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Assistant Professor of Pediatrics Division of Endocrinology Department of Pediatrics The University of North Carolina at Chapel Hill Chapel Hill, North Carolina 27599-7039
Address all correspondence and requests for reprints to: Ali S. Calikoglu, M.D., Department of Pediatrics, University of North Carolina School of Medicine, Campus Box 7039, Chapel Hill, North Carolina 27599. E-mail: asc{at}med.unc.edu.
Leydig cell’s principle function is to produce testosterone from cholesterol. In mammals, the ontogenesis of Leydig cell function involves at least two generations of cells. The first generation begins to develop during fetal life and is responsible for the masculinization of the male urogenital system in utero. Although most of the fetal Leydig cells regress in the first 3 months of life, some persist into adult life (1, 2). The second Leydig cell population appears during puberty and produces the testosterone required for the onset of spermatogenesis and maintenance of male reproductive function.
Morphological and functional maturation of the adult Leydig cells appears to be dependent on LH stimulation. Mice lacking either circulating LH or the LH receptor (3, 4, 5, 6) fail to demonstrate the normal postnatal increase in Leydig cell numbers and have low or undetectable serum androgen levels (5, 6, 7, 8). Furthermore, treatment of LH-deprived rats with LH or human chorionic gonadotropin (hCG) restores, at least partially, the structure and function of Leydig cells (9, 10, 11, 12). Similarly, treatment of hypogonadal mouse with daily injections of LH produces a marked increase in most steroidogenic enzyme activity (13). Many in vitro studies using several Leydig cell types have confirmed and extended these observations in vivo (reviewed in Refs.14, 15).
The fetal population of Leydig cells in mice, however, does not appear to require gonadotropins during this period. Mice lacking LH (7, 8) exhibit normal testicular androgen levels and Leydig cell numbers during fetal development. Very recent studies have shown that mice devoid of LH receptors masculinize normally in utero, again showing that fetal testicular testosterone production is sufficient without LH stimulation (5). Because other pituitary hormones, including FSH, GH, TSH, and prolactin, have the capacity either directly or indirectly to stimulate testicular function (15), it is plausible to that one or more of those pituitary hormones regulates fetal testicular function. Arguing against this, however, is the finding that mice with targeted disruption of the 
-subunit gene, common to both gonadotropins and to TSH (and having reduced levels of GH and prolactin), masculinize normally in utero (4). In addition, mice with disruptions in either the FSH ß-subunit or the FSH receptor genes exhibit normal intrauterine masculinization (16, 17, 18). Similarly, null mutant mice for the thyroid-specific enhancer binding protein (T/ebp or Nkx2.1) gene have normal masculinization at birth even though they lack a pituitary gland. Interestingly, however, these mice have markedly reduced androgen levels (90–95% reduction) in late gestation. Taken together, these observations indicate that early fetal testicular steroidogenesis is either constitutive or the result of stimulation by paracrine or autocrine factors or by placental or other non-pituitary-derived humoral factors.
In this issue of Endocrinology, O’Shaughnessy et al. (19) report a novel control mechanism for fetal testicular steroidogenesis. To identify the growth factors and receptors that participate in the control of fetal Leydig cell function, they compared fetal and adult mouse testis expressed sequence tag libraries using a virtual subtraction strategy. Among the genes specific for fetal testis was melanocortin type 2 receptor. Because ACTH is the ligand for this receptor, a series of studies were performed to explore whether ACTH can control testicular testosterone production. Fetal and early neonatal mouse testis tissues responded to ACTH in a dose-dependent fashion similar to that seen with hCG, whereas testis tissue or primary cell cultures derived from adult mouse testis were not responsive to ACTH. These findings suggest that ACTH regulates testosterone production in fetal, but not in the adult testis. The finding that testes differentiation and testosterone levels are not altered in POMC null mutant mice suggests that ACTH is not the sole stimulator of fetal testes testosterone production.
Because there are fundamental differences in regulation of sexual development between human and mice, the relevance of these findings in mouse for human testicular functions is not clear. Although LH is not essential for Leydig cell differentiation in mice, the proliferation and differentiation of Leydig cell precursors after wk 10 of gestation and postnatally in man are LH/hCG dependent. In contrast, the functional differentiation of Leydig cells in early human fetal life appears to be LH/hCG independent. Evidence for this comes from a patient with an inactivating mutation of LH/hCG receptor that resulted in a complete loss of receptor function. This patient exhibited female external genitalia but had vas deferens and epididymis (20). Because these Wolffian duct-derived structures can only be formed in the presence of Leydig cell androgens in early fetal development, the above findings suggest that the initial functional differentiation of Leydig cells and their capacity to produce testosterone are independent of hCG. In addition, it has been reported that chronic ACTH secretion stimulated androgen production in a boy with X-linked adrenal hypoplasia due to a mutation in Dax1 gene (21). Given the adrenal hypoplasia in this boy, Leydig cells were likely source of the androgen production. These observations suggest that ACTH may be capable of stimulating testicular steroidogenesis in man under at least some circumstances.
Patients with congenital adrenal hyperplasia (CAH) often develop testicular masses described as adrenal rest tumors, which are presumably the result of chronic ACTH excess (22). Similar tumors also have been reported in patients with other disorders characterized by elevated plasma ACTH levels, such as Nelson’s syndrome (23) and Addison’s disease (24). Such tumors may regress when ACTH levels are reduced by the institution or intensification of glucocorticoid therapy, suggesting that the tumors are ACTH dependent. Because the adrenal develops in the immediate vicinity of the gonads, adrenal cortical tissue may adhere to the gonad, and this aberrant adrenal tissue may descend with the testis. It has been proposed, therefore, that the gonadal tumors in patients with CAH arise from aberrant adrenal tissue. The results of O’Shaughnessy et al. (19), however, introduce another possibility—that is, these masses originate from ACTH-sensitive fetal Leydig cells. Supporting this speculation is the finding that Leydig cells born during fetal life remain in the testis past puberty. Further support for this conjecture is that testicular adrenal rest tumors histologically resemble Leydig cell tumors (25, 26). Therefore, it may be more accurate to identify these tumors as ACTH-responsive gonadal tumors rather than adrenal rest tumors.
If this speculation is valid, a similar ACTH-responsive cell population should be present in the ovaries because ACTH-responsive tumors have been reported in the ovaries of patients with CAH. The observations that females with CAH frequently develop clinical, biochemical, and ultrasonographic findings of polycystic ovary syndrome (27) support the notion that ACTH may involve in ovarian steroidogenesis.
In summary, ACTH appears certain to contribute to the control of fetal testicular steroidogenesis. Because masculinization occurs in individuals with pituitary aplasia, however, it also is very likely that there are more players in this arena. Further studies are needed to verify these findings; to identify other nonpituitary hormones, growth factors, and receptors involved in the control of fetal testicular steroid production; to explore the functions of the melanocortin receptors expressed in the testis; and to investigate whether ovaries express melanocortin type 2 receptor and therefore whether ACTH has any role in ovarian steroidogenesis.
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Footnotes |
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Received May 20, 2003.
Accepted for publication May 23, 2003.
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References |
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 Top References |
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-subunit produces hypogonadal and hypothyroid mice. Gene Dev 9:2007–2019
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