Effect of Medications for Gastric Acid-Related Symptoms on Total Motile Sperm Count and Concentration: A Case-Control Study in Men of Subfertile Couples from the Netherlands.

INTRODUCTION: Gastric acid-related symptoms are highly prevalent in the general population (21-40%), and more than 11% of individuals use medication for the treatment of these symptoms. The uptake of micronutrients is dependent on the gastrointestinal potential of hydrogen (pH). OBJECTIVE: We hypothesized that medication affecting gastrointestinal pH reduces the availability of B vitamins, thereby deranging one-carbon metabolism and detrimentally affecting spermatogenesis. METHODS: This explorative nested case-control study in men of subfertile couples investigated associations between medication used for gastric acid-related symptoms and semen parameters. We included 40 men using medication for gastric acid-related symptoms and 843 men not using medication. Semen analyses were performed between 70 days before and 21 days after the visit. RESULTS: The use of medication was associated with a twofold higher risk of a low total motile sperm count [TMSC <1 × 106, odds ratio (OR) 2.090, p = 0.049] and negatively with sperm concentration (ß -0.320, p = 0.028). Red blood cell folate was positively associated with TMSC (ß 0.257, p = 0.026), sperm count (ß 1.679, p = 0.013) and ejaculate volume (ß 0.120, p = 0.023), and total homocysteine (tHcy) was negatively associated with sperm count (ß -0.077, p = 0.021). CONCLUSION: Here we delineate associations between the use of medication for gastric acid-related symptoms and poor semen quality in men of subfertile couples. The use of medication for gastric acid-related symptoms is associated with a twofold higher risk of a low TMSC and a decreased sperm concentration. Although these findings warrant further research on causality, the associations between folate, tHcy and semen quality emphasize the importance of preconception counselling in male subfertility.

Preconception folic acid use influences the follicle fluid proteome.

BACKGROUND: The investigation of the human follicle fluid proteome has gained much interest in the search of new markers as predictors for in vitro fertilization and intracytoplasmic sperm injection (IVF/ICSI) treatment outcome. Follicular fluid folate, as substrate of one carbon (1-C) metabolism, affects follicular metabolism and oocyte and embryo quality. From this background, we aim to identify a folate-related follicle fluid proteome that associates with IVF/ICSI treatment outcome. METHODS: In a nested case-control study embedded in a periconception cohort, we performed qualitative and quantitative proteomic analyses using nanoflow LC-MS/MS and TMT labelling in 30 monofollicular fluid samples from women undergoing IVF/ICSI treatment of which 15 used and 15 did not use a folic acid supplement. The protein data are analysed using scaffold proteome Software and differential abundances are expressed as Log2-fold change. Blood samples were obtained before and after treatment for determination of biomarkers of 1-C metabolism and estradiol. RESULTS: We identified 227 uniquely expressed proteins in follicular fluid. In folic acid supplement users compared to nonusers, we established a lower abundance of C-reactive protein (-2.03; P = < 0.01) and higher abundances of apolipoproteins from high-density lipoprotein (HDL), most notably A-I (+1.28; P = < 0.01) and C-I (+1.11; P = 0.016). CONCLUSION: Preconception folic acid supplement use is associated with suppression of the inflammatory pathway and upregulation of the HDL pathway in human follicular fluid, being a preferential source of cholesterol for steroid hormone synthesis. Studies are needed on the tissue specificity and on the beneficial effects of embryo quality and IVF/ICSI treatment outcome of the proteome of these pathways.

The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism.

BACKGROUND Most reproductive failures originate during the periconceptional period and are influenced by the age and the lifestyle of parents-to-be. We advance the hypothesis that these failures can arise as a partial consequence of derangements to one-carbon (1-C) metabolism (i.e. metabolic pathways that utilize substrates/cofactors such as methionine, vitamin B12, folate). 1-C metabolic pathways drive the synthesis of proteins, biogenic amines and lipids required for early growth, together with the synthesis and methylation of DNA and histones essential for the regulation of gene expression. We review how deficiencies in periconceptional 1-C metabolism affect fertility and development together with underlying mechanisms derived from animal studies. METHODS A literature search was performed using PubMed and bibliographies of all relevant original research articles and reviews. RESULTS We define 'periconception' as a 5-6-month period in women embracing oocyte growth, fertilization, conceptus formation and development to Week 10 of gestation (coinciding with the closure of the secondary palate in the embryo). During this period significant epigenetic modifications to chromatin occur that correspond with normal development. Subtle variations in 1-C metabolism genes and deficiencies in 1-C substrates/cofactors together with poor lifestyle, such as smoking and alcohol consumption, disturb 1-C metabolism and contribute to subfertility and early miscarriage and compromise offspring health. Procedures used in assisted reproduction can also disturb these metabolic pathways and contribute to poor pregnancy outcomes. CONCLUSIONS Evidence presented indicates that parental nutrition and other lifestyle factors during the periconceptional period can affect reproductive performance via 1-C metabolic pathways. This knowledge provides opportunities for treatment and prevention of reproductive failures and future non-communicable diseases.

Body mass index and central adiposity are associated with sperm quality in men of subfertile couples.

BACKGROUND: The incidence of overweight and obesity in men of reproductive ages is rising, which may affect fertility. Therefore, this study aims to assess the associations between BMI, central adiposity and sperm parameters in men of subfertile couples. METHODS: Ejaculate volume (ml), sperm concentration (millions per ml), percentage of progressive motile and immotile spermatozoa and total motile sperm count (millions) were measured in 450 men of subfertile couples visiting a tertiary outpatient clinic for reproductive treatment and preconception counseling. RESULTS: Overweight was negatively associated with the percentage of progressive motility type A [ß -0.32 (SE 0.2), P=0.036] and positively associated with the percentage of immotility type C [ß 0.21 (SE 0.07), P=0.002]. Obesity was negatively associated with ejaculate volume [ß-0.23 (SE 0.1), P=0.02], sperm concentration [ß -0.77 (SE 0.3), P=0.006] and total motile sperm count [ß -0.91 (SE 0.3), P=0.007]. Waist circumference≥102 cm, a measure for central adiposity, was inversely associated with sperm concentration [ß -0.69 (SE 0.2), P=0.001] and total motile sperm count [ß-0.62 (SE 0.3), P=0.02]. All associations remained significant after adjustment for age, ethnicity, active and passive smoking, alcohol and medication use and folate status. CONCLUSIONS: This study shows that in particular, sperm concentration and total motile sperm count in men of subfertile couples are detrimentally affected by a high BMI and central adiposity. The effect of weight loss on sperm quality and fertility needs further investigation.

Proteomic analysis of the microenvironment of developing oocytes.

We utilized a setup based on extensive pre-fractionation of proteolytic peptides and nanoflow reversed-phase LC-MS/MS to identify the (sub)proteome of human follicular fluid (FF). In this in-depth screen, 246 specific proteins were identified, the majority of which are involved in coagulation- and immune-response pathways. Our aim is to define a set of FF protein markers, which could predict oocyte quality.

Preconception folic acid use modulates estradiol and follicular responses to ovarian stimulation.

BACKGROUND: Folate is a methyl donor. Availability of folate affects DNA methylation profiles and thereby gene expression profiles. We investigated the effects of low-dose folic acid use (0.4 mg/d) on the ovarian response to mild and conventional ovarian stimulation in women. METHODS: In a randomized trial among subfertile women, 24 and 26 subjects received conventional and mild ovarian stimulation, respectively. Blood samples were taken during the early follicular phase of the cycle prior to treatment and on the day of human chorionic gonadotropin administration for determination of serum total homocysteine, anti-Müllerian hormone (AMH), estradiol, and folate. Folic acid use was validated by questionnaire and serum folate levels. Preovulatory follicles were visualized, counted, and diameters recorded using transvaginal ultrasound. The relation between folic acid use and ovarian response was assessed using linear regression analysis. RESULTS: Folic acid use modified the ovarian response to ovarian stimulation treatment. The estradiol response was higher in nonfolic acid users receiving conventional treatment [ß(interaction) = 0.52 (0.07-0.97); P = 0.03], and this effect was independent of serum AMH levels and the preovulatory follicle count. In the conventional treatment, the mean follicle number was also greater in nonusers compared with the users group (14.1 vs. 8.9, P = 0.03). CONCLUSION: Low-dose folic acid use attenuates follicular and endocrine responses to conventional stimulation, independent of AMH and follicle count. The nature of this observation suggests that the effect of folic acid is most prominent during early follicle development, affecting immature follicles. Deleterious effects of folate deficiency, like DNA hypomethylation and oxidative stress, can help to explain our observations.