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Sex Differences in Androgen Receptors of the Human Mamillary Bodies Are Related to Endocrine Status Rather Than to Sexual Orientation or Transsexuality

Graduate School of Neurosciences, Netherlands Institute for Brain Research (F.P.M.K., A.F.-G., M.F., E.M.K., D.F.S.), 1105 Amsterdam, The Netherlands; Department of Pharmacobiology, CINVESTAV (A.F.-G.), and División de Investigaciones en Neurociencias, IMP (A.F.-G.), México City, México; and Research Institute for Endocrinology, Reproduction, and Metabolism, Department of Pediatrics, Free University Amsterdam (M.F.), Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: F. P. M. Kruijver, M.D., or D. F. Swaab, M.D., Ph.D., Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands. E-mail: f.kruijver{at}nih.knaw.nl

In a previous study we found androgen receptor (AR) sex differences in several regions throughout the human hypothalamus. Generally, men had stronger nuclear AR immunoreactivity (AR-ir) than women. The strongest nuclear labeling was found in the caudal hypothalamus in the mamillary body complex (MBC), which is known to be involved in aspects of cognition and sexual behavior. The present study was carried out to investigate whether the sex difference in AR-ir of the MBC is related to sexual orientation or gender identity (i.e. the feeling of being male or female) or to circulating levels of androgens, as nuclear AR-ir is known to be up-regulated by androgens. Therefore, we studied the MBC in postmortem brain material from the following groups: young heterosexual men, young homosexual men, aged heterosexual castrated and noncastrated men, castrated and noncastrated transsexuals, young heterosexual women, and a young virilized woman. Nuclear AR-ir did not differ significantly between heterosexual and homosexual men, but was significantly stronger than that in women. A female-like pattern of AR-ir (i.e. no to weak nuclear staining) was observed in 26- to 53-yr-old castrated male-to-female transsexuals and in old castrated and noncastrated men, 67–87 yr of age. In analogy with animal studies showing strong activational effects of androgens on nuclear AR-ir, the present data suggest that nuclear AR-ir in the human MBC is dependent on the presence or absence of circulating levels of androgen. The group data were, moreover, supported by the fact that a male-like AR-ir (i.e. intense nuclear AR-ir) was found in a 36-yr-old bisexual noncastrated male-to-female transsexual and in a heterosexual virilized woman, 46 yr of age, with high levels of circulating testosterone. In conclusion, the sexually dimorphic AR-ir in the MBC seemed to be clearly related to circulating levels of androgens and not to sexual orientation or gender identity. The functional implications of these alterations are discussed in relation to reproduction, cognition, and neuroprotection.

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