Is the cardiometabolic health of adolescents conceived through ART worse than that of their counterparts conceived without ART?
The majority of cardiometabolic and vascular health parameters of ...adolescents conceived through ART are similar or more favourable, than those of their counterparts of similar age and conceived without ART.
It has been proposed that the cardiometabolic health of offspring conceived with ART may be unfavourable compared to that of their counterparts conceived without ART. The literature pertaining to cardiometabolic health of offspring conceived after ART is contradictory, but generally suggests unfavourable cardiometabolic health parameters, such as an increase in blood pressure (BP), vascular dysfunction and adiposity, as well as unfavourable glucose and lipid profiles. With over 8 million children and adults born through ART worldwide, it is important to investigate whether these early signs of adverse cardiometabolic differences persist into adolescence and beyond.
The Growing Up Healthy Study (GUHS) is a prospective cohort study that recruited 303 adolescents and young adults conceived after ART (aged 13-21 years) and born between 1991 and 2001 in Western Australia. Their health parameters, including cardiometabolic factors, were assessed and compared with counterparts from the Raine Study Generation 2 (Gen2). The 2868 Gen2 participants were born 1989-1992 and are representative of the Western Australian adolescent population. At ∼17 years of age (2013-2017), 163 GUHS participants replicated assessments previously completed by Gen2 at a similar age.
Cardiometabolic parameters were compared between a total of 163 GUHS and 1457 Gen2 adolescents. Separate male (GUHS n = 81, Gen2 n = 735) and female (GUHS n = 82, Gen2 n = 722) analyses were conducted. Assessments consisted of a detailed questionnaire including health, lifestyle and demographic parameters, anthropometric assessments (height, weight, BMI, waist circumference and skinfold thickness), fasting serum biochemistry, arterial stiffness and BP (assessed using applanation tonometry). Abdominal ultrasonography was used to assess the presence and severity of hepatic steatosis, and thickness of abdominal fat compartments. Non-alcoholic fatty liver disease (NAFLD) was diagnosed if there was sonographic fatty liver in the absence of significant alcohol consumption. Chi2, Fisher's exact and Mann-Whitney U tests, performed in SPSS V25, examined cohort differences and generalized estimating equations adjusted for the following covariates: singleton vs non-singleton pregnancy, birthweight (z-score), gestational age, BMI, smoking, alcohol consumption in the past 6 months and parent cardiovascular status. Arterial stiffness measures and waist circumference were additionally adjusted for height, and female analyses were additionally adjusted for use of oral contraceptives in the preceding 6 months.
In adjusted analyses, GUHS females had a lower BMI (22.1 vs 23.3 kg/m2, P = 0.014), and thinner skinfolds (triceps, subscapular, mid-abdominal; 16.9 vs 18.7 mm, P = 0.021, 13.4 vs 15.0 mm, P = 0.027, 19.7 vs 23.2 mm, P < 0.001, respectively), whereas males were not significantly different. Waist circumference was lower in GUHS adolescents (males: 78.1 vs 81.3 cm, P = 0.008, females: 76.7 vs 83.3 cm, P = 0.007). There were no significant differences between the two groups in glucose, insulin, homeostatic model assessment for insulin resistance, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), alanine aminotransferase and high-sensitivity C-reactive protein in both sexes. In females, serum triglycerides were lower in GUHS adolescents (1.0 vs 1.2 mmol/l, P = 0.029). GUHS males had higher serum HDL-C (1.1 vs 1.0 mmol/l, P = 0.004) and a lower TC/HDL-C ratio (3.2 vs 3.6, P = 0.036). There were no significant differences in the prevalence of NAFLD or steatosis severity scores between the cohorts in males and females. GUHS females had less subcutaneous adipose tissue (9.4 vs 17.9 mm, P < 0.001), whereas GUHS males had greater visceral adipose thickness (44.7 vs 36.3 mm, P < 0.001). There was no significant difference in pre-peritoneal adipose thickness. Pulse wave velocity was lower in GUHS males (5.8 vs 6.3 m/s, P < 0.001) and heart rate corrected augmentation index was lower in GUHS females (-8.4 vs -2.7%, P = 0.048). There were no significant differences in BP or heart rate in males or females between the two groups.
Despite the substantial study size and the unique study design of the ART cohort, we were unable to differentiate between different types of ART, due to the low number of ICSI cycles (e.g. IVF vs ICSI), draw definite conclusions, or relate the outcomes to the cause of infertility. Considering the differences in time points when both cohorts were studied, external factors could have changed, which could not be accounted for. Given the observational nature of this study, causation cannot be proven.
Contrary to our hypothesis and previous findings focussing mainly on childhood, this study reports mostly similar or favourable cardiometabolic markers in adolescents conceived with ART compared to those conceived without ART. The greater visceral adipose thickness, particularly present in males, requires further investigation. While these findings are generally reassuring, future well-designed and appropriately powered studies are required to definitively address the issue of cardiometabolic health in ART adults.
This project was supported by NHMRC project grant number 1042269 and R.J.H. received education grant funding support from Ferring Pharmaceuticals. R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia.
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Does mental health and behaviour differ between those conceived with and those conceived without ART?
Our study observed less externalizing behaviour (delinquent/aggressive), and more parent-reported ...internalizing behaviour, as well as more (clinical) depression at age 14 years, in adolescents conceived after ART compared to their non-ART counterparts.
Health outcomes of ART-conceived offspring may differ from those conceived without ART, and previous studies have reported differences in behaviour and mental health, particularly in childhood.
The Growing Up Healthy Study (GUHS) is a prospective cohort study, investigating the long-term health of offspring conceived after ART (aged 14, 17 and 20 years), in the two operational fertility clinics in Western Australia 1991-2001 (n = 303). Their long-term health outcomes were compared to those of offspring conceived without ART from the Raine Study Generation 2 (Gen2) born 1989-1991 (n = 2868). Both cohorts are representative of the local adolescent population.
Mental health parameters and behaviour were assessed at ages 14 and 17 years, through the parent completed 'Child Behaviour Checklist' (CBCL; ART versus non-ART: age 14 years: N = 150 versus N = 1781, age 17 years: N = 160 versus N = 1351), and the adolescent completed equivalent 'Youth Self-Report' (YSR; age 14 years: by N = 151 versus N = 1557, age 17 years: N = 161 and N = 1232). Both tools generate a T-score (standardized for age and sex) for internalizing (withdrawn, somatic complaints, anxious/depressed), externalizing (delinquent/aggressive behaviour) and total behaviour. Adolescents also completed the 'Beck Depression Inventory for Youth' (BDI-Y; age 14 years: N = 151 versus N = 1563, age 17 years: N = 161 versus N = 1219). Higher scores indicate poorer mental health and behaviour on all the above tools. Parent-reported doctor-diagnosed conditions (anxiety, behavioural problems, attention problems and depression) were also univariately compared between the cohorts. In addition, univariate comparisons were conducted between the GUHS adolescents and Gen2 adolescents born to subfertile parents (time to pregnancy >12 months), as well as between offspring born to subfertile versus fertile parents within the Gen2 cohort. A subgroup analysis excluding offspring born preterm (<37 weeks' gestation) or at low birthweight (<2500 g) was also performed. Generalized estimating equations that account for correlated familial data were adjusted for the following covariates: non-singleton, primiparity, primary caregiver smoking, family financial problems, socio-economic status and both maternal and paternal ages at conception.
At both 14 and 17 years of age, ART versus non-ART-conceived adolescents reported lower mean T-scores for externalizing problems (age 14 years: 49 versus 51, P = 0.045, age 17 years: 49 versus 52, P < 0.001). A similar effect was reported by parents, although not significant (age 14 years: P = 0.293, age 17 years: P = 0.148). Fewer ART-conceived adolescents reported a T-score above the clinical cut-off for externalizing behaviour (≥60; age 14 years: 7.3% versus 16.3%, P = 0.003, age 17 years: 8.1% versus 19.7%, P < 0.001). At both ages, no differences in internalizing behaviour were reported by adolescents (age 14 years: P = 0.218, age 17 years: P = 0.717); however, higher mean scores were reported by parents of the ART-conceived adolescents than by parents of the non-ART conceived adolescents (age 14 years: 51 versus 48, P = 0.027, age 17 years: 50 versus 46, P < 0.001). No differences in internalizing behaviour above the clinical cut-off (T-score ≥ 60) were observed. At age 17 years, parents who conceived through ART reported higher total behaviour scores than those parents who conceived without ART (48 versus 45, P = 0.002). At age 14 years, ART versus non-ART-conceived adolescents reported significantly higher mean scores on the BDI-Y (9 versus 6, P = 0.005); a higher percentage of adolescents with a score indicating clinical depression (≥17; 12.6% versus 8.5%, aOR 2.37 (1.18-4.77), P = 0.016), as well as more moderate/severe depression (≥21; 9.3% versus 4.0%, P = 0.009). At age 17 years, no differences were reported on the BDI-Y. There was also a higher percentage of parent-reported doctor-diagnosed anxiety in the ART cohort (age 14 years: 8.6% versus 3.5%, P = 0.002, at age 17 years: 12.0% versus 4.5%, P < 0.001). Removing adolescents born preterm or at low birthweight did not alter the above results. Comparing outcomes between GUHS adolescents and Gen2 adolescents born to subfertile parents, as well as between those born to subfertile versus fertile parents within Gen2, did not alter results for CBCL and YSR outcomes. Those born to subfertile parents showed higher rates of clinical depression than those born to fertile parents at age 14 years (13.7% versus 6.9%, P = 0.035).
The main limitation of the study is the time difference between the GUHS and Gen2 assessments. Even though we have adjusted for covariates, additional socio-economic and lifestyle factors affecting behaviour and mental well-being could have changed. We were unable to differentiate between different types of ART (e.g. IVF versus ICSI), owing to the low number of ICSI cycles at the time of study. Fertility sub-analyses need to be replicated in larger cohorts to increase power, potentially using siblingship designs. Lastly, selection bias may be present.
The reported lower prevalence of externalizing behaviour (delinquent/aggressive), and higher prevalence of internalizing behaviour, as well as more (clinical) depression at age 14 years, in ART versus non-ART-conceived adolescents, is in line with some previous studies, mostly conducted in childhood. It is reassuring that differences in the rates of depression were not observed at age 17 years, however, these findings require replication. As the use of ART is common, and mental health disorders are increasing, knowledge about a potential association is important for parents and healthcare providers alike.
This project was funded by an NHMRC Grant (Hart et al., ID 1042269). R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia.
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Abstract
STUDY QUESTION
Are there differences in thyroid function between adolescents and young adults conceived with and without ART?
SUMMARY ANSWER
This study demonstrated no evidence of clinically ...relevant differences in thyroid function between adolescents and young adults conceived with and without ART.
WHAT IS KNOWN ALREADY
Studies to date have reported an increase in subclinical hypothyroidism in offspring conceived after ART. It has been suggested that the increase in maternal estrogen (E2) after fresh embryo transfers could affect thyroid function of the offspring. Suboptimal thyroid function at a young age can cause irreversible damage to the central nervous system, which makes early detection and correct treatment essential.
STUDY DESIGN, SIZE, DURATION
The Growing Up Healthy Study (GUHS) is a prospective cohort study, which aimed to recruit all adolescents born after conception with ART between 1991 and 2001 in the study area. The included participants (n = 303, aged 13–20 years) completed various health assessments. Depending on the age at enrolment, participants completed thyroid assessments at the 14- or 20-year follow-up. The outcomes of these replicated thyroid assessments were compared to those of participants conceived without ART from the Raine Study Generation 2 (Gen2). The Gen2 participants (n = 2868) were born between 1989 and 1992 and have been recognized to be representative of the local population.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Thyroid function assessments were compared between n = 134 GUHS and n = 1359 Gen2 adolescents at age 14 years and between n = 47 GUHS and n = 914 Gen2 young adults at age 20 years. The following mean thyroid hormone concentrations were compared between the cohorts: thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4) and thyroid peroxidase antibodies (TPOAb). The prevalence of the following thyroid hormone profiles, based on individual thyroid hormone concentrations, was compared: euthyroidism, subclinical and overt hypo- and hyperthyroidism and thyroid autoimmunity. Outcomes were compared between the cohorts, and univariately between fresh embryo transfers (ET) and frozen ET (FET) within the GUHS. The correlation between maternal peak E2 concentrations (pE2) and fT4 was assessed within the GUHS.
MAIN RESULTS AND THE ROLE OF CHANCE
All mean thyroid function outcomes fell within the normal range. At both ages, we report no differences in TSH concentrations. At age 14 years, lower fT3 concentrations (4.80 versus 5.35 pmol/L, P < 0.001) and higher fT4 concentrations (12.76 versus 12.19 pmol/L, P < 0.001) were detected in the GUHS adolescents compared to Gen2 adolescents. At age 20 years, higher fT3 and fT4 concentrations were reported in GUHS adolescents (4.91 versus 4.63 pmol/L, P = 0.012; 13.43 versus 12.45 pmol/L, P < 0.001, respectively) compared to Gen2 participants. No differences in the prevalence of subclinical and overt hypo- and hyperthyroidism or thyroid autoimmunity were demonstrated between the cohorts at age 14 and 20 years. Thyroid function did not differ between ET and FET, and no correlation between pE2 and fT4 was reported.
LIMITATIONS, REASONS FOR CAUTION
The observational nature of the study limits the ability to prove causation. Furthermore, the comparison of ET and FET offspring at age 20 years may be lacking power. We were unable to differentiate between different types of ART (e.g. IVF versus ICSI) owing to the low number of ICSI cycles at the time of study. As ART laboratory and clinic data were collected contemporaneously with the time of treatment, no other data pertaining to the ART cycles were sought retrospectively; hence, some factors could not be accounted for.
WIDER IMPLICATIONS OF THE FINDINGS
This study does not support previous findings of clinically relevant differences in thyroid function when comparing a cohort of adolescents conceived after ART to counterparts conceived without ART. The minor differences detected in fT3 and fT4 were considered not biologically relevant. Although these findings appear reassuring, they warrant reinvestigation in adulthood.
STUDY FUNDING/COMPETING INTERESTS
This project was funded by an NHMRC Grant (Hart et al., ID 1042269). R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director and a shareholder of PIVET Medical Centre, Perth, Western Australia.
TRIAL REGISTRATION NUMBER
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Studies of drug-cell interactions in cancer model systems are essential in the preclinical stage of rational drug design, which relies on a thorough understanding of the mechanisms underlying ...cytotoxic activity and biological effects, at a molecular level. This study aimed at applying complementary vibrational spectroscopy methods to evaluate the cellular impact of two Pt(ii) and Pd(ii) dinuclear chelates with spermine (Pt2Spm and Pd2Spm), using cisplatin (cis-Pt(NH3)2Cl2) as a reference compound. Their effects on cellular metabolism were monitored in a human triple-negative metastatic breast cancer cell line (MDA-MB-231) by Raman and synchrotron-radiation infrared microspectroscopies, for different drug concentrations (2-8 μM) at 48 h exposure. Multivariate data analysis was applied (unsupervised PCA), unveiling drug- and concentration-dependent effects: apart from discrimination between control and drug-treated cells, a clear separation was obtained for the different agents studied - mononuclear vs. polynuclear, and Pt(ii) vs. Pd(ii). Spectral biomarkers of drug action were identified, as well as the cellular response to the chemotherapeutic insult. The main effect of the tested compounds was found to be on DNA, lipids and proteins, the Pd(ii) agent having a more significant impact on proteins while its Pt(ii) homologue affected the cellular lipid content at lower concentrations, which suggests the occurrence of distinct and unconventional pathways of cytotoxicity for these dinuclear polyamine complexes. Raman and FTIR microspectroscopies were confirmed as powerful non-invasive techniques to obtain unique spectral signatures of the biochemical impact and physiological reaction of cells to anticancer agents.
Mobile marine species can exhibit vast movements both horizontally and vertically. Spatial analysis of vertical movements may help improve an understanding of the processes that influence space use. ...Previously, vertical space use of basking sharks (
Cetorhinus maximus
) in the north-east Atlantic described movements largely within waters of the continental shelf during summer and autumn months, with few records of detailed vertical behaviour during winter. We use archival satellite telemetry data from 32 basking sharks (12 females, 6 males, and 14 of unknown sex measuring 4–5 m (
n
= 6), 5–6 m (
n
= 10), 6–7 m (
n
= 7), 7–8 m (
n
= 8), and 8–9 m (
n
= 1) estimated total length) tracked over 4 years (2012–2015). The satellite tags provided depth and temperature data for a cumulative 4489 days (mean 140 ± 97 days per shark, range 10–292 days) to describe vertical space use and thermal range of basking sharks in the north-east Atlantic. Basking sharks exhibit seasonality in vertical space use, revealing repeated ‘yo-yo’ movement behaviour with periods of occupancy at depths greater than 1000 m in late winter/early spring. Describing seasonal vertical space use in marine megavertebrates can increase knowledge of movements throughout their environment including physiological and morphological constraints to movement, nutrient transfer, and overlap with anthropogenic threats to inform future conservation strategies.
Summary Background Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown. We investigated the effects of different blood-pressure targets on the ...rate of recurrent stroke in patients with recent lacunar stroke. Methods In this randomised open-label trial, eligible patients lived in North America, Latin America, and Spain and had recent, MRI-defined symptomatic lacunar infarctions. Patients were recruited between March, 2003, and April, 2011, and randomly assigned, according to a two-by-two multifactorial design, to a systolic-blood-pressure target of 130–149 mm Hg or less than 130 mm Hg. The primary endpoint was reduction in all stroke (including ischaemic strokes and intracranial haemorrhages). Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov , number NCT 00059306. Findings 3020 enrolled patients, 1519 in the higher-target group and 1501 in the lower-target group, were followed up for a mean of 3·7 (SD 2·0) years. Mean age was 63 (SD 11) years. After 1 year, mean systolic blood pressure was 138 mm Hg (95% CI 137–139) in the higher-target group and 127 mm Hg (95% CI 126–128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0·81, 95% CI 0·64–1·03, p=0·08), disabling or fatal stroke (0·81, 0·53–1·23, p=0·32), and the composite outcome of myocardial infarction or vascular death (0·84, 0·68–1·04, p=0·32) with the lower target. The rate of intracerebral haemorrhage was reduced significantly (0·37, 0·15–0·95, p=0·03). Treatment-related serious adverse events were infrequent. Interpretation Although the reduction in stroke was not significant, our results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial. Funding National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS)
Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition.
To examine the safety and efficacy of 28 days of once-daily ...Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa.
105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R).
The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs -0.032L±0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49).
Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.
Animal migration is ubiquitous in nature with individuals within a population often exhibiting varying movement strategies. The basking shark (Cetorhinus maximus) is the world's second largest fish ...species, however, a comprehensive understanding of their long-term wider-ranging movements in the north-east Atlantic is currently lacking. Seventy satellite tags were deployed on basking sharks over four years (2012-2015) off the west coast of Scotland and the Isle of Man. Data from 28 satellite tags with attachment durations of over 165 days reveal post-summer ranging behaviours. Tagged sharks moved a median minimum straight-line distance of 3,633 km; achieving median displacement of 1,057 km from tagging locations. Tagged individuals exhibited one of three migration behaviours: remaining in waters of UK, Ireland and the Faroe Islands; migrating south to the Bay of Biscay or moving further south to waters off the Iberian Peninsula, and North Africa. Sharks used both continental shelf areas and oceanic habitats, primarily in the upper 50-200 m of the water column, spanning nine geo-political zones and the High Seas, demonstrating the need for multi-national cooperation in the management of this species across its range.
Abstract
STUDY QUESTION
Are early signs of metabolic disorder in late adolescence associated with features of impaired testicular function many years before the majority seek parenthood?
SUMMARY ...ANSWER
Adolescents with features of metabolic disorder at 17 years, or insulin resistance (IR) at 20 years of age, show impaired testicular function and altered hormone levels compared to those without metabolic disorder.
WHAT IS KNOWN ALREADY
Controversial evidence suggests a recent decline in sperm production potentially linked to environmental influences, but its cause remains unclear. Concomitant increases in obesity and diabetes suggest that lifestyle factors may contribute to this decline in testicular function. Although obesity has been associated with adverse testicular function in some studies, it remains unclear whether poor testicular function merely reflects, or causes, poor metabolic health. If metabolic disorder were present in adolescence, prior to the onset of obesity, this may suggest that metabolic disorder maybe a precursor of impaired testicular function.
STUDY DESIGN, SIZE, DURATION
The Western Australian Pregnancy Cohort (Raine) Study is a longitudinal study of children born in 1989–1991 who have undergone detailed physical assessments since birth (1454 male infants born). At 17 years of age, 490 boys underwent a hepatic ultrasound examination, serum cytokine assessment (n = 520) and a metabolic assessment (n = 544). A further metabolic assessment was performed at 20 years (n = 608). Testicular assessment was performed at 20 years; 609 had reproductive hormones measured, 404 underwent a testicular ultrasound and 365 produced a semen sample.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Testicular volume was estimated by ultrasonography, and semen analysis was performed according to World Health Organization guidelines. Concentrations of LH, FSH and inhibin B (inhB) in serum were measured by immunoassay and total testosterone by liquid chromatography-mass spectrometry.
At 17 years of age, a liver ultrasound examination was performed to determine the presence of non-alcoholic fatty liver disease (NAFLD), and serum analysed for the cytokines interleukin-18 and soluble tumour necrosis factor receptor 1 and 2 (sTNFR1, sTNFR2).
At 17 and 20 years of age, fasting blood samples were analysed for serum liver enzymes, insulin, glucose, triglycerides (TG), total cholesterol, high density lipoprotein and low density lipoprotein cholesterol, high sensitivity C-reactive protein and uric acid. The homoeostatic model assessment (HOMA) was calculated and approximated IR was defined by a HOMA >4. Anthropometric data was collected and dual energy X-ray absorptiometry measurement performed for lean and total fat mass. As at this young age the prevalence of metabolic syndrome was expected to be low, a two-step cluster analysis was used using waist circumference, TGs, insulin, and systolic blood pressure to derive a distinct high-risk group with features consistent with the metabolic syndrome and increased cardiometabolic risk.
MAIN RESULTS AND THE ROLE OF CHANCE
Men at age 17 years with increased cardiometabolic risk had lower concentrations of serum testosterone (medians: 4.0 versus 4.9 ng/mL) and inhB (193.2 versus 221.9 pg/mL) (P < 0.001 for both) compared to those within the low risk metabolic cluster. Men with ultrasound evidence of NAFLD (n = 45, 9.8%) had reduced total sperm output (medians: 68.0 versus 126.00 million, P = 0.044), testosterone (4.0 versus 4.7 ng/mL, P = 0.005) and inhB (209.1 versus 218.4 pg/mL, P = 0.032) compared to men without NAFLD.
Men with higher concentrations of sTNFR1 at 17 years of age had a lower sperm output and serum concentration of inhB, with an increase in LH and FSH (all P < 0.05 after adjustment for age, BMI, abstinence and a history of cryptorchidism, varicocele, cigarette smoking, alcohol and drug use), compared to those without an elevated sTNFR1. Multivariable regression analysis, adjusting for confounders, demonstrated that men in the high-risk metabolic cluster at 20 years had a lower serum testosterone and inhB (P = 0.003 and P = 0.001, respectively). A HOMA-IR > 4 was associated with a lower serum testosterone (P = <0.001) and inhB (P = 0.010) and an increase in serum FSH (P = 0.015).
LIMITATIONS, REASONS FOR CAUTION
This study is limited by the sample size and multiple comparisons, and causality cannot be proven from an observational study. Due to a 3-year interval between some metabolic assessments and assessment of testicular function, we cannot exclude the introduction of a bias into the study, as some of the participants and their testicular function will not have been fully mature at the 17-year assessment.
WIDER IMPLICATIONS OF THE FINDINGS
Irrespective of a proven causation, our study findings are important in that a significant minority of the men, prior to seeking parenthood, presented co-existent features of metabolic disorder and signs of testicular impairment. Of particular note is that the presence of NAFLD at 17 years of age, although only present in a minority of men, was associated with an almost 50% reduction in sperm output at 20 years of age, and that the presence of IR at 20 years was associated with a 20% reduction in testicular volume.
STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by Australian NHMRC (Grant Numbers 634457, 35351417 and 403981) and received support from the Raine Medical Research Foundation, The Telethon Kids Institute, University of Western Australia, Women and Infants Research Foundation, Curtin University and Edith Cowan University. D.A.D., J.E.D., N.M., L.A.A., R.-C.H., T.A.M., J.K.O., L.J.B. have nothing to declare. R.J.H. is Medical Director of Fertility Specialists of Western Australia, has equity interests in Western IVF, and has received grant support from MSD, Merck-Serono and Ferring Pharmaceuticals. RMcL has equity interests in the Monash IVF Group. R.J.N. has equity interests in FertilitySA, and has received grant support from Merck Serono and Ferring Pharmaceuticals. D.J.H. has received institutional grant funding (but no personal income) for investigator-initiated testosterone pharmacology studies from Lawley and Besins Healthcare and has provided expert testimony to anti-doping tribunals and for testosterone litigation.
This abstract was awarded the Fertility Society of Australia clinical exchange award for the oral presentation at ESHRE, Barcelona, in 2018.
Summary
We explored the association between adiponectin levels and bone strength in paralyzed men with spinal cord injury. We found that bone strength was inversely associated with circulating ...adiponectin levels. Thus, strength estimates and adiponectin levels may improve fracture risk prediction and detection of response to osteogenic therapies following spinal cord injury.
Purpose
Previous research has demonstrated an inverse relationship between circulating adiponectin and bone mineral density, suggesting that adiponectin may be used as a biomarker for bone health. However, this relationship may reflect indirect effects on bone metabolism via adipose-mediated mechanical pathways rather than the direct effects of adipokines on bone metabolism. Thus, we explored the association between circulating adiponectin levels and bone strength in 27 men with spinal cord injury.
Methods
Plasma adiponectin levels were quantified by ELISA assay. Axial stiffness and maximal load to fracture of the distal femur were quantified via finite element analysis using reconstructed 3D models of volumetric CT scans. We also collected information on timing, location, and cause of previous fractures.
Results
Axial stiffness and maximal load were inversely associated with circulating adiponectin levels (
R
2
= 0.44,
p
= 0.01;
R
2
= 0.58,
p
= 0.05) after adjusting for injury duration and lower extremity lean mass. In individuals with post-SCI osteoporotic fractures, distal femur stiffness (
p
= 0.01) and maximal load (
p
= 0.005) were lower, and adiponectin was higher (
p
= 0.04) than those with no fracture history.
Conclusions
Based on these findings, strength estimates may improve fracture risk prediction and detection of response to osteogenic therapies following spinal cord injury. Furthermore, our findings suggest that circulating adiponectin may indeed be a feasible biomarker for bone health and osteoporotic fracture risk in paralyzed individuals with spinal cord injury.
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