Next Article in Journal
Evaluating Nutrient-Based Indices against Food- and Diet-Based Indices to Assess the Health Potential of Foods: How Does the Australian Health Star Rating System Perform after Five Years?
Next Article in Special Issue
Myoprotective Whole Foods, Muscle Health and Sarcopenia: A Systematic Review of Observational and Intervention Studies in Older Adults
Previous Article in Journal
Higher Cardiorespiratory Fitness Levels May Attenuate the Detrimental Association between Weight Status, Metabolic Phenotype and C-Reactive Protein in Adolescents—A Multi-Cohort Study
Previous Article in Special Issue
A Mediterranean Diet Is Positively Associated with Bone and Muscle Health in a Non-Mediterranean Region in 25,450 Men and Women from EPIC-Norfolk
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Nutrients
Volume 12
Issue 5
10.3390/nu12051457
nutrients-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Effects of Dietary or Supplementary Micronutrients on Sex Hormones and IGF-1 in Middle and Older Age: A Systematic Review and Meta-Analysis

by
Ryan Janjuha
1,
Diane Bunn
2,
Richard Hayhoe
1,
Lee Hooper
1,
Asmaa Abdelhamid
1,
Shaan Mahmood
1,
Joseph Hayden-Case
1,
Will Appleyard
1,
Sophie Morris
1 and
Ailsa Welch
1,*
1
Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4 7TJ, UK
2
School of Health Sciences, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4 7TJ, UK
*
Author to whom correspondence should be addressed.
Nutrients 2020, 12(5), 1457; https://doi.org/10.3390/nu12051457
Submission received: 12 March 2020 / Revised: 29 April 2020 / Accepted: 6 May 2020 / Published: 18 May 2020
(This article belongs to the Special Issue Diet, Lifestyle and Healthy Ageing)
Browse Figures
Review Reports Versions Notes

Abstract

:
Observational research suggests that micronutrients may be protective for sarcopenia, a key health issue during ageing, potentially via effects on hormone synthesis and metabolism. We aimed to carry out a systematic review of RCTs investigating effects of increasing dietary or supplemental micronutrient intake on sex hormones and IGF-1 in individuals aged 45 years or older. We searched MEDLINE, EMBASE and Cochrane databases for RCTs reporting the effects of different micronutrients (vitamins A, C, D, or E; carotenoids; iron; copper; zinc; magnesium; selenium; and potassium) on sex hormones or IGF-1. Of the 26 RCTs identified, nine examined effects of vitamin D, nine of multi-nutrients, four of carotenoids, two of selenium, one of zinc, and one of vitamin E. For IGF-1 increasing vitamin D (MD: −0.53 nmol/L, 95% CI: −1.58, 0.52), multi-nutrients (MD: 0.60 nmol/L, 95% CI −1.12 to 2.33) and carotenoids (MD −1.32 nmol/L; 95% CI −2.76 to 0.11) had no significant effect on circulating concentrations. No significant effects on sex hormones of other micronutrients were found, but data were very limited. All trials had significant methodological limitations making effects of micronutrient supplementation on sex hormones unclear. Further high quality RCTs with physiological doses of micronutrients in people with low baseline intakes or circulating concentrations, using robust methodology, are required to assess effects of supplementation adequately.

1. Introduction

Sarcopenia is a major problem, involving loss of skeletal muscle mass and function with age, a process beginning at approximately 40 years in both men and women [1,2,3]. One mechanism for its onset, is the age-related decline in the endocrine system, including the secretion of sex hormones and insulin-like growth hormone-1 (IGF-1) [4]. Recent evidence suggests that certain micronutrients may be protective for sarcopenia, and also important for hormone synthesis and metabolism, particularly during the decrease in endogenous secretion that occurs during aging [4]. This decrease in hormone secretion is also associated with increases in risks of falls, osteoporosis, fractures, cardiovascular disease and all-cause mortality [5,6,7,8,9,10,11,12,13,14,15,16].
The endocrine system decline with age [4] includes a decrease in testosterone concentrations of 0.5%–1% per year in men, and of oestrogen in women, that begins around 30 years of age [17,18]. The decline in testosterone concentrations in men is associated with loss of muscle mass and strength [19,20], and furthermore testosterone/dihydrotestosterone (DHT) supplementation can increase muscle strength [21]. Similarly, oestrogen concentrations, which decline more rapidly during the menopause in women [22], are closely linked to muscle strength [23]. Evidence from randomised controlled trials (RCTs) suggests oestrogen replacement therapy reduces the decline in strength of post-menopausal women [22] via a reduction in ‘FOXO3’ activation and ‘MuRF1’ protein expression [24].
The concentration of other endocrine hormones, (Dehydroepiandrosterone, DHEAS; Sex-Hormone Binding Globulin, SHBG; and Insulin-like Growth Factor-1, IGF-1) are also associated with skeletal muscle [25,26] and may be involved in the aetiology of sarcopenia since circulating concentrations change with age. DHEAS [27], which is converted into the active forms of testosterone and oestrogen, and stimulates production of IGF-1 [18], declines with age and relates to loss of muscle mass and strength [17]. SHBG transports testosterone, oestrogen, and other steroids in the blood, and increases with age thus reducing free testosterone and oestrogen [28,29,30]. The age-related decline in IGF-1 [31] is relevant due to its roles in promoting myoblast proliferation and differentiation, as well as formation of muscle fibres during normal growth, and in response to injury [32]. Alongside improving muscle hypertrophy and strength, IGF-1 also suppresses muscle inflammation and fibrosis, and is associated with skeletal muscle mass and strength [32,33,34,35,36]. Therefore, increasing concentrations of circulating IGF-1 and sex hormones may be potentially beneficial for preventing sarcopenia as well as certain non-communicable diseases and conditions of aging.
Micronutrients are potentially important for sex hormone synthesis and metabolism, particularly during the age-related decline in the endocrine system. Previous research from in-vitro, in-vivo or observational studies found that certain micronutrients including vitamin D [37,38,39,40,41,42,43,44,45,46,47], vitamin E [48,49,50], vitamin A [51], lycopene [52], iron [53], magnesium [54,55,56], selenium [57,58,59,60] or zinc [58,60,61,62,63,64,65,66,67] were associated with either androgen metabolism, testosterone concentrations or SHBG. Associations have also been found between oestrogen and vitamins C, D, E, A, and carotenoids, including lycopene [48,68,69,70,71]. IGF-1 has also been associated with lycopene [72,73,74,75], magnesium [55], selenium [57] or zinc [61,62,76,77], iron/ferritin [78] and copper [79]. These studies indicate the relevance of micronutrients to the endocrine system, although many were in individuals in young adulthood and their effects in older age have been less studied to date.
The mechanisms for the role of micronutrients in synthesis of sex hormones and IGF-1 include the involvement in steroidogenesis, via the involvement of prostaglandins, on the precursors of sex hormones, for vitamins D, E, the carotenoids, zinc and selenium, as well the effects of vitamin C [38,39,40,41,42,43,44,45,46,47,48,49,50,52,60,64,65,68,69,71,79,80,81,82,83,84,85,86], and effects on transporter proteins. Zinc is also an inhibitor of two enzymes, aromatase and 5α-reductase, that are involved in testosterone metabolism [60].
Intake of micronutrients, micronutrient deficiency, as well as protein intake, may be also important in determining the onset of sarcopenia [38,76,77,87,88,89,90,91,92,93,94,95,96]. Recent observational and animal studies found that vitamins C, D, E, and carotenoids and the minerals magnesium, selenium, iron and zinc are relevant to muscle mass and physical performance [76,77,88,89,92,97,98,99]. The mechanisms for the action of these nutrients include involvement in collagen and carnitine synthesis, for vitamin C, activities on skeletal muscle cell differentiation and proliferation, for vitamin D [38] and synthesis of protein and mitochondrial function, for magnesium [38,76,77,87,88,89,90,91,92,93,94,95,96,97].
Further mechanisms for changes in hormones and the musculoskeletal system that occur during aging are the associated increases in low grade circulating inflammatory cytokines and of ROS (Reactive Oxygen Species) [93]. A number of micronutrients act as endogenous antioxidants with the capacity to reduce ROS and circulating inflammatory cytokines. These micronutrients include vitamins A, C, E, the carotenoids [100,101,102,103,104,105], zinc [60,106], magnesium [55] and selenium [57,60]. Therefore, improving intakes or rectifying micronutrient deficiency could potentially affect both the onset of sarcopenia as well as sex hormone and IGF-1 metabolism, via a number of mechanisms, during aging. Improvements in micronutrient intake could be achieved through increased consumption of dietary whole foods, e.g., oranges (rich in vitamin C); or via supplementation of vitamins and minerals, e.g., single component or multivitamin tablets.
We are unaware of any previous systematic reviews that have investigated the importance of micronutrient intakes on sex hormones and IGF-1 in middle and older aged people at risk of sarcopenia. Therefore, given the potential role for micronutrients to influence secretion of these hormones during aging, and the importance of these sex hormones to the aetiology of sarcopenia, we conducted a systematic review (SR) to investigate the effects of dietary or supplemental intake of specified micronutrients and changes in concentration of sex hormones and IGF-1. We included adults aged 45 years or older, since this is the age at which recognisable declines in muscle mass and function, sex hormones and IGF-1 start to occur [107].

2. Materials and Methods

The systematic review was conducted in accordance with the Cochrane collaboration guidelines and reported using the PRISMA 2009 checklist [108,109]. The protocol was registered with the International prospective register of systematic reviews (PROSPERO), registration ID: CRD42018098657 [110].

2.1. Search Methods

Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE were searched to 2nd April 2019 using the ‘Population, intervention, comparators, outcomes, study design’ (PICOS) Framework (see Table 1) without date restrictions. The search strategy can be viewed in Supplementary Table S1, A, but in brief, a MEDLINE search was developed and adapted for EMBASE and Cochrane, and search limiters were used for RCTs as per the ‘Scottish Collegiate Network’ [111].

2.2. Eligibility Criteria

We included randomised controlled trials (RCTs) that assessed the effects of additional micronutrients in adults aged at least 45 years on primary outcomes. The primary outcomes were changes or differences in sex hormone concentrations, including: androgens (androstenediol, androstenedione, dihydrotestosterone and testosterone), oestrogens (E2, estradiol, estriol, and estrone), DHEAS, SHBG, and IGF-1 (see Supplementary Table S1, A). Relevant micronutrients were those with known or potential relevance to sex hormone or IGF-1 metabolism and physiology, as well as sarcopenia, and included any one, or combination, of vitamin A [48,69]; vitamin C [76]; vitamin D [38,39,40,41,42,43,44,45,46,47]; vitamin E [48,50]; carotenoids [69]; or the minerals zinc [64,65], magnesium [54], selenium, potassium [76,77], iron/ferritin [78] and copper [79].
Where studies included groups of individuals with varying age ranges, they were included if the mean age was greater than 45 years, or more than 75% of individuals were older than 45 years (in both treatment arms). We included studies that used any micronutrient or hormone extraction method, including biomarkers from blood, plasma, red blood cells, body fat, urine, hair, and nails. We excluded studies where the age of the population was unclear, or where participants stopped, started, or changed, hormonal medication, during a study. Where RCTs examined micronutrients in conjunction with another intervention, e.g., exercise, the study was included only if the comparator group received the same non-dietary intervention. Studies that included participants on active dialysis, or with kidney or liver disease [112], were excluded as these are known to affect endogenous sex hormones and IGF-1 [113,114]. In-vitro studies and studies that used foods as interventions without a reported dose of an eligible nutrient were also excluded. We accepted trials of multivitamins or multi-nutrient studies that included further compounds, other than the micronutrients previously listed. This is because some studies may have used combined vitamins for an intervention and provided information. Studies that fell into this category were reported separately, and were defined as two or more different multi-nutrients in the intervention group compared to placebo. We excluded non-English language papers that we were unable to translate within the research team.

2.3. Study Selection

Study selection was conducted in a two-phase process. Screening of titles and abstracts against inclusion/exclusion criteria (Supplementary Table S2, B) was carried out independently by two reviewers (RJ and one of DB, AA, RH, AW, SM, JC, WA). Potential titles and abstracts identified by any reviewer were collected in full text and subsequently assessed against the inclusion/exclusion criteria by at least 2 reviewers. Any disagreements were discussed, a third reviewer was not needed to clarify consensus on eligibility.

2.4. Data Extraction

We created and tested a data extraction form for this review (Supplementary Table S3, C). Data extracted included: publication details, aims, objectives, country, setting, design, dates, funding, recruitment method, ethical review, participant demographics, intervention descriptions (including: micronutrient type and extraction methods) and outcomes (method of extraction and hormone type). Data extraction and risk of bias assessment was completed independently in duplicate by RJ and another review team member. We were unable to contact authors on any queries regarding data due to time constraints.

2.5. Risk of Bias (Quality Assessment)

Risk of bias assessment was based on the Cochrane Risk of Bias tool (https://handbook-5-1.cochrane.org/chapter_8/table_8_5_a_the_cochrane_collaborations_tool_for_assessing.htm) (Supplementary Table S4, D) [115]. Alongside the typical seven standard domains, we included three further items: ‘hormonal treatment’ bias, where participants may be taking medication(s) that influence sex hormones; ‘sponsorship’ bias, where funding by companies may have influenced the outcome of results; and ‘outcome measurement’ bias, which concerns the differences in accuracy of extraction methods. The Journal of Clinical Endocrinology and Metabolism [116] recommends measurement of sex hormones to be conducted using mass spectrometry, as this conveys the highest degree of accuracy, and lowest bias. Studies that used other (less reliable) methods of hormone extraction, e.g., direct immunoassay [117] or electro chemiluminescent assay [118], were assessed to be at high risk of outcome measurement bias.

2.6. Data Synthesis and Statistical Analysis

Meta-analyses were performed only where at least two trials could be combined. We used a random effects model in ‘Review Manager (RevMan) [Computer program] [119]. We produced the forest plots using ‘end data’ for intervention and placebo groups. Outcomes were ‘continuous’ and data for IGF-1, testosterone, and SHBG, reported in non-standard units were converted using an online tool (http://unitslab.com/node/230). Where meta-analysis was not possible or data could not be converted or utilised, results were narratively reported. Some studies reported data as ‘median’ values so could not be included in a meta-analysis, but have been included in some forest plots to help illustrate overall effects. Sensitivity analysis, using fixed-effects meta-analysis, was carried out where at least two trials were combined. Comparison between random and fixed effects meta-analysis allowed small study bias to be assessed [120]. We also intended to use funnel plots to assess small study (publication) bias; but as no meta-analysis included at least 10 studies, this was not useful.

3. Results

A total of 7623 titles and abstracts were identified from the three separate databases. After the removal of duplicates, 5444 papers remained, of which 5043 were excluded based on title and abstract screening. The remaining 400 studies were assessed in full text, leaving a total of 26 eligible studies. The majority of excluded studies (n = 374) were excluded due to the population age or study design. A summary overview of the selection process is provided in Figure 1.
The 26 eligible RCTs examined a range of micronutrients: vitamin D (9, 35%), multi-nutrients (9, 35%), carotenoids (4, 15%), selenium (2, 8%), vitamin E (1, 4%) and zinc (1, 4%). Briefly, a total of 2443 participants were examined. Interventions ranged from 4 weeks to 48 months and participants were mostly males (~64%). Some studies (9, 35%) included individuals who either had a histological diagnosis of prostate cancer or colon cancer, evidence of increasing prostate specific antigen (PSA), or a family history of cancer. Other studies (8, 31%) examined individuals with metabolic syndrome (including obesity) and/or cardiovascular disease. Different races/ethnic groups were also studied, including: Asian, Black, Latino and White. Details of the study characteristics can be found in Supplementary Table S5, E. An overview of the risk of bias for RCTs is shown in Figure 2. We found no trials assessing effects of vitamins A or C, potassium, iron or copper on our outcomes.

3.1. Risk of Bias of Included RCTs

Methods of minimising selection bias were poorly reported, with 54% (14/26) and 77% (20/26) of RCT studies being unclear in methodology of ‘randomisation’ and ‘allocation concealment’, respectively (Figure 2). Many studies (58%, or 15/26) minimised performance bias by blinding participants and study personnel, and a smaller proportion (42%, or 11/26) successfully reported blinding of outcomes. Incomplete outcome data was minimised, as was the influence of hormonal treatments on sex hormones (mainly through comprehensive exclusion criteria). Only a small proportion of studies (~12%) advised participants to change their dietary habits in addition to any intervention or placebo. The majority of studies (88%, or 23/26) reported serum blood concentrations, with 12% (3/26) estimating micronutrient intake from dietary assessment questionnaires. Although extraction using serum analysis for micronutrients may pick up coagulants and other trace elements, there appears to be a non-significant variation between plasma and serum values. It is unclear whether the coagulants or trace elements would influence supplemented or non-supplemented cohorts differently. It is worth noting, Olmedilla-Alonso et al. [121] found retinol, gamma- and alpha-tocopherol serum values were positively biased (mean difference of less than: 0.05, 0.01 and 0.7 µmol/L, respectively) when compared to plasma values [121]. However, this is unlikely to influence our results as we only identified one trial with vitamin E within our systematic review. Only 8% (2/26) of studies measured sex hormones using the gold standard recommendation of mass spectrometry [122].

3.2. Vitamin D

Nine studies assessed effects of vitamin D on relevant outcomes [116,123,124,125,126,127,128,129,130] but no studies assessed effects on androstenediol, androstenedione, dihydrotestosterone, estriol, or DHEAS. Vitamin D doses varied from 100 IU [130], through 1000 IU [125], 4000 IU [129], 20,000 IU [128] up to 40,000 IU [123], and one was unclear [126]. Baseline vitamin D status was low in some trials [128,129], normal in some [127] and unknown in others [123,124]. Study duration ranged from 6 weeks [130] through 1 year [116,123,125], up to 36 months [129].

3.2.1. Effects of Vitamin D on IGF-1

Four studies [123,124,125,131] assessed the effects of vitamin D supplementation on IGF-1 over 4 weeks to 12 months. We presented the Kamycheva trial [123] as two groups, severely obese (study participants with >35 kg/m2) and non-severely obese (other participants), as results were presented this way in the paper. Meta-analysis demonstrated no significant effects of the intervention (mean difference: −0.53 nmol/L, 95% CI: −1.58, 0.52, 3 RCTs, I2 0%, Figure 3). One trial [124] could not be included in the meta-analysis because it was not possible to convert the units of IGF-1 used (μg/10E06 platelets) to nmol/L. This was a 4-week RCT that confirmed a statistically non-significant mean difference of 0.007 μg/10E06 platelets, p = 0.413 between intervention and placebo post intervention. The four included trials randomised 447 participants (mean age: 55.2, 59% males, including dropouts) from Norway [123], USA [124,125] and Austria [131]. Studies used a variety of vitamin D dosages: 400 IU [124] 1000 IU [125], 2800 IU [131] and 40,000 IU [123].
Major sources of bias within these studies included randomisation procedures (sequence generation and allocation concealment) and blinding (Figure 3). Only one trial was at low risk of attrition bias, and no studies used ‘mass spectrometry’ to measure sex hormone concentrations, so all were at high risk of outcome assessment bias.
The lack of effect of increasing vitamin D on IGF-1 was confirmed in the set of trials which supplemented with vitamin D and other compounds (two or more micronutrients) (Figure 3). Combining all the trials increasing vitamin D (individually or as part of a broader intervention) suggests little or no effect on IGF-1 (MD: −0.27 nmol/L, 95% CI −1.20 to 0.67, I2 0%). This did not differ in sensitivity analysis using fixed-effects meta-analysis (MD: −0.27 nmol/L, 95% CI −1.20 to 0.67, I2 0%). The difference in effect size between fixed- and random-effects meta-analysis suggests that there may be some small study bias present.
The effect of differing baseline vitamin D status, doses and study duration were assessed in sub-grouping. There were no differences between subgroups in any analysis (p ≥ 0.85 for all subgroupings, not shown).

3.2.2. Effects of Vitamin D on Testosterone

Five trials reported effects of vitamin D on testosterone. They included 754 participants (54% male) from China [126], The Netherlands [127], Austria [128], Germany [129] and USA [116]. All included women were post-menopausal. Only two studies could be combined in meta-analysis, suggesting no effect of vitamin D on free testosterone (MD 0.00, 95% CI −0.00 to 0.00, I2 0%, Figure 4). The effect did not differ in sensitivity analysis using fixed-effects meta-analysis, suggesting a lack of small study bias, although with only two trials this is difficult to assess. The other trials (shown in Figure 4 though not combined in meta-analysis) reported data as medians and interquartile ranges [127,128]. One study did not specify which type of testosterone was measured and did not provide enough data to be included [126].
The two trials that could be combined appeared to have adequate randomisation and blinding, though only one had adequate allocation concealment. Neither was at a low risk of outcome measurement bias.

3.2.3. Effects of Vitamin D on Oestradiol

Two trials assessed effects of vitamin D on oestradiol, but could not be combined in meta-analysis. Individually, neither found a statistically significant effect of supplementation [116,126].

3.2.4. Effects of Vitamin D on SHBG

Three studies reported effects of vitamin D on SHBG, randomising 445 participants (51% male) [116,128,129]. Meta-analysis of two RCTs suggested a small though non-statistically significant increase in SHBG with vitamin D (MD 4.18 nmol/L, 95% CI −1.28 to 9.64, I2 0%, Figure 5), but data from the third trial contradicted this finding. Two of the three trials were at low risk of selection bias, and all were well blinded, and one used a low risk method of outcome assessment (Figure 5).

3.3. Multi-Nutrients

Nine studies assessed effects of multi-nutrients (defined as two or more different micronutrients in the intervention group) on relevant outcomes, but no studies assessed effects on androstenediol, androstenedione, E2, estradiol, estriol, estrone, or DHEAS. Those studies that also included vitamin D within the multi-nutrient interventions are also covered in Section 3.2.

3.3.1. Effects of Multi-Nutrient Supplements on IGF-1

Seven of the nine studies identified as multi-nutrient interventions [130,132,133,134,135,136,137] reported on IGF-1, suggesting little or no effect (MD: 0.60 nmol/L, 95% CI −1.12 to 2.33, I2 0%, 519 participants, Figure 6). Effects did not differ in fixed-effects meta-analysis (MD: 0.60 nmol/L, 95% CI −1.12 to 2.33), suggesting that small study bias is not an issue here.
The Jensen et al. study [137] analysed data using a ‘per-protocol’ method which introduced potential bias [138], since the 20% of study participants withdrew. All seven studies measured micronutrient concentrations from blood samples, but none used mass-spectrometry to measure sex hormone concentrations, and many were unclear on selection bias and blinding.

3.3.2. Effects of Multi-Nutrients on Testosterone

Two trials carried out in the Netherlands reported effects of multi-nutrient interventions on testosterone in men with rising levels of prostate-specific antigen (117 males, mean age: 72), and reported opposing findings (Figure 6). We were unable to meta-analyse these findings as Kranse did not provide any measure of variance. However, Hoenjet, 2005 [139] suggested no effect on testosterone concentrations (p = 0.28), while Kranse, 2005 [140] (cross-over trial) suggested significant reductions in testosterone but reported different numbers in different places in their paper, so the effect size was unclear (p = 0.02). Both trials were at unclear risk of selection bias and low risk of blinding problems.

3.3.3. Effects of Multi-Nutrients on Dihydrotestosterone and SHBG

The same two trials (Kranse, 2005; and Hoenjet, 2005) also assessed the effect of multi-nutrient supplementation on Dihydroteststerone and SHBG (Figure 6), but again Kranse provided no measure of variance and two different effect sizes, so could not be pooled. Multi-nutrient supplementation in Kranse, 2005, reportedly significantly decreased Dihydrotestosterone, but the effect size was unclear (p = 0.005), whereas, in Hoenjet 2005, non-significant findings were reported (MD: 0.1 nmol/L, 95% CI −0.1 to 0.2, p = 0.72). After supplementation with multi-nutrients, both studies reported non-significant decreases in SHBG.

3.4. Carotenoids

Four trials assessed the effects of carotenoids on relevant outcomes, but none assessed the effects on androgens (androstenediol, androstenedione, dihydrotestosterone or testosterone), oestrogens (E2, estradiol, estriol, or estrone), DHEAS or SHBG.

Effects of Carotenoids on IGF-1

Four studies [52,80,81,82] examined the effects of lycopene, all using ‘Lyco-O-Mato’ (containing ~15 mg lycopene, plus 1.5 mg phytoene, 1.4 mg phytofluene, 0.4 mg beta-carotene, and 5 mg alpha tocopherol). Meta-analysis of 278 randomised participants (mean age: 63.0, 75% male) showed a non-significant decrease in IGF-1 as a result of the added carotenoids (MD −1.32 nmol/L; 95% CI −2.76 to 0.11, I2 0%, Figure 6). None of the trials were at low risk of selection bias, but two were at low risk from issues around blinding (performance and detection bias), and none used mass-spectrometry to measure hormone concentrations (Figure 7).
Trials of carotenoids as part of multi-nutrient supplementation (Figure 7), confirmed a small non-significant decrease in IGF-1 (MD: −0.39, 95% CI −2.90 to 0.11, I2 0%). These trials also demonstrated significant sources of bias (see earlier).
Overall effects of carotenoids (in either individual or multi-nutrient studies) suggested no important effect of carotenoids on IGF-1 (MD: −1.09, 95% CI −2.34 to 0.16, I2 0%), which did not differ in sensitivity analysis using fixed effects meta-analysis (MD: −1.09, 95% CI −2.34 to 0.16). This suggested minimal small study bias.

3.5. Selenium

Two studies assessed effects of selenium on testosterone, but no studies assessed effects on oestrogens (E2, estradiol, estriol, or estrone), DHEAS, SHBG, IGF-1 or androgens other than testosterone.

Effects of Selenium on Testosterone

Two studies in the Czech Republic examined the effects of 240 μg of selenium (as selenomethionine) on testosterone. Both intervention and placebo also received 570 mg of silymarin, an extract of milk thistle [141,142]. Both suggested no significant effects on testosterone.

3.6. Vitamin E

One study assessed the effects of Vitamin E on DHEAS, but no studies assessed the effects on androgens (androstenediol, androstenedione, dihydrotestosterone and testosterone), oestrogens (E2, estradiol, estriol, and estrone), SHBG, or IGF-1.

Effects of Vitamin E on DHEAS

Amsterdam 2005 [143] found that 200 mg vitamin E (as dl-alpha-tocopheryl acetate) over 15 months lead to a significant decrease in DHEAS in the supplemented group (p < 0.02) but not the placebo group (p > 0.05). The authors concluded there was no overall significant benefit to vitamin E supplementation.

3.7. Zinc

One study assessed effects of zinc on IGF-1, but no studies assessed effects on androgens (androstenediol, androstenedione, dihydrotestosterone and testosterone), oestrogens (E2, estradiol, estriol, and estrone), DHEA or SHBG.

Effects of Zinc on IGF-1

A Swiss trial by Rodondi, 2009 [61] (n = 69, mean age 85, 86% female) reported that supplementation of 30 mg/day of zinc (alongside 15 g whey protein + 5 g amino acids) increased serum IGF-1 over a week compared to protein alone (+48.2% vs. +22.4%, respectively; p < 0.027), but there was no statistically significant difference between groups at 4 weeks (+29.2% vs. +45.8%; p > 0.05).

4. Discussion

We found 26 trials assessing effects of micronutrient supplementation, but no trials assessing effects of vitamins A or C, potassium, iron, or copper, on our outcomes. Data from nine trials suggested that supplementation with vitamin D had little or no effect on IGF-1, with or without other micronutrient compounds. Vitamin D also failed to significantly alter testosterone or oestradiol, and the effects on SHBG and other outcomes were unclear. The multinutrient trials did not suggest statistically significant increases in IGF-1, and the effects on testosterone, dihydrotestosterone and SHBG were unclear. Data were very limited for effects of other micronutrients. Four trials suggested that carotenoids slightly reduce IGF-1 and this was reinforced with the inclusion of other micronutrients (though none of the relationships were statistically significant). Selenium appears to have little effect on testosterone (2 trials), vitamin E had no effect on DHEAS, and zinc had little or no effect on IGF-1 (a single trial each).
Despite our systematic search including a large range of relevant micronutrients and hormones, we only identified studies that investigated effects of vitamin D, multi-nutrients, the carotenoids, selenium, vitamin E, and zinc, on sex hormones and IGF-1. To the best of our knowledge, this is the first systematic review examining the relationship between this range of micronutrients, sex hormones and IGF-1 in people of middle and older age. We conducted the review using established Cochrane methodology [115].
Despite the biochemical, physiological and mechanistic roles of micronutrients for hormone synthesis in older age our review found a paucity of trials and little direct evidence of significant effects of micronutrient supplementation [38,39,40,41,42,43,44,45,46,47,48,49,50,52,60,64,65,68,69,71,79,80,81,82,83,84,85,86]. Since the age-related decline in sex-hormones and IGF-1 not only increases the risk of sarcopenia, but also a number of conditions of aging, including falls, osteoporosis, fractures, cardiovascular disease and all-cause mortality, this is unfortunate [5,6,7,8,9,10,11,12,13,14,15,16].

Limitations of the Available Data

Whilst we identified 26 RCTs of adults aged at least 45 years that met our eligibility criteria, when grouped by micronutrient and sex-hormone, the number of studies in each category was small (between one and nine studies per nutrient), and many had methodological limitations. A number of the studies had small sample sizes or lack of control for dietary or lifestyle determinants in the intervention and control groups [52,80,82] and one study [137,138] also analysed data using a ‘per-protocol’ method which may have introduced bias elements of bias [138].
For multi-nutrient interventions the composition of the nutrients varied substantially [130,132,133,134,135,136] with some containing more than 20 different micronutrients [132,137], making it difficult to attribute benefit to any specific micronutrient. A number of studies also included additional protein making it difficult to isolate any specific effects of micronutrients from those of protein [61,132,137,144,145]. The baseline nutritional status of participants was not taken into account in a number of studies despite baseline status or deficiency being likely to determine the response to interventions. Some studies also included dietary advice to increase sources of calcium, which may have affected the results of the intervention.
Whilst we found no significant effect of the supplementation of micronutrients on circulating sex hormones and IGF-1, the scale of effects for the few studies that included IGF-1 ranged between mean differences for vitamin D of −0.53 nmol/L (95% CI: −1.58, 0.52), for multi-nutrients of 0.60 nmol/L (95% CI −1.12 to 2.33) and carotenoids of −1.32 nmol/L (95% CI −2.76 to 0.11). This compares with the difference for IGF-1 between age groups 50–54 years to 70–74 years of −3.4 nmol/L [146,147]. Although the effect sizes found with micronutrients and IGF-1 in our analysis were non-significant, and smaller than with age, these differences may have potential importance if found to be significant in future well-designed trials.

5. Recommendations for Future Studies

Although our systematic review demonstrated no conclusive effects of the supplementation of micronutrients on sex hormones in middle- and older-aged people, we recommend that larger RCTs are conducted specifically targeting the micronutrients where we found little or no existing research (magnesium, zinc, vitamins A, C and E, iron, copper and potassium). Future RCTs should be of sufficient size and include baseline and follow-up measures of dietary intake (such as with food frequency questionnaires), as well as using blood concentrations of the relevant micronutrients. This would clarify whether micronutrient supplementation is only beneficial to depleted individuals or whether it can provide additional benefit to those with adequate micronutrient status. Direct measurements of micronutrient status have advantages as they are independent of potential reporting bias, are integrated measurements of intake and other physiological and lifestyle influences on status, such as smoking habit, and can be used to determine whether supplementation results in improved micronutrient status [148,149,150]. Furthermore, dosages of micronutrients should be designed to rectify any pre-existing micronutrient deficiency. Additionally, extraction of hormones should be performed using mass spectrometry, and SHBG should be measured to account for changes to free oestrogen and testosterone that may occur during the intervention. Other known lifestyle factors that affect circulating sex hormones and IGF-1, such as smoking habit and BMI should also be recorded [146,147]. An optimal follow-up time has yet to be elucidated but we would recommend a minimum of 6 months, and that endocrine and nutritional measurements be taken at 3 month intervals until the study is complete.

6. Conclusions

Effects of micronutrient supplementation on sex hormones and IGF-1 are unclear. Further high quality RCTs with physiological doses of micronutrients in people with low baseline intakes or circulating concentrations, using robust methodology, are required to assess effects adequately.

Supplementary Materials

The following are available online at https://www.mdpi.com/2072-6643/12/5/1457/s1, Table S1, E: Search Strategy Form, Table S2, B: Inclusion/Exclusion Form, Table S3, C: Data Extraction Form, Table S4, D: Systematic review Cochrane Risk of Bias Form, Table S5, E: Table of Characteristics of RCTs (n = 26).

Author Contributions

Conceptualization, A.W.; methodology, A.W., L.H., D.B., A.A., R.J.; formal analysis, L.H., R.J., A.A., D.B.; writing—original draft preparation, R.J., A.W., D.B., A.A.; writing—review and editing, A.W., D.B., A.A., L.H., R.H.; data extraction and screening, R.J., D.B., A.A., A.W., R.H., L.H., S.M., J.H.-C., W.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding but was partly funded by MRES funding to R.J. from Norwich Medical School.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Epidemiologic and methodologic problems in determining nutritional status of older persons. Proceedings of a conference. Albuquerque, New Mexico, October 19–21, 1988. Am. J. Clin. Nutr. 1989, 50 (Suppl. 5), 1121–1235.
  2. Boss, G.R.; Seegmiller, J.E. Age-Related Physiological Changes and Their Clinical Significance. West. J. Med. 1981, 135, 434–440. [Google Scholar] [PubMed]
  3. Marzetti, E.; on behalf of the SPRINTT Consortium; Calvani, R.; Tosato, M.; Cesari, M.; Di Bari, M.; Cherubini, A.; Collamati, A.; D’Angelo, E.; Pahor, M.; et al. Sarcopenia: An overview. Aging Clin. Exp. Res. 2017, 29, 11–17. [Google Scholar] [CrossRef] [PubMed]
  4. Marty, E.; Liu, Y.; Samuel, A.; Or, O.; Lane, J. A review of sarcopenia: Enhancing awareness of an increasingly prevalent disease. Bone 2017, 105, 276–286. [Google Scholar] [CrossRef] [PubMed]
  5. Vandenput, L.; Mellström, D.; A Laughlin, G.; Cawthon, P.M.; A Cauley, J.; Hoffman, A.R.; Karlsson, M.K.; Rosengren, B.E.; Ljunggren, Ö.; Nethander, M.; et al. Low Testosterone, but Not Estradiol, Is Associated With Incident Falls in Older Men: The International MrOS Study. J. Bone Min. Res. 2017, 32, 1174–1181. [Google Scholar] [CrossRef]
  6. Roddam, A.W.; Appleby, P.; Neale, R.E.; Dowsett, M.; Folkerd, E.; Tipper, S.; Allen, N.E.; Key, T.J. Association between endogenous plasma hormone concentrations and fracture risk in men and women: The EPIC-Oxford prospective cohort study. J. Bone Min. Metab. 2009, 27, 485–493. [Google Scholar] [CrossRef]
  7. Khaw, K.-T.; Dowsett, M.; Folkerd, E.; Bingham, S.; Wareham, N.; Luben, R.N.; Welch, A.; Day, N. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 2007, 116, 2694–2701. [Google Scholar] [CrossRef] [Green Version]
  8. Guadalupe-Grau, A.; Carnicero, J.A.; Losa-Reyna, J.; Tresguerres, J.; Gomez-Cabrera, M.C.; Castillo, C.; Alfaro-Acha, A.; Rosado-Artalejo, C.; Rodríguez-Mañas, L.; Garcia-Garcia, F.J. Endocrinology of Aging From a Muscle Function Point of View: Results from the Toledo Study for Healthy Aging. J. Am. Med. Dir. Assoc. 2017, 18, 234–239. [Google Scholar] [CrossRef]
  9. Clegg, D.; Hevener, A.L.; Moreau, K.L.; Morselli, E.; Criollo, A.; Van Pelt, R.E.; Vieira-Potter, V.J. Sex Hormones and Cardiometabolic Health: Role of Estrogen and Estrogen Receptors. Endocrinology 2017, 158, 1095–1105. [Google Scholar] [CrossRef]
  10. Diamanti-Kandarakis, E.; Dattilo, M.; Macut, Đ.; Duntas, L.H.; Gonos, E.S.; Goulis, D.G.; Kanaka-Gantenbein, C.; Kapetanou, M.; Koukkou, E.G.; Lambrinoudaki, I.; et al. MECHANISMS IN ENDOCRINOLOGY: Aging and anti-aging: A Combo-Endocrinology overview. Eur. J. Endocrinol. 2017, 176, R283–R308. [Google Scholar] [CrossRef]
  11. Horstman, A.M.; Dillon, E.L.; Urban, R.J.; Sheffield-Moore, M. The role of androgens and estrogens on healthy aging and longevity. J. Gerontol. A Biol. Sci. Med. Sci. 2012, 67, 1140–1152. [Google Scholar] [CrossRef] [Green Version]
  12. Yeap, B.B.; Alfonso, H.; Chubb, S.A.P.; Center, J.R.; Beilin, J.; Hankey, G.J.; Almeida, O.P.; Golledge, J.; Norman, P.; Flicker, L. U-Shaped Association of Plasma Testosterone, and no Association of Plasma Estradiol, with Incidence of Fractures in Men. J. Clin. Endocrinol. Metab. 2020, 105. [Google Scholar] [CrossRef] [PubMed]
  13. Moreau, K.L.; Babcock, M.C.; Hildreth, K.L. Sex differences in vascular aging in response to testosterone. Biol. Sex Differ. 2020, 11, 18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Karlamangla, A.S.; Burnett-Bowie, S.M.; Crandall, C.J. Bone Health during the Menopause Transition and Beyond. Obstet. Gynecol. Clin. N. Am. 2018, 45, 695–708. [Google Scholar] [CrossRef] [PubMed]
  15. Hidayat, K.; Du, X.; Shi, B.M. Sex hormone-binding globulin and risk of fracture in older adults: Systematic review and meta-analysis of observational studies. Osteoporos Int. 2018, 29, 2171–2180. [Google Scholar] [CrossRef]
  16. Brundle, C.; Heaven, A.; Brown, L.; Teale, E.; Young, J.; West, R.; Clegg, A. Convergent validity of the electronic frailty index. Age Ageing 2019, 48, 152–156. [Google Scholar] [CrossRef]
  17. Morley, J.E. Hormones and Sarcopenia. Curr. Pharm. Des. 2017, 23, 4484–4492. [Google Scholar] [CrossRef]
  18. Maggio, M.; Lauretani, F.; Ceda, G.P. Sex hormones and sarcopenia in older persons. Curr. Opin. Clin. Nutr. Metab. Care 2013, 16, 3–13. [Google Scholar] [CrossRef]
  19. Baumgartner, R.N.; Waters, D.L.; Gallagher, D.; Morley, J.E.; Garry, P.J. Predictors of skeletal muscle mass in elderly men and women. Mech. Ageing Dev. 1999, 107, 123–136. [Google Scholar] [CrossRef]
  20. Mouser, J.G.; Loprinzi, P.D.; Loenneke, J.P. The association between physiologic testosterone levels, lean mass, and fat mass in a nationally representative sample of men in the United States. Steroids 2016, 115, 62–66. [Google Scholar] [CrossRef]
  21. Ottenbacher, K.J.; Ottenbacher, M.E.; Ottenbacher, A.J.; Acha, A.A.; Ostir, G.V. Androgen Treatment and Muscle Strength in Elderly Males: A Meta-Analysis. J. Am. Geriatr. Soc. 2006, 54, 1666–1673. [Google Scholar] [CrossRef]
  22. Tiidus, P.M. Benefits of Estrogen Replacement for Skeletal Muscle Mass and Function in Post-Menopausal Females: Evidence from Human and Animal Studies. Eurasian J. Med. 2011, 43, 109–114. [Google Scholar] [CrossRef] [PubMed]
  23. Samson, M.M.; Meeuwsen, I.B.; Crowe, A.; Dessens, J.A.; Duursma, S.A.; Verhaar, H.J. Relationships between physical performance measures, age, height and body weight in healthy adults. Age Ageing 2000, 29, 235–242. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Park, Y.-M.; Keller, A.C.; Runchey, S.S.; Miller, B.F.; Kohrt, W.M.; Van Pelt, R.E.; Kang, C.; Jankowski, C.M.; Moreau, K.L. Acute estradiol treatment reduces skeletal muscle protein breakdown markers in early- but not late-postmenopausal women. Steroids 2019, 146, 43–49. [Google Scholar] [CrossRef] [PubMed]
  25. Velders, M.; Diel, P. How sex hormones promote skeletal muscle regeneration. Sports Med. 2013, 43, 1089–1100. [Google Scholar] [CrossRef]
  26. Taekema, D.G.; Ling, C.H.; Blauw, G.J.; Meskers, C.G.; Westendorp, R.G.J.; De Craen, A.J.M.; Maier, A.B. Circulating levels of IGF1 are associated with muscle strength in middle-aged- and oldest-old women. Eur. J. Endocrinol. 2011, 164, 189–196. [Google Scholar] [CrossRef] [Green Version]
  27. Warner, M.; Gustafsson, J.A. DHEA-a precursor of ERbeta ligands. J. Steroid Biochem. Mol. Biol. 2015, 145, 245–247. [Google Scholar] [CrossRef]
  28. Selby, C. Sex hormone binding globulin: Origin, function and clinical significance. Ann. Clin. Biochem. 1990, 27 Pt 6, 532–541. [Google Scholar] [CrossRef]
  29. Liu, P.Y.; Beilin, J.; Nguyen, T.V.; Center, J.R.; Meier, C.; Leedman, P.J.; Seibel, M.; A Eisman, J.; Handelsman, D.J. Age-Related Changes in Serum Testosterone and Sex Hormone Binding Globulin in Australian Men: Longitudinal Analyses of Two Geographically Separate Regional Cohorts. J. Clin. Endocrinol. Metab. 2007, 92, 3599–3603. [Google Scholar] [CrossRef] [Green Version]
  30. Longcope, C.; Goldfield, S.R.; Brambilla, D.J.; McKinlay, J. Androgens, estrogens, and sex hormone-binding globulin in middle-aged men. J. Clin. Endocrinol. Metab. 1990, 71, 1442–1446. [Google Scholar] [CrossRef]
  31. Pang, A.L.-Y.; Chan, W.-Y. Chapter 22-Molecular Basis of Diseases of the Endocrine System. In Essential Concepts in Molecular Pathology; Coleman, W.B., Tsongalis, G.J., Eds.; Academic Press: San Diego, CA, USA, 2010; pp. 289–307. [Google Scholar]
  32. Philippou, A.; Barton, E.R. Optimizing IGF-I for skeletal muscle therapeutics. Growth Horm. IGF Res. 2014, 24, 157–163. [Google Scholar] [CrossRef] [Green Version]
  33. Secco, M.; Bueno, C.; Vieira, N.M.; Almeida, C.; Pelatti, M.; Zucconi, E.; Bartolini, P.; Vainzof, M.; Miyabara, E.; Okamoto, O.K.; et al. Systemic delivery of human mesenchymal stromal cells combined with IGF-1 enhances muscle functional recovery in LAMA2 dy/2j dystrophic mice. Stem Cell Rev. 2013, 9, 93–109. [Google Scholar] [CrossRef] [PubMed]
  34. Rybalko, V.Y.; Pham, C.B.; Hsieh, P.-L.; Hammers, D.W.; Merscham-Banda, M.; Suggs, L.J.; Farrar, R.P. Controlled delivery of SDF-1alpha and IGF-1: CXCR4(+) cell recruitment and functional skeletal muscle recovery. Biomater. Sci. 2015, 3, 1475–1486. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Bucci, L.; Yani, S.L.; Fabbri, C.; Bijlsma, A.Y.; Maier, A.B.; Meskers, C.G.; Narici, M.; Jones, D.A.; McPhee, J.S.; Seppet, E.; et al. Circulating levels of adipokines and IGF-1 are associated with skeletal muscle strength of young and old healthy subjects. Biogerontology 2013, 14, 261–272. [Google Scholar] [CrossRef] [PubMed]
  36. Mohamad, M.I.; Khater, M.S. Evaluation of insulin like growth factor-1 (IGF-1) level and its impact on muscle and bone mineral density in frail elderly male. Arch. Gerontol. Geriatr. 2015, 60, 124–127. [Google Scholar] [CrossRef]
  37. Harrison, P. Low Vitamin D Tied to Testosterone Dip in Healthy Men 2015 [Vitamin D and Testosterone]. Available online: https://www.medscape.com/viewarticle/845483 (accessed on 4 March 2020).
  38. Ceglia, L.; Harris, S.S. Vitamin D and its role in skeletal muscle. Calcif Tissue Int. 2013, 92, 151–162. [Google Scholar] [CrossRef]
  39. Azadi-Yazdi, M.; Nadjarzadeh, A.; Khosravi-Boroujeni, H.; Salehi-Abargouei, A. The Effect of Vitamin D Supplementation on the Androgenic Profile in Patients with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Clinical Trials. Horm. Metab. Res. 2017, 49, 174–179. [Google Scholar] [CrossRef] [Green Version]
  40. Zhao, D.; Ouyang, P.; De Boer, I.H.; Lutsey, P.L.; Farag, Y.M.; Guallar, E.; Siscovick, D.S.; Post, W.S.; Kalyani, R.R.; Billups, K.L.; et al. Serum vitamin D and sex hormones levels in men and women: The Multi-Ethnic Study of Atherosclerosis (MESA). Maturitas 2017, 96, 95–102. [Google Scholar] [CrossRef] [Green Version]
  41. Rafiq, R.; Van Schoor, N.; Sohl, E.; Zillikens, M.; Oosterwerff, M.; Schaap, L.; Lips, P.; De Jongh, R. Associations of vitamin D status and vitamin D-related polymorphisms with sex hormones in older men. J. Steroid Biochem. Mol. Boil. 2016, 164 (Suppl. C), 11–17. [Google Scholar] [CrossRef]
  42. Chin, K.Y.; Ima-Nirwana, S.; Wan Ngah, W.Z. Vitamin D is significantly associated with total testosterone and sex hormone-binding globulin in Malaysian men. Aging Male 2015, 18, 175–179. [Google Scholar] [CrossRef]
  43. Lerchbaum, E.; Pilz, S.; Trummer, C.; Rabe, T.; Schenk, M.; Heijboer, A.C.; Obermayer-Pietsch, B. Serum vitamin D levels and hypogonadism in men. Andrology 2014, 2, 748–754. [Google Scholar] [CrossRef]
  44. Anic, G.M.; Albanes, D.; Rohrmann, S.; Kanarek, N.; Nelson, W.G.; Bradwin, G.; Rifai, N.; McGlynn, K.A.; Platz, E.A.; Mondul, A.M. Association between serum 25-hydroxyvitamin D and serum sex steroid hormones among men in NHANES. Clin. Endocrinol. 2016, 85, 258–266. [Google Scholar] [CrossRef] [PubMed]
  45. Chang, E.M.; Kim, Y.S.; Won, H.J.; Yoon, T.K.; Lee, W.S. Association between Sex Steroids, Ovarian Reserve, and Vitamin D Levels in Healthy Nonobese Women. J. Clin. Endocrinol. Metab. 2014, 99, 2526–2532. [Google Scholar] [CrossRef] [PubMed]
  46. Jorde, R.; Grimnes, G.; Hutchinson, M.S.; Kjaergaard, M.; Kamycheva, E.; Svartberg, J. Supplementation with vitamin D does not increase serum testosterone levels in healthy males. Horm. Metab. Res. 2013, 45, 675–681. [Google Scholar] [CrossRef] [PubMed]
  47. Hammoud, A.O.; Wayne Meikle, A.; Matthew Peterson, C.; Stanford, J.; Gibson, M.; Carrell, D.T. Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters. Asian J. Androl. 2012, 14, 855–859. [Google Scholar] [CrossRef] [Green Version]
  48. Mumford, S.L.; Browne, R.W.; Schliep, K.C.; Schmelzer, J.; Plowden, T.C.; A Michels, K.; Sjaarda, L.; Zarek, S.M.; Perkins, N.; Messer, L.; et al. Serum Antioxidants Are Associated with Serum Reproductive Hormones and Ovulation among Healthy Women. J. Nutr. 2016, 146, 98–106. [Google Scholar] [CrossRef] [Green Version]
  49. Barella, L.; Rota, C.; Stocklin, E.; Rimbach, G. Alpha-tocopherol affects androgen metabolism in male rat. Ann. New York Acad. Sci. 2004, 1031, 334–336. [Google Scholar] [CrossRef]
  50. Hartman, T.J.; Dorgan, J.F.; Woodson, K.; Virtamo, J.; A Tangrea, J.; Heinonen, O.P.; Taylor, P.R.; Barrett, M.J.; Albanes, D. Effects of long-term alpha-tocopherol supplementation on serum hormones in older men. Prostate 2001, 46, 33–38. [Google Scholar] [CrossRef]
  51. Hogarth, C.A.; Griswold, M.D. The key role of vitamin A in spermatogenesis. J. Clin. Investig. 2010, 120, 956–962. [Google Scholar] [CrossRef] [Green Version]
  52. Kucuk, O.; Sarkar, F.H.; Sakr, W.; Djuric, Z.; Pollak, M.N.; Khachik, F.; Li, Y.W.; Banerjee, M.; Grignon, D.; Bertram, J.S.; et al. Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy. Cancer Epidemiol. Biomark. Prev. 2001, 10, 861–868. [Google Scholar]
  53. Rotter, I.; Kosik-Bogacka, D.I.; Dolegowska, B.; Safranow, K.; Kuczynska, M.; Laszczynska, M. Analysis of the relationship between the blood concentration of several metals, macro- and micronutrients and endocrine disorders associated with male aging. Environ. Geochem. Health 2016, 38, 749–761. [Google Scholar] [CrossRef]
  54. Rotter, I.; Kosik-Bogacka, D.; Dolegowska, B.; Safranow, K.; Karakiewicz, B.; Laszczynska, M. Relationship between serum magnesium concentration and metabolic and hormonal disorders in middle-aged and older men. Magnes. Res. 2015, 28, 99–107. [Google Scholar] [CrossRef] [PubMed]
  55. Maggio, M.; Ceda, G.; Lauretani, F.; Cattabiani, C.; Avantaggiato, E.; Morganti, S.; Ablondi, F.; Bandinelli, S.; Dominguez, L.-J.; Barbagallo, M.; et al. Magnesium and anabolic hormones in older men. Int. J. Androl. 2011, 34 Pt 2, e594–e600. [Google Scholar] [CrossRef]
  56. Cinar, V.; Polat, Y.; Baltaci, A.K.; Mogulkoc, R. Effects of magnesium supplementation on testosterone levels of athletes and sedentary subjects at rest and after exhaustion. Biol. Trace Elem. Res. 2011, 140, 18–23. [Google Scholar] [CrossRef] [PubMed]
  57. Maggio, M.; Ceda, G.; Lauretani, F.; Bandinelli, S.; Dall’Aglio, E.; Guralnik, J.M.; Paolisso, G.; Semba, R.D.; Nouvenne, A.; Borghi, L.; et al. Association of plasma selenium concentrations with total IGF-1 among older community-dwelling adults: The InCHIANTI study. Clin. Nutr. 2010, 29, 674–677. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Oluboyo, A.; Adijeh, R.U.; Onyenekwe, C.C.; O Oluboyo, B.; Mbaeri, T.C.; Odiegwu, C.N.; O Chukwuma, G.; Onwuasoanya, U.F. Relationship between serum levels of testosterone, zinc and selenium in infertile males attending fertility clinic in Nnewi, south east Nigeria. Afr. J. Med. Med. Sci. 2012, 41, 51–54. [Google Scholar] [PubMed]
  59. Hawkes, W.C.; Turek, P.J. Effects of dietary selenium on sperm motility in healthy men. J. Androl. 2001, 22, 764–772. [Google Scholar]
  60. Darago, A.; Klimczak, M.; Stragierowicz, J.; Stasikowska-Kanicka, O.; Kilanowicz, A. The Effect of Zinc, Selenium, and Their Combined Supplementation on Androgen Receptor Protein Expression in the Prostate Lobes and Serum Steroid Hormone Concentrations of Wistar Rats. Nutrients 2020, 12, 153. [Google Scholar] [CrossRef] [Green Version]
  61. Rodondi, A.; Ammann, P.; Ghilardi-Beuret, S.; Rizzoli, R. Zinc increases the effects of essential amino acids-whey protein supplements in frail elderly. J. Nutr. Health Aging 2009, 13, 491–497. [Google Scholar] [CrossRef]
  62. Blostein-Fujii, A.; DiSilvestro, R.A.; Frid, D.; Katz, C.; Malarkey, W. Short-term zinc supplementation in women with non-insulin-dependent diabetes mellitus: Effects on plasma 5’-nucleotidase activities, insulin-like growth factor I concentrations, and lipoprotein oxidation rates in vitro. Am. J. Clin. Nutr. 1997, 66, 639–642. [Google Scholar] [CrossRef] [Green Version]
  63. Vivoli, G.; Fantuzzi, G.; Bergomi, M.; Tonelli, E.; Gatto, M.; Zanetti, F.; Del Dot, M. Relationship between zinc in serum and hair and some hormones during sexual maturation in humans. Sci. Total Environ. 1990, 95, 29–40. [Google Scholar] [CrossRef]
  64. Shafiei Neek, L.; Gaeini, A.A.; Choobineh, S. Effect of zinc and selenium supplementation on serum testosterone and plasma lactate in cyclist after an exhaustive exercise bout. Biol. Trace Elem. Res. 2011, 144, 454–462. [Google Scholar] [CrossRef] [PubMed]
  65. Kilic, M.; Baltaci, A.K.; Gunay, M.; Gokbel, H.; Okudan, N.; Cicioglu, I. The effect of exhaustion exercise on thyroid hormones and testosterone levels of elite athletes receiving oral zinc. Neuro Endocrinol. Lett. 2006, 27, 247–252. [Google Scholar] [PubMed]
  66. Ebisch, I.M.; Thomas, C.M.; Peters, W.H.; Braat, D.D.; Steegers-Theunissen, R.P. The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Hum. Reprod. Update 2007, 13, 163–174. [Google Scholar] [CrossRef] [PubMed]
  67. Ebisch, I.M.W.; Pierik, F.H.; De Jong, F.H.; Thomas, C.M.G.; Steegers-Theunissen, R.P.M. Does folic acid and zinc sulphate intervention affect endocrine parameters and sperm characteristics in men? Int. J. Androl. 2006, 29, 339–345. [Google Scholar] [CrossRef] [PubMed]
  68. Vihtamaki, T.; Parantainen, J.; Koivisto, A.M.; Metsa-Ketela, T.; Tuimala, R. Oral ascorbic acid increases plasma oestradiol during postmenopausal hormone replacement therapy. Maturitas 2002, 42, 129–135. [Google Scholar] [CrossRef]
  69. Maggio, M.; De Vita, F.; Lauretani, F.; Bandinelli, S.; Semba, R.D.; Bartali, B.; Cherubini, A.; Cappola, A.R.; Ceda, G.; Ferrucci, L. Relationship between Carotenoids, Retinol, and Estradiol Levels in Older Women. Nutrients 2015, 7, 6506–6519. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  70. Lerchbaum, E. Vitamin D and menopause—A narrative review. Maturitas 2014, 79, 3–7. [Google Scholar] [CrossRef]
  71. Lerchbaum, E.; Obermayer-Pietsch, B. Vitamin D and fertility: A systematic review. Eur. J. Endocrinol. 2012, 166, 765–778. [Google Scholar] [CrossRef]
  72. Karas, M.; Amir, H.; Fishman, D.; Danilenko, M.; Segal, S.; Nahum, A.; Koifmann, A.; Giat, Y.; Levy, J.; Sharoni, Y. Lycopene interferes with cell cycle progression and insulin-like growth factor I signaling in mammary cancer cells. Nutr. Cancer 2000, 36, 101–111. [Google Scholar] [CrossRef]
  73. Liu, C.; Lian, F.; Smith, D.E.; Russell, R.M.; Wang, X.D. Lycopene supplementation inhibits lung squamous metaplasia and induces apoptosis via up-regulating insulin-like growth factor-binding protein 3 in cigarette smoke-exposed ferrets. Cancer Res. 2003, 63, 3138–3144. [Google Scholar]
  74. Hirsch, K.; Atzmon, A.; Danilenko, M.; Levy, J.; Sharoni, Y. Lycopene and other carotenoids inhibit estrogenic activity of 17beta-estradiol and genistein in cancer cells. Breast Cancer Res. Treat. 2007, 104, 221–230. [Google Scholar] [CrossRef] [PubMed]
  75. Kanagaraj, P.; Vijayababu, M.R.; Ravisankar, B.; Anbalagan, J.; Aruldhas, M.M.; Arunakaran, J. Effect of lycopene on insulin-like growth factor-I, IGF binding protein-3 and IGF type-I receptor in prostate cancer cells. J. Cancer Res. Clin. Oncol. 2007, 133, 351–359. [Google Scholar] [CrossRef] [PubMed]
  76. Welch, A.A. Nutritional influences on age-related skeletal muscle loss. Proc. Nutr. Soc. 2014, 73, 16–33. [Google Scholar] [CrossRef] [Green Version]
  77. Van Dronkelaar, C.; van Velzen, A.; Abdelrazek, M.; van der Steen, A.; Weijs, P.J.M.; Tieland, M. Minerals and Sarcopenia; The Role of Calcium, Iron, Magnesium, Phosphorus, Potassium, Selenium, Sodium, and Zinc on Muscle Mass, Muscle Strength, and Physical Performance in Older Adults: A Systematic Review. J. Am. Med. Dir. Assoc. 2018, 19, 6–11. [Google Scholar] [CrossRef]
  78. Liu, Z.; Ye, F.; Zhang, H.; Gao, Y.; Tan, A.; Zhang, S.; Xiao, Q.; Zhang, B.; Huang, L.; Ye, B.; et al. The association between the levels of serum ferritin and sex hormones in a large scale of Chinese male population. PLoS ONE 2013, 8, e75908. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Aihara, K.; Nishi, Y.; Hatano, S.; Kihara, M.; Ohta, M.; Sakoda, K.; Uozumi, T.; Usui, T. Zinc, copper, manganese, and selenium metabolism in patients with human growth hormone deficiency or acromegaly. J. Pediatr. Gastroenterol. Nutr. 1985, 4, 610–615. [Google Scholar] [CrossRef]
  80. Walfisch, S.; Walfisch, Y.; Kirilov, E.; Linde, N.; Mnitentag, H.; Agbaria, R.; Sharoni, Y.; Levy, J. Tomato lycopene extract supplementation decreases insulin-like growth factor-I levels in colon cancer patients. Eur. J. Cancer Prev. 2007, 16, 298–303. [Google Scholar] [CrossRef]
  81. Vrieling, A.; Voskuil, D.W.; Bonfrer, J.M.; Korse, C.M.; Van Doorn, J.; Cats, A.; Depla, A.C.; Timmer, R.; Witteman, B.J.; E Van Leeuwen, F.; et al. Lycopene supplementation elevates circulating insulin-like growth factor binding protein-1 and -2 concentrations in persons at greater risk of colorectal cancer. Am. J. Clin. Nutr. 2007, 86, 1456–1462. [Google Scholar] [CrossRef] [Green Version]
  82. Gann, P.H.; Deaton, R.J.; Rueter, E.E.; Van Breemen, R.B.; Nonn, L.; Macias, V.; Han, M.; Ananthanarayanan, V. A Phase II Randomized Trial of Lycopene-Rich Tomato Extract Among Men with High-Grade Prostatic Intraepithelial Neoplasia. Nutr. Cancer 2015, 67, 1104–1112. [Google Scholar] [CrossRef] [Green Version]
  83. Darago, A.; Sapota, A.; Matych, J.; Nasiadek, M.; Skrzypinska-Gawrysiak, M.; Kilanowicz, A. The correlation between zinc and insulin-like growth factor 1 (IGF-1), its binding protein (IGFBP-3) and prostate-specific antigen (PSA) in prostate cancer. Clin. Chem. Lab. Med. 2011, 49, 1699–1705. [Google Scholar] [CrossRef]
  84. Lerchbaum, E.; Trummer, C.; Schwetz, V.; Pachernegg, O.; Heijboer, A.C.; Pilz, S.; Obermayer-Pietsch, B. Vitamin D and Testosterone in Healthy Men: A Randomized Controlled Trial. J. Clin. Endocrinol. Metab. 2017, 102, 4292–4302. [Google Scholar] [CrossRef] [PubMed]
  85. Lerchbaum, E.; Rabe, T. Vitamin D and female fertility. Curr. Opin. Obstet. Gynecol. 2014, 26, 145–150. [Google Scholar] [CrossRef] [PubMed]
  86. Lundqvist, J.; Norlin, M.; Wikvall, K. 1alpha,25-Dihydroxyvitamin D3 affects hormone production and expression of steroidogenic enzymes in human adrenocortical NCI-H295R cells. Biochim. Biophys. Acta 2010, 1801, 1056–1062. [Google Scholar] [CrossRef] [PubMed]
  87. Sayer, A.A. Sarcopenia. BMJ 2010, 341, 1. [Google Scholar] [CrossRef]
  88. Hayhoe, R.P.G.; Lentjes, M.A.H.; Mulligan, A.A.; Luben, R.N.; Khaw, K.T.; Welch, A.A. Cross-sectional associations of dietary and circulating magnesium with skeletal muscle mass in the EPIC-Norfolk cohort. Clin. Nutr. 2019, 38, 317–323. [Google Scholar] [CrossRef] [Green Version]
  89. Welch, A.A.; Jennings, A.; Kelaiditi, E.; Skinner, J.; Steves, C.J. Cross-sectional associations between dietary antioxidant vitamins C,E and carotenoid intakes and sarcopenic indices in women aged 18–79 years. Calcif. Tissue Int. 2020, 106, 331–342. [Google Scholar] [CrossRef] [Green Version]
  90. Cameron, D.; Welch, A.A.; Adelnia, F.; Bergeron, C.M.; Reiter, D.A.; Dominguez, L.J.; Ferrucci, L. Age and function are more closely associated with intracellular magnesium as assessed by 31P Magnetic Resonance Spectroscopy, than with serum mangesium. Front. Physiol. 2019, 10, 1454. [Google Scholar] [CrossRef]
  91. Landi, F.; Camprubi-Robles, M.; E Bear, D.; Cederholm, T.; Malafarina, V.; Welch, A.A.; Cruz-Jentoft, A.J.; Landi, F. Muscle loss: The new malnutrition challenge in clinical practice. Clin. Nutr. 2019, 38, 2113–2120. [Google Scholar] [CrossRef] [Green Version]
  92. Welch, A.A.; Skinner, J.; Hickson, M. Dietary Magnesium May Be Protective for Aging of Bone and Skeletal Muscle in Middle and Younger Older Age Men and Women: Cross-Sectional Findings from the UK Biobank Cohort. Nutrients 2017, 9, 1189. [Google Scholar] [CrossRef] [Green Version]
  93. Welch, A.A.; Kelaiditi, E.; Jennings, A.; Steves, C.J.; Spector, T.D.; MacGregor, A. Dietary Magnesium Is Positively Associated With Skeletal Muscle Power and Indices of Muscle Mass and May Attenuate the Association Between Circulating C-Reactive Protein and Muscle Mass in Women. J. Bone Min. Res. 2016, 31, 317–325. [Google Scholar] [CrossRef] [Green Version]
  94. Semba, R.D.; Lauretani, F.; Ferrucci, L. Carotenoids as protection against sarcopenia in older adults. Arch. Biochem. Biophys. 2007, 458, 141–145. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Cermak, N.M.; Res, P.T.; de Groot, L.C.; Saris, W.H.; van Loon, L.J. Protein supplementation augments the adaptive response of skeletal muscle to resistance-type exercise training: A meta-analysis. Am. J. Clin. Nutr. 2012, 96, 1454–1464. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Hickson, M. Nutritional interventions in sarcopenia: A critical review. Proc. Nutr. Soc. 2015, 74, 378–386. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Chung, E.; Mo, H.; Wang, S.; Zu, Y.; Elfakhani, M.; Rios, S.R.; Chyu, M.-C.; Yang, R.-S.; Shen, C.-L. Potential roles of vitamin E in age-related changes in skeletal muscle health. Nutr. Res. 2018, 49, 23–36. [Google Scholar] [CrossRef]
  98. Takisawa, S.; Funakoshi, T.; Yatsu, T.; Nagata, K.; Aigaki, T.; Machida, S.; Ishigami, A. Vitamin C deficiency causes muscle atrophy and a deterioration in physical performance. Sci. Rep. 2019, 9, 4702. [Google Scholar] [CrossRef] [Green Version]
  99. Demirbag, R.; Yilmaz, R.; Erel, O. The association of total antioxidant capacity with sex hormones. Scand Cardiovasc. J. 2005, 39, 172–176. [Google Scholar] [CrossRef]
  100. Van Poppel, G.; Goldbohm, R.A. Epidemiologic evidence for beta-carotene and cancer prevention. Am. J. Clin. Nutr. 1995, 62 (Suppl. 6), 1393s–1402s. [Google Scholar] [CrossRef]
  101. Sharoni, Y.; Danilenko, M.; Dubi, N.; Ben-Dor, A.; Levy, J. Carotenoids and transcription. Arch. Biochem. Biophys. 2004, 430, 89–96. [Google Scholar] [CrossRef]
  102. Davison, G.W.; Ashton, T.; George, L.; Young, I.S.; McEneny, J.; Davies, B.; Jackson, S.K.; Peters, J.R.; Bailey, D.M. Molecular detection of exercise-induced free radicals following ascorbate prophylaxis in type 1 diabetes mellitus: A randomised controlled trial. Diabetologia 2008, 51, 2049. [Google Scholar] [CrossRef] [Green Version]
  103. Alessio, H.M.; Goldfarb, A.H.; Cao, G. Exercise-induced oxidative stress before and after vitamin C supplementation. Int. J. Sport Nutr. 1997, 7, 1–9. [Google Scholar] [CrossRef]
  104. Rokitzki, L.; Logemann, E.; Huber, G.; Keck, E.; Keul, J. alpha-Tocopherol supplementation in racing cyclists during extreme endurance training. Int. J. Sport Nutr. 1994, 4, 253–264. [Google Scholar] [CrossRef] [PubMed]
  105. McAnulty, S.R.; McAnulty, L.S.; Nieman, D.C.; Morrow, J.D.; Shooter, L.A.; Holmes, S.; Heward, C.; Henson, D.A. Effect of alpha-tocopherol supplementation on plasma homocysteine and oxidative stress in highly trained athletes before and after exhaustive exercise. J. Nutr. Biochem. 2005, 16, 530–537. [Google Scholar] [CrossRef] [PubMed]
  106. De Oliveira Kde, J.; Donangelo, C.M.; de Oliveira, A.V., Jr.; da Silveira, C.L.; Koury, J.C. Effect of zinc supplementation on the antioxidant, copper, and iron status of physically active adolescents. Cell Biochem. Funct. 2009, 27, 162–166. [Google Scholar] [CrossRef] [PubMed]
  107. Landi, F.; Calvani, R.; Tosato, M.; Martone, A.M.; Fusco, D.; Sisto, A.; Ortolani, E.; Savera, G.; Salini, S.; Marzetti, E. Age-Related Variations of Muscle Mass, Strength, and Physical Performance in Community-Dwellers: Results From the Milan EXPO Survey. J. Am. Med. Dir. Assoc. 2017, 18, 88 e17–88 e24. [Google Scholar] [CrossRef]
  108. Reviews, C.S. Cochrane Handbook for Systematic Reviews of Interventions. Available online: http://community.cochrane.org/handbook (accessed on 4 March 2020).
  109. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; Group, T.P. Preferred reporting items for sytematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009, 6, e100009. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. PRISMA. The PRISMA Checklist: Prisma-statement.org. 2009. Available online: http://prisma-statement.org/documents/PRISMA%202009%20checklist.pdf (accessed on 4 March 2020).
  111. Network SIG. SIGN 50: A Guideline Developers Handbook 2019. Available online: https://www.sign.ac.uk/sign-50 (accessed on 4 March 2020).
  112. Schmidt, A.; Luger, A.; Hörl, W.H. Sexual hormone abnormalities in male patients with renal failure. Nephrol. Dial. Transplant. 2002, 17, 368–371. [Google Scholar] [CrossRef] [Green Version]
  113. Moller, S.; Becker, U. Insulin-like growth factor 1 and growth hormone in chronic liver disease. Dig. Dis. 1992, 10, 239–248. [Google Scholar] [CrossRef]
  114. Oh, Y. The insulin-like growth factor system in chronic kidney disease: Pathophysiology and therapeutic opportunities. Kidney Res. Clin. Pract. 2012, 31, 26–37. [Google Scholar] [CrossRef] [Green Version]
  115. Cochrane. Cochrane Handbook 2017. Available online: http://handbook-5-1.cochrane.org/ (accessed on 4 March 2020).
  116. Handelsman, D.J.; Wartofsky, L. Requirement for Mass Spectrometry Sex Steroid Assays in the Journal of Clinical Endocrinology and Metabolism. J. Clin. Endocrinol. Metab. 2013, 98, 3971–3973. [Google Scholar] [CrossRef] [Green Version]
  117. Stanczyk, F.Z.; Cho, M.M.; Endres, D.B.; Morrison, J.L.; Patel, S.; Paulson, R.J. Limitations of direct estradiol and testosterone immunoassay kits. Steroids 2003, 68, 1173–1178. [Google Scholar] [CrossRef]
  118. Vieira, J.G.H.; Nakamura, O.H.; Ferrer, C.M.; Tachibana, T.T.; Endo, M.H.K.; Carvalho, V.M. The importance of methodology in serum testosterone measurement: Comparison between a direct immunoassay and a method based on high performance liquid chromatography and tandem mass spectrometry (HPLC/MS-MS). Arq. Bras. Endocrinol. Metabol. 2008, 52, 1050–1055. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Cochran. Review Manager 5 (ReVMan5) [Computer Program]. Version 5.3: Copenhagen: The Nordic Cochrane Centre, The Cochran Collaboration. 2014. Available online: http://Community.cochrane.org/ (accessed on 4 March 2020).
  120. Page, M.J.; Higgins, J.P.T.; Sterne, J.A.C. Chapter 13: Assessing risk of bias due to missing results in a synthesis. In Cochrane Handbook for Systematic Reviews of Interventions Version 60; Higgins, J.P.T., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M.J., Welch, V.A., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2019. [Google Scholar]
  121. Olmedilla-Alonso, B.; Granado-Lorencio, F.; Blanco-Navarro, I. Carotenoids, retinol and tocopherols in blood: Comparability between serum and plasma (Li-heparin) values. Clin. Biochem. 2005, 38, 444–449. [Google Scholar] [CrossRef] [PubMed]
  122. Kamycheva, E.; Berg, V.; Jorde, R. Insulin-like growth factor I, growth hormone, and insulin sensitivity: The effects of a one-year cholecalciferol supplementation in middle-aged overweight and obese subjects. Endocrine 2013, 43, 412–418. [Google Scholar] [CrossRef] [PubMed]
  123. Gee, J. Phase II Open Label, Multi-Center Clinical Trial of Modulation of Intermediate Endpoint Biomarkers by 1α-Hydroxyvitamin D2 in Patients With Clinically Localized Prostate Cancer and High Grade Pin. Prostate 2013, 73, 970–978. [Google Scholar] [CrossRef] [Green Version]
  124. Sinha-Hikim, I.; Duran, P.; Shen, R.; Lee, M.; Friedman, T.C.; Davidson, M.B. Effect of long term vitamin D supplementation on biomarkers of inflammation in Latino and African-American subjects with pre-diabetes and hypovitaminosis D. Horm. Metab. Res. 2015, 47, 280–283. [Google Scholar] [CrossRef] [Green Version]
  125. Mason, C.; Tapsoba, J.D.D.; Duggan, C.; Imayama, I.; Wang, C.-Y.; Korde, L.A.; Stanczyk, F.; McTiernan, A. Effects of vitamin D supplementation during weight loss on sex hormones in postmenopausal women. Menopause 2016, 23, 645–652. [Google Scholar] [CrossRef] [Green Version]
  126. Zhang, R.H.; Chen, K.J.; Lu, D.X.; Zhu, X.F.; Ma, X.C. A clinical study of Yigu capsule in treating postmenopausal osteoporosis. Chin. J. Integr. Med. 2005, 11, 97–103. [Google Scholar]
  127. Heijboer, A.C.; Oosterwerff, M.; Schroten, N.F.; Eekhoff, E.M.; Chel, V.G.; De Boer, R.A.; Blankenstein, M.; Lips, P. Vitamin D supplementation and testosterone concentrations in male human subjects. Clin. Endocrinol. 2015, 83, 105–110. [Google Scholar] [CrossRef]
  128. Lerchbaum, E.; Trummer, C.; Theiler-Schwetz, V.; Kollmann, M.; Wölfler, M.; Heijboer, A.C.; Pilz, S.; Obermayer-Pietsch, B. Effects of vitamin D supplementation on androgens in men with low testosterone levels: A randomized controlled trial. Eur. J. Nutr. 2018, 58, 3135–3146. [Google Scholar] [CrossRef] [Green Version]
  129. Zittermann, A.; Ernst, J.B.; Prokop, S.; Fuchs, U.; Dreier, J.; Kuhn, J.; Knabbe, C.; Berthold, H.; Gouni-Berthold, I.; Gummert, J.F.; et al. Vitamin D supplementation does not prevent the testosterone decline in males with advanced heart failure: The EVITA trial. Eur. J. Nutr. 2019, 58, 673–680. [Google Scholar] [CrossRef]
  130. Bonjour, J.P.; Benoit, V.; Pourchaire, O.; Rousseau, B.; Souberbielle, J.C. Nutritional approach for inhibiting bone resorption in institutionalized elderly women with vitamin D insufficiency and high prevalence of fracture. J. Nutr. Health Aging 2011, 15, 404–409. [Google Scholar] [CrossRef] [PubMed]
  131. Trummer, C.; Theiler-Schwetz, V.; Pandis, M.; Grübler, M.R.; Verheyen, N.; Gaksch, M.; Zittermann, A.; März, W.; Aberer, F.; Lang, A.; et al. Effects of Vitamin D Supplementation on IGF-1 and Calcitriol: A Randomized-Controlled Trial. Nutrients 2017, 9, 623. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  132. Persson, M.; Hytter-Landahl, A.; Brismar, K.; Cederholm, T. Nutritional supplementation and dietary advice in geriatric patients at risk of malnutrition. Clin. Nutr. 2007, 26, 216–224. [Google Scholar] [CrossRef] [PubMed]
  133. Holick, M.F.; Lamb, J.; Lerman, R.H.; Konda, V.R.; Darland, G.; Minich, D.M.; Desai, A.; Chen, T.; Austin, M.; Kornberg, J.; et al. Hop rho iso-alpha acids, berberine, vitamin D3 and vitamin K1 favorably impact biomarkers of bone turnover in postmenopausal women in a 14-week trial. J. Bone Miner. Metab. 2010, 28, 342–350. [Google Scholar] [CrossRef]
  134. Lamb, J.; Holick, M.F.; Lerman, R.H.; Konda, V.R.; Minich, D.M.; Desai, A.; Chen, T.; Austin, M.; Kornberg, J.; Chang, J.-L.; et al. Nutritional supplementation of hop rho iso-alpha acids, berberine, vitamin D(3), and vitamin K(1) produces a favorable bone biomarker profile supporting healthy bone metabolism in postmenopausal women with metabolic syndrome. Nutr. Res. 2011, 31, 347–355. [Google Scholar] [CrossRef]
  135. Alehagen, U.; Johansson, P.; Aaseth, J.; Alexander, J.; Brismar, K. Increase in insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 1 after supplementation with selenium and coenzyme Q10. A prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens. PLoS ONE 2017, 12, e0178614. [Google Scholar] [CrossRef]
  136. Torbergsen, A.C.; Watne, L.O.; Frihagen, F.; Wyller, T.B.; Mowe, M. Effects of nutritional intervention upon bone turnover in elderly hip fracture patients. Randomized controlled trial. Clin. Nutr. ESPEN 2019, 29, 52–58. [Google Scholar] [CrossRef]
  137. Jensen, C.; Holloway, L.; Block, G.; Spiller, G.; Gildengorin, G.; Gunderson, E.; Butterfield, G.; Marcus, R. Long-term effects of nutrient intervention on markers of bone remodeling and calciotropic hormones in late-postmenopausal women. Am. J. Clin. Nutr. 2002, 75, 1114–1120. [Google Scholar] [CrossRef]
  138. Ranganathan, P.; Pramesh, C.S.; Aggarwal, R. Common pitfalls in statistical analysis: Intention-to-treat versus per-protocol analysis. Perspect. Clin. Res. 2016, 7, 144–146. [Google Scholar] [CrossRef]
  139. Hoenjet, K.M.; Dagnelie, P.C.; Delaere, K.P.; Wijckmans, N.E.; Zambon, J.V.; Oosterhof, G.O. Effect of a nutritional supplement containing vitamin E, selenium, vitamin c and coenzyme Q10 on serum PSA in patients with hormonally untreated carcinoma of the prostate: A randomised placebo-controlled study. Eur. Urol. 2005, 47, 433–439. [Google Scholar] [CrossRef]
  140. Kranse, R.; Dagnelie, P.C.; Van Kemenade, M.C.; De Jong, F.H.; Blom, J.H.; Tijburg, L.B.; Weststrate, J.A.; Schröder, F.H. Dietary intervention in prostate cancer patients: PSA response in a randomized double-blind placebo-controlled study. Int. J. Cancer 2005, 113, 835–840. [Google Scholar] [CrossRef] [PubMed]
  141. Vidlar, A.; Vostálová, J.; Ulrichová, J.; Student, V.; Krajicek, M.; Vrbkova, J.; Simanek, V. The safety and efficacy of a silymarin and selenium combination in men after radical prostatectomy-a six month placebo-controlled double-blind clinical trial. Biomed. Pap. 2010, 154, 239–244. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. Vostalova, J.; Vidlar, A.; Ulrichova, J.; Vrbkova, J.; Simanek, V.; Student, V. Use of selenium-silymarin mix reduces lower urinary tract symptoms and prostate specific antigen in men. Phytomedicine 2013, 21, 75–81. [Google Scholar] [CrossRef] [PubMed]
  143. Van Amsterdam, J.; van der Horst-Graat, J.; Bischoff, E.; Steerenberg, P.; Opperhuizen, A.; Schouten, E. The effect of vitamin E supplementation on serum DHEA and neopterin levels in elderly subjects. Int. J. Vitam. Nutr. Res. 2005, 75, 327–331. [Google Scholar] [CrossRef] [PubMed]
  144. Zhu, K.; Meng, R.; A Kerr, D.; Devine, A.; Solah, V.; Binns, C.W.; Prince, R.L. The effects of a two-year randomized, controlled trial of whey protein supplementation on bone structure, IGF-1, and urinary calcium excretion in older postmenopausal women. J. Bone Miner. Res. 2011, 26, 2298–2306. [Google Scholar] [CrossRef] [PubMed]
  145. Larouche, D.; Hanna, M.; Chang, S.L.; Jacob, S.; Têtu, B.; Diorio, C. Evaluation of Antioxidant Intakes in Relation to Inflammatory Markers Expression within the Normal Breast Tissue of Breast Cancer Patients. Integr. Cancer Ther. 2017, 16, 485–495. [Google Scholar] [CrossRef]
  146. Watts, E.L.; Appleby, P.N.; Albanes, D.; Black, A.; Chan, J.M.; Chen, C.; Cirillo, P.M.; Cohn, B.A.; Cook, M.B.; Donovan, J.L.; et al. Circulating sex hormones in relation to anthropometric, sociodemographic and behavioural factors in an international dataset of 12,300 men. PLoS ONE 2017, 12, e0187741. [Google Scholar] [CrossRef] [Green Version]
  147. Watts, E.L.; Perez-Cornago, A.; Appleby, P.N.; Albanes, D.; Ardanaz, E.; Black, A.; Bueno-De-Mesquita, H.B.; Chan, J.M.; Chen, C.; Chubb, S.P.; et al. The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies. Int. J. Cancer 2019, 145, 3244–3256. [Google Scholar] [CrossRef]
  148. Bingham, S.A.; Cassidy, A.; Cole, T.J.; Welch, A.; Runswick, S.A.; Black, A.E.; Thurnham, D.; Bates, C.; Khaw, K.T.; Key, T.J.A.; et al. Validation of weighed records and other methods of dietary assessment using the 24 h urine nitrogen technique and other biological markers. Br. J. Nutr. 1995, 73, 531–550. [Google Scholar] [CrossRef] [Green Version]
  149. A Bingham, S.; Luben, R.N.; Welch, A.; Low, Y.L.; Khaw, K.T.; Wareham, N.; Day, N. Associations between dietary methods and biomarkers, and between fruits and vegetables and risk of ischaemic heart disease, in the EPIC Norfolk Cohort Study. Int. J. Epidemiol. 2008, 37, 978–987. [Google Scholar] [CrossRef] [Green Version]
  150. Hayhoe, R.P.G.; Lentjes, M.A.H.; Mulligan, A.A.; Luben, R.N.; Khaw, K.T.; Welch, A.A. Carotenoid dietary intakes and plasma concentrations are associated with heel bone ultrasound attenuation and osteoporotic fracture risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort. Br. J. Nutr. 2017, 117, 1439–1453. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Nutrients 12 01457 g001 550
Figure 1. PRISMA Flowchart.
Figure 1. PRISMA Flowchart.
Nutrients 12 01457 g001
Nutrients 12 01457 g002 550
Figure 2. Risk of bias of included RCTs, assessed for each domain and each included trial, based on the Cochrane Risk of Bias tool [120]. +: low risk of bias, ?: unclear risk of bias, -: high risk of bias. Carot, carotenoids; multi, multi-nutrient; vit D, vitamin D; vit E, vitamin E. Please refer to Supplementary Table S5, E to find detailed information on the studies and reference details.
Figure 2. Risk of bias of included RCTs, assessed for each domain and each included trial, based on the Cochrane Risk of Bias tool [120]. +: low risk of bias, ?: unclear risk of bias, -: high risk of bias. Carot, carotenoids; multi, multi-nutrient; vit D, vitamin D; vit E, vitamin E. Please refer to Supplementary Table S5, E to find detailed information on the studies and reference details.
Nutrients 12 01457 g002
Nutrients 12 01457 g003 550
Figure 3. Forest plot assessing effects of increasing vitamin D intake and vitamin D amongst other nutrients, on IGF-1 (nmol/L). Multi, multi-nutrient; vit D, vitamin D. Please refer to Supplementary Table S5, E to find detailed information on the studies and reference details.
Figure 3. Forest plot assessing effects of increasing vitamin D intake and vitamin D amongst other nutrients, on IGF-1 (nmol/L). Multi, multi-nutrient; vit D, vitamin D. Please refer to Supplementary Table S5, E to find detailed information on the studies and reference details.
Nutrients 12 01457 g003
Nutrients 12 01457 g004 550
Figure 4. Forest plot assessing effects of increasing vitamin D on free testosterone (nmol/L). Vit D, vitamin D. Please refer to Supplementary Table S5, E to find detailed information on the studies and reference details.
Figure 4. Forest plot assessing effects of increasing vitamin D on free testosterone (nmol/L). Vit D, vitamin D. Please refer to Supplementary Table S5, E to find detailed information on the studies and reference details.
Nutrients 12 01457 g004
Nutrients 12 01457 g005 550
Figure 5. Forest plot showing effects of increasing vitamin D on SHBG (nmol/L). Vit D, vitamin D. Please refer to Supplementary Table S5, E to find detailed information on the studies and reference details.
Figure 5. Forest plot showing effects of increasing vitamin D on SHBG (nmol/L). Vit D, vitamin D. Please refer to Supplementary Table S5, E to find detailed information on the studies and reference details.
Nutrients 12 01457 g005
Nutrients 12 01457 g006 550
Figure 6. Forest plot assessing the effects of multi-nutrient interventions on sex hormones and IGF-1 (nmol/L). Multi, multi-nutrient. Please refer to Supplementary Table S5, E to find detailed information on the studies and reference details.
Figure 6. Forest plot assessing the effects of multi-nutrient interventions on sex hormones and IGF-1 (nmol/L). Multi, multi-nutrient. Please refer to Supplementary Table S5, E to find detailed information on the studies and reference details.
Nutrients 12 01457 g006
Nutrients 12 01457 g007 550
Figure 7. Forest plot assessing effects of increasing carotenoids (lycopene) and carotenoids amongst other nutrients on IGF-1 (nmol/L). Carot, carotenoids; multi, multi-nutrient. Please refer to Supplementary Table S5, E to find detailed information on the studies and reference details.
Figure 7. Forest plot assessing effects of increasing carotenoids (lycopene) and carotenoids amongst other nutrients on IGF-1 (nmol/L). Carot, carotenoids; multi, multi-nutrient. Please refer to Supplementary Table S5, E to find detailed information on the studies and reference details.
Nutrients 12 01457 g007
Table
Table 1. PICO Framework for search strategy. See Supplementary Tables (Table S1, A to Table S5, E), for further details.
Table 1. PICO Framework for search strategy. See Supplementary Tables (Table S1, A to Table S5, E), for further details.
PHumans, adults only, aged >45 years.
IMicronutrients
C-
OSex hormones and IGF-1
SRandomised controlled trials (RCTs)

Share and Cite

MDPI and ACS Style

Janjuha, R.; Bunn, D.; Hayhoe, R.; Hooper, L.; Abdelhamid, A.; Mahmood, S.; Hayden-Case, J.; Appleyard, W.; Morris, S.; Welch, A. Effects of Dietary or Supplementary Micronutrients on Sex Hormones and IGF-1 in Middle and Older Age: A Systematic Review and Meta-Analysis. Nutrients 2020, 12, 1457. https://doi.org/10.3390/nu12051457

AMA Style

Janjuha R, Bunn D, Hayhoe R, Hooper L, Abdelhamid A, Mahmood S, Hayden-Case J, Appleyard W, Morris S, Welch A. Effects of Dietary or Supplementary Micronutrients on Sex Hormones and IGF-1 in Middle and Older Age: A Systematic Review and Meta-Analysis. Nutrients. 2020; 12(5):1457. https://doi.org/10.3390/nu12051457

Chicago/Turabian Style

Janjuha, Ryan, Diane Bunn, Richard Hayhoe, Lee Hooper, Asmaa Abdelhamid, Shaan Mahmood, Joseph Hayden-Case, Will Appleyard, Sophie Morris, and Ailsa Welch. 2020. "Effects of Dietary or Supplementary Micronutrients on Sex Hormones and IGF-1 in Middle and Older Age: A Systematic Review and Meta-Analysis" Nutrients 12, no. 5: 1457. https://doi.org/10.3390/nu12051457

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop