Unexplained Infertility: Causes, Testing & Natural Treatment in Toronto

Unexplained Infertility: Naturopathic Treatment

Unexplained infertility is diagnosed when a couple has been unable to conceive after 12 months of regular unprotected intercourse (or 6 months if the woman is over 35), and standard fertility investigations, including semen analysis, ovarian reserve testing, basic hormonal screening, and assessment of tubal patency, return normal results. It accounts for approximately 10-15% of infertility cases.

Unexplained infertility is probably the most frustrating of fertility diagnoses because it leaves couples wondering why they can’t conceive. There are specific fertility tests that fertility clinics don’t do, and other aspects of fertility that can’t necessarily be measured.  For the former, patients often seek naturopathic care. For the latter, as a naturopathic doctor, I would treat them as if these issues were a problem since we can’t test to confirm whether they are or aren’t, and there is no harm in treating “as if”.

Factors that may Cause Unexplained Infertility

Endometriosis: 

The only definitive test for this is laparoscopic surgery. Most women with infertility have never had a laparoscopy done; a number of women with unexplained infertility may have undiagnosed endometriosis. Conservative estimates put the incidence of undiagnosed endometriosis at 11% of the population.

Undetected hormone imbalance

Did you know that most fertility clinics do not test ALL of your hormones? The standard tests run by fertility clinics include LH, FSH, estradiol, progesterone and prolactin.  Some of my patients haven’t even had something as basic as a 7-day post-ovulation progesterone level tested.  Additional tests that may be relevant to your fertility include: DHEAs, testosterone, DHT, androstenedione, repeated prolactin measurements, 7-day post-ovulation progesterone, and thyroid hormone tests (TSH, free T3, free T4, reverse T3, anti-TPO and anti-thyroglobulin antibodies). Thorough and complete hormone testing provides answers as to why you are struggling and what to do about it.

Implantation failure

Implantation requires the right hormonal mix and normal nitric oxide levels. Nitric oxide plays an important role in endometrial functions such as receptivity, implantation, and menstruation. Appropriate immune function is also important for the endometrial lining to receive the embryo.

Undiagnosed Celiac Disease

In one recent study, patients with unexplained infertility, recurrent miscarriage or intrauterine growth restriction (IUGR) were found to have a significantly higher risk of Celiac Disease than the general population.

Oxidative stress

A certain amount of oxidative stress is part of conception. Too much oxidative stress is detrimental to fertility. There may be a threshold for reactive oxygen species, above which conception may not occur.

Genetics

Undetected genetic defects, such as MTHFR mutation, may contribute to infertility through undermethylation (detoxification) and/or impaired DNA synthesis.

Sperm DNA Fragmentation

A DNA Fragmentation Index (DFI) of greater than 20 is considered to cause a reduced chance of natural pregnancy. In contrast, a DFI greater than 30 is associated with a very low chance of achieving pregnancy by natural conception or by insemination.  A DNA fragmentation test may or may not have been performed as part of the male partner’s sperm count.

Pelvic Inflammatory Disease

Having a history of pelvic inflammatory disease has been associated with a higher incidence of infertility.

Beyond Standard Testing: What a Naturopathic Fertility Workup Actually Investigates

A standard fertility workup through a reproductive endocrinologist covers the essentials: semen analysis, transvaginal ultrasound for antral follicle count, HSG for tubal patency, and a basic hormonal panel. When all of those return “normal” and no cause is identified, the diagnosis becomes “unexplained.” What it really means is that the investigation stopped before it was complete.

With my background as a hospital medical laboratory technologist in biochemistry, hematology, and microbiology, I read lab results differently than most clinicians, and I order tests that rarely appear in a conventional fertility workup. Here is what I investigate and why each marker matters:

Thyroid antibodies (anti-TPO and anti-thyroglobulin):

Thyroid autoimmunity can be present even when TSH is entirely normal. Anti-thyroid antibodies are independently associated with increased miscarriage risk and reduced IVF success rates in euthyroid women, likely through immune dysregulation at the implantation site.¹

Free T3 and free T4 (not just TSH):

TSH reflects pituitary signalling, not actual thyroid hormone availability at the cellular level. Low-normal free T3 impairs endometrial receptivity and luteal phase adequacy even when TSH falls within the standard reference range.

Fasting insulin and HOMA-IR:

Insulin resistance disrupts ovulation and implantation through multiple mechanisms: elevated insulin levels drive androgen production, suppress SHBG, impair endometrial glucose uptake, and is frequently present in women with no outward signs of PCOS and normal fasting glucose.²

Dihydrotestosterone (DHT) and total testosterone:

Androgen excess beyond what a standard testosterone test captures can indicate adrenal or ovarian dysfunction that is driving poor follicular development without meeting the threshold for a formal PCOS diagnosis.

DHEA-S:

Distinguishes adrenal from ovarian androgen sources, which changes the treatment approach, and low DHEA-S in women over 35 is associated with diminished ovarian reserve independent of AMH.

Prolactin:

Mildly elevated prolactin, below the threshold most labs flag as abnormal, is sufficient to suppress LH pulsatility, shorten the luteal phase, and impair implantation. Standard labs often miss subclinical hyperprolactinemia.

Homocysteine:

Elevated homocysteine reflects impaired methylation, is associated with recurrent pregnancy loss, and identifies women who need methylfolate rather than folic acid, regardless of MTHFR genotype.³

MTHFR genotype (C677T and A1298C):

MTHFR polymorphisms impair the conversion of folic acid to its active form, 5-methyltetrahydrofolate (5-MTHF). Women with these variants who supplement folic acid rather than methylfolate may have persistent methylation deficits despite apparent compliance with prenatal supplementation recommendations. Naturopathic doctors in Ontario cannot order genetic tests.

Ferritin:

Iron deficiency without anemia, ferritin below 30 mcg/L, is sufficient to cause anovulation. Hemoglobin can be entirely normal while ferritin is low enough to disrupt ovulatory function.

25-OH Vitamin D:

Vitamin D receptors are present on granulosa cells, endometrial cells, and testicular Sertoli cells. Deficiency, highly prevalent in Ontario given our latitude, is associated with reduced implantation rates, increased endometriosis severity, and impaired sperm motility.⁴

High-sensitivity CRP (hsCRP):

A marker of low-grade systemic inflammation. Chronic subclinical inflammation impairs endometrial receptivity and is associated with implantation failure in the absence of any structural pathology.

Anti-nuclear antibodies (ANA) and anti-phospholipid antibodies:

Autoimmune activity below the threshold for a formal diagnosis can disrupt implantation and early placentation. Antiphospholipid antibodies, in particular, are associated with recurrent early pregnancy loss and are frequently not tested until after a third miscarriage under standard protocols. Naturopathic doctors in Ontario cannot order antiphospholipid antibodies.

Natural killer cell activity:

Elevated uterine natural killer cell activity is a proposed mechanism in unexplained implantation failure and recurrent miscarriage, though the evidence base is still developing and testing is not yet standardized across Canadian labs.

Sperm DNA Fragmentation: The Male Factor Test Most Clinics Don’t Order

A standard semen analysis measures count, motility, and morphology. What it does not measure is the structural integrity of the DNA inside each sperm cell. A man can have a completely normal semen analysis and still have sperm DNA fragmentation rates high enough to prevent fertilization, cause early embryo arrest, or contribute to recurrent miscarriage.⁵

Sperm DNA fragmentation (SDF) is assessed using the DNA Fragmentation Index (DFI). A DFI above 15–25% (thresholds vary by laboratory method) is associated with significantly reduced natural conception rates and reduced IVF success rates, even when conventional semen parameters are normal. A 2019 meta-analysis of 5,765 IVF cycles found high SDF was independently associated with lower clinical pregnancy rates and higher miscarriage rates after both IVF and ICSI.⁶

Clinically relevant causes of elevated SDF include: oxidative stress (the most common and most modifiable driver), infection or subclinical genital tract inflammation, elevated scrotal temperature from varicocele or occupational heat exposure, smoking, obesity, advanced paternal age, and exposure to environmental toxins including pesticides and BPA.

Naturopathic treatment of elevated SDF targets the underlying driver. For oxidative stress, by far the most common cause, antioxidant therapy with vitamin C, vitamin E, CoQ10, zinc, selenium, and N-acetylcysteine (NAC) has demonstrated statistically significant reductions in DFI in randomized controlled trials.⁷ Abstinence interval also matters: frequent ejaculation (every 1–2 days) reduces DFI by minimizing the time sperm spend exposed to reactive oxygen species in the epididymis.

SDF testing is not routinely offered through Ontario fertility clinics but is available through specialized andrology labs. I can guide couples through accessing this testing when the standard workup returns normal and conception has not occurred.

What Naturopathic Treatment for Unexplained Infertility Actually Involves

Treatment is built around what your workup reveals, not a generic fertility protocol. That said, the following interventions form the evidence-based foundation of naturopathic care for unexplained infertility:

Dietary modification – anti-inflammatory and low glycemic

The fertility diet is not a generic “eat clean” instruction. It is a specific dietary pattern: low-glycemic-index, high in antioxidants, adequate in plant and animal protein, rich in omega-3 fatty acids, and low in processed carbohydrates, trans fats, and alcohol. The 2018 Nurses’ Health Study II found that women following a pro-fertility dietary pattern had a 66% lower risk of ovulatory infertility compared to women eating a typical Western diet.⁸ I provide individualized dietary guidance based on your specific lab findings – insulin resistance, inflammatory markers, and nutritional deficiencies all change the specifics of what your diet needs to address.

Targeted antioxidant supplementation for egg and sperm quality

Oxidative stress is one of the most consistently identified mechanisms in both unexplained female infertility and elevated sperm DNA fragmentation. The following are the most evidence-supported antioxidants in reproductive medicine:

• CoQ10 (ubiquinol, 200–600 mg/day): Supports mitochondrial function in oocytes; RCT evidence for improved ovarian response and embryo quality in women with diminished ovarian reserve.⁹
• Melatonin (1–3 mg at bedtime): Follicular fluid melatonin is a primary antioxidant protecting the developing oocyte from oxidative damage; oral supplementation increases follicular fluid melatonin concentrations and has been associated with improved fertilization rates.¹⁰
• N-acetylcysteine (NAC, 600 mg/day): Glutathione precursor; supports both endometrial receptivity and sperm DNA integrity.
• Vitamin C and E: Synergistic antioxidants; combined supplementation has demonstrated reductions in sperm DNA fragmentation in RCTs.
• Zinc: Required for both testosterone synthesis and oocyte maturation; deficiency impairs meiotic spindle formation.

Dosing is individualized and adjusted based on test results, not applied uniformly.

MTHFR and methylation support

Women with MTHFR polymorphisms require 5-methyltetrahydrofolate (5-MTHF) rather than folic acid, along with methylated B12 (methylcobalamin) and B6 (pyridoxal-5-phosphate) to support the methylation cycle. Elevated homocysteine, the functional marker of methylation impairment, is directly associated with recurrent pregnancy loss and implantation failure and is correctable through targeted B vitamin supplementation.³

Nitric oxide and endometrial receptivity

L-arginine is a precursor to nitric oxide, which plays a role in uterine blood flow and endometrial development. Some evidence supports L-arginine supplementation to improve endometrial thickness in women with a thin lining and poor uterine perfusion, though the evidence base is smaller than that for antioxidant therapy and is not appropriate for all patients.

When I refer back to the fertility clinic

Naturopathic treatment is not a reason to delay or avoid conventional fertility medicine when it is indicated. I work alongside reproductive endocrinologists, not instead of them. Circumstances that warrant prompt referral or concurrent medical management include: age 35 or older with more than 6 months of unsuccessful conception attempts, FSH above 12 IU/L or AMH below 0.5 pmol/L indicating diminished ovarian reserve, suspected uterine structural abnormality, or any finding on workup that requires medical or surgical intervention. If you are already working with a fertility clinic, naturopathic care integrates with your protocol. I communicate with your medical team when appropriate and do not recommend interventions that would conflict with your stimulation or transfer cycle.

How Long Does Naturopathic Treatment for Unexplained Infertility Take?

The minimum meaningful treatment window is three months. This is not arbitrary; it reflects the biology of both egg and sperm development. Oocytes undergo a maturation process that begins approximately 90 days before ovulation. Interventions targeting egg quality antioxidant supplementation, dietary change, and correction of nutritional deficiencies require this full window to influence the oocyte that will actually be released or retrieved. Sperm have a similar 72- to 74-day production cycle, which is why improvements in sperm parameters after treatment take at least 3 months to appear on a repeat semen analysis.

Within that three-month window, measurable changes in lab markers (insulin, inflammatory markers, nutritional levels, thyroid antibodies) often occur earlier, sometimes within 6–8 weeks, which provides objective evidence that treatment is working before the full reproductive cycle has completed.

For women with hormonal dysregulation, cycle irregularities, or autoimmune findings, 3-6 months is a more realistic timeline to establish a stable, optimized reproductive environment. This does not mean waiting 6 months before pursuing assisted reproduction if that is already planned; it means starting naturopathic support as early as possible so that the treatment window aligns with your IVF or IUI preparation rather than delaying it.

Celiac Disease and Unexplained Infertility

The association between undiagnosed celiac disease and infertility is stronger than most fertility workups reflect. A 2014 meta-analysis (Tersigni et al.) found significantly higher rates of unexplained infertility in women with undiagnosed celiac disease compared to the general population, along with increased rates of miscarriage and intrauterine growth restriction. A 2022 systematic review and meta-analysis by Schiepatti et al. in Nutrients confirmed and extended these findings, reporting that women with untreated celiac disease had significantly higher rates of adverse reproductive outcomes — and that adherence to a strict gluten-free diet substantially reduced these risks.¹¹

The proposed mechanisms include: nutrient malabsorption (iron, folate, zinc, and vitamin D – all directly relevant to fertility), immune dysregulation with elevated anti-tTG antibodies that may cross-react with placental trophoblasts, and systemic inflammation from ongoing gluten exposure.

Testing for celiac disease (anti-tTG IgA, anti-DGP IgG, and total IgA) is a straightforward blood test that is not routinely included in a fertility workup but can be added to any requisition. It is particularly relevant for women with unexplained infertility, recurrent miscarriage, a history of iron deficiency anemia resistant to supplementation, or a first-degree relative with celiac disease.

Unexplained Infertility References:

1. Huang Y, Xie B, Li J, Hang F, Hu Q, Jin Y, Qin R, Yu J, Luo J, Liao M, Qin A. Prevalence of thyroid autoantibody positivity in women with infertility: a systematic review and meta-analysis. BMC Women’s Health. 2024 Nov 27;24(1):630. doi: 10.1186/s12905-024-03473-6. PMID: 39604908; PMCID: PMC11600930.
2. Purwar A, Nagpure S. Insulin Resistance in Polycystic Ovarian Syndrome. Cureus. 2022 Oct 16;14(10):e30351. doi: 10.7759/cureus.30351. PMID: 36407241; PMCID: PMC9665922.
3. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Thomas CM, Eskes TK. Homocysteine and folate levels as risk factors for recurrent early pregnancy loss. Obstet Gynecol. 2000 Apr;95(4):519-24. doi: 10.1016/s0029-7844(99)00610-9. PMID: 10725483.
4. Grundmann M, von Versen-Höynck F. Vitamin D – roles in women’s reproductive health? Reprod Biol Endocrinol. 2011 Nov 2;9:146. doi: 10.1186/1477-7827-9-146. PMID: 22047005; PMCID: PMC3239848.
5. Andrabi SW, Ara A, Saharan A, Jaffar M, Gugnani N, Esteves SC. Sperm DNA Fragmentation: causes, evaluation and management in male infertility. JBRA Assist Reprod. 2024 Jun 1;28(2):306-319. doi: 10.5935/1518-0557.20230076. PMID: 38289201; PMCID: PMC11152411.
6. Tan J, Taskin O, Albert A, Bedaiwy MA. Association between sperm DNA fragmentation and idiopathic recurrent pregnancy loss: a systematic review and meta-analysis. Reprod Biomed Online. 2019 Jun;38(6):951-960. doi: 10.1016/j.rbmo.2018.12.029. Epub 2018 Dec 22. PMID: 30979611.
7. Majzoub A, Agarwal A. Systematic review of antioxidant types and doses in male infertility: Benefits on semen parameters, advanced sperm function, assisted reproduction and live-birth rate. Arab J Urol. 2018 Jan 2;16(1):113-124. doi: 10.1016/j.aju.2017.11.013. PMID: 29713542; PMCID: PMC5922223.
8. Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Diet and lifestyle in the prevention of ovulatory disorder infertility. Obstet Gynecol. 2007 Nov;110(5):1050-8. doi: 10.1097/01.AOG.0000287293.25465.e1. PMID: 17978119.
9. Xu Y, Nisenblat V, Lu C, Li R, Qiao J, Zhen X, Wang S. Pretreatment with coenzyme Q10 improves ovarian response and embryo quality in low-prognosis young women with decreased ovarian reserve: a randomized controlled trial. Reprod Biol Endocrinol. 2018 Mar 27;16(1):29. doi: 10.1186/s12958-018-0343-0. PMID: 29587861; PMCID: PMC5870379.
10. Tamura H, Nakamura Y, Korkmaz A, Manchester LC, Tan DX, Sugino N, Reiter RJ. Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril. 2009 Jul;92(1):328-43. doi: 10.1016/j.fertnstert.2008.05.016. Epub 2008 Sep 18. PMID: 18804205.
11. Rostami K, Steegers EA, Wong WY, Braat DD, Steegers-Theunissen RP. Coeliac disease and reproductive disorders: a neglected association. Eur J Obstet Gynecol Reprod Biol. 2001 Jun;96(2):146-9. doi: 10.1016/s0301-2115(00)00457-7. PMID: 11384797.
12. Franasiak JM, Alecsandru D, Forman EJ, Gemmell LC, Goldberg JM, Llarena N, Margolis C, Laven J, Schoenmakers S, Seli E. A review of the pathophysiology of recurrent implantation failure. Fertil Steril. 2021 Dec;116(6):1436-1448. doi: 10.1016/j.fertnstert.2021.09.014. Epub 2021 Oct 19. Erratum in: Fertil Steril. 2022 Mar;117(3):653. doi: 10.1016/j.fertnstert.2022.01.002. PMID: 34674825.
13. Tersigni C, Castellani R, de Waure C, Fattorossi A, De Spirito M, Gasbarrini A, Scambia G, Di Simone N. Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms. Hum Reprod Update. 2014 Jul-Aug;20(4):582-93. doi: 10.1093/humupd/dmu007. Epub 2014 Mar 11. PMID: 24619876.
14. Karatas, A. and Eroz, R. and Bahadır, A. and Keskİn, F. and Ozlu, T. and Ozyalvaclı, M. E., 20143124136, English, Journal article, Switzerland, doi:10.1159/000357442, 1423-002X 0378-7346, 77, (2), Basel, Gynecologic and Obstetric Investigation, (89–93), S Karger AG, Endothelial nitric oxide synthase gene polymorphisms (promoter -786T/C, exon 894 G/T and intron G10T) in unexplained female infertility., (2014)
15. Oleszczuk K, Augustinsson L, Bayat N, Giwercman A, Bungum M. Prevalence of high DNA fragmentation index in male partners of unexplained infertile couples. Andrology. 2013 May;1(3):357-60. doi: 10.1111/j.2047-2927.2012.00041.x. Epub 2012 Dec 14.
16. Chwalisz K1, Garfield RE. Role of nitric oxide in implantation and menstruation. Hum Reprod. 2000 Aug;15 Suppl 3:96-111.
17. Elizabeth H. Ruder, a Terryl J. Hartman,b and Marlene B. Goldmanc. Impact of oxidative stress on female fertility. Curr Opin Obstet Gynecol. 2009 Jun; 21(3): 219–222.
18. Lalouschek W, Aull S, Serles W, Wolfsberger M, Deecke L, Pabinger-Fasching I, Mannhalter C. The relation between erythrocyte volume and folate levels is influenced by a common mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (C677T). J Investig Med. 2000 Jan;48(1):14-20.
19. Buck Louis GM, Hediger ML, Peterson CM, Croughan M, Sundaram R, Stanford J, Chen Z, Fujimoto VY, Varner MW, Trumble A, Giudice LC; ENDO Study Working Group. Incidence of endometriosis by study population and diagnostic method: the ENDO study. Fertil Steril. 2011 Aug;96(2):360-5. doi: 10.1016/j.fertnstert.2011.05.087. Epub 2011 Jun 29.
20. In a study involving women diagnosed with infertility from 200-2013, it was found that those with pelvic inflammatory disease had significantly higher rates of infertility than controls. Females with obesity, thyroid problems, ovarian abscesses, and bacterial infections also had higher rates of infertility.  Source: Relationships between female infertility and female genital infections and pelvic inflammatory disease: a population-based nested controlled study. 2018. Clinics, 73.