Alpha-Fetoproteine und ihre Rolle in Bezug auf pränatale Hormone

Eine interessante Studie zur Wirkung pränataler Hormone:

Zuerst eine kleine Zusammenfassung der Studie:

The classic view of sexual differentiation in mammalian species holds that sex differences in the brain and behavior develop under the influence of estrogens derived from the neural aromatization of testosterone: the brain develops as male in the presence of estrogens and as female in their absence. In agreement with this view, it has been proposed that the female brain needs to be protected from estrogens produced by the placenta and that alpha-fetoprotein (AFP) – a major fetal plasma protein present in many developing vertebrate species and produced transiently in great quantities by the hepatocytes of the fetal liver– is the most likely candidate to achieve this protection because of its estrogen-binding capacity. However, the idea that the female brain develops in the absence of estrogens and the role of AFP in protecting the brain against the differentiating action of estrogens have been challenged. First, there is accumulating evidence that the normal development of the female brain might actually require the presence of estrogens. Second, the presence of AFP within neurons in the absence of any evidence for local AFP synthesis suggests that AFP is transported from the periphery into the brain. It was thus proposed as well that AFP acts as a carrier, which actively transports estrogens into target brain cells and, by doing so, has an active role in the development of the female brain. The availability of AFP mutant mice (AFP-KO) now finally allowed us to resolve this longstanding controversy concerning the role of AFP in brain sexual differentiation, and thus to determine whether prenatal estrogens contribute to the development of the female brain. We showed that the brain and behavior of female AFP-KO mice were masculinized and defeminized. However, when estrogen production was blocked by fetal treatment with an aromatase inhibitor, the feminine phenotype of these mice was rescued. These results clearly demonstrate that the principal action of prenatal estrogen exposure is to defeminize the brain and that AFP normally binds estradiol circulating in the female fetus and thereby protects the developing brain from defeminization.

Der Abstract der Studie:

Alpha-fetoprotein (AFP) is a well-known diagnostic biomarker used in medicine to detect fetal developmental anomalies such as neural tube defects or Down’s syndrome, or to follow up the development of tumors such as hepatocellular carcinomas. However, and despite the fact that the protein was discovered almost half a century ago, little was known about its physiological function. The study of Afp knock-out mice uncovered a surprising function of AFP: it is essential for female fertility and for expression of normal female behaviors, and this action is mediated through its estrogen binding capacity. AFP sequestrates estrogens and by so doing protects the female developing brain from deleterious (defeminizing/masculinizing) effects of these hormones.

Quelle: Alpha-Fetoprotein: From a Diagnostic Biomarker to a Key Role in Female Fertility

Das pränatale Testosteron wird an der Blut-Hirn-Schranke, wenn ich es richtig verstehe, in Östrogene umgewandelt. die dann die eigentliche Maskulinisierung des Gehirns bewirken. Damit Frauen nicht auch durch Östrogene maskulinisiert werden gibt es einen Schutzmechanismus, bei dem die Alpha-Fetoproteine dieses Östrogen bei Frauen binden und so das Gehirn schützen.

Die Studie bezieht sich jetzt auf Mäuse, die genetisch so gestaltet worden sind, dass sie keine Alpha-Fetoproteine mehr produzieren. Diese sind dann zum einen unfruchtbar und zum anderen zeigen sie nicht das normale weibliche Verhalten.

Aus der Studie:

Alpha-fetoprotein (AFP), discovered about half a century ago (Bergstrand and Czar, 1956; Abelev et al. 1963), is the major serum fetal protein in mammals. AFP is actively produced and secreted during the fetal life by the liver hepatocytes, the visceral endoderm of the yolk sac and, to a lesser extent, by the intestine and the kidneys (Sell and Becker, 1978; Andrews et al. 1982; Belayew and Tilghman, 1982). The concentration of this protein in the fetal serum reaches the order of several mg/ml, and its synthesis decreases dramatically in the first weeks after birth to reach only trace amounts in adulthood (Sell and Becker, 1978; Belayew and Tilghman, 1982). It is then essentially produced by the liver.

Es ist also ein Protein, welches vor der Geburt produziert wird und nach der Geburt stark reduziert wird. Es kommt auch bei den anderen Säugetieren vor.

AFP produced by the embryo is secreted in the amniotic fluid and is also able to cross the placental barrier to reach the maternal blood circulation, where its titer is used as a diagnostic marker to reveal developmental anomalies of the fetus (Haddow et al. 1979; Brownbill et al. 1995; Newby et al. 2005). Abnormally high levels of AFP in the maternal serum indicates elevated risk for neural tube defects of the fetus such as spina bifida or anencephaly (Leighton et al. 1975), whereas abnormally low levels indicates elevated risk for a Down’s syndrome (Cuckle et al. 1984).

Measurements of the AFP levels in the maternal serum are undertaken at 14–22 weeks of each pregnancy and are part, along with unconjugated estradiol, human chorionic gonadotropin and inhibin A, of the quadruple test for antenatal Down’s syndrome screening (Wald et al. 2003). Abnormal AFP levels can also be indicative of other fetal pathologies (for review see Mizejewski, 2004).

Ein Stoff, der aus anderen Gründen getestet wird und Auswirkungen auf das geschlechtliche Verhalten hat, könnte sehr interessant sein, weil dann theoretisch eine Menge Daten ausgewertet werden können.

Und aus den Ergebnissen der Knock-Out Mäuse:

In addition to being sterile, female AFP KO mice are defeminized (they show a diminution of female behavior) and masculinized (they exhibit some male characteristics): in the presence of a sexually active male, they do not exhibit the female typical behavior of lordosis (posture with raised head and rump, and deflected tail, to facilitate copulation) and they show a male pattern of distribution of tyrosine hydroxylase expressing neurons in sexually dimorphic areas of the hypothalamus (Bakker et al. 2006).

Scheint ein ähnlicher Effekt wie bei CAH zu sein. Was ja auch ganz gut passen würde. Nur wäre es hier eben nicht ein Zuviel an Testosteron, sondern ein zuwenig an Protein, das normalerweise den Stoff abfängt, in den Testosteron umgewandelt wird.

Und zu der Übertragung auf Menschen:

Translation of the observed results to human still needs to be tested. There are diverging views in the literature as to whether human AFP can or cannot bind estrogens. In either case, it appears that human AFP-derived peptides are able to display some anti-estrogenic activity (Vakharia and Mizejewski, 2000; Bennett et al. 2002; Mizejewski et al. 2004). AFP-derived peptides are under investigation as chemopreventive agents for estrogen-dependent breast cancers and other tumors (Bennett et al. 2006, Mizejewski et al. 2006). Androgens could also, in the human, play a more important role than estrogens in sexual brain differentiation. In that case the sex hormone binding globulin, able to bind both estrogens and androgens, could then play a significant role.

In conclusion, our work demonstrates that the function of AFP extends well beyond its traditional marker role for developmental anomalies of the fetus or liver tumors. AFP plays a crucial role (at least in rodents) in the control of female fertility through its anti-estrogenic action

Hier ist also noch einiges unklar. Ich finde es aber ein sehr interessantes Thema.

Andere Studien, die ich gefunden habe:

In order to investigate whether a sex difference exists in alpha-fetoprotein serum concentration, blood samples were collected from 133 adult men, 52 adult women, 239 pregnant women at different ages of gestation, 16 girls and 18 boys at birth, and seven girls and seven boys during the first week of life. In the case of 15 boys and 10 girls, blood samples were also collected from their mothers at the time of delivery. Serum AFP was measured by a radioimmunoassay method. In all neonates the mean value was 625 times higher than in all mothers at the time of delivery and 13,000 times higher than in adults. No difference was found between mothers of girls and those of boys both during pregnancy and at the time of delivery. However, at birth, the fetal AFP serum concentration was 1.8 (p < 0.001) times higher in boys than in girls. This sex difference was maintained during the first week of life. The half-life of serum AFP was 5 to 6 days in the neonate. The origin and the possible physiologic significance of such sex difference in AFP deserve further investigations.

Quelle: Serum alpha-fetoprotein in adults, in women during pregnancy, in children at birth, and during the first week of life: A sex difference

Ein Streit scheint gerade ausgetragen zu werden zu der Frage, inwieweit die Vorgänge vergleichbar sind:

Danach wäre bei Menschen eher SHGB für den gleichen Effekt zuständig

Motta-Mena and Puts (2017) have recently reviewed the endocrinological substrates of human female sexuality. We feel that it is necessary to point out a shortcoming in their review, since their claim that estrogen “has a limited role, if any, in masculinizing the human brain and behavior” does not stand up to close scrutiny, especially when applied to females.

The first line of evidence used by the authors to support this argument concerns the putatively low binding affinity for estrogen that human alpha-fetoprotein (AFP) has. However, this is insufficient evidence for the argument that “then ovarian estrogens would presumably cross the blood-brain barrier and masculinize the human female brain”. The authors disregard that the sex hormone-binding globulin (SHBG) has a similar function to rodent AFP in humans, binding to endogenous estrogens with high affinity (Hong et al., 2015; Varshney and Nalvarte, 2017).

Motta-Mena and Puts’s (2017) second line of evidence is based on genetically male (46, XY) CAIS individuals who develop feminine gender expression despite producing normal-to-high male levels of testosterone. This line of evidence is based on genetic males and cannot be extrapolated to females (cf. Koebele and Bimonte-Nelson, 2015).

As third line of evidence, Motta-Mena and Puts state that human males with mutations rendering the aromatase enzyme dysfunctional typically present as normal males. This claim is based on a sample size of two men (Grumbach and Auchus, 1999), which is inadequate to draw wider conclusions. Cooke et al. (2017) helpfully review several more cases to support this hypothesis. This line of evidence, however, also concerns men and cannot be extrapolated to females.

Recent reviews have argued that estrogen aromatized through testosterone is required for masculinization of the male brain (Cooke et al., 2017; Varshney and Nalvarte, 2017). However, Motta-Mena and Puts’s (2017) review—especially the second and third points discussed above—rightfully calls for a critical readjustment of that hypothesis in human males.
What we highlight is that in rats and supposedly in humans, brain masculinization occurring when testosterone is aromatized into estrogen
affects the size of the hypothalamic preoptic area SDN-POA (Cooke et al., 2017; Morris et al., 2004). This area controls sexual behavior and is larger
in males than in females due to cell death occurring naturally after 4 years postnatally (Morris et al., 2004; Swaab and Hofman, 1988). Treating developing female rats with estradiol or other estrogens—including the xenoestrogens genistein and zearalenone—increases the volume of the SDN-POA, reducing female-typical sexual behavior and increasing male-typical sexual behavior (de Jonge et al., 1988; Döhler et al., 1984; Faber and Hughes, 1991; MacLusky and Naftolin, 1981). These findings correspond with the effect of prenatal diethylstilbestrol (DES) exposure on women. A synthetic estrogen, prenatal DES exposure increases women’s likelihood of behaving bisexually or homosexually in adulthood, indicating heightened brain masculinization (Ehrhardt et al., 1985; Meyer-Bahlburg et al., 1995; cf. similar findings in rhesus monkeys by Goy and Deputte, 1996). Whether DES exposure affects the size of the SDN-POA in humans is not known, but in female rats, pre- and postnatal treatment with DES increases SDN-POA size to match that of a male (Döhler et al., 1984; Tarttelin and Gorski, 1988).

Importantly, while SHBG has high binding affinity to endogenous estrogens, it has low or zero binding affinity to a number of xenoestrogens,
including DES and genistein, which bind to estrogen receptors with moderate to strong affinity (Hong et al., 2015). This can potentially lead to
heightened estrogenic masculinization in women, as in those exposed to DES.
Taken together, these observations question Motta-Mena and Puts’s (2017) conclusion that estrogen “has a limited role, if any, in masculinizing
the human brain and behavior

 

Und die Antwort darauf:

Human genetic males are unlike rodent males in that neither the ability to convert testosterone to estrogen nor a functional estrogen receptor (ER) appears necessary for male-typical behavior, but a functional androgen receptor (AR) is required. Brain masculinization is probably mainly AR-mediated in human genetic males. ER binding may nevertheless have important masculinizing or defeminizing effects in human genetic females. Probably the strongest available evidence on this issue is derived from females exposed to synthetic estrogens in utero due to their mother’s treatment with DES. As we review, the totality of evidence from this population indicates little or no effect of estrogens on sexuality in genetic females. In addition, if brain masculinization were ER-mediated in humans, it seems unlikely that sex hormone-binding globulin would bind estrogens so effectively as to prevent them from masculinizing the brain. In sum, current evidence suggests that estrogen plays a limited role in masculinizing the human brain and behavior.

Quelle: Is human brain masculinization estrogen receptor-mediated? Reply to Luoto and Rantala

Finde ich als Gebiet interessant. Vielleicht kennt sich jemand da schon besser aus und kann mir etwas mehr dazu sagen