Infertility affects up to 1 in 7 couples worldwide. One-third of cases are due to Polycystic Metabolic Ovarian Syndrome (PMOS); male factor contributes in roughly half of couples; while 15 to 30% of cases are idiopathic. Beyond a standard workup, functional lab testing offers valuable complementary insight for couples struggling with infertility – leading to therapeutics to address contributing factors and health risks associated with infertility.
The vaginal microbiome, idiopathic infertility, and failed embryo transfer
Studies have uncovered a unique vaginal bacterial signature (including bacteria that cause bacterial vaginosis (BV)) in patients with idiopathic infertility. BV has been associated with preclinical pregnancy loss and poor assisted reproductive technology (ART) outcomes. Patients with fewer vaginal Lactobacilli had lower rates of successful embryo implantation compared to those with higher levels (PMID: 33091407). While research on treating the vaginal microbiome to improve reproductive outcomes is limited, a cohort of patients with PMOS and unexplained infertility had significantly higher cumulative pregnancy rates when BV was screened and treated (PMID: 23199811). Additionally, a systematic review looking at the effect of probiotic supplementation on reproductive tract microbiota and IVF outcomes found that longer-duration of treatment and individualized regimens increased Lactobacilli abundance and were associated with improved results (PMID: 42401851).
The Vaginosis Profile by Doctor's Data incorporates microscopy, gram stain, and culture for bacteria or yeast along with susceptibility testing allowing providers to properly treat bacterial vaginosis or low lactobacillus abundance, which is essential for preconception care.
Gut dysbiosis and its ties to PMOS, impaired spermatogenesis, and infertility
Differences in gut microbiota abundance have been seen in fertile vs infertile women (PMID: 32801476), and gut-directed therapeutics have had encouraging results, although some treatments have yet to be tested in humans. Fecal microbiota transplant from younger to older mice restored ovarian function and improved fertility (PMID: 41776310). People with PMOS tend to have lower levels of short chain fatty acid producers in the digestive tract. Probiotics have been shown to support insulin sensitivity and reduce androgens, improving cycle regularity and ovulation rates (PMIDs: 38421576, 36062569). Gut dysbiosis has also been implicated in male infertility, mainly through preclinical research and observational human studies associating specific gut taxa with abnormal spermatozoa. Research on therapeutics is limited, but a systematic review of 4 RCTs found that probiotic supplementation in men with idiopathic infertility reduced reactive oxygen species in semen and improved sperm motility (PMID: 38530761)
The GI360TM by Doctor’s Data is a stool test that utilizes PCR and culture to assess abundance of bacterial species, including those that produce SCFA’s - leading to actionable treatment insights for patients with PMOS and/or infertility (including males), such as dietary changes or specific probiotic supplementation.
Nicotinamide Adenine Dinucleotide (NAD+), egg quality, and mitochondrial function
Loss of egg quality with age accompanies declining levels of the metabolic cofactor NAD+. A recent study showed altered NAD+ metabolism in women with recurrent miscarriage (PMID: 41170824). However, the impact of NAD+ precursors on human fertility is still an evolving field of research. Intravenous NAD+ was associated with meaningful improvements in egg maturity, fertilization, and early embryo quality in women with diminished ovarian reserve in a small, preliminary, open-label study. Supplementation with the NAD precursor nicotinamide mononucleotide (NMN) may protect eggs during cryopreservation and support the efficiency of ART, according to preclinical research (PMID: 32755581). Precursor supplementation can also benefit patients with PMOS, as nicotinamide riboside (NR) may improve insulin resistance, inflammation, and mitochondrial function, all which are potential contributing factors in infertility (PMID: 38698835).
The NAD Profile by Doctor’s Data measures both reduced and oxidized forms of NAD to ensure proper mitochondrial function and cellular energy metabolism, which are essential for reproductive health. Testing NAD levels in patients with infertility may reveal a need for supplementation, and retesting after supplementation can ensure safe therapeutic dosages.
Metabolic Syndrome linking infertility with cardiometabolic risk
Males with metabolic syndrome have lower testosterone levels and lower sperm count, motility, and viability (PMID: 37839720). Women with metabolic syndrome had lower live birth rates after ovulation induction (16.5% vs 27%) independent of obesity (PMID: 33852887). Insulin resistance, one of the core components of metabolic syndrome, increases the risk of infertility in females with irregular cycles. For ART patients, insulin resistance negatively affects embryo quality and endometrial tolerance, increasing risk of recurrent embryo failure (PMID: 38348417).
Infertility is increasingly recognized as a marker of cardiometabolic risk, as it often signals underlying insulin resistance. For example, history of infertility conferred 15% and 20% greater risk of type 2 diabetes in males and females, respectively, independent of BMI (PMID: 25596853). A systematic review of 10 RCTs in infertile patients with PMOS found that improving insulin sensitivity increased pregnancy rates, regardless of the intervention, and independent of BMI change (PMID: 33859621).
The Metabolomic Profile by Doctor's Data evaluates seven biomarkers that may reflect a patient’s risk of developing Metabolic syndrome with possible sequelae of type 2 diabetes and coronary artery disease. This profile would be essential for any patient with infertility or PMOS, and addressing the findings can lead to therapeutics that are both supportive of fertility as well as preventive of subsequent cardiometabolic risk.
Hormones, their metabolism, and impact on ovulation and implantation
Hyperandrogenism, which occurs in conditions like PMOS, insulin resistance, and congenital adrenal hyperplasia, can contribute to infertility by arresting follicle growth - with potential downstream effects including anovulation, poor egg quality and impaired uterine receptivity.
The HuMapTM by Doctor's Data can reveal urinary hormone and metabolite patterns associated with the above-mentioned conditions, such as increased 5-alpha reduced androgen metabolites, or increased 17-hydroxyprogesterone. Midluteal levels of progesterone and its metabolites in urine can help to confirm ovulation status. The HuMapTM also includes the oxidative stress marker, 8-hydroxy-2-deoxyguanosine (8-OHdG). Oxidative stress can be an underlying factor in both male and female infertility. Elevated urinary 8-OHdg was negatively associated with sperm motility and positively associated with exposure to disinfection byproducts in male infertility patients (PMID: 33189401).
Mineral deficiencies and toxic exposures
Minerals like selenium, zinc, and copper are essential for maintaining male and female reproductive health. Zinc deficiency may increase the likelihood of failed embryo transfer. Exposure to toxic metals such as cadmium and lead are associated with decreased sperm count and poor reproductive outcomes including recurrent miscarriage (PMID: 39683462).
Urine Toxic & Essential Elements Profile by Doctor’s Data provides broad coverage of toxic elements alongside key nutrient elements that can impact fertility.
Functional evaluation of methylation in the context of fertility
The Methylation Profile by Doctor’s Data can reveal when insufficient B12 or folate in the context of MTHFR variants (C677T, A1298C) negatively alters methylation, evident by a homocysteine elevation or decreased SAM/SAH ratio. This shift induces oxidative stress, damaging both sperm and egg quality. Altered DNA methylation and hyperhomocysteinemia can lead to pregnancy complications, fetal growth restriction, and even early pregnancy loss (PMID: 37248348). Repleting levels of folate and B12 to lower homocysteine and support methylation can potentially improve reproductive outcomes.
A thorough functional workup for couples with infertility can reveal underlying factors that when treated, may support reproductive success, while also benefiting hormone balance, digestive function, metabolic health, methylation, nutritional status, and toxin burden – enhancing overall health and reducing long-term risks.
