Identification of drug‐induced hyper‐ or hypoprolactinemia in the female rat based on general and reproductive toxicity study parameters

Abstract

Observations associated with drug-induced hyper- or hypoprolactinemia in rat toxicology studies may be similar and include increased ovarian weight due to increased presence of corpora lutea. Hyperprolactinemia may be distinguished if mammary gland hyperplasia with secretion and/or vaginal mucification is observed. Reproductive toxicity study endpoints can differentiate hyper- from hypoprolactinemia based on their differential effects on estrous cycles, mating, and fertility. Although the manifestations of hyper- and hypoprolactinemia in rats generally differ from that in humans, mechanisms of drug-related changes in prolactin synthesis/release can be conserved across species and pathologically increased or decreased prolactin levels may compromise some aspect of reproductive function in all species.

Differential responses to JNJ‐37822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague–Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics

“…In addition JNJ‐37822681‐treated monkeys elicited hypoactivity, apathy, hunched posture, recumbency and inability to hold on to the cage. These motor disorders were consistent with reports of dyskinesias and locomotor depressant changes occurring in monkeys with various other antipsychotics (Casey, ; Fukuoka et al ., ; Goldstein & Snyder, ; Liebman & Neale, ; Peacock & Gerlach, ; Porsolt & Jalfre, ; Rehm et al ., ; Varty et al ., ; Weiss et al ., ). Catalepsy‐associated behavior in monkeys reflected by static postures and unusual positions occurring for prolonged periods of time have been described as well (Auclair et al ., ; Kumar et al ., ).…”

“…These findings are in line with the common notion that compared to other species, including humans, the rat is prone to hyperprolactinemia and its sequelae (Ben‐Jonathan et al ., ; Hargreaves & Harleman, ; Rehm et al ., ). In rat toxicology studies with dopamine D 2 receptor antagonists prolactin‐mediated tissue changes commonly occur in the female genital tract, male genital tract and male and female mammary glands (Ben‐Jonathan et al ., ; Hargreaves & Harleman, ; Rehm et al ., ). Owing to the species‐specific luteotropic effects of prolactin a classic hallmark of hyperprolactinemia in female rats is pseudopregnancy characterized by decreased cyclic activity resulting in an increased number of rats being in permanent diestrus.…”

Effects of sulpiride and ethylene glycol monomethyl ether on endometrial carcinogenicity in Donryu rats

“…D2 antagonists, such as sulpiride, have an inhibitory effect on dopamine secretion and promote PRL release in the pituitary gland, resulting in the preservation of functional CL, as PRL has stimulatory effects on luteal cells. The resulting serum P4 elevation produces a pseudopregnant state and disrupts the estrous cycle in rats (Rehm et al, ). From these reports, the high ovarian weights induced by sulpiride treatment in the present study corresponded to histological luteal cell hypertrophy, indicating the maintenance of functional CL.…”

Scientific and Regulatory Policy Committee (SRPC) Paper

“…Since the pituitary lactotrophs are under negative regulation by hypothalamic dopamine, rat and mouse reproductive biology are very sensitive to any effect on the dopaminergic system (Freeman et al 2000;Rehm, Stanislaus, and Wier 2007). Changes of the dopaminergic/PRL system in rodents can lead to effects associated with altered P4 levels ( Table 1) and, indirectly, signs of increased estrogen effects secondary to hypoprolactinemia and shifts in the P4/E2 balance (Harleman et al 2012).…”