PRINCIPLES OF TOXICOLOGY

216 REPRODUCTIVE TOXICOLOGY
gonadotropin released by the pituitary gland. Gonadotropin secretion is in turn regulated by gonadotropin
releasing hormone (GnRH), secreted by the hypothalamic portion of the brain. This hierarchical
arrangement, where the hypothalamus regulates the pituitary which in turn regulates the gonads, is
known as the hypothalamic-pituitary-gonadal axis. The hypothalamic-pituitary-gonadal axis is illustrated
for both males and females in Figure 11.2. From a toxicological perspective, this arrangement
creates even more sites where toxic responses may have an impact on reproduction. With this in mind,
it is not surprising that some compounds generally considered to affect the central nervous system,
can impact Leydig cell function and male reproduction.
The toxic effects of ethanol are wide ranging and complex. Experimental evidence for direct
testicular toxicity is not clear; however, it is clear that alcoholics suffer decreased testosterone levels
and subsequently, decreased gonadal function. In alcoholics, the ability to stimulate testosterone
production appears to be impaired. Experimentally, it can be demonstrated that ethanol affects LH
release. It is clear that alcohol interferes with male reproduction by affecting endocrine regulation, and
ultimately, in part, Leydig cell production of testosterone, but the relative contributions of direct
testicular action and toxic responses elsewhere in the regulatory axis are not known.
A variety of other drugs and industrial compounds also affect male reproduction through endocrinerelated
mechanisms. These include the anti-hypertensive drug propanolol, the opiates, and tetrahydrocannabinol
(THC). The use of such drugs is pertinent to occupational toxicology, since their effects
can confound observations on reproductive impairment related to direct occupational exposure. Carbon
disulfide, the pesticide chlordecone, and the phthalates are examples of industrial chemicals that can
disrupt the endocrine axis.
Besides the potential impact on spermatogenesis, there is another aspect of toxicity to the
hypothalamic-pituitary-gonadal axis that affects male reproductive function. Both libido, or behavioral
drive, and physical aspects, such as penile erection and ejaculation, are controlled by the central nervous
system. Libido is controlled primarily by androgens and any of the drugs or industrial compounds that
can dysregulate the endocrine axis and affect androgen production can affect libido. Alcohol and THC
Figure 11.2 The hypothalamic-pituitary-gonadal axis for human males and females illustrating the sequence of
control from the brain to the secretion of gonadotropins by the pituitary, to the production of steroid hormones in
the gonads. The major hormonal products and their contribution to regulatory feedback loops are indicated.
GnRH—Gonadotropin Releasing Hormone.