Mechanisms of Ovarian Steroid Regulation of
Norepinephrine Receptor-Mediated Signal
Transduction in the Hypothalamus: Implications
for Female Reproductive Physiology
Anne M. Etgen,*
,
†
,1
Michael A. Ansonoff,* and Arnulfo Quesada*
*Department of Neuroscience and †Department of Psychiatry, Albert Einstein College
of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461
Received August 9, 2000; accepted March 1, 2001
In many mammalian species, the ovarian steroid hor-
mones estradiol (E
2
) and progesterone (P) act in the
hypothalamus and preoptic area to coordinate the tim-
ing of female sexual receptivity with ovulation. We study
lordosis behavior, an important component of sexual
receptivity in rats, and its regulation by E
2
and P as a
model system for understanding how hormonal modu-
lation of synaptic neurotransmission influences repro-
ductive physiology and behavior. Our findings suggest
that E
2
and P extensively regulate synaptic communica-
tion involving the catecholamine norepinephrine (NE) in
the hypothalamus. Estrogen priming shifts the balance
of postsynaptic NE receptor signaling in the hypothala-
mus and preoptic area away from -adrenergic activa-
tion of cAMP synthesis toward
1
-adrenergic signaling
pathways. Attenuation of -adrenergic signal transduc-
tion is achieved by receptor–G-protein uncoupling, ap-
parently due to stable receptor phosphorylation. E
2
modification of
1
-adrenergic signaling includes both
increased expression of the
1B
-adrenoceptor subtype
and a dramatic, P-induced reconfiguration of the bio-
chemical responses initiated by agonist activation of
1
-adrenoceptors. Among these is the emergence of
1
-adrenergic receptor coupling to cGMP synthesis. We
also present evidence that estrogen promotes novel,
functional interactions between insulin-like growth fac-
tor-1 (IGF-1) and
1
-adrenergic receptor signaling in the
hypothalamus and preoptic area. Thus, estrogen ampli-
fication of signaling mediated by
1
-adrenoceptors is
multifaceted, involving changes in gene expression (of
the
1B
-adrenoceptor), switching of receptor linkage to
previously inactive intracellular pathways, and the pro-
motion of cross talk between IGF-1 and NE receptors.
We propose that this hormone-dependent remodeling of
hypothalamic responses to NE maximizes reproductive
success by coordinating the timing of the preovulatory
release of gonadotropins with the period of behavioral
receptivity in female rodents. © 2001 Academic Press
In rodents, sequential exposure of specific neuronal
populations in the hypothalamus (HYP) to the ovarian
steroids estradiol (E
2
) and progesterone (P) is suffi-
cient to permit full expression of female reproductive
behaviors (Barfield, Rubin, Glaser, and Davis, 1982;
Feder, 1984; Pfaff, 1980; Pfaff, Schwartz-Giblin, Mc-
Carthy, and Kow, 1994). Estradiol and P action in the
HYP and preoptic area (POA) also regulates the re-
lease of pituitary luteinizing hormone (LH), which
triggers ovulation, thereby ensuring that the period of
behavioral sexual receptivity coincides with the opti-
mal time for fertilization (Etgen, Ungar, and Petitti,
1992; Freeman, 1994; Pfaff, 1980). A long-range goal of
our research program is to identify E
2
- and P-depen-
dent changes in chemical neurotransmission in the
HYP and POA that mediate the neuroendocrine inte-
gration of reproductive behavior and the preovulatory
LH surge. We (Etgen, Chu, Fiber, Karkanias, and Mo-
rales, 1999; Etgen et al., 1992) and others (McEwen,
Biegon, Davis, Krey, Luine, McGinnis, Paden, Parsons,
and Rainbow, 1982) have hypothesized that hormonal
regulation of reproduction involves changes in synap-
tic activity of the HYP–POA neurons governing LH
release and lordosis behavior. The monoamine neuro-
transmitter norepinephrine (NE) has been implicated
as a neurochemical mediator of both lordosis behavior
and the preovulatory LH surge (Crowley, 1986; Etgen
et al., 1992; Freeman, 1994; Herbison, 1997; Kalra,
1
To whom correspondence and reprint requests should be ad-
dressed. Fax: (718) 430-8654. E-mail: etgen@aecom.yu.edu.
Hormones and Behavior 40, 169–177 (2001)
doi:10.1006/hbeh.2001.1676, available online at http://www.idealibrary.com on
0018-506X/01 $35.00
Copyright © 2001 by Academic Press
All rights of reproduction in any form reserved. 169