Comparison of Estetrol Exposure between Women and Mice to Model Preclinical Experiments and Anticipate Human Treatment.

Estetrol (E4) is a natural estrogen with promising therapeutic applications in humans. The European Medicines Agency and the Food and Drug Administration have approved the use of 15 mg E4/3 mg drospirenone for contraceptive indication. Phase III clinical trials with 15-20 mg E4 for the relief of climacteric complaints are currently running.

A multicenter, randomized, placebo-controlled study to select the minimum effective dose of estetrol in postmenopausal participants (E4Relief): part 2-vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life.

Objective: A phase 2 study showed that 15 mg estetrol (E4) alleviates vasomotor symptoms (VMS). Here, we present the effects of E4 15 mg on vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life.

Methods: In a double-blind, placebo-controlled study, postmenopausal participants (n = 257, 40-65 y) were randomized to receive E4 2.

A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety.

Objective: The aim of this study was to select the minimum effective dose of estetrol (E4) for the treatment of vasomotor symptoms in postmenopausal women.

Methods: This was a multicenter, randomized, double-blind, placebo-controlled study. Postmenopausal women (n = 257, of whom 32 were hysterectomized) aged 40 to 65 years, with ≥7 moderate to severe hot flushes (HFs) per day, or 50 or more moderate to severe HFs weekly, received 2.

Role for the membrane estrogen receptor alpha in the sexual differentiation of the brain.

Estrogens exert pleiotropic effects on multiple physiological and behavioral responses. Male and female sexual behavior in rodents constitutes some of the best-characterized responses activated by estrogens in adulthood and largely depend on ERα. Evidence exists that nucleus- and membrane-initiated estrogen signaling cooperate to orchestrate the activation of these behaviors both in short- and long-term.

Kisspeptin Expression in the Human Infundibular Nucleus in Relation to Sex, Gender Identity, and Sexual Orientation.

Context: Since the discovery of its central role in reproduction, our functional neuroanatomical knowledge of the hypothalamic kisspeptin system is predominantly based on animal studies. Although sex differences in kisspeptin expression have been shown in humans in adulthood, the developmental origin of this sex difference is unknown.

Objectives: Our objectives were to determine the following: 1) when during development the sex difference in kisspeptin expression in the infundibular nucleus would emerge and 2) whether this sex difference is related to sexual orientation or transsexuality.

Absence of Female-Typical Pheromone-Induced Hypothalamic Neural Responses and Kisspeptin Neuronal Activity in α-Fetoprotein Knockout Female Mice.

Pheromones induce sexually dimorphic neuroendocrine responses, such as LH secretion. However, the neuronal network by which pheromones are converted into signals that will initiate and modulate endocrine changes remains unclear. We asked whether 2 sexually dimorphic populations in the anteroventral periventricular and periventricular nuclei that express kisspeptin and tyrosine hydroxylase (TH) are potential candidates that will transduce the olfactory signal to the neuroendocrine system.

Sex differences in the neurokinin B system in the human infundibular nucleus.

Context: The recent report that loss-of-function mutations in either the gene encoding neurokinin B (NKB) or its receptor (NK3R) produce gonadotropin deficiencies in humans strongly points to NKB as a key regulator of GnRH release.

Objectives: We used NKB immunohistochemistry on postmortem human brain tissue to determine: 1) whether the human NKB system in the infundibular nucleus (INF) is sexually dimorphic; 2) at what stage in development the infundibular NKB system would diverge between men and women; 3) whether this putative structural difference is reversed in male-to-female (MtF) transsexual people; and 4) whether menopause is accompanied by changes in infundibular NKB immunoreactivity.

Methods: NKB immunohistochemical staining was performed on postmortem hypothalamus material of both sexes from the infant/pubertal period into the elderly period and from MtF transsexuals.

Rapid activation of phosphorylated mitogen-activated protein kinase after sexual stimulation in male mice.

We mapped cells immunoreactive for the phosphorylated form (p44/p42) of the mitogen-activated protein kinase (pMAPK--also known as ERK1/2) in the brain of male mice after exposure to female olfactory cues or after the display of male copulatory behaviors. Exposure to soiled bedding from estrous females or the display of coital behaviors rapidly (within 10 min) induced MAPK phosphorylation in most of the brain regions known to be involved in the processing of olfactory cues (main and accessory olfactory bulbs, amygdala, and medial preoptic area) and in the control of copulatory behavior (amygdala and medial preoptic area). MAPK phosphorylation thus seems to be a useful marker to study short-term neural activation associated with the expression of specific behaviors.

Behavioral effects of brain-derived estrogens in birds.

In birds as in other vertebrates, estrogens produced in the brain by aromatization of testosterone have widespread effects on behavior. Research conducted with male Japanese quail demonstrates that effects of brain estrogens on all aspects of sexual behavior, including appetitive and consummatory components as well as learned aspects, can be divided into two main classes based on their time course. First, estrogens via binding to estrogen receptors regulate the transcription of a variety of genes involved primarily in neurotransmission.

The underestimated role of olfaction in avian reproduction?

Until the second half of the 20th century, it was broadly accepted that most birds are microsmatic if not anosmic and unable to detect and use olfactory information. Exceptions were eventually conceded for species like procellariiforms, vultures or kiwis that detect their food at least in part based on olfactory signals. During the past 20-30 years, many publications have appeared indicating that this view is definitely erroneous.

Site-specific effects of anosmia and cloacal gland anesthesia on Fos expression induced in male quail brain by sexual behavior.

In rats, expression of the immediate early gene, c-fos observed in the brain following male copulatory behavior relates mostly to the detection of olfactory information originating from the female and to somatosensory feedback from the penis. However, quail, like most birds, are generally considered to have a relatively poorly developed sense of smell. Furthermore, quail have no intromittent organ (e.

Estradiol, a key endocrine signal in the sexual differentiation and activation of reproductive behavior in quail.

In Japanese quail, estrogen's effects on sexual behavior can be divided into three classes based on the underlying mechanisms and time-course of action and release. During embryonic life, the embryonic ovary secretes large amounts of estrogens. In contrast to what is observed in mammals where sexual differentiation essentially proceeds via masculinization of the males, in quail, females are demasculinized by their endogenous ovarian estrogens, an effect that can be blocked by injection of an aromatase inhibitor and mimicked in male embryos by an injection of estradiol.

Sexual behavior activity tracks rapid changes in brain estrogen concentrations.

Estrogens are classically viewed as hormones that bind to intracellular receptors, which then act as transcription factors to modulate gene expression; however, they also affect many aspects of neuronal functioning by rapid nongenomic actions. Brain estrogen production can be regulated within minutes by changes in aromatase (estrogen synthase) activity as a result of calcium-dependent phosphorylations of the enzyme. To determine the effects of rapid changes in estrogen availability on male copulatory behavior, we mimicked in male mice the rapid upregulation and downregulation of brain estrogen concentration that should occur after inactivation or activation of aromatase activity.

Rapid effects of aromatase inhibition on male reproductive behaviors in Japanese quail.

Non-genomic effects of steroid hormones on cell physiology have been reported in the brain. However, relatively little is known about the behavioral significance of these actions. Male sexual behavior is activated by testosterone partly through its conversion to estradiol via the enzyme aromatase in the preoptic area (POA).

The effects of aromatase inhibition on testosterone-dependent conditioned rhythmic cloacal sphincter movements in male Japanese quail.

Male Japanese quail produce a foam that, along with semen, is transferred to the quail hen during copulation. This foam has been reported to increase fertility, prolong sperm motility, and enhance sperm competition. Action of the cloacal sphincter muscles in response to visual exposure to a female produces the foam.