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Medical Research Council Human Reproductive Sciences Unit The Queen’s Medical Research Institute Edinburgh EH16 4TJ, Scotland, United Kingdom
Address all correspondence and requests for reprints to: Richard M. Sharpe, Medical Research Council Human Reproductive Sciences Unit, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. E-mail: r.sharpe{at}hrsu.mrc.ac.uk.
In human males, as in other male primates, the first 3–4 months after birth are a period of considerable activity for the testis and for the hypothalamic-pituitary axis (1). In this period, Sertoli cells proliferate, and some degree of germ cell development occurs at a time when gonadotropin, testosterone, and inhibin B levels are at adult or higher levels (1). Interest in the perinatal period of testis development has been heightened by the growing acceptance that so-called "testicular dysgenesis syndrome" (TDS) may arise during this period (2, 3). TDS comprises four disorders that affect newborn or young adult males—namely, cryptorchidism, hypospadias, testicular germ cell cancer (TGCT), and some cases of low sperm counts/subfertility. It is hypothesized (2) that these, and perhaps related disorders, may have a common origin in fetal life as the result of abnormal development of the testis and its constituent cell types. However, understanding about the causes of TDS and the mechanisms that may lead to subsequent testicular dysfunction is superficial, primarily because of the practical problems in relating events in perinatal life to testis function some 20–40 yr later; prospective studies require extreme patience (not least from the funders), whereas retrospective studies suffer from the usual inaccuracies of recall, lack of appropriate samples, or measurements. However, as with advances made from the study of individuals with specific genetic mutations, perhaps the sensible approach in such circumstances is to take note of whatever information and insights nature herself provides. Thus, one of the most illuminating developments in TDS has been the comparison of the frequency of TDS disorders in two Nordic countries, Denmark and Finland. Such studies have shown that all of the TDS disorders are considerably more prevalent in Denmark than in Finland (2, 3, 4, 5, 6). Moreover, the fact that the incidence of TGCT has been increasing progressively in both countries over the past 50 yr or so (7) indicates that this fascinating difference must involve environmental as well as genetic factors.
But what causes TDS disorders and their different incidence in Denmark and Finland? Clues have come from epidemiological studies, which have shown that fetal growth restriction is an important risk factor, whereas hormonal factors (low androgen action) may also be important (2, 3); notably, each of the TDS disorders is also a risk factor for each of the other disorders (2). But such factors provide little to guide researchers as to mechanisms (and causes). Now, important new insight is provided by Main et al. (8) in this issue of JCEM. This study has extended the Denmark-Finland comparison by evaluating testis size and growth and reproductive hormone levels in blood in approximately 1700 normal boys (with normal weight for gestational age) from birth to 3–18 months of age. It has shown that newborn Finnish boys have slightly, but significantly, larger testes at birth than do Danish boys. However, it is what happens to testis growth in the next 3 months that is quite remarkably different, with Finnish boys showing a 3-fold greater increment in testis size in this period than do their Danish counterparts. This difference is accompanied by higher blood levels of FSH and inhibin B in the Finnish boys, suggesting that the higher FSH levels are driving a higher rate of Sertoli cell proliferation, and hence a higher level of inhibin B due to the higher number of Sertoli cells (9). It is important to remember that, at this stage in development, the key determinant of change in testis size is the number of Sertoli cells, which proliferate in fetal and early postnatal life (10), and that final Sertoli cell number is the primary determinant of sperm count in adulthood (10). Therefore, the higher average sperm counts in adult Finnish men, when compared with similar Danish men (4), may have their origins in different rates of Sertoli cell proliferation perinatally.
In contrast to the major difference in FSH and inhibin B levels between Danish and Finnish 3-month-old boys, there was no evidence for any difference in testosterone or LH levels (8). This is of interest because of evidence emerging in the past 2 yr from studies in transgenic mice that androgens may also promote Sertoli cell proliferation, at least during fetal life (11). Because deficiency in androgen action is also viewed as a likely central feature of TDS (2, 3), the lack of any obvious difference in blood testosterone levels at age 3 months between both normal Danish and Finnish boys (8) and boys from the same two countries with cryptorchidism (12) raises an important issue. It questions the importance of testosterone levels/action in TDS disorders, at least insofar as testosterone levels in blood postnatally may reflect what has gone before in fetal life. Alternatively, it questions the relevance to TDS of the new findings (8) of hormonal and testis growth differences between normal 3-month-old Danish and Finnish boys.
Whatever the answer to the foregoing questions, the new findings tell us that the set-up program for testis development appears to work less well in Danish than in Finnish newborn boys. The challenge is to work out how such a difference arises mechanistically. Does it simply reflect a genetic difference in FSH secretion? If so, does this arise because of "programming" differences in hypothalamic or pituitary function, or does it have its origins in the testes, the latter more in tune with the TDS hypothesis? The current belief is that negative feedback by inhibin B to regulate FSH secretion does not operate before puberty in human males (9), suggesting that the different FSH levels in Danish and Finnish boys are more likely to have a central rather than a testicular origin. However, because it is accepted that testicular steroids play a key role in programming of brain functions in fetal life, including the setting up of feedback loops, it is still possible that different programming of FSH secretion could have its origins in differences in testosterone secretion by the fetal testis between Danish and Finnish boys. If such a difference exists, it is well hidden, and the only evidence of such a difference comes from the different prevalence of TDS disorders in the two countries. Without the means to noninvasively measure fetal testicular and/or blood testosterone levels (measurement of levels in maternal blood does not provide a good guide; see Ref. 13), this possibility must remain in the realm of speculation.
So how should the findings by Main et al. (8) be followed up? The first logical deduction is that if such a difference exists between Finland and Denmark, then there must surely be similar between-country or ethnic differences elsewhere. We need look no further than North America, where it is well established that Caucasian and African-American men show a dramatic difference in the prevalence of TGCT in adulthood (higher in Caucasians) (14), which is remarkably similar to the difference in prevalence between Danes and Finns (7) and is consistent with an ethnic difference in risk of TDS disorders. It would therefore be instructive if studies similar to those comparing Danish and Finnish boys could be conducted in North America to compare Caucasian and African-American boys. Whether the rates of cryptorchidism and hypospadias might also be lower in African-American boys in North America than in their Caucasian counterparts, as is the case between Danish and Finnish boys (5, 6), would also be illuminating.
It also needs to be established whether the Danish-Finnish difference in testis growth and hormone levels is solely the result of genetic differences or whether there is an environmental/lifestyle component to the observed differences and, if so, how important this is. In this regard, the finding by Main et al. (8) of a significant relationship between weight for gestational age and testis size in normal boys is of particular interest, especially because this relationship was most pronounced at birth. Because being born small for gestational age is a risk factor for all of the TDS disorders (2, 5, 6), it seems that this relationship has something important to tell us about testis development in general, as well as the pathways via which TDS is induced. It is also to be hoped that use of an animal model, which centers around induction of TDS disorders in rats by certain phthalate esters (15), will prove instructive, especially because recent findings suggest that there may be major between-rat strain differences in susceptibility to such effects (Gray, L. E., personal communication, poster to be presented at the summer meeting of the Society for the Study of Reproduction), a difference that echoes the Danish-Finnish differences discussed above. If the mechanisms via which TDS disorders are induced in this animal model can be elucidated, they may provide insights that can then guide further (and far more difficult) studies in humans to uncover the mechanisms that underlie TDS. The hope is that these can link together the phthalate effects in animals and the nutritional/growth effects in humans.
Another important message from Main et al. (8) is the reminder of just how dynamic a period the first 3–4 months after birth are for testis development/function in boys. This reminder could be timely. This neonatal period of testicular activity (also called "mini-puberty" and "the neonatal testosterone rise") appears to be unique to primates, but its precise role(s), other than to increase Sertoli cell number and to increase growth of the penis (1, 16), is unclear. The fact that this period is when parental choice about bottle feeding of infants occurs reminds us that such interventions could have consequences of which we are unaware. In this regard, the fact that as many as one third of all infants in the United States are now fed with soy formula milk (SFM) in this period (17) should at least give pause for thought, if not concern. SFM contains high levels of plant estrogens, and it is well established that estrogens can suppress FSH secretion and potentially inhibit testosterone production by the testis, based on a range of laboratory animal studies (18). Indeed, recent data from marmoset monkeys fed as infants with SFM suggest that this feeding attenuates the neonatal testosterone rise (19) and may have long-term consequences for testis composition and cell function (20), although not all of these changes are necessarily adverse. If nothing else, such findings reinforce the message from Main et al. (8) that early postnatal life plays a critical role in shaping the future function of the testis and determining its constituent somatic and germ cell numbers (1). We would therefore be wise to give more thought to what environmental or lifestyle factors (of the parents) might impinge on these developmental processes during this critical phase. More generally, the stimulating insights that have emerged from the series of studies comparing testis development and disorders between Denmark and Finland serve as a reminder that there are many such differences that are already known about and are probably filed away in our minds as "variations." But their study may have the potential to give us dramatic new insights in just the same way as has the study by Main et al. (8).
Footnotes
Abbreviations: SFM, Soy formula milk; TDS, testicular dysgenesis syndrome; TGCT, testicular germ cell cancer.
Received May 5, 2006.
Accepted May 9, 2006.
References
This article has been cited by other articles:
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  E.A.M. Kuijper, J. van Kooten, J.I.M.L. Verbeke, M. van Rooijen, and C.B. Lambalk Ultrasonographically measured testicular volumes in 0- to 6-year-old boys Hum. Reprod., April 1, 2008; 23(4): 792 - 796. [Abstract] [Full Text] [PDF]
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