Monash Institute of Reproduction and Development, Monash University, Clayton, Victoria 3168, Australia
Address all correspondence and requests for reprints to: D. M. de Kretser, Monash Institute of Reproduction and Development, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail: david.de.kretser{at}med.monash.edu.au.
The two functions of the testis, sperm production and testosterone secretion, are linked to the two anatomical compartments of the testis, the seminiferous tubules and Leydig cells, respectively. This structural partitioning has often led to a functional separation, especially in view of the fact that LH controls Leydig cell secretion of testosterone, which, together with FSH, controls spermatogenesis. The results of the study of Andersson et al. in this issue of the JCEM (1) emphasize that spermatogenic dysfunction is often associated with impaired Leydig cell dysfunction. They showed that between 12 and 15% of men with diminished spermatogenesis had lower testosterone levels or higher LH concentrations than 97.5% of a population of fertile men. Their study provides substantive support for a concept developed from several smaller studies conducted over the past 30 yr. Several studies of men with spermatogenic disorders had identified that, in some men, testosterone levels were frankly below or were close to the lower limit of the normal range and were accompanied by elevated levels of LH (2, 3). The latter group was considered to be in a state of compensated Leydig cell failure (4), a state characterized by a low testosterone to LH ratio, as described by Andersson et al. (1). Further support for subnormal Leydig cell function in these men with spermatogenic damage came from their poor response to human chorionic gonadotropin (hCG) stimulation (5), with those who had the most severely impaired spermatogenesis showing the lowest testosterone response.
There was not universal support for this concept because some studies could not confirm the data (6, 7). However, often these studies were conducted on insufficient numbers of men and used assays with poorly characterized normal ranges. This issue, particularly for measurements of testosterone, has been emphasized in the recent study by Wang et al. (8), who showed that assay precision and the determination of normal ranges were poor, leading to difficulties in the accurate diagnosis of androgen deficiency. One of the strengths of the present study is the use of a large number (n = 318) of fertile men, a control group from whom normal ranges could be determined. Furthermore, the use of a common set of assays to measure the hormone levels in both populations further reduces the possibility of error.
The concept of Leydig cell dysfunction associated with spermatogenic damage has been conclusively demonstrated in rodent models (9, 10). In these studies, spermatogenic damage was induced in normal rats by a variety of agents such as irradiation, induction of cryptorchidism, vitamin A deficiency, or the use of the chemotherapeutic agent hydroxyurea (10). The affected rats demonstrated elevated levels of LH accompanied by lower testosterone concentrations. It was unclear whether the Leydig cell dysfunction resulted from a direct effect of the agent used to cause the spermatogenic damage or whether it was secondary to the impaired seminiferous tubule function. In elegant experiments, Aoki and Fawcett (11) showed that the implantation of threads impregnated with cyproterone acetate into the rat testis was followed by focal disruption of spermatogenesis in the vicinity of the implant. Surprisingly, they showed that the Leydig cells adjacent to these tubules showed hypertrophy, leading to the concept that there was local control of the Leydig cells by the adjacent seminiferous tubules. Functional correlates for this concept emerged from studies of unilateral cryptorchidism and efferent duct ligation, both of which cause spermatogenic damage in one testis (12, 13). The Leydig cells in the damaged testis were hypertrophic and responded to hCG in vitro by increased testosterone production but also exhibited a marked decrease in LH receptor levels (12). Further proof of this concept emerged from studies wherein spermatogenesis was disrupted temporarily by exposure of the testis to heat for 15 min (14). These studies showed that, in addition to germ cell damage, Sertoli cell function was impaired and the Leydig cells became hyperresponsive to hCG in vitro with normal function returning when the basal germ cells progressively restored spermatogenesis. The nature of the signals that mediate this cross-compartment communication between seminiferous tubules and Leydig cells still remain elusive.
It is possible that local control mechanisms may account for the impaired Leydig cell function noted in the studies of Andersson et al. (1). However, in addition to raising the issue of local control mechanisms, they also suggested that disordered Leydig cell function may be a marker of the testicular dysgenesis syndrome (TDS), as proposed by Skakkebaek et al. (15). They proposed that a range of male reproductive problems involving testicular and genital malformations are symptoms of a single underlying entity, TDS. They noted in their current study that, when cryptorchidism was self-reported in either the fertile or infertile population, it was accompanied by lower sperm counts, lower serum inhibin B concentrations (a marker of Sertoli cell function), and higher LH and lower testosterone to LH ratios. They propose that these data support the possibility that impaired androgen production may be an additional marker of TDS.
It is not possible to determine whether disordered androgen production is a manifestation of TDS or results from disruption of local control mechanisms between the seminiferous tubules and Leydig cells. However, the elegant study of Wallace et al. (16) showed that, in a group of men with normal testicular function, the exposure of their testes to chemotherapy for their lymphoma resulted in the development of azoospermia, low inhibin B levels, and Leydig cell dysfunction as shown by a low testosterone to LH ratio. This observation shows that, when normal human testes are exposed to an agent that causes severe spermatogenic damage, Leydig cell dysfunction occurs. This information and the results from the rodent studies discussed earlier indicate that Leydig cell dysfunction can occur when normal testes are exposed to agents that damage spermatogenesis, in the absence of any underlying "congenital" lesion representing TDS.
It is important to manage Leydig cell dysfunction appropriately. Male infertility in which severe spermatogenic damage causes untreatable infertility and is accompanied by Leydig cell dysfunction and frank androgen deficiency probably occurs in approximately 1 in 2035 men. The presence of the androgen deficiency must be recognized and treated appropriately. This requirement may cause a dilemma for the endocrinologist because these men often are seeking fertility. The remarkable advances using testicular sperm retrieval combined with intracytoplasmic sperm injection have enabled men with only a few testicular sperm to achieve pregnancies (17). Even men with Kinefelters syndrome with azoospermia may have focal areas of spermatogenesis in their tiny testes, which can yield sufficient sperm to achieve pregnancies (18). Replacement testosterone treatment, by suppressing FSH, may render these focal areas of spermatogenesis inactive. It may therefore be necessary to evaluate the use of hCG treatment to boost testosterone levels or to consider searching for sperm and cryopreserving them before commencing androgen treatment. Unfortunately, hCG treatment may not restore testosterone levels to normal because the testosterone response to hCG is often subnormal in these men (5). It is important that these men are not left untreated because their quality of life is diminished and the long-term consequences of osteoporosis are serious.
The issue arises as to the appropriate management of men in whom testosterone levels are in the low to normal range when accompanied by elevated levels of LH, i.e. state of compensated Leydig cell failure. These men could also be at risk of developing androgen deficiency later in life. It is well recognized that men achieve their peak testosterone levels between the ages of 25 and 30 yr and the levels decline thereafter at about 1% per year, with approximately 510% becoming frankly androgen deficient by 6570 yr of age (19, 20). Are the men identified by Andersson et al. (1) with compensated Leydig cell failure those who are at greater risk of an accentuated decline in testosterone levels, thereby ultimately presenting with the androgen deficiency of ageing? LH and testosterone levels should be evaluated in early-morning blood samples in men with infertility presenting with severely depleted sperm production. If they are found to be in a state of compensated Leydig cell failure, they should be advised of the potential to develop androgen deficiency and urged to have their testosterone and LH levels monitored at 2-yearly intervals. Furthermore, because obesity has been identified as a significant risk factor for the development of androgen deficiency of ageing (21), these men should be counseled accordingly.
Andersson et al. (1) identify a proportion of infertile men in their study with elevated estradiol (E2) levels and another group showed elevated E2 to testosterone ratios suggestive of increased aromatase activity. They pointed out that several studies in which LH or hCG appear to elevate aromatase activity in Leydig cells. This implicates increased LH levels as a cause of the elevated E2 to testosterone ratio. Because E2 can cause a local autocrine block in steroidogenesis at the 17-hydroxylase and the 17,20-desmolase steps, the elevated E2 levels could be responsible, at least in part, for the inability of the Leydig cells to fully restore testosterone levels (22). The action of aromatase inhibitors in such men would be worthy of investigation. Additionally, Sertoli cells also express aromatase activity under FSH control and many of these men have increased FSH levels. There is a lack of information on how Sertoli cells in tubules with germ cell damage function in terms of aromatase activity. This topic requires further investigation.
Footnotes
Abbreviations: E2, Estradiol; hCG, human chorionic gonadotropin; TDS, testicular dysgenesis syndrome.
Received April 20, 2004.
Accepted May 17, 2004.
References