Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Abstract

Leydig cells (LCs) are the cells of the testis that have as their primary function the production of testosterone. LCs are a common target of compounds tested in rodent carcinogenicity bioassays. The number of reviews on Leydig cell tumors (LCTs) has increased in recent years because of its common occurrence in rodent bioassays and the importance in assessing the relevance of this tumor type to humans. To date, there have been no comprehensive reviews to identify all the compounds that have been shown to induce LCTs in rodents or has any review systematically evaluated the epidemiology data to determine whether humans were at increased risk for developing LCTs from exposure to these agents. This review attempts to fill these deficiencies in the literature by comparing the cytology and ontogeny of the LC, as well as the endocrine and paracrine regulation of both normal and tumorigenic LCs. In addition, the pathology of LCTs in rodents and humans is compared, compounds that induce LC hyperplasia or tumors are enumerated, and the human relevance of chemical-induced LCTs is discussed. There are plausible mechanisms for the chemical induction of LCTs, as typified by agonists of estrogen, gonadotropin releasing hormone (GnRH), and dopamine receptors, androgen receptor antagonists, and inhibitors of 5alpha-reductase, testosterone biosynthesis, and aromatase. Most of these ultimately involve elevation in serum luteinizing hormone (LH) and/or LC responsiveness to LH as proximate mediators. It is expected that further work will uncover additional mechanisms by which LCTs may arise, especially the role of growth factors in modulating LC tumorigenesis. Regarding human relevance, the pathways for regulation of the hypothalamo-pituitary-testis (HPT) axis of rats and humans are similar, such that compounds that either decrease testosterone or estradiol levels or their recognition will increase LH levels. Hence, compounds that induce LCTs in rats by disruption of the HPT axis pose a risk to human health, except for possibly two classes of compounds (GnRH and dopamine agonists). Because GnRH and prolactin receptors are either not expressed or are expressed at very low levels in the testes in humans, the induction of LCTs in rats by GnRH and dopamine agonists would appear not to be relevant to humans; however, the potential relevance to humans of the remaining five pathways of LCT induction cannot be ruled out. Therefore, the central issue becomes what is the relative sensitivity between rat and human LCs in their response to increased LH levels; specifically, is the proliferative stimulus initiated by increased levels of LH attenuated, similar, or enhanced in human vs. rat LCs? There are several lines of evidence that suggest that human LCs are quantitatively less sensitive than rats in their proliferative response to LH, and hence in their sensitivity to chemically induced LCTs. This evidence includes the following: (1) the human incidence of LCTs is much lower than in rodents even when corrected for detection bias; (2) several ...

RITA—Registry of Industrial Toxicology Animal data: The application of historical control data for Leydig cell tumors in rats

“…Cook et al 1999). The mean for LC adenomas in the Charles River compilation, comprising 2146 male SD rats, is with 2.4% also in this range (Giknis and Clifford 2004).…”

“…A c c e p t e d M a n u s c r i p t Nolte et al: RITA -The application of historical control data for Leydig cell tumors in rats -4 -LC hyperplasias and adenomas have been induced in rats by a large variety of chemical compounds and by different mode of actions (for review see Cook et al 1999). Due to the arbitrary criteria for differentiation between LC hyperplasia and adenoma, the risk is high that a compound inducing exclusively LC hyperplasia may be falsely interpreted to induce also LC adenomas if tested in a strain with a low background incidence of LC adenomas (Davis TE 1995).…”

“…Dependency on mean age at necropsy: LC tumors generally occur in older animals (Cook et al 1999). In F344 rats their occurrence before 1 year age is rare but rises rapidly before and after 2 years of age (Turek andDesjardins 1979, Boorman et al 1990).…”

“…Their incidence varies according to strain, ranging from 1 -5% in Sprague Dawley rats (Cook et al 1999) to nearly 100% in F344 rats (e.g. Mitsumori and Elwell 1988).…”

“…Mitsumori and Elwell 1988). LC tumors occur less frequently in mice with an incidence of less than 1% to 2.5% (Cook et al 1999). …”