Dr. Shannon Iselin, ND
Subheadline
How metabolomic assessment of oxidative stress, mitochondrial function, and nutrient sufficiency may help optimize reproductive outcomes beyond conventional fertility markers.
Short Description
This article explores the potential role of organic acid testing in identifying hidden metabolic contributors to poor IVF outcomes, including oxidative stress, mitochondrial dysfunction, and nutrient insufficiency. Through a clinical case, it illustrates how a more personalized, metabolomics-informed naturopathic approach may improve egg and sperm quality when conventional fertility markers appear normal.
Introduction
In vitro fertilization (IVF) has advanced dramatically over the past two decades, yet a persistent clinical challenge remains: patients with “normal” conventional markers who consistently produce too few or poor-quality embryos.
Anti-Müllerian hormone (AMH), follicle counts, and semen analysis offer useful but incomplete snapshots of reproductive potential. They describe quantity more reliably than quality. For many couples, the frustrating reality is repeated IVF cycles yielding few or no euploid embryos despite reassuring baseline findings.
In naturopathic and integrative fertility care, clinicians commonly focus on optimizing factors known to influence egg and sperm quality, including thyroid function, insulin sensitivity, micronutrient status, and vitamin D levels. These foundational assessments are essential and often lead to meaningful improvements in reproductive outcomes.
However, when egg and/or sperm quality are in question, many treatment protocols remain empiric and guided by general physiologic principles rather than patient-specific metabolic insight. In many cases, we are treating physiology we assume is present, rather than physiology we have directly assessed.
Organic acid testing offers a potential next step: a tool that may help clinicians move beyond generalized support toward more targeted, individualized strategies based on underlying metabolic patterns.
Oxidative Stress and Gamete Quality
Reactive oxygen species (ROS) are not inherently harmful; in fact, they play essential roles in cellular signaling and sperm capacitation. However, when ROS production exceeds antioxidant defenses, oxidative stress can impair both sperm and oocyte integrity.
Male Factor: DNA Integrity, Morphology, and Motility
Sperm are particularly vulnerable to oxidative damage due to their high polyunsaturated fatty acid content and limited intrinsic antioxidant capacity. Excess ROS has been associated with reduced motility, membrane damage, and poor morphology. Elevated DNA fragmentation, in turn, has been linked to lower fertilization rates, impaired embryo development, and increased miscarriage risk. 1
Female Factor: Oocyte Competence
In oocytes, oxidative stress disrupts spindle formation, mitochondrial function, and chromosomal segregation. These processes are critical for meiotic accuracy and embryo viability. As women age, mitochondrial efficiency declines and ROS production increases, contributing to reduced oocyte competence and higher rates of aneuploidy. 2
Mitochondria: The Energetic Engine of Fertility
Mitochondria are central to reproductive success. Oocytes contain the highest mitochondrial density of any cell in the human body, reflecting the enormous energy demand required for meiotic division, fertilization, and early embryonic development.
In sperm, mitochondrial function drives motility and contributes to fertilization capacity. Impaired mitochondrial activity has been associated with reduced sperm quality and altered fertilization dynamics. 3
Where Conventional Fertility Assessment Falls Short
Despite the well-established roles of redox balance and mitochondrial function in reproductive physiology, these processes are not directly assessed in standard fertility evaluations. As a result, many patients with repeated poor IVF outcomes are told that their results are “unexplained” or attributed primarily to age.
While ICSI (Intracytoplasmic Sperm Injection) can improve fertilization rates, its use may also obscure more subtle impairments in sperm function. Standard semen analysis parameters have relatively broad reference ranges and may not fully capture functional deficits such as oxidative stress or DNA integrity. 4
Where Organic Acid Testing Fits
Organic acid testing is a urinary metabolomic assessment that reflects patterns in:
- Mitochondrial function (e.g., Krebs cycle intermediates)
- Fatty acid oxidation
- Oxidative stress and glutathione status
- Nutrient cofactor sufficiency (e.g., B vitamins)
While OAT is not a diagnostic tool for infertility, it provides a “pattern-recognition” lens into systemic metabolic stressors that plausibly impact gamete quality.
What is Organic Acid Testing?
Organic acid testing (OAT) is a comprehensive urinary metabolomic profile that measures organic acids- compounds produced during central metabolic pathways. Historically, these markers were used in acute clinical settings to screen for Inborn Errors of Metabolism (IEMs) in neonatal care.
In a modern integrative context, OAT has evolved into a functional assessment used to identify subtle metabolic imbalances rather than overt disease. By measuring byproducts of cellular respiration and nutrient metabolism, the test provides a snapshot of:
- Mitochondrial Efficiency: Indicators of the Citric Acid (Krebs) Cycle, which reveal how effectively a patient converts macronutrients into ATP.
- Nutrient Cofactor Demand: Indirect markers for B-vitamins (e.g., B12, B6, Folate) and antioxidants like glutathione.
- Neurotransmitter Metabolism: Byproducts of dopamine and serotonin turnover.
- Microbial Overgrowth: Metabolites derived from intestinal yeast or bacteria that may contribute to systemic inflammation.
In integrative reproductive medicine, OAT is now utilized to map a patient’s metabolic “fingerprint.” Unlike standard blood work, which provides a static snapshot of nutrient levels in circulation, OAT measures the metabolic byproducts of cellular activity. This allows clinicians to identify specific energetic or oxidative bottlenecks, the functional gaps where cellular machinery is struggling to perform. In the high-stakes environment of IVF, the shift from ‘sufficient’ levels to optimal metabolic function may represent a critical avenue for improving gamete preparation.
Clinical Case: A Turning Point
A 36-year-old female and 38-year-old male presented following three IVF retrievals resulting in only one euploid embryo per cycle, despite a “normal” AMH of 1.9 ng/mL and WHO-standard semen parameters.
- Findings: OAT revealed elevated oxidative stress and impaired mitochondrial function for both partners.
- Intervention: A 6-month protocol focused on CoQ10, L-carnitine, glutathione precursors, and polyphenol-rich nutrition.
- Outcome: A final retrieval using the same stimulation protocol resulted in three euploid embryos from a single cycle.
Targeted Naturopathic Interventions
Addressing these factors requires a multifaceted approach. A recent meta-analysis suggests CoQ10 pretreatment may improve IVF/ICSI outcomes in women with diminished ovarian reserve, although broader applicability remains under investigation.4 Conversely, evidence for general antioxidant supplementation is mixed, with some studies showing benefits for male infertility while others remain inconsistent.5 This variability underscores the importance of individualized rather than indiscriminate supplementation.
Limitations and Considerations
Organic acid testing has not been validated for predicting IVF outcomes and reflects systemic metabolism rather than tissue-specific reproductive function.
Observed improvements may be influenced by multiple variables, and results should be interpreted within the broader clinical context.
Conclusion
Fertility reflects cellular health, metabolic resilience, and energy production. Oxidative stress and mitochondrial dysfunction are important and potentially modifiable contributors.6
By expanding beyond conventional markers, clinicians can move from empiric protocols toward precision-based care. Organic acid testing may offer a valuable tool to guide this transition.
References:
- Esteves SC, Zini A, Coward RM. Sperm DNA fragmentation and fertility outcomes: to treat or not to treat? Asian J Androl. 2021;23(2):109-116. doi:10.4103/aja.aja_52_20
- May-Panloup P, Boucret L, Chao de la Barca JM, et al. Ovarian ageing: the role of mitochondria in oocytes and surrounding cells. Hum Reprod Update. 2021;27(3):543-566. doi:10.1093/humupd/dmaa060
- Agarwal A, Parekh N, Panner Selvam MK, et al. Male oxidative stress infertility (MOSI): proposed terminology and clinical practice guidelines for management of idiopathic male infertility. World J Mens Health. 2019;37(3):296-312. doi:10.5534/wjmh.190055
- Smits RM, Mackenzie-Proctor R, Fleischer K, Showell MG. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2022;5(5):CD007411. doi:10.1002/14651858.CD007411.pub5
- Xu Y, Nisenblat V, Lu C, et al. Pretreatment with coenzyme Q10 improves ovarian response and embryo quality in low-prognosis women with IVF/ICSI: a systematic review and meta-analysis. Reprod Biol Endocrinol. 2018;16(1):29. doi:10.1186/s12958-018-0343-0
- Henkel R, et al. Role of mitochondria and redox state in sperm and oocyte health. Gynecol Reprod Endocrinol Metab. 2024;5(1):27-33.
Bio:
Dr. Shannon Iselin, ND is an associate naturopathic physician at Flora Naturopathics, a telemedicine-based functional medicine practice. She specializes in fertility, hormone health, and integrative reproductive medicine, with a clinical focus on optimizing preconception physiology and IVF outcomes. A graduate of the University of Arizona and Sonoran University of Health Sciences, Dr. Iselin utilizes individualized, evidence-informed approaches that integrate functional testing, nutrition, and lifestyle medicine. She works closely with patients at all stages of the fertility journey, from preconception optimization to navigating complex assisted reproductive care.
Instagram: @dr.iselin
