Why we lose interest in sex: Do neurosteroids play a role?

Origins of libido 

Sexual arousal or libido is a state of behavior motivated toward the attainment of sexual pleasure that may ultimately culminate in orgasm. This complex behavior requires the ability to become sexually interested. The stimulation of sexual interest involves the interaction of various cell types within specific regions of the brain, including the medial and central amygdala ( Figure 1 ). Male copulatory behavior requires activation of dopaminergic pathways in the medial preoptic area (MPOA), while female arousal involves the ventral medial hypothalamus (VMH).1, 2

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Figure 1. Brain centers critical in libido

Some pathways and hormones have been identified as being important for sexual behavior. Many studies have focused on the conflicting roles of neuropeptides, such as oxytocin and β-endorphin, and neurotransmitters, like dopamine, in the brain, 1 but perhaps the most significant factor in the regulation of sexual motivation is the action of steroid hormones.

Roles of steroid hormones in libido 

Neuroactive steroids derived from peripheral tissues profoundly affect libido. For instance, increased levels of the stress-related adrenal steroid cortisol may reduce desire directly as well as indirectly by affecting gonadal steroid levels. This is evident in the male where the loss of testosterone by castration leads to an unambiguous, catastrophic decline in sexual behavior and erectile function; testosterone replacement restores both activities. 3 Other conditions that reduce or eliminate testosterone production or androgen receptor activity, such as hypogonadism, aging, or androgen insensitivity syndrome, also affect sexual behavior.3, 4 The effects of testosterone on sexual behavior are mediated through direct effects on the brain and through its conversion in the brain to estrogen. Sites of action include estrogen and androgen receptors in the MPOA, VMH, amygdala, and mamillary nuclei in the brain.

Gonadal estrogen may be important for female sexual drive as well. Diminution of libido in women can follow ovariectomy or menopause. 5 In rodent models, castration or deletion of the progesterone, androgen, or estrogen receptors effectively eliminates sexual behavior.1, 4 Within the brain, the primary sites of action for estrogen and progesterone-dependent sexual behavior include nuclei in the VMH and the arcuate nucleus in the hypothalamus. However, a requirement for estrogen or androgen is less clear in human females where libido is a product of interrelated biological and psychological factors. 1 Variations in only one component may be insufficient to influence the final outcome.

Treatment strategies for a loss of libido 

Today there are limited treatments available for a patient experiencing a loss in sexual desire. For male patients, this problem is typically addressed through testosterone replacement or the administration of dopamine agonists.1, 2 For female patients, a loss of libido after menopause may be corrected in some cases by estrogen replacement especially in combination with androgens.1, 5

While testosterone plays a major role in human sexual behavior, the risks involved with steroid replacement therapy for both men and women can be substantial, especially in more susceptible elderly patients. 3 For instance, testosterone replacement in the male may have undesirable side effects that include testicular atrophy, decreased sperm count, sleep apnea, weight gain, acne, polycythemia, and possibly increased progression of prostate cancer and vascular disease.6, 7, 8

Steroid supplementation to improve libido is not available for premenopausal women due to adverse effects on pregnancy and lactation. 9 There are risks for post-menopausal women as well, including acne, hirsutism, balding, deepening of the voice, cardiovascular disease, possible breast cancer, adverse lipid effects, and liver disease. Furthermore, testosterone replacement does not always lead to an improvement in libido, as seen, for example, in the generally weak effects on libido from the proposed low-dose testosterone patch for women. 1 These associated problems coupled with some unreasonable expectations of steroid replacement for treating problems in sexual behavior point to the need for greater understanding of the mechanisms by which libido occurs and is maintained. Through such understanding, more specific, better designed therapies may be developed and utilized.

While testosterone production by the testes is required for male libido, it is not sufficient. Men can experience a loss of desire without a reduction in testosterone levels. Women similarly experience losses of desire in the absence of changes in gonadal hormone levels. These problems are generally ascribed to psychogenic causes, such as depression or societal influences, and especially affect women.1, 5, 6, 7, 8, 9, 10 There are no clinical therapies to address these specific issues, although treatments for the underlying depression are certainly available. Professional counseling represents one strategy to deal with this situation, but is not a reliable method of treatment because it is unclear to what extent inherent biological problems are involved.

Neurosteroids 

Ongoing basic research suggests that a better therapy might involve steroids normally produced within the brain. Such steroids, called “neurosteroids,” are synthesized de novo from cholesterol in specific neuronal and glial populations.11, 12, 13, 14 The ability of the brain to synthesize neurosteroids is acquired early during embryonic development.12, 15 Many types of neurosteroids are the same as those made in the adrenal cortex and gonads, like progesterone and dehydroepiandrosterone (DHEA) sulfate. More unusual steroids are also produced such as 3α,5α-tetrahydroprogesterone (allopregnanolone), 3α,5α-tetrahydrodeoxycorticosterone, and the androgen 3α-androstanediol.

Studies indicate a broad spectrum of functions for neurosteroids in the central and peripheral nervous systems. Neurosteroids rapidly and potently alter neuronal excitability through allosteric binding of receptors in the cell membrane, such as the N-methyl-D-aspartic acid (NMDA), sigma type-1, and α-aminobutyric acid (GABA)-A receptors. 9 These compounds can potentiate or inhibit GABAergic neurotransmission, with the positive modulator allopregnanolone having 20- and 200-fold higher potency than benzodiazepines and barbiturates, respectively. 14 In addition to these “nongenomic effects,” neurosteroids may act through traditional steroid receptors to exert genomic effects. Neurosteroids, present in the hypothalamus and hippocampus, are known to be connected with libido in addition to anxiety, sedative/hypnotic effects, neuronal development, learning, memory, and neuroprotection. Studies involving such local actions of neurosteroids represent some of the most promising and exciting areas of investigation.14, 15

Neurosteroids and libido 

Neurosteroids and the proteins responsible for their synthesis from cholesterol are found in structures critical for sexual desire in males and females, such as the amygdala, medial preoptic area (MPOA), and ventral medial hypothalamus (VMH)12, 13 (see Figure 1). These areas are rich in receptors affected by neurosteroids.

Neurosteroids elicit different responses in males and females. Animal studies link neurosteroids to the regulation of the hypothalamic-pituitary-gonadal axis, including both enhancement and suppression of sexual motivation and behavior. For instance, activation of hypothalamic GABA-A receptors by allopregnanolone, a neuroactive metabolite of progesterone, in female rats can lead to suppression of ovulation and can have either positive or negative effects on sexual behavior.16, 17 The inhibition of gonadotropin-releasing hormone (GnRH) in the hypothalamus by allopregnanolone release can be antagonized by pregnenolone sulfate. 18 In addition, 3α-androstanediol attenuates lordosis and promotes aggression in female rats, probably through GABA-A receptor inhibition in the medial basal hypothalamus and MPOA. 19 Moreover, problems that interfere with sexual behavior and function such as depression and premenstrual syndrome correlate with changes in serum neurosteroid levels in humans. 14

In male mice, a commonly used performance test for sexual behavior involving preference for the odors of estrous females was enhanced by intra-cerebroventricular administration of the progesterone metabolite 3α-hydroxy-4-pregnen-20-one and reduced by pregnenolone sulfate.20, 21 Because androgens and progesterone are synthesized in the brain, some of the effects of these steroids on sexual behavior may be mediated in part by their local synthesis. For instance, administration of estradiol rapidly induces copulatory behavior in male rats. 22 Although estrogen derived from the aromatization of gonadal testosterone is critical to maintain sensitivity for sexual stimulation in the male, these and later studies suggest that copulatory behavior can be triggered by estrogen produced de novo in the brain itself.

Future of neurosteroids 

Research on neurosteroids is still in its infancy. Clinical applications of neurosteroids for mental illness, memory enhancement, and slowing neurodegenerative disease are also indicated from basic research. For example, preliminary testing indicates that the synthetic neurosteroid ganaxolone may provide the first specific treatment for catamenial epilepsy. 14 The ultimate potential of neurosteroids for treating problems of poor libido remains uncertain but may represent a key pharmacologic approach. DHEA, derived from both endogenous and peripheral sources, can positively impact loss of libido and well-being in older populations, although these results remain controversial.1, 14

We are only beginning to understand the roles of neurosteroids in the brain. Given the potent effect of various neurosteroids on receptors involved in libido, it is likely that this new class of steroids will increase our understanding of the mechanism by which patients lose sexual desire and perhaps offer a more effective treatment methodology.