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Prolactin (PRL) is a polypeptide hormone that is mainly synthesized and secreted by lactotroph cells of the anterior pituitary gland. The actions of prolactin are mediated by its transmembrane receptor, PRLR. The principal role attributed to PRL is to stimulate the proliferation and differentiation of the mammary cells required for lactation, but studies of animal models have assigned more than 300 separate actions to this hormone in various species. Hyperprolactinaemia is the prototypical pathological state associated with this hormone. Indeed, hyperprolactinaemia is the most common cause of amenorrhoea due to hypogonadotropic anovulation and is one of the most prevalent endocrine causes of infertility in women. In recent years, the study of conditional or complete Prlr  -/- mouse models had improved the understanding concerning the regulation of gonadotroph and lactotroph axes. It is now demonstrated that prolactin exerts autocrine or paracrine actions on lactotroph cells in vivo. One of the major advances was to better understand, using mouse models, the impact of hyperprolactinemia on gonadotroph axis. It is now accepted that hypogonadotropic hypogonadism in patients with hyperprolactinemia is mediated by a decrease of hypothalamic kisspeptin secretion. Gonadotroph axis can be restored by intravenous administration of kisspeptin. However, the mechanisms of lactotroph tumorigenesis in Prlr  -/- animals remain incompletely understood and transposable to the human species, since the only patient with biallelic PRLR loss-of-function mutation leading to complete prolactin resistance that has been described so far did not have pituitary adenoma visible on MRI., (© Société de Biologie, 2023.)

As longevity expands, women are spending a third of their existence in menopause and beyond. The vast majority suffer from symptoms that negatively impact their quality of life. Systemic vasomotor symptoms (VMS) are the classic cluster affecting 80% of peri- and post-menopausal women. Once thought to be relatively brief, they sometimes persist more than 10 years. Compelling, yet enigmatic, is the recent finding that women with bothersome and long VMS compared with age-matched peers often have worst underlying preclinical markers of cardiovascular disease (CVD).Local vulvovaginal and urinary symptoms, now termed genitourinary syndrome of menopause (GSM), are seen in 50% of postmenopausal women, and it negatively impacts quality of life. Estrogen remains the most effective treatment for both VMS and GSM, for osteoporosis prevention, and for symptom relief as well as chronic disease prevention in women who experience premature menopause whether from primary ovarian insufficiency (POI) or iatrogenic etiologies. For women who have contraindications to estrogen therapy or who personally object, a panoply of nonhormonal modalities can be offered to treat both systemic and local menopausal symptoms. A historical review of estrogen studies reveals why its persona has vacillated from hero to villain (after the WHI) and back to hero. The "timing hypothesis" and its underlying mechanism shed light on the pleiotropic nature of estrogen. Finally reviewed is the compelling argument from notable thought-leaders that estrogen, in those without contraindications, should be considered for primary prevention of cardiovascular disease as well as the prevention of chronic disease.

Hyperglycemia, hyperlipidemia, and free radicals result in platelet activation and atherogenesis. Kisspeptin (KP) is able to regulate metabolism, hemostasis, and the development of atherosclerosis. We examined whether platelet aggregation of streptozotocin-induced diabetic rats depends on the inducer type and if KP-13 and RF-9 (a kisspeptin receptor modifier) can influence platelet function. We measured the speed and the maximum of aggregation, along with the area under the curve. Serum glucose and calcium levels and urine formation of diabetic animals increased, while the body mass and platelet count decreased. Collagen was the most effective inducer of platelet aggregation. The aggregability of nondiabetic platelets was elevated in the presence of 5 × 10 -8 mol/L KP-13. This effect was less expressed in diabetic animals. The effectivity of RF-9 was stronger than that of KP-13 in nondiabetic platelets, however it was ineffective in diabetic animals. RF-9 pre-treatment did not change the effects of 5 × 10 -8 mol/L KP-13 in either animal group. The in vivo activation of diabetic platelets, which may be due to elevated serum calcium, induces thrombocytopenia and may lead to reduced in vitro aggregability. We could not demonstrate the antagonistic effect of RF-9 against KP-13 in isolated platelets.

The endocrine and exocrine functions of the gonads are controlled by the gonadotrope axis, whose master regulator is the hypothalamic decapeptide GnRH. The Kisspeptin/Neurokinin B (Kp/NkB) neuronendocrine system is the main physiologic regulator of GnRH neurons. The Kp/NkB system is currently considered the key mediator for the hypothalamic negative feedback exerted by sex steroids and prolactin, as well as by various metabolic signals. Intrinsic alterations or regulatory abnormalities of Kp/NkB system lead to various gonadotrope axis puberty and fertility dysfunctions. Molecular inactivations of Kp/NkB system actors are associated with some forms of congenital hypogonadotropic hypogonadism without anosmia. The Kp/NkB System is also involved in a few forms of precocious puberty. Finally, the Kp/NKB system is also implicated in gonadotrope axis alterations leading to functional hypothalamic amenorrhea or hyperprolactinemia. NkB is particularly and directly involved in vasomotor menopausal hot flushes mechanism. Various Kp/NkB agonist/antagonist compounds have been developed during the last ten years, and are currently being evaluated in humans. These molecules have potential applications not only in rare genetic diseases with Kp/NkB alterations, but also in various gonadotrope axis-related diseases or in vitro fertilization. The administration of NkB antagonists in menopausal women represents a real therapeutic advance because of their impressive effect in controlling vasomotor menopausal hot flushes., (© 2017 Elsevier Masson SAS. Tous droits réservés.)

Kisspeptin has been implicated in cardiovascular control. Eicosanoids play a crucial role in the activation of platelets and the regulation of vascular tone. In the present study, we investigated the effect of kisspeptins on eicosanoid synthesis in platelets and aorta in vitro. Platelets and aorta were isolated from Wistar-Kyoto rats. After preincubation with different doses of kisspeptin, samples were incubated with [1-(14)C]arachidonic acid (0.172 pmol/mL) in tissue culture Medium 199. The amount of labeled eicosanoids was measured with liquid scintillation, after separation with overpressure thin-layer chromatography. Kisspeptin-13 stimulated the thromboxane synthesis. The dose-response curve was bell-shaped and the most effective concentration was 2.5 × 10(-8) mol/L, inducing a 27% increase. Lipoxygenase products of platelets displayed a dose-dependent elevation up to the dose of 5 × 10(-8) mol/L. In the aorta, kisspeptin-13 induced a marked elevation in the production of 6-keto-prostaglandin F1α, the stable metabolite of prostacyclin, and lipoxygenase products. Different effects of kisspeptin on cyclooxygenase and lipoxygenase products indicate that beyond intracellular Ca(2+) mobilization, other signaling pathways might also contribute to its actions. Our data suggest that kisspeptin, through the alteration of eicosanoid synthesis in platelets and aorta, may play a physiologic and (or) pathologic role in the regulation of vascular tone.