CHAPTER 25The Gonads: Development & Function of the Reproductive System 421exposure to GnRH pulses of the frequency that exist at this
time. This self-priming effect of GnRH is important in pro-
ducing a maximum LH response.
The nature and the exact location of the GnRH pulse gener-
ator in the hypothalamus are still unsettled. However, it is
known in a general way that norepinephrine and possibly epi-
nephrine in the hypothalamus increase GnRH pulse frequen-
cies. Conversely, opioid peptides such as the enkephalins and
β-endorphin reduce the frequency of GnRH pulses.
The down-regulation of pituitary receptors and the conse-
quent decrease in LH secretion produced by constantly ele-
vated levels of GnRH has led to the use of long-acting GnRH
analogs to inhibit LH secretion in precocious puberty and in
cancer of the prostate.
Feedback Effects
Changes in plasma LH, FSH, sex steroids, and inhibin during
the menstrual cycle are shown in Figure 25–25, and their feed-
back relations are diagrammed in Figure 25–32. During the
early part of the follicular phase, inhibin B is low and FSH is
modestly elevated, fostering follicular growth. LH secretion is
held in check by the negative feedback effect of the rising plas-
ma estrogen level. At 36 to 48 h before ovulation, the estrogen
feedback effect becomes positive, and this initiates the burst of
LH secretion (LH surge) that produces ovulation. Ovulation
occurs about 9 h after the LH peak. FSH secretion also peaks,
despite a small rise in inhibin, probably because of the strong
stimulation of gonadotropes by GnRH. During the luteal
phase, the secretion of LH and FSH is low because of the ele-
vated levels of estrogen, progesterone, and inhibin.
It should be emphasized that a moderate, constant level of
circulating estrogen exerts a negative feedback effect on LH
secretion, whereas during the cycle, an elevated estrogen level
exerts a positive feedback effect and stimulates LH secretion.
It has been demonstrated that in monkeys estrogens must also
be elevated for a minimum time to produce positive feedback.
When circulating estrogen was increased about 300% for 24 h,
only negative feedback was seen; but when it was increased
about 300% for 36 h or more, a brief decline in secretion was
followed by a burst of LH secretion that resembled the midcy-
cle surge. When circulating levels of progesterone were high,
the positive feedback effect of estrogen was inhibited. There is
evidence that in primates, both the negative and the positive
feedback effects of estrogen are exerted in the mediobasal
hypothalamus, but exactly how negative feedback is switched
to positive feedback and then back to negative feedback in the
luteal phase remains unknown.Control of the Cycle
In an important sense, regression of the corpus luteum (luteol-
ysis) starting 3 to 4 d before menses is the key to the menstrual
cycle. PGF 2 α appears to be a physiologic luteolysin, but this
prostaglandin is only active when endothelial cells producing
ET-1 (see Chapter 33) are present. Therefore, it appears that at
least in some species luteolysis is produced by the combined
action of PGF 2 α and ET-1. In some domestic animals, oxytocin
secreted by the corpus luteum appears to exert a local luteolytic
effect, possibly by causing the release of prostaglandins. Once
luteolysis begins, the estrogen and progesterone levels fall and
the secretion of FSH and LH increases. A new crop of follicles
develops, and then a single dominant follicle matures as a result
of the action of FSH and LH. Near midcycle, estrogen secretion
from the follicle rises. This rise augments the responsiveness of
the pituitary to GnRH and triggers a burst of LH secretion. The
resulting ovulation is followed by formation of a corpus lu-
teum. Estrogen secretion drops, but progesterone and estrogen
levels then rise together, along with inhibin B. The elevated le-
vels inhibit FSH and LH secretion for a while, but luteolysis
again occurs and a new cycle starts.Reflex Ovulation
Female cats, rabbits, mink, and some other animals have long
periods of estrus, during which they ovulate only after copula-
tion. Such reflex ovulation is brought about by afferent im-
pulses from the genitalia and the eyes, ears, and nose thatFIGURE 25–32 Feedback regulation of ovarian function.
The cells of the theca interna provide androgens to the granulosa cells,
and theca cells also produce the circulating estrogens that inhibit the
secretion of GnRH, LH, and FSH. Inhibin from the granulosa cells inhib-
its FSH secretion. LH regulates the thecal cells, whereas the granulosa
cells are regulated by both LH and FSH. The dashed arrows indicate in-
hibitory effects and the solid arrows stimulatory effects.
AndrogensGnRHLHEstrogenic
effectsEstrogenFSHTheca
internaGranu-
losaInhibin BHypothalamusAnterior
pituitaryOvary