A look at the latest research

Tachykinin-Kisspeptin System’s Role in Reproduction Identified

Researchers may have identified a system that acts as a central coordinator for reproduction, according to a paper recently published in Endocrinology.
Investigators led by Victor M. Navarro, PhD, of Brigham and Women’s Hospital and Harvard Medical School, noted that the mechanisms that control kisspeptin release have become a hot topic in reproductive endocrinology, but no one has quite been able to pin down “the precise neuroendocrine events that determine the action of Kiss1 neurons and translate their message into congruent GnRH secretion.”

Kiss1 neurons were recently implicated in coexpressing neurokinin B (NKB) and dynorphin A, and NKB belongs to family of peptides, along with substance P (SP), and neurokinin A (NKA), called tachykinins. The authors wrote that NKB “has emerged as a regulator of kisspeptin release in the arcuate nucleus (ARC), whereas the roles of SP and NKA regulation remain unknown.” So Navarro and his team set out to understand the roles of SP and NKA in the central regulation of GnRH release, “as well as to determine the expression and regulation of Tac1 mRNA in the hypothalamus and localization of the tachykinin receptors, through a series of genetic, functional, and histological studies in the mouse.”

The authors presented a series of experiments: First, central infusion of specific agonists for the receptors of SP (neurokinin receptor 1, NK1R), NKA (NK2R), and NKB (NK3R) each induced gonadotropin release in adult male and ovariectomized, estradiol-replaced female mice, which was absent in Kiss1r-/- mice, indicating a kisspeptin-dependent action. The NK2R agonist, however, decreased LH (luteinizing hormone) release in ovariectomized-sham replaced females, as documented for NK3R agonists but in contrast to the NK1R agonist, which further increased LH release. Second, Tac1 (encoding SP and NKA) expression in the ARC and ventromedial nucleus was inhibited by circulating estradiol but did not colocalize with Kiss1 mRNA. Third, about half of isolated ARC Kiss1 neurons expressed Tacr1 (NK1R) and 100% Tacr3 (NK3R); for anteroventral-periventricular Kiss1 neurons and GnRH neurons, approximately one-fourth expressed Tacr1 and one-tenth Tacr3; Tacr2 (NK2R) expression was absent in all cases.

Based on these three sets of results, the researchers concluded that they had identified roles of tachykinins in the central control of GnRH release through SP and NKA, which activate Kiss1 and possibly GnRH, pointing to a better understanding of the roles of these substances in reproductive endocrinology.

Relaxin-3’s Sex-Specific Role in Food Intake

Relaxin-3 (RLN3) may play a different role in the different sexes when it comes to food intake, according to research recently published in Endocrinology.

RLN3 is mainly confined to the central nervous system, mostly in the forebrain in the parts that control food intake and stress response, and previous studies suggested that there may be sex-specific regulation of hypothalamic-pituitary-adrenal (HPA) axis activity by RLN3.

So investigators led by Elena Timofeeva, PhD, of the Centre de Recherche de l’Institut de Cardiologie et de Pneumologie de Québec, wanted to compare the acute eff ects of intracerebroventricular (icv) administration of RLN3 on food intake, body weight (BW) gain plasma corticosterone, and c-fos mRNA expression in the paraventricular hypothalamic nucleus (PVN) and corticotropinreleasing factor (CRF) mRNA expression in the PVN, central amygdala (CeA), hypothalamic medial preoptic area (MPOA), and bed nucleus of the stria terminalis (BST) in male and female rats.

The team injected RLN3 into the rats’ lateral ventricles at 25, 200, and 800 pmol concentrations, and they found that RLN3 at 25 pmol increased food intake at 30 and 60 minutes after injection in female but not male rats. They continued: “Female rats also showed higher increase in relative to BW food intake (mg/g BW) for all RLN3 concentrations at 30 minutes and for 800 pmol of RLN3 at 60 minutes. Moreover, RLN3 at 800 pmol significantly increased 24-hour BW gain in female but not male rats.

The female rats also showed significantly increased CRF mRNA expression in the BST but not PVN after 800 pmol of RLN3, and overall more sensitivity and stronger food intake increase in response to RLN3 than their male counterparts. The authors wrote that the results showed “higher sensitivity of female rats to the orexigenic effects of RLN3. In contrast, HPA axis activation in response to RLN3 was higher in male rats.” They concluded, “The differential effects of RLN3 on CRF expression in the PVN and bed nucleus of the stria terminalis may contribute to the sex-specific difference in the behavioral response.”

New Drug Approved to Treat Hypoparathyroidism

The FDA recently approved Natpara® (parathyroid hormone) as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism. The drug is a bioengineered replica of human PTH and is expected to be available in the second quarter of 2015.

The FDA approval of Natpara was supported by 12 pharmacology studies and four company-sponsored efficacy and safety studies. The pivotal Phase 3 study, known as REPLACE, was a randomized, double-blind, placebo-controlled study and the largest clinical trial conducted to date in patients with hypoparathyroidism. The study results were published in The Lancet Diabetes and Endocrinology.

“Patients with hypoparathyroidism may benefit from having a replica of the actual human parathyroid hormone molecule that they are lacking,” Tamara Vokes, MD, professor of medicine at the University of Chicago, and program director of the University of Chicago Fellowship Training Program in Diabetes, Endocrinology, and Metabolism, said in a release. “In clinical studies, Natpara has been shown to control hypocalcemia in patients with hypoparathyroidism and reduce their need for oral calcium and active vitamin D.”

Because of the potential risk of osteosarcoma, Natpara is recommended only for patients who cannot be well-controlled on calcium supplements and active forms of vitamin D alone. The drug was not studied in patients with hypoparathyroidism caused by calciumsensing receptor mutations or in patients with acute post-surgical hypoparathyroidism.

Women Diagnosed with PCOS Twice as Likely to be Hospitalized

Women diagnosed with polycystic ovary syndrome (PCOS) have an increased risk of developing heart disease, diabetes, mental health conditions, reproductive disorders, and cancer of the lining of the uterus than healthy women, according to a new study published in the Journal of Clinical Endocrinology & Metabolism.

The population-based retrospective cohort study led by Roger Hart, MD, MRCOG, FRANZCOG, CREI, of the University of Western Australia and Fertility Specialists of Western Australia, in Perth, Australia, examined health records for 2,566 women ages 15 and older who were diagnosed with PCOS during a hospital visit in Western Australia between 1997 and 2011. This population’s records were compared to hospitalization records for 25,660 women of similar ages, who were identified using voter registration records. Researchers tracked the participants’ hospitalization records until the women reached a median age of 35.8 years.

Researchers analyzing the data found women who were diagnosed with PCOS were more likely to be hospitalized for reasons unrelated to reproductive health or injury than their counterparts. Women who had PCOS were more likely to have miscarriages, ectopic pregnancies, or other gynecological conditions such as irregular menstrual periods and endometriosis. Women who had PCOS also had a higher rate of endometrial cancer or cancer of the lining of the uterus.

Women diagnosed with PCOS were hospitalized more often for mental health disorders such as depression, stress, and anxiety than other study participants. A PCOS diagnosis also was associated with a higher risk of late onset diabetes, high blood pressure, heart disease, asthma, and musculoskeletal disorders.

“We found women who have PCOS are particularly prone to developing metabolic and cardiovascular disease,” Hart says. “Since only 25 percent of the women we studied were older than 40, we anticipate the rate of diagnosis would rise as these women continue to age.”

“PCOS has profound implications for a women’s reproductive health as well as her long-term risk of chronic illness,” Hart continues. “Our study indicates women who have PCOS have twice as many hospital admissions as women without the condition. Additional health care resources should be directed to address the risks facing this population.”

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