Estradiol Masculinizes Hypothalamus?

Jeff Bloomquist jbquist at
Tue Mar 19 19:56:08 EST 1996

marcroy at (Marc Roy) wrote:

> Certainly estradiol can masculinize hypothalamic structures and behavior
> in rats, mice and some other species.  However, we need to be very careful
> about generalizing to all species.  For example,  female guinea pigs are
> behaviorally masculinized with prenatally administered
> dihydrotestosterone, a nonaromatizable estrogen (Goldfoot and van der
> Werff ten Bosch, Hormones and Behavior, 6:139-148, 1975). Similar findings
> have been reported in rhesus monkeys by Goy (in Fetal Endocrinology, Novy
> and Resko Eds, pp 319-229, 1981; and in Recent Advances in Primatology,
> civeers and Hebert, Eds., pp 449-462, 1978).  Male guinea pigs exposed to
> the aromatase inhibitor ATD in utero show no changes in any male-typical
> reproductive behaviors (Roy, Physiology and Behavior 51:105-109, 1991).  
>     These kinds of findings call into question the universality of the
> idea that estrogens masculinize the hypothalamus and reproductive
> behavior.

Regarding the extrapolation from non-human mammals or non-human primates
to humans, I agree that generalizations are often made in research. 
However, these model limitations are what we have to work with.  Your
dihydrotestosterone argument is interesting and, admittedly, I have not
looked into this personally but how much is known about the
structure-activity relationship of androgen binding to nuclear hormone
receptors?  Perhaps, although dihydrotestosterone is chemically classified
as an estrogen, it interacts with a subclass of receptors that recognize
testosterone.  This particular aspect of gene regulation, from the
standpoint of classifying the nuclear hormone receptors (some 30+ to
date), has only really opened up in the last 5 years.  Noting this, the
question also arises as to 'how' these receptors recognize so many
different chemicals.  Many are know to coalesce with up to 3-5 other
proteins, forming a complex that recognizes certain DNA docking domains. 
Alternatively, since this system is apparently very adaptable (i.e.,
recall the Ah receptor and associated gene cassettes, which respond to a
variety of phytoalexins and environmental toxins), could a chemical of a
slightly different structure (e.g., dihydrotestosterone) impose allosteric
changes on an estrogen receptor which enhance binding to gene docking
sites normally accepting testosterone-receptor complexes? 

Penetti Degerstrom wrote (earlier in this thread):
> Alpha-fetoprotein binds estrogen so only testosterone enters the
> cell (during critical period in pregnancy) and is aromatized to estradiol
> after entering. Could defects in this mechanism be the cause for 
> homosexual behavior?

Since the aromatase apparently metabolizes testosterone to estradiol,
would this not suggest that estradiol binding is normal in developing male
fetuses?  Supplementation of estrogenic compounds during pregnancy (see
DES, Gorsky, and LeVay comments earlier in thread) has been documented to
cause feminizing effects on male fetuses, however estradiol apparently is
not 'recognized' by male fetal tissues as an estrogen in the classic
sense.  Therefore, it appears that the guinea pig experiments using ATD
(the aromatase inhibitor) which did not cause changes in male offspring
sexual behavior may result from the actions of testosterone only.  Perhaps
both estradiol and testosterone are responsible for certain aspects of
pre-natal male development and behavior.  Have any additional
physiological studies on ATD-treated male guinea pigs been performed to
determine whether some differences exist when compared with control
animals?  Is there any information available on the aromatase pathway in

Mike Kirby

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