Hormone Therapy in Menopause.

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.

Effects of kisspeptin on diabetic rat platelets.

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 effect of kisspeptin on the regulation of vascular tone.

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.

[Prolactin and its receptor: From animal models to pituitary pathophysiology]. / La prolactine et son récepteur : Des modèles animaux à la physiopathologie hypophysaire.

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.

Title: La prolactine et son récepteur : Des modèles animaux à la physiopathologie hypophysaire. Abstract: La prolactine (PRL), hormone de la lactation par excellence, est majoritairement synthétisée et sécrétée par les cellules lactotropes de l'antéhypophyse. Ses actions sont médiées par le récepteur transmembranaire de la prolactine (PRLR). Alors que plus de 300 fonctions différentes ont été attribuées à cette hormone selon les espèces, son rôle chez l'Homme reste limité au développement de la glande mammaire et à l'allaitement. Les pathologies en lien avec la PRL sont essentiellement celles rencontrées en cas d'hypersécrétion de cette hormone. En effet, l'hyperprolactinémie entraîne l'altération du fonctionnement de l'axe gonadotrope chez l'homme comme chez la femme. Ainsi, l'hyperprolactinémie est une étiologie fréquente d'hypogonadisme hypogonadotrope acquis et l'une des principales causes d'anovulation et d'infertilité chez la femme. Ces dernières années, les études de modèles murins invalidés pour le PRLR, de manière globale ou conditionnelle dans l'hypophyse, ont permis d'apporter de nouveaux éléments dans la compréhension de la régulation des axes gonadotrope et lactotrope. Il est maintenant démontré que la prolactine exerce des actions autocrines ou paracrines sur les cellules lactotropes in vivo. Une des avancées majeures a été de mieux comprendre, à l'aide des modèles murins, l'impact de l'hyperprolactinémie sur l'axe gonadotrope. C'est ainsi qu'il a pu être établi que, comme chez les rongeurs, l'hypogonadisme hypogonadotrope chez les patientes atteintes d'hyperprolactinémie est médié par un déficit de sécrétion de kisspeptine hypothalamique, et que l'axe gonadotrope peut être restauré par l'administration intraveineuse de kisspeptine. Les mécanismes de tumorigenèse lactotrope des animaux Prlr −/− restent cependant incomplètement compris et transposables dans l'espèce humaine, puisque, jusqu'à présent, l'unique patiente porteuse d'une mutation bi-allélique perte de fonction du PRLR ayant fait l'objet d'une publication présentait une imagerie hypophysaire sans anomalie.

[Hot flushes and breast cancer with positive hormone receptors: Mechanisms and management]. / Bouffées de chaleur et cancer du sein avec récepteurs hormonaux positifs : mécanismes et prise en charge.

Breast cancer is the most frequently diagnosed cancer in women and the first cause of cancer death in France. Among the different subtypes of breast cancer, the predominant form is characterized by positive hormone receptors (more than 70% of breast cancers). Hormone therapy thus plays a key role in the strategy of management of these cancers both in adjuvant and metastatic situations. The two types of adjuvant hormone therapy used are selective estrogen receptor modulators and aromatase inhibitors. Fulvestrant, an anti-estrogen, is used alone or in combination with other molecules in metastatic situations. Hot flashes are one of the symptoms most frequently reported by patients under hormone therapy. Hormone replacement therapy, which is currently the most effective treatment for hot flashes, is contraindicated in patients with a personal history of breast cancer. Various therapeutic classes of drugs have been tested in this indication but without real efficacy in the various studies carried out to date, and moreover associated with non-negligible side effects. The recent discovery of the implication of the kisspeptin system located at the hypothalamic level in the mechanism of genesis of hot flashes opens the way to possible new symptomatic treatments for hot flashes. Neurokinin 3 receptor antagonists have shown encouraging preliminary results in postmenopausal cancer-free patients and could be considered in patients in hormonal therapy for breast cancer. Broader additional studies are needed to confirm these initial results.

Contrôle de l'axe gonadotrope : nouveaux aspects physiologiques et thérapeutiques: Control of the gonadotrope axis: new physiologic and therapeutic aspects.

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.