Article written by Ann Shippy MD, author of The Preconception Revolution
A 31-year-old patient sits across from me and says, “My friends are all freezing their eggs. Should I be doing that too?”
It is a question I hear constantly. And while oocyte cryopreservation is a legitimate tool for specific situations, the way it is being marketed has created a damaging assumption: that fertility is a fixed, steadily declining resource that technology must eventually rescue.
What that narrative misses entirely is that women hold meaningful biological influence over their egg quality as follicles mature into oocytes. When we address the biological environment in which eggs develop, including metabolic health, mitochondrial function, nutrient status, and toxic exposures, reproductive potential can extend well beyond the timelines that dominate conventional fertility conversations. The same is true for male fertility.
From early follicular recruitment through final maturation, oocytes are highly responsive to metabolic signals, mitochondrial function, nutrient availability, and environmental exposures. These inputs influence not only egg quality, but also fertilization, implantation, and early embryonic development. Importantly, many of these factors are dynamic and modifiable.
This reframes the conversation.
The question becomes not only “how many eggs remain?”, but “what conditions are shaping their quality in the months leading up to ovulation?”
A Systems Model of Fertility
Fertility is not governed by a single variable. It reflects the integration of multiple biological systems that together determine the quality of both eggs and sperm:
- Mitochondrial function provides the energy required for meiosis, fertilization, and early embryo development
- Metabolic health regulates insulin signaling, inflammation, and hormonal balance
- Toxic burden influences endocrine signaling, oxidative stress, and epigenetic programming
- Microbiome and immune balance shape hormone metabolism and endometrial receptivity
- Epigenetic regulation determines gene expression patterns passed to the next generation
When these systems are aligned, reproductive potential improves. When they are disrupted, outcomes decline, often independent of chronological age alone.
This systems-based perspective does not always replace assisted reproductive technologies, but it expands the window of opportunity. It recognizes that both natural conception and assisted reproductive technology (ART) outcomes are influenced by the biological terrain in which gametes develop.
In this article, we’ll explore the mechanisms underlying this model, review the current evidence, and outline a practical clinical framework for optimizing fertility.
A Crisis Hidden in Plain Sight: The Epidemiological Picture
Before reshaping the clinical conversation, it helps to understand the scale of what we are dealing with.
In 2017, a landmark meta-regression analysis by Levine, Swan and colleagues documented a 52.4% decline in sperm concentration and a 59.3% decline in total sperm count among men from North America, Europe, Australia, and New Zealand between 1973 and 2011. A 2022 follow-up extended the analysis globally and found the decline had accelerated: among unselected men, the annual rate of decline doubled from 1.16% post-1972 to 2.64% post-2000. This is a significant trend.
WHO estimates the global prevalence of infertility at approximately 17.5% of adults, roughly one in six people worldwide. ART cycles in the U.S. have more than doubled over the past 15 years, yet the underlying drivers of infertility are rarely addressed before intervention.
One such driver is the increasing consumption of ultra-processed food (UPF). Multiple studies show inverse associations between ultra-processed food intake and sperm concentration, total count, and progressive motility. For instance, data from a 2025 controlled crossover feeding trial that placed healthy men aged 20 to 35 on a UPF diet for three weeks found trends toward reduced sperm motility and FSH, with testosterone declining in the isocaloric arm and phthalate metabolite levels trending upward, suggesting reproductive harm that is not simply a consequence of excess caloric intake. This is also reflected in global statistics – sperm counts have declined roughly 60% since the 1970s, concurrent with the rise of the processed food environment.
Another major contributor is environmental pollution, particularly exposure to endocrine-disrupting chemicals (EDCs). A 10-year systematic review of 14 observational studies found consistent inverse associations between EDC exposure and reproductive outcomes in both sexes. In particular, BPA, its analogs – phthalates and PFAS, and persistent organic pollutants were each associated with reduced sperm quality, disrupted ovulatory function, increased rates of premature ovarian insufficiency, and higher rates of endometriosis.
These are the real world, toxic conditions in which our patients are attempting to conceive a new, healthy life.
The Science of Egg Quality: Mitochondria, Oxidative Stress, and the Limits of the Aging Model
To understand why metabolic and environmental optimization directly influences fertility, we need to go to the cellular level. Mitochondria are the engines of reproduction and egg quality is fundamentally related to cellular energy.
Egg cells contain the highest mitochondrial density of any cell in the human body, estimated at 100,000 to 600,000 copies of mitochondria DNA per mature oocyte. These mitochondria power fertilization, the first cell divisions, and early embryonic development. When mitochondrial output is compromised, the developmental competence of the egg is compromised with it.
Reactive oxygen species (ROS) play a key role here. They’ve been described as “gatekeepers of gamete competence” , since oocyte maturation, sperm capacitation, and early embryo development each require ROS signaling within a narrow redox range. Too little blunts the required signaling; too much damages mitochondrial DNA (mtDNA), impairs oxidative phosphorylation, and disrupts spindle assembly. Environmental toxins, nutrient deficiencies, and chronic inflammation all push ROS outside this optimal range.
Research published in Frontiers in Endocrinology (2024) shows that dysregulation of mtDNA copy number, whether insufficient to meet the energy demands of meiosis or abnormally elevated as a cellular stress response, is associated with higher rates of aneuploidy (abnormal number of chromosomes) and impaired implantation potential. Mitochondrial dysfunction disrupts the energy-dependent processes of spindle formation and chromosome alignment during meiosis. Age can be one contributor to this decline, but the proximate cause is mitochondrial dysfunction, not years on the calendar.
There is good news however – emerging research suggests that mitochondria in oocytes may resist the age-related accumulation of mutations observed in somatic tissues, supporting the view that modifiable factors play a meaningful role in the fertility decline seen clinically.
Targeted, nutrient-based therapies may also help. For example, CoQ10 supplementation has been found to improve pregnancy rates compared to placebo or no treatment, including in women with PCOS. A 2024 meta-analysis focused on women with diminished ovarian reserve found that taking CoQ10 before IVF or ICSI was significantly associated with improved clinical pregnancy rates. CoQ10 plays a critical role in cellular energy production within the mitochondria and acts as a powerful antioxidant within the oocyte.
Another key nutrient for mitochondrial health is NAD⁺ – a central cofactor in mitochondrial energy production and DNA repair. Its levels decline with age in multiple tissues, including the ovary. Preclinical studies over the past several years have shown that restoring NAD⁺ levels, particularly through precursors such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), can improve mitochondrial function, enhance oocyte quality, and increase fertility outcomes in aged animal models. While human data are still emerging, these findings reinforce the concept that age-related declines in fertility are closely tied to bioenergetic insufficiency, and that targeting NAD⁺ metabolism may represent a promising strategy to support ovarian function.
Endocrine-Disrupting Chemicals (EDC) Impair Reproductive Biology
Multiple EDC classes, particularly phthalates and PFAS, interfere with signaling between the hypothalamus, pituitary, and gonads. Phthalates alter LH and FSH secretion, reduce testosterone synthesis in Leydig cells, and impair the hormonal environment required for follicular maturation. BPA binds estrogen receptors (ERa and ERb), can interfere with the LH surge, and has been detected in follicular fluid at concentrations sufficient to induce epigenetic changes in developing oocytes.
BPA, organophosphate pesticides, and heavy metals, including cadmium and lead, generate excess ROS (reactive oxygen species) within follicular and seminal environments. This directly damages mtDNA, lipid membranes, and the spindle apparatus, and represents a primary mechanism linking toxic exposure to aneuploidy and implantation failure.
Epidemiological and experimental research shows that phthalates can speed up the loss of a woman’s egg supply by pushing dormant follicles to activate sooner and then die off. This drains the ovarian reserve faster than normal aging would.
EDC exposures during preconception can also alter DNA methylation patterns and histone modifications in gametes in ways that appear heritable. Research in both rodent models and human populations suggests that some EDC-induced epigenetic changes in sperm and eggs can be transmitted to subsequent generations, a finding with profound implications for generational health.
Toxic burden is both measurable and modifiable, as can be seen with how organic food consumption reduces urinary pesticide metabolites within days. A small-scale 2019 UC Berkeley study found that after just six days on an all-organic diet, urinary levels of 13 different pesticide metabolites dropped an average of 60.5%, with the chlorpyrifos metabolite falling 61% and malathion metabolites falling 95%.
Polymorphism analysis of key detoxification loci (CYP1A1, GSTP1, MTHFR) stratifies patients by capacity to metabolize and excrete xenoestrogens. Because folliculogenesis is a months-long process, early identification of impaired clearance allows for targeted preconception intervention during the window in which oocyte quality is established.
This is one of the most encouraging conversations in preconception care: our patients are active participants, not passive recipients, in the quality of the eggs they will ovulate a season from now. Guiding them to eat as organically as possible is among the most accessible and rewarding interventions we can offer.
Metabolic Health, Insulin Resistance, and the Hormonal Terrain of Fertility
Metabolic dysfunction is the most common and most treatable driver of impaired fertility encountered in clinical practice. Insulin resistance exerts multimechanistic disruption of reproductive physiology and remains underdiagnosed in reproductive-age women.
Insulin resistance affects an estimated 35 to 80% of women with PCOS, depending on the population and diagnostic criteria used, making it one of the most important root causes of the anovulatory infertility that defines this condition.
When the body becomes resistant to insulin, compensatory hyperinsulinemia follows, with profound consequences for reproductive health: it drives excess androgen production in the ovarian theca cells, suppresses SHBG, raises free testosterone, and disrupts the precise pulsatile LH signaling the body needs for healthy follicular development. The result is a hormonal environment that simply cannot support normal ovulation.
Subclinical insulin resistance in women who do not meet PCOS criteria also impairs implantation, increases miscarriage risk, and reduces ART success rates. This is where utilizing a continuous glucose monitor and/or including fasting insulin, HOMA-IR, and post-load glucose responses in fertility workups, not just HbA1c makes a difference.
Insulin resistance drives chronic low-grade inflammation (elevated IL-6, TNF-alpha, and CRP) that disrupts the endometrial environment required for implantation. Elevated inflammatory markers are independently associated with impaired embryo implantation and early pregnancy loss.
Even subclinical hypothyroidism (TSH above 2.5 mIU/L in the preconception period) could result in impaired ovulation and elevated miscarriage risk. TPO antibodies (autoantibody against thyroid peroxidase; primary marker for Hashimoto’s) are present in a significant proportion of women with recurrent pregnancy loss. To identify this early, use full thyroid lab panels, including free T4 and free T3 (to quantify circulating active hormone), reverse T3 (to identify impaired peripheral conversion), Thyroglobulin Ab (TgAb, autoantibody against thyroglobulin), and Thyroid Receptor Ab (TRAb, autoantibody against the TSH receptor), not simply TSH.
The Gut-Fertility Axis
The estrobolome, the subset of gut microbiome genes capable of metabolizing estrogens, plays a central role in regulating circulating estrogen levels. Dysbiosis impairs estrogen metabolism and can contribute to estrogen dominance, endometriosis, uterine fibroids, and impaired follicular development.
Gut health also governs nutrient absorption of key fertility nutrients including folate, zinc, selenium, and omega-3 fatty acids; regulates systemic immune balance and autoimmune processes that impair fertility; and modulates the HPG axis through the gut-brain-endocrine connection. Advanced comprehensive stool testing is a valuable component of the preconception and fertility workup, particularly in patients with unexplained infertility or recurrent pregnancy loss.
Taming Inflammation: Three Hidden Drivers of Reproductive Dysfunction
Chronic inflammation sits at the intersection of every system discussed above. It impairs hormone signaling, damages egg and sperm quality, disrupts endometrial receptivity, and increases miscarriage risk. It also alters epigenetic programming in gametes in ways that can be passed to the next generation. In clinical practice, three sources of inflammation are consistently underidentified and under-treated in preconception and fertility patients: histamine imbalance, oxalate overload, and subclinical autoimmunity.
Histamine intolerance and oxalate overload are another two frequently overlooked drivers of reproductive dysfunction. Histamine plays a role in endometrial receptivity, and oxalate overload contributes to oxidative stress and mitochondrial impairment. Identifying and addressing these patterns can make a meaningful difference in patients with otherwise unexplained infertility.
Histamine Imbalance
Histamine plays active roles in reproductive health, supporting blood flow, immune tolerance of the embryo, and uterine contractility for implantation. The problem is excess. When the clearance enzymes DAO (gut) and HNMT (intracellular) are impaired by genetic variants, nutrient deficiencies in B6, B12, magnesium, or folate, or gut dysbiosis, histamine accumulates to levels that drive inflammation, increase vascular permeability, and trigger immune responses that could cause spontaneous abortion, as supported by research showing reduced DAO activities in pregnancy complications including threatened and missed abortion . The estrogen-histamine relationship is clinically important: estrogen stimulates histamine release and inhibits DAO, while progesterone counteracts it. Women with estrogen dominance are therefore disproportionately affected around ovulation and menstruation. Fungal overgrowth compounds the picture by directly producing histamine and further impairing DAO function.
Oxalate Overload
When oxalates accumulate through high dietary intake, dysbiosis, nutrient deficiencies, or impaired metabolism, they deposit in reproductive tissues and generate oxidative stress that injures mtDNA, cell membranes, and the spindle apparatus. Elevated oxalates have been associated with ovarian dysfunction, as demonstrated by the significantly increased prevalence of calcium oxalate kidney stones in women with PCOS, endometrial inflammation, impaired implantation, miscarriage, as well as in men with sperm abnormalities. A bidirectional relationship with fungal overgrowth compounds the burden: fungi produce oxalates as metabolic byproducts while reducing the gut bacteria that degrade them. A graduated dietary reduction combined with calcium citrate at meals, magnesium, vitamin B6, and gut repair avoids oxalate dumping while steadily lowering the inflammatory load.
Subclinical Autoimmunity
It’s not surprise that the immune system imbalances, such as chronic inflammation and autoimmunity can significantly impact fertility. An interesting finding from a recent meta-analysis illustrates this clearly: ANA (antinuclear antibody) positivity was found in 24.4% of women with unexplained infertility compared to 8.5% in fertile controls, a pattern that warrants clinical attention even where statistical significance remains under investigation. Antiphospholipid antibodies deserve particular attention, as they drive placental insufficiency and thrombosis associated with recurrent early losses. The clinical opportunity is significant: subclinical autoimmunity, addressed systematically before conception through gut repair, detoxification, methylation support, and targeted nutrition, is often reversible.
A Functional Medicine Framework for Fertility Optimization
Fertility optimization can be approached systematically across two core phases:
1. Assess the Terrain
Identify the biological factors shaping egg and sperm quality:
- Metabolic health: insulin resistance, inflammation
- Hormonal balance: thyroid, sex hormones
- Nutrient status: methylation, micronutrients
- Toxic burden: EDCs, heavy metals, mycotoxins
- Microbiome & immune function: gut health, autoimmunity
- Male factor: semen quality and DNA fragmentation
2. Optimize the System (3–6 Months)
Target the key drivers of reproductive dysfunction:
- Stabilize metabolism: low glycemic, high nutrient density diet, CGM-guided personalization
- Support mitochondria: CoQ10, carnitine, NAD, targeted nutrients
- Replete deficiencies: methylation, omega-3s, minerals
- Reduce toxic burden: diet, environment, detox pathways
- Repair the gut: address dysbiosis, restore integrity
- Calm inflammation: address histamine, oxalates, immune triggers
Case Vignette: Ryann
I had been working with a patient (we will call her Ryann) on general health optimization for about a year when, at thirty-four, she and her husband decided to start a family. After twelve months of trying without success, she came to me frustrated and ready to pursue IVF. Before going that route, I asked her to let me take a closer look. Her TSH was 4.1, within standard range but not optimal for conception, and full thyroid antibody testing revealed an elevated TPO Ab. Genetic testing identified a homozygous MTHFR C677T variant, meaning her ability to convert folate into active methylfolate was significantly impaired. Her heavy metal challenge with DMPS showed an elevated mercury level, despite a low-mercury diet. Her husband’s concurrent workup revealed elevated inflammation from SIBO and gluten intolerance. We addressed each finding in sequence: thyroid support, replacement of standard folic acid with methylfolate and a full methylated B complex, and a targeted detoxification protocol over 6 months. Her husband was optimized concurrently. Within three months of completing the protocol, Ryann conceived naturally at 35, without IVF. She went on to have a second child after a postpartum nutritional rebuild, and at 41, a surprise third pregnancy. What had presented as unexplained infertility was a combination of subclinical thyroid dysfunction, impaired methylation, and toxic burden; none of which appeared on a standard fertility panel.
The Presumptive Path Toward IVF
Egg freezing and IVF are genuinely powerful tools, and many families would not exist without them. But the way these options are often presented can subtly assume that a patient will eventually need them.
In business, this is called a “presumptive close”: the assumption that a sale will occur before the full conversation has taken place. In fertility medicine, this dynamic appears as an early clinical assumption that IVF will eventually be necessary, and therefore eggs should be preserved as soon as possible. When that assumption drives the encounter, the window to optimize the biological terrain that supports natural conception, or that meaningfully improves ART outcomes, is often missed entirely.
This matters even for patients who do proceed to ART. It takes approximately 90 to 120 days for a follicle to develop from a primordial stage to a mature oocyte. Every IVF patient has a window in which functional medicine intervention can influence the quality of the eggs that will be retrieved. Sperm DNA fragmentation, which is strongly associated with miscarriage and implantation failure even when standard semen parameters look normal, can improve meaningfully within a 72-day sperm cycle when the underlying metabolic and environmental drivers are addressed.
Case Vignette: Holly
Holly came to me after four consecutive miscarriages in a single year. She had been evaluated by some of New York’s top reproductive specialists and none had found a cause. Her history included a child with mitochondrial dysfunction and developmental delays, years of undiagnosed toxic mold exposure, and an initial workup showing elevated markers of oxidative stress, immune dysregulation, and nutrient deficiencies. Comprehensive stool testing revealed a parasitic infection, a finding that was likely contributing to both her recurrent losses and her underlying immune dysregulation. Her cycle had become irregular in the aftermath of her losses. We worked through a phased protocol: parasite treatment and gut repair first, followed by targeted nutritional repletion, detoxification support, and cycle restoration. Her cycle regularized within 6 months and oxidative stress markers improved. Holly conceived naturally at 37. After relocating and facing renewed mold exposure, she returned for a full preconception reset. Following that protocol, she conceived again naturally at 42. Her third child has been healthy from birth, the outcome that becomes possible when toxic burden, gut dysfunction, and mitochondrial impairment are treated as root causes rather than as background noise.
Final Thoughts
True fertility preservation does not begin at a fertility clinic. It begins with optimizing the biological systems that allow eggs and sperm to develop into healthy embryos and thriving children.
I’m encouraged by my patients who were told they would never conceive become pregnant naturally in their 30’s and 40’s after addressing these underlying systems. That clinical experience is what inspired me to write The Preconception Revolution and drives my ongoing work through Every Life Well and Every Baby Well.
As functional medicine clinicians, we are uniquely positioned to ask not just “can we help this patient become pregnant?” but “what does this patient’s body need to be ready to create and sustain a new, healthy life?” That question, answered early and systematically, changes outcomes not just for our patients but for generations to come.
Author Bio: Ann Shippy, MD
Ann Shippy, MD is a board-certified internal medicine physician, certified functional medicine practitioner, and leading voice in the emerging preconception movement: a new paradigm that views the months and years before pregnancy as the most powerful window to influence a child’s lifelong health. A former chemical engineer at IBM, she brings a rare systems-based and data-driven approach to uncovering the root causes of illness, infertility, and chronic disease.
Her latest book, The Preconception Revolution: A Science-Backed Path to Your Fertility and Generational Health (Forefront Books, foreword by Mark Hyman, MD), provides a groundbreaking roadmap for men and women to prepare their bodies for healthy pregnancies and optimize generational wellness. Through her Austin-based medical practice and online programs, Dr. Shippy has helped couples conceive healthy babies well into their 40s using science-backed protocols, advanced lab testing and precision functional strategies.
Her expertise has been featured on Dr Phil, NBC News, Good Housekeeping, Goop, and MindBodyGreen, and in the documentaries Supplements Revealed and Mark Hyman’s Broken Brain. A sought-after speaker on national stages, she has presented to thousands at TEDx, PaleoFX, Dave Asprey’s Biohacking Conference and other leading wellness events. Dr. Shippy holds degrees from Rensselaer Polytechnic Institute, Washington University in St. Louis, and The University of Texas. She serves on the Texas Nutrition Advisory Committee, where she plays a role developing new dietary guidelines for the state of Texas.
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