Human Reproduction, Vol. 15, (Suppl. 1), pp. 14-27, 2000
Progesterone, progestagens and the central
nervous system
A.R.Genazzani1'3, M.Stomati1, A.Morittu1, F.Bernardi1,
P.Monteleone, E.Casarosa1, R.Gallo1, C.Salvestroni1 and
M.Luisi2
'Department of Reproductive Medicine and Child Development, Division
of Gynecology and Obstetrics, University of Pisa, and 2 Endocrine Research
Unit, Council of National Research (C.N.R.), Pisa, Italy
3
To whom correspondence should be addressed at: Department of Obstetrics and
Gynecology, University of Pisa, Via Roma 35, 56100 Pisa, Italy
Oestrogen, progestagens and androgens are able to modulate several brain
functions. Receptors for gonadal steroids have been identified in several
brain areas: amygdala, hippocampus, cortex, basal forebrain, cerebellum,
locus coeruleus, midbrain rafe nuclei, glial cells, pituitary gland, hypothalamus and central grey matter. The mechanism of action of sex steroids
at this level is similar to that observed in the peripheral target organs,
including both genomic and non-genomic effects. The increased use of sex
steroid hormone derivative therapies has lead to study of the biochemical
and metabolic properties of the different progestin molecules available in
hormonal therapies. In particular, experimental and clinical studies focused
the attention of researchers on interactions between oestrogens and progestins
in the neuroendocrine control of the brain functions and its clinical implications. Moreover, steroids are also synthesized de novo in the brain or may
be derived from the conversion of blood-borne precursors, suggesting that
the brain is also a source of steroids, named neurosteroids. Neurosteroids
exert non-classical rapid actions as allosteric agonists of y-aminobutyric acid
receptor A (GABAA) and also modulate classic neurotransmitters in the
brain. In addition, progesterone derivatives, e.g. pregnanolone, and 3a 5aOH THP (allopregnanolone) are synthesized de novo by astrocytes and
oligodendrocites starting from cholesterol. Physiological or pathological
modifications of the synthesis and release of neurosteroids play a relevant
role in the control of brain function.
Key words: androgens/CNS/oestrogen/progestagens
Introduction
The brain is an organ whose development and activities are modulated by several
endogenous and exogenous stimuli and there is a large body of evidence that
14
Human Reproduction Volume 15 Supplement 1 2000
© European Society of Human Reproduction and Embryology
Progesterone, progestagens and the CNS
Noradrenaline
Dopamine
Serotonin
Acetyl choline
(3 - endorphin
NPY
CRF
GABA
Melatonin
GnRH
SRIH
TRH
CGRP
androgens
Figure 1. Neurotransmitters and neuropeptides modulated by sex hormones. NYP = neuropeptide Y:
CRF = corticotrophin-releasing factor; GABA = y-aminobutyric acid; GnRH = gonadotrophin-releasing
hormone; SRIH = serotonin receptor inhibiting hormone; TRH = thyrotrophin-releasing hormone: and
CGRP = calcitonin gene-related peptide.
indicates the actions of sex steroid hormones within the brain. Endogenous and
exogenous steroid hormones are able to modulate brain function through the
binding with specific receptors. Receptors for gonadal steroids have been
identified in several brain areas: amygdala, hyppocampus, cortex, basal forebrain,
cerebellum, locus coeruleus, midbrain rafe nuclei, glial cells, pituitary gland,
hypothalamus and central grey matter (Speroff et al, 1995; Alonso-Soleis et al,
1996; Genazzani et al, 1996).
The mechanism of action of oestrogens, androgens and progestins in the brain
is similar to that observed in the peripheral target organs, including both genomic
and non-genomic effects. Through the classical genomic mechanisms, steroids
induce slower long-term actions on neurons by activating specific intracellular
receptors that modulate gene transcription and protein synthesis. Thus, gonadal
steroids modulate the synthesis, release and metabolism of many neuropeptides
and neuroactive transmitters and the expression of their receptors (Figure 1)
(Alonso-Soleis et al, 1996; Panay and Studd, 1998; Sundstrom et al, 1999). In
particular, among the neurotransmitters, noradrenaline, dopamine, y-aminobutyric
acid (GABA), acetylcholine, serotonin and melatonin are regulated by sex steroid
hormones. The neuropeptides directly modulated by gonadal hormones include
opioid peptides, gonadotrophin-releasing hormone (GnRH), corticotrophinreleasing factor (CRF), neuropeptide Y (NPY) and galanin.
On the other hand, steroid hormones exert very rapid effects that cannot be
attributed to genomic mechanisms. In fact, throughout specific non-genomic
mechanisms, oestrogens, androgens and progestagens modulate electrical
excitability, synaptic functioning, and morphological features (Fuxe et al, 1981;
Matsumoto, 1991; McEwen and Wooley, 1994; Mong and McCarthy, 1999). The
interaction of genomic and non-genomic mechanisms allows for a wide range of
sex steroid actions in the regulation of cerebral functions.
Classical knowledge and recent developmental data on the effects of sex
15
A.R.Genazzani et ah
steroid hormones on the brain are derived by in-vitro and in-vivo studies. Only
a few clinical trials have been carried out on the effects of exogenous sex steroids
on the central nervous system (CNS) in humans. The increased use of sex steroid
hormone derivative therapies has lead to studies of the biochemical and metabolic
properties of the different progestin molecules available in hormonal therapies.
In particular, attention has been focused on the interactions between oestrogens
and progestins in the neuroendocrine control of the brain functions and its clinical
implications. In fact, each progestin molecule is able to bind to the progesterone
receptor and exert its specific progestative effect. However, the different kinds
of molecules may either interfere with other sex steroid hormone or other
substance receptors, thus exerting multiple effects in each target tissue.
The identification in the CNS of steroids synthesized de novo or derived from
blood-borne precursors has suggested that the brain is not only a target but also
a source of steroids, named neurosteroids (Mellon, 1994). Progesterone is not
only produced in the ovaries and adrenal gland but it is also synthesized in the
cerebral glial cells and for this reason is considered a neurosteroid. Progesterone
derivatives such as pregnanolone, and 3a 5a-OH THP (allopregnanolone) are
also synthesized de novo by astrocytes and oligodendrocites starting from
cholesterol. Neurosteroids exert non-classical rapid actions as allosteric agonists
of GABA receptor A (GABAA) and also modulate classic neurotransmitters in
the brain (Mellon, 1994). Several studies have shown a relationship between the
fluctuation of the synthesis and release of neurosteroids and psychological
symptoms, e.g. depression, anxiety and irritability (Paul and Purdy, 1992;
Mellon, 1994).
Progestins and CNS: experimental studies
Progesterone and its derivative compounds modulate the synthesis and the
release of several neurotransmitters and neuropeptides in response to specific
physiological or pathological stimuli. In particular among the brain areas, the
hypothalamus and the anterior pituitary lobe are considered the two principal
targets of androgens, oestrogens and progestagens. At the hypothalamic level,
the principal target for sex steroid hormones are those neurons producing the
pulsatile release of GnRH. The release of GnRH depends upon the complex and
co-ordinated inter-relationships between gonadal steroids, pituitary gonadotrophins and neuroendocrine systems. The interplay of these control mechanisms is
governed by peripheral feed-back signals, but the input from higher brain areas
may also modify the GnRH secretion. The anterior pituitary lobe is the bestknown target tissue for endogenous or exogenous sex steroid hormones. It is
possible to detect luteinizing hormone (LH) and follicle stimulating hormone
(FSH) as the expression of pituitary cell activity. The synthesis and release of
FSH and LH by gonadotrophic cells depends upon the peripheral control of
gonadal hormones and the hypothalamic GnRH.
In the literature, several pieces of data are available on the effects of oestrogens
16
Progesterone, progestagens and the CNS
and progestagens on the hypothalamus and anterior pituitary in experimental
models. Experimental studies on female rats show a significant increase in the
hypothalamic concentration of GnRH after surgical ovariectomy when compared
with fertile control rats (Mishell et al., 1977; Genazzani and Petraglia, 1990).
Oestradiol benzoate treatment induces a significant reduction in GnRH concentration to values similar to those found in fertile rats. Moreover, the treatment of
ovariectomized female rats with oestradiol benzoate in association with different
types of progestins, progesterone, norethisterone enantate (NET), desogestrel and
medroxyprogesterone acetate (MAP), induced different results with respect to
rats given oestradiol alone (Mishell et al., 1977; Genazzani and Petraglia,
1990). Progesterone and NET treatment increased GnRH concentrations in the
mediobasal hypothalamus of ovariectomized rats, while the rats treated with
desogestrel or MAP did not show any changes in GnRH concentrations compared
with ovariectomized rats. When progestins were chronically administered with
oestradiol benzoate, progesterone and NET reversed the effects on the GnRH
induced by oestradiol benzoate alone, while desogestrel and MAP were not
active in rats (Mishell et al., 1977; Genazzani and Petraglia, 1990).
At the pituitary level, the content of LH was significantly higher in
ovariectomized rats than in fertile control rats. The administration of oestradiol
benzoate alone to ovariectomized rats induced a significant increase in LH that
counteracted the effect of ovariectomy. The chronic treatment of ovariectomized
rats with progesterone or NET alone significantly reduced LH concentration.
Desogestrel and MAP administration did not induce significant changes. All
progestins, given in association with oestradiol benzoate in ovariectomized rats,
blocked the increase in LH induced by oestradiol benzoate alone (Mann and
Barraclough, 1973; Genazzi et al., 1990). Surgical ovariectomy induced a
significant increase in plasma LH concentrations in fertile female rats, while
oestradiol benzoate administration reduced circulating LH concentrations to
values similar to those of the fertile control group. Progesterone and different
progestins were inactive in counteracting the effects of oestradiol benzoate on
plasma LH concentrations in rats (Mann and Barraclough, 1973; Mishell et al.,
1977; Labrie et al, 1979; Genazzani and Petraglia, 1990; Bohus et al., 1991).
In summary, these data support the evidence that progesterone and NET may
act on the hypothalamus-pituitary axis. Desogestrel and MAP did not influence
the inhibitory effects of oestradiol benzoate at the hypothalamic level, but all
gestagens were able to modulate the oestrogen effects on pituitary cells.
Gonadal hormones modulate the activity of the hypothalamic and extrahypothalamic noradrenergic, dopaminergic, serotoninergic neurons (Figure 2).
Experimental trials in castrated female rats showed an impairment of the
catecholaminergic neurons with an increase in noradrenaline release and a
decrease in dopamine. Oestrogen administration was able to decrease the
release of noradrenaline, to increase the dopaminergic neuronal activity and the
dopamine release from the medio-basal hypothalamus. The effect of oestrogens
in modulating adrenergic receptors appears to be bimodal by up-regulating the
al-edrenergic and down-regulating the (3-adrenergic receptor activity (Plotsky
17
A.R.Genazzani et al.
f monoamino oxidase activity
tnoradrenaline and
dopamine turnover
f catechol-o-methyl transf. activity
progesterone
and metabolites
G A B A A receptor agonist
t serotonine turnover
potentiate the gabaergic
anxiolytic effect
mood disturbances
(depression)
Figure 2. Effects of progesterone and metabolites on monoamino oxidase, catechol-O-methyl transferase
activity, y-aminobutyric acid receptor A (GABAA) and serotonin.
et al, 1989; Bohus et al, 1991; Etgen and Karkanias, 1994). Few data are
available regarding the effects of progesterone and progestins in experimental or
clinical models on the catecholaminergic system. The association of progesterone
and oestrogen in ovariectomized female rats suppressed oestrogenic effects on
noradrenergic neurons in the pineal gland (Etgen and Karkanias, 1994). In the
rabbit, oestradiol and progesterone enhance noradrenaline release, leading to an
increase of the hypothalamus neuronal activity and to the expression of lordosis
behaviour (Etgen and Karkanias, 1994; Genazzani et al, 1996; Panay and
Studd, 1998).
The serotoninergic system is also modulated by gonadal steroids. In female
rats, the hypothalamic serotonin content varies throughout the oestrus cycle and
it has been demonstrated that oestradiol produces an acute biphasic up- and
down-regulation of serotonin receptors: an early increase in serotonin receptors
concentration is followed by a delayed decrease (Biegon et al, 1980). Oestrogens
can also modify the concentration and the availability of serotonin, by increasing
the rate of degradation of monoamino oxidase (MAO), the enzyme that catabolizes
serotonin (Luine and McEwan, 1977). Experimental data have demonstrated that
oestrogen displaces tryptophan from its binding sites to plasma albumin (in this
manner tryptophan is more available in the brain to be metabolized into serotonin)
and enhances the transport of serotonin (Luine and McEwan, 1977). In animal
studies, progesterone increased serotonin turnover in ovariectomized rat in the
limbic structures (Dickinson and Curzon, 1986). The effects of progesterone
following stress altered the 5-hydroxytryptamine (5-HT) metabolism in several
regions of the rat brain: 5-HT concentration are significantly higher when
compared to those of rats stressed alone (Ladisch, 1977). Moreover, the activity
of MAO and catechol-(9-methyl transferase (COMT) in rat brain is increased by
progesterone treatment (Luine et al., 1975; Holzbauer and Youdin, 1993).
Neuropeptides, e.g. NPY and galanin, influence central behaviour and neuro18
Progesterone, progestagens and the CNS
endocrine functions by stimulating the pulsatile release of GnRH and gonadotrophins. Experimental studies showed that oestrogens are able to stimulate the
NPY synthesis and release in the hypothalamus. In castrated female rats, gonadal
steroid deficiency reduces neurosecretion of NPY-producing neurons (Speroff
et al., 1995; Panay and Studd, 1998). Oestrogen administration increases NPY
content in the median eminence and the synthesis of NPY in arcuate nucleus,
by inducing NPY gene expression. Indeed, recent findings demonstrate several
interactions between NPY and (3-endorphin neurons in the hypothalamus, and
hence both oestrogens and progestagens may indirectly exert modulatory effects
on NPY, inducing (3-endorphin release. Galanin is a 29 amino acid neuropeptide
isolated from the anterior pituitary gland of rats and humans, whose synthesis is
under the control of oestrogen (Kaplan et al., 1988).
Galanin stimulates the hypothalamic GnRH release through a prostaglandin
E2 (PGE2) and al-adrenoreceptor-related mechanism and a common pulsegenerator modulation between galanin and NPY has been postulated (Kaplan
.et al, 1988).
Among those neuropeptides regulated by gonadal steroids, endogenous opioids
exert inhibitory or stimulatory signals on GnRH hypothalamic neurons. Oestrogens
directly modulate endogenous opioid activity and directly stimulate opioid
receptor expression. In particular, attention has been focused on (3-endorphin, the
most important and biologically active endogenous opioid peptide, that shows
behavioural, analgesic, thermoregulatory and neuroendocrine properties
(Genazzani and Petraglia, 1984; Etgen and Karkanias, 1994). Experimental and
clinical studies have demonstrated that variations in central and peripheral
(3-endorphin concentrations may be considered as one of the markers of
neuroendocrine functions (Adler et al., 1980; Aleem and Mclntosh, 1985;
Genazzani and Petraglia, 1988). Experimental evidence shows that (3-endorphin
reduces circulating LH concentrations by inhibiting GnRH secretion and decreasing sexual activity (Genazzani and Petraglia, 1987). Changes in hypothalamic
and pituitary [3-endorphin content and serum concentrations has been related to
the oestrous cycle in rats, thus suggesting a role for oestrogens and progesterone
in the control of the peptide synthesis and release. In-vitro experimental evidence
suggests that the injection of (3-endorphin is able to decrease circulating LH
concentrations by inhibiting the release of GnRH. Chronic treatment with
progesterone or different progestins (MAP, NET, desogestrel) with or without
oestradiol benzoate administration induces different effects on the hypothalamic
and pituitary content of (3-endorphin in ovariectomized female rats (Genazzani
and Petraglia, 1990). In the anterior pituitary lobe, the effect of the ovariectomy
was a significant reduction in (3-endorphin concentrations in comparison with
fertile rats, while the administration of oestradiol produced a restoration of the
(3-endorphin content. When progesterone, NET or MAP were given alone, they
did not modify the concentrations of the peptide while the concentrations
significantly increased after desogestrel administration. In ovariectomized rats,
the treatment with oestradiol benzoate plus progestins reversed the effect
induced by oestradiol benzoate alone (Genazzani and Petraglia, 1990). In the
19
A.R.Genazzani et al.
neurointermediate lobe, ovariectomy in female fertile rats produced a decrease
in (3-endorphin content. The treatment with oestradiol benzoate alone or with
progesterone, desogestrel and MAP induced an increase in (3-endorphin concentrations to the values of fertile controls, while NET was not active in counteracting
the effect of the ovariectomy. Progesterone and progestin treatment, in association
with oestradiol benzoate, did not modify the effect of oestradiol benzoate alone
(Genazzani and Petraglia, 1990). At the hypothalamic level, surgical ovariectomy
did not modify (3-endorphin concentrations in the hypothalamus of female
rats. The administration of oestradiol benzoate, NET and progesterone in
ovariectomized rats induced a significant increase in peptide concentrations,
while desogestrel and MAP were inactive (Backstrom et al., 1983).
Progestagens and CNS: clinical findings
Generally, an association has been reported between oestrogen and the amelioration of mood and well-being in women, while the effects of progesterone and
progestagens are considered to be negative. In fact, a close relationship between
mood and behavioural impairment and hormonal variations may occur during
the menstrual cycle. In particular, symptoms are related to the cyclic modifications
of synthesis, release and circulating concentrations of oestrogens, progestagens
and androgens. Generally, the follicular and pre-ovulatory phase are periods
related to a state of well-being. These two phases are characterized by higher
circulating concentrations of oestradiol (Backstrom et al., 1983). After ovulation
starts, a progressive increase of negative mood symptoms occurs in relationship
to the rise in circulating progesterone concentrations. The symptom peak occurs
5-6 days after the maximum progesterone concentrations at the mid-luteal phase.
The symptoms were most severe during the last 5 premenstrual days, thus
inducing so-called premenstrual syndrome in many women. In non-ovulatory
cycles (either spontaneous or induced by GnRH agonist treatment), the symptom
variations disappear (Muse et al., 1984; Hammarback and Backstrom, 1988;
Hammarback and Ekholm, 1991; Mortola et al., 1991; Mezrow et ah, 1994).
It is possible to divide the exogenous administration of sex steroid hormones
into oestro-progestin administration in fertile women and hormone replacement
therapy (HRT) in post-menopausal women. The increased use of sex steroid
hormone derivatives in the last 30 years has lead to the study of the biochemical
and metabolic properties of the different molecules available in hormonal
therapies. In particular, attention has been focused on the interactions between
oestrogens and progestins in the control of psychophysical functions, mood,
well-being and cognitive functions.
The oestrogen used in contraceptive pills is ethinyl oestradiol, a synthetic
oestrogen used at different concentrations, while in HRT conjugated equine
oestrogens, natural oestrogens (17(3-oestradiol, oestrone, oestriol) or synthetic
oestrogens (oestradiol valerate, benzoate, enantate, undecilate) are commonly
used. Several kinds of progestagens are available and each molecule may exert
20
Progesterone, progestagens and the CNS
- progesterone and progesterone like derivatives:
micronized progesterone
dehydroprogesterone
medrogestone
nomegestrol acetate
CH3
f^T
CX-)
- MOl OH-progesterone derivatives:
medroxyprogesterone acetate
ciproterone acetate
clormadinone acetate
megestrol acetate
(^X
o^^-
O—1
J
- 19 nortesterone derivatives:
noretisterone
noretisterone acetate
desogestrel
gestodene
norgestimate
OH
H
c^Arc=CH
^v-
f j [XJ—i
Figure 3. Progestagen compounds used in contraceptive pills and in hormone replacement therapy (HRT).
multiple effects within the brain. Among the progestagen molecules used in oral
contraceptives, it is possible to identify different types of synthetic compounds
(Figure 3). Some pills contain molecules derived from the 19-nortesterone,
characterized by the presence of a 17(3-ethinylic group, which can be divided in
two groups, the first containing 13-methylenic group (noretisterone, noretindrone,
noretinodrel) and the second, 13-ethylenic group (levonorgestrel and its derivative
molecules with lower androgenic activity: desogestrel, gestodene, norgestimate).
Other progestins used are the 17|3-OH-progesterone derivatives (cyproterone
acetate) that exert anti-androgenic effects.
At present, few studies have investigated the effects of oral contraceptive
treatments and, in particular, of progestagens on psychophysiological and
behavioural functions. Some retrospective studies, investigating the causes of
discontinuation of oral contraceptives, reported negative mood changes in -30%
of women. Women treated with low doses of progestagens experienced fewer
psychophysical symptoms than those treated with higher concentrations. In
treated women, symptoms develop as soon as the women start to take the
combined pill and gradually increase in severity until the end of the treatment.
Among the different types of progestagen used, the molecules containing
the 13-ethylenic group appear to be less symptom-provoking. The derivative
compounds produced after metabolization of exogenous progestagens form a
major contribution to the modulation of psychophysiological function. For
example, micronized progesterone given orally is metabolized to 3oc-5a-OH THP
and the higher circulating concentrations of this metabolite may induce sedation
(Arafat etal., 1988). Experimental studies have demonstrated an anxiolytic effect
of large dosages of progesterone, which is mediated by the 5ot-reduced metabolites
(Zwain and Yen, 1999). This effect is also found in patients affected by
21
A.R.Genazzani et al.
premenstrual symptoms; women treated with oral micronized progesterone
described beneficial effects. On the contrary, the administration of vaginal
progesterone is not followed by higher concentration of metabolites in the
circulation and the treatment with vaginal progesterone had no beneficial effects
over placebo in patients suffering from premenstrual syndrome (Backstrom et al.,
1992; Graham et al, 1992).
In HRT, different progestagen molecules are used in association with oestrogens.
It is possible to associate natural progesterone or a progestin (synthetic compound
with progestative functions). Among progestins used in HRT, it is possible to
identify some compounds derived from progesterone and other molecules derived
from 19-nortestosterone (Figure 3). The most commonly used progesterone
derivatives are cyproterone acetate, medroxyprogesterone, medrogestone, and
dehydrogesterone; among the 19-nortestosterone derivatives: noretisterone,
noretisterone acetate and levonorgestrel.
Some studies have investigated the effects of exogenous progestagen treatment
used in post-menopausal women undergoing HRT on mood and cognitive
functions. The oestro-progestagen sequential replacement therapy restores the
pattern of hormonal variation during an ovulatory menstrual cycle, while
oestrogen treatment alone is similar to an anovulatory cycle. Women on sequential
treatments develop a cyclicity in their mood and physical signs. In many of these
studies, negative effects by progesterone on the brain have been reported that
produce, in some patients, a state of dysphoric mood (Hammerback et al., 1985;
Magos et al., 1986). Women undergoing only oestrogen replacement therapy do
not show any mood variations during the treatment.
Negative mood modification by progestagens has been demonstrated in clinical
trials using different combinations of oestrogen and progestin compounds:
conjugated equine oestrogens and medroxyprogesterone acetate (Sherwin, 1991),
oestrogen implants and nortesterone (Magos et al., 1986), percutaneous oestradiol
and lynestronol (Hoist et al., 1989), and ethinyl oestradiol and levonorgestrel
(Dennerstein and Burrows, 1979). These actions are probably due to the active
metabolites of progesterone, e.g. allopregnanolone, 17-OH pregnanolone and 17OH progesterone. These metabolites can be formed systemically or locally by
progesterone. It is possible to speculate that progestagens and their metabolites
may negatively influence mood throughout the enhancement of MAO activity
and GAB A inhibitory action that induce a lowering of brain excitability (Figure 2).
Several studies have focused attention on the effect of administering oestroprogestin compounds on the opioidergic system. In women, changes in the
plasma (3-endorphin concentration during the menstrual cycle and, in particular,
the increase in circulating (3-endorphin concentrations during the periovulatory
days appear to be related to ovulatory function (Genazzani and Lucchesi, 1997).
These data confirm the specific role of gonadal hormones in the modulation of
the opioidergic system, the peak is related to ovarian function. The (3-endorphin
increase during the periovulatory phase seems to be related to the typical midcycle
increase in plasma oestradiol concentrations (Comitini and Petraglia, 1989).
A decrease in plasma (3-endorphin concentrations has been shown in post22
Progesterone, progestagens and the CNS
menopausal women after surgical or spontaneous menopause (Linghtman
and Jacobs, 1981; Genazzani and Petraglia, 1984). The decrease of plasma
[3-endorphin has also been related to the pathogenesis of mood, behaviour and
nociceptive disturbances of post-menopausal period (McLoughin and Grossman,
1984; Stomati et al., 1997). Oestrogen treatment ameliorates the opiatergic
activity and increases circulating (3-endorphin concentrations to premenopausal
values. Moreover, the administration of different progestagens does not modify
the positive effect of oestrogen on the opioidergic system (Stomati et al., 1997).
Regarding the effects of progestins on neurovegetative symptoms and cognitive
functions the few data available suggest that progestins do not modify the positive
effects of oestrogen (Sherwin and Gelfand, 1989; Sherwin, 1991; Backstrom
et al, 1992).
Neurosteroids
Recently, the attention focused on GABA-mediated modulation of the
hypothalamic-pituitary-gonadal axis has led to the identification of the brain as
a source of sex steroid hormones, named neurosteroids that bind to GABAA
receptors. The term neurosteroids has subsequently come to also include progesterone, its metabolites and other steroids produced in the brain from blood-borne
precursors. The neurosteroids have a 3oc-hydroxy-A5 structure and the first step
in the synthesis of these compounds is the chain cleavage of cholesterol, involving
cytochrome P-450 activity. The glial cells contain the cytochrome P-450 and are
able to transform the classical steroid hormones to a variety of neuroactive
compounds. Neurosteroids influence brain function via both genomic and nongenomic mechanisms; the first includes the modulation of calcium channel currents
and of chloride channel opening (Palumbo et al., 1995). Electrophysiological
and ligand experiments have shown that allopregnanolone, pregnanolone and
allotetrahydro deoxycorticosterone act as GABAA agonists while progesterone, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate
(DHEA-S) exert a non-competitive antagonist action on the GABAA receptor.
In addition, neurosteroids may modulate neural function by acting on glial
cells, activating myelinization. In these complex ways, neurosteroids appear to
be involved in the modulation of behavioural mechanism and psychological
phenomena, e.g. the response to stressful stimuli, anxiety, seizure disorders,
memory, depression and sleep. Recently, the relationship between neurosteroids
and the hypothalamic-pituitary-gonadal (HPG) axis has been investigated
(Bernardi et al., 1998). In female rats, brain allopregnanolone concentrations
change according to the oestrous cycle: the hypothalamic allopregnanolone
concentration is lower in pro-oestrous than in dioestrous or in oestrous, while
the opposite is observed in the hippocampus. In addition, the modifications
of hippocampal allopregnanolone concentration from prepuberty to adulthood
suggests that neurosteroids may modulate the neuroendocrine changes occurring
in the pubertal period. Evidence that the central injection of allopregnanolone
23
A.R.Genazzani et al.
has an inhibitory effect on ovulation and that the antiserum to allopregnanolone
enhances ovulation and sexual behaviour, support the role of allopregnanolone
as an inhibitor of the hypothalamus-pituitary control of the ovulatory process.
These findings suggest a role for allopregnanolone as a neuromodulator in the
central mechanisms related to the HPG axis. In addition, an age-related variation
of allopregnanolone in serum and in cerebral areas has been described in rats
(Barbaccia and Rossetti et al., 1995). These data and the increase of cerebral
allopregnanolone values under stressful conditions suggest that the stress-induced
increase and the age-related decrease of allopregnanolone may have important
behavioural and/or neuroendocrine consequences (Genazzani and Petraglia, 1990).
Rat adrenal glands express a 5oc-steroid-reductase and produce allopregnanolone,
with a significant increase of the steroid adrenal contents in aged rats. The
synthesis of pregnane compounds by the rat ovary has been clearly demonstrated
and a novel highly-specific radioimmunoassay has been able to detect
allopregnanolone in rat testis, showing a serum-parallel age-related increase
(Barbaccia et al., 1995; Genazzani and Bernardi, 1999). In humans, variations
in plasma allopregnanolone concentration throughout the menstrual cycle have
been reported (Wang and Seippel, 1996). High concentrations were observed in
the luteal phase of the menstrual cycle with controversial results on the possible
involvement of allopregnanolone in premenstrual syndrome (Schmidt et al.,
1994; Wang and Seippel, 1996). Recent data seem to confirm that women
suffering from premenstrual syndrome have low concentrations of allopregnanolone (unpublished data). Moreover, neurosteroids may be implicated in the
memory mechanism, modulating the acquisition or the loss of memory, thus
suggesting that the reduced memory performances that occur in humans with
ageing could be related also to a modification of the steroidogenesis. Further
studies are necessary to better clarify whether additional sites of production of
neurosteroids exist. The elucidation of the exact role of neurosteroids in the
regulation of the reproductive function might help to understand the modification
of cerebral activity, mood and sexual behaviour associated with the fluctuation
of sex steroid concentrations.
Conclusions
These data support the idea that different oestrogen, progestin and androgen
molecules used alone or in association exert several effects on brain functions.
Gonadal hormones are of primary importance for physiological brain function,
acting both on development and on the maintenance of female behaviour,
cognition and reproductive function. New aspects on the complex and fascinating
mechanism of brain function opened up with the finding that the CNS is also a
source of neuroactive steroids. However, at present, the information on the
implications of sex steroid hormones as control mechanisms of the brain function
is inconclusive. Every year different kind of molecules, numerous routes and
24
Progesterone, progestagens and the CNS
regimens of administration are available in HRT. Further studies are required to
explain the specific role of endogenous and exogenous sex steroid on the CNS.
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