Page 321 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

288 SECTION | II Organ Toxicity

VetBooks.ir of estrogens during estrus, while metestrus represents
the opposite shift in the endocrine milieu (estrogen dom-
inance to progesterone dominance) (Senger, 2003;
Evans et al., 2007).
The durations of the various stages of the estrous cycle
vary with species and can, depending on the animal in
question, either occur throughout the year, multiple times
within an ovulatory season that is dependent on photope-
riod (long-day or short-day polyestrous animals) or only
once a year (Senger, 2003). The domestic bitch does not
have a metestrus and, in fact, is actually most receptive to
copulation when estradiol is declining and there is a
unique, preovulatory surge in progesterone. This endo-
crine environment predisposes the bitch to cystic endome-
trial hyperplasia and pyometra following exposure to
some xenoestrogens and progestagens. Felids, which are FIGURE 17.4 The endocrine regulation of ovarian function and the
induced (reflex) ovulators, like ferrets, mink, camelids feedback loops for the hypothalamic pituitary gonadal (ovarian) axis
and rabbits, the period of time following an estrus in in the female are depicted. This figure was adapted, with permission,
which copulation has not occurred has been described as from Wilker and Ellington (2006) (modifications courtesy of Don
Connor and Howard Wilson).
post-estrus rather than metestrus because there is no
increase in progesterone secretion following the end of
Ganjam, 2017). A primary follicle is transformed into a
sexual receptivity (Senger, 2003). Anestrus is the time
secondary follicle when there are several layers of granu-
period during which reproductive cyclicity ceases and can
losa cells. Preantral follicles (primary and secondary folli-
be seasonal (estradiol and progesterone production are at
cles) become antral (tertiary) follicles, when fluid from
basal levels) or can be associated with various endocrine
the granulosa cells of secondary follicles coalesces to
milieus related to species of animal, pregnancy, lactation,
form an antrum (Evans et al., 2007; Evans and Ganjam,
stress and/or pathological conditions, some of which can
2017).
be induced by xenobiotics.
Cyclic increases in FSH concentrations facilitate
recruitment antral follicles. Granulosa cells can produce
Follicular Development activin which is thought to provide positive feedback to
the anterior pituitary, further increasing gonadotropic
The general sequence of endocrine and morphological
FSH secretion (Figure 17.4)(Senger, 2003; Wilker and
changes occurring during the estrous cycle involves a
Ellington, 2006). Recruited antral follicles, which are
variety of positive and negative feedback loops affecting
gonadotropin sensitive, undergo several waves of follicu-
the hypothalamic pituitary gonadal axis and leads to
lar development beginning in metestrus and ending in
the development of antral follicles, the primary source of
proestrus (Ginther, 1992; Senger, 2003; Evans et al.,
estrogens, and, eventually, the formation of corpora lutea,
2007). The final wave of one or more dominant follicles,
which produce progesterone (Figures 17.3 and 17.4).
destined for ovulation, rather than atresia, produces the
During the time of year when females are exhibiting
large amounts of estrogens typical of estrus and required
reproductive cyclicity, there are cyclic alterations in the
for sexual receptivity and the preovulatory estrous surges
pattern of hypothalamic GnRH secretion from the tonic
in GnRH and LH secretion (Senger, 2003).
and surge centers, which interact with the anterior pitui-
tary to influence the relative amounts of FSH and LH
secreted by anterior pituitary gonadotropes. Over the Ovarian Follicular Synthesis of Estrogens
course of the ovulatory season, many (up to several hun- The production of estrogens (predominantly estradiol) by
dred or more) primordial follicles leave the reserve pool antral follicles is accomplished by a mechanism termed
in a cyclic fashion (under the influence of FSH) and enter the “two-cell or two-gonadotropin model,” which can
the active pool of follicles (primary follicles) undergoing vary somewhat between species (Senger, 2003; Evans
growth and differentiation (folliculogenesis) and eventu- et al., 2007; Evans and Ganjam, 2017). Cells from the
ally atresia or ovulation (Senger, 2003; Evans et al., 2007; theca interna and/or granulosa cells (depending on the
Evans and Ganjam, 2017). The oocyte in the developing species) produce progesterone from pregnenolone synthe-
follicle grows in size, the zona pellucida is formed and sized from cholesterol and, under the influence of rela-
the granulosa cells surrounding the oocyte undergo mito- tively low concentrations of LH, theca interna cells
sis and further differentiation (Senger, 2003; Evans and convert this progesterone into androgens and, ultimately,