Context The effects of COVID-19 on the thyroid axis remain uncertain. Recent evidence has been conflicting, with both thyrotoxicosis and suppression of thyroid function reported. Objective We aimed to detail the acute effects of COVID-19 on thyroid function and determine if these effects persisted on recovery from COVID-19. Design A cohort observational study was conducted. Participants and Setting Adult patients admitted to Imperial College Healthcare National Health Service Trust, London, UK, with suspected COVID-19 between March 9 to April 22, 2020, were included, excluding those with preexisting thyroid disease and those missing either free thyroxine (FT4) or thyrotropin (TSH) measurements. Of 456 patients, 334 had COVID-19 and 122 did not. Main Outcome Measures TSH and FT4 measurements were recorded at admission, and where available, in 2019 and at COVID-19 follow-up. Results Most patients (86.6%) presenting with COVID-19 were euthyroid, with none presenting with overt thyrotoxicosis. Patients with COVID-19 had a lower admission TSH and FT4 compared to those without COVID-19. In the COVID-19 patients with matching baseline thyroid function tests from 2019 (n = 185 for TSH and 104 for FT4), TSH and FT4 both were reduced at admission compared to baseline. In a complete case analysis of COVID-19 patients with TSH measurements at follow-up, admission, and baseline (n = 55), TSH was seen to recover to baseline at follow-up. Conclusions Most patients with COVID-19 present with euthyroidism. We observed mild reductions in TSH and FT4 in keeping with a nonthyroidal illness syndrome. Furthermore, in survivors of COVID-19, thyroid function tests at follow-up returned to baseline.

BACKGROUND. Sex, emotion, and reproduction are fundamental and tightly entwined aspects of human behavior. 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 behaviors, and is a likely candidate system for the integration of behavior with the hormonal reproductive axis. We investigated the effects of kisspeptin, a recently identified key reproductive hormone, on limbic brain activity and behavior.METHODS. Using a combination of functional neuroimaging and hormonal and psychometric analyses, we compared the effects of kisspeptin versus vehicle administration in 29 healthy heterosexual young men.RESULTS. We demonstrated that kisspeptin administration enhanced 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.CONCLUSIONS. Collectively, our data provide evidence of an undescribed role for kisspeptin in integrating sexual and emotional brain processing with reproduction in humans. These results have important implications for our understanding of reproductive biology and are highly relevant to the current pharmacological development of kisspeptin as a potential therapeutic agent for patients with common disorders of reproductive function.FUNDING. National Institute for Health Research (NIHR), Wellcome Trust (Ref 080268), and the Medical Research Council (MRC).

Infertility affects one in six of the population and increasingly couples require treatment with assisted reproductive techniques. In vitro fertilization (IVF) treatment is most commonly conducted using exogenous FSH to induce follicular growth and human chorionic gonadotropin (hCG) to induce final oocyte maturation. However, hCG may cause the potentially life-threatening iatrogenic complication “ovarian hyperstimulation syndrome” (OHSS), which can cause considerable morbidity and, rarely, even mortality in otherwise healthy women. The use of GnRH agonists (GnRHas) has been pioneered during the last two decades to provide a safer option to induce final oocyte maturation. More recently, the neuropeptide kisspeptin, a hypothalamic regulator of GnRH release, has been investigated as a novel inductor of oocyte maturation. The hormonal stimulus used to induce oocyte maturation has a major impact on the success (retrieval of oocytes and chance of implantation) and safety (risk of OHSS) of IVF treatment. This review aims to appraise experimental and clinical data of hormonal approaches used to induce final oocyte maturation by hCG, GnRHa, both GnRHa and hCG administered in combination, recombinant LH, or kisspeptin. We also examine evidence for the timing of administration of the inductor of final oocyte maturation in relationship to parameters of follicular growth and the subsequent interval to oocyte retrieval. In summary, we review data on the efficacy and safety of the major hormonal approaches used to induce final oocyte maturation in clinical practice, as well as some novel approaches that may offer fresh alternatives in future.

AimsTo investigate the effect of kisspeptin on glucose‐stimulated insulin secretion and appetite in humans.Materials and methodsIn 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose‐stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose‐stimulated insulin secretion in vitro in human pancreatic islets and a human β‐cell line (EndoC‐βH1 cells).ResultsKisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose‐stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men.ConclusionsCollectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin‐based therapies for reproductive and potentially metabolic conditions.

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, METHODS Study 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 kisspeptin-54 (Single: 14/31, 45%, Double: 21/31, 71%; absolute difference +26%, CI 2–50%, P = 0.042).Patients receiving two doses of kisspeptin-54 had a variable LH-response following the second kisspeptin dose, which appeared to be dependent on the LH-response following the first kisspeptin injection. Patients who had a lower LH-rise following the first dose of kisspeptin had a more substantial ‘rescue’ LH-response following the second dose of kisspeptin. The variable LH-response following the second dose of kisspeptin resulted in a greater proportion of patients achieving an oocyte yield ≥60%, but without also increasing the frequency of ovarian over-response and moderate OHSS (Single: 1/31, 3.2%, Double: 0/31, 0%).LIMITATIONS, REASONS FOR CAUTIONFurther studies are warranted to directly compare kisspeptin-54 to more established triggers of oocyte maturation.WIDER IMPLICATIONS OF THE FINDINGSTriggering final oocyte maturation with kisspeptin is a novel therapeutic option to enable the use of fresh embryo transfer even in the woman at high risk of OHSS.STUDY FUNDING/COMP...

SummaryBackgroundHot 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 [15·99–23·42]; adjusted estimate of difference 29·66 [17·39–42·87], p<0·0001). Treatment was well tolerated. Three participants developed a transaminase rise (alanine aminotransferase 4·5–5·9 times the upper limit of normal) with a normal bilirubin 28 days after starting MLE4901, which normalised within 90 days.InterpretationTreatment with a neurokinin 3 receptor antagonist (MLE4901) could be practice changing as it safely and effectively relieves hot flush symptoms without the need for oestrogen exposure. Larger scale studies of longer duration are now indicated.FundingUK Medical Research Council and National Institute for Health Research.

BACKGROUND. Kisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders. METHODS. We conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1Rmediated inositol monophosphate (IP 1) and Ca 2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices. RESULTS. In healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU•h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP 1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012). CONCLUSION. Taken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders. TRIAL REGISTRATION. International Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.

Context The COVID-19 pandemic continues to exert an immense burden on global health services. Moreover, up to 63% of patients experience persistent symptoms, including fatigue, after acute illness. Endocrine systems are vulnerable to the effects of COVID-19 as many glands express the ACE2 receptor, used by the SARS-CoV-2 virion for cellular access. However, the effects of COVID-19 on adrenal and thyroid gland function after acute COVID-19 remain unknown. Objectives Our objectives were to evaluate adrenal and thyroid gland function in COVID-19 survivors. Design A prospective, observational study was undertaken. Setting Clinical Research Facility, Imperial College NHS Healthcare Trust. Participants Seventy patients ≥ 18 years at least 3 months after diagnosis of COVID-19 were included. Intervention Participants attended a research study visit (08:00-09:30), during which a short Synacthen test (250 µg IV bolus), and thyroid function assessments were performed. Results All patients had a peak cortisol ≥450 nmol/l after Synacthen, consistent with adequate adrenal reserve. Basal and peak serum cortisol did not differ according to disease severity or history of dexamethasone treatment during COVID-19. There was no difference in baseline or peak cortisol after Synacthen or in thyroid function tests, or thyroid status, in patients with fatigue (n=44) compared to those without (n=26). Conclusions Adrenal and thyroid function ≥3 months after presentation with COVID-19 was preserved. Whilst a significant proportion of patients experienced persistent fatigue, their symptoms were not accounted for by alterations in adrenal or thyroid function. These findings have important implications for the clinical care of patients after COVID-19.