Male Reproductive Pathology: Hazard Characterization and Mitigation in
Nonclinical Safety
Justin D. Vidal, DVM, PhD, DACVP
Director and Head of Pathology
Safety Assessment, Upper Merion
GlaxoSmithKline
justin.2.vidal@gsk.com
Introduction
Prior to administering the first dose in healthy male volunteers, often the sum total of the
assessment on the male reproductive system falls on the study pathologist! According to ICH
Harmonized Tripartite Guidelines Detection of Toxicity to Reproduction for Medicinal Products
& Toxicity to Male Fertility S5(R2): Information on potential effects on spermatogenesis can be
derived from repeated dose toxicity studies and histopathology of the testis has been shown to be
the most sensitive method for the detection of effects on spermatogenesis. As such the
toxicologic pathologist is required to have a sound understanding of spermatogenesis, stageaware evaluation of the testis, and normal physiology and endocrinology in order to carefully
and thoroughly screen and evaluate potential xenobiotic-related effects on the male reproductive
system. In addition, the toxicologic pathologist’s role often extends beyond study pathology as
this information and understanding is critical to the hazard characterization and mitigation of risk
in nonclinical safety.
As described in Vidal et al, 2013, several key issues need to be considered before considering the
potential impact of a male reproductive finding in a nonclinical study:
 In general, the regulatory viewpoint is that any detectable, drug-induced change in
spermatogenesis or sperm parameters is considered adverse, regardless of whether the
change affects fertility in the test species.
 There is relatively good concordance between animal models and man (e.g. glycol
ethers, lead, 1,2- dibromochloropropane, various marketed compounds)
 Testicular toxicants will often demonstrate species differences between rat and dog,
with one being sensitive and the other showing no effect
 Since spermatogenesis and its regulation are basically similar between mammalian
species, neither species is considered more or less relevant to man than the other.
 NHP is not considered any more relevant to man than rat or dog and regardless of how
many species are resistant versus sensitive, risk assessment will generally be based on
the most sensitive species.
When presented with a new finding in the male reproductive system, a number of questions need
to be addressed:
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Is the finding biologically relevant to humans?
Does it impact the clinical protocol or informed consent?
Is it patients with advanced disease/limited therapeutic options?
Is there a large exposure margin?
What is the time course/development of the lesion(s)?
Is it reversible?
Do you know the mechanism?
Can you monitor in the clinic?
Feedback from clinicians and regulatory agencies often include questions about reversibility,
potential mechanism, and/or clinical monitoring and in many cases additional nonclinical studies
are needed. While these questions are very similar to what would be asked for toxicity in any
organ system, there are a number of unique features that make working with the male
reproductive system a challenge including: the blood testis barrier, duration of spermatogenesis
and impact on timing of onset and recovery, and difficulty in clinical monitoring. The
approach(s) to addressing these questions in light of these challenges will be reviewed and
discussed using case examples of tool compounds.
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