madman
Super Moderator
Androgen receptors in sexual activity and their clinical implications
The androgen receptor (AR) plays a critical role in mediating the effects of testosterone on sexual development, libido, and sexual functions in men and women.
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The androgen receptor (AR) plays a critical role in mediating the effects of testosterone on sexual development, libido, and sexual functions in men and women. Here with is an overview and opinion on the role of the AR and the CAG repeat polymorphism with the AR gene in the area of sexual desire, libido, and erectile function, highlighting clinical aspects. Additionally, potential implications are discussed in terms of the CAG repeat polymorphism on sexual health and future directions for research in this area.
Androgens, particularly testosterone, play a crucial role in regulating sexual desire, libido, and sexual function. The AR is a nuclear hormone receptor that is expressed in various tissues, including the brain, reproductive organs, and skeletal muscle. It functions as a transcription factor, modulating the expression of target genes in response to androgen binding. The AR mediates these effects by interacting with androgen response elements in the DNA and regulating the transcription of genes involved in sexual development and function.1
The AR gene, located on the X chromosome, contains a polymorphic trinucleotide sequence in exon 1 known as the CAG repeats, which has been associated with variations in AR function and subsequent clinical implications in sexual activity. Within the actual AR protein, this translates to a polyglutamine stretch located in the N-terminal domain of the receptor. This repeat varies in length among individuals, with the number of CAG repeats, or glutamine residues in the AR protein, mostly ranging from 8 to 35. Repeats >35 lead to an irregular degradation of the AR protein, which results in the neurologic picture of X-linked spinobulbar muscular atrophy. Affected individuals with this disease exhibit marked signs of testosterone deficiency often in conjunction with normal testosterone levels, such as gynecomastia, depression, loss of libido, and disturbed glucose tolerance in addition to their progressive muscular weakness.1
The CAG repeat length has been associated with variations in AR function—specifically, a shorter CAG repeat length is associated with increased AR transcriptional activity, while a longer one leads to reduced activity. Mitigation of androgen activity can already be observed in individuals with CAG repeats >24, with the attenuation process being especially in those men who have serum testosterone concentrations within the normal range and, hence, enough substrate to bind to the receptor.2 In women who have 2 alleles, usually the mean of both alleles is calculated because the inactivation process is more or less random (with a little bias toward the longer allele).3
The process is, in addition, modulated by tissue-specific AR coactivators that bind to the named polyglutamine stretch. Thus, different cell types exhibit variations in androgen response in relation to serum testosterone concentrations as well as AR gene CAG repeat length.1
The role of the CAG repeat polymorphism of the AR gene cannot be detached from serum testosterone concentrations. There has to be a significant amount of testosterone, the substrate, to bind to the receptor to reveal variances within its functionality. Thus, men with classical or functional testosterone deficiency often exhibit similar symptoms, irrespective of their number of CAG repeats, simply because there is not enough testosterone to elicit the full AR-related response in DNA transcription. However, in men with normal serum testosterone concentrations, symptoms of testosterone deficiency can sometimes be observed.1,2,4 This is, in many cases, related to longer CAG repeats within the AR gene. For example, lower libido and erectile dysfunction in aging men are influenced by serum testosterone concentrations and the CAG repeat length. Thus, androgen action is at least a 2-dimensional process in terms of the primary and inducing entities.1,4
The AR plays a vital role in the development of sexual desire and libido in men and women. In men, testosterone binding to the AR in the brain stimulates sexual thoughts, fantasies, and desire. Similarly, in women, androgens, including testosterone, contribute to the regulation of sexual desire.3 The AR CAG repeat polymorphism has been associated with differences in sexual desire and libido, with shorter CAG repeats potentially linked to higher sexual desire in both sexes. Several studies have explored the association between the AR CAG repeat polymorphism and libido. Men with shorter CAG repeats have higher sexual desire scores than those with longer CAG repeats. Similarly, women with shorter CAG repeats have a stronger libido as well as greater sexual satisfaction, while women with longer CAG repeats are more likely to experience insufficient lubrication and pain during intercourse. This is especially the case in women after menopause.3
Androgens contribute to the maintenance of penile tissue structure and function, including the regulation of smooth muscle tone and nitric oxide production. Several studies have examined the association between the AR CAG repeat polymorphism and erectile function in men. A decreased AR function due to longer CAG repeats has been associated with an increased risk of erectile dysfunction in men. Men with longer CAG repeats have a higher prevalence of erectile dysfunction than those with shorter CAG repeats; correspondingly, men with shorter CAG repeats have higher erectile function scores.2,4
There are clinical implications. The AR and its CAG repeat polymorphism modulate sexual activity in men and women. Variations in AR function due to CAG repeat length may influence sexual desire, libido, and erectile function or lubrication. Shorter CAG repeats have been associated with higher sexual desire and a lower risk of erectile dysfunction. Conversely, longer CAG repeats have been linked to lower sexual desire and an increased risk of erectile dysfunction. A longer length of the AR gene CAG repeat tract seems to lower testosterone therapy–induced improvements in sexual functions, especially in older men. In patients who were hypogonadal and receiving testosterone therapy, generalized linear models revealed that the number of AR gene CAG triplets was independently and inversely associated with erectile function, sexual desire, and intercourse satisfaction, whereas changes in total testosterone levels were independently and positively associated with these parameters.4
It is not recommended to assess the CAG repeat length in every patient with sexual symptoms. Such a determination via gene sequence techniques should be restricted to (1) patients who are assessed with normal serum testosterone concentrations while exhibiting symptoms of testosterone deficiency and (2) patients with hypogonadism who do not respond sufficiently to testosterone therapy.
Further research is needed to elucidate the mechanisms by which the AR and its CAG repeat polymorphism influence sexual desire, libido, and erectile function in men and women.
Investigating the interplay of genetic factors, hormonal status, and environmental factors will provide a more comprehensive understanding of the clinical implications of AR polymorphism in sexual health. Such knowledge may pave the way for personalized approaches to address sexual dysfunction and improve sexual well-being.
