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Abstract 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.

BACKGROUNDHypoactive sexual desire disorder (HSDD) is characterized by a persistent deficiency of sexual fantasies and desire for sexual activity, causing marked distress and interpersonal difficulty. It is the most prevalent female sexual health problem globally, affecting approximately 10% of women, but has limited treatment options. Melanocortin 4 receptor (MC4R) agonists have emerged as a promising therapy for women with HSDD, through unknown mechanisms. Studying the pathways involved is crucial for our understanding of normal and abnormal sexual behavior.METHODSUsing psychometric, functional neuroimaging, and hormonal analyses, we conducted a randomized, double-blinded, placebo-controlled, crossover clinical study to assess the effects of MC4R agonism compared with placebo on sexual brain processing in 31 premenopausal heterosexual women with HSDD.RESULTSMC4R agonism significantly increased sexual desire for up to 24 hours after administration compared with placebo. During functional neuroimaging, MC4R agonism enhanced cerebellar and supplementary motor area activity and deactivated the secondary somatosensory cortex, specifically in response to visual erotic stimuli, compared with placebo. In addition, MC4R agonism enhanced functional connectivity between the amygdala and the insula during visual erotic stimuli compared with placebo.CONCLUSIONThese data suggest that MC4R agonism enhanced sexual brain processing by reducing self-consciousness, increasing sexual imagery, and sensitizing women with HSDD to erotic stimuli. These findings provide mechanistic insight into the action of MC4R agonism in sexual behavior and are relevant to the ongoing development of HSDD therapies and MC4R agonist development more widely.TRIAL REGISTRATIONClinicalTrials.gov NCT04179734.FUNDINGThis is an investigator-sponsored study funded by AMAG Pharmaceuticals Inc., the Medical Research Council (MRC) (MR/T006242/1), and the National Institute for Health Research (NIHR) (CS-2018-18-ST2-002 and RP-2014-05-001).

Distressing low sexual desire, termed Hypoactive Sexual Desire Disorder (HSDD), affects approximately 10% of women and 8% of men. In women, the ‘top-down’ theory of HSDD describes hyperactivity in higher-level cognitive brain regions, suppressing lower-level emotional/sexual brain areas. However, it is unknown how this neurofunctional disturbance compares to HSDD in men. To investigate this, we employed task-based functional MRI in 32 women and 32 men with HSDD to measure sexual-brain processing during sexual versus non-sexual videos, as well as psychometric questionnaires to assess sexual desire/arousal. We demonstrate that women had greater activation in higher-level and lower-level brain regions, compared to men. Indeed, women who had greater hypothalamic activation in response to sexual videos, reported higher psychometric scores in the evaluative (r = 0.55, P = 0.001), motivational (r = 0.56, P = 0.003), and physiological (r = 0.57, P = 0.0006) domains of sexual desire and arousal after watching the sexual videos in the scanner. By contrast, no similar correlations were observed in men. Taken together, this is the first direct comparison of the neural correlates of distressing low sexual desire between women and men. The data supports the ‘top-down’ theory of HSDD in women, whereas in men HSDD appears to be associated with different neurofunctional processes.

Subfertility affects one in seven couples and is defined as the inability to conceive after 1 year of regular unprotected intercourse. This article describes the initial clinical evaluation and investigation to guide diagnosis and management. The primary assessment of subfertility is to establish the presence of ovulation, normal uterine cavity and patent fallopian tubes in women, and normal semen parameters in men. Ovulation is supported by a history of regular menstrual cycles (21–35 days) and confirmed by a serum progesterone >30 nmol/L during the luteal phase of the menstrual cycle. Common causes of anovulation include polycystic ovary syndrome (PCOS), hypothalamic amenorrhoea (HA) and premature ovarian insufficiency (POI). Tubal patency is assessed by hysterosalpingography, hystero-contrast sonography, or more invasively by laparoscopy and dye test. The presence of clinical or biochemical hyperandrogenism, serum gonadotrophins (luteinising hormone/follicle stimulating hormone) / oestradiol, pelvic ultrasound to assess ovarian morphology / antral follicle count, can help establish the cause of anovulation. Ovulation can be restored in women with PCOS using letrozole (an aromatase inhibitor), clomifene citrate (an oestrogen antagonist) or exogenous gonadotrophin administration. If available, pulsatile gonadotrophin releasing hormone therapy is the preferred option for restoring ovulation in HA. Spermatogenesis can be induced in men with hypogonadotrophic hypogonadism with exogenous gonadotrophins. Unexplained subfertility can be treated with in vitro fertilisation after 2 years of trying to conceive. Involuntary childlessness is associated with significant psychological morbidity; hence, expert assessment and prompt treatment are necessary to support such couples.

Anti-tumour necrosis factor (TNF) therapy has revolutionised patient prognosis in rheumatoid arthritis. In the UK, continuing anti-TNF therapy requires a sustained response as determined by the disease activity score in 28 joints (DAS28). Adherence to disease modifying anti-rheumatic drugs (DMARDs) is low but little is known about adherence to biological therapies and its association to treatment response. We investigated the association of adherence to subcutaneous anti-TNF therapy and DAS28 in people with rheumatoid arthritis. Participants were recruited to the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS), a large UK multicentre, prospective, observational, cohort study. Demographic information for patients receiving subcutaneous anti-TNF therapy and disease characteristics were assessed at baseline. Self-reported adherence was defined as whether the biological agent was taken on the day agreed with the health-care professional and recorded at 3 and 6 months. DAS28 was recorded at baseline and after 3 and 6 months of therapy. Descriptive statistics, multivariate logistic regression, and linear regression statistics were used to analyse the data. Data were collected for 392 patients with median disease duration of 7 years (IQR 3–15). Adherence data were collected in 286 patients, of whom 57 (20%) reported non-adherence with biological therapy. Older age, reported adherence at 6 months, and being ever non-adherent during the study period were significantly associated with a poorer DAS28 response to anti-TNF therapy after adjustment for disease duration, age at baseline, sex, concurrent DMARDs, non-steroidal anti-inflammatory drug (NSAID) use, and marital status (p=0·017, p=0·047, and p=0·014, respectively). Logistic regression analysis showed that neither demographic (age, sex, and marital status) nor clinical data (disease duration, NSAID and DMARD use, and baseline DAS28) predicted non-adherence. Patients with rheumatoid arthritis who reported not taking their biological drug on the day agreed with their health-care professional had poorer clinical outcomes than did those who did take their drug, emphasising the need for strict adherence to biological therapy in patients with this condition. NIHR Manchester Musculoskeletal Biomedical Research Unit.

Abstract Context The hormone kisspeptin has crucial and well-characterized roles in reproduction. Emerging data from animal models also suggest that kisspeptin has important metabolic effects including modulation of food intake. However, to date there have been no studies exploring the effects of kisspeptin on brain responses to food stimuli in humans. Objective This work aims to investigate the effects of kisspeptin administration on brain responses to visual food stimuli and psychometric parameters of appetite, in healthy men. Design A double-blinded, randomized, placebo-controlled, crossover study was conducted. Participants Participants included 27 healthy, right-handed, eugonadal men (mean ± SEM: age 26.5 ± 1.1 years; body mass index 23.9 ± 0.4 kg/m2). Intervention Participants received an intravenous infusion of 1 nmol/kg/h of kisspeptin or rate-matched vehicle over 75 minutes. Main Outcome Measures Measurements included change in brain activity on functional magnetic resonance imaging in response to visual food stimuli and change in psychometric parameters of appetite, during kisspeptin administration compared to vehicle. Results Kisspeptin administration at a bioactive dose did not affect brain responses to visual food stimuli or psychometric parameters of appetite compared to vehicle. Conclusions This is the first study in humans investigating the effects of kisspeptin on brain regions regulating appetite and demonstrates that peripheral administration of kisspeptin does not alter brain responses to visual food stimuli or psychometric parameters of appetite in healthy men. These data provide key translational insights to further our understanding of the interaction between reproduction and metabolism.

Abstract Disclosure: J. Tsoutsouki: None. E. Mills: None. M. Phylactou: None. S.A. Clarke: None. L. Thurston: None. L. Yang: None. B. Patel: None. P. Eng: None. C. Izzi-Engbeaya: None. E.C. Alexander: None. P. Bech: None. M. Swedrowska: None. B. Forbes: None. A. Abbara: None. A.N. Comninos: None. W.S. Dhillo: None. Background: The neuropeptide kisspeptin is known to activate the reproductive axis primarily by stimulating kisspeptin receptors on hypothalamic GnRH neurons. However, recent rodent evidence has identified an extra-hypothalamic population of GnRH neurons in the olfactory bulb, which also express kisspeptin receptors. Intranasal kisspeptin administration may directly activate these extra-hypothalamic olfactory bulb-GnRH neurons, triggering reproductive hormone release and revealing a novel olfactory-reproductive pathway. Herein, we compare the reproductive hormone responses to intranasal and intravenous kisspeptin administration in humans, providing mechanistic insights and highlighting the potential of intranasal kisspeptin as an effective and non-invasive delivery route. Methods: Healthy male participants received 12.8 nmol/kg of kisspeptin-54 via either intranasal delivery (n=12) or intravenous bolus injection (n=5). Reproductive hormone levels were measured every 15 minutes for 6 hours following administration. The mean maximum increase in reproductive hormones from baseline and the median time to peak response between the two groups were analyzed using an unpaired t-test and Mann-Whitney test, respectively. Results: Both intranasal and intravenous kisspeptin-54 elicited significant reproductive hormone responses. The peak LH response was lower with intranasal, compared to intravenous administration (mean change from baseline ± SEM [IU/L]: 4.5 ± 0.6 intranasal vs. 11.3 ± 1.4 intravenous, p<0.0001). However, intranasal kisspeptin-54 induced a markedly earlier LH peak, with a median time of 38 minutes, compared to 300 minutes for intravenous administration (p=0.0002). A similar pattern was observed for FSH, with a peak of 0.7 ± 0.2 above baseline at 38 minutes following intranasal, compared to 2.3 ± 0.22 above baseline at 345 minutes with intravenous kisspeptin-54 administration (p=0.0003 for magnitude, p=0.0002 for timing). The peak testosterone responses did not differ significantly between intranasal and intravenous kisspeptin-54 (p=0.1864), although the median peak occurred earlier following intranasal (165 minutes), compared to intravenous administration (345 minutes; p=0.0116). No adverse effects were reported with either delivery route. Discussion: The significantly faster onset of reproductive hormone responses following intranasal compared to intravenous kisspeptin-54 administration suggests a direct olfactory-reproductive pathway, likely mediated by kisspeptin receptors on olfactory GnRH neurons. These findings have significant clinical implications for the therapeutic use of kisspeptin in managing common reproductive and psychosexual disorders, whilst also providing evidence for a novel kisspeptin-mediated olfactory-reproductive pathway in humans. Presentation: Sunday, July 13, 2025

Despite being the most common female sexual health complaint worldwide, current treatment options for hypoactive sexual desire disorder (HSDD) are limited in their safety and effectiveness. The hormone kisspeptin is a key endogenous activator of the reproductive hormonal axis with additional emerging roles in sexual and emotional behavior; however, its effects in women with HSDD are unknown. To test the hypothesis that kisspeptin enhances sexual and attraction brain processing in women with HSDD. This randomized clinical trial was double-masked and placebo controlled with a 2-way crossover. The trial was conducted in a university research setting in the UK from October 2020 to April 2021. Eligible participants were premenopausal women with HSDD. Functional neuroimaging, psychometric, and hormonal analyses were employed to investigate the effects of kisspeptin administration on brain processing, in response to erotic stimuli (erotic videos) and facial attraction (face images of varying attractiveness). Data were analyzed from May to December 2021. A 75-minute intravenous infusion of kisspeptin-54 (1 nmol/kg/h) vs equivalent-rate placebo infusion. Blood oxygen level-dependent responses across the whole brain and regions of interest during kisspeptin vs placebo administration in response to erotic and facial attraction stimuli. Of the 40 participants who were randomized, 32 women completed both kisspeptin and placebo visits, with a mean (SE) age of 29.2 (1.2) years. Kisspeptin administration resulted in modulations in sexual and facial attraction brain processing (deactivation of the left inferior frontal gyrus: Z max, 3.76; P = .01; activation of the right postcentral and supramarginal gyrus: Z max, 3.73; P < .001; deactivation of the right temporoparietal junction: Z max 4.08; P = .02). Furthermore, positive correlations were observed between kisspeptin-enhanced hippocampal activity in response to erotic videos, and baseline distress relating to sexual function (r = 0.469; P = .007). Kisspeptin's enhancement of posterior cingulate cortex activity in response to attractive male faces also correlated with reduced sexual aversion, providing additional functional significance (r = 0.476, P = .005). Kisspeptin was well-tolerated with no reported adverse effects. These findings lay the foundations for clinical applications for kisspeptin in women with HSDD. ISRCTN trial registry identifier: ISRCTN17271094.

Abstract Disclosure: E. Mills: None. J. Tsoutsouki: None. L. Thurston: None. M. Phylactou: None. B. Patel: None. L. Yang: None. S. Clarke: None. M. Young: None. E. Alexander: None. S. Nyunt: None. A. Yeung: None. M. Choudhury: None. A. Newman: None. P. Bech: None. A. Abbara: None. M. Swedrowska: None. B. Forbes: None. A. Comninos: None. W. Dhillo: None. Background: Kisspeptin administration by intravenous or subcutaneous routes activates hypothalamic GnRH neurons to stimulate downstream reproductive hormone release and is under rapid development for treating common reproductive disorders, including hypothalamic amenorrhea (HA). However, these invasive routes limit patient acceptability and clinical use. Intranasal administration offers a novel non-invasive delivery route, which would be clinically preferable to patients and clinicians. Herein, we compare the reproductive endocrine responses after intranasal kisspeptin administration in healthy women to women with HA. Methods: Randomized, double-blinded, placebo-controlled, crossover study in 12 healthy (ovulatory) women during the follicular phase (mean age ± SEM 22.1 ± 0.9 yrs, BMI 22.1 ± 0.8 kg/m2) and 10 women with HA (age 25.8 ± 2.7 yrs, BMI 19.9 ± 1.3 kg/m2). After intranasal delivery of kisspeptin-54 (12.8 nmol/kg) or 0.9% saline (placebo), reproductive hormones were measured every 15 minutes for 4 hours. Groups were compared by unpaired t-tests. Results: Intranasal kisspeptin-54 administration rapidly and robustly stimulated gonadotropin release in both study cohorts. However, LH and FSH release were significantly augmented in women with HA, compared to healthy women: mean area under the curve (AUC) for the change in LH across 4 hours 96.0 ± 45.8 h·IU/L (healthy women) vs. 600.6 ± 146.7 h·IU/L (women with HA) (P = 0.002). Consistently, mean AUC for the change in FSH was -36.1 ± 23.4 h·IU/L (healthy women) vs. 474.9 ± 237.3 h·IU/L (women with HA) (P = 0.02). The mean maximal increase in LH following kisspeptin-54 was over three-fold greater in women with HA at 4.4 ± 0.2 IU/L vs. 1.4 ± 0.3 IU/L in healthy women (P < 0.001). Similarly, the mean maximal increase in FSH was over ten-fold greater in women with HA at 3.1 ± 0.3 IU/L vs. 0.3 ± 0.1 IU/L in healthy women (P = 0.03). Summary: Intranasal kisspeptin robustly stimulates reproductive hormone release in healthy women, with an even greater stimulation in women with HA. Therefore, intranasal kisspeptin offers not only a novel, effective, safe, and non-invasive route of administration for the management of reproductive disorders but also a potential simple diagnostic test to identify women with HA. Presentation: Sunday, July 13, 2025

Abstract Disclosure: E.G. Mills: None. L. Thurston: None. L. Yang: None. S. Suladze: None. T. Hunjan: None. M. Phylactou: None. B. Patel: None. S.A. Clarke: None. A.J. Shah: None. C. Izzi-Engbeaya: None. J. Tsoutsouki: None. P. Bech: None. N. Ertl: None. L. Demetriou: None. M.B. Wall: None. D. Goldmeier: None. A. Abbara: None. A.N. Comninos: None. W.S. Dhillo: None. Background: The neuropeptide kisspeptin is a critical endogenous activator of the reproductive system. Due to its key role in regulating reproductive and behavioural processes, there has been escalating interest in targeting kisspeptin-pathways to treat reproductive and psychosexual disorders. However, conflicting evidence from pre-clinical animal models proposes that kisspeptin can have an anxiolytic, anxiogenic or have no effects on anxiety. Given the rapid development of kisspeptin-based therapeutics, it is important to clarify kisspeptin’s effects on anxiety in humans. Herein, we report the largest study examining the effects of kisspeptin on psychometric measures of anxiety and circulating cortisol levels in humans. Methods: Ninety-three eugonadal participants (n=29 healthy men, n=32 men with low sexual desire, n=32 women with low sexual desire) completed a double-blind, randomised, placebo-controlled, crossover study. Participants attended twice: once for intravenous infusion of kisspeptin-54 (1nmol/kg/h) over 75mins and for a rate-matched placebo. Blood sampling took place at 15-minute intervals from -30 to 75mins to measure circulating kisspeptin, LH, testosterone and cortisol [in men] and oestradiol [in women]. The validated ‘State-Trait Anxiety Inventory (STAI) Y2-Trait’ was completed prior to the infusions to exclude abnormal anxiety traits, with all scores within normal limits. Participants also completed the ‘STAI Y1-State’ before and prior to the end of the infusions to assess for any dynamic effects of the infusions on anxiety. Results: Ninety-three participants (mean age ±SD 30.9±8.7yrs, BMI 24.0±3.7kg/m2) completed the study. Intravenous kisspeptin significantly increased serum LH to similar levels previously described using this administration protocol, confirming that the dose was biologically active (P<0.001). Importantly, state anxiety was unaltered by kisspeptin, compared to placebo (mean difference in ‘STAI Y1-State’ scores during the infusions: kisspeptin -0.03±8.11, placebo 0.77±8.08, P=0.43). Moreover, kisspeptin had no effect on circulating cortisol compared to placebo during the 75minute study period (P=0.92). As expected, kisspeptin had no significant effects on downstream sex-steroid levels during the 75minute study period, thereby excluding these as confounders. Discussion: This is the largest study demonstrating that a biologically active dose of kisspeptin to healthy volunteers and patients with psychosexual disorders does not affect psychometric measures of anxiety and associated circulating cortisol levels. Given that animal studies have yielded conflicting results, this provides important clinical data and reassurance that kisspeptin administration in humans does not induce anxiety and so informs the rapid development of kisspeptin-based therapeutics for reproductive and psychosexual disorders. Presentation: 6/3/2024