, and therefore different sexual lifestyles between Japanese and Caucasians, may partly explain some of the inconsistent findings[16]. Another study reported[59] differences in sexual behaviour in Japanese males living in Japan (42-94 years of age) and compared them with American males. It was concluded that 1) Age of first sexual intercourse in American males was seven years earlier than in Japanese males, 2) Frequency of sexual intercourse before 40 years of age was higher, but that after 40 years was less than that of American males, 3) The age at which sexual intercourse was no longer practised was almost the same in the two countries. Interestingly, a connection between the time of first sexual intercourse and eating habits was also investigated. They concluded that the age of first intercourse in subjects who ate green or yellow vegetables daily was significantly later than in those who never or only occasionaly ate these vegetables. No reliable data comparing the sexual activity levels of Caucasian and Asian men with regard to development of prostatic neoplasm exists till date.

4 Conclusion

This review has attempted to provide an overview of the literature addressing various aspects of reproductive endocrinology with a certain specificity regarding Asian men. Asian men residing in Asia seem to be relatively protected from clinical but not latent manifestations of prostatic neoplasm. Migration to an area with a higher prevalence reduces this difference but does not undo it. Explanations offered for the observed lower rate of clinical  prostatic neoplasm risk in Asian men are: 1) a reduction in 5-reductase level, 2) decreased levels of androgenic ketosteroid precursors of 5-reduced androgen metabolites, 3) the decreased presence of a p53 mutation, 4) a higher CAG-repeat length of the androgen receptor, 5) a possible higher level of physical activity, 6) differences in sexual activity. Furthermore, Asian men present azoospermia earlier in response to contraceptive steroids. Possible explanations offered for the observed differences in response to contraceptive steroids are: 1) differences in testicular structure and decreased spermatogenic potential, 2) an earlier and more marked suppression in LH secretion by exogenous androgens.

Possible explanations for these observations may be due to differences in genetically and/or environmentally determined levels of peripheral testosterone metabolism. Not surprisingly, it has been difficult to disentangle the genetic factors from environmental factors. A potential role has been attributed to dietary factors such as higher intake of phytoestrogens in Asians. These might affect 5-reductase levels and/or SHBG levels, thus having an impact on the biological efficacy of circulating androgens. Furthermore levels of physical and sexual activity may also be significant for the observed differences in reproductive endocrinology between Asian and Caucasian men.

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Correspondence to: Professor Louis Gooren, Endo/AZVU, P.O.Box 7057, 1007 MB Amsterdam, The Netherlands.
Tel: +31-20-444 4444 ext. 199   Fax: +31-20-444 0502  
e-mail:  ljg.gooren@azvu.nl
Received 2000-02-24    Accepted 2000-02-25