Specialist services for management of individuals identifying as transgender in New Zealand.

AIMS: In light of the rising number of referrals to secondary level services of people who identify as transgender, and the Human Rights Commission concerns regarding the care of this group in New Zealand, we felt it was timely to determine the availability of services for people who identify as transgender and whether there are variations in management protocols. METHODS: We contacted 100 physicians involved in providing a secondary level service to care for people who identify as transgender, and asked them to complete a questionnaire about the services available in their region. This questionnaire consisted of two parts, a 'general questionnaire', which focussed on the consultants' understanding of services available locally, and a 'clinical questionnaire', which presented hypothetical clinical case histories and asked respondents to indicate how they would manage the case. RESULTS: Sixty-two of the physicians responded. Of these, 18 (45% of the 40 physicians that answered the question) believed they could access a psychological or psychiatric opinion in the public sector for a patient who identifies as transgender, whereas 28 (82% of the 34 that answered the question) knew of access in the private sector. There was a conflict of opinion on the availability of psychological and surgical services in several DHBs where there was more than one clinician responding. This may reflect the case experience of individual clinicians. There was restricted access to common surgical procedures in the public sector, and about half of respondents did not know if techniques were available locally. CONCLUSIONS: Our results support the development of specialist care services in tertiary centres in addition to the secondary services already available in New Zealand for people who identify as transgender. Development of multidisciplinary management and improved access to psychological support services for individual cases is required.

The effects of kisspeptin-54 on blood pressure in humans and plasma kisspeptin concentrations in hypertensive diseases of pregnancy.

AIMS: To investigate (i) if kisspeptin administration alters heart rate (HR) or blood pressure (BP) in healthy male and female volunteers, (ii) whether circulating plasma kisspeptin concentrations in healthy pregnant women and women with hypertensive diseases of pregnancy correlate with BP and (iii) whether women with hypertensive diseases of pregnancy have altered plasma kisspeptin concentrations. METHODS: We have previously reported the effects of administration of kisspeptin-54 on gonadotrophin secretion in healthy male and female volunteers. In these studies, cardiovascular parameters were not a primary endpoint. However, data were also collected on BP and HR for 4h post administration of kisspeptin-54. Blood samples were taken from 105 women in the third trimester of pregnancy (27 women with hypertensive diseases of pregnancy and 78 controls). Samples were assayed for plasma kisspeptin immunoreactivity (IR). RESULTS: Administration of kisspeptin was not associated with significant changes in HR or BP in healthy men or women. There was no significant correlation between plasma kisspeptin concentration and BP in healthy pregnant women or in those with hypertensive diseases of pregnancy. No significant differences in plasma kisspeptin-IR concentrations were observed between women with hypertensive diseases of pregnancy and normotensive pregnant controls, plasma kisspeptin concentrations ±SE: controls 2878 ± 157pmol l(-1) ; pregnancy-induced hypertension 2696 ± 299pmoll(-1) (95% CI vs. controls -514, 878pmoll(-1) ); pre-eclampsia 3519 ± 357 (95% CI vs. controls -1644, 362pmoll(-1) ). CONCLUSIONS: Elevation of plasma kisspeptin-IR is not associated with an alteration in BP in humans.

Bowels control brain: gut hormones and obesity.

Food intake and energy expenditure are tightly regulated by the brain, in a homeostatic process that integrates diverse hormonal, neuronal and metabolic signals. The gastrointestinal tract is an important source of such signals, which include several hormones released by specialized enteroendocrine cells. These hormones exert powerful effects on appetite and energy expenditure. This Review addresses the physiological roles of peptide YY, pancreatic polypeptide, islet amyloid polypeptide, glucagon-like peptide 1, glucagon, oxyntomodulin, cholecystokinin and ghrelin and discusses their potential as targets for the development of novel treatments for obesity.

Kisspeptin is released from human prostate cancer cell lines but plasma kisspeptin is not elevated in patients with prostate cancer.

Kisspeptin, the product of the KiSS-1 gene, inhibits metastasis and stimulates the hypothalamo-pituitary-gonadal axis. Kisspeptin is therefore a putative target in the treatment of hormone-sensitive malignancies. Prostatic carcinoma remains a significant cause of mortality despite improvements in therapy. The role of kisspeptin in prostatic carcinoma remains undefined. We therefore aimed to investigate release of kisspeptin by prostatic cancer cell lines; investigate expression of KiSS-1 in human prostate tissue; investigate whether patients with prostate carcinoma have elevated plasma kisspeptin. 1) Culture medium from prostatic carcinoma cell lines LNCaP, DU145 and PC3 was assayed for kisspeptin immunoreactivity (-IR). Kisspeptin-IR release was detectable from all three cell lines. The effect of hydroxyflutamide, gefitinib and resveratrol on kisspeptin-IR release from these cell lines was also investigated. No effect of the drugs tested on release of kisspeptin-IR was observed. 2) Expression of KiSS-1 in human prostate tissue (n=4) was investigated using in situ hybridisation. Expression of KiSS-1 was detected in human prostate tissue. 3) Plasma kisspeptin-IR was compared in 92 patients with prostatic carcinoma and 73 male controls. Kisspeptin-IR was not detected in the plasma of either patients with prostate cancer or control patients. We have therefore shown for the first time the release of kisspeptin-IR by prostatic carcinoma cell lines. We have also shown that KiSS-1 is expressed in human prostate tissue, and that circulating levels of kisspeptin-IR are not elevated in patients with prostatic carcinoma. Further work is required to determine the role of kisspeptin in the prostate.

Obesity treatment: novel peripheral targets.

Our knowledge of the complex mechanisms underlying energy homeostasis has expanded enormously in recent years. Food intake and body weight are tightly regulated by the hypothalamus, brainstem and reward circuits, on the basis both of cognitive inputs and of diverse humoral and neuronal signals of nutritional status. Several gut hormones, including cholecystokinin, glucagon-like peptide-1, peptide YY, oxyntomodulin, amylin, pancreatic polypeptide and ghrelin, have been shown to play an important role in regulating short-term food intake. These hormones therefore represent potential targets in the development of novel anti-obesity drugs. This review focuses on the role of gut hormones in short- and long-term regulation of food intake, and on the current state of development of gut hormone-based obesity therapies.

Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis.

BACKGROUND: Kisspeptin is a critical regulator of normal reproductive function. A single injection of kisspeptin in healthy human volunteers potently stimulates gonadotropin release. However, the effects of kisspeptin on gonadotropin release in women with hypothalamic amenorrhea (HA) and the effects of repeated administration of kisspeptin to humans are unknown. AIM: The aim of this study was to determine the effects of acute and chronic kisspeptin administration on gonadotropin release in women with HA. METHODS: We performed a prospective, randomized, double-blinded, parallel design study. Women with HA received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline (n = 5 per group) for 2 wk. Changes in serum gonadotropin and estradiol levels, LH pulsatility, and ultrasound measurements of reproductive activity were assessed. RESULTS: On the first injection day, potent increases in serum LH and FSH were observed after sc kisspeptin injection in women with HA (mean maximal increment from baseline within 4 h after injection: LH, 24.0 +/- 3.5 IU/liter; FSH, 9.1 +/- 2.5 IU/liter). These responses were significantly reduced on the 14th injection day (mean maximal increment from baseline within 4 h postinjection: LH, 2.5 +/- 2.2 IU/liter, P < 0.05; FSH, 0.5 +/- 0.5 IU/liter, P < 0.05). Subjects remained responsive to GnRH after kisspeptin treatment. No significant changes in LH pulsatility or ultrasound measurements of reproductive activity were observed. CONCLUSION: Acute administration of kisspeptin to women with infertility due to HA potently stimulates gonadotropin release, but chronic administration of kisspeptin results in desensitization to its effects on gonadotropin release. These data have important implications for the development of kisspeptin as a novel therapy for reproductive disorders in humans.

Differential patterns of neuronal activation in the brainstem and hypothalamus following peripheral injection of GLP-1, oxyntomodulin and lithium chloride in mice detected by manganese-enhanced magnetic resonance imaging (MEMRI).

We have used manganese-enhanced magnetic resonance imaging (MEMRI) to show distinct patterns of neuronal activation within the hypothalamus and brainstem of fasted mice in response to peripheral injection of the anorexigenic agents glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and lithium chloride. Administration of both GLP-1 and OXM resulted in a significant increase in signal intensity (SI) in the area postrema of fasted mice, reflecting an increase in neuronal activity within the brainstem. In the hypothalamus, GLP-1 administration induced a significant reduction in SI in the paraventricular nucleus and an increase in the ventromedial hypothalamic nucleus whereas OXM reduced SI in the arcuate and supraoptic nuclei of the hypothalamus. These data indicate that whilst these related peptides both induce a similar effect on neuronal activity in the brainstem they generate distinct patterns of activation within the hypothalamus. Furthermore, the hypothalamic pattern of signal intensity generated by GLP-1 closely matches that generated by peripheral injection of LiCl, suggesting the anorexigenic effects of GLP-1 may be in part transmitted via nausea circuits. This work provides a framework by which the temporal effects of appetite modulating agents can be recorded simultaneously within hypothalamic and brainstem feeding centres.

Imaging appetite-regulating pathways in the central nervous system using manganese-enhanced magnetic resonance imaging.

The global increase in obesity has led to a redoubling of efforts directed at understanding the control of energy homeostasis. Insight into the mechanisms which govern appetite regulation is central to understanding the pathophysiology of obesity and the design of effective therapeutic interventions. Exploitation of hormonal satiety signals secreted by the gut requires greater insight into their interaction with central nervous system (CNS) circuits of appetite control. Manganese-enhanced magnetic resonance imaging is a novel technique, recently adapted to investigate the effects of gut peptides on CNS appetite circuits. Using manganese ion accumulation as a marker of neuronal activity, changes in signal intensity in key appetite centres within the hypothalamus following peripheral injection of gut hormones have been demonstrated. Manganese-enhanced magnetic resonance imaging offers several advantages over methodologies currently used for the study of gut hormone interactions with the CNS and has the potential for application in fields beyond appetite regulation.

Can gut hormones control appetite and prevent obesity?

The current obesity epidemic is fuelled by the availability of highly palatable, calorie-dense food, and the low requirement for physical activity in our modern environment. If energy intake exceeds energy use, the excess calories are stored as body fat. Although the body has mechanisms that act to maintain body weight over time, they primarily defend against starvation and are less robust in preventing the development of obesity. Knowledge of this homeostatic system that controls body weight has increased exponentially over the last decade and has revealed new possibilities for the treatment of obesity and its associated comorbidities. One therapeutic target is the development of agents based on the gastrointestinal hormones that control appetite. This review discusses the hormones oxyntomodulin, peptide YY, glucagon-like peptide 1, pancreatic polypeptide, and ghrelin and their emerging potential as anti-obesity treatments.

PYY3-36 injection in mice produces an acute anorexigenic effect followed by a delayed orexigenic effect not observed with other anorexigenic gut hormones.

Peptide YY (PYY) is secreted postprandially from the endocrine L cells of the gastrointestinal tract. PYY(3-36), the major circulating form of the peptide, is thought to reduce food intake in humans and rodents via high-affinity binding to the autoinhibitory neuropeptide Y (NPY) receptor within the arcuate nucleus. We studied the effect of early light-phase injection of PYY(3-36) on food intake in mice fasted for 0, 6, 12, 18, 24, and 30 h and show that PYY(3-36) produces an acute anorexigenic effect regardless of the duration of fasting. We also show evidence of a delayed orexigenic effect in ad libitum-fed mice injected with PYY(3-36) in the early light phase. This delayed orexigenic effect also occurs in mice administered a potent analog of PYY(3-36), d-Allo Ile(3) PYY(3-36), but not following injection of other anorectic agents (glucagon-like-peptide 1, oxyntomodulin, and lithium chloride). Early light-phase injection of PYY(3-36) to ad libitum-fed mice resulted in a trend toward increased levels of hypothalamic NPY and agouti-related peptide mRNA and a decrease in proopiomelanocortin mRNA at the beginning of the dark phase. Furthermore, plasma levels of ghrelin were increased significantly, and there was a trend toward decreased plasma PYY(3-36) levels at the beginning of the dark phase. These data indicate that PYY(3-36) injection results in an acute anorexigenic effect followed by a delayed orexigenic effect.

Gastrointestinal satiety signals.

The increasing prevalence of obesity worldwide has imparted renewed impetus to the study of the mechanisms of appetite regulation. Digestion and nutrient absorption take place in the gastrointestinal (GI) tract, whereas food intake is controlled by neuronal circuits in the central nervous system. The need for gut-brain cross talk is therefore clear. It is now recognized that hormones released into the circulation from the GI tract in response to nutritional stimuli form a key component of this gut-brain axis. Peptides such as glucagon-like peptide-1, oxyntomodulin, pancreatic polypeptide, and peptide YY3-36 reduce food intake in both animal models and in humans. Physiologically, such peptides are thought to act as satiety signals and meal terminators. Here, we review the current state of the field of the effects of gut hormone action on appetite control.

The temporal sequence of gut peptide CNS interactions tracked in vivo by magnetic resonance imaging.

Hormonal satiety signals secreted by the gut play a pivotal role in the physiological control of appetite. However, therapeutic exploitation of the gut-brain axis requires greater insight into the interaction of gut hormones with CNS circuits of appetite control. Using the manganese ion (Mn2+) as an activity-dependent magnetic resonance imaging (MRI) contrast agent, we showed an increase in signal intensity (SI) in key appetite-regulatory regions of the hypothalamus, including the arcuate, paraventricular, and ventromedial nuclei, after peripheral injection of the orexigenic peptide ghrelin. Conversely, administration of the anorexigenic hormone peptide YY(3-36) caused a reduction in SI. In both cases, the changes in SI recorded in the hypothalamic arcuate nucleus preceded the effect of these peptides on food intake. Intravenous Mn2+ itself did not significantly alter ghrelin-mediated expression of the immediate early gene product c-Fos, nor did it cause abnormalities of behavior or metabolic parameters. We conclude that manganese-enhanced MRI constitutes a powerful tool for the future investigation of the effects of drugs, hormones, and environmental influences on neuronal activity.

Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase of the menstrual cycle in women.

CONTEXT: Kisspeptin, the endogenous ligand of the G protein-coupled receptor 54, is a key regulator of the hypothalamo-pituitary-gonadal (HPG) axis. GPR54-null mice exhibit reproductive dysfunction, and exogenous kisspeptin potently stimulates the HPG axis in rodents, primates, and human males. The effects of kisspeptin administration to human females are unknown. OBJECTIVE: Our objective was to investigate the effects of kisspeptin on LH release during the menstrual cycle in female volunteers. DESIGN: Bolus sc kisspeptin-54 was administered to female volunteers, and plasma gonadotropins were measured. SETTING: The study took place at a hospital clinical research facility. VOLUNTEERS: Subjects were healthy female volunteers with regular menstrual cycles. INTERVENTION: 1) Volunteers received a sc bolus injection of kisspeptin-54 (0, 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 nmol/kg; n = 3-4 per dose) in the follicular phase; and 2) volunteers (n = 8) received a sc bolus injection of either kisspeptin-54 (0.4 nmol/kg) or saline in random order during each phase of the menstrual cycle. MAIN OUTCOME MEASURES: Plasma gonadotropins were measured. RESULTS: 1) Kisspeptin-54 caused a dose-dependent increase in mean LH over time at doses from 0.2-6.4 nmol/kg. 2) Kisspeptin-54 increased plasma LH compared with saline injection in all phases of the cycle. The effect of kisspeptin was greatest in the preovulatory phase and least in the follicular phase of the cycle [mean increase in LH over baseline (IU/liter) +/- sem for follicular phase was 0.12 +/- 0.17; preovulatory phase, 20.64 +/- 2.91 (P < 0.001 vs. follicular phase); luteal phase, 2.17 +/- 0.79 (P < 0.01 vs. follicular phase)]. CONCLUSION: Elevation of plasma kisspeptin in human females potently stimulates LH release in the preovulatory phase and provides a novel mechanism for manipulation of the HPG axis in women.

Differential hypothalamic neuronal activation following peripheral injection of GLP-1 and oxyntomodulin in mice detected by manganese-enhanced magnetic resonance imaging.

The anorexigenic gut hormones oxyntomodulin (OXM) and glucagon-like peptide-1 (GLP-1) are thought to physiologically regulate appetite and food intake. Using manganese-enhanced magnetic resonance imaging, we have shown distinct patterns of neuronal activation in the hypothalamus in response to intraperitoneal injections into fasted mice of 900 and 5400 nmol/kg OXM or 900 nmol/kg GLP-1. Administration of OXM at either dose resulted in a reduced rate of signal enhancement, reflecting a reduction in neuronal activity, in the arcuate, paraventricular, and supraoptic nuclei of the hypothalamus. Conversely, GLP-1 caused a reduction in signal enhancement in the paraventricular nucleus only and an increase in the ventromedial hypothalamic nucleus. Our data show that these two apparently similar peptides generate distinct patterns of activation within the hypothalamus, suggesting that GLP-1 and OXM may act via different hypothalamic pathways.

Plasma kisspeptin is raised in patients with gestational trophoblastic neoplasia and falls during treatment.

Kisspeptin is a 54-amino acid peptide, encoded by the anti-metastasis gene KiSS-1, that activates G protein-coupled receptor 54 (GPR54). The kisspeptin-GPR54 system is critical to normal reproductive development. KiSS-1 gene expression is increased in the human placenta in normal and molar pregnancies. Circulating kisspeptin is dramatically increased in normal pregnancy, but levels in GTN have not previously been reported. The present study was designed to determine whether plasma kisspeptin levels are altered in patients with malignant GTN. Thirty-nine blood samples were taken from 11 patients with malignant GTN at presentation during and after chemotherapy. Blood was also sampled from nonpregnant and pregnant volunteers. Plasma kisspeptin IR and hCG concentrations were measured. Plasma kisspeptin IR concentration in nonpregnant (n = 16) females was <2 pmol/l. Plasma kisspeptin IR in females was 803 +/- 125 pmol/l in the first trimester of pregnancy (n = 13), 2,483 +/- 302 pmol/l in the third trimester of pregnancy (n = 7), and <2 pmol/l on day 15 postpartum (n = 7). Plasma kisspeptin IR and hCG concentrations in patients with malignant GTN were elevated at presentation and fell during and after treatment with chemotherapy in each patient (mean plasma kisspeptin IR: prechemotherapy 1,363 +/- 1,076 pmol/l vs. post-chemotherapy <2 pmol/l, P < 0.0001; mean plasma hCG: prechemotherapy 227,191 +/- 152,354 U/l vs. postchemotherapy 2 U/l, P < 0.0001). Plasma kisspeptin IR strongly positively correlated with plasma hCG levels (r(2) = 0.99, P < 0.0001). Our results suggest that measurement of plasma kisspeptin IR may be a novel tumor marker in patients with malignant GTN.

Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males.

CONTEXT: Mutation of the G protein-coupled receptor 54 is associated with a failure of reproductive function. The endogenous neuropeptide agonist for G protein-coupled receptor 54, kisspeptin, potently stimulates the hypothalamic-pituitary-gonadal axis in rodents and primates. OBJECTIVE: The present study was designed to determine the effects of elevating circulating kisspeptin levels on LH, FSH, and testosterone in male volunteers. DESIGN: This was a double-blind, placebo-controlled, crossover study. SETTING: This was a hospital-based study. PARTICIPANTS: Male volunteers (n = 6) were recruited. INTERVENTIONS: Each volunteer received a 90-min i.v. infusion of kisspeptin-54 (4 pmol/kg x min) and a control infusion of saline (0.9%) in random order. MAIN OUTCOME MEASURE: Plasma LH, FSH, and testosterone concentrations were measured. RESULTS: Kisspeptin-54 infusion significantly increased plasma LH, FSH, and testosterone concentrations compared with saline infusion (mean 90-min LH: kisspeptin, 10.8 +/- 1.5 vs. saline, 4.2 +/- 0.5 U/liter, P < 0.001; mean 90-min FSH: kisspeptin, 3.9 +/- 0.7 vs. saline, 3.2 +/- 0.6 U/liter, P < 0.001; mean 180-min testosterone: kisspeptin, 24.9 +/- 1.7 vs. saline, 21.7 +/- 2.2 nmol/liter, P < 0.001). The plasma half-life of kisspeptin-54 was calculated to be 27.6 +/- 1.1 min. The mean metabolic clearance rate was 3.2 +/- 0.2 ml/kg x min, and the volume of distribution was 128.9 +/- 12.5 ml/kg. CONCLUSION: Elevation of plasma concentrations of kisspeptin in human males significantly increases circulating LH, FSH, and testosterone levels. Kisspeptin infusion provides a novel mechanism for hypothalamic-pituitary-gonadal axis manipulation in disorders of the reproductive system.