A Practical Approach, Second Edition=Ronald D. Ho.pdf

TESTING FOR REPRODUCTIVE TOXICITY 461F. Histopathological Evaluation of the Female Reproductive Organs1. OvariesNumerous articles, 123 chapters, 124–127 reviews, 128,129,131 and books 130 have been written concerningthe ovary and ovulation. A detailed description of ovarian histology and ovulation is beyond thescope of this chapter. The ovary serves a number of functions that are critical to reproductiveactivity, including ovulation of oocytes and production of hormones. The developing ovarianfollicles produce estrogen, while the corpora lutea formed after ovulation produce progesterone.Histopathological evaluation of the three major compartments of the ovary (i.e., follicular, luteal,and interstitial) plus the capsule and stroma should be performed to reveal possible toxicologicalconditions. 132–134 Methods described below can be used to quantify ovarian follicular development.Delayed ovulation can alter oocyte viability and cause trisomy and polyploidy in the conceptus.135–137 Altered follicular development, ovulation failure, or altered corpus luteum formation orfunction can result in disruption of cyclicity and reduced fertility. Therefore, significant increasesin follicular atresia, evidence of oocyte toxicity, interference with ovulation, or altered corpusluteum formation or function should be considered adverse female reproductive effects. In addition,significant changes in folliculogenesis or luteinization (e.g., increased cystic follicles, luteinizedfollicles), altered puberty, and/or premature reproductive senescence should be considered adversefemale reproductive effects.2. UterusThe histological appearance of the normal uterus fluctuates according to the stage of the estrous cycleand pregnancy. The endometrium consists of simple columnar epithelium with simple tubular glandswith little or no branching. During proestrus, the epithelium becomes more cuboidal, possibly a resultof compression and stretching of the dilated uterus. During proestrus and estrus, inflammatory cells(mostly neutrophils) infiltrate the myometrium and endometrial stroma. Inhibition of ovarian activitywith the resultant reduction in steroid secretion can result in endometrial hypoplasia and atrophy, aswell as altered vaginal cytology. Uterine hypertrophy and hyperplasia can also be caused by prolongedestrogen or progesterone treatment, respectively. Significant dose-related increases in endometrialhyperplasia, hypoplasia, or aplasia should be considered adverse female reproductive effects.3. OviductsThe oviducts are not routinely examined histologically in reproductive toxicity studies, althoughgross and histological evaluations of the oviduct for anomalies induced during development (agenesis,segmental aplasia, and hypoplasia) can be performed. Oviductal hypoplasia or hyperplasiacan occur because of reduced estrogen stimulation or prolonged estrogenic stimulation, respectively.Significant dose-related increases in oviductal hyperplasia or hypoplasia should be consideredadverse female reproductive effects.4. Vagina and External GenitaliaDevelopmental abnormalities of the vagina (agenesis, hypoplasia, dysgenesis) can be due to geneticfactors, prenatal toxicant exposure, or may have an unknown etiology. In utero exposure of femalesto agents that disrupt reproductive tract development can cause development of ambiguous externalgenitalia (e.g., masculinization of female rodents with increased anogenital distance). 138 Errors ingender determination can be made when observing newborn pups with ambiguous external genitalia,© 2006 by Taylor & Francis Group, LLC