Influence of endogenous and exogenous sex hormones on plasma brain-derived neurotrophic factor
Influence of endogenous and exogenous sex hormones on plasma brain-derived neurotrophic factor
S.Begliuomini 2 3
E.Casarosa 2 3
N.Pluchino 2 3
E.Lenzi 2 3
M.Centofanti 2 3
L.Freschi 2 3
M.Pieri 2 3
A.D.Genazzani 1 2
S.Luisi 0 2
Andrea R.Genazzani 2 3
0 Department of Pediatric Obstetrics and Reproductive Medicine, Division of Obstetrics and Gynecology, University of Siena , Siena , Italy
1 Department of Obstetrics and Gynecology, University of Modena , Modena , Italy
2 Gynecology and Obstetrics, University of Pisa , Via Roma 35, 56100 Pisa , Italy. Tel.:
3 Department of Reproductive Medicine and Child Development, Division of Gynecology and Obstetrics, University of Pisa , Pisa , Italy
BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a mediator of neuronal plasticity and influences learning, memory and cognitive behaviour. The aim of this study is to assess plasma BDNF variations according to hormonal status. METHODS: A total of 60 subjects were included: 20 fertile ovulatory women, 15 amenorrhoeic women and 25 postmenopausal women. Blood samples were collected after overnight fasting. For 5 out of the 20 fertile women, samples were collected every 2 days throughout the whole menstrual cycle. Following basal evaluation, 10 out of 25 postmenopausal women were administered a hormone replacement therapy (HRT) and reevaluated after 6 months of treatment. Plasma BDNF concentrations were measured by enzyme-linked immunosorbent assay. In fertile women, estradiol (E2), progesterone and gonadotrophins were also assessed. RESULTS: In fertile women, luteal phase levels of plasma BDNF were significantly higher than follicular phase levels (P < 0.001). BDNF increased from early follicular phase up to Day 14 of the cycle, reaching a pre-ovulatory peak, similar to E2. A second rise took place during mid-luteal phase, with a peak on Day 24. Amenorrhoeic subjects, as well as postmenopausal women, showed significantly lower plasma BDNF levels compared with fertile females (P < 0.001). BDNF was positively correlated with E2 and progesterone and negatively correlated with menopausal age. HRT restored BDNF levels to those present in fertile women during the follicular phase. CONCLUSIONS: Plasma BDNF levels are influenced by hormonal status. Modifications in BDNF circulating levels during the menstrual cycle suggest a potential role for gonadal sex hormones (E2 and progesterone) in regulating neurotrophin expression.
brain-derived neurotrophic factor/hormone replacement therapy/menopause/ovarian cycle/sex hormones
Introduction
Brain-derived neurotrophic factor (BDNF) is a member of the
neurotrophin family (NT) and is abundantly expressed in the
central and peripheral nervous system, particularly in the
hippocampus, cerebral cortex (especially in the temporal and
occipital area, insula, motor and sensitive cortex) and
amygdala (Murer et al., 2001). Its chemical structure is that
of a small homodimeric protein (P.M. 28 kDa), containing a
cystine cluster (cystine knot motif) and a b-antiparallel strand
that confer a 3D extended configuration, which is typical of
other growth factors [transforming growth factor-b2,
plateletderived growth factor, vascular endothelial growth factor
(VEGF)], thus suggesting a probable common evolution (Van
Kesteren et al., 1998).
BDNF is known to cross the blood-brain barrier in both
directions, and a physiologically relevant amount of circulating
BDNF might derive from neurons and glia cells of the central
nervous system (Pan et al., 1998; Karege et al., 2002a,b).
Although it was originally described in the nervous system,
BDNF has been shown to be expressed in a variety of
nonneuronal cells (Yamamoto et al., 1996). In fact, potential
additional sources are represented by vascular endothelial
and smooth muscle cells (Donovan et al., 1995; Nakahashi
et al., 2000). Moreover, evidences suggest that elements of
the immune system, such as activated macrophages and
lymphocytes, could contribute to BDNF production (Gielen
et al., 2003).
BDNF is already present in fetal life and its expression
rises to a maximal level after birth, promoting neuronal
outgrowth and differentiation in neonates (Con Over and
Yancopoulos, 1997). In adults, it plays a predominant
functional role: it has been shown to induce long-lasting
# The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
All rights reserved. For Permissions, please email:
changes in synaptic plasticity, neurotransmitter and
neuropeptide production and excitability (Kang and Schuman,
1995; Li et al., 1998; Carter et al., 2002) and to play a
key role in learning, memory and behaviour (Hall et al.,
2000; Egan et al., 2003).
BDNF is also present in human plasma and, since platelets
represent a major storage site of BDNF in peripheral blood,
serum levels are higher than plasma levels. It has been
shown that plasma concentrations decrease significantly
with age or weight gain, whe (...truncated)