PRINCIPLES OF TOXICOLOGY

11.2 FEMALE REPRODUCTIVE TOXICOLOGY 221
early stages of embryonic development occur in the uterine tube, and then the embryo moves down to
the uterus to implant. All of this transport requires a patent lumen in the oviduct, and the movement
occurs due to a combination of ciliary beating and muscular action. In other words, the tract is more
than a transport tube and appropriate biological function is required to support the early embryo in
particular.
Atrophy of the oviduct or uterus can clearly prevent the transport of the germ cells and embryo.
Cadmium can produce such atrophy, and presumably other metals which cause overall tissue degeneration
could as well. For cadmium, the response is a general metabolic inhibition of the cells in the
reproductive tract, leading to cell death and declining organ weight. Not surprisingly, uterine, as well
as ovarian, cyclicity is impaired. Lead is another example of a metal that may directly affect the cells
lining the uterus, subsequently interfering with proper uterine cyclicity.
The features responsible for moving the germ cells and early embryo appear to be a potential target
for some components of cigarette smoke. Experimental exposures have resulted in both increases in
muscular related oviductal and uterine motility and immobilization of the cilia lining the oviduct. The
pertinence of these observations to human exposures and the observed effects of smoking are not clear.
However, the potential outcomes, improper migration of the germ cells precluding fertilization, or the
early embryo preventing proper implantation, are consistent with the overall decreased fertility and
increases in irregular cyclicity reported for smokers.
Hormonal Regulation of Reproductive Function and Associated Toxicity
Endocrine regulation of female reproduction is even extremely complex. The hypothalamic-pituitarygonadal
axis is present in females, and GnRH release and the timing of changes in the relative levels
of the two major gonadotropins, LH and follicle stimulating hormone (FSH) are linked to the ovarian
follicular cycle (Figure 11.2). This is accomplished by endocrine feedback loops involving the steroid
hormones estrogen and progesterone, as well as some protein hormones.
In a simplified form, the female endocrine cycle can be considered to start with increasing levels
of FSH production by the pituitary during the early stages of folliculogenesis (Figure 11.4). As the
follicles develop, the granulosa cells surrounding the oocyte are a major source of estrogens. As the
estrogen levels increase, FSH production is shut down and production of the other gonadotropin, LH
increases. When the follicle is fully mature, there is a surge of LH release, directing ovulation and the
subsequent formation of a progesterone secreting tissue, the corpus luteum, at the site where the follicle
had been. Progesterone levels rise and support the establishment of a pregnancy. Progesterone also
causes the levels of both gonadotropins to drop. If there is no pregnancy the corpus luteum degenerates
and progesterone levels decline, releasing the inhibition of gonadotropin secretion. FSH can again rise,
starting the cycle over. For the human, this is the point where menses occurs, lasting through the early
stages of the next follicular cycle.
Disruptions at the gonad, pituitary, or hypothalamus during the preovulatory stages can cause a
failure of folliculogeneis, and there will be no ovulation for the affected cycle. Later disruptions can
cause a failure of the corpus luteum maintenance, preventing the establishment of pregnancy if the egg
had been fertilized, or causing a shortened cycle. Alternatively, interference with luteal degeneration
can cause a cycle extension and this may be manifest as delayed menstruation. It is clear that there are
plenty of opportunities for endocrine disrupting toxicants to interfere with both the follicular cycle and
the ability to maintain a pregnancy.
There are examples of toxicants that can interfere with female hormonal regulation. Lead toxicity,
for instance, is associated with decreased progesterone production. This may in part explain its
historical use as an abortofacient, since progesterone is the key hormone for establishing and
maintaining pregnancy. The actual mechanism of lead-induced progesterone inhibition is not clear.
However, the established effects of lead on the neuroendocrine system could reasonably be expected
to interfere with the hypothalamic or pituitary secretion patterns required for the luteal phase of the
cycle.