Kisspeptin and GnRH Pulse Generation - Kisspeptin Signaling in Reproductive Biology - page 305

Putative Mechanisms Underlying the Negative Feedback Actions
of Steroid Hormones
Mechanisms of the negative feedback action of gonadal steroids can be, at least in
part, explained by the schema shown in Fig. 14.6b. Progesterone is a potent inhibi-
tor of pulsatile GnRH secretion in many species. KNDy neurons contain Dyn and
receptors for P [ 64 , 87 ], and P increases the expression of Dyn [ 97 ]. Therefore, it is
suggested that P enhances the inhibitory drive of Dyn/KOR signaling, leading to a
reduction in the frequency of burst activities in KNDy neurons (Fig. 14.6b). This
speculation is in concert with the previous fi nding that blockade of Dyn/KOR sig-
naling reverses the inhibitory effect of P on pulsatile LH secretion in rats [ 126 ] and
sheep [ 127 ]. It appears that Dyn/KOR signaling may play a critical role in determin-
ing the length of the refractory period after the burst in KNDy neurons.
One aspect of E2 negative feedback is a decrease in the amplitude (amount) of
LH secretion. The expression of not only NKB [ 57 , 128 , 129 ] but also NK3R [ 57 ],
in the ARC, is decreased by E2, suggesting that E2 acts to attenuate the stimulatory
drive of NKB/NK3 signaling. Figure 14.6b indicates that such E2 action would lead
to “thinning” of the burst of KNDy neurons, which might be refl ected as a marked
decrease in the duration of the MUA volley after E2 treatment (Fig. 14.2c ). Given
that the release of kisspeptin to GnRH neuronal projections in the ME is mainly
under the control of the burst activity of KNDy neurons (Fig. 14.6a), the shortening
of the burst of KNDy neurons by E2 would result in a decline in the amount of
GnRH released during each pulse. This may represent one aspect of the negative
feedback action of E2. Moreover, it has been indicated in many species that E2 also
reduces the expression of kisspeptin in the ARC [ 85 , 87 , 106 , 130 ], which may also
contribute to the decreased amount of GnRH released per pulse.
The other aspect of the E2 action is its negative effect on the frequency of GnRH/
LH pulses. It has been shown that E2 also reduces the frequency of the MUA volley
and LH pulses in several species, including rats [ 38 ], monkeys [ 30 ], and goats
(Fig. 14.2 [ 42 , 44 , 53 ]), although this action of E2 seems less conspicuous in sheep
[ 131 , 132 ]. Because the inhibitory effect of E2 is much smaller than P (Fig. 14.2 ), it
seems unlikely that Dyn/KOR signaling mediates the E2 action. Instead, other
mechanisms may also be involved in the negative feedback action of E2. One
possible mechanism is the alteration of neuronal excitability. It is possible that E2
reduces the excitability of KNDy neurons through modifying electrophysiological
properties of the cell membrane, as shown in mouse GnRH neurons [ 133 ], leading
to the attenuation of spontaneous activity of individual neurons. This would
decrease, in a stochastic manner, the occurrence of the random activity that initiates
the bursting process in the KNDy neuron. Although highly speculative, it is sug-
gested that neuronal mechanisms involving E2 actions in KNDy neurons, such as
the excitability for example, are associated with the pathway of the control of GnRH
secretion by nutrition, because the inhibitory infl uence of several nutritional stress-
ors on the GnRH pulse generator is more conspicuous in the presence of E2 than its
absence [ 32 , 46 , 134 , 135 ].