Design, Implementation, and Evaluation of an Intensive Course on Issues in Women's Health and Gender-Based Medicine.

Objectives: Sex and gender have profound effects on disease prevalence, presentation, and outcome, but these issues are not covered in depth in standard medical school curricula. To improve understanding of women's health, an intensive 1-month class was offered to fourth-year medical students.

Methods: The class combined background lectures on the biological and social determinants of women's health with presentations on specific medical conditions by practicing clinicians and students.

Hypothalamic-Pituitary-Gonadal Axis Disorders Impacting Fertility in Both Sexes and the Potential of Kisspeptin-Based Therapies to Treat Them.

Impaired function of the hypothalamic-pituitary-gonadal (HPG) axis can lead to a vast array of reproductive disorders some of which are inherited or acquired, but many are of unknown etiology. Among the clinical consequences of HPG impairment, infertility is quite common. According to the latest report from the World Health Organization, the global prevalence of infertility during a person's lifetime is a staggering 17.

The PI3K/Akt Pathway in Meta-Inflammation.

Obesity is a global epidemic representing a serious public health burden as it is a major risk factor for the development of cardiovascular disease, stroke and all-cause mortality. Chronic low-grade systemic inflammation, also known as meta-inflammation, is thought to underly obesity's negative health consequences, which include insulin resistance and the development of type 2 diabetes. Meta-inflammation is characterized by the accumulation of immune cells in adipose tissue, a deregulation in the synthesis and release of adipokines and a pronounced increase in the production of proinflammatory factors.

Shaping Microglial Phenotypes Through Estrogen Receptors: Relevance to Sex-Specific Neuroinflammatory Responses to Brain Injury and Disease.

In mammals, 17-estradiol (E), the primary endogenous estrogen, maintains normal central nervous system (CNS) function throughout life and influences brain responses to injury and disease. Estradiol-induced cellular changes are mediated through the activation of nuclear and extranuclear estrogen receptors (ERs), which include ER, ER, and the G-protein coupled receptor, GPER1. ERs are widely expressed throughout the brain, acting as transcriptional effectors or rapidly initiating membrane and cytoplasmic signaling cascades in practically all brain cells including microglia, the resident immune cells of the CNS.

Targeted Deletion of PTEN in Kisspeptin Cells Results in Brain Region- and Sex-Specific Effects on Kisspeptin Expression and Gonadotropin Release.

Kisspeptin-expressing neurons in the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC) of the hypothalamus relay hormonal and metabolic information to gonadotropin-releasing hormone neurons, which in turn regulate pituitary and gonadal function. Phosphatase and tensin homolog (PTEN) blocks phosphatidylinositol 3-kinase (PI3K), a signaling pathway utilized by peripheral factors to transmit their signals. However, whether PTEN signaling in kisspeptin neurons helps to integrate peripheral hormonal cues to regulate gonadotropin release is unknown.

Loss of PI3K p110 in the Adipose Tissue Results in Infertility and Delayed Puberty Onset in Male Mice.

Deletion of PI3K catalytic subunit p110 in adipose tissue (aP2-Cre/p110, -/- hereafter) results in increased adiposity, glucose intolerance, and liver steatosis. Because this endocrine organ releases hormones like leptin, which are important in reproductive physiology, we investigated the reproductive phenotype of -/- males. Compared to controls, -/- males displayed delayed onset of puberty accompanied by a reduction in plasma LH levels and testicular weight.

Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor α in kisspeptin neurons.

Hypothalamic kisspeptin (Kiss1) neurons express estrogen receptor α (ERα) and exert control over GnRH/LH secretion in female rodents. It has been proposed that estradiol (E2) activation of ERα in kisspeptin neurons in the arcuate nucleus (ARC) suppresses GnRH/LH secretion (negative feedback), whereas E2 activation of ERα in kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) mediates the release of preovulatory GnRH/LH surges (positive feedback). To test these hypotheses, we generated mice bearing kisspeptin cell-specific deletion of ERα (KERαKO) and treated them with E2 regimens that evoke either negative or positive feedback actions on GnRH/LH secretion.

Kisspeptin cell-specific PI3K signaling regulates hypothalamic kisspeptin expression and participates in the regulation of female fertility.

Hypothalamic kisspeptin neurons integrate and translate cues from the internal and external environments that regulate gonadotropin-releasing hormone (GnRH) secretion and maintain fertility in mammals. However, the intracellular signaling pathways utilized to translate such information into changes in kisspeptin expression, release, and ultimately activation of the kisspeptin-receptive GnRH network have not yet been identified. PI3K is an important signaling node common to many peripheral factors known to regulate kisspeptin expression and GnRH release.

PI3K: An Attractive Candidate for the Central Integration of Metabolism and Reproduction.

In neurons, as in a variety of other cell types, the enzyme phosphatidylinositol-3-kinase (PI3K) is a key intermediate that is common to the signaling pathways of a number of peripheral metabolic cues, including insulin and leptin, which are well known to regulate both metabolic and reproductive functions. This review article will explore the possibility that PI3K is a key integrator of metabolic and neural signals regulating gonadotropin releasing hormone (GnRH)/luteinizing hormone (LH) release and explore the hypothesis that this enzyme is pivotal in many disorders where gonadotropin release is at risk. Although the mechanisms mediating the influence of metabolism and nutrition on fertility are currently unclear, the strong association between metabolic disorders and infertility is undeniable.

Timing and completion of puberty in female mice depend on estrogen receptor alpha-signaling in kisspeptin neurons.

Puberty onset is initiated by activation of neurons that secrete gonadotropin-releasing hormone (GnRH). The timing and progression of puberty may depend upon temporal coordination of two opposing central mechanisms--a restraint of GnRH secretion before puberty onset, followed by enhanced stimulation of GnRH release to complete reproductive maturation during puberty. Neuronal estrogen receptor α (ERα) has been implicated in both controls; however, the underlying neural circuits are not well understood.

Male-biased effects of gonadotropin-releasing hormone neuron-specific deletion of the phosphoinositide 3-kinase regulatory subunit p85alpha on the reproductive axis.

GnRH neurosecretion is subject to regulation by insulin, IGF-I, leptin, and other neuroendocrine modulators whose effects may be conveyed by activation of phosphoinositide 3-kinase (PI3K)-mediated pathways. It is not known, however, whether any of these regulatory actions are exerted directly, via activation of PI3K in GnRH neurons, or whether they are primarily conveyed via effects on afferent circuitries governing GnRH neurosecretion. To investigate the role of PI3K signaling in GnRH neurons, we used conditional gene targeting to ablate expression of the major PI3K regulatory subunit, p85alpha, in GnRH neurons.

Fasting-induced suppression of LH secretion does not require activation of ATP-sensitive potassium channels.

Reproductive hormone secretions are inhibited by fasting and restored by feeding. Metabolic signals mediating these effects include fluctuations in serum glucose, insulin, and leptin. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose sensing and many actions of insulin and leptin in neurons, we assessed their role in suppressing LH secretion during food restriction.

Neuroendocrine consequences of androgen excess in female rodents.

Androgens exert significant organizational and activational effects on the nervous system and behavior. Despite the fact that female mammals generally produce low levels of androgens, relative to the male of the same species, increasing evidence suggests that androgens can exert profound effects on the normal physiology and behavior of females during fetal, neonatal, and adult stages of life. This review examines the effects of exposure to androgens at three stages of development--as an adult, during early postnatal life and as a fetus, on reproductive hormone secretions in female rats.

Ovarian steroids stimulate adenosine triphosphate-sensitive potassium (KATP) channel subunit gene expression and confer responsiveness of the gonadotropin-releasing hormone pulse generator to KATP channel modulation.

The ATP-sensitive potassium (K(ATP)) channels couple intracellular metabolism to membrane potential. They are composed of Kir6.x and sulfonylurea receptor (SUR) subunits and are expressed in hypothalamic neurons that project to GnRH neurons.

Regulation of KATP channel subunit gene expression by hyperglycemia in the mediobasal hypothalamus of female rats.

The ATP-sensitive potassium (K(ATP)) channels are gated by intracellular adenine nucleotides coupling cell metabolism to membrane potential. Channels comprised of Kir6.2 and SUR1 subunits function in subpopulations of mediobasal hypothalamic (MBH) neurons as an essential component of a glucose-sensing mechanism in these cells, wherein uptake and metabolism of glucose leads to increase in intracellular ATP/ADP, closure of the channels, and increase in neuronal excitability.

Estrogen receptors in neuropeptide Y neurons: at the crossroads of feeding and reproduction.

Hypothalamic neuropeptide Y (NPY) neurons function as physiological integrators in at least two different neuroendocrine systems - one governing feeding and the other controlling reproduction. Estrogen might modulate both systems by regulating NPY gene expression; it might reduce food intake by suppressing NPY expression, and evoke reproductive hormone surges by stimulating it. How can estrogen exert opposing effects in an ostensibly homogeneous NPY neuronal population? Recent work with immortalized NPY-producing cells suggests that the ratio of estrogen receptor alpha:estrogen receptor beta can determine the direction and temporal pattern of transcriptional responses to estrogen.

The role of progestin receptors and the mitogen-activated protein kinase pathway in delta opioid receptor facilitation of female reproductive behaviors.

The present study investigated the role of the progestin receptor (PR) and the mitogen-activated protein kinase (MAPK) pathway in the facilitation of lordosis behavior by the delta opioid receptor agonist [D-Pen(2), D-Pen(5)]-enkephalin (DPDPE). Ovariectomized, estrogen-primed rats were treated with the PR antagonist RU486 or the MAPK inhibitor PD98059 prior to intraventricular (icv) infusion of DPDPE. Both RU486 and PD98059 blocked receptive and proceptive behaviors induced by DPDPE at 60 min, and RU486 continued to inhibit estrous behavior at 90 min.

Participation of growth factor signal transduction pathways in estradiol facilitation of female reproductive behavior.

Estradiol (E(2)) regulates female reproductive behavior (lordosis) by acting on estrogen-sensitive neurons. We recently showed that E(2) facilitation of lordosis behavior requires concurrent activation of brain IGF-I receptors. The present study confirmed this finding and sought to identify the downstream signaling pathways involved in estrogen/IGF-I priming of lordosis.

Estrogen modulation of mu-opioid receptor-stimulated [35S]-GTP-gamma-S binding in female rat brain visualized by in vitro autoradiography.

The mu-opioid receptor (OR) is involved in several aspects of female reproductive neuroendocrinology, such as the control of gonadotropin release and the display of lordosis behavior. Even though the neuroendocrine events modulated by mu-ORs are steroid hormone-dependent, few studies have shown how steroid hormones such as estrogen and/or progesterone can affect mu-OR function. Therefore, the present study investigated if in vivo estrogen or estrogen plus progesterone treatment of ovariectomized (OVX) rats affects mu-OR coupling to its G proteins.

The role of delta-opioid receptors in estrogen facilitation of lordosis behavior.

The present study investigated the role of delta-opioid receptors (ORs) in estrogen facilitation of female rat reproductive behavior (lordosis). Infusion of 2 microg of the selective delta-OR agonist [D-Pen(2),D-Pen(5)]-enkephalin (DPDPE), into the third ventricle facilitated lordosis behavior in ovariectomized (OVX) rats injected with estrogen (E) 48 and 24 h before behavioral testing. Pretreatment with the selective delta-OR antagonist naltrindole (NTDL) blocked DPDPE effects on lordosis behavior.

Activation of mu-opioid receptors inhibits lordosis behavior in estrogen and progesterone-primed female rats.

The present study investigated the effect of highly selective mu-opioid receptor (OR) agonists on lordosis behavior in ovariectomized rats treated with 3 microg of estradiol benzoate followed 48 h later by 200 microg of progesterone. Ventricular infusion of the endogenous mu-OR agonists endomorphin-1 and -2 suppressed receptive behavior in a time- and dose-dependent fashion. At 6 microg, both endomorphin-1 and -2 inhibited lordosis behavior within 30 min.