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Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis.
Hudson, J, Cruickshank, M, Quinton, R, Aucott, L, Aceves-Martins, M, Gillies, K, Bhasin, S, Snyder, PJ, Ellenberg, SS, Grossmann, M, et al
The lancet. Healthy longevity. 2022;3(6):e381-e393
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Hypogonadism is caused by testosterone deficiency and results in diminished sexual function, muscle wastage, weakness, osteoporosis, and reduced quality of life. Testosterone supplementation is used as a therapy for hypogonadism but there is some doubt on its safety, and it may come with serious side effects such as heart attacks. This systematic review and meta-analysis aimed to determine the effect of testosterone supplementation on heart health. The results showed that heart disease risk was unaffected by testosterone supplementation and there was a trend for fewer deaths following treatment. It was concluded that testosterone did not affect short-medium-term heart attack risk, however there was a lack of evidence in the long-term. This study could be used by healthcare professionals to understand that testosterone supplementation may be of benefit to individuals who need it without increasing their risk for heart attacks.
Abstract
BACKGROUND Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. METHODS We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. FINDINGS 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17-1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81-1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92-1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82-1·15]; p=0·69), smoking status (interaction 1·68 [0·41-6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89-4·82; p=0·025) were not associated with cardiovascular risk. INTERPRETATION We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. FUNDING National Institute for Health Research Health Technology Assessment Programme.
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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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Molecular Regulators of Muscle Mass and Mitochondrial Remodeling Are Not Influenced by Testosterone Administration in Young Women.
Horwath, O, Moberg, M, Hirschberg, AL, Ekblom, B, Apró, W
Frontiers in endocrinology. 2022;13:874748
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Testosterone is a sex hormone normally found in higher amounts in adult males than females. Testosterone plays a number of important roles, including influencing muscle size and strength. Treatment with testosterone has been shown to increase lean mass and muscle strength in women as well as men. However, female-only studies are limited, and the precise mechanisms underlying these changes are not well understood. This randomised control trial examined the effect of testosterone administration on regulators of muscle protein turnover and mitochondrial function in muscle samples collected from young women. 48 healthy, pre-menopausal women were assigned to receive either 10mg of transdermal testosterone gel per day, or a placebo, for 10 weeks. Muscle samples were collected via biopsy before and after the intervention. Testosterone administration did not appear to have a significant effect on androgen receptors, 5-alpha reductase, anabolic signalling, or mitochondrial remodelling in muscle tissue. The researchers concluded that improvements in muscle size and oxidative capacity following testosterone administration cannot be explained by changes in protein expression related to muscle protein turnover or mitochondrial remodelling. The authors went on to suggest that the small sample size in this study may have reduced the ability to detect small but biologically relevant changes in protein levels. Within the research, there is large variability among studies in terms of sex, age, route of administration and length of treatment, which makes putting these findings into context of the wider literature difficult.
Abstract
Testosterone (T) administration has previously been shown to improve muscle size and oxidative capacity. However, the molecular mechanisms underlying these adaptations in human skeletal muscle remain to be determined. Here, we examined the effect of moderate-dose T administration on molecular regulators of muscle protein turnover and mitochondrial remodeling in muscle samples collected from young women. Forty-eight healthy, physically active, young women (28 ± 4 years) were assigned in a random double-blind fashion to receive either T (10 mg/day) or placebo for 10-weeks. Muscle biopsies collected before and after the intervention period were divided into sub-cellular fractions and total protein levels of molecular regulators of muscle protein turnover and mitochondrial remodeling were analyzed using Western blotting. T administration had no effect on androgen receptor or 5α-reductase levels, nor on proteins involved in the mTORC1-signaling pathway (mTOR, S6K1, eEF2 and RPS6). Neither did it affect the abundance of proteins associated with proteasomal protein degradation (MAFbx, MuRF-1 and UBR5) and autophagy-lysosomal degradation (AMPK, ULK1 and p62). T administration also had no effect on proteins in the mitochondria enriched fraction regulating mitophagy (Beclin, BNIP3, LC3B-I, LC3B-II and LC3B-II/I ratio) and morphology (Mitofilin), and it did not alter the expression of mitochondrial fission- (FIS1 and DRP1) or fusion factors (OPA1 and MFN2). In summary, these data indicate that improvements in muscle size and oxidative capacity in young women in response to moderate-dose T administration cannot be explained by alterations in total expression of molecular factors known to regulate muscle protein turnover or mitochondrial remodeling.
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Manipulation of Dietary Intake on Changes in Circulating Testosterone Concentrations.
Zamir, A, Ben-Zeev, T, Hoffman, JR
Nutrients. 2021;13(10)
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Androgens, like testosterone, are steroid hormones commonly associated with reproduction. However, they also govern metabolic functions, body composition and growth. Higher levels of circulating androgens enhance athletic performance by supporting metabolic activities such as protein production, regeneration and growth and by inhibiting breakdown processes. Manipulating testosterone to enhance athletic performance without the use of anabolic steroids hormones has been of much interest. As macro-and micronutrients can influence androgen hormones, this review examined whether specific energy and nutrient intake can ‘naturally’ manipulate testosterone levels. The authors describe the metabolic functions of testosterone before exploring the current evidence on selected plant extracts and nutrients and their impact on aromatase activity. Inhibiting aromatase can prevent androgens from being converted into oestrogen and thus may help to raise circulating androgens. Discussed are a range of plant-derived compounds, flavonoids, macronutrients and micronutrients (Vitamin D, Zinc and Magnesium) and their impact on testosterone levels. The authors conclude that the nutrients discussed have some supportive evidence, yet overall findings are inconclusive due to limited studies. Regarding macronutrients more research is available, and the evidence supports that low energy intake negatively impacts testosterone levels and performance. Whereby supplementation of vitamins crucial to testosterone production seems to provide value in cases of deficiency further research is required. This article yields an overview of plant compounds, macro-and micronutrients and their potential impact on circulating testosterone levels. While low energy intake and nutrient deficiencies appears to be unfavourable, the absence of clear evidence on other compounds would warrant further case-specific investigations.
Abstract
Elevations in the circulating concentration of androgens are thought to have a positive effect on the anabolic processes leading to improved athletic performance. Anabolic-androgenic steroids have often been used by competitive athletes to augment this effect. Although there has been concerted effort on examining how manipulating training variables (e.g., intensity and volume of training) can influence the androgen response to exercise, there has been much less effort directed at understanding how changes in both macronutrient and micronutrient intake can impact the androgen response. Thus, the focus of this review is to examine the effect that manipulating energy and nutrient intake has on circulating concentrations of testosterone and what the potential mechanism is governing these changes.
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Long-term effects of a three-component lifestyle intervention on emotional well-being in women with Polycystic Ovary Syndrome (PCOS): A secondary analysis of a randomized controlled trial.
Jiskoot, G, Dietz de Loos, A, Beerthuizen, A, Timman, R, Busschbach, J, Laven, J
PloS one. 2020;15(6):e0233876
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Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder affecting women in their reproductive years. The condition is often associated with higher rates of depression and anxiety, particularly with a Body Mass Index (BMI) of >30. As weight-loss has shown to improve a host of symptoms experienced in PCOS, the authors sought to investigate whether weight-loss would also lead to a reduction in depressive symptoms. This secondary analysis of a longitudinal, randomised trial of 155 women, compared a combined lifestyle intervention of diet advice, eating behaviour, exercise and standardised Cognitive Behaviour Therapy (CBT) to standard advice for weight reduction. Over a 12-months the chosen lifestyle interventions demonstrated a sustained improvement in self-assessed depression scores, though independent of weight-loss. However, weight-loss itself was closely linked with improved body image and self-esteem. Additional monitoring of hormones (androgens, insulin, cortisol) and calculations for insulin sensitivity (HOMA-IR ) did not show any direct link with depressive scores. This study affirms the benefit of integrative lifestyle approaches on emotional well-being in women with PCOS. Practitioners might find it of interest that improvements in emotional well-being can occur independent of weight loss in individuals experiencing depressive symptoms with PCOS.
Abstract
Many women with Polycystic Ovary Syndrome (PCOS) report high depression rates. The relationship between PCOS and these high depression rates is unclear. Two-component lifestyle interventions have revealed short-term effects on depression scores in this group of women. In general, 3-component interventions including diet, exercise, and cognitive behavioral therapy (CBT) are more effective in the long-term to improve emotional well-being. This has not yet been studied in women with PCOS. This study examined the effect of 20 CBT lifestyle (LS) sessions combined with a healthy diet and physical therapy with or without 9 months additional feedback through Short Message Service (SMS) via mobile phone, compared to care as usual (CAU, involving advice to lose weight). In this secondary analysis, 155 women with PCOS and a BMI above 25 kg/m2 were eligible. Depression scores decreased significantly in the LS programme compared to CAU (P = 0.045). In both the LS programme without SMS (P = 0.036) and the LS programme with SMS (P = 0.011) depression scores decreased while no change was observed in CAU (P = 0.875). Self-esteem scores improved significantly in the LS programme compared to CAU (P = 0.027). No differences in body image scores were observed in LS participants compared to CAU (P = 0.087), although body image improved significantly in both the LS without SMS (P = 0.001) and with SMS (P = 0.008) study arms. We found no significant mediating role by androgens in the relationship between LS participants and emotional well-being. Only weight-loss mediated the relationship between LS and self-esteem. To conclude, a three-component lifestyle intervention programme with or without additional SMS resulted in significant improvements in depression and self-esteem compared to CAU, in women with PCOS, obesity, and a wish to achieve a pregnancy. Testosterone, androstenedione, DHEA, insulin, HOMA-IR, and cortisol did not mediate this effect. Weight loss mediated the effects on self-esteem but not on depression and body-image. This suggests that lifestyle treatment independent of weight loss can reduce depression and body-image, but both lifestyle treatment and weight loss can improve self-esteem. Thus, a three-component lifestyle intervention based on CBT could prove successful in improving mood in women with PCOS who are overweight or obese and attempting to become pregnant.
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Mechanisms Underlying Metabolic Syndrome-Related Sarcopenia and Possible Therapeutic Measures.
Rubio-Ruiz, ME, Guarner-Lans, V, Pérez-Torres, I, Soto, ME
International journal of molecular sciences. 2019;20(3)
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Sarcopenia is a multifactorial process in which losses occur in both muscle mass and function. Although several studies indicate an association between sarcopenia and metabolic syndrome (MetS), the connection has not been extensively reviewed. The aim of this study is to examine the relationship between sarcopenia and MetS to better understand the mechanisms underlying disease and assess current therapeutic options. According to the existing literature, this study found insulin resistance, inflammation and obesity to be major underlying factors of MetS-related sarcopenia. Based on this information, the authors suggest the best option for managing MetS-related sarcopenia is preventative lifestyle change around diet and exercise until a consensus on a therapeutic treatment can be established.
Abstract
Although there are several reviews that report the interrelationship between sarcopenia and obesity and insulin resistance, the relation between sarcopenia and the other signs that compose the metabolic syndrome (MetS) has not been extensively revised. Here, we review the mechanisms underlying MetS-related sarcopenia and discuss the possible therapeutic measures proposed. A vicious cycle between the loss of muscle and the accumulation of intramuscular fat might be associated with MetS via a complex interplay of factors including nutritional intake, physical activity, body fat, oxidative stress, proinflammatory cytokines, insulin resistance, hormonal changes, and mitochondrial dysfunction. The enormous differences in lipid storage capacities between the two genders and elevated amounts of endogenous fat having lipotoxic effects that lead to the loss of muscle mass are discussed. The important repercussions of MetS-related sarcopenia on other illnesses that lead to increased disability, morbidity, and mortality are also addressed. Additional research is needed to better understand the pathophysiology of MetS-related sarcopenia and its consequences. Although there is currently no consensus on the treatment, lifestyle changes including diet and power exercise seem to be the best options.
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Short-Term Exercise Training Inconsistently Influences Basal Testosterone in Older Men: A Systematic Review and Meta-Analysis.
Hayes, LD, Elliott, BT
Frontiers in physiology. 2018;9:1878
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The levels of testosterone decrease as men age and is associated with accelerated ageing. Approaches to increase testosterone levels may therefore be of benefit. There are complications with administering testosterone and so exercise has been proposed as a non-pharmacological intervention to increase serum testosterone in older males. The purpose of this review and meta-analysis was to look at suitable studies linking exercise and testosterone levels in older males and to see whether types of exercise (endurance, resistance and interval training) made a difference. There is a belief that resistance exercise increases basal testosterone over time. However, this was not observed in this meta-analysis. HIIT (high intensity interval training), and endurance training showed the most promise for increasing basal testosterone in older men. There is a need for more studies to improve the quality of available evidence and at present, exercise is probably the best non-pharmacological countermeasure to loss of muscle function with human aging.
Abstract
Background: The age-associated decrease in testosterone is one mechanism suggested to accelerate the aging process in males. Therefore, approaches to increase endogenous testosterone may be of benefit. The aim of this paper was to undertake a Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-accordant meta-analysis concerning the effect of exercise on total (TT), bioavailable (bio-T), free (free-T), and salivary (sal-T) testosterone in older males. Methods: Databases were searched up to and including 20th February 2018 for the terms "testosterone AND exercise AND aging AND males," "testosterone AND exercise AND old AND males," "testosterone AND training AND aging AND males," and "testosterone AND training AND old AND males". From 1259 originally identified titles, 22 studies (randomized controlled trials; RCTs; n = 9, and uncontrolled trials; UCTs; n = 13) were included which had a training component, participants ≥60 years of age, and salivary or serum testosterone as an outcome measure. Meta-analyses were conducted on change to testosterone following training using standardized difference in means (SDM) and random effects models. Results: The overall SDM for endurance training, resistance training, and interval training was 0.398 (95% CI = 0.034-0.761; P = 0.010), -0.003 (95% CI = -0.330-0.324; P = 0.986), and 0.283 (95% CI = 0.030-0.535; P = 0.028), respectively. Resistance training exhibited a qualitative effect of hormone fraction whereby free-T resulted in the greatest SDM (0.253; 95% CI = -0.043-0.549; P = 0.094), followed by TT (0.028; 95% CI = -0.204-0.260; P = 0.813), and resistance training negatively influenced bio-T (-0.373; 95% CI = -0.789-0.042; P = 0.078). Due to the small number of studies, subgroup analysis was not possible for endurance training and interval training studies. Conclusions: Data from the present investigation suggests that resistance training does not significantly influence basal testosterone in older men. Magnitude of effect was influenced by hormone fraction, even within the same investigation. Aerobic training and interval training did result in small, significant increases in basal testosterone. The magnitude of effect is small but the existing data are encouraging and may be an avenue for further research.
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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.