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Age-Dependent Relationships Between Disease Risk and Testosterone Levels: Relevance to COVID-19 Disease.
Muehlenbein, M, Gassen, J, Nowak, T, Henderson, A, Morris, B, Weaver, S, Baker, E
American journal of men's health. 2023;17(2):15579883221130195
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A growing body of research finds that in men, testosterone levels may be prognostic of clinical outcomes related to coronavirus disease 2019 (COVID-19 disease). The presence of pre-existing chronic conditions in many patients with COVID-19 disease further complicates the relationship among testosterone and severe outcomes. The aim of this study was to examine whether pre-existing conditions for severe COVID-19 disease were related to serum-free testosterone levels in men who had not been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. This study obtained data from men (n = 142) who participated in the longitudinal study Waco COVID Survey. All data included in the study was collected as part of the initial intake survey and first laboratory appointment. Results show that serum-free testosterone levels decreased as a function of age. In fact, greater burden of pre-existing conditions for severe COVID-19 disease was related to lower testosterone levels among men younger than 40 years of age. Furthermore, in men older than 40 years of age the decrease in testosterone that accompanies aging attenuated the effect of the clinical risk score on free testosterone levels. Authors conclude that their findings add important insights into the complex role of androgens in chronic and infectious diseases and contribute to the growing body of literature on the relationship between chronic disease and men’s testosterone levels.
Abstract
Testosterone levels in men appear to be prognostic of a number of disease outcomes, including severe COVID-19 disease. Testosterone levels naturally decline with age and are lower in individuals with a number of comorbidities and chronic conditions. Low testosterone may therefore be both a cause and a consequence of illness, including COVID-19 disease. The present project examines whether preexisting conditions for severe COVID-19 disease were themselves related to serum-free testosterone levels in men who had not been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. A clinical risk score for severe COVID-19 disease was computed based on the results of previously published meta-analyses and cohort studies, and relationships between this score and testosterone levels were tested in 142 men ages 19 to 82 years. Greater burden of preexisting conditions for severe COVID-19 disease was related to lower testosterone levels among men younger than 40 years of age. In older men, the decrease in testosterone that accompanies aging attenuated the effect of the clinical risk score on free testosterone levels. Given that older age itself is a predictor of COVID-19 disease severity, these results together suggest that the presence of preexisting conditions may confound the relationship between testosterone levels and COVID-19 disease outcomes in men. Future research examining relationships among testosterone and outcomes related to infectious and chronic diseases should consider potential confounds, such as the role of preexisting conditions.
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Testosterone does not affect lower urinary tract symptoms while improving markers of prostatitis in men with benign prostatic hyperplasia: a randomized clinical trial.
Rastrelli, G, Cipriani, S, Lotti, F, Cellai, I, Comeglio, P, Filippi, S, Boddi, V, Della Camera, PA, Santi, R, Boni, L, et al
Journal of endocrinological investigation. 2022;45(7):1413-1425
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Benign prostatic hyperplasia (BPH) — also called benign prostate enlargement — is frequent in aging populations, with a 40 – 50% prevalence in men aged 50–60 years and up to 90% in men older than 80 years. The aim of this study was to verify whether testosterone therapy (TTh) in men with BPH, metabolic syndrome (MetS) and low testosterone is able to improve lower urinary tract symptoms (LUTS) and intraprostatic inflammation. This study is a double blind, randomised 24-week clinical trial in men with low testosterone and MetS and a candidate for prostate surgery for BPH. Patients (n=144) were centrally randomised 1:1 to one of the two groups; TTh or placebo. Results show that TTh administered for 24 weeks is a safe option and it improves prostatic inflammatory features thus ameliorating one of the pathogenic components of BPH. However, there were no differences in improvements of the urinary symptoms between both groups (TTh and placebo). Authors conclude that decreased inflammation is not accompanied by a consistent improvement in urinary symptoms, and that their findings show the safety of TTh in subjects with BPH of surgical significance.
Abstract
PURPOSE Benign Prostatic Hyperplasia (BPH) is a result of prostate inflammation, frequently occurring in metabolic syndrome (MetS). Low testosterone is common in MetS. A randomized clinical trial was designed to evaluate if 24 weeks of testosterone therapy (TTh) in BPH men with MetS and low testosterone improve urinary symptoms and prostate inflammation. METHODS One-hundred-twenty men with MetS waitlisted for BPH surgery were enrolled. They were categorized into normal testosterone (TT ≥ 12 nmol/L and cFT ≥ 225 pmol/L; n = 48) and testosterone deficient (TD) (TT < 12 nmol/L and/or cFT < 225 pmol/L; n = 72) then randomized to testosterone gel 2% (5 g/daily) or placebo for 24 weeks. At baseline and follow-up, questionnaires for urinary symptoms and trans-rectal ultrasound were performed. Prostate tissue was collected for molecular and histopathological analyses. RESULTS No differences in the improvement of urinary symptoms were found between TTh and placebo (OR [95% CI] 0.96 [0.39; 2.37]). In TD + TTh, increase in prostate but not adenoma volume was observed (2.64 mL [0.07; 5.20] and 1.82 mL [- 0.46; 0.41], respectively). Ultrasound markers of inflammation were improved. In a subset of 61 men, a hyper-expression of several pro-inflammatory genes was found in TD + placebo when compared with normal testosterone. TTh was able to counteract this effect. For 80 men, the inflammatory infiltrate was higher in TD + placebo than in normal testosterone (0.8 points [0.2; 1.4]) and TD + TTh men (0.9 points [0.2; 1.5]). CONCLUSIONS Twenty-four weeks of TTh in TD men with BPH and MetS improves ultrasound, molecular and histological proxies of prostate inflammation. This does not result in symptom improvement.
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Oxidative Stress and Inflammation Are Associated With Age-Related Endothelial Dysfunction in Men With Low Testosterone.
Babcock, MC, DuBose, LE, Witten, TL, Stauffer, BL, Hildreth, KL, Schwartz, RS, Kohrt, WM, Moreau, KL
The Journal of clinical endocrinology and metabolism. 2022;107(2):e500-e514
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Serum testosterone declines gradually with age at a rate of ~1% per year after the third decade. Vascular aging, featuring endothelial dysfunction mediated by oxidative stress and inflammation, is a major risk factor for the development of age-associated cardiovascular disease (CVD). The aim of this study was to examine the effects of low testosterone on cardiovascular aging in men. This study is a cross-sectional study which recruited 58 healthy men of all races/ethnic backgrounds aged 50-75 years (middle-aged/older) and 18-40 years (young). Results show that middle-aged/older men with lower testosterone have evidence of “accelerated” vascular aging, as indicated by a greater age-associated endothelial dysfunction of large arteries compared with their age-matched peers. The greater macrovascular endothelial dysfunction in middle-aged/older men with chronically low testosterone was independent of CVD risk factors or symptoms of androgen deficiency. Furthermore, increased systemic oxidative stress and inflammation are mechanistically linked to the greater age-associated endothelial dysfunction in middle-aged/older men with lower testosterone. Authors conclude that normal physiological levels of testosterone may be beneficial to cardiovascular health by attenuating the age-related decline in endothelial function.
Abstract
CONTEXT Vascular aging, including endothelial dysfunction secondary to oxidative stress and inflammation, increases the risk for age-associated cardiovascular disease (CVD). Low testosterone in middle-aged/older men is associated with increased CVD risk. OBJECTIVE We hypothesized that low testosterone contributes to age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. METHODS This cross-sectional study included 58 healthy, nonsmoking men categorized as young (N = 20; age 29 ± 4 years; testosterone 500 ± 58 ng/dL), middle-aged/older with higher testosterone (N = 20; age 60 ± 6 years; testosterone 512 ± 115 ng/dL), and middle-aged/older lower testosterone (N = 18; age 59 ± 8 years; testosterone 269 ± 48 ng/dL). Brachial artery flow-mediated dilation (FMDBA) was measured during acute infusion of saline (control) and vitamin C (antioxidant). Markers of oxidative stress (total antioxidant status and oxidized low-density lipoprotein cholesterol), inflammation (interleukin [IL]-6 and C-reactive protein [CRP]), and androgen deficiency symptoms were also examined. RESULTS During saline, FMDBA was reduced in middle-aged/older compared with young, regardless of testosterone status (P < 0.001). FMDBA was reduced in middle-aged/older lower testosterone (3.7% ± 2.0%) compared with middle-aged/older higher testosterone (5.7% ± 2.2%; P = 0.021), independent of symptoms. Vitamin C increased FMDBA (to 5.3% ± 1.6%; P = 0.022) in middle-aged/older lower testosterone but had no effect in young (P = 0.992) or middle-aged/older higher testosterone (P = 0.250). FMDBA correlated with serum testosterone (r = 0.45; P < 0.001), IL-6 (r = -0.41; P = 0.002), and CRP (r = -0.28; P = 0.041). CONCLUSION Healthy middle-aged/older men with low testosterone appear to have greater age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. These data suggest that low testosterone concentrations may contribute to accelerated vascular aging in men.
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Time-restricted eating effects on performance, immune function, and body composition in elite cyclists: a randomized controlled trial.
Moro, T, Tinsley, G, Longo, G, Grigoletto, D, Bianco, A, Ferraris, C, Guglielmetti, M, Veneto, A, Tagliabue, A, Marcolin, G, et al
Journal of the International Society of Sports Nutrition. 2020;17(1):65
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Adequate nutrition is important for elite athletes, as nutrient availability influences energy expenditure, body composition, performance and exercise-induced immune responses. Time-restricted eating (TRE) is a form of intermittent fasting that has received much interest in recent years. Previous research of TRE suggested beneficial effects on performance in untrained individuals, by allowing weight loss whilst maintaining muscle functions. These qualities are of interest for endurance cyclists hence the authors of this study sought to investigate the impact of TRE in elite cyclists. Sixteen under-23 year old, elite cyclists were randomly assigned to eat within a TRE window of 8-hr or 15hr window during a 4-week, high-level endurance training phase. Both groups consumed their full estimated energy needs and markers such as fat and fat-free mass, VO2 max, basal metabolism, blood counts, anabolic hormones and inflammatory markers were measured. As a result, TRE produced weight loss, improved body composition and increased peak power output in relation to body weight without compromising aerobic performance. Furthermore, the TRE pattern proved helpful in mitigating some of the exercise-induced suppressions of the immune system. The authors concluded that TRE could be considered as part of a performance nutrition plan in endurance athletes. Particularly where there is a need to reduce body fat mass or for the management of training-induced depression of the immune system and associated respiratory infection susceptibility. This can be of clinical relevance in the support of endurance athletes.
Abstract
BACKGROUND Although there is substantial interest in intermittent fasting as a dietary approach in active individuals, information regarding its effects in elite endurance athletes is currently unavailable. The present parallel randomized trial investigated the effects of a particular intermittent fasting approach, called time-restricted eating (TRE), during 4 weeks of high-level endurance training. METHODS Sixteen elite under-23 cyclists were randomly assigned either to a TRE group or a control group (ND). The TRE group consumed 100% of its estimated daily energy needs in an 8-h time window (from 10:00 a.m. to 6:00 p.m.) whilst energy intake in the ND group was distributed in 3 meals consumed between 7:00 a.m. and 9:00 p.m. Fat and fat-free mass were estimated by bioelectrical impedance analysis and VO2max and basal metabolism by indirect gas analyzer. In addition, blood counts, anabolic hormones (i.e. free testosterone, IGF-1) and inflammatory markers (i.e. IL-6, TNF-α) were assessed. RESULTS TRE reduced body weight (- 2%; p = 0.04) and fat mass percentage (- 1.1%; p = 0.01) with no change in fat-free mass. Performance tests showed no significant differences between groups, however the peak power output/body weight ratio (PPO/BW) improved in TRE group due to weight loss (p = 0.02). Free testosterone and IGF-1 decreased significantly (p = 0.01 and p = 0.03 respectively) in TRE group. Leucocyte count decreased in ND group (p = 0.02) whilst the neutrophils-to-lymphocytes ratio (NLR) decreased significantly (p = 0.03) in TRE group. CONCLUSIONS Our results suggest that a TRE program with an 8-h feeding window elicits weight loss, improves body composition and increases PPO/BW in elite cyclists. TRE could also be beneficial for reducing inflammation and may have a protective effect on some components of the immune system. Overall, TRE could be considered as a component of a periodized nutrition plan in endurance athletes. TRIAL REGISTRATION This trial was retrospectively registered at clinicaltrials.gov as NCT04320784 on 25 March 2020.
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Effects of resveratrol on VEGF & HIF1 genes expression in granulosa cells in the angiogenesis pathway and laboratory parameters of polycystic ovary syndrome: a triple-blind randomized clinical trial.
Bahramrezaie, M, Amidi, F, Aleyasin, A, Saremi, A, Aghahoseini, M, Brenjian, S, Khodarahmian, M, Pooladi, A
Journal of assisted reproduction and genetics. 2019;36(8):1701-1712
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Polycystic ovary syndrome (PCOS) is a condition in women characterised by disruptions in the ovulation cycle and hormonal imbalances causing infertility. There are several biological mechanisms involved in the development of PCOS, including hormonal imbalance. Recently, high levels of a protein known as VEGF, which stimulates the formation of new blood vessels, has been detected in the ovaries of women with PCOS and is thought to be involved in its development. Resveratrol is a herbal supplement, which has been shown in animal studies to reduce VEGF. This randomised control trial of 61 women with PCOS aimed to determine if there was a similar effect in humans. The results showed that VEGF was decreased following the supplementation of resveratrol, and that it also helped to achieve a more normal hormonal balance. As a result, this improved the quality of embryos, but did not increase the rate of fertility. It was concluded that resveratrol may be of benefit to women with PCOS by decreasing the production of VEGF and helping to achieve a better hormonal balance in women with PCOS.
Abstract
OBJECTIVES Management options for PCOS, as the most prevalent endocrine disorder in women of reproductive age, using natural supplements have a high priority for physicians, especially based on the etiological pathways. Therefore, this study was conducted to describe the effect of resveratrol on the angiogenesis pathway, for management of PCOS through assessing VEGF, HIF1 gene expression, and laboratory parameters. METHODS In this triple-blind RCT, PCOS was confirmed in ICSI candidates based on the Rotterdam criteria. Sixty-two patients that met the inclusion criteria were randomly assigned to two groups. All patients took resveratrol 800 mg/day or placebo for 40 days orally from the beginning of their previous menstruation cycle until the oocyte retrieval day. The serum levels of different hormones were measured, and the expression of HIF1 & VEGF genes was quantified by real-time PCR. RESULTS As for the laboratory hormone assay in 61 PCOS patients, a significant mean difference was seen in the FSH, LH, TSH, and testosterone between the two groups (P < 0.05). The results showed a reduction in the expression of VEGF & HIF1 genes under the effect of resveratrol in the granulosa cells (P = 0.0001). The number of mature oocytes, cleavage rate, fertilization rate, and fertility rate were not significantly different between the two groups (P > 0.05), but the high-quality oocyte rate and high-quality embryo rate were higher in the resveratrol group (P < 0.05). CONCLUSIONS Based on the results, resveratrol may improve some outcomes of PCOS patients, probably through changing the serum levels of some sex hormones and expression of VEGF & HIF1 genes in the angiogenesis pathway of granulosa cells.
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Testosterone Deficiency, Weakness, and Multimorbidity in Men.
Peterson, MD, Belakovskiy, A, McGrath, R, Yarrow, JF
Scientific reports. 2018;8(1):5897
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With age, the occurrence of total testosterone (TT) deficiency in men also increases. Such deficiency can have a detrimental impact on the musculoskeletal system leading to bone and muscle loss, increasing the risk of cardiovascular disease and all-cause mortality. Hence muscle weakness is a known a predicitve factor for chronic disease. Whereby reference ranges have been set for testosterone levels in young healthy men, uncertainty exists about optimal levels throughout different age ranges, ethnicities and in concurrence with diseases. This observational study evaluated how TT deficiency and muscle weakness assessed via grip strength, relates to chronic health conditions in men. The study included 2399 young, middle-aged, and older men in the US, with a diverse ethnic backgrounds, who presented with and without testosterone deficiency. The findings indicated that TT levels were highest amongst young men, yet no particular difference was seen in levels between middle-aged and older men. Grip strength decreased in the higher age categories. Chronic health conditions were more common in young and older men who displayed testosterone deficiencies, whilst low testosterone and reduced grip strength were linked to the presence of chronic disease in all age groups. Overall the study confirmed previous research, that in men with testosterone deficiency chronic disease was much more prevalent, even after accounting for other variables. The study also observed a much lower average of TT levels in young men compared to previous research, in mostly white males. Thus testosterone deficiency appears much more common in men of all ages when including a variety of ethnic groups. As low testosterone may play an early, causal role in the chronic disease process, continuous monitoring of testosterone levels through the life span may aid the early identification of chronic disease development or disease progression. Further research is needed on the independent and joint effects of low TT and muscular weakness. From a clinical perspective, this study affirms that low testosterone in men is a presenting risk factor for chronic disease and that chronic disease is commonly accompanied by low testosterone. It also highlights some unsettled aspects around reference ranges of testosterone
Abstract
The purposes of this study were to evaluate the association between total testosterone (TT) deficiency and weakness on multimorbidity in men. Analyses were performed to examine the prevalence of multimobidity among young, middle-aged, and older men, with and without testosterone deficiency. Multivariate logistic models were also used to determine the association between age-specific TT tertiles and multimorbidity, adjusting for key sociodemographic variables, as well as a secondary analysis adjusted for grip strength. Multimorbidity was more prevalent among men with testosterone deficiency, compared to normal TT in the entire group (36.6% vs 55.2%; p < 0.001); however, differences were only seen within young (testosterone deficiency: 36.4%; normal TT: 13.5%; p < 0.001) and older men (testosterone deficiency: 75.0%; normal TT: 61.5%; p < 0.001). Robust associations were found between the age-specific low-TT (OR: 2.87; 95%CI: 2.14-3.83) and moderate-TT (OR: 1.67; 95%CI: 1.27-2.20) tertiles (reference high-TT) and multimorbidity. Secondary analysis demonstrated that both low TT (OR: 1.82; 95%CI: 1.29-2.55) and moderate-TT (OR: 1.31; 95%CI: 1.01-1.69) were associated with multimorbidity, even after adjusting for obesity (OR: 1.75; 95%CI: 1.07-2.87) and NGS (OR: 1.21 per 0.05 unit lower NGS). Low TT and weakness in men were independently associated with multimorbidity at all ages; however, multimorbidity was more prevalent among young and older men with testosterone deficiency.
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The effects of d-aspartic acid supplementation in resistance-trained men over a three month training period: A randomised controlled trial.
Melville, GW, Siegler, JC, Marshall, PWM
PloS one. 2017;12(8):e0182630
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D-aspartic acid (DAA) is an amino acid that is currently purported as a testosterone-boosting supplement. Research has shown that DAA supplementation increases testosterone levels in untrained men, however in trained men has been shown to produce no effect. The aim of this study was to evaluate the effects of DAA to alter testosterone levels over three months of resistance training in 22 men. Participants were randomised to receive DAA or placebo and performed 12 weeks of supervised resistance training. Blood analyses and muscle measurements were assessed at baseline, six weeks and 12 weeks. This study found that DAA supplementation is ineffective in trained men at changing testosterone levels or positively affecting training outcomes. According to these findings, the authors suggest future studies further exploring the effects of supplementation in a trained population.
Abstract
CONTEXT Research on d-aspartic acid (DAA) has demonstrated increases in total testosterone levels in untrained men, however research in resistance-trained men demonstrated no changes, and reductions in testosterone levels. The long-term consequences of DAA in a resistance trained population are currently unknown. OBJECTIVE To evaluate the effectiveness of DAA to alter basal testosterone levels over 3 months of resistance training in resistance-trained men. DESIGN Randomised, double-blind, placebo controlled trial in healthy resistance-trained men, aged 18-36, had been performing regular resistance training exercise for at least 3 d.w-1 for the previous 2 years. Randomised participants were 22 men (d-aspartic acid n = 11; placebo n = 11) (age, 23.8±4.9 y, training age, 3.2±1.5 y). INTERVENTION D-aspartic acid (6 g.d-1, DAA) versus equal-weight, visually-matched placebo (PLA). All participants performed 12 weeks of supervised, periodised resistance training (4 d.w-1), with a program focusing on all muscle groups. MEASURES Basal hormones, total testosterone (TT), free testosterone (FT), estradiol (E2), sex-hormone-binding globulin (SHBG) and albumin (ALB); isometric strength; calf muscle cross-sectional area (CSA); calf muscle thickness; quadriceps muscle CSA; quadriceps muscle thickness; evoked V-wave and H-reflexes, were assessed at weeks zero (T1), after six weeks (T2) and after 12 weeks (T3). RESULTS No change in basal TT or FT were observed after the intervention. DAA supplementation (n = 10) led to a 16%, 95% CI [-27%, -5%] reduction in E2 from T1-T3 (p<0.01). The placebo group (n = 9) demonstrated improvements in spinal responsiveness (gastrocnemius) at the level of the alpha motoneuron. Both groups exhibited increases in isometric strength of the plantar flexors by 17%, 95% CI [7%, 28%] (p<0.05) as well as similar increases in hypertrophy in the quadriceps and calf muscles. CONCLUSIONS The results of this paper indicate that DAA supplementation is ineffective at changing testosterone levels, or positively affecting training outcomes. Reductions in estradiol and the blunting of peripheral excitability appear unrelated to improvements from resistance training. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry ACTRN12617000041358.
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Hormonal and metabolic effects of polyunsaturated fatty acids in young women with polycystic ovary syndrome: results from a cross-sectional analysis and a randomized, placebo-controlled, crossover trial.
Phelan, N, O'Connor, A, Kyaw Tun, T, Correia, N, Boran, G, Roche, HM, Gibney, J
The American journal of clinical nutrition. 2011;93(3):652-62
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5-10% of women of reproductive age are thought to be affected by polycystic ovary syndrome (PCOS). Women with PCOS don’t ovulate and have high levels of androgens (‘male’ hormones) such as testosterone. Dietary changes are often recommended for women with PCOS, yet the optimal diet for managing the condition has not been defined. Long-chain polyunsaturated fatty acids (PUFAs), in particular omega-3s, may influence various aspects of metabolic health in ways that are beneficial for women with PCOS. The objectives of this study were to determine the link between PUFAs and hormonal aspects of PCOS, to investigate the effects of omega-3 supplementation, and to support the findings with cellular studies. Participants were given 4 mg of either omega-3 supplementation or an olive oil placebo every day for 6 weeks. There was a 6-week rest period, after which the women crossed over to receive the alternative treatment for a further 6 weeks. Women who had higher levels of circulating androgens at the start of the study tended to have both higher omega-6 levels and omega-6:omega-3 ratios. After taking omega-3 supplements, testosterone levels were significantly reduced, particularly in those women who experienced more substantial falls in the ratio of omega-6:omega-3. Alongside this, the researchers found that ovarian cells sourced from cows increased production of androgens when treated with omega-6, but not omega-3. The authors concluded that supplementation with omega-3 PUFAs improves hormonal balance in women with PCOS.
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) is characterized by an adverse metabolic profile. Although dietary changes are advocated, optimal nutritional management remains uncertain. Polyunsaturated fatty acids (PUFAs), particularly long-chain (LC) n-3 (omega-3) PUFAs, improve metabolic health, but their therapeutic potential in PCOS is unknown. OBJECTIVES We aimed to determine the associations between plasma PUFAs and metabolic and hormonal aspects of PCOS to investigate the efficacy of LC n-3 PUFA supplementation and to support the findings with mechanistic cellular studies. DESIGN We selected a cross-sectional PCOS cohort (n = 104) and conducted a principal component analysis on plasma fatty acid profiles. Effects of LC n-3 PUFA supplementation on fasting and postprandial metabolic and hormonal markers were determined in PCOS subjects (n = 22) by a randomized, crossover, placebo-controlled intervention. Direct effects of n-6 (omega-6) compared with n-3 PUFAs on steroidogenesis were investigated in primary bovine theca cells. RESULTS Cross-sectional data showed that a greater plasma n-6 PUFA concentration and n-6:n-3 PUFA ratio were associated with higher circulating androgens and that plasma LC n-3 PUFA status was associated with a less atherogenic lipid profile. LC n-3 PUFA supplementation reduced plasma bioavailable testosterone concentrations (P < 0.05), with the greatest reductions in subjects who exhibited greater reductions in plasma n-6:n-3 PUFA ratios. The treatment of bovine theca cells with n-6 rather than with n-3 PUFAs up-regulated androstenedione secretion (P < 0.05). CONCLUSIONS Cross-sectional data suggest that PUFAs modulated hormonal and lipid profiles and that supplementation with LC n-3 PUFAs improves androgenic profiles in PCOS. In bovine theca cells, arachidonic acid modulated androstenedione secretion, which suggests an indirect effect of n-3 PUFAs through the displacement of or increased competition with n-6 PUFAs. This trial was registered at clinicaltrials.gov as NCT01189669.