Estrogen receptor‐α distribution in the human hypothalamus in relation to sex and endocrine status

Abstract

The present study reports the first systematic rostrocaudal distribution of estrogen receptor-alpha immunoreactivity (ERalpha-ir) in the human hypothalamus and its adjacent areas in young adults. Postmortem material taken from 10 subjects (five male and five female), between 20 and 39 years of age, was investigated. In addition, three age-matched subjects with abnormal levels of estrogens were studied: a castrated, estrogen-treated 50-year-old male-to-female transsexual (T1), a 31-year-old man with an estrogen-producing tumor (S2), and an ovariectomized 46-year-old woman (S8). A strong sex difference, with more nuclear ERalpha-ir in women, was observed rostrally in the diagonal band of Broca and caudally in the medial mamillary nucleus. Less robust sex differences were observed in other brain areas, with more intense nuclear ERalpha-ir in men, e.g., in the sexually dimorphic nucleus of the medial preoptic area, paraventricular nucleus, and lateral hypothalamic area, whereas women had more nuclear ERalpha-ir in the suprachiasmatic nucleus and ventromedial nucleus. No nuclear sex differences in ERalpha were found, e.g., in the central part of the bed nucleus of the stria terminalis. In addition to nuclear staining, ERalpha-ir appeared to be sex-dependently present in the cytoplasm of neurons and was observed in astrocytes, plexus choroideus, and other non-neuronal cells. ERalpha-ir in T1, S2, and S8 suggested that most of the observed sex differences in ERalpha-ir are "activational" (e.g., ventromedial nucleus/medial mamillary nucleus) rather than "organizational." Species similarities and differences in ERalpha-ir distribution and possible functional implications are discussed.

Sexual differentiation of the human brain in relation to gender identity and sexual orientation

“…Women showed more nuclear ERβ staining in the SCN, the SON, the PVN, the INF and the MMN (75). Observations in subjects with abnormal hormone levels showed, in most areas, ERβ immunoreactivity distribution patterns that were consistent with the level of circulating estrogens, suggesting that the majority of the reported sex differences in ERβ immunoreactivity are "activational" rather than "organizational" in nature (76,77). In the BSTc, differences in sex hormone receptors such as ERα, ERβ, the AR and progesterone receptor (PR), are present from fetal age onward.…”

Molecular and Cellular Determinants of Estrogen Receptor α Expression

“…Within the human hypothalamus, the distribution of ER␣ is concentrated in the band of Broca, the medial mamillary nucleus, the medial preoptic area, the paraventricular nucleus, the lateral hypothalamus, the suprachiasmatic nucleus, and the ventromedial nucleus. Sex differences in ER␣ levels were observed in these nuclei, implying that estrogens and/or androgens regulate hu- (32). Specific evidence for estradiol-mediated up-regulation of ER␣ levels in the human suprachiasmatic nucleus (controlling circadian functions) has been shown previously (33).…”

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

“…However, sex differences are present in the relative levels of expression in hypothalamic subnuclei involved in reproductive processes, which may be determined early in life (Khünemann et al, 1994;Orikasa et al, 2002;Ikeda et al, 2003). In the human hypothalamus, sex differences were also revealed by closer analysis of their subcellular distribution to the nucleus, cytoplasm, and nerve terminals (Kruijver et al, 2002). In contrast, a lack of overall sex differences in ER expression levels was notable in the hippocampal regions, where estradiol-responsiveness is known to be sexually dimorphic (Weiland et al, 1997).…”