In asserting that a masculinizing role of estrogen (derived via intracellular aromatization) is paradoxically incompatible with a feminizing role of estrogen, Rucklidge (1995) has overlooked the critical temporal distinction between the sensitive windows for these effects. The fact that the neural substrate (including but not limited to estrogen receptor populations) is profoundly different inP10 female rats, combined with the fact that physiological levels of ovarian estrogen are much lower than those used to exogenously induce masculinization, it should not be surprising that estrogen could exert different effects (masculinizing versus feminizing) on males versus females in two different developmental time-frames.
(a) Androgen-based masculinization begins prenatally in male rats,
as supported, for example, by data showing the critical role of the
gestational day 18 (G18) fetal androgen surge in masculinizing
reproductive behavior (Ward, 1983) and cortical thickness asymmetry
(Fleming et al., 1986).
(b) Masculinizing effects seen with administration of aromatizable
testosterone propionate (TP) to female rodents prior to postnatal
days 8-10 (P8 - P10) are NOT seen when TP is administered outside
this early sensitive window (e.g., Fitch & Denenberg, 1995; Rhees
et al., 1990a & 1990b; Wagner & Clemens, 1989).
(c) Ovarian secretion of estrogen does not begin until
approximately P12 in female rats (Carson & Smith, 1986; Dohler &
Wuttke, 1975). Thus the window of masculinization in the rodent
appears to have "closed" before the ovaries even become active.
(d) Levels of alpha-fetoprotein start to decline around P10 in the
rat, and are at trace levels by weaning, consistent with a
potentially active role of ovarian estrogen in this later time
frame (Raynaud et al., 1971; Raynaud, 1973; MacLusky & Naftolin,
1981).
2. In sum, males appear to be masculinized by testicular androgens converted intracellularly to estrogen in the prenatal/early postnatal period (in rodents). Both males and females are apparently protected against maternal estrogen by alpha-fetoprotein (AFP, aka feto-neonatal estrogen binding protein, or FEBP) during this time frame. At some point following the "close" of this sensitive window to masculinizing estrogen effects, levels of AFP begin to decline and the neonatal ovary begins to secrete estrogen. The convergence of these factors can explain how feminization via ovarian estrogen can be temporally separated from estrogenic masculinization, an assertion supported by numerous findings of later than P10 feminizing effects of estrogen in rodents (Bloch & Gorski, 1988; Fitch & Denenberg, 1995; Gerall et al., 1973; Munoz-Cueto et al., 1990; Pappas et al., 1979; Stewart & Cygan, 1980).
3. The next question is how the same hormone could have different effects at different times in males and females (i.e., why doesn't ovarian estrogen exert masculinizing effects in females?). There are three likely mediating factors for these temporally dichotomous effects.
(a) Neural estrogen receptor populations vary in topographic
distribution and density as a function of gender (Brown et al.,
1990; DonCarlos & Handa, 1994; Kuhnemann et al., 1994; Sandhu et
al., 1986) and postnatal age (MacLusky et al., 1979a & b; Miranda
& Toran-Allerand, 1992; O'Keefe & Handa, 1990; Shugrue et al.,
1990).
(b) Physiological levels of ovarian estrogen are significantly
lower than exogenous estrogen levels typically used to induce
experimental masculinizing effects.
(c) The impact of the same variable on a substrate in developmental
"flux" is likely to differ dramatically depending on the
time-point. For example, ischemic neural injury induced in rats on
P1, during critical periods of neuromigration, exerts profoundly
different effects from these same insults administered just 4 days
later (Dvorak & Feit, 1977; Suzuki & Choi, 1991).
4. In sum, it appears that early "high-dose" levels of intra-cellular estrogen masculinize, while later and lower levels of estrogen feminize, at least in the rodent model, and at least for the variety of structural and behavior phenomena that have been studied. Thus different sensitive windows can apparently produce different developmental consequences from the same hormone (estrogen). A perfect example of this temporal distinction is provided by Stewart and Cygan (1980; see also Stewart et al., 1979), who showed significant masculinizing effects on open field activity in female rats with early high dose estrogen treatment (25 ug estradiol benzoate on P2 and 3), as compared to feminizing effects on open field behavior with later low dose estrogen replacement in ovariectomized rats (Silastic implants of estradiol 17B on P30-40, delivering physiological levels of about 108 pg/ml serum).
5. This distinction is recognized, to some degree, by Rucklidge herself in asserting that "estrogen exerts different effects depending on ... the behavior being investigated, and the critical period of that behavior." (1995, par. 8) We would assert that this principle can be more generally applied, in as much as the sensitive window for masculinizing and feminizing effects of estrogen on a wide variety of functional and structural phenomena appear to be temporally separate (G18 to P8 - 10 in males, and > P10 in females) in the rodent models which have been well studied.
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