Publications
118 results found
Comninos A, Demetriou L, Wall M, et al., 2018, Modulations of human resting brain connectivity by Kisspeptin enhance sexual and emotional Functions, JCI insight, Vol: 3, Pages: 1-11, ISSN: 2379-3708
BACKGROUND. Resting brain connectivity is a crucial component of human behavior demonstrated by disruptions in psychosexual and emotional disorders. Kisspeptin, a recently identified critical reproductive hormone, can alter activity in certain brain structures but its effects on resting brain connectivity and networks in humans remain elusive.METHODS. We determined the effects of kisspeptin on resting brain connectivity (using functional neuroimaging) and behavior (using psychometric analyses) in healthy men, in a randomized double-blinded 2-way placebo-controlled study.RESULTS. Kisspeptin’s modulation of the default mode network (DMN) correlated with increased limbic activity in response to sexual stimuli (globus pallidus r = 0.500, P = 0.005; cingulate r = 0.475, P = 0.009). Furthermore, kisspeptin’s DMN modulation was greater in men with less reward drive (r = –0.489, P = 0.008) and predicted reduced sexual aversion (r = –0.499, P = 0.006), providing key functional significance. Kisspeptin also enhanced key mood connections including between the amygdala-cingulate, hippocampus-cingulate, and hippocampus–globus pallidus (all P < 0.05). Consistent with this, kisspeptin’s enhancement of hippocampus–globus pallidus connectivity predicted increased responses to negative stimuli in limbic structures (including the thalamus and cingulate [all P < 0.01]).CONCLUSION. Taken together, our data demonstrate a previously unknown role for kisspeptin in the modulation of functional brain connectivity and networks, integrating these with reproductive hormones and behaviors. Our findings that kisspeptin modulates resting brain connectivity to enhance sexual and emotional processing and decrease sexual aversion, provide foundation for kisspeptin-based therapies for associated disorders of body and mind.
Abbara A, Clarke S, Eng PC, et al., 2018, A SINGLE BOLUS OF THE KISSPEPTIN ANALOGUE, MVT-602, INDUCES A MORE PROLONGED LH SURGE THAN KISSPEPTIN-54 DURING THE FOLLICULAR PHASE OF HEALTHY WOMEN, 74th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM), Publisher: ELSEVIER SCIENCE INC, Pages: E103-E103, ISSN: 0015-0282
Mills EGA, Dhillo WS, Comninos AN, 2018, Kisspeptin and the control of emotions, mood and reproductive behaviour, J Endocrinol, Vol: 239, Pages: R1-R12
Reproduction is fundamental for the survival of all species and requires meticulous synchronisation of a diverse complement of neural, endocrine and related behaviours. The reproductive hormone kisspeptin (encoded by the KISS1/Kiss1 gene) is now a well-established orchestrator of reproductive hormones, acting upstream of gonadotrophin-releasing hormone (GnRH) at the apex of the hypothalamic–pituitary–gonadal (HPG) reproductive axis. Beyond the hypothalamus, kisspeptin is also expressed in limbic and paralimbic brain regions, which are areas of the neurobiological network implicated in sexual and emotional behaviours. We are now forming a more comprehensive appreciation of extra-hypothalamic kisspeptin signalling and the complex role of kisspeptin as an upstream mediator of reproductive behaviours, including olfactory-driven partner preference, copulatory behaviour, audition, mood and emotion. An increasing body of research from zebrafish to humans has implicated kisspeptin in the integration of reproductive hormones with an overall positive influence on these reproductive behaviours. In this review, we critically appraise the current literature regarding kisspeptin and its control of reproductive behaviour. Collectively, these data significantly enhance our understanding of the integration of reproductive hormones and behaviour and provide the foundation for kisspeptin-based therapies to treat related disorders of body and mind.
Abbara A, Clarke S, Eng PC, et al., 2018, Clinical and biochemical characteristics of patients presenting with pituitary apoplexy, Endocrine Connections, Vol: 7, Pages: 1058-1066, ISSN: 2049-3614
PurposeTo review the clinical and biochemical characteristics and clinical outcome of patients presenting with pituitary apoplexy to a tertiary centre.MethodsWe retrospectively reviewed the clinical features, predisposing factors, biochemistry and clinical outcome of patients presenting with pituitary apoplexy to Imperial College Healthcare NHS Trust between 1991 and 2015.ResultsWe identified 64 patients with pituitary apoplexy (more complete clinical records were available in 52 patients). The median age at presentation was 46.7 years (IQR 31.5–57.0 years). Pituitary apoplexy was the first presentation of pituitary disease in 38/52 of patients and predisposing factors were identified in 28/52. Pituitary apoplexy predominantly occurred in patients with non-functioning pituitary adenomas (47/52). Headache was most commonly described as sudden onset, severe, lateralising to the frontal or temporal regions. Symptoms of meningeal irritation were reported in 7/18 and visual abnormalities in 22/35. A pre-treatment serum cortisol <100 nmol/L was recorded in 12/31 of patients. All patients with visual disturbance had some resolution of their visual symptoms whether managed surgically (14/14) or conservatively (5/5), although pituitary endocrine function did not fully recover in any patient.ConclusionsIn conclusion, these data describe the clinical features of pituitary apoplexy to aid the clinician in diagnosing this rare emergency presentation of pituitary disease. Prospective multicentre studies of the presentation of pituitary apoplexy are required to further characterise presentation and outcomes.
Mills EG, Dhillo WS, Comninos AN, 2018, Kisspeptin and the control of emotions, mood and reproductive behaviour, Journal of Endocrinology, Vol: 239, Pages: R1-R12, ISSN: 1479-6805
Reproduction is fundamental for the survival of all species and requires meticulous synchronisation of a diverse complement of neural, endocrine and related behaviours. The reproductive hormone kisspeptin (encoded by the KISS1/kiss1 gene), is now a well-established orchestrator of reproductive hormones, acting upstream of gonadotrophin releasing hormone (GnRH) at the apex of the hypothalamic-pituitary-gonadal (HPG) reproductive axis. Beyond the hypothalamus, kisspeptin is also expressed in limbic and paralimbic brain regions, which are areas of the neurobiological network implicated in sexual and emotional behaviours. We are now forming a more comprehensive appreciation of extra-hypothalamic kisspeptin signalling and the complex role of kisspeptin as an upstream mediator of reproductive behaviours, including olfactory-driven partner preference, copulatory behaviour, audition, mood and emotion. An increasing body of research from zebrafish to humans has implicated kisspeptin in the integration of reproductive hormones with an overall positive influence on these reproductive behaviours. In this review, we critically appraise the current literature regarding kisspeptin and its control of reproductive behaviour. Collectively, these data significantly enhance our understanding of the integration of reproductive hormones and behaviour and provide the foundation for kisspeptin-based therapies to treat related disorders of body and mind.
Abbara A, Clarke S, Nesbitt A, et al., 2018, Interpretation of serum gonadotropin levels in hyperprolactinemia, Neuroendocrinology, Vol: 107, Pages: 105-113, ISSN: 0028-3835
Background/Aims: Hyperprolactinemia is a common cause of amenorrhea due to hypogonadotropic hypogonadism. Prolactin is hypothesized to impede the reproductive axis through an inhibitory action at the hypothalamus. However, limited data exists to aid the interpretation of serum gonadotropins in the context of hyperprolactinemia. Methods: Serum gonadotropin values were reviewed in 243 patients with elevated serum monomeric prolactin due to discrete etiologies at a tertiary reproductive endocrine centre between 2012 and 2015. The cause of hyperprolactinemia was categorized by an experienced endocrinologist / pituitary multidisciplinary team, unless superseded by histology. The most frequently encountered diagnoses were Microprolactinoma (n=88), Macroprolactinoma (n=46), Non-Functioning Pituitary Adenoma (NFPA) (n=72), Drug-Induced Hyperprolactinemia (DIH) (n=22) and Polycystic Ovarian Syndrome (PCOS) (n=15). Results: In patients with prolactinoma and modestly raised serum prolactin levels (<4000 mU/L), increasingly FSH-predominant gonadotropin values were observed with rising prolactin level, consistent with a progressive reduction in hypothalamic GnRH pulsatility. Patients with prolactinoma and higher prolactin values (>4000 mU/L) were more likely to have a reduction in serum levels of both FSH and LH, consistent with direct pituitary gonadotrope dysfunction. Patients with macroadenoma and extremes of serum gonadotropin values (either serum FSH or LH >8 IU/L) were more likely to have NFPA than prolactinoma. Patients with polycystic ovarian syndrome (PCOS) and hyperprolactinemia had LH-predominant secretion in keeping with increased GnRH pulsatility despite a raised prolactin level. Conclusion: The pattern of gonadotropin secretion in patients may reflect the etiology of hyperprolactinemia.
Yang L, Comninos AN, Dhillo WS, 2018, Intrinsic links among sex, emotion, and reproduction, Cellular and Molecular Life Sciences, Vol: 75, Pages: 2197-2210, ISSN: 1420-682X
Species survival is dependent on successful reproduction. This begins with a desire to mate, followed by selection of a partner, copulation and in monogamous mammals including humans, requires emotions and behaviours necessary to maintain partner bonds for the benefit of rearing young. Hormones are integral to all of these stages and not only mediate physiological and endocrine processes involved in reproduction, but also act as neuromodulators within limbic brain centres to facilitate the expression of innate emotions and behaviours required for reproduction. A significant body of work is unravelling the roles of several key hormones in the modulation of mood states and sexual behaviours; however, a full understanding of the integration of these intrinsic links among sexual and emotional brain circuits still eludes us. This review summarises the evidence to date and postulates future directions to identify potential psycho-neuroendocrine frameworks linking sexual and emotional brain processes with reproduction.
Abbara A, Islam R, Clarke SA, et al., 2018, Clinical parameters of ovarian hyperstimulation syndrome following different hormonal triggers of oocyte maturation in IVF treatment., Clin Endocrinol (Oxf), Vol: 88, Pages: 920-927
OBJECTIVE: Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic condition, predominantly related to the hormone used to induce oocyte maturation during IVF treatment. Kisspeptin is a hypothalamic neuropeptide that has recently been demonstrated to safely trigger final oocyte maturation during IVF treatment even in women at high risk of OHSS. However, to date, the safety of kisspeptin has not been compared to current hormonal triggers of oocyte maturation. DESIGN: We conducted a retrospective single-centre cohort study investigating symptoms and clinical parameters of early OHSS in women at high risk of OHSS (antral follicle count or total number of follicles on day of trigger ≥23) triggered with human chorionic gonadotrophin (hCG) (n = 40), GnRH agonist (GnRHa; n = 99) or kisspeptin (n = 122) at Hammersmith Hospital IVF unit, London, UK (2013-2016). RESULTS: Clinical Parameters of OHSS: Median ovarian volume was larger following hCG (138 ml) than GnRHa (73 ml; P < .0001), and in turn kisspeptin (44 ml; P < .0001). Median ovarian volume remained enlarged 20-fold following hCG, 8-fold following GnRHa and 5-fold following kisspeptin compared to prestimulation ovarian volumes. Mean (±SD) ascitic volumes were lesser following GnRHa (9 ± 44 ml) and kisspeptin (5 ± 8 ml) than hCG (62 ± 84 ml; P < .0001). Symptoms of OHSS were most frequent following hCG and least frequent following kisspeptin. Diagnosis of OHSS: The odds ratio for OHSS diagnosis was 33.6 (CI 12.6-89.5) following hCG and 3.6 (CI 1.8-7.1) following GnRHa, when compared to kisspeptin. CONCLUSION: Triggering oocyte maturation by inducing endogenous gonadotrophin release is preferable to the use of exogenous hCG in women at high risk of OHSS.
Abbara A, Narayanaswamy S, Izzi-Engbeaya C, et al., 2018, Hypothalamic response to kisspeptin and pituitary response to GnRH are preserved in healthy older men, Neuroendocrinology, Vol: 106, ISSN: 0028-3835
Background: Male testosterone levels decline by 1% per year from the age of 40yrs. Whilst a primary testicular deficit occurs, hypothalamic or pituitary dysregulation may also coexist. This study aimed to compare the hypothalamic response to kisspeptin and the pituitary response to GnRH of older men with those of young men. Methods: Following 1 hour of baseline sampling, healthy older men (n=5, mean age 59.3±2.9yrs) received a 3 hour intravenous infusion (IVI) of either: vehicle, kisspeptin-54 0.1, 0.3, 1.0nmol/kg/h, or GnRH 0.1nmol/kg/h on 5 different study days. Serum gonadotropins and total testosterone were measured every 10 minutes and compared to young men (n=5/group) (mean age 28.9±2.0yrs) with a similar BMI (24 kg/m2) who underwent the same protocol. Results: Kisspeptin and GnRH significantly stimulated serum gonadotropin release in older men compared to vehicle (P<0.001 for all groups). Gonadotropin response to kisspeptin was at least preserved in older men when compared with young men. At the highest dose of kisspeptin (1.0nmol/kg/h), a significantly greater LH (P=0.003) response was observed in older men. The FSH response to GnRH was increased in older men (P=0.002), but the LH response was similar (P=0.38). Serum testosterone rises following all doses of kisspeptin (P≤0.009) were reduced in older men. Conclusions: Our data suggests that healthy older men without late onset hypogonadism (LOH) have preserved hypothalamic response to kisspeptin and pituitary response to GnRH, but impaired testicular response. Further work is required to investigate the use of kisspeptin to identify hypothalamic deficits in men with LOH.
Comninos A, Yang L, Abbara A, et al., 2018, Frequent falls and confusion: recurrent hypoglycaemia in a patient with tuberous sclerosis complex, Clinical Case Reports, Vol: 6, Pages: 904-909, ISSN: 2050-0904
Recurrent hypoglycaemia is common, but its presentation is often insidious resulting in delays in diagnosis and significant morbidity. We describe a case of an insulinoma presenting with falls and confusion in a patient with Tuberous Sclerosis, demonstrating the importance of early hypoglycaemia identification and a potential shared molecular pathogenesis.
Lehman MN, Coolen LM, Steiner RA, et al., 2018, The 3rd World Conference on Kisspeptin, "Kisspeptin 2017: Brain and Beyond": Unresolved questions, challenges and future directions for the field, Journal of Neuroendocrinology, Vol: 30, ISSN: 0953-8194
The 3rd World Conference on Kisspeptin, “Kisspeptin 2017: Brain and Beyond” was held on 30-31 March at the Rosen Centre Hotel in Orlando, Florida, providing an international forum for multidisciplinary scientists to meet and share cutting-edge research on kisspeptin biology and its relevance to human health and disease. The meeting built upon previous world conferences focused on the role of kisspeptin and associated peptides in the control of gonadotrophin-releasing hormone (GnRH) secretion and reproduction. Based on recent discoveries, the scope of this meeting was expanded to include functions of kisspeptin and related peptides in other physiological systems, including energy homeostasis, pregnancy, ovarian and uterine function, and thermoregulation. In addition, discussions addressed the translation of basic knowledge of kisspeptin biology to the treatment of disease, with the goal of seeking consensus about the best approaches to improve human health. The 2-day meeting featured a nontraditional structure, with each day starting with poster sessions followed by lunch discussions and facilitated large-group sessions with short presentations to maximise the exchange of new, unpublished data. Topics were identified by a survey prior to the meeting, and focused on major unresolved questions, important controversies and future directions in the field. Finally, career development activities provided mentoring for trainees and junior investigators, as well as networking opportunities for those individuals with established researchers in the field. Overall, the meeting was rated as a success by attendees and covered a wide range of lively and provocative discussion topics on the changing nature of the field of “kisspeptinology” and its future.
Abbara A, Vuong LN, Ho VNA, et al., 2018, Follicle size on day of trigger most likely to yield a mature Oocyte, Frontiers in Endocrinology, Vol: 9, ISSN: 1664-2392
Objective: To identify follicle sizes on the day of trigger most likely to yield a mature oocyte following hCG, GnRH agonist (GnRHa), or kisspeptin during IVF treatment.Design: Retrospective analysis to determine the size of follicles on day of trigger contributing most to the number of mature oocytes retrieved using generalized linear regression and random forest models applied to data from IVF cycles (2014–2017) in which either hCG, GnRHa, or kisspeptin trigger was used.Setting: HCG and GnRHa data were collected at My Duc Hospital, Ho Chi Minh City, Vietnam, and kisspeptin data were collected at Hammersmith Hospital, London, UK.Patients: Four hundred and forty nine women aged 18–38 years with antral follicle counts 4–87 were triggered with hCG (n = 161), GnRHa (n = 165), or kisspeptin (n = 173).Main outcome measure: Follicle sizes on the day of trigger most likely to yield a mature oocyte.Results: Follicles 12–19 mm on the day of trigger contributed the most to the number of oocytes and mature oocytes retrieved. Comparing the tertile of patients with the highest proportion of follicles on the day of trigger 12–19 mm, with the tertile of patients with the lowest proportion within this size range, revealed increases of 4.7 mature oocytes for hCG (P < 0.0001) and 4.9 mature oocytes for GnRHa triggering (P < 0.01). Using simulated follicle size profiles of patients with 20 follicles on the day of trigger, our model predicts that the number of oocytes retrieved would increase from a mean 9.8 (95% prediction limit 9.3–10.3) to 14.8 (95% prediction limit 13.3–16.3) oocytes due to the difference in follicle size profile alone.Conclusion: Follicles 12–19 mm on the morning of trigger administration were most likely to yield a mature oocyte following hCG, GnRHa, or kisspeptin.
Prague JK, Dhillo W, Roberts R, et al., 2018, Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action, Menopause, Vol: 25, ISSN: 1530-0374
Objective: Seventy percent of postmenopausal women experience vasomotor symptoms, which can be highly disruptive and persist for years. Hormone therapy and other treatments have variable efficacy and/or side effects. Neurokinin B signaling increases in response to estrogen deficiency and has been implicated in hot flash (HF) etiology. We recently reported that a neurokinin 3 receptor (NK3R) antagonist reduces HF in postmenopausal women after 4 weeks of treatment. In this article we report novel data from that study, which shows the detailed time course of this effect.Methods: Randomized, double-blind, placebo-controlled, single-center, crossover trial of an oral NK3R antagonist (MLE4901) for vasomotor symptoms in women aged 40 to 62 years, experiencing ≥7 HF/24 hours some of which were reported as bothersome or severe (Clinicaltrials.gov NCT02668185). Thirty-seven women were randomized and included in an intention-to-treat analysis. To ascertain the therapeutic profile of MLE4901, a post hoc time course analysis was completed.Results: By day 3 of treatment with MLE4901, HF frequency reduced by 72% (95% CI, −81.3 to −63.3%) compared with baseline (51 percentage point reduction compared with placebo, P < 0.0001); this effect size persisted throughout the 4-week dosing period. HF severity reduced by 38% compared with baseline by day 3 (95% CI, −46.1 to −29.1%) (P < 0.0001 compared with placebo), bother by 39% (95% CI, −47.5 to −30.1%) (P < 0.0001 compared with placebo), and interference by 61% (95% CI, −79.1 to −43.0%) (P = 0.0006 compared with placebo); all continued to improve throughout the 4-week dosing period (to −44%, −50%, and −70%, respectively by day 28, all P < 0.0001 compared with placebo).Conclusions: NK3R antagonism rapidly relieves vasomotor symptoms without the need for estrogen exposure.
Comninos AN, Dhillo WS, 2018, Emerging Roles of Kisspeptin in Sexual and Emotional Brain Processing, NEUROENDOCRINOLOGY, Vol: 106, Pages: 195-202, ISSN: 0028-3835
- Author Web Link
- Cite
- Citations: 29
Abbara A, Clarke S, Islam R, et al., 2017, A second dose of kisspeptin safely optimizes oocyte maturation in women undergoing in IVF treatment: a phase 2 randomized controlled trial, Human Reproduction, Vol: 32, Pages: 1915-1924, ISSN: 1460-2350
STUDY QUESTIONCan increasing the duration of LH-exposure with a second dose of kisspeptin-54 improve oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS)?SUMMARY ANSWERA second dose of kisspeptin-54 at 10 h following the first improves oocyte yield in women at high risk of OHSS.WHAT IS KNOWN ALREADYKisspeptin acts at the hypothalamus to stimulate the release of an endogenous pool of GnRH from the hypothalamus. We have previously reported that a single dose of kisspeptin-54 results in an LH-surge of ~12–14 h duration, which safely triggers oocyte maturation in women at high risk of OHSS.STUDY DESIGN, SIZE, DURATIONPhase-2 randomized placebo-controlled trial of 62 women at high risk of OHSS recruited between August 2015 and May 2016. Following controlled ovarian stimulation, all patients (n = 62) received a subcutaneous injection of kisspeptin-54 (9.6 nmol/kg) 36 h prior to oocyte retrieval. Patients were randomized 1:1 to receive either a second dose of kisspeptin-54 (D; Double, n = 31), or saline (S; Single, n = 31) 10 h thereafter. Patients, embryologists, and IVF clinicians remained blinded to the dosing allocation.PARTICIPANTS/MATERIALS, SETTING, METHODSStudy participants: Sixty-two women aged 18–34 years at high risk of OHSS (antral follicle count ≥23 or anti-Mullerian hormone level ≥40 pmol/L).Setting: Single centre study carried out at Hammersmith Hospital IVF unit, London, UK.Primary outcome: Proportion of patients achieving an oocyte yield (percentage of mature oocytes retrieved from follicles ≥14 mm on morning of first kisspeptin-54 trigger administration) of at least 60%.Secondary outcomes: Reproductive hormone levels, implantation rate and OHSS occurrence.MAIN RESULTS AND THE ROLE OF CHANCEA second dose of kisspeptin-54 at 10 h following the first induced further LH-secretion at 4 h after administration. A higher proportion of patients achieved an oocyte yield ≥60% following a second dose of kisspepti
Abbara A, Clarke SA, Islam R, et al., 2017, A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of OHSS: a phase 2 randomized controlled trial, Human Reproduction, Vol: 32, Pages: 1915-1924, ISSN: 1460-2350
STUDY QUESTIONCan increasing the duration of LH-exposure with a second dose of kisspeptin-54 improve oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS)?SUMMARY ANSWERA second dose of kisspeptin-54 at 10 h following the first improves oocyte yield in women at high risk of OHSS.WHAT IS KNOWN ALREADYKisspeptin acts at the hypothalamus to stimulate the release of an endogenous pool of GnRH from the hypothalamus. We have previously reported that a single dose of kisspeptin-54 results in an LH-surge of ~12–14 h duration, which safely triggers oocyte maturation in women at high risk of OHSS.STUDY DESIGN, SIZE, DURATIONPhase-2 randomized placebo-controlled trial of 62 women at high risk of OHSS recruited between August 2015 and May 2016. Following controlled ovarian stimulation, all patients (n = 62) received a subcutaneous injection of kisspeptin-54 (9.6 nmol/kg) 36 h prior to oocyte retrieval. Patients were randomized 1:1 to receive either a second dose of kisspeptin-54 (D; Double, n = 31), or saline (S; Single, n = 31) 10 h thereafter. Patients, embryologists, and IVF clinicians remained blinded to the dosing allocation.PARTICIPANTS/MATERIALS, SETTING, METHODSStudy participants: Sixty-two women aged 18–34 years at high risk of OHSS (antral follicle count ≥23 or anti-Mullerian hormone level ≥40 pmol/L).Setting: Single centre study carried out at Hammersmith Hospital IVF unit, London, UK.Primary outcome: Proportion of patients achieving an oocyte yield (percentage of mature oocytes retrieved from follicles ≥14 mm on morning of first kisspeptin-54 trigger administration) of at least 60%.Secondary outcomes: Reproductive hormone levels, implantation rate and OHSS occurrence.MAIN RESULTS AND THE ROLE OF CHANCEA second dose of kisspeptin-54 at 10 h following the first induced further LH-secretion at 4 h after administration. A higher proportion of patients achieved an oocyte yield ≥60% following a second dose of kisspepti
Islam R, Abbara A, Clarke S, et al., 2017, Ovarian volume as a surrogate marker of ovarian recovery following ovarian stimulation with different triggers of oocyte maturation: kisspeptin, GnRH agonist and human chorionic gonadotropin, 33rd Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 457-457, ISSN: 0268-1161
Prague JK, Roberts RE, Comninos AN, et al., 2017, Neurokinin 3 receptor antagonism is a highly effective, novel treatment for menopausal hot flushes with rapid onset: a phase 2, randomised, double-blind, placebo-controlled trial, Lancet, Vol: 389, Pages: 1809-1820, ISSN: 0140-6736
BackgroundHot flushes affect 70% of menopausal women and often severely impact physical, psychosocial, sexual, and overall wellbeing. Hormone replacement therapy is effective but is not without risk. Neurokinin B signalling is increased in menopausal women, and has been implicated as an important mediator of hot flushes.MethodsThis phase 2, randomised, double-blind, placebo-controlled, single-centre, crossover trial assessed the effectiveness of an oral neurokinin 3 receptor antagonist (MLE4901) on menopausal hot flushes. Eligible participants were healthy women aged 40–62 years, having seven or more hot flushes in every 24 h of which some were reported as being severe or bothersome, who had not had a menstrual period for at least 12 months, and who had not been taking any medication shown to improve menopausal flushes in the preceding 8 weeks. Participants received 4 weeks of MLE4901 (40 mg, orally, twice daily) and placebo (orally, twice daily) in random order separated by a 2 week washout period. Randomisation was completed by a central computer, and participants were allocated to treatment number in numerical order. The primary outcome was the total number of hot flushes during the final week of both treatment periods. Analyses were by intention to treat and per protocol using generalised linear mixed models and standard crossover analysis. All analyses were prespecified in the study protocol. The trial is registered at ClinicalTrials.gov, number NCT02668185.Findings68 women were screened between Feb 3 and Oct 10, 2016, of which 37 were randomly assigned and included in an intention-to-treat analysis. 28 participants completed the trial and were included in a per-protocol analysis. MLE4901 significantly reduced the total weekly number of hot flushes by 45 percentage points (95% CI 22–67) compared with the placebo (intention-to-treat adjusted means: placebo 49·01 [95% CI 40·81–58·56] vs MLE4901 19·35 [15·99&nda
Prague JK, Roberts RE, Comninos AC, et al., 2017, Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial, Lancet, Vol: 389, Pages: 1809-1820, ISSN: 1474-547X
BackgroundHot flushes affect 70% of menopausal women and often severely impact physical, psychosocial, sexual, and overall wellbeing. Hormone replacement therapy is effective but is not without risk. Neurokinin B signalling is increased in menopausal women, and has been implicated as an important mediator of hot flushes.MethodsThis phase 2, randomised, double-blind, placebo-controlled, single-centre, crossover trial assessed the effectiveness of an oral neurokinin 3 receptor antagonist (MLE4901) on menopausal hot flushes. Eligible participants were healthy women aged 40–62 years, having seven or more hot flushes in every 24 h of which some were reported as being severe or bothersome, who had not had a menstrual period for at least 12 months, and who had not been taking any medication shown to improve menopausal flushes in the preceding 8 weeks. Participants received 4 weeks of MLE4901 (40 mg, orally, twice daily) and placebo (orally, twice daily) in random order separated by a 2 week washout period. Randomisation was completed by a central computer, and participants were allocated to treatment number in numerical order. The primary outcome was the total number of hot flushes during the final week of both treatment periods. Analyses were by intention to treat and per protocol using generalised linear mixed models and standard crossover analysis. All analyses were prespecified in the study protocol. The trial is registered at ClinicalTrials.gov, number NCT02668185.Findings68 women were screened between Feb 3 and Oct 10, 2016, of which 37 were randomly assigned and included in an intention-to-treat analysis. 28 participants completed the trial and were included in a per-protocol analysis. MLE4901 significantly reduced the total weekly number of hot flushes by 45 percentage points (95% CI 22–67) compared with the placebo (intention-to-treat adjusted means: placebo 49·01 [95% CI 40·81–58·56] vs MLE4901 19·35 [15·99&nda
Comninos A, Wall M, Demetriou L, et al., 2017, Kisspeptin modulates sexual and emotional brain processing in humans, Journal of Clinical Investigation, Vol: 127, Pages: 709-719, ISSN: 1558-8238
Background. Sex, emotion, and reproduction are fundamental and tightly entwined aspects of human behaviour. At a population level in humans, both the desire for sexual stimulation and the desire to bond with a partner are important precursors to reproduction. However, the relationships between these processes are incompletely understood. The limbic brain system has key roles in sexual and emotional behaviours, and is a likely candidate system for the integration of behaviour with the hormonal reproductive axis. We investigated the effects of kisspeptin, a recently identified key reproductive hormone, on limbic brain activity and behaviour.Methods. Using a combination of hormonal, functional neuroimaging and psychometric analyses we compared the effects of kisspeptin versus vehicle administration in 29 healthy heterosexual young men.Results. We demonstrate that kisspeptin enhances limbic brain activity specifically in response to sexual and couple-bonding stimuli. Furthermore, kisspeptin’s enhancement of limbic brain structures correlated with psychometric measures of reward, drive, mood and sexual aversion providing functional significance. In addition, kisspeptin administration attenuated negative mood.Conclusion. Collectively, our data provide evidence of a novel role for kisspeptin in the integration of sexual and emotional brain processing with reproduction in humans, and have important implications for our understanding of reproductive biology highly relevant to the current pharmacological development of kisspeptin as a potential therapeutic agent for patients with common disorders of reproductive function.
jayasena C, abbara A, comninos A, et al., 2016, Novel circulating placental markers prokineticin-1, soluble fms-like tyrosine kinase-1, soluble endoglin and placental growth factor and risk of late miscarriage, Human Reproduction, Vol: 31, Pages: 2681-2688, ISSN: 0268-1161
STUDY QUESTION Are novel circulating placental markers prokineticin-1 (PK-1), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng) and placental growth factor (PlGF) associated with late miscarriage in asymptomatic first trimester pregnant women?SUMMARY ANSWER Increased serum sFlt-1 or PlGF, but not sEng or PK-1, were significantly associated with reduced miscarriage risk after adjustment for age, BMI, gestational age, smoking and blood pressure.WHAT IS KNOWN ALREADY Abnormal placental development is observed in two-thirds of miscarriages. Identifying women at high risk of late miscarriage could help diagnose potentially treatable causes of miscarriage such as infection, thrombosis or immunological disease. Recently, the circulating placental markers PK-1, sFlt-1, sEng and PlGF have been identified; however, it is not known if circulating levels of these markers are associated with late miscarriage.STUDY DESIGN, SIZE, DURATION A single-centre observational cohort study with prospectively collected data was carried out at a tertiary care centre 2010–2012, in 993 asymptomatic pregnant women. Plasma PK-1, and serum sEng, sFlt-1 and PlGF were measured once in each patient during the antenatal booking visit, and pregnancy outcome was monitored prospectively. Less than 1% of patients were lost to follow-up. Multiples of median (MOM) levels were calculated to adjust for gestational age.PARTICIPANTS/MATERIALS, SETTING, METHODS Nine-hundred and ninety-three asymptomatic pregnant women attending antenatal clinic for a routine booking antenatal appointment were recruited to the study, of whom 12 were lost to follow-up and excluded from analysis. Of the cohort, 50 of the remaining 981 women suffered late miscarriage.MAIN RESULTS AND THE ROLE OF CHANCE Gestation-adjusted sEng, sFlt-1 and PlGF levels were 11% (P < 0.01), 36% (P < 0.001) and 30% (P < 0.001), respectively, lower in women who later suffered miscarriage compared with unaffected pregnanc
Narayanaswamy S, Prague J, Jayasena C, et al., 2016, Investigating the KNDy hypothesis in humans by co-administration of kisspeptin, neurokinin B and naltrexone in men, Journal of Clinical Endocrinology & Metabolism, Vol: 101, Pages: 3429-3436, ISSN: 1945-7197
Context: A subpopulation of hypothalamic neurons co-localise three neuropeptides namely kisspeptin, neurokinin B (NKB) and dynorphin collectively termed KNDy neurons. Animal studies suggest they interact to affect pulsatile GnRH release (KNDy hypothesis); kisspeptin stimulates, NKB modulates and dynorphin (an opioid) inhibits. Objective: To investigate the KNDy hypothesis in humans, we assessed for the first time the effects of co-administration of kisspeptin-54, NKB and an opioid receptor antagonist, naltrexone on LH pulsatility (surrogate marker for GnRH pulsatility) and gonadotropin release. Design, setting and participants: Ethically approved prospective, single-blinded placebo-controlled study. Healthy male volunteers (n=5/group) attended our research facility for 8 study visits. Intervention and main outcome measure: After 1h baseline blood sampling, participants received a different intervention at each visit: oral 50mg naltrexone (NAL), 8h intravenous infusions of vehicle, 2.56nmol/kg/h NKB (NKB), 0.1nmol/kg/h kissspeptin-54 (KP) alone and in combination. Frequent blood sampling to measure plasma gonadotropins and sex steroids was conducted and LH pulsatility was determined using blinded deconvolution analysis. Results: All kisspeptin and naltrexone containing groups potently increased LH and LH pulsatility (p<0.001 vs vehicle). NKB alone did not affect gonadotropins. NKB+KP had significantly lower increases in gonadotropins compared with kisspeptin alone (p<0.01). NAL+KP was the only group to significantly increase LH pulse amplitude (p<0.001 vs vehicle).Conclusions: Our results suggest significant interactions between the KNDy neuropeptides on LH pulsatility and gonadotropin release in humans. This has important implications for improving our understanding of GnRH pulse generation in humans.
Abbara A, Clarke S, Nesbitt A, et al., 2016, Gonadotrophin secretion is a useful adjunct in the assessment of patients with hyperprolactinaemia, Publisher: OXFORD UNIV PRESS, Pages: 98-98, ISSN: 0268-1161
Salem V, Izzi-Engbeaya C, Coello C, et al., 2016, Glucagon increases energy expenditure independently of brown adipose tissue activation in humans, Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 18, Pages: 72-81, ISSN: 1462-8902
Aims: To investigate, for a given energy expenditure (EE) rise, the differential effects of glucagon infusion and cold exposure on brown adipose tissue (BAT) activation in humans.Methods: Indirect calorimetry and supraclavicular thermography was performed in 11 healthy male volunteers before and after: cold exposure; glucagon infusion (at 23 °C); and vehicle infusion (at 23 °C). All volunteers underwent ¹⁸F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT scanning with cold exposure. Subjects with cold-induced BAT activation on ¹⁸F-FDG PET/CT (n = 8) underwent a randomly allocated second ¹⁸F-FDG PET/CT scan (at 23 °C), either with glucagon infusion (n = 4) or vehicle infusion (n = 4).Results: We observed that EE increased by 14% after cold exposure and by 15% after glucagon infusion (50 ng/kg/min; p < 0.05 vs control for both). Cold exposure produced an increase in neck temperature (+0.44 °C; p < 0.001 vs control), but glucagon infusion did not alter neck temperature. In subjects with a cold-induced increase in the metabolic activity of supraclavicular BAT on ¹⁸F-FDG PET/CT, a significant rise in the metabolic activity of BAT after glucagon infusion was not detected. Cold exposure increased sympathetic activation, as measured by circulating norepinephrine levels, but glucagon infusion did not.Conclusions: Glucagon increases EE by a similar magnitude compared with cold activation, but independently of BAT thermogenesis. This finding is of importance for the development of safe treatments for obesity through upregulation of EE.
Narayanaswamy S, Jayasena CN, Ng N, et al., 2015, Subcutaneous infusion of kisspeptin-54 stimulates gonadotrophin release in women and the response correlates with basal oestradiol levels, Clinical Endocrinology, Vol: 84, Pages: 939-945, ISSN: 1365-2265
Background and objective: Kisspeptin stimulates hypothalamic GnRH secretion resulting in gonadotrophin release and has potential as a future therapeutic. Chronic subcutaneous infusion of kisspeptin via a pump (similar to an insulin pump) may provide an alternative route of administration in the future. We investigated for the first time in humans, the gonadotrophin response to subcutaneous (SC) infusions of kisspeptin-54 in healthy women. Women are markedly more responsive to exogenous kisspeptin in the late follicular phase pre-ovulation when oestradiol levels are naturally high. Therefore we further investigated whether there was a correlation between baseline oestradiol levels and LH response to kisspeptin. Design and patients: A prospective, single-blinded placebo-controlled study. Healthy women (n=4) received an 8 hour SC infusion of kisspeptin-54 0.1, 0.3 or 1.0nmol/kg/h or saline in the early follicular phase of 4 separate menstrual cycles. Gonadotrophins and oestradiol were measured every 10 minutes during the infusions. Results: SC infusion of kisspeptin-54 increased LH and FSH. The LH response to SC infusion of kisspeptin-54 (0.3 and 1.0nmol/kg/h) positively correlated with baseline oestradiol levels (p<0.001). Further statistical analyses showed that in the 1.0nmol/kg/h group a 100pmol/L rise in baseline oestradiol was associated with a 1.0 IU/L increase in LH.Conclusions: Kisspeptin administered via a SC infusion could be a viable future therapeutic route of administration for patients with infertility. Baseline oestradiol levels may be an important determinant of the gonadotropin response to kisspeptin treatment in women and should be taken into consideration when evaluating gonadotrophin response.
Abbara A, Jayasena CN, Christopoulos G, et al., 2015, Efficacy of kisspeptin-54 to trigger oocyte maturation in women at high risk of OHSS during IVF therapy, Journal of Clinical Endocrinology and Metabolism, Vol: 100, Pages: 3322-3331, ISSN: 0368-1610
Context:In Vitro Fertilization (IVF) treatment is an effective therapy for infertility, but can result in the potentially life-threatening complication ‘ovarian hyperstimulation syndrome’ (OHSS).Objective:To investigate whether kisspeptin-54 can be used to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.Design:Phase 2 multi-dose open label randomized clinical trial carried out during 2013–2014.Setting:Hammersmith Hospital IVF unit, London, UK.Patients:Sixty women at high risk of developing OHSS Intervention:Following a standard recombinant FSH/GnRH antagonist protocol, patients were randomized to receive a single injection of kisspeptin-54 to trigger oocyte maturation using an adaptive design for dose allocation (3.2nmol/kg, n=5; 6.4nmol/kg, n=20; 9.6nmol/kg, n=15; 12.8nmol/kg, n=20). Oocytes were retrieved 36hrs after kisspeptin-54 administration, assessed for maturation, and fertilized by intra-cytoplasmic sperm injection (ICSI) with subsequent transfer of one or two embryos. Women were routinely screened for the development of OHSS.Main Outcome Measure:Oocyte maturation was measured by oocyte yield (percentage of mature oocytes retrieved from follicles ≥14mm on ultrasound). Secondary outcomes include rates of OHSS and pregancy. Results:Oocyte maturation occurred in 95% of women. Highest oocyte yield (121%) was observed following 12.8nmol/kg kisspeptin-54, which was +69% (CI -16%,+153%) greater than following 3.2nmol/kg. At all doses of kisspeptin-54, biochemical pregnancy, clinical pregnancy and live birth rates per transfer (n=51) were 63%, 53% and 45%, respectively. Highest pregnancy rates were observed following 9.6nmol/kg kisspeptin-54 (85%, 77% and 62%, respectively). No woman developed moderate, severe or critical OHSS.Conclusion:Kisspeptin-54 is a promising approach to effectively and safely trigger oocyte
Jayasena CN, Abbara A, Narayanaswamy S, et al., 2015, Direct comparison of the effects of intravenous kisspeptin-10, kisspeptin-54 and GnRH on gonadotrophin secretion in healthy men, Human Reproduction, Vol: 30, Pages: 1934-1941, ISSN: 1460-2350
study question: How potently does the novel hypothalamic stimulator of reproduction, kisspeptin, increase gonadotrophin secretionwhen compared with GnRH in healthy men?summaryanswer: At the doses tested, intravenous administration of either of two major kisspeptin isoforms, kisspeptin-10 and -54, wasassociated with similar levels of gonadotrophin secretion in healthy men; however, GnRH was more potent when compared with either kisspeptinisoform.what is known already: Kisspeptin-10 and -54 are naturally occurring hormones in the kisspeptin peptide family which potently stimulatesendogenous GnRH secretion from the hypothalamus, so have the potential to treat patients with reproductive disorders. Rodent studiessuggest that kisspeptin-54 is more potent when compared with kisspepitn-10; however, their effects have not previously been directly comparedin humans, or compared with direct pituitary stimulation of gonadotrophin secretion using GnRH.study design, size and duration: A single-blinded placebo controlled physiological study was performed from January to December2013. Local ethical approval was granted, and five participants were recruited to each dosing group.participants/materials, setting, methods: Healthy men were administered vehicle, kisspeptin-10, kisspeptin-54 andGnRH intravenously for 3 h on different study days. Each hormone was administered at 0.1, 0.3 and 1.0 nmol/kg/h doses (n ¼ 5 subjects pergroup). Regular blood sampling was conducted throughout the study to measure LH and FSH. Study visits were conducted at least a week apart.main results and the role of chance: Serum LH and FSH levels were 3-fold higher during GnRH infusion when comparedwith kisspeptin-10 and 2-fold higher when compared with kisspeptin-54 [mean area under the curve serum LH during infusion (in hours timesinternational units per litre, h.IU/l): 10.81+1.73, 1.0 nmol/kg/h kisspeptin-10; 14.43+1.27, 1.0 nmol/kg/h kisspeptin-54; 34.06+5.18,1.0 nmol/kg/h GnRH, P , 0.001 versus kis
Abbara A, Jayasena CN, Christopoulos G, et al., 2015, Kisspeptin-54 safely and effectively triggers oocyte maturation in women at high risk of the ovarian hyperstimulation syndrome (OHSS), 31st Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 68-68, ISSN: 0268-1161
Jayasena CN, Comninos AN, Narayanaswamy S, et al., 2015, The identification of elevated urinary kisspeptin-immunoreactivity during pregnancy, ANNALS OF CLINICAL BIOCHEMISTRY, Vol: 52, Pages: 395-398, ISSN: 0004-5632
- Author Web Link
- Cite
- Citations: 9
Comninos AN, Anastasovska J, Sahuri-Arisoylu M, et al., 2015, Kisspeptin signaling in the amygdala modulates reproductive hormone secretion, Brain Structure & Function, Vol: 221, Pages: 2035-2047, ISSN: 1863-2661
Kisspeptin (encoded by KISS1) is a crucial activator of reproductive function. The role of kisspeptin has been studied extensively within the hypothalamus but little is known about its significance in other areas of the brain. KISS1 and its cognate receptor are expressed in the amygdala, a key limbic brain structure with inhibitory projections to hypothalamic centers involved in gonadotropin secretion. We therefore hypothesized that kisspeptin has effects on neuronal activation and reproductive pathways beyond the hypothalamus and particularly within the amygdala. To test this, we mapped brain neuronal activity (using manganese-enhanced MRI) associated with peripheral kisspeptin administration in rodents. We also investigated functional relevance by measuring the gonadotropin response to direct intra-medial amygdala (MeA) administration of kisspeptin and kisspeptin antagonist. Peripheral kisspeptin administration resulted in a marked decrease in signal intensity in the amygdala compared to vehicle alone. This was associated with an increase in luteinizing hormone (LH) secretion. In addition, intra-MeA administration of kisspeptin resulted in increased LH secretion, while blocking endogenous kisspeptin signaling within the amygdala by administering intra-MeA kisspeptin antagonist decreased both LH secretion and LH pulse frequency. We provide evidence for the first time that neuronal activity within the amygdala is decreased by peripheral kisspeptin administration and that kisspeptin signaling within the amygdala contributes to the modulation of gonadotropin release and pulsatility. Our data suggest that kisspeptin is a ‘master regulator’ of reproductive physiology, integrating limbic circuits with the regulation of gonadotropin-releasing hormone neurons and reproductive hormone secretion.
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.