The Year In Neuroendocrinology

Abstract

At the “Year In Neuroendocrinology” session during the 2009 meeting of The Endocrine Society, I highlighted recent progress in three main areas of neuroendocrinology: neural mechanisms of action of estradiol, GnRH regulation, and epigenetics. In the area of neural mechanisms of action of estradiol, we have seen the list of estrogen receptors continue to expand and that neurosteroid synthesis is rapidly regulated by the social environment; that brain sexual differentiation can occur via the action of estradiol in upstream neurons without the need of estrogen receptors in affected neurons; and that a particular xenoestrogen can block the effects of estradiol and testosterone in brain synapses. In the area of GnRH regulation, kisspeptin continues to be a major player in reproductive endocrinology; neurokinin B should be added to the growing list of critical peptides involved in puberty and reproduction; and RFamide-related peptides have a direct role in regulation of gonadotropin-releasing neurons as a gonadotropin-inhibiting hormone. Finally, in the epigenetics field, we learned that the same principles of importance of parental care in epigenetic regulation in hippocampal glucocorticoid receptors in rats applies to humans and may explain some long-term effects of childhood abuse on the hypothalamic-pituitary-adrenal axis. It is difficult, if not impossible, to predict which findings will have an enduring impact on the field. It will be interesting to look back, 10 yr from now, to see whether the papers that were chosen were in fact well cited and whether they were influential in driving additional research in neuroendocrinology.

In the “Year In Neuroendocrinology” session at the 2009 meeting of The Endocrine Society, I highlighted just a few of the major contributions in this broad field of the past 12–18 months. Neuroendocrinology is a vast discipline, including neurosecretion; the relationship of the brain and pituitary gland to all of the endocrine systems; the effects of hormones in the brain; the regulation of behavior, cognition, and mood; environmental regulation of neuroendocrine systems; sexual differentiation; and so much more. Thousands of papers are published annually in some aspect of this field. To devise a strategy to highlight at least some of the most significant papers, a large network of colleagues representing a wide array of expertise in neuroendocrinology was consulted for nominations of papers. From approximately 30 respondents, a total of about 125 papers were nominated. Fortunately, there was some consensus on the top papers. Likewise, there was agreement on the top areas. A list of three main areas was developed, which included neural mechanisms of action of estradiol, GnRH regulation, and epigenetics. The papers that were discussed in the session were organized around these three themes.

A Few Words on Stress and Obesity

Two important areas that were not covered because of time constraints were stress and obesity. “Early Life Stress Enhances the Vulnerability to Chronic Psychosocial Stress in Experimental Colitis in Adult Mice” by Veenema et al. (1) and “Hypothalamic IKKβ/NF-κB and Endoplasmic Reticulum Stress Link Overnutrition to Energy Balance and Obesity” by Zhang et al. (2), although nominated and noteworthy, were not discussed in the session. Nevertheless, because of their potential importance to the fields, they received brief mention.

Neural Mechanisms of Action of Estradiol

To introduce the first main area, a recent editorial in Endocrinology, “An Estrogen by Any Other Name,” (3) was referred to. In this editorial, I asked colleagues to be very specific with terminology when referring to steroid hormones. The editorial suggested that the term estrogen not be used to mean estradiol, estrone, estriol, Premarin, phytoestrogen, etc., each of which are, of course, in the class of estrogens. Use of the term estrogen for any or all of these compounds confuses the field and the public. Similarly, for example, medroxyprogesterone acetate is not progesterone, yet both medroxyprogesterone acetate and progesterone may be considered progestins. The amusing poem, “An Estrogen by Any Other Name,” written by Jon Levine in response to this editorial, provides a humorous reminder of the importance of precision with this terminology:

• Estradiol is a most potent estrogen,

• Progesterone is a progestin or progestagen,

• If you’re ever so perverse,

• To get these reversed,

• You’ll never be publishing in Endo again.

It was pointed out in the session that the last line was a joke.

History of neural mechanisms of action of estradiol

Some history will serve to ground this first discussion. In the early 1960s, Elwood Jensen (4) reported evidence of specific uptake of estrogens, and then of‘ estrogen receptors (ERs) in reproductive tissues. Richard Michael (5) reported the uptake of an estrogen by cat neurons, which was the first indication of estradiol being taken up into the brain. In the late 1960s, Eisenfeld (6) as well as Kahwanago et al. (7) reported the presence of specific estradiol binding in the brain, and Zigmond and McEwen (8) reported saturable cell nuclear uptake of estradiol in specific brain areas. Then, in 1986, Geoffrey Greene et al. (9) reported the sequence of the ER gene, which later became known as the ERα gene, when Kuiper et al. (10) cloned the second ER gene, ERβ. Both of these genes are expressed in the brain.

Since then, there have been persistent reports of alternate mechanisms of action, particularly to explain some rapid actions of estradiol. In many cases, these reports were more or less ignored, because they contradicted then-existing dogma. In 1979, for example, Richard Pietras and Clara Szego published “Estrogen Receptors in Uterine Plasma Membrane,” (11) which, it is fair to say, was not wildly embraced by the field of endocrinology. In 1992, ER immunoreactivity was reported, not only in the expected location of cell nuclei but also in the soma and in processes far from cell nuclei (12). Using electron microscopic techniques, ER immunoreactivity was observed in axon terminals, in dendrites, including distal dendrites, and in some cases, in postsynaptic densities. The concept of ERs in these locations was not widely embraced by the field until years later.

We now know, though, that ERs are present in many subcellular locations and signal through multiple pathways (Fig. 1). In the classical genomic pathway, estradiol binds to ERs, and then the ER binds to estrogen response elements, resulting in changes in gene transcription. An alternate mechanism is the nonclassical genomic pathway, in which estradiol binds with ERα, which then binds to a transcription factor, potentially resulting in transcription of other genes. Finally, there is a nonclassical, nongenomic pathway, in which membrane receptors or receptors in other locations signal through protein kinase cascades, resulting in phosphorylation of transcription factors that then may result in transcription of yet other genes.

Fig. 1.

Estradiol signals through ERα via multiple pathways, as discussed in the text. 1) Classical genomic pathway; 2) nonclassical genomic pathway; 3) nonclassical, nongenomic pathway. Adapted from figure provided by Dr. Jon Levine.

Estradiol and LH: negative feedback

From that historical launch pad, five papers in the area of neural mechanisms of action of estradiol were discussed. The first, “p21-Activated Kinase Mediates Rapid Estradiol-Negative Feedback Actions in the Reproductive Axis” (13), followed up on work published in 2007 by Glidewell-Kenney et al. (14). In the earlier paper, the authors reported that the classical, estrogen response element (ERE)-dependent pathway mediates estradiol action on the LH surge mechanism in female mice, whereas nonclassical pathways are responsible for the effect of estradiol on negative feedback of LH. These researchers used the NERKI (nonclassical estrogen receptor knock-in) mouse, developed by Larry Jameson’s lab in 2002, which has a mutant ERα allele by gene knock-in. This ERα does not bind to DNA and can signal only through membrane-initiated or ERE-independent genomic pathways. Because the NERKI mouse has the classical genomic pathway knocked out, if estradiol remains effective, it must be through an alternate mechanism: either the nonclassical genomic or the nonclassical nongenomic pathway. LH secretion remains normal in wild-type female mice with ovaries intact, because negative feedback is functional (Fig. 2). Removal of the ovaries, however, releases the negative feedback, resulting in elevated levels of LH. Administering estradiol benzoate then restores LH levels to about that of an ovary-intact animal. In contrast, ERα knockout (ERαKO) mice lack that mechanism. These animals with ovaries intact have very high LH levels; ovariectomy has no effect on LH levels, and likewise, estradiol does nothing. The NERKI mice, in contrast, are much more similar to the wild-type animals. Ovary-intact mice have fairly low LH levels, ovariectomy increases the levels, and replacing estradiol results in a return to ovary-intact levels. Therefore, the ERE-independent, ERα signaling pathway is sufficient for rapid negative feedback on LH by estradiol in female NERKI mice.

Fig. 2.

The ERE-independent ERα signaling pathway is sufficient for rapid negative feedback on LH by estradiol in female mice. ERα^+/+, wild-type mouse; ERα^−/−, ERαKO; ERα^−/AA, NERKI mouse (nonclassical estrogen receptor knock-in); Intact, ovary-intact mice; OVX, ovariectomized mice; OVX+EB, ovariectomized mice injected with estradiol benzoate. [Reproduced with permission from Z. Zhao et al.: Proc Natl Acad Sci USA 106:7221, 2009 (13 ). ©National Academy of Sciences USA.]

Next, these researchers looked at phosphorylation of p21-activated kinase (PAK1) in the medial preoptic nucleus. In wild-type and in NERKI mice, estradiol increases phosphorylation of PAK1; in ERαKO animals, however, estradiol is without effect. Therefore, the ERE-independent ERα signaling pathway is sufficient for estradiol-induced phosphorylation of PAK1 in this brain area. From these findings, together with the finding that intracerebral ventricular infusion of a PAK inhibitor blocks estradiol’s negative feedback on LH, the researchers concluded that PAK1 activation leads to negative feedback of LH by estradiol, and it does so through a nonclassical ER signaling pathway in the brain, not by the classical genomic mechanism.

G protein-coupled receptor 30 (GPR30) membrane receptor

The next paper concerns the GPR30 membrane receptor. The search for mechanisms of rapid effects of estradiol has been an extremely active area of investigation recently. Several forms of what appear to be membrane receptors that mediate some of estradiol’s action have been identified: the membrane-associated ERα (15), ER-X (16), STX-sensitive receptors (17), another novel G protein-coupled receptor that binds the nonsteroidal diphenylacrylamide compound STX, and finally, the controversial GPR30 (18). Noel et al. (19) asked whether GPR30 is involved in the rapid increase in LH secretion by estradiol in monkeys. As expected, estradiol induced a rapid increase (within 10 min) in GnRH secretion in primary cultures of GnRH neurons (Fig. 3). GnRH was elevated and then returned to baseline when estradiol was removed. Next, they tested whether a nuclear membrane-impermeable estradiol dendrimer conjugate (EDC) developed by the Katzenellenbogens and cell membrane- impermeable estradiol-BSA conjugate (BSA-conjugated estradiol) induce the same effect as estradiol, that is, short-latency GnRH release from GnRH cell cultures. They found that although the BSA and the dendrimer controls were without effect, the EDC and the estradiol-BSA conjugate each induced a rapid increase similar to that of estradiol. Although to a slightly lesser extent and of shorter duration than estradiol, these two modified forms of estradiol are capable of inducing GnRH release. These authors further demonstrated that some GnRH neurons express GPR30 immunoreactivity. Additional evidence that GPR30 is involved in GnRH release was provided by knockdown of GPR30 by small interfering RNA, which completely blocked some of the cellular effects of estradiol on GnRH neurons. A GPR30 agonist, in contrast, induced some of the same effects as estradiol. Therefore, there is strong evidence that GPR30 is involved in GnRH release, at least in monkey GnRH primary cultures. Although this does not prove that GPR30 is an ER, this work demonstrated conclusively that it is an important protein in the regulation of GnRH release.

Fig. 3.

EDC (nuclear membrane impermeable) and estradiol-BSA (E₂-BSA; cell membrane impermeable) induce short-latency GnRH (referred to as LHRH in this figure) release from GnRH monkey primary cell cultures. Dendrimer (DC) and BSA controls are without effect. [Reproduced with permission from S. D. Noel et al.: Mol Endocrinol 23:349, 2009 (19 ). ©The Endocrine Society.]

Neurosteroid synthesis regulation and social interaction

The third paper in this area is on neurosteroid synthesis. We first learned that there were ERs in the brain in the 1960s, contrary to the earlier belief that the brain could serve as a negative control tissue for peripheral reproductive tissues. Much later, we learned that the brain synthesizes steroid hormones and is itself an endocrine gland. That is, some areas of the brain have the synthetic capacity for a number of hormones. In fact, the next paper demonstrates not only that synthesis of steroid hormone in the brain is regulated but also that regulation also responds to social environmental input. Remage-Healey et al. (20) investigated whether neurosteroid synthesis is acutely regulated during social interactions. That is, do levels of the hormones either increase or decrease during social interactions? These investigators performed in vivo microdialysis of auditory parts of the brain of male zebra finches, primarily the caudomedial nidopallium (NCM), whereas the males had social interactions with females in adjacent cages. Upon exposure of males to a female, estradiol levels rapidly increased with no change in testosterone levels. When the female was removed, the levels returned to baseline (Fig. 4). Surprisingly, therefore, estradiol, rather than testosterone, rapidly increases within the NCM in males during social interactions. In contrast, in female zebra finch, exposure to male song increased estradiol, which again returned to baseline when the auditory stimulus was removed. Testosterone levels decreased during exposure and increased afterward. Furthermore, the authors demonstrated that glutamate retrodialysis within the NCM decreased estradiol levels in that area, whereas γ-aminobutyric acid caused an increase in testosterone levels in that area. Therefore, besides being synthesized in the brain, the gonadal hormones estradiol and testosterone are regulated by environmental stimulation, at least in zebra finches.

Fig. 4.

Concentrations of estradiol increase, and testosterone decreases, within auditory area, NCM, in response to male song playback, not white noise control, in female zebra finches. Levels return to baseline after cessation of playback. [Adapted with permission from L. Remage-Healey et al.: Nat Neurosci 11:1327, 2008 (20 ). ©Macmillan Publishers Ltd.]

Sexual differentiation of the brain

The fourth paper in this area is based on a 1959 study by Phoenix, Goy, Gerall, and Young (21) (see also recent editorial, Ref. 22). Dendritic spines in the brain are sites of excitatory input to neurons. In rats, males have two times the number of dendritic spines and longer spines in some brain areas than females. Females can be masculinized by neonatal injection of testosterone (via metabolism to estradiol), making them excellent models for study of sexual differentiation of the ultrastructure of the brain. Using spinophilin as a proxy for dendritic spines, Schwarz et al. (23) reported that the glutamate agonist N-methyl-d-aspartic-acid (NMDA) had the same effect as estradiol in masculinizing the number of dendritic spines and hypothalamic neurons in neonatal female rats (Fig. 5). They also found out that blocking α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-type glutamate receptors with NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo [f]quinoxaline-7-sulfonamide), in turn, blocked the action of estradiol on spinophilin in neonatal females. They then showed that estradiol increases glutamate release from hypothalamic neurons via phosphatidylinositol-3 kinase and that estradiol-induced glutamate release activates MAPK in postsynaptic neurons. This then induces dendritic spine formation by a non-protein-synthesis-dependent mechanism.

Fig. 5.

The glutamate agonist NMDA has same effect as estradiol on masculinizing number of dendritic spines in hypothalamic neurons (i.e. increasing number of spines/primary dendrites and increasing total dendritic length) in female rats. [Reproduced with permission from J. M. Schwarz et al.: Neuron 58:584, 2009 (23 ). ©Elsevier.]

Figure 6 depicts testosterone entering a neuron, where it is converted by aromatase to estradiol and binds to ERs. Through a process involving phosphatidylinositol-3 kinase, glutamate is released postsynaptically and binds to NMDA receptors on the downstream neuron via a pathway that involves MAPK. Spinophilin increases and more dendritic spines are formed, thereby transforming the neuron from one with the characteristics of a female into one that has characteristics of a male. In this paper, the authors concluded that estradiol can act in one neuron to alter the morphology of another with no need for the presence of ERs in the second neuron. This transneuronal mechanism is one of the many processes by which estradiol causes a lasting change in one component of sexual differentiation of the brain, that is, changes in synaptic patterning. Taken together with other work on sexual differentiation of the brain, these experiments suggest that there is tremendous heterogeneity in the mechanisms by which estradiol can act on neurons.

Fig. 6.

Estradiol influences dendritic spines in postsynyaptic neurons via glutamate release as discussed in text. Figure provided by Dr. Margaret McCarthy.

Xenestrogen: bisphenol A (BPA)

The fifth paper in the area of neural mechanisms of action of estradiol is on the neural effects of the xenoestrogen BPA. Leranth et al. (24) asked the question, does BPA influence synaptogenesis in the brain of nonhuman primates? As in the previous study discussed, these researchers looked at changes in spine synapses, but they analyzed ultrastructural changes directly. Specifically, they studied ultrastructural changes that can influence the way neurons communicate with each other and that are believed to be involved in the regulation by estradiol of brain functions, including cognition and mood. Young adult female green African monkeys were administered estradiol, BPA, or both via mini-pumps for 28 d. Their brains were then examined for the number of spine synapses. In four brain areas, the CA1 region of the hippocampus, the dentate gyrus, the CA3 region of the hippocampus, and the prefrontal cortex, estradiol induced a significant increase in the number of spine synapses, whereas BPA was without effect (Fig. 7). In animals that received both substances, BPA almost completely blocked the effects of estradiol. These results were in contrast to most other work, which has focused on the estrogenic effects of BPA.

Fig. 7.

The number of spine synapses in CA1 stratum radiatum (CA1sr), CA3 stratum lucidum and radiatum (CA3sl/sr), dentate gyrus stratum moleculare (DGsm), and layer II/III of PFC of vehicle-treated (control), estradiol benzoate-treated (EB), BPA-treated (BPA), and EB/BPA-treated (EB/BPA) monkeys. [Reproduced with permission from C. Leranth et al.: Proc Natl Acad Sci USA 105:14187, 2008 (24 ). ©National Academy of Sciences USA.]

In a related paper, Leranth et al. (25) reported the same effect in male rats. In male rats, testosterone induces spine synapses. In this paper, the authors reported that testosterone increased the number of spine synapses, whereas BPA by itself was without effect. Just as was the case with estradiol in female monkeys, however, BPA completely abolished the effect of testosterone when the two compounds were administered together. Thus, under the conditions used in these experiments, BPA blocked the effects of an estrogen and an androgen on the neural ultrastructure in female monkeys and male rats, respectively, by an as-yet unspecified mechanism.

GnRH Regulation

The next area that was discussed was GnRH regulation.

Role of kisspeptin in adults

Although we have learned a great deal about kisspeptin and its role in puberty since its discovery a few years ago, we still have a lot more to learn about this very important molecule. In the first paper on GnRH that was discussed, Clarkson et al. (26) asked, what is the role of kisspeptin and its GPR54 receptor in GnRH regulation beyond its role in puberty? Through double-label immunohistochemistry, they found that some cell nuclei, which expressed kisspeptin in mouse rostral periventricular areas, also expressed ERα, and the same was true for progestin receptors. Between 40 and 60% of the kisspeptin neurons also coexpress ERα, and about 60% of them coexpress progestin receptors. They also looked at GPR54-null (mice lacking the receptor for kisspeptin) and KiSS-1-null mice (mice lacking the gene for kisspeptin). They reported that both GPR54 and KiSS-1 are essential for GnRH neuron activation and the LH surge in adult mice (Fig. 8). Injection of estradiol and progesterone into ovariectomized wild-type mice induces an LH surge. However, in contrast to wild-type mice, the LH surge is completely absent in GPR54 and KiSS-1 knockout animals. Additionally, we know that many GnRH neurons about to undergo an LH surge express Fos (protooncogene) in their cell nuclei, often a sign of neuronal activation. Whereas Fos is induced in more than 50% of the GnRH neurons in wild-type animals, in both types of knockout mice, this was completely abolished. As a control, the authors reported that GPR54-null mice had normal hormone-induced Fos expression in kisspeptin neurons. Thus, kisspeptin signaling through its GPR54 receptor is essential for the activation of GnRH neurons that, in turn, is required for LH release and ovulation. These results demonstrated clearly that the function of kisspeptin is not limited to puberty.

Fig. 8.

In both, GPR54 and Kiss-1 null mice, the LH surge in response to estradiol and progesterone is blocked, as is percent GnRH neurons expressing Fos immunoreactivity. [Reproduced with permission from E. Ducret et al.: Endocrinology 150:2799, 2009 (29 ). ©The Endocrine Society.]

Neurokinin B and reproduction

In the second paper on GnRH regulation that was discussed, Topaloglu et al. (27) reported on four human pedigrees with severe normosmic idiopathic hypogonadotropic hypogonadism (nIHH), or gonadal congenital gonadotropin deficiency and pubertal failure, in which all affected individuals were homozygous for loss-of-function mutations in either the TAC3 gene (which encodes neurokinin B) or the TACR3 gene (which encodes the neurokinin 3 receptor). In short, each pedigree had deficiencies or missense mutations in the TAC3 gene or the TACR3 gene (Fig. 9). Earlier evidence for a relationship between neurokinin B and kisspeptin comes from work in ewes (28) in which it had been reported that kisspeptin-expressing neurons coexpress neurokinin B immunoreactivity. Taken together, these studies suggest that neurokinin B should be added to kisspeptin as a critical signal in the suite of neurochemical inputs activating the reproductive axis at puberty. It is likely that both kisspeptin and neurokinin B are potential targets for pharmaceutical intervention for fertility disorders.

Fig. 9.

Identification of a rare missense mutation in TAC3 (left panel) and TACR3 (right panel) associated with nIHH (normosmic idiopathic hypogonadotropic hypogonadism). Left panel, Pedigree used to identify region on chromosome 12 harboring genetic defect causing nIHH with detail of subset of genes in critical interval; right panel, critical region on chromosome 4 showing homozygosity (black) in all affected individuals, with known or predicted genes in region indicated by vertical black bars. [Adapted with permission from A. K. Topaloglu et al.: Nat Genet 41:354, 2009 (27 ). ©Macmillan Publishers Ltd.]

RFamide as gonadotropin-inhibiting hormone (GnIH)

The final paper on GnRH regulation concerns RFamide-related peptides (RFRPs), specifically, the putative GnIH (29). Ducret et al. (29) used cell-attached electrophysiology, which allows recordings of GnRH neuron cell firing to be made without perturbing the inside of the cell, on a GnRH-green fluorescent protein mouse model to determine whether the neuropeptide RFRP-3, an ortholog of avian GnIH, directly modulates the excitability of GnRH neurons. Indeed, between 20 and 40% of GnRH neurons were inhibited when this putative GnIH ortholog was administered at the highest doses (doses were from 10 nm to 1 μm; Fig. 10). Thus, RFRP-3 can directly inhibit GnRH neuron firing in mice. Therefore, in addition to its effect on the pituitary that has been shown very recently, its role as a GnIH in mammals includes a direct effect on GnRH neuron excitability.

Fig. 10.

RFRP-3 exerts a dose-dependent action on GnRH neurons in the anteroventral periventricular nucleus in female mice. The histogram shows the percentage of GnRH neurons responding to RFRP-3 at 10 nm, 100 nm, and 1 μm.

Epigenetics

The last area that was discussed was epigenetics and is the most translational of all the studies that were presented. The paper by McGowan et al. (30) was included not only because of the excitement that it has generated but also because it demonstrates clearly that what we learn from mice and rats really can inform us about humans. Mother rats lick and groom their young, which causes demethylation of the promoter for the hippocampal glucocorticoid receptor and, in turn, results in a permanent increase in expression of the glucocorticoid receptor in the hippocampus. As adults, females who were regularly licked as pups express high hippocampal levels of glucocorticoid receptors and low glucocorticoid levels in response to stress, and they express high levels of licking and grooming behaviors once they become mothers. Conversely, the animals that received low levels of licking and grooming show exactly the opposite. Thus, in rats, maternal care influences hypothalamic-pituitary-adrenal (HPA) function through epigenetic programming of glucocorticoid receptor expression. Knowing that in humans, childhood abuse alters HPA stress responses and increases the risk of suicide, these researchers obtained postmortem hippocampi from suicide victims with a history of childhood abuse, from suicide victims with no childhood abuse, and from controls (nonsuicide, nonabused). To determine whether childhood abuse is associated with long-term changes in glucocorticoid receptor regulation in the hippocampi of humans as it is in rats, they examined glucocorticoid receptor levels. They found high levels of glucocorticoid receptors in controls and in suicide nonabused victims and significantly lower levels in the suicide victims who had been abused as children. Going one step further, they investigated whether human suicide victims who have been abused as children have higher levels of methylation of the promoter of the hippocampal glucocorticoid receptor, which would explain the decreased glucocorticoid expression levels (as had been reported in rats). As predicted, there was increased methylation of this neuron-specific glucocorticoid receptor promoter in hippocampus of abused victims and lower levels of methylation in the control group and in nonabused suicide victims (Fig. 11). The far-reaching conclusion of this work is that the mechanism for the epigenetic regulation of hippocampal glucocorticoid receptor expression by parental care first described in rats seems to translate to humans.

Fig. 11.

Increased methylation of the NR3C1 (neuron-specific glucocorticoid receptor) promoter in the hippocampus of suicide victims abused in childhood (suicide abused), contrasted with nonsuicide and suicide/nonabused controls. [Reproduced with permission from P. O. McGowan et al.: Nat Neurosci 12:342, 2009 (30 ). ©Macmillan Publishers Ltd.]

Conclusions

To summarize, topics were presented in three main areas: neural mechanisms of action of estradiol, GnRH regulation, and epigenetics. In the estradiol area, the past couple of years have shown that the list of ERs is exploding; that neurosteroid synthesis, at least in birds, is rapidly regulated by the environment; that sexual differentiation in the brain can occur via the action of estradiol in upstream neurons without the need of ERs in affected neurons; and that the xenoestrogen BPA, under some conditions, blocks the effects of estradiol and testosterone on brain synapses. As for GnRH regulation, kisspeptin continues to be a major player in reproductive endocrinology, neurokinin B can be added to the growing list of critical peptides involved in puberty and reproduction, and RFRPs have a direct role in regulation of gonadotropin-releasing neurons as a GnIH. Finally, in the field of epigenetics, the same principles of importance in parental care in epigenetic regulation in hippocampal glucocorticoid receptors in rats applies to humans. This work may explain some of the long-term effects of childhood abuse on the HPA axis.

The papers presented in the “Year in Neuroendocrinology” session are but a small sampling of important papers published in the past 12–18 months. Each of them continues a developing story or begins a new story in this field. It must be reemphasized that the choices were purely subjective with input from a large number of colleagues. It will be fascinating to look back in 10 yr to determine whether each of these papers was as influential to the field as was predicted.