The gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are glycoproteins produced by gonadotrope cells of the anterior pituitary gland. The two hormones act on somatic cells of the gonads in both males and females to regulate fundamental aspects of reproductive physiology, including gametogenesis and steroidogenesis. In males, LH stimulates testosterone production and sperm maturation. FSH also regulates spermatogenesis, though the importance of the hormone in this process differs across species. In females, FSH stimulates ovarian follicle maturation. Follicles are structures composed of oocytes surrounded by two types of somatic cells, granulosa and theca cells. FSH stimulates granulosa cells to proliferate and to increase their production of the aromatase enzyme. LH stimulates theca cells to make androgens, which are converted into estrogens by aromatase in granulosa cells. A surge of LH also stimulates ovulation of mature follicles. Gonadotropin-releasing hormone (GnRH) from the brain is the principal stimulator of gonadotropin synthesis and secretion from the pituitary. The sex steroids (androgens and estrogens) that are produced by the gonads in response to the gonadotropins feedback to the brain and pituitary gland. In the brain, these hormones usually slow the release of GnRH through a process called negative feedback, which in turn leads to decreases in FSH and LH. The steroids also modulate the sensitivity of the pituitary to GnRH in addition to directly regulating expression of the genes that encode the gonadotropin subunits. These effects are gene- and species-specific. In females, estrogens also have positive feedback actions in the brain and pituitary in a reproductive cycle stage-dependent manner. This positive feedback promotes GnRH and LH release, leading to the surge of LH that triggers ovulation. The gonadotropins are dimeric proteins. FSH and LH share a common α-subunit but have hormone-specific subunits, FSHβ and LHβ. The β subunits provide a means for differential regulation and action of the two hormones. In the case of FSH, there is a second gonadal feedback system that specifically regulates the FSHβ subunit. The gonads produce proteins in the transforming growth factor β (TGFβ) family called inhibins, which come in two forms (inhibin A and inhibin B). The ovary produces both inhibins whereas the testes make inhibin B alone. Inhibins selectively suppress FSH synthesis and secretion, without affecting LH. The pituitary produces additional TGFβ proteins called activins, which are structurally related to inhibins. Activins, however, stimulate FSH synthesis by promoting transcription of the FSHβ subunit gene. Inhibins act as competitive receptor antagonists, binding to activin receptors and blocking activin action, and thereby leading to decreases in FSH. Together, GnRH, sex steroids, activins, and inhibins modulate and coordinate gonadotropin production and action to promote proper gonadal function and fertility.
Daniel J. Bernard, Yining Li, Chirine Toufaily, and Gauthier Schang
Paul E. Micevych and Melinda A. Mittelman-Smith
In the last two decades of the 20th century, key findings in the field of estrogen signaling completely changed our understanding of hormones: first, steroidogenesis was demonstrated in the CNS; second, a vast majority of cells in the nervous system were shown to have estrogen receptors; third, a second nuclear estrogen receptor (ERß) was cloned; and finally, “nuclear” receptors were shown to be present and functional in the cell membrane. Shortly thereafter, even more membrane estrogen receptors were discovered. Steroids (estrogens, in particular) began to be considered as neurotransmitters and their receptors were tethered to G protein-coupled receptor signaling cascades. In some parts of the brain, levels of steroids appeared to be independent of those found in the circulation and yet, circulating steroids had profound actions on the brain physiology. In this review, we discuss the interaction of peripheral and central estrogen action in the context of female reproduction—one of the best-studied aspects of steroid action. In addition to reviewing the evidence for steroidogenesis in the hypothalamus, we review membrane-localized nuclear receptors coupling to G protein-signaling cascades and the downstream physiological consequences for reproduction. We will also introduce newer work that demonstrates cell signaling for a common splice variant of estrogen receptor-α (ERα), and membrane action of neuroprogesterone in regulating estrogen positive feedback.
Ashlyn Swift-Gallant and S. Marc Breedlove
While prenatal sex hormones guide the development of sex-typical reproductive structures, they also act on the developing brain, resulting in sex differences in brain and behavior in animal models. Stemming from this literature is the prominent hypothesis that prenatal neuroendocrine factors underlie sex differences in human sexual orientation, to explain why most males have a preference for female sexual partners (gynephilia), whereas most females display a preference for male sexual partners (androphilia). Convergent evidence from experiments of nature and indirect markers of prenatal hormones strongly support a role for prenatal androgens in same-same sexual orientations in women, although this finding is specific to a subset of lesbians who are also gender nonconforming (“butch”). More gender-conforming lesbians (“femmes”) do not show evidence of increased prenatal androgens. The literature has been more mixed for male sexual orientation: some report evidence of low prenatal androgen exposure, while others report evidence of high androgen levels and many other studies find no support for a role of prenatal androgen exposure in the development of androphilia in males. Recent evidence suggests there may be subgroups of gay men who owe their sexual orientation to distinct biodevelopmental mechanisms, which could account for these mixed findings. Although this research is young, it is similar to findings from lesbian populations, because gay men who are more gender nonconforming, and report a preference for receptive anal sex, differ on markers of prenatal development from gay men who are more gender conforming and report a preference for insertive anal sex. This chapter concludes with future research avenues including assessing whether multiple biodevelopmental pathways underlie sexual orientation and whether neuroendocrine factors and other biological mechanisms (e.g., immunology, genetics) interact to promote a same-sex sexual orientation.
Dayna L. Averitt, Rebecca S. Hornung, and Anne Z. Murphy
The modulatory influence of sex hormones on acute pain, chronic pain disorders, and pain management has been reported for over seven decades. The effect of hormones on pain is clearly evidenced by the multitude of chronic pain disorders that are more common in women, such as headache and migraine, temporomandibular joint disorder, irritable bowel syndrome, chronic pelvic pain, fibromyalgia, rheumatoid arthritis, and osteoarthritis. Several of these pain disorders also fluctuate in pain intensity over the menstrual cycle, including headache and migraine and temporomandibular joint disorder. The sex steroid hormones (estrogen, progesterone, and testosterone) as well as some peptide hormones (prolactin, oxytocin, and vasopressin) have been linked to pain by both clinical and preclinical research. Progesterone and testosterone are widely accepted as having protective effects against pain, while the literature on estrogen reports both exacerbation and attenuation of pain. Prolactin is reported to trigger pain, while oxytocin and vasopressin have analgesic properties in both sexes. Only in the last two decades have neuroscientists begun to unravel the complex anatomical and molecular mechanisms underlying the direct effects of sex hormones and mechanisms have been reported in both the central and peripheral nervous systems. Mechanisms include directly or indirectly targeting receptors and ion channels on sensory neurons, activating pain excitatory or pain inhibitory centers in the brain, and reducing inflammatory mediators. Despite recent progress, there remains significant controversy and challenges in the field and the seemingly pleiotropic role estrogen plays on pain remains ambiguous. Current knowledge of the effects of sex hormones on pain has led to the burgeoning of gender-based medicine, and gaining further insight will lead to much needed improvement in pain management in women.
Lily Yan, Laura Smale, and Antonio A. Nunez
Circadian rhythms are endogenous daily rhythms evident in behavior and physiology. In mammals, these rhythms are controlled by a hierarchical network of oscillators showing a coherent circadian coordination or coupling. The hypothalamic suprachiasmatic nucleus (SCN) sits on top of the hierarchy and coordinates the phase of oscillators in other brain regions and in peripheral organs, including endocrine glands. The phase of the SCN oscillator, in reference to the daily light-dark cycle, is identical across mammalian species regardless of whether they are most active during the day or night, that is, diurnal or nocturnal. However, the extra-SCN or peripheral oscillators are out of phase and are often reversed by 180° across diurnal and nocturnal mammals. In the endocrine system, with the notable exception of the pattern of pineal melatonin secretion, which features elevated levels at night regardless of the activity profile of the species, most endocrine rhythms show a 180° reversal when diurnal and nocturnal species are compared. There is also evidence of differences between nocturnal and diurnal species with respect to their rhythms in sensitivity or responsiveness to hormonal stimulation. One of the major unanswered questions in the field of comparative endocrinology relates to the mechanism responsible for the differential coupling in diurnal and nocturnal mammals of extra-SCN oscillators and overt circadian rhythms with the SCN oscillator and the light dark cycle. Viable hypotheses include species-specific switches from excitation to inhibition at key nodes between the SCN and its targets, the presence of extra-SCN signals that converge on SCN targets and reverse the outcome of SCN signals, and changes in oscillatory parameters between the oscillator of the SCN and those outside the SCN resulting in an anti-phase coupling among key oscillators.
Eliot A. Brenowitz
Animals produce communication signals to attract mates and deter rivals during their breeding season. The coincidence in timing results from the modulation of signaling behavior and neural activity by sex steroid hormones associated with reproduction. Adrenal steroids can influence signaling for aggressive interactions outside the breeding season. Androgenic and estrogenic hormones act on brain circuits that regulate the motivation to produce and respond to signals, the motor production of signals, and the sensory perception of signals. Signal perception, in turn, can stimulate gonadal development.
Understanding of the brain mechanisms regulating reproductive behaviors in female laboratory animals has been aided greatly by our knowledge of estrogen receptors in the brain. Hypothalamic neurons that express the gene for estrogen receptor-alpha regulate activity in the neural circuit for the simplest female reproductive response, lordosis behavior. In turn, many of the neurotransmitter inputs to the critical hypothalamic neurons have been studied using electrophysiological and neurochemical techniques. The upshot of all of these studies is that lordosis behavior presents the best understood set of mechanisms for any mammalian behavior.