The Effects of Testosterone on the Brain of Transgender Men.

Transgender men (TM) experience an incongruence between the female sex assigned when they were born and their self-perceived male identity. Some TM seek for a gender affirming hormone treatment (GAHT) to induce a somatic transition from female to male through continuous administration of testosterone. GAHT seems to be relatively safe. However, testosterone produces structural changes in the brain as detected by quantitative magnetic resonance imaging. Mainly, it induces an increase in cortical volume and thickness and subcortical structural volume probably due to the anabolic effects. Animal models, specifically developed to test the anabolic hypothesis, suggest that testosterone and estradiol, its aromatized metabolite, participate in the control of astrocyte water trafficking, thereby controlling brain volume.

Effects of adult male rat feminization treatments on brain morphology and metabolomic profile.

Body feminization, as part of gender affirmation process of transgender women, decreases the volume of their cortical and subcortical brain structures. In this work, we implement a rat model of adult male feminization which reproduces the results in the human brain and allows for the longitudinal investigation of the underlying structural and metabolic determinants in the brain of adult male rats undergoing feminization treatments. Structural MRI and Diffusion Tensor Imaging (DTI) were used to non-invasively monitor in vivo cortical brain volume and white matter microstructure over 30 days in adult male rats receiving estradiol (E2), estradiol plus cyproterone acetate (CA), an androgen receptor blocker and antigonadotropic agent (E2 + CA), or vehicle (control). Ex vivo cerebral metabolic profiles were assessed by 1H High Resolution Magic Angle Spinning NMR (1H HRMAS) at the end of the treatments in samples from brain regions dissected after focused microwave fixation (5 kW). We found that; a) Groups receiving E2 and E2 + CA showed a generalized bilateral decrease in cortical volume; b) the E2 + CA and, to a lesser extent, the E2 groups maintained fractional anisotropy values over the experiment while these values decreased in the control group; c) E2 treatment produced increases in the relative concentration of brain metabolites, including glutamate and glutamine and d) the glutamine relative concentration and fractional anisotropy were negatively correlated with total cortical volume. These results reveal, for the first time to our knowledge, that the volumetric decreases observed in trans women under cross-sex hormone treatment can be reproduced in a rat model. Estrogens are more potent drivers of brain changes in male rats than anti-androgen treatment.

Effects of Adult Female Rat Androgenization on Brain Morphology and Metabolomic Profile.

Androgenization in adult natal women, as in transsexual men (TM), affects brain cortical thickness and the volume of subcortical structures. In order to understand the mechanism underlying these changes we have developed an adult female rat model of androgenization. Magnetic resonance imaging and spectroscopy were used to monitor brain volume changes, white matter microstructure and ex vivo metabolic profiles over 32 days in androgenized and control subjects. Supraphysiological doses of testosterone prevents aging decrease of fractional anisotropy values, decreased general cortical volume and the relative concentrations of glutamine (Gln) and myo-Inositol (mI). An increase in the N-acetylaspartate (NAA)/mI ratio was detected d. Since mI and Gln are astrocyte markers and osmolytes, we suspect that the anabolic effects of testosterone change astrocyte osmolarity so as to extrude Mi and Gln from these cells in order to maintain osmotic homeostasis. This mechanism could explain the brain changes observed in TM and other individuals receiving androgenic anabolic steroids.

Differential regional brain responses to induced maternal behavior in rats measured by cytochrome oxidase immunohistochemistry.

Maternal behavior (MB) in rats is expressed under neural control of vomeronasal structures. Some of these regions exert an inhibitory role, such as the accessory olfactory bulb (AOB), while others exert an excitatory role, such as the medial preoptic area (MPOA). In previous studies, using 2-DG as a marker for neuron activity at neuron terminal level, we reported that AOB showed a decrease and MPOA an increase when compared with control rats (non-exposed to pups) during the display of MB. In the present study we used a different indicator of neuronal metabolic activity - cytochrome oxidase (COx) - to assess the activity of the same brain regions in relation to induced MB. The induced-MB females showed increased COx expression in the MPOA and reduced COx activity in the AOB in comparison with the control, non-MB group, consistent with our previous findings using 2-DG. Present results provide further evidence of a facilitatory role of MPOA and an inhibitory role of AOB in MB induction.

The effects of partial and complete masculinization on the sexual differentiation of nuclei that control lordotic behavior in the male rat.

Male rats, under certain experimental conditions, may show lordosis, the typical expression of female sexual receptivity. This work studies the sexual morphological pattern of facilitatory and inhibitory structures that control lordosis. Three groups of males were neonatally subjected to a gradient of androgen exposure (castrated plus injected oil (GxM+oil); castrated plus androstenedione treated (GxM+AND); and sham operated [CM]); a group of control females (CF) was also added. Lordotic response after these different hormonal and neonatal surgical treatments, as well as the volume or number of neurons in facilitatory (ventromedial nucleus of the hypothalamus [VMN]) and inhibitory (the intermediate region of the lateral septum [LSi] and accessory olfactory bulb [AOB]) nuclei involved in lordosis was studied in adults. The inhibition of lordosis in the males seems to be associated to the neonatal presence of testosterone and the consequent masculinization of the VMN, VMNvl, LSi and AOB. It is suggested that one of the functions of the sex differences consistently seen in these structures might be to inhibit the lordosis response in the male.

Environmental prenatal stress alters sexual dimorphism of maternal behavior in rats.

The prenatal external environment can affect fetuses, altering the maternal behavior that they express when mature. In the present study, environmental prenatal stress (EPS) was applied to pregnant rats in their final week of gestation, and when their female offspring reached maturity, the long latency effect of the stress on those offspring was ascertained on their induced maternal behavior (MB), accessory olfactory bulb (AOB) morphology and plasma levels of ACTH and corticosterone (Cpd B). EPS reduced: the percentage of these virgins that showed induced MB, their retrieval of foster pups, the time spent crouching, and the quality of nest building; it also increased the incidence of their cannibalism of foster pups. The EPS-treated females presented a male-like pattern of induced MB. They showed increased plasma levels of ACTH and Cpd B and increased numbers of mitral cells in the AOB. These findings provide evidence that stress applied to the pregnant rat produces long-lasting behavioral, neuroanatomical and hormonal alterations in the female offspring that can be observed when they reach maturity.

Sexual dimorphism in the vomeronasal system of the rabbit.

Studies have shown that the vomeronasal system (VNS), an olfactory neural network that participates in the control of reproductive physiology and behavior, is sexually dimorphic in the rat. These works have also shown two main characteristics of brain sexual dimorphism: (a) dimorphism appears in neural networks related to reproduction and (b) it can present two morphological patterns: one in which males present greater morphological measures than females (male > female) and another in which the opposite is true (female > male). The present work extends the hypothesis to the rabbit, as a representative species of Lagomorpha. In addition, the locus coeruleus (LC), which is known to send rich noradrenergic projections to VNS structures, was also studied. Sex differences were found in: (a) the number of mitral, and dark and light granule cells (female > male) of the accessory olfactory bulb (AOB); (b) the medial amygdala (Me) and its dorsal (Med) and ventral (Mev) subdivisions, males showing greater values than females in volume and number of neurons, while in the posteromedial cortical amygdala (PMCo or C(3)), females show greater density of neurons than males and (c) the posteromedial division of the bed nucleus of the stria terminalis (BSTMP) in which males have more neurons than females. No sex differences were seen in the bed nucleus of the accessory olfactory tract (BAOT) and the LC. These results evidence that, as it was observed in rodents, sex differences are also seen in the VNS of Lagomorpha and that these sex differences present the two morphological patterns seen in Rodentia. Differences between orders are discussed with respect to the species-specific physiological and behavioral peculiarities.