Androgenzeptoren und Verhalten

John Mannings Buch „The Finger Book“ enthält neben vielem zur Digit Ratio auch einen interessanten Beitrag zur Arbeitsweise der Androgenrezeptoren:

Testosterone influences the expression of many genes which in turn influence other genes, and so it has an immensely influential „cascade“ effect on the body. However, before this cascade can be activated testosterone must first bind to a receptor molecule, the androgen receptor; the hormone receptor complex then exerts its effect on the genes. The androgen receptor is therefore very important, as its structure determines our sensitivity to testosterone. Hte andorgen receptor is a protein which, in common with all other proteins, is made up of building blocks known as amino acids. One such amino acid, glutamine, is found in large numbers i an particular part of the receptor molecule. it is the length of this glutamine chain that is important in determining our sensitivity to testosterone. In general the average number of glutamines per receptor molecule is around twenty to twenty-two, altough the normal range is from eleven to thirty. If you have eleven glutamines ypur testosterone-receptor complex is very effective in switching on the testosterone cascade, but as the number of glutamines increases the sensitivity to testosterone reduces, so that an individual with thirty glutamines will have mild testosterone insensitivity.

Eine schwerer Form wäre es, wenn der Körper aufgrund sehr zahlreicher Wiederholungen überhaupt kein Testosteron mehr erkennt (CAIS). Eine andere Beschreibung habe ich auch noch hier gefunden:

The trait of interest in this article affects the transcription, or message-relaying effect of the androgen receptor. The androgen receptor binds testosterone normally, and travels to the cell nucleus (where the DNA is compartmentalized), but is unable to turn on and off the appropriate cell functions to the same degree as men who are more androgenized.

This trait, called the CAG repeat polymorphism (CAG), refers to a glutamine-tag attached to the androgen receptor. CAG refers to the DNA sequence of the gene that produces the androgen receptor.7 It takes three nucleotides (the building-block units of DNA) to code for one amino acid in protein chain; CAG is the sequence of cytosine-adenine-guanine, which codes for the amino acid glutamine.

Ironically, the androgen receptor gene is located on the X chromosome, which necessarily comes from the mother (assuming you are a male). Called the ‘sex chromosomes,’ females have 2 X (or XX), while men have an X and a Y (XY). One might think men who carry an extra X chromosome (XXY), a syndrome called Klinefelter’s, might be at an advantage— but in reality, these men have low serum (blood) testosterone concentration, small testicles, suffer from infertility, and are prone to gynecomastia.

The CAG would not appear to have a function, coding for a redundant stretch of glutamine inserted in a receptor that is otherwise identical to the androgen receptor of all normal men. However, as has been readily demonstrated, the longer the glutamine chain, the less efficient the androgen receptor is at turning on or off the genes that create the healthy male physiology. (…)

When testosterone enters a cell (for the biology geeks, this is restricted to the genomic effects of testosterone), it binds with an androgen receptor. There are different co-factors in the various cell types (skeletal muscle, fat, liver, etc.) that either enhance or impair the ability of the receptor to connect with and stimulate the cell to respond.9 These co-factors attach onto the testosterone-androgen receptor complex and travel as a unit to the nucleus, and bind to the chromosomes (DNA) at specific androgen response elements— think of it as assigned parking spaces. The complex then dimerizes (pairs up with another complex) to actually turn on the testosterone-sensitive genes.

Genes are information; they do not function as anything other than data storage. In order for the information they contain to become new cell structures or change function, the information has to re-enter the cell in a form that the machinery of the cell can understand. This occurs through transcription. Transcription creates a ‘chemical memo,’ or instructions from the head office. The longer the CAG repeat, the higher the degree of separation, and the less likely the message is to be affected.

Eine interessante Studie zu Hormonrezeptoren und Transsexualität ist die Folgende:

Studies of genetic males with single gene mutations that impair testosterone formation or action and consequently prevent development of the normal male phenotype provide unique insight into the control of gender role behavior. 46,XY individuals with either of two autosomal recessive mutations [17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) deficiency or steroid 5α-reductase 2 (5α-R2) deficiency] have a female phenotype at birth and are raised as females but frequently change gender role behavior to male after the expected time of puberty. In contrast, genetic males with mutations that impair profoundly the function of the androgen receptor are also raised as females and have consistent female behavior as adults. Furthermore, the rare men with mutations that impair estrogen synthesis or the estrogen receptor have male gender role behavior. These findings indicate that androgens are important determinants of gender role behavior (and probably of gender identity) and that this action is mediated by the androgen receptor and not the result of conversion of androgen to estrogen. The fact that all genetic males with 17β-HSD3 or 5α-R2 deficiency do not change gender role behavior indicates that other factors are also important determinants of this process.

Quelle: Androgens, Androgen Receptors, and Male Gender Role Behavior

Zur Transsexualität hatte ich auch in dem Artikel „Transsexualität, Androgenrezeptoren und Gene“ etwas geschrieben.

Die Wirkung der Androgenrezeptoren wirkt sich auch auf die Digit Ratio aus:

The second to fourth digit ratio (2D:4D) is sexually dimorphic, with lower mean values in males compared to females. It has been suggested that the sex difference in 2D:4D is determined prenatally, 2D:4D is negatively related to prenatal testosterone and positively to prenatal oestrogen, and that 2D:4D is a marker for levels of sex steroids during brain organisation. There is growing evidence that many sex-dependent behaviours are correlated with 2D:4D. However, there is no direct evidence for an effect of prenatal sex steroids on the digit ratio. The response to prenatal testosterone is dependent on the amount produced and the foetal sensitivity to the hormone. Variation in the X-linked androgen receptor gene (AR) determines sensitivity to testosterone. Alleles of AR with low numbers of CAG triplets respond to testosterone with high transactivational activity, while high numbers of CAG’s are associated with increased insensitivity to testosterone. We show in a sample of 50 men (49 Caucasian subjects, 1 Caucasian/Chinese subject) that 2D:4D is a phenotypic correlate of AR structure. Right-hand 2D:4D was positively correlated with CAG number and individuals with low 2D:4D in their right hand compared to left hand had AR alleles with low CAG numbers. We discuss the implications of our findings for our understanding of the aetiology of 2D:4D, its relationships with sex-dependent behaviours, and the evolutionary implications of variation in 2D:4D and AR.

Quelle: The second to fourth digit ratio and variation in the androgen receptor gene (Manning)

Wenn man dann bedenkt, dass die Digit Ratio mit für das Geschlecht typischen Verhalten in Verbindung steht, dann wird deutlich, dass diese Faktoren Auswirkungen haben.

Auch in Tieren läßt sich ein Zusammenhang von Testosteron, den Rezeptoren und Verhalten nachweisen:

The purpose of this study was 2-fold: 1) to use gonadal steroid hormone exposures in the physiological range to assess the relative roles of testosterone (T), estradiol (E2), and dihydrotestosterone (DHT) in the expression of male sexual behavior, and 2) to determine whether androgen receptor (AR) or estrogen receptor (E2R) occupation is increased after exposure to these various gonadal steroid hormones. Sexually experienced, castrated male rats implanted sc with Silastic capsules containing T, 10% E2, DHT, 10% E2 plus DHT, or blanks provided hormone levels in the physiological range. Copulatory behavior was measured on days 2–4, 5–7, 10–12, and 14–16 of steroid treatment. Although T, E2, and E2 plus DHT treatments all activated mounting, only T was effective in restoring ejaculation in 100% of the males. DHT alone had no effect on any aspect of male sexual behavior. Brains of males given these various hormone treatments were assayed for both cell nuclear AR and cell nuclear E2R binding in the hypothalamus, preoptic area, amygdala, and septum. Results indicate that when hormone levels in the physiological range were employed, T and DHT bind primarily to AR, whereas E2 binds to E2R. In a second experiment, 0.5% E2 plus DHT was found to yield AR and E2R levels comparable to those in rats receiving T capsules. Male rats bearing these capsules showed virtually no sexual behavior, demonstrating that elevation of AR and E2R levels comparable to those generated by T is not sufficient to induce male sexual behavior. We then measured intact AR and E2R levels and determined that in intact males E2R levels were higher than in T-treated males. These E2R levels could be replicated using 1.0% E2. Males exposed to 1.0% E2 plus DHT failed to display male sexual behavior. These data suggest that 1) relatively high and prolonged levels of E2R occupation are required for estrogen activation of male sexual behavior, 2) high levels of AR occupation induced by DHT are not sufficient to activate male sexual behavior, and 3) in intact male rats T, acting via androgen receptors, plays a primary role in mediating the expression of masculine sexual behavior. (Endocrinology 124: 618–626,1989)

Quelle: Evidence for a Role of Testosterone-Androgen Receptor Interactions in Mediating Masculine Sexual Behavior in Male Rats

Und zu den körperlichen Effekten der verschiedenen Stärken der Rezeptoren:

The androgen testosterone and its metabolite dihydrotestosterone exert their effects on gene expression and thus effect maleness via the androgen receptor (AR). A diverse range of clinical conditions starting with complete androgen insensitivity has been correlated with mutations in the AR. Subtle modulations of the transcriptional activity induced by the AR have also been observed and frequently assigned to a polyglutamine stretch of variable length within the N-terminal domain of the receptor. This stretch is encoded by a variable number of CAG triplets in exon 1 of the AR gene located on the X chromosome. First observations of pathologically elongated AR CAG repeats in patients with X-linked spino-bulbar muscular atrophy showing marked hypoandrogenic traits were supplemented by partially conflicting findings of statistical significance also within the normal range of CAG repeat length: an involvement of prostate tissue, spermatogenesis, bone density, hair growth, cardiovascular risk factors and psychological factors has been demonstrated. The highly polymorphic nature of glutamine residues within the AR protein implies a subtle gradation of androgenicity among individuals within an environment of normal testosterone levels providing relevant ligand binding to ARs. This modulation of androgen effects may be small but continuously present during a man’s lifetime and, hence, exerts effects that are measurable in many tissues as various degrees of androgenicity and represents a relevant effector of maleness. It remains to be elucidated whether these insights are important enough to become part of individually useful laboratory assessments.

Quelle: The CAG repeat polymorphism within the androgen receptor gene and maleness

Die Unterschiedlichen Wirkungsgrade zeigen auch, dass auch innerhalb der Biologie alle Typen, von sehr geschlechtertypisch bis zu sehr untypisch vorhanden sein können.

Eine andere Studie stellt eine Verbindung zu Verbrechen her:

Androgens mediate their functions through androgen receptors (AR). The two triplet repeats in the AR gene (CAG and GGN) are highly polymorphic among various populations and have been extensively studied in diverse clinical conditions and antisocial personality disorders. Several studies have reported either higher levels of testosterone among rapists or the correlation of shorter CAG repeats with criminal activities. However, to date, no study has analyzed AR gene in rapists worldwide, and no study has been conducted on criminals from Indian subcontinent. Therefore, we have analyzed the AR-CAG repeat length in 645 men, of which 241 were convicted for rape, 107 for murder, 26 for both murder and rape, and 271 were control males. The aim was to explore if there was any correlation between CAG repeat length and criminal behavior. The study revealed significantly shorter CAG repeats in the rapists (mean 18.44 repeats) and murderers (mean 17.59 repeats) compared to the control men (mean 21.19 repeats). The criminals who committed murder after rape had a far shorter mean repeat length (mean 17.31 repeats) in comparison to the controls or those convicted of rape or murder alone. In short, our study suggests that the reduced CAG repeats in the AR gene are associated with criminal behavior. This, along with other studies, would help in understanding the biological factors associated with the antisocial or criminal activities.

Quelle: Reduced CAG repeats length in androgen receptor gene is associated with violent criminal behavior

Das passt zu den Ergebnissen, dass ein hoher Testosteronwert sich auf die Empathie auswirken kann. Bei einigen schlägt dann vielleicht diese niedrigere soziale Angepaßtheit, die daraus resultiert, in Gewalt um.

Zu den Auswirkungen pränataler Hormone vergleiche auch: Pränatales Testosteron und „genderbezogenes Verhalten“