Geschlechterunterschiede : Typen und Mechanismen

Ein interessanter Artikel fasst einiges aus dem Gebiet der Geschlechterunterschiede kurz zusammen:

Interessant als kurzen Überblick finde ich die Einteilung der Geschlechterunterschiede:

  • Type I – sexual dimorphism Endpoint consists of two forms, one more prevalent in males and the other more prevalent in females. Endpoint may be present in one sex and absent in the other. Copulatory behavior, bird song, nurturing, postpartum aggression, courtship displays
  • Type II – sex differences Endpoint exists on a continuum and average is different between males and females. Pain thresholds, food preferences and intake, odor detection, fear, anxiety, learning, memory, stress responding, sensory processing
  • Type III – sex convergence & divergence Endpoint is the same in males and females but neural underpinnings are different. Alternatively, a sex difference may appear only in response to a challenge such as injury or stress. Parental behavior, problem solving strategies, response to stress

Also einmal verschiedene Ausprägungen bei den Geschlechtern, dann verschiedene Ausprägungen im Schnitt der Geschlechter, wobei es prinzipiell alle Zwischenstufen in jedem Geschlecht gibt, also verschiedene Häufungen und relativ gleiches Verhalten mit verschiedenen Mechanismen, die in bestimmten Fällen auch zu einer anderen Reaktion führen.

Und zu den Anfängen der Forschung:

The study of sex differences in the brain can trace its origins back to the mid 1800’s, when Arnold Berthold removed the testes from roosters and noted that they became less aggressive and lost interest in hens. He concluded that “The testis acts on the blood, and the blood acts on the whole organism”. The modern era of behavioral endocrinology began with the pioneering work of Frank A. Beach in the 1940s but is more clearly demarcated by the iconic report of Phoenix, Goy, Gerall and Young in 1959, which articulated the Organizational/activational hypothesis of hormone action (see (Becker et al., 2002). This theory states that gonadally derived steroid hormones early in development organize the substrate controlling adult sexual behavior, creating permanent sex differences in neural circuits, and that this organized substrate is then activated by the sex-specific hormonal milieu of adulthood. The same principles were applied to sexual differentiation of bird song some 15 years later and included the discovery of highly dimorphic song control nuclei (Arnold et al., 1996; Wade and Arnold, 2004). These observations spawned a cottage industry of research into the hormonal and neural control of reproductive physiology and behavior that has revealed numerous sex differences at every level of organization in the brain (Pfaff et al., 2002). Yet the field has remained a subdiscipline within neuroscience–interesting, but not mainstream.

Es ist denke ich wichtig sich bewußt zu machen, dass die Regelung von Geschlechterunterschieden über Hormone  im Tierreich sehr weit verbreitet ist. Vögel und Säugetiere sind evolutionstechnisch gesehen weit von einander entfernt. Sie trennen jedenfalls 100 Millionen Jahre. Es ist also ein sehr altes System, das auch bei den Säugetieren, insbesondere der Maus, gut erforscht ist. Es ist schwieriger zu erklären, dass es beim Menschen nicht genutzt wird, gerade weil dieser am Körper deutliche Zeichen eines unterschiedlichen Selektionsdrucks zeigt als das es dort nicht mehr vorhanden ist.

Und zu dem Mechanismus an sich:

A central part of explaining sex differences is to identify the factors that makes a trait different in males and females. A good first experiment is to ask if the sex difference is caused by gonadal hormones, as hormones induce the large majority of sex differences. You can either ask, is my adult sex difference determined by steroid hormones in adulthood (Figure 1)? Or, is my adult sex difference the consequence of developmental exposure to steroids (Figure 2)? The emphasis on development stems from the overwhelming evidence supporting an early sensitive period, usually perinatal, for the organizational or enduring effects of hormones. Puberty should be considered as well, as it has recently been recognized as an additional sensitive period for enduring effects of hormones (Sisk and Zehr, 2005). Regardless of the timing of the sensitive period, the approach you take depends on a number of considerations, including the species you are studying and the question you are asking. Moreover, in humans one is constrained by the inability to manipulate hormones except in adulthood, or to assess intracerebral steroid concentrations. Thus, one has to rely instead on serum or saliva assays, indirect markers of developmental steroid exposure (Breedlove, 2010), or so-called “experiments of nature” (Hines, 2010) in which individuals are developmentally exposed to exaggerated amounts of steroid (i.e. congenital adrenal hyperplasia) or are insensitive to or produce inadequate amounts of steroid (i.e. androgen insensitivity, silencing mutations in genes for ER or aromatase). Nonetheless, in any study a comprehensive analysis would include assessment of both developmental and adult hormonal effects, but this is often neither practical nor necessary.

Soweit für Leser dieses Blogs nichts ungewöhnliches. Die Hormone bewirken entweder noch im Mutterleib (pränatal) oder um die Geburt herum (perinatal) eine „Vorformatierung“ des Gehirns. Die Schwierigkeiten beim Menschen sind ebenfalls klar: Menschenexperimente kann man nur sehr eingeschränkt durchführen, es bleiben insofern gerade die Sonderfälle, bei denen „die Natur“ die Experimente bereitstellt.

The importance of early life programming pervades all of neuroscience but is perhaps best exemplified in the profound impact of hormones on the developing brain to “organize” or “program” the brain as male or female across the life span. Many sex differences are developmentally organized and then activated, or revealed, by the action of adult steroids, but this is not always the case. Moreover, one can never assume that there is a timepoint when there are no sex differences. Even primary cell cultures of neural cells from an early age show sex differences (Carruth et al., 2002; Nunez and McCarthy, 2008). In addition, sex differences in adulthood are frequently traced to developmental origins.

Auch hier muss man sich eben bewusst sein, dass wir nicht einfach nach Blaupausen gebaut werden, sondern langsam wachsen. Geschlechterunterschiede müssen nicht bereits am Anfang voll ausgestaltet sein, sie können auch später entstehen oder weiterentwickelt werden. Wichtige Zeitpunkte sind eben die pränatale Phase und später die Pubertät.

Unlike drugs for which doses in neonates can be scaled down from adults as a function of bodyweight, steroids are impacted by circulating binding globulins that are present in newborns but not adults. Moreover, some steroids are both a primary ligand of receptors and metabolic precursor to other biologically active steroids. In rats and mice, testosterone exerts masculinizing effects on the brain and spinal cord, but testosterone is also converted to estradiol by aromatization and this steroid exerts distinct masculinizing effects. Some endpoints are responsive only to estrogens, others only to androgens while still others seem to require both. You can distinguish these possibilities by using non-aromatizable androgens, direct administration of estrogens, inhibitors of aromatization or selective steroid receptor antagonists. Mutant mice that lack specific functional steroid receptors can also help distinguish the receptors that mediate the steroid effects, although a complication is that receptor knock-outs often do not allow one to discriminate between neonatal and adult effects of the hormone. Because of the potent masculinizing effects of estrogens, rodents have evolved a protective mechanism against the high circulating levels of this steroid in the pregnant dam in the form of alpha-fetoprotein, a steroid binding globulin that sequesters estrogens in the circulation of the fetus and prohibits (perhaps selectively) its entry into the brain. As a result, when studying the masculinizing effects of estradiol on the neonatal rodent brain, doses need to be as much as ten times higher than that given to the adult. In primates, the dominant masculinizing hormones are androgens. Dosage is less of an issue in this case since alpha-fetoprotein does not bind androgens and therefore does not block masculinization. Details on the administration of exogenous hormones and quantification of endogenous hormones and phases of the female reproductive cycle can be found in (Becker et al., 2005).

Auch dies wird leider häufig übersehen. Es ist nicht einfach nur Testosteron oder andere Hormone direkt, sondern eben auch der dazugehörige Apparat, der zu unterschiedlichen Wirkungen führen kann. Wenn die Rezeptoren beispielsweise das Hormon nicht erkennen oder schwächer erkennen oder es aus bestimmten Gründen nicht an der richtigen Stelle umgewandelt wird, dann kann dies zu entsprechenden Veränderungen bzw. vom Schnitt abweichenden Verhalten führen.

Serious consideration of the potential for genetic contributions to sex differences in the brain is relatively new to the scene. The previous hegemony of hormones was the result of a combination of factors, not the least of which were technical difficulties of separating hormonal and genetic influences. A limited tool set is now available, limited in that it is mostly restricted to mice, but information gained provides a spring board for investigation of other animal models and humans. The Four-Core-Genotypes model consists of genetically modified mice in which the testis-determining gene, Sry, which initiates testicular development from the bipotential gonad, has been moved from the Y chromosome to an autosome (Figure 4). This produces XX mice that develop testes as well as XY mice that lack Sry and therefore develop ovaries. Comparison of these genotype/gonad phenotype reversed animals to those in which genotype and gonads are matched distinguishes between sex differences directly driven by X or Y genes, versus those driven by hormonal products of the gonads. To date this model system has confirmed the supremacy of hormones for most of the first type of sex differences, sex dimorphisms directly relevant to reproduction, but has revealed a genetic basis to several of the second type of sex difference, those related to social behavior, habit formation and nociception (Arnold and Chen, 2009). Similar conclusions were found in a parallel approach in which SF-1 knockout mice develop without gonads; in this model neural sex differences directly associated with reproduction were largely, but not completely, absent in agonadal XX vs. XY mice, but others persisted (Budefeld et al., 2008). Mice lacking functional steroid receptors or synthetic enzymes further expand the arsenal of models for separating hormonal from genetic effects.

An Mäusen lässt sich natürlich besser forschen als an Menschen. Aber die  Ergebnisse bei den Mäusen zeigen, wie ein solches System bei Säugetieren funktionieren kann. Natürlich lässt sich das nicht direkt übertragen und beim Menschen könnten beispielsweise bestimmte Verhaltensunterschiede eher genetisch oder eher hormonell sein, unabhängig von der Maus.