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Review |
From the Scott Department of Urology, Baylor College of Medicine, Houston, Texas.
| Correspondence to: Dr Steven R. King, Room N730, Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 (e-mail: srking100{at}yahoo.com). |
| Received for publication April 15, 2008; accepted for publication June 16, 2008. |
Although gonadal and adrenal steroids heavily impact sexual function at the
level of the brain, the nervous system also produces its own steroids de novo
that may regulate sexual behavior and reproduction. Current evidence points to
important roles for neurosteroids in sexual and gender-typical behaviors,
control of ovulation, and behaviors that strongly influence sexual interest
and motivation like aggression, anxiety and depression. At the cellular level,
neurosteroids act through stimulating rapid changes in excitability and direct
activation of membrane receptors in neurons. Thus, unlike peripheral steroids,
neurosteroids can have immediate and specific effects on select neuronal
pathways to regulate sexual function.
Key words: Erectile dysfunction, hormone, steroidogenesis, libido, sexual behavior
-reduced
steroids, 3,5-tetrahydrodeoxycorticosterone (THDOC),
3-androstanediol, 3,5-tetrahydroprogesterone
(allopregnanolone) and 3,5β-tetrahydroprogesterone (pregnanolone)
(Compagnone and Mellon, 2000)
(Figure 2). Steroid sulfates
like DHEA-sulfate (DHEA-S) and pregnenolone sulfate may also be produced de
novo in the primate brain, with the rodent brain generating sulfated or
lipid-associated steroids (Weill-Engerer
et al, 2002; Kriz et al,
2005; Ebner et al,
2006).
|
|
Neurosteroid Receptor Targets
Although peripheral steroids generally influence target tissues via
classical nuclear steroid receptors to cause long-term genomic changes,
neurosteroids have more immediate, nongenomic effects. Neurosteroids act at G
protein–coupled and ligand-gated ion channel membrane receptors to
elicit rapid changes that occur within seconds to milliseconds. Glycine
receptors, metabotropic sigma type 1 receptors, and ionotropic glutamate
receptors like the N-methyl-D-aspartic acid (NMDA)
receptor are among the neuronal receptor targets of neurosteroids
(Rupprecht and Holsboer, 1999)
(Table).
|
Neurosteroids can also allosterically modulate and directly activate
-aminobutyric acid type A (GABAA) receptors at levels that
are found in the brain (Gee et al,
1995; Lambert et al,
2003; Reddy, 2004;
Belelli and Lambert, 2005). In
this manner, neurosteroids significantly impact phasic and tonic inhibition of
neurons through synaptic and extrasynaptic GABAA receptors,
respectively. Through changes in GABAA channel chloride currents,
nanomolar levels of 5-reduced androstanediol, allopregnanolone, and
THDOC reduce neuronal excitability with a 20- to 200-fold higher efficacy than
benzodiazepines and barbiturates (Morrow
et al, 1987; Gee et al,
1995; Brot et al,
1997; Weir et al,
2004). On the other hand, pregnenolone sulfate and DHEA-S
antagonize GABAA channel activity (Majewska et al,
1986,
1990;
Majewska and Schwartz,
1987).
Neurosteroids may also alter neuronal function through plasma
membrane–localized estrogen receptors
(Chaban et al, 2004) and G
protein–coupled membrane progesterone receptors
(Zhu et al, 2003). Other
receptor targets include 1-adrenergic
(Dong et al, 2005), neuronal
nicotinic acetylcholine (Bertrand et al,
1991; Bullock et al,
1997) and dopamine type 1 (D1) receptors
(Frye et al, 2004)
(Table).
Thus, local synthesis and release of neurosteroids can precisely and rapidly alter neuronal function in a manner not achievable by neuroactive steroids infiltrating the nervous system from the serum. In this manner, neurosteroids may regulate key aspects of male and female reproduction.
Neurosteroids and Sexual Function
During follicular development, ovarian estrogen and progesterone regulate
follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release
directly at the anterior pituitary and indirectly by regulating hypothalamic
secretion of gonadotropin-releasing hormone (GnRH). As well, the culminating
LH surge that triggers the process leading to ovulation is an
estrogen-dependent response. This situation is one example where a peripheral
steroid, estrogen, likely acts in a rapid manner similar to neurosteroids.
The release of GnRH for the LH surge also requires progesterone acting through hypothalamic progesterone receptors (Chappell et al, 1999; Chappell and Levine, 2000). Recent data indicate that the source of this progesterone is astrocytes in the hypothalamus stimulated to produce steroid by activation of estrogen-sensitive membrane receptors by estradiol. Administration of supraphysiologic amounts of estrogen (50 µg) to ovariectomized (OVX)/adrenalectomized (ADX) rats induces de novo progesterone synthesis specifically in the medial basal hypothalamus and the LH surge through release of GnRH (Micevych et al, 2003; Soma et al, 2005). Inhibition of hypothalamic progesterone synthesis blocks the LH surge (Micevych et al, 2003). Importantly, estrogen stimulates this progesterone synthesis only in postpubertal and not in neonatal astrocytes (Micevych et al, 2007).
Estrogen also stimulates allopregnanolone synthesis in the hypothalamus and anterior pituitary, as shown in OVX animals (Genazzani et al, 2004). There, allopregnanolone can potentiate activation of postsynaptic GABAA receptors on GnRH neurons of diestrous female mice (Sullivan and Moenter, 2003). Through activation of these receptors, allopregnanolone induces GnRH release (El-Etr et al, 1995). The decline in this steroid that occurs with age in the hypothalamus may thus contribute to age-related changes in ovarian function (Genazzani et al, 2004).
The facilitatory effect of allopregnanolone on GnRH release may be site-specific. Activation of hypothalamic GABAA receptors by intracerebroventricular (ICV)-delivered allopregnanolone, which provides access to the ventromedial nucleus (VMN), suppresses ovulation (Genazzani et al, 1995).
Sulfated neurosteroids can also regulate GnRH release. DHEA-S inhibits postsynaptic GABAA receptor activation in GnRH neurons of diestrous female mice (Sullivan and Moenter, 2003) and pregnenolone sulfate potentiates glutamate or NMDA-stimulated GnRH release through the NMDA receptor by hypothalamic neurons (El-Etr et al, 2006).
At the same time, a GABAA receptor modulator and
allopregnanolone precursor produced by the pituitary,
3-hydroxy-4-pregnen-20-one (3HP), can selectively inhibit basal
and GnRH-stimulated FSH secretion in both sexes
(Beck et al, 1997;
Wiebe and Wood, 1987;
Wood and Wiebe, 1989;
Wiebe et al, 1997). This
rapid, nongenomic effect is mediated by calcium and protein kinase C signaling
pathways utilized by GnRH and is not because of any further metabolism to
allopregnanolone (Dhanvantari and Wiebe,
1994; Wiebe et al,
1994).
Thus, neurosteroids may regulate gonadotropin release in both the female and the male. A further observation whose significance is unclear at the present time is that LH itself can regulate neuronal pregnenolone production (Liu et al, 2007).
Little else is known about the participation of neurosteroids in male
reproduction and sexual differentiation of the brain. Male rats do exhibit
higher cerebellar levels of StAR, P450scc, and aromatase mRNAs
(Lavaque et al, 2006). The
extent to which neurosteroids like 3HP may affect secretion of FSH or
LH is unclear. Unlike in females, estrogen does not induce hypothalamic
progesterone production to stimulate GnRH release in castrated ADX males
(Micevych et al, 2003).
However, locally produced allopregnanolone may be involved. Allopregnanolone
potentiation of GABAA channel activity reduces basal GnRH release
in hypothalamic cultures (Calogero et al,
1998). This suppression is selectively overcome by pregnenolone
sulfate.
Neurosteroids and Sexual Behavior
Female Sexual Behavior—
Emerging data indicate a vital role for neurosteroids in the control of
female sexual behaviors that are critical for successful reproduction
(King and Lamb, 2006).
Receptive behaviors as shown in rodents require the action of ovarian estrogen
on the hypothalamus, which increases progesterone receptor number in the
ventral portion of the VMN (Pfaff and
Schwartz-Giblin, 1988). Progesterone then acts through these
receptors to facilitate lordosis and appropriate tactile stimulation. Locally
produced allopregnanolone may also have a vital role. Participation in paced
mating behavior specifically increases levels of allopregnanolone in specific
regions of the CNS, including the midbrain and hippocampus
(Frye et al, 2007).
Allopregnanolone or THDOC infused into the ventral tegmental area (VTA)
enhances and maintains progesterone-facilitated lordosis in estrogen-primed
OVX rats and hamsters (Frye and DeBold,
1993; Frye and Gardiner,
1996). Inhibition of 3β-hydroxysteroid dehydrogenase (HSD) or
5-reductase activity in the VTA attenuates lordosis, and infusion of
allopregnanolone into the VTA rescues this behavior
(Frye and Vongher, 2001;
Petralia et al, 2005).
D1 and GABAA receptors acting through cAMP pathways in
the VTA may be the primary mechanism by which neuronally derived
allopregnanolone as well as progesterone may promote this responsiveness
(Frye,
2001a,b;
Frye et al, 2004;
Petralia and Frye, 2004).
However, the effect of allopregnanolone on sexual activity is site-specific. Allopregnanolone levels selectively fluctuate in the ventral medial hypothalamus with the ovarian cycle, with its lowest levels reached at proestrus, when sexual receptivity and lordotic behavior coincide with rising serum estrogen and progesterone concentration (Genazzani et al, 1995). The ICV administration of allopregnanolone suppresses sexual behavior by OVX rats, possibly through actions in the VMN (Genazzani et al, 1995; Laconi and Cabrera, 2002). This suggests that circulating allopregnanolone (as opposed to neurosteroid allopregnanolone in the VTA) in intact animals is inhibitory through its access to the VMN.
Indeed, ICV injection of antiserum against allopregnanolone during proestrus augments lordosis (Genazzani et al, 1995). Thus, female sexual behavior may be a product of facilitation by progesterone and disinhibition by serum-derived and possibly locally synthesized allopregnanolone in the VMN, whereas in the VTA, where the progesterone receptor is absent, neurosteroid allopregnanolone augments VMN activity.
At the same time, systemic administration of high doses of allopregnanolone can induce lordosis by itself in estrogen-primed progesterone receptor–knockout OVX aged females (Frye et al, 2006b). This observation implies that this steroid can rescue losses in receptivity with aging, when progesterone receptor levels in the VMN are compromised because of reduced central allopregnanolone levels and neurons may have increased sensitivity to allopregnanolone and GABAA-channel activity (Genazzani et al, 2004). A previous report noted that high doses of estrogen by itself also elicit lordosis independently of progesterone receptor action (Apostolakis et al, 2000). It is possible, then, that estrogen can stimulate receptive behavior through changes in allopregnanolone production in the CNS.
Infusion of 5-reduced androstanediol has similar paradoxical effects
on lordosis and further promotes aggression in female rats, possibly through
GABAA receptor inhibition in the medial preoptic area (POA) and VMN
(Frye et al,
1996a,b,c).
Neurosteroids are also implicated in mediating the preference for male odors
by female rats and pheromone-stimulated release of GnRH and ovulation
(More, 2006). Therefore,
neurosteroids may act at several points in the CNS to regulate sexual
motivation and receptive behavior.
Male Sexual Behavior— Neurosteroids may also influence male sexual behavior through GABAA receptors. Allopregnanolone has been shown in male rats to potentiate GABAA channel activity in neurons in the medial POA, a region that also produces neurosteroids and is essential for sexual interest, erection, copulation, and ejaculation (Haage and Johansson, 1999; Uchida et al, 2002; Haage et al, 2005). Pregnenolone sulfate opposes the effects of allopregnanolone.
Progesterone may also inhibit sexual behavior. Loss of the progesterone receptor or subcutaneous infusion of antiprogestin RU486 enhances mount and intromission frequency in the absence of changes in testosterone or testicular function (Schneider et al, 2005). However, it is unclear in this case whether it is progesterone derived from the serum, from local synthesis in the CNS, or in combination that is inhibitory.
On the other hand, estradiol rapidly induces copulatory behavior through actions in the medial POA and amygdala (Balthazart et al, 2004; Huddleston et al, 2003, 2006). It is unclear whether local synthesis of estrogen is involved; however, gonadal sources of this steroid, including those generated from aromatization of testosterone in the brain, are clearly critical for sexual behavior and maintenance of sensitivity for sexual stimulation.
Neurosteroids may also regulate sensitivity to odor cues relevant to male
sexual interest. Neurosteroids are generated in components of the vomeronasal
pathway key for relaying stimulatory signals from the odors of estrous females
to the POA and bed nucleus of the stria terminalis. Consistent with this
observation, pheromone preference for estrous females by male rodents is
enhanced by ICV administration of 3HP and reduced by pregnenolone
sulfate (Kavaliers et al,
1994; Kavaliers and Kinsella,
1995).
Other evidence for roles of neurosteroids in sexual and gender-typical behaviors comes from avian models. All of the enzymes necessary for neurosteroidogenesis, including StAR, are present in the adult and developing songbird (London et al, 2006; London and Schlinger, 2007). Sex-dependent differences in time and level of de novo estrogen synthesis in the brain determine the establishment of a key neuronal circuit for male song in the zebra finch independently of the presence of gonadal steroids (Wade and Arnold, 1996; Holloway and Clayton, 2001; Forlano et al, 2006).
In the quail, melatonin-regulated diurnal changes in brain levels of the
neurosteroid 7-hydroxypregnenolone occur in males but not in females,
resulting in correspondingly higher locomotor activity
(Tsutsui et al, 2008).
Neurosteroids, Anxiety, and Depression in Sexual and Gender-Typical Behaviors
Neurosteroids also affect anxiety, stress, and mood, all of which strongly
impact sexual behavior. 5-reduced steroids allopregnanolone or THDOC
have anxiolytic, analgesic, and sedative effects in large part through
GABAA receptors (Lambert et al,
2003). Inhibition of 5-reductase activity in the amygdala
increases anxiety and depression (Verleye
et al, 2005; Walf et al,
2006). Declines in anxiety elicited by the anxiolytic drug
etifoxine correlate with increased CNS levels of anxiolytic allopregnanolone
in sham-operated and gonadectomized (GDX)/ADX rats
(Verleye et al, 2005). Serum
levels of the steroid also rise upon treatment in the intact animals,
suggesting an additional contribution from peripheral sources. Similarly,
anxiogenic drugs increase levels of anxiolytic steroids in the brain and the
serum (Barbaccia et al,
1996a,b).
Pregnenolone and its sulfate conjugate increase anxiety and oppose anxiolytic and sedative effects induced by benzodiazepines and alcohol (Melchior and Ritzmann, 1994; Meieran et al, 2004; Strous et al, 2006). Lower doses (0.1 µg/kg vs 1.0 µg/kg) of pregnenolone sulfate administered intraperitoneally causes anxiolysis (Melchior and Ritzmann, 1994), possibly reflecting in part conversion to anxiolytic allopregnanolone.
In women, libido is not clearly dependent on gonadal status, but relies
more on psychological factors such as societal influences and depression
(Avis et al, 2005). Anxiolytic
neurosteroids may therefore impact sexual interest. As with sexual
receptivity, the effect of these neurosteroids, at least as measured in
rodents, is site-specific. Inhibition of allopregnanolone production through
infusion of the 5-reductase inhibitor finasteride (Proscar)
systemically or into the hippocampus increases social interactions of estrous
females, whereas the inhibitor decreases such interactions when put into the
amygdala of receptive females (Rhodes and
Frye, 2001; Walf et al,
2006).
On the other hand, infusion of allopregnanolone into the VTA in diestrus raises social interactions in female rats, along with paced mating behavior to levels similar to those observed in proestrus (Frye and Rhodes, 2008). Infusion of allopregnanolone into other parts of the brain, the substantia nigra and the central gray, did not reproduce these effects. The changes observed in social activities associated with sexual behaviors in proestrus may therefore involve allopregnanolone generation in the brain elicited by ovarian steroids.
In this manner, neurosteroids are part of a larger role in mood and adaptation to stress. Pregnenolone may improve mood, and anxiolytic DHEA is antidepressant (Strous et al, 2006). Postpartum depression and anxiety may also involve anxiogenic neurosteroids as well as the actions of peripheral steroids on the CNS (Maayan et al, 2004, 2005).
In men, depression is an important factor in many cases of erectile dysfunction, and thus, neurosteroids that affect depression may be involved. Some effects of neurosteroids in depression in the male also appear to be gender-dependent. Experiments using a postnatal stress model reveal a lower sensitivity of adult male rats to repeated exposures of ICV-administered allopregnanolone than females, as measured by anxiety-related behavior, like reduced grooming (Zimmerberg et al, 1999).
Social isolation stress also reduces brain 5-reductase and
allopregnanolone levels in males in an androgen-dependent manner, causing
increased aggressive behavior in a resident-intruder test and increased
contextual fear responses (Dong et al,
2001; Pinna et al,
2004,
2005). These changes are
restricted to select neurons with outputs to the amygdala and BLA
glutamatergic neurons in the amygdala, all of which can alter emotional
responses (Agís-Balboa et al,
2007). Fluoxetine (Prozac) rescues the decline in allopregnanolone
and change in aggressiveness (Pinna et al,
2003).
Other experiments also link aggressiveness by male rodents to neurosteroids. Chronic treatment with DHEA inhibits aggressiveness by GDX male mice toward lactating female intruders and correlates with specific declines in measured pregnenolone sulfate levels in the brain (Young et al, 1991). Inhibition of 3βHSD activity increases pregnenolone but not pregnenolone sulfate levels and also reduces belligerence (Young et al, 1996). It is not clear that this change in behavior is simply caused by lowered progesterone levels in the CNS. Progesterone receptor–knockout males exhibit reduced aggressiveness only toward infants, not toward adult males, and progesterone increases this aggressive behavior in wild-type mice (Schneider et al, 2003). Similar effects on behavior and pregnenolone sulfate levels by DHEA are reported for androgenized females (Robel et al, 1995). Androstanediol self-administration, which results in higher CNS levels of the steroid, also decreases aggressiveness and may be rewarding in male hamsters (Frye et al, 2006a). Through mediating changes in psychological parameters such as anxiety and stress, neurosteroids may therefore have additional roles in regulating sexual interest and gender-typical behaviors.
The Future of Neurosteroids in the Clinic
Currently, neurosteroids are being developed as a part of palliative or
therapeutic approaches to treat psychological disorders, addictive behaviors,
neurological disorders, and neurodegenerative conditions
(Strous et al, 2006). A
synthetic form of allopregnanolone, ganaxolone, is in phase II trials for
treating seizures (Nohria and Giller,
2007). Neurosteroids can also be prophylactic against age-related
changes in nervous system function. Treatments that directly target sexual and
reproductive dysfunctions do not yet exist, although, as indicated above,
current gonadal replacement strategies to address problems of libido may act
in part through the induction of local neurosteroid synthesis. Moreover,
therapies that address other conditions such as mood disorders may positively
impact sexual desire. Early experimental trials have met with mixed success
(Strous et al, 2006;
Uzunova et al, 2006). Most
notably, DHEA does not reliably improve mood in subjects treated with the
steroid (Strous et al,
2006).
One concern in the use of systemic steroidal therapies is that they alter neurosteroid levels not only in the target region of the brain but throughout the brain and the circulation, potentially resulting in adverse or opposing effects on other parts of the brain or on other tissues. Although intrahippocampal administration of pregnenolone sulfate improves memory in aging rats, systemic administration may also increase belligerence, among other effects (Vallée et al, 1997). Also, certain neurosteroids can have differential effects on target cells, depending on concentration and length of treatment.
A final consideration is that in the absence of lowered neurosteroid production, neurosteroid supplementation may not augment their activity. For instance, addition of estrogen to rat hippocampal neurons supports cell survival and proliferation only when endogenous estrogen synthesis is blocked (Fester et al, 2006). This is an important consideration in the human because, unlike in rodent models, clinical studies have yet to link depression to a deficiency in antidepressive neurosteroids (Uzunova et al, 2006). Consequently, neurosteroids are eyed as a novel treatment for diseases in which neurosteroid production is compromised, such as Alzheimer and Niemann-Pick type C (Griffin et al, 2004; Chen et al, 2007; Wang et al, 2007; Liu et al, 2008). Their application can also assist in survival and remyelination of nerves damaged because of injury or disease (Schumacher et al, 2007).
An alternative approach is to use drugs that specifically increase neurosteroid concentrations. The antipsychotic agents clozapine and olanzapine may improve schizophrenia by increasing brain allopregnanolone synthesis (Marx et al, 2006). Similarly, the reduction in aggression induced by fluoxetine may be directly caused by increased allopregnanolone levels in the CNS, because the drug is effective at levels 10-fold lower than those that block serotonin reuptake (Pinna et al, 2003). Negative side effects of drugs may also be explained by neurosteroid modulation. Notably, preliminary studies indicate that, as in the rodent, finasteride may increase depression in men as a result of the loss of allopregnanolone (eg, Altomare et al, 2002; Rahimi-Ardabili et al, 2006). This raises the possibility that lowered levels of the neurosteroid contribute to the reduced sexual desire reported for some patients. Treatment strategies that take into account effects on neurosteroids and the development of drugs that singularly target neurosteroid biosynthesis may therefore provide superior therapies for patients.
Conclusion
The full role of neurosteroids in sexual behavior and reproduction is
unclear. Neurosteroids may also indirectly promote and preserve sexual
function through roles in neuronal growth and development and neuroprotection
in the CNS and PNS. Moreover, determination of which functions are truly
governed by neurosteroids, neuroactive steroids generated from peripheral
sources, or a combination of the 2 is still under investigation. Future gains
in the application of neurosteroids for the treatment of sexual dysfunctions
necessitate a clearer delineation of the roles of these compounds in the
nervous system and how they complement the influence of gonadal and adrenal
steroids.
Acknowledgments
The author is grateful to Drs Ede M. Apostolakis and Dolores J. Lamb for helpful discussions.
Footnotes
Research support was provided by NIH grant DK61548, the Lalor Foundation, and the International Society for Sexual and Impotence Research.
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