Twenty published studies. Four biological systems. One transparent reference document — built for the women who want to read the science before they trust the formula.
Most supplement brands cite "science." We show ours.
The supplement industry runs on vague language — "clinically tested," "science-backed," "research-grade." Words that signal credibility without taking the risk of being checked. We decided to take the opposite approach.
Every formulation decision for NATANEA was made by reading published research. This page exists so you can read it too. Every study below is linked directly to PubMed or NCBI — the same primary sources used by clinicians, researchers, and OB-GYNs.
These studies are about individual botanicals or biological mechanisms — not about NATANEA itself. We do not yet have a clinical trial on the finished formula, and we will not pretend otherwise.
What you'll find on this page
Five sections. Read in order or jump to what matters to you.
01
Hormonal signaling & phytoestrogens
How specific botanicals modulate the hypothalamic-pituitary-ovarian axis — the master signaling pathway that governs follicle development, ovulation timing, and luteal phase function.
Significant reduction in TRH-stimulated prolactin release (p<0.05). Luteal phase deficiencies normalized: shortened luteal phases lengthened and mid-luteal progesterone deficits resolved. Two patients in the Vitex group became pregnant during the trial.
Limitations & context
Small sample size. Focused specifically on women with latent hyperprolactinemia, not a general fertility population. The dose (20 mg of a specific extract) is brand-dependent and may not directly translate to other Vitex preparations.
Why this matters for NATANEA: This is the foundational clinical trial establishing Vitex as a hormone-modulating botanical. Its findings on luteal phase normalization and progesterone signaling are the mechanistic backbone of why NATANEA features Vitex centrally.
Over three months, the percentage of patients with an irregular cycle fell from 9.1% to 0.1% and breast tenderness from 39.9% to 0.8%; bleeding intensity and quality-of-life measures also improved. Tolerability was high.
Limitations & context
Observational design without placebo control — meaningful effect size estimation is limited. Open-label nature introduces expectancy bias. However, the very large sample size strengthens external validity.
Why this matters for NATANEA: This is one of the largest modern observational datasets on Vitex in real-world use. The three-month window mirrors the NATANEA 90-day protocol and the effects observed inform the duration we recommend.
Vitex agnus-castus extracts for female reproductive disorders: a systematic review of clinical trials
van Die MD, Burger HG, Teede HJ, Bone KM
Population
Pooled data from 13 randomized controlled trials. Total ~1,000 women across the trials. Indications: PMS, PMDD, mastalgia, hyperprolactinemia, infertility, menopausal symptoms.
Method
Systematic review following PRISMA-style methodology. Studies assessed for quality and clinical outcomes. Both placebo-controlled and active-comparator trials included.
Key findings
Evidence supports therapeutic effect of Vitex agnus-castus for premenstrual syndrome and cyclical mastalgia. Mixed but generally favorable results for luteal phase defects and subfertility. Tolerability profile generally good across trials.
Limitations & context
Heterogeneity in preparations, doses, and outcome measures between trials makes meta-analysis difficult. Some included trials had methodological weaknesses (small N, short duration).
Why this matters for NATANEA: This synthesis confirms that the clinical signal supporting Vitex isn't a single trial — it's a consistent pattern across more than a decade of independent research, which is a much stronger basis for inclusion in a formula.
American Journal of Obstetrics & Gynecology·2017·Meta-analysis (PRISMA)·N = 17 RCTs
The treatment of premenstrual syndrome with preparations of Vitex agnus castus: a systematic review and meta-analysis
Verkaik S, Kamperman AM, van Westrhenen R, Schulte PFJ
Population
17 RCTs of Vitex agnus castus in women with PMS or PMDD; 14 included in quantitative meta-analysis. Trials varied in duration (≥2 cycles minimum).
Method
Systematic review and meta-analysis following PRISMA guidelines. Searched Cochrane Central, MEDLINE, Embase, PsycINFO through January 2016. Included randomized controlled trials with minimum 2-cycle duration. Two independent reviewers assessed eligibility.
Key findings
Thirteen of 14 studies with placebo, dietary supplements, or herbal preparations as controls reported positive effects of Vitex agnus castus on total premenstrual symptoms. Pooled effect size favored Vitex.
Limitations & context
The authors note high risk of bias, high heterogeneity, and risk of publication bias across included studies — they explicitly caution that pooled treatment effects should be viewed as exploratory and may overestimate true effect. Call for high-quality trials.
Why this matters for NATANEA: Published in one of the world's leading OB-GYN journals, this is the most rigorous synthesis to date. Even when the authors apply maximum methodological skepticism, the directional signal for Vitex remains positive across 13 of 14 trials.
Systematic Review of Black Cohosh (Cimicifuga racemosa) for Management of Polycystic Ovary Syndrome-Related Infertility
Fan CW, Cieri-Hutcherson NE, Hutcherson TC
Population
Aggregated clinical and preclinical data on Cimicifuga racemosa across applications: menopausal symptoms, perimenopausal hormonal regulation, mood, and reproductive support.
Method
Comprehensive narrative and systematic review of pharmacology, clinical trials, and mechanism studies. Evaluated both estrogenic and non-estrogenic mechanisms.
Key findings
Compared with clomiphene citrate, black cohosh groups showed improvements in hormone regulation and endometrial thickness; three RCTs reported improved pregnancy rates with black cohosh added to clomiphene. Short-term use appeared safe. The authors note the overall evidence base is still limited in quality.
Limitations & context
Heterogeneity in extract preparations between studies. Most evidence is in peri/post-menopausal populations rather than preconception. Translation to fertility outcomes is mechanistic rather than direct.
Why this matters for NATANEA: Establishes Black Cohosh's mechanistic role at the hypothalamic-pituitary level — relevant to the upstream regulation of ovulation. Justifies inclusion in NATANEA as a supporting botanical for HPO axis modulation.
Adding phytoestrogens to clomiphene induction in unexplained infertility patients — a randomized trial
Shahin AY, Ismail AM, Zahran KM, Makhlouf AM
Population
119 women with unexplained infertility and recurrent clomiphene failure. Group I (n=60) received clomiphene + oral Cimicifuga racemosa 120 mg/day (days 1–12); Group II (n=59) clomiphene alone.
Method
Prospective randomized controlled trial. Standard clomiphene protocol with addition of Cimicifuga racemosa in the intervention group. Outcomes: cycle parameters, endometrial thickness, pregnancy rate.
Key findings
Endometrial thickness, serum progesterone and clinical pregnancy rate were significantly higher when Cimicifuga racemosa was added (pregnancy 36.7% vs 13.6%, P<0.01; endometrium 8.9 vs 7.5 mm, P<0.001), without adverse endometrial effects.
Limitations & context
Single-center study. Specific to assisted conception protocol — not directly studying women in natural cycles. Use of clomiphene as co-intervention means effect of Cimicifuga alone cannot be isolated.
Why this matters for NATANEA: Direct clinical evidence that Black Cohosh complements rather than disrupts ovulation induction. The endometrial finding is particularly relevant — it suggests a permissive effect for implantation.
Fertility and Sterility·2004·RCT (prospective, controlled)·N = IVF-ET patients
Phytoestrogens may improve the pregnancy rate in in vitro fertilization-embryo transfer cycles: a prospective, controlled, randomized trial
Unfer V, Casini ML, Costabile L, et al.
Population
Women undergoing IVF-embryo transfer cycles. Randomized to luteal phase support with progesterone alone vs progesterone + phytoestrogens.
Method
Patients received either intramuscular progesterone (50 mg daily) plus placebo or progesterone plus phytoestrogen tablets (1,500 mg/day of soy isoflavones — 40-45% genistein, 40-45% daidzein, 10-20% glycitein) for luteal phase support starting evening of oocyte retrieval.
Key findings
Statistically significant higher values for implantation rate, clinical pregnancy rate, and ongoing pregnancy/delivered rate in patients receiving progesterone + phytoestrogens compared to progesterone + placebo.
Limitations & context
Specific to IVF-ET context with high-dose phytoestrogens for luteal support. Not directly testing natural conception. Authors note 'more studies are necessary' to confirm the hypothesis.
Why this matters for NATANEA: Published in Fertility and Sterility — one of the world's most authoritative reproductive medicine journals. Demonstrates that phytoestrogens can play a measurable role in supporting reproductive outcomes when properly dosed.
International Journal of Molecular Sciences (MDPI)·2023·Prospective cohort·N = 60
Phytoestrogens present in follicular fluid and urine are positively associated with IVF outcomes following single euploid embryo transfer
Sirrs C, et al.
Population
60 women attending IVI-RMA New Jersey undergoing IVF with single frozen embryo transfer (SET/FET) of good-quality euploid blastocyst after PGT-A analysis.
Method
Concentrations of two phytoestrogens (daidzein and genistein) measured in follicular fluid and urine via UPLC-MS/MS on day of vaginal oocyte retrieval. Correlated with clinical IVF outcomes. Adjusted for age, BMI, race/ethnicity, smoking.
Key findings
Higher follicular fluid phytoestrogen concentrations were significantly associated with: higher serum estradiol, enhanced probability of implantation, clinical pregnancy, and live birth. Higher urine phytoestrogen concentrations were significantly associated with improved oocyte maturation, fertilization potential, and increased probability of clinical pregnancy and live birth.
Limitations & context
Observational cohort design — correlation, not causation. Small sample (N=60) but well-characterized. The phytoestrogens measured (daidzein, genistein) primarily come from soy in the diet, not directly from supplementation.
Why this matters for NATANEA: First study to directly measure phytoestrogens in follicular fluid and connect those concentrations to actual reproductive outcomes. Provides biological plausibility for the inclusion of plant-derived estrogen-receptor active compounds in preconception formulas.
Why low-grade inflammation matters for oocyte quality — and how the inflammatory state of the follicular microenvironment shapes reproductive outcomes.
Reproduction (journal of the Society for Reproduction and Fertility)·2025·Review·N = N/A (review)
The effect of chronic inflammation on female fertility
Ameho et al.
Population
Synthesis of in vivo, in vitro, and clinical data on follicular fluid inflammatory markers and reproductive outcomes.
Method
Comprehensive review of mechanisms linking systemic and follicular inflammation to oocyte quality, ovarian reserve, and reproductive aging.
Key findings
Low-grade chronic inflammation alters the follicular microenvironment in ways that compromise oocyte maturation and meiotic competence. Inflammatory cytokines in follicular fluid (IL-6, TNF-α, NLRP3 pathway activity) correlate with poorer oocyte quality and lower implantation rates in IVF cycles. The follicular fluid composition during the ~85-day antral phase is biologically modifiable.
Limitations & context
As a review, this is a synthesis of mechanisms rather than a new clinical trial. Translation from inflammatory marker reduction to clinical pregnancy outcomes is plausible but still being characterized.
Why this matters for NATANEA: This is the scientific basis for NATANEA's 'four systems' framing. Reducing systemic inflammation isn't just a wellness concept — published in a top reproductive biology journal, it's part of how the follicular environment is shaped during the ~85-day window before ovulation.
Oxidative Stress and the NLRP3 Inflammasome: Focus on Female Fertility and Reproductive Health
Moustakli E, Stavros S, Katopodis P, et al.
Population
Aggregated preclinical and clinical data on NLRP3 inflammasome activity in ovarian tissue.
Method
Review of molecular biology, in vitro studies on granulosa cells, and emerging clinical data linking NLRP3 activity to follicular function.
Key findings
Activation of the NLRP3 inflammasome in granulosa cells leads to release of pro-inflammatory cytokines (IL-1β, IL-18) that disrupt follicular development and oocyte maturation. Modulating NLRP3 activity is emerging as a therapeutic strategy for fertility-related inflammatory states (PCOS, advanced maternal age, endometriosis).
Limitations & context
Most data is preclinical. Translation to clinical supplementation strategies is still in early phase.
Why this matters for NATANEA: Provides molecular-level explanation for why inflammation matters in the preconception window. Supports the mechanistic rationale for including anti-inflammatory botanicals in NATANEA.
Cell Journal (Yakhteh)·2020·Preclinical (mouse)·N = Mouse model
Effects of licorice (Glycyrrhiza glabra) extract on follicular development and oocyte maturation in a PCOS mouse model
Mehrabadi S, et al.
Population
Mouse model of polycystic ovary syndrome (PCOS) induced by dehydroepiandrosterone (DHEA). Treatment vs untreated controls.
Method
Mice were treated with licorice extract during the experimental period. Outcomes included follicular morphology, oocyte maturation rate, and ovarian inflammatory markers.
Key findings
Licorice extract improved follicular development and oocyte maturation parameters in the PCOS mouse model. Associated reduction in ovarian inflammatory markers.
Limitations & context
Preclinical (mouse) data only. Doses in mice are not directly translatable to humans. NATANEA contains licorice at a much lower dose (150 mg) than the doses used in human RCTs for hormonal effects (1.5-3 g) — this study describes mechanism, not equivalence.
Why this matters for NATANEA: Provides mechanistic preclinical support for licorice's role in modulating ovarian inflammation. Honestly noted: human clinical evidence at NATANEA's licorice dose remains limited.
The physiological timeline that explains why preconception support is a quarter-year commitment — and why three months isn't a marketing number but a biological reality.
Folliculogenesis and the timetable of ovarian follicle development
Williams CJ, Erickson GF
Population
Comprehensive review of human ovarian physiology drawing on decades of foundational research (including Gougeon 1986).
Method
Synthesis of histological, ultrasound, and biochemical data describing the progression of primordial follicles through preantral, antral, and preovulatory stages.
Key findings
Folliculogenesis from primordial recruitment to ovulation spans approximately 1 year. The gonadotropin-sensitive antral phase — when follicles are most metabolically responsive to systemic influences (nutrition, inflammation, hormonal signals) — lasts approximately 85 days.
Limitations & context
This is a foundational reference for human ovarian physiology, not a clinical trial. The timeline is well-established but individual variation exists.
Why this matters for NATANEA: This is the literal scientific basis for the NATANEA 90-day protocol. The oocyte you will ovulate in three months is currently entering its gonadotropin-dependent maturation phase. Supporting the follicular environment during this window is the biological logic behind the protocol duration.
Complementary Therapies in Medicine·2019·Meta-analysis (DBRCT)·N = Multiple RCTs
Vitex agnus-castus in premenstrual syndrome: a meta-analysis of double-blind randomised controlled trials
Csupor D, et al.
Population
Pooled analysis of double-blind randomized controlled trials of Vitex agnus-castus in women with premenstrual syndrome.
Method
PRISMA-guided meta-analysis. Searched PubMed, Embase, Cochrane Central, Web of Science. PICOS framework. Random effects model. Focus on properly characterized VAC preparations.
Key findings
Remission of PMS symptoms was 2.57 times more likely in women taking Vitex agnus-castus than those receiving placebo. Effect was robust across properly characterized VAC preparations.
Limitations & context
Meta-analytic heterogeneity exists between studies. Limited to PMS endpoint — not directly fertility outcomes, though PMS is itself a marker of cyclical hormonal dysregulation.
Why this matters for NATANEA: Confirms that the cyclical regularizing effect of Vitex is reproducible across rigorously designed trials. PMS improvement is itself a downstream indicator of restored cycle physiology — the same restoration sought in the preconception window.
The morning layer of the protocol. How β-Nicotinamide Mononucleotide (NMN) — a direct precursor to NAD⁺ — supports mitochondrial function and sirtuin activity in the oocyte as it matures. The mechanistic foundation is strongest in animal models; the human evidence is early and concentrated in advanced maternal age, diminished ovarian reserve, and IVF/IVM. We present it exactly as it stands.
Cell Reports·2020·Preclinical (mouse)·N = Mouse model
NAD⁺ Repletion Rescues Female Fertility during Reproductive Aging
Bertoldo MJ, Listijono DR, Ho WHJ, et al.
Population
Aged female mice modelling reproductive ageing.
Method
NAD⁺ was raised using its precursor NMN; oocyte quality and fertility measures were compared against untreated aged controls.
Key findings
The loss of oocyte quality with age tracked alongside falling NAD⁺ levels; restoring NAD⁺ with NMN rejuvenated oocyte quality and restored fertility measures.
Limitations & context
Animal data. Results in mice are not directly translatable to human dosing or outcomes — this establishes the mechanism, not clinical equivalence.
Why this matters for NATANEA: Foundational evidence that the NAD⁺ pathway — the biology NATANEA CATALYST is designed to support — is causally linked to oocyte quality during reproductive ageing.
Cell Reports·2020·Preclinical (mouse)·N = Mouse model
Nicotinamide Mononucleotide Supplementation Reverses the Declining Quality of Maternally Aged Oocytes
Miao Y, et al.
Population
Maternally aged mice.
Method
In vivo NMN supplementation in aged mice; oocyte NAD⁺, meiotic competence, ovulation and fertilization outcomes were assessed against controls.
Key findings
NMN restored NAD⁺ and improved oocyte quality — supporting ovulation, meiotic competence and fertilization ability by helping maintain normal spindle and chromosome structure.
Limitations & context
Animal data only; mouse dosing does not translate directly to humans. Mechanistic evidence, not a clinical outcome.
Why this matters for NATANEA: Tests NMN itself — not just NAD⁺ — in vivo, and links it to the oocyte-quality machinery the morning dose is intended to support.
NMN supplementation rescues mitochondrial and energy metabolism functions and ameliorates inflammatory states in the ovaries of aging mice
Liang J, Huang F, Hao X, Zhang P, Chen R.
Population
Aging mice; ovarian tissue analysis.
Method
NMN was supplemented in aging mice; ovarian NAD⁺, mitochondrial and energy-metabolism function, ovulated-oocyte quality and inflammatory markers were measured.
Key findings
NMN restored ovarian NAD⁺, improved mitochondrial function and cellular energy metabolism, raised the quality of ovulated oocytes, and lowered the expression of pro-inflammatory factors.
Limitations & context
Animal data only. Demonstrates an ovarian mechanism, not human efficacy.
Why this matters for NATANEA: Connects NMN to both the energy/mitochondrial axis and the inflammatory axis at the ovarian level — the bridge between the morning cellular layer and the wider follicular environment.
Fertility & Sterility·2024·Human · IVM · advanced maternal age
NMN supplementation enhances the developmental potential of in-vitro-maturation oocytes in advanced-maternal-age women by safeguarding mitochondrial function
Population
Oocytes from women of advanced maternal age, matured in vitro (IVM).
Method
NMN was added during in-vitro maturation of oocytes; high-quality embryo and blastocyst formation rates were compared against controls.
Key findings
Adding NMN during in-vitro maturation was associated with markedly higher rates of high-quality embryos and blastocysts compared with controls.
Limitations & context
Early human data limited to an IVM laboratory setting in advanced maternal age — not a trial of everyday oral supplementation, and not a fertility-outcome promise.
Why this matters for NATANEA: One of the first human-tissue signals that NMN can support oocyte developmental potential by safeguarding mitochondrial function.
Human Reproduction (ESHRE)·2025·Human · diminished ovarian reserve
NMN — a NAD⁺ precursor — as a strategy for fertility outcomes in young women with diminished ovarian reserve (retrospective analysis)
Sen Sharma D.
Population
Young low-prognosis women with diminished ovarian reserve.
Method
Retrospective analysis comparing ovarian response and oocyte/embryo quality in women who received NMN pretreatment versus those who did not.
Key findings
In young low-prognosis women with diminished ovarian reserve, NMN pretreatment was associated with a stronger ovarian response to stimulation and improved oocyte and embryo quality.
Limitations & context
Retrospective design — association, not proof of causation — in a specific low-prognosis IVF population. Early human evidence, not a preconception-outcome promise.
Why this matters for NATANEA: Adds a human signal in diminished ovarian reserve that aligns with the animal mechanism: supporting NAD⁺ may support ovarian response and oocyte quality.
American Journal of Obstetrics & Gynecology·2025·Preclinical (mouse) + human oocyte (translational)·N = Mouse models + 220 human immature oocytes (54 young, 27 AMA)
Nicotinamide mononucleotide supplementation improves oocyte developmental competence in different ovarian damage conditions
Escrich L, Galiana Y, Grau N, et al.
Population
Mouse models of diminished ovarian reserve, primary ovarian insufficiency and chemotherapy damage; plus germinal-vesicle oocytes from young (≤35) and advanced-maternal-age (>38) women undergoing IVF.
Method
Oral and in-vitro NMN supplementation; NAD⁺ and ROS levels, mitochondrial distribution, oocyte maturation, fertilization and preimplantation embryo development assessed against controls.
Key findings
NMN recovered NAD⁺ levels, redistributed mitochondria to support proper meiotic spindle assembly, and recovered fertilization rate in damaged-ovary mouse models. In human oocytes, in-vitro NMN (100 µM) improved nuclear competence and activation of immature oocytes from advanced-maternal-age women.
Limitations & context
Largely preclinical; the human arm uses in-vitro oocyte rescue, not everyday oral supplementation, and is not a fertility-outcome promise.
Why this matters for NATANEA: Extends the NMN/NAD⁺ mechanism into human oocyte tissue across several ovarian-damage models — reinforcing the cellular layer NATANEA CATALYST is designed to support.
Most studies referenced on this page examine a single botanical at a specific dose. NATANEA is a multi-botanical formula. The combined effects of NATANEA's complete formula have not been studied in a randomized trial of the finished product — and we will not claim otherwise.
On NMN and the morning layer: the cellular-energy evidence for β-Nicotinamide Mononucleotide (NMN) is real but early. The strongest data — that restoring NAD⁺ supports oocyte quality and mitochondrial function — come from animal models, and the human work to date is concentrated in IVF/IVM and diminished-ovarian-reserve settings rather than everyday preconception use. NATANEA CATALYST delivers NMN at 500 mg in the morning to support NAD⁺ levels through the preconception window — a structure-function role, not a proven fertility outcome. We will not overstate it.
On Wild Yam: we include 15 mg of Wild Yam root extract for traditional botanical reasons. Wild Yam does not convert to progesterone in the human body. Other brands make this claim. They are wrong, and we will not repeat the error.
This level of disclosure is unusual in the supplement industry. We think that's a problem worth fixing.
From research to formula
How this research informs NATANEA's design.
The 90-day protocol is not a marketing choice — it reflects the actual timeline of antral folliculogenesis documented in the foundational ovarian physiology literature (Gougeon 1986 / Williams & Erickson 2012). The oocyte you'll ovulate in three months is already entering its gonadotropin-dependent maturation phase right now.
The choice of Vitex as the central botanical reflects three decades of clinical research — from Milewicz 1993 through Szabó 2024 — converging on the same finding: Vitex normalizes luteal phase progesterone signaling in women with subtle hormonal dysregulation, the exact profile NATANEA is built around.
We do not promise outcomes. We promise alignment between what the evidence supports and what the bottle contains.
Ready to begin?
NATANEA: a 90-day botanical protocol for the preconception window.
Hormonal signaling support. Inflammation balance. Cycle regularity. Built on the research above.
These statements have not been evaluated by the Food and Drug Administration. NATANEA is not intended to diagnose, treat, cure or prevent any disease. The research referenced on this page concerns individual botanical compounds or biological mechanisms, not the NATANEA finished formula. Always consult a qualified healthcare provider before starting any supplement, especially when planning a pregnancy or during preconception.