Galanin neurons in the intermediate nucleus (InM) of the human hypothalamus in relation to sex, age, and gender identity.

The intermediate nucleus (InM) in the preoptic area of the human brain, also known as the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the interstitial nucleus of the anterior hypothalamus-1 (INAH-1) is explored here. We investigated its population of galanin-immunoreactive (Gal-Ir) neurons in relation to sex, age, and gender identity in the postmortem brain of 77 subjects. First we compared the InM volume and number of Gal-Ir neurons of 22 males and 22 females in the course of aging. In a second experiment, we compared for the first time the InM volume and the total and Gal-Ir neuron number in 43 subjects with different gender identities: 14 control males (M), 11 control females (F), 10 male-to-female (MtF) transsexual people, and 5 men who were castrated because of prostate cancer (CAS). In the first experiment we found a sex difference in the younger age group (<45 years of age), i.e., a larger volume and Gal-Ir neuron number in males and an age difference, with a decrease in volume and Gal-Ir neuron number in males > 45 years. In the second experiment the MtF transsexual group presented an intermediate value for the total InM neuron number and volume that did not seem different in males and females. Because the CAS group did not have total neuron numbers that were different from the intact males, the change in adult circulating testosterone levels does not seem to explain the intermediate values in the MtF group. Organizational and activational hormone effects on the InM are discussed.

Estrogen-receptor-beta distribution in the human hypothalamus: similarities and differences with ER alpha distribution.

This study reports the first systematic rostrocaudal distribution of estrogen receptor beta immunoreactivity (ER beta-ir) in the human hypothalamus and adjacent areas in five males and five females between 20-39 years of age and compares its distribution to previously reported ER alpha in the same patients. ER beta-ir was generally observed more frequently in the cytoplasm than in the nucleus and appeared to be stronger in women. Basket-like fiber stainings, suggestive for ER beta-ir in synaptic terminals, were additionally observed in various areas. Men showed more robust nuclear ER beta-ir than women in the medial part of the bed nucleus of the stria terminalis, paraventricular and paratenial nucleus of the thalamus, while less intense, but more nuclear, ER beta-ir appeared to be present in, e.g., the BSTc, sexually dimorphic nucleus of the medial preoptic area, diagonal band of Broca and ventromedial nucleus. Women revealed more nuclear ER beta-ir than men of a low to intermediate level, e.g., in the suprachiasmatic, supraoptic, paraventricular, infundibular, and medial mamillary nucleus. These data indicate potential sex differences in ER beta expression. ER beta-ir expression patterns in subjects with abnormal hormone levels suggests that there may be sex differences in ER beta-ir that are "activational" rather than "organizational" in nature. Similarities, differences, potential functional, and clinical implications of the observed ER alpha and ER beta distributions are discussed in relation to reproduction, autonomic-function, mood, cognition, and neuroprotection in health and disease.

Sex differences in the hypothalamus in the different stages of human life.

Quite a number of structural and functional sex differences have been reported in the human hypothalamus and adjacent structures that may be related to not only reproduction, sexual orientation and gender identity, but also to the often pronounced sex differences in prevalence of psychiatric and neurological diseases. One of the recent focuses of interest in this respect is the possible beneficial effect of sex hormones on cognition in Alzheimer patients. The immunocytochemical localization of estrogen receptors (ER) alpha, beta and androgen receptors has shown that there are indeed numerous targets for sex hormones in the adult human brain. Observations in the infundibular nucleus have, however, indicated that in this brain area the hyperactivity resulting from a lack of estrogens in the menopause seems to protect females against Alzheimer changes, in contrast to males. It is thus quite possible that estrogen replacement therapy may, in these brain areas, lead to inhibition of neuronal metabolism and thus to the same proportion of Alzheimer changes as are observed in men. Knowledge about the functional sex differences in the brain and the effect of sex hormones on neuronal metabolism may thus provide clues not only for the possible beneficial effects of these hormones (e.g., on cognition or hypertension), but also on possible central side effects of estrogen replacement therapy.

Estrogen receptor-alpha distribution in the human hypothalamus in relation to sex and endocrine status.

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 hypothalamus.

Functional sex differences in reproduction, gender and sexual orientation and in the incidence of neurological and psychiatric diseases are presumed to be based on structural and functional differences in the hypothalamus and other limbic structures. Factors influencing gender, i.e., the feeling to be male or female, are prenatal hormones and compounds that change the levels of these hormones, such as anticonvulsants, while the influence of postnatal social factors is controversial. Genetic factors and prenatal hormone levels are factors in the determination of sexual orientation, i.e. heterosexuality, bisexuality or homosexuality. There is no convincing evidence for postnatal social factors involved in the determination of sexual orientation. The period of overt sexual differentiation of the human hypothalamus occurs between approximately four years of age and adulthood, thus much later than is generally presumed, although the late sexual differentiation may of course be based upon processes that have already been programmed in mid-pregnancy or during the neonatal period. The recently reported differences in a number of structures in the human hypothalamus and adjacent structures depend strongly on age. Replication of these data is certainly necessary. Since the size of brain structures may be influenced by premortem factors (e.g. agonal state) and postmortem factors (e.g. fixation time), one should not only perform volume measurements, but also estimate a parameter that is not dependent on such factors as, i.e., total cell number of the brain structure in question. In addition, functional differences that depend on the levels of circulating hormones in adulthood have been observed in several hypothalamic and other brain structures. The mechanisms causing sexual differentiation of hypothalamic nuclei, the pre- and postnatal factors influencing this process, and the exact functional consequences of the morphological and functional hypothalamic differences await further elucidation.