In rodents, there is compelling evidence indicating that dynamic cell-to-cell communications involving cross talk between astroglial cells (such as astrocytes and specialised ependymoglial cells known as tanycytes) and neurones are important in regulating the secretion of gonadotrophin-releasing hormone (GnRH), the neurohormone that controls both sexual maturation and adult reproductive function. However, whether such astroglial cell-GnRH neurone interactions occur in the human brain is not known. In the present study, we used immunofluorescence to examine the anatomical relationship between GnRH neurones and glial cells within the hypothalamus of five women. Double-staining experiments demonstrated the ensheathment of GnRH neurone perikarya by glial fibrillary acidic protein (GFAP)-immunoreactive astrocyte processes in the periventricular zone of the tuberal region of the hypothalamus. GFAP immunoreactivity did not overlap that of GnRH at the GnRH neurone's projection site (i.e. the median eminence of the hypothalamus). Rather, human GnRH neuroendocrine fibres were found to be closely associated with vimentin or nestin-immunopositive radial glial processes likely belonging to tanycytes. In line with these light microscopy data, ultrastructural examination of GnRH-immunoreactive neurones showed numerous glial cells in direct apposition to pre-embedding-labelled GnRH cell bodies and/or dendrites in the infundibular nucleus, whereas postembedding immunogold-labelled GnRH nerve terminals were often seen to be enwrapped by glial cell processes in the median eminence. GnRH nerve button were sometimes visualised in close proximity to fenestrated pituitary portal blood capillaries and/or evaginations of the basal lamina that delineate the pericapillary space. In summary, these data demonstrate that GnRH neurones morphologically interact with astrocytes and tanycytes in the human brain and provide evidence that glial cells may contribute physiologically to the process by which the neuroendocrine brain controls the function of GnRH neurones in humans.
We investigated the effects of an artificial menstrual cycle on brain structure and activity in young women using metabolic magnetic resonance imaging (MRI). We show that the activation of the hypothalamo-pituitary-gonadal axis during the pill-free interval of low-dose combined oral contraceptive use is associated with transient microstructural and metabolic changes in the female hypothalamus but not in the thalamus, a brain structure unrelated to reproductive control, as assessed by water diffusion and proton magnetic resonance spectra measurements. Our results provide neuroanatomical insights into the mechanism by which sex steroid hormones mediate their central effects and raise the intriguing possibility that specific regions of the neuroendocrine brain use ovarian cycle-dependent plasticity to control reproduction in humans. These MRI-based physiological studies may pave the way for the development of new diagnostic and treatment strategies in the central loss of reproductive competence in human syndromes, such as hypothalamic amenorrhea.
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