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Review

Emerging Roles for Neurosteroids in Sexual Behavior and Function

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.

Abstract

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

View larger version (141K): [in this window] [in a new window]   Figure 1. Localization of steroidogenic acute regulatory (StAR) protein in areas of the CNS critical for sexual behavior and function. Immunohistochemistry reveals StAR-containing neurons in the lateral preoptic area (LPOA) and glia in the anterior commissure (ac) in wild-type mice (A). On the other hand, a similar section containing the medial preoptic area (MPOA) from a StAR-knockout mouse has a lack of specific staining for StAR (B). Scale bar = 50 µm. Low-power magnification of StAR labeling in the anterior hypothalamus including the arcuate nucleus (ARC), adjacent to the third ventricle (3V) in a wild-type mouse (C). Scale bar = 100 µm. Neurons immunopositive for StAR in the arcuate nucleus (D) and medial POA (E). Arrow in (D) indicates a neuron with an apparently unstained nucleus, characteristic of mitochondrial StAR protein labeling. Scale bar = 25 µm. Reprinted with permission from King et al (2002).

View larger version (14K): [in this window] [in a new window]   Figure 2. Major synthetic pathways for neurosteroids. Those produced prior to conversion by forms of 3β-hydroxysteroid dehydrogenase (HSD) (dotted box) generally have different effects than progesterone and its metabolites. The identities of precise enzyme isoforms utilized in specific regions of the nervous system are ambiguous for 3HSD, 17βHSD, and 5-reductase (5Red). Recent data implicate isoforms of P450 2D or very low levels of P450c21 as responsible for the production of DOC in the CNS (Kishimoto et al, 2004). The presence of sulfotransferase (SULT), Cyp21, and aldosterone synthase/Cyp11B2 (Cyp11AS) in the CNS is controversial (Gomez-Sanchez et al, 2005). Cyp19 indicates aromatase; Prog, progesterone; Preg, pregnenolone.

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 (GABA_A) 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 GABA_A receptors, respectively. Through changes in GABA_A 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 GABA_A 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 GABA_A 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 GABA_A 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 GABA_A 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 GABA_A 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 GABA_A 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 GABA_A 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 GABA_A-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 GABA_A 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 GABA_A receptors. Allopregnanolone has been shown in male rats to potentiate GABA_A 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 GABA_A 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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