Hypothalamus Males and Females

Several hypothalamic nuclei are sexually dimorphic, i.e. there are clear differences in both structure and function between males and females.

Some differences are apparent even in gross neuroanatomy: most notable is the sexually dimorphic nucleus within the preoptic area, which is present only in males. However most of the differences are subtle changes in the connectivity and chemical sensitivity of particular sets of neurons.

The importance of these changes can be recognised by functional differences between males and females. For instance, males of most species prefer the odor and appearance of females over males, which is instrumental in stimulating male sexual behavior. If the sexually dimorphic nucleus is lesioned, this preference for females by males diminishes. Also, the pattern of secretion of growth hormone is sexually dimorphic, and this is one reason why in many species, adult males are much larger than females.

Responses to ovarian steroids

Other striking functional dimorphisms are in the behavioral responses to ovarian steroids of the adult. Males and females respond differently to ovarian steroids, partly because the expression of estrogen-sensitive neurons in the hypothalamus is sexually dimorphic, i.e. estrogen receptors are expressed in different sets of neurons.

Estrogen and progesterone can influence gene expression in particular neurons or induce changes in cell membrane potential and kinase activation, leading to diverse non-genomic cellular functions. Estrogen and progesterone bind to their cognate nuclear hormone receptors, which translocate to the cell nucleus and interact with regions of DNA known as hormone response elements (HREs) or get tethered to another transcription factor's binding site. Estrogen receptor (ER) has been shown to transactivate other transcription factors in this manner, despite the absence of an estrogen response element (ERE) in the proximal promoter region of the gene. ERs and progesterone receptors (PRs) are generally gene activators, with increased mRNA and subsequent protein synthesis following hormone exposure.

Male and female brains differ in the distribution of estrogen receptors, and this difference is an irreversible consequence of neonatal steroid exposure. Estrogen receptors (and progesterone receptors) are found mainly in neurons in the anterior and mediobasal hypothalamus, notably:

the preoptic area (where LHRH neurons are located)
the periventricular nucleus (where somatostatin neurons are located)
the ventromedial hypothalamus (which is important for sexual behavior).

Gonadal steroids in neonatal life of rats

In neonatal life, gonadal steroids influence the development of the neuroendocrine hypothalamus. For instance, they determine the ability of females to exhibit a normal reproductive cycle, and of males and females to display appropriate reproductive behaviors in adult life.

If a ''female rat'' is injected once with testosterone in the first few days of postnatal life (during the "critical period" of sex-steroid influence), the hypothalamus is irreversibly masculinized; the adult rat will be incapable of generating an LH surge in response to estrogen (a characteristic of females), but will be capable of exhibiting ''male'' sexual behaviors (mounting a sexually receptive female).
By contrast, a ''male rat'' castrated just after birth will be ''feminized'', and the adult will show ''female'' sexual behavior in response to estrogen (sexual receptivity, lordosis behavior).

Androgens in primates

In primates, the developmental influence of androgens is less clear, and the consequences are less understood. Within the brain, testosterone is aromatized to (estradiol), which is the principal active hormone for developmental influences. The human testis secretes high levels of testosterone from about week 8 of fetal life until 5–6 months after birth (a similar perinatal surge in testosterone is observed in many species), a process that appears to underlie the male phenotype. Estrogen from the maternal circulation is relatively ineffective, partly because of the high circulating levels of steroid-binding proteins in pregnancy.

Human Sexual Orientation and the Hypothalamus

According to D.F. Swaab, "Neurobiological research related to sexual orientation in humans is only just gathering momentum, but the evidence already shows that humans have a vast array of brain differences, not only in relation to gender, but also in relation to sexual orientation." Specifically, there are similarities between the hypothalamuses in heterosexual men (HeM) and homosexual women (HoW) and also between homosexual men (HoM) and heterosexual women (HeW).

Swaab first reported on the relationship between sexual orientation in males and the hypothalamus's "clock", the suprachiasmatic nucleus (SCN). In 1990, Swaab and Hofman reported that the SCN of HoM was significantly larger than HeM. Then in 1995, Swaab et al linked brain development to sexual orientation by treating male rats both pre- and postnatally with ATD, a testosterone blocker in the brain. This produced an enlarged SCN and bisexual behavior in the adult male rats. In 1991, LeVay showed that part of the sexually dimorphic nucleus (SDN), the interstitial nuclei of the anterior hypothalamus (INAH) 3, is twice as large in HeM as HoM and HeW.

In 2004 and 2006, two studies by Berglund, Lindström, and Savic used Positron Emition Tomography (PET) to observe how the hypothalamus responds to smelling common odors, the scent of testosterone found in male sweat, and the scent of estrogen found in female urine. These studies showed that the hypothalamus of HeM and HoW both respond to estrogen. Also, the hypothalamus of HoM and HeW both respond to testosterone. The hypothalamus of all four groups did not respond to the common odors, which produced a normal olfactory response in the brain.

Other influences upon hypothalamic development

Sex steroids are not the only important influences upon hypothalamic development; in particular, pre-pubertal stress in early life determines the capacity of the adult hypothalamus to respond to an acute stressor. Unlike gonadal steroid receptors, glucocorticoid receptors are very widespread throughout the brain; in the paraventricular nucleus, they mediate negative feedback control of CRF synthesis and secretion, but elsewhere their role is not well understood.