Or Hypoprolactinemia in the Female Rat Based on General and Reproductive Toxicity Study Parameters
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& 2007 Wiley-Liss, Inc. Birth Defects Research (Part B) 80:253–257 (2007) Review Article Identification of Drug-Induced Hyper- or Hypoprolactinemia in the Female Rat Based on General and Reproductive Toxicity Study Parameters Sabine Rehm,Ã Dinesh J. Stanislaus, and Patrick J. Wier GlaxoSmithKline, King of Prussia, Pennsylvania 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. Birth Defects Res (Part B) 80:253–257, 2007. r 2007 Wiley-Liss, Inc. Key words: female rats; hyperprolactinemia; hypoprolactinemia; fertility; toxicity INTRODUCTION and cocaine, and agents that inhibit monoamine oxidases (enzymes that degrade dopamine), such as phenelzine Prolactin is mainly synthesized in the pituitary and is and also amphetamines, are known to increase the involved in many different biologic functions including central dopaminergic tone resulting in a decrease in behavior, immunology, endocrinology, metabolism, and plasma prolactin levels (Woodman, 1997). In addition to reproduction (Woodman, 1997; Yen and Jaffe, 1999). dopamine and agents that alter dopamine content in the Genetic analysis using knockout and transgenic mice brain, other agents such as neurotransmitters can inhibit contributed significantly in understanding the role of (g-aminobutyric acid) or stimulate (serotonin, substance prolactin in target organ function (Bole-Feysot et al., P, histamine, and beta-endorphins) prolactin release from 1998; Bartke, 1999; Ormany et al., 2003; Flint et al., 2006). the pituitary (Woodman, 1997). Also neuropeptides such Effects in knockout mouse models have been grouped as as oxytocin, vasoactive intestinal peptide (VIP), thyro- the reproduction-lactation phenotype, the bone pheno- tropin-releasing hormone, and angiotensin II can stimu- type, and the behavior phenotype (Goffin et al., 1999; late prolactin release from the pituitary (Yuan and Pan, Kelly et al., 2001). 2002). Dopamine is the predominant factor inhibiting pro- In rat general toxicity studies, observations associated lactin release from the pituitary and, therefore, drug- with induced hyper- or hypo-prolactinemia can appear induced mechanisms of hyper- or hypoprolactinemia quite similar; for example, both result in increased ovary usually involve interactions with the dopaminergic weight and an increased presence (number and/or size) system (O’Conner et al., 1996; Table 1). Therefore, of corpora lutea (CL) (Gopinath et al., 1987). The dopamine antagonists, such as antipsychotic drugs following describes how hyper- vs. hypoprolactinemia sulperide or risperidone, will cause an increase in serum can be differentiated in the absence of plasma hormone prolactin, while dopamine agonists, such as amantina- data. dine and bromocriptine, are responsible for decreased prolactin levels (Baptista et al., 2000; Moro et al., 2001). Agents that alter the dopamine content in the tuber- oinfundibular system in the brain can also alter the *Correspondence to: Sabine Rehm,GlaxoSmithKline, 709 Swedeland Rd, plasma prolactin concentrations (Yen and Jaffe, 1999; PO Box 1539, King of Prussia PA 19406-0939. E-mail: [email protected] Vijayan and McCann, 1979; Libertun and McCann, 1976; Received 21 May 2007; Accepted 22 May 2007 Leadem and Kalra, 1985). Dopamine re-uptake inhibi- Published online in Wiley InterScience (www.interscience.wiley.com) tors, such as tricyclic antidepressants, amphetamines, DOI: 10.1002/bdrb.20126 254 REHM ET AL. Table 1 Following hypophysectomy, which significantly Examples of Drug Classes Modulating Prolactin decreases prolactin levels, the life span of CL in the non-pregnant rat is extended by 6–9 months, while Prolactin-stimulating Prolactin-inhibiting exogenous prolactin accelerates the regression of CL in these rats. Thus, increased numbers of CLs observed Dopamine receptor Dopamine receptor antagonists agonists during microscopic evaluation of the ovaries in repeat Haloperidol Bromocriptine dose toxicity studies may suggest a drug-induced Metoclopramide a-ergocriptine impairment of prolactin secretion. Neuroleptics/antipsychotics Monoamine oxidase Dopamine antagonists, which block the inhibitory (MOA) inhibitors effect of dopamine on prolactin release, or other Remoxipride Deprenyl treatments that cause sustained prolactin increases, may Selective serotonin re-uptake 5HT receptor antagonists cause pseudopregnancy and preserve functional corpora inhibitors(SSRIs) lutea (Manson and Mattson, 1992). As a consequence, Fluoxetine Ketanserin ovarian weights are increased and hypertrophic CL can Methysergide be noted grossly and/or microscopically (Yuan and Quipazine Foley, 2002). However, prolactin can also have antig- Antihistamines Antidepressants (other) onadotrophic effects as seen during lactation, following Cimetidine Bupropion pituitary transplants, or administration of high-dose Opioids Opioid antagonist Morphine Naltrexone dopamine antagonists causing markedly increased Naloxone prolactin concentrations, decreased ovarian weights, and an extended anovulatory period (Smith, 1980; Data are from Woodman (1997); Piacentini et al. (2003); Lacau- Baptista et al., 2000; Lacruz et al., 2000; Moro et al., 2001). Mengido et al. (1996). Effects on Mammary Gland OBSERVATIONS IN RAT GENERAL TOXICITY STUDIES ASSOCIATED WITH HYPER- Prolactin is the hormone primarily responsible for OR HYPO-PROLACTINEMIA mammary gland differentiation, lobuloalveolar growth, and synthesis of all major milk components (Knight and Increased Ovarian Weight and Increased Number Peaker, 1982; Bole-Feysot et al., 1998; Brisken et al., 1999; and/or Size of Corpora Lutea Kelly et al., 2002). Therefore, depending on study In rats, prolactin has both luteotrophic and luteolytic duration and degree of hyperprolactinemia, mammary actions, depending on the stage of the estrous cycle, or if gland hyperplasia and lactogenic secretion may be cervical stimulation has occurred (as during mating), or apparent in female rats (Gopinath et al., 1987; Lucas if the rat is pregnant. (Niswender and Nett, 1988; et al., 2007). Woodman, 1997). Luteotrophic actions of prolactin, as part of the luteotrophic complex, involve maintenance of Increased Food Consumption and Body Weight CL through the induction of luteinizing hormone (LH) Gain in Female Rats receptors in luteal cells, which secrete progesterone in The role of prolactin in food consumption and body response to stimulation by LH (Bole-Feysot et al., 1998). weight gain is unclear. Dose-and time-dependent In the cycling rat, a nocturnal prolactin surge occurs increased food consumption and body weight gain may during proestrus, concomitantly with the pre-ovulatory be observed in hyperprolactinemic female, but not in LH surge, then returns to baseline levels for the male, rats (Moore et al., 1986; Heil, 1999). Likewise, a sex remainder of the estrous cycle. This prolactin surge is difference was observed for body weight gain in female thought to produce a luteolytic response in the cohort of but not in male rats treated with antipsychotic drugs CLs from prior cycles (Wuttke et al., 1971; Smith et al., sulperide or risperidone (Lacruz et al., 2000; Baptista 1975). During mating, cervical stimulation activates a et al., 2002). Mechanisms for this sex difference in rats neuroendocrine reflex of circadian nocturnal prolactin remain unclear but inhibition of leptin by increased surges, which maintain CL and its secretion of proges- prolactin levels may be one of the pathways involved terone. If a sterile mating occurs or females are artificially (Dennis et al., 2003; Sone and Osamura, 2001). Obesity is stimulated cervically during proestrus, the neuroendo- also one significant side effect of some antipsychotic crine reflex activates circadian prolactin surges that drugs, such as sulperide, that are also associated with maintain CL for approximately 12 days, after which hyperproplactinemia (Bhavnani and Levin, 1996). In- luteolysis occurs coincident with sexual receptivity and a creased body weight gain and food consumption due to return to estrous cyclicity. This phenomenon is referred hyperprolactinemia may possibly result from increased to as pseudopregnancy. metabolic activity since prolactin has been shown to As mentioned, the prolactin surge in proestrus has a affect energy metabolism by modulating ATPase activity luteolytic effect, inducing regression of non-funtional in monkey brains (Bole-Feysot et al., 1998). CL of the previous cycle. Therefore, inhibition of the proestrus prolactin surge or sustained inhibition of prolactin, as noted with ergocornine or with dopamine Vaginal Mucification and Increased Number agonists, will prevent luteolysis causing increased of Diestrus Vaginal Epithelia numbers of persisting CL (Wuttke et al., 1971; Wutke Vaginal mucification is observed with hyperprolacti- and Meites, 1971).