The impact of nicotinamide mononucleotide on ovarian health: A comprehensive literature review of preclinical evidence and therapeutic potential

Inyoung Kang; Jaewang Lee

doi:10.5653/cerm.2026.09488

Clin Exp Reprod Med > Epub ahead of print

Kang and Lee: The impact of nicotinamide mononucleotide on ovarian health: A comprehensive literature review of preclinical evidence and therapeutic potential

Review Article

Clinical and Experimental Reproductive Medicine 2026;cerm.2026.09488.

Published online: August 4, 2026

DOI: https://doi.org/10.5653/cerm.2026.09488

The impact of nicotinamide mononucleotide on ovarian health: A comprehensive literature review of preclinical evidence and therapeutic potential

Inyoung Kang¹

, Jaewang Lee^1,²

¹Division of Biopharmaceutical Sciences, Department of Senior Healthcare, Eulji University, Uijeongbu, Republic of Korea

²Department of Biomedical Laboratory Sciences, Eulji University, Seongnam, Republic of Korea

Corresponding author: Jaewang Lee Department of Biomedical Laboratory Sciences, Eulji University, 553 Sanseong-daero, Sujeong-gu, Seongnam 13135, Republic of Korea
Tel: +82 31-740-7144 Fax: +82-31-740-7211 E-mail: wangjaes@gmail.com

*This study was supported by Eulji University (EJRG-26-18).

Received April 8, 2026 Revised May 11, 2026 Accepted May 14, 2026

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Nicotinamide mononucleotide (NMN), a key precursor of nicotinamide adenine dinucleotide (NAD⁺), has recently emerged as a promising therapeutic candidate for age-related diseases. This review critically evaluates preclinical evidence regarding the effects of NMN on ovarian health, with particular emphasis on its potential to attenuate ovarian aging, improve follicular reserve, and restore endocrine function. Animal studies have demonstrated that NMN supplementation enhances mitochondrial function, reduces oxidative stress, and modulates sirtuin activity in ovarian tissue. These effects contributed to improved oocyte quality, delayed ovarian senescence, and prolonged reproductive lifespan. In models of chemotherapy-induced ovarian insufficiency and age-related ovarian decline, NMN administration was associated with increased folliculogenesis and normalization of hormonal profiles. Furthermore, the anti-inflammatory and anti-apoptotic properties of NMN suggest potential therapeutic applications in conditions such as premature ovarian insufficiency and polycystic ovary syndrome. Despite encouraging findings in rodent models, clinical translation remains limited. This review summarizes the key molecular pathways influenced by NMN, including the NAD⁺/sirtuin-1 (SIRT1) axis, and highlights important gaps in current knowledge. Collectively, the available evidence underscores the therapeutic potential of NMN while emphasizing the need for well-designed human studies to establish its efficacy and safety in reproductive medicine.

Keywords: Nicotinamide mononucleotide; Nutrition; Ovary; Reproductive endocrine

Introduction

Ovarian aging is a major determinant of female reproductive capacity and endocrine health. Unlike many somatic tissues, the ovary undergoes an early and progressive decline characterized by depletion of the follicular reserve, reduced oocyte quality, and impaired hormone production. These changes contribute not only to infertility and menopause but also to broader systemic health risks, including osteoporosis, cardiovascular disease, and cognitive dysfunction [1]. As childbearing is increasingly delayed worldwide, interest in strategies aimed at preserving ovarian function has grown substantially.

Mitochondrial dysfunction and oxidative stress are considered major drivers of ovarian aging [2]. In parallel, an age-related decline in nicotinamide adenine dinucleotide (NAD⁺), a critical regulator of cellular metabolism and sirtuin activity, has been implicated in multiple aging-associated disorders [3]. Consequently, restoration of NAD⁺ levels has emerged as a potential therapeutic strategy for improving ovarian function. Nicotinamide mononucleotide (NMN), a biosynthetic precursor of NAD⁺, has attracted considerable attention because of its ability to enhance intracellular NAD⁺ availability and improve mitochondrial homeostasis. Preclinical studies have demonstrated that NMN supplementation can attenuate several hallmarks of ovarian aging. In aged murine models, NMN restored ovarian NAD⁺ levels, improved mitochondrial function, enhanced oocyte quality, and promoted follicular development through pathways associated with sirtuin-1 (SIRT1) activation [4-11]. Additional studies reported anti-inflammatory and anti-apoptotic effects that contributed to preservation of ovarian reserve and endocrine function [13-15]. Beyond natural aging models, NMN has also demonstrated protective effects against chemotherapy-induced ovarian injury and has been investigated as a potential therapeutic candidate for reproductive disorders such as polycystic ovary syndrome (PCOS) [8,16].

Despite encouraging preclinical findings, clinical translation remains limited. Although early human studies have supported the safety and bioavailability of NMN [17,18], evidence regarding its effects on female reproductive function remains insufficient. Furthermore, the long-term consequences of NAD⁺ modulation in hormone-sensitive tissues, as well as the optimal dosage and timing of treatment, have yet to be clarified [11,15,17].

This review summarizes current preclinical evidence regarding the effects of NMN on ovarian physiology and dysfunction. Particular emphasis is placed on mechanisms involving NAD⁺/SIRT1 signaling, mitochondrial metabolism, oxidative stress, and cellular survival pathways, while also discussing current limitations and future directions for clinical application.

Mechanistic classification: molecular and cellular pathways mediated by NMN in ovarian tissue

NMN exerts beneficial effects on ovarian function primarily by augmenting intracellular NAD⁺ levels, thereby activating signaling pathways involved in mitochondrial maintenance, DNA repair, anti-inflammatory responses, and cellular metabolism [19-22].

1. NAD⁺/SIRT1 axis

The NAD⁺-dependent deacetylase SIRT1 is a key mediator of the ovarian response to NMN supplementation. SIRT1 promotes genomic stability, protects against oxidative stress, and preserves telomere integrity in granulosa cells and oocytes [23,24]. Studies have shown that NMN-induced activation of SIRT1 increases the expression of antioxidant enzymes, including superoxide dismutase 2 and catalase, modulates the forkhead box O3a (FOXO3a) transcription factor, and enhances mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) [25-28]. These effects preserve mitochondrial membrane potential and reduce reactive oxygen species accumulation, a major contributor to oocyte aging.

2. DNA damage response and apoptosis inhibition

Ovarian aging is associated with the accumulation of DNA double-strand breaks and impaired DNA repair mechanisms [29,30]. NMN restores NAD⁺ levels required for poly(ADP-ribose) polymerase 1 (PARP1) activity, a DNA damage sensor involved in base excision repair [31]. By facilitating PARP1-mediated DNA repair and preventing adenosine triphosphate (ATP) depletion, NMN reduces apoptosis in oocytes and granulosa cells [32,33]. Concurrently, NMN decreases the expression of the pro-apoptotic protein B cell leukemia/lymphoma 2 (BCL2) associated X protein (Bax) while increasing levels of the anti-apoptotic protein Bcl-2, thereby promoting follicular survival [32].

3. Inflammation modulation

Low-grade chronic inflammation in aging ovaries is characterized by increased nuclear factor kappa B (NF-κB) activation, elevated cytokine release, including tumor necrosis factor-alpha and interleukin-1 beta, and immune-cell infiltration. NMN suppresses NF-κB nuclear translocation and reduces inflammatory cytokine expression in granulosa cells, thereby improving the follicular microenvironment and preventing fibrosis [5,13].

4. Mitochondrial bioenergetics and oxidative stress

NMN improves mitochondrial function by increasing the NAD⁺/nicotinamide adenine dinucleotide with hydrogen (NADH) ratio, thereby enhancing oxidative phosphorylation and ATP production. In addition, NMN stimulates mitophagy through SIRT3- and AMP-activated protein kinase (AMPK)-mediated signaling pathways, facilitating the removal of dysfunctional mitochondria and preserving bioenergetic homeostasis [34-36].

5. Hormonal regulation and steroidogenesis

Preclinical studies have demonstrated that NMN influences ovarian steroidogenesis. By restoring granulosa-cell viability and mitochondrial cholesterol transport through steroidogenic acute regulatory protein activity, NMN enhances estradiol synthesis and contributes to normalization of estrous cyclicity and endocrine profiles in aged animals [5,32]. In addition, several studies suggest that NMN may improve ovarian health by enhancing steroid hormone production and mitigating age-related endocrine dysfunction [37].

The physiological regulation of the NAD⁺ salvage pathway should also be considered when evaluating the clinical applicability of NMN. In mammalian tissues, NAD⁺ is primarily regenerated through the salvage pathway, in which nicotinamide is converted to NMN by nicotinamide phosphoribosyltransferase (NAMPT), followed by conversion of NMN to NAD⁺ via NMN adenylyltransferases. The activity of this pathway is tightly regulated by aging, metabolic status, circadian rhythm, inflammation, and cellular stress. Notably, age-associated declines in NAMPT expression and increased NAD⁺ consumption by enzymes such as cluster of differentiation 38 (CD38) and PARPs contribute to systemic NAD⁺ depletion. Therefore, the efficacy of NMN supplementation may depend not only on precursor availability but also on the functional integrity of endogenous salvage pathways and NAD⁺-consuming networks. A more comprehensive understanding of these regulatory mechanisms will be essential for optimizing the therapeutic application of NMN in reproductive aging and ovarian dysfunction.

Model-based evidence: preclinical models assessing NMN’s efficacy in ovarian health

1. Naturally aged mice

NMN is being investigated in naturally aged mouse models to assess its potential to mitigate age-related decline and improve healthspan. Studies using C57BL/6 mice, a common strain in aging research, have shown that NMN supplementation can attenuate several age-related physiological changes. In naturally aged mouse models, NMN supplementation has been associated with reduced age-associated weight gain, enhanced energy metabolism, increased physical activity, improved insulin resistance, and improved ocular function [38-40]. With respect to reproductive health, NMN has also been shown to improve fertilization, blastocyst formation, and hatching rates, particularly in models of ovarian damage [4,10,41].

2. Chemotherapy-induced ovarian insufficiency

In mice, NMN supplementation has shown promise in mitigating the adverse effects of chemotherapy on ovarian health and fertility. Specifically, NMN may improve oocyte quality, increase fertilization rates, and enhance embryo development in chemotherapy-treated mice by increasing NAD⁺ levels and reducing oxidative stress [10]. In mouse models of chemotherapy-induced ovarian insufficiency, NMN may help restore ovarian NAD⁺ levels, which are commonly reduced after chemotherapy-related injury [42]. NMN administration in these models also improves oocyte quality, fertilization, and preimplantation embryo development by supporting cellular energy production, DNA repair, and antioxidant mechanisms [43].

3. In vitro models: granulosa and oocyte culture systems

Human granulosa cells and mouse cumulus–oocyte complexes cultured with NMN exhibited improved survival, mitochondrial function, and meiotic progression [5,16]. NMN-treated oocytes showed reduced fragmentation, increased ATP production, and improved developmental competence after in vitro fertilization (IVF) [10,44].

4. Translational limitations and gaps

Despite compelling results from rodent models, species differences, short treatment durations, and the absence of chronic exposure studies limit translation to humans [45,46]. Furthermore, the effects of NMN on ovarian reserve in nonhuman primates and on long-term reproductive capacity remain underexplored [5,47,48].

Clinical translation and safety considerations

Despite extensive preclinical evidence supporting the efficacy of NMN in attenuating ovarian aging and dysfunction, clinical translation remains at an early stage. Because NMN is increasingly marketed as an over-the-counter nutraceutical, its pharmacokinetics, safety profile, and potential reproductive implications in humans require careful evaluation.

1. Human pharmacokinetics and bioavailability

Several small-scale clinical studies have investigated the bioavailability and pharmacodynamics of NMN in healthy adults. Oral NMN is well absorbed and increases circulating NAD⁺ levels within hours of administration, without serious adverse effects [49,50]. Huang et al. [51] reported a multicenter, randomized, double-blind, parallel-group, placebo-controlled study evaluating the efficacy and safety of Uthever (EffePharm Ltd.), an orally administered NMN supplement, in middle-aged and older adults. After oral administration, increased NAD⁺/NADH levels at day 30 and day 60 suggested that Uthever may raise cellular NAD⁺ levels, which may be associated with higher energy levels and anti-aging effects [51]. Kim et al. [52] administered 250 mg of NMN daily for 12 weeks to investigate the effects of time-dependent NMN intake in older adults. They reported that afternoon NMN intake improved lower-limb function and reduced drowsiness in older adults [52]. Gao et al. [53] provided additional evidence suggesting that NMN may improve sleep quality in patients with chronic insomnia. However, none of these studies assessed reproductive endpoints or hormonal profiles.

2. Safety concerns in reproductive-age women

The safety of NAD⁺-modulating agents such as NMN in reproductive-age women has not been fully characterized. Although animal models suggest ovarian benefits, translation to women requires caution because hormonal regulation and folliculogenesis are highly sensitive to metabolic interventions. One concern is that NAD⁺ modulation could inadvertently disrupt the finely tuned balance of hypothalamic–pituitary–ovarian axis signaling or overstimulate sirtuin activity, with unknown long-term endocrine consequences [54,55]. Moreover, the effects of chronic NMN supplementation during pregnancy or lactation remain unexamined. Preclinical evidence suggests possible epigenetic effects of NAD⁺ on embryonic development and germline cells, raising questions about intergenerational outcomes [56,57].

3. Regulatory status and ethical oversight

NMN is currently regulated as a dietary supplement in many countries, including the United States and South Korea; therefore, it is not subject to the rigorous safety and efficacy evaluations required for pharmaceutical agents. This regulatory gap creates challenges for establishing dosage guidelines, contraindications, and interactions with fertility treatments, including assisted reproductive technology and hormone therapy.

In reproductive medicine, particularly for women considering conception or undergoing IVF, any intervention that affects ovarian metabolism or oocyte epigenetic stability warrants thorough ethical review and validation in clinical trials [58].

4. Clinical research gaps

To date, no registered clinical trials have directly investigated the effects of NMN on female fertility, ovarian reserve, anti-Müllerian hormone (AMH) levels, antral follicle count, or pregnancy outcomes. This represents a major knowledge gap and underscores the urgent need for rigorously designed randomized controlled trials (RCTs) that evaluate reproductive endpoints and are stratified by age and baseline ovarian function.

Potential clinical applications and patient populations

Although NMN has not yet been clinically approved for reproductive applications, several patient populations may benefit from its targeted use if efficacy and safety are established. On the basis of preclinical findings and relevant pathophysiological mechanisms, four key groups may be considered potential candidates for NMN-based interventions in reproductive health.

1. Women of advanced reproductive age

Female reproductive aging is characterized by reduced oocyte quality, mitochondrial dysfunction, and increased oxidative damage. Preclinical studies have demonstrated that NMN supplementation enhances NAD⁺ levels and SIRT1 activity in oocytes, thereby improving meiotic spindle assembly and embryo development [4]. In women aged >35 years attempting conception, particularly those undergoing IVF, NMN may serve as a metabolic adjuvant to improve oocyte competence and response to ovarian stimulation. Adjunctive NMN therapy may also reduce age-related aneuploidy risk by improving chromosomal segregation.

2. Cancer survivors with iatrogenic ovarian insufficiency

Young women undergoing chemotherapy frequently experience premature ovarian insufficiency (POI) due to gonadotoxicity. In murine models, NMN protects ovarian reserve by reducing oxidative stress and apoptosis after exposure to chemotherapeutic agents [10,14,42]. Therefore, NMN could be evaluated as a gonadoprotective agent in adolescent or adult cancer patients, potentially as a co-administered therapy during chemotherapy to preserve endocrine and reproductive function. However, this application would require careful oncologic safety profiling because NMN may affect cellular metabolism and proliferation.

3. Women with metabolic dysregulation (e.g., PCOS)

PCOS is characterized by hyperandrogenism, insulin resistance, and mitochondrial dysfunction in ovarian cells. Recent studies have shown that NMN ameliorates hyperinsulinemia and restores ovulatory cyclicity in PCOS-like mouse models by activating the AMPK–SIRT1 axis [20,59-61]. NMN may provide dual metabolic and reproductive benefits in PCOS and could serve as an alternative or adjunct to metformin in select populations.

4. Perimenopausal women seeking endocrine stabilization

NMN has shown the capacity to enhance estradiol production and preserve ovarian steroidogenic capacity in aged models [5,62]. In perimenopausal women with irregular menses, vasomotor symptoms, and declining fertility, NMN might serve as a nonhormonal modulator of ovarian endocrine output. This approach could potentially delay the menopausal transition or reduce menopausal symptom burden while preserving natural hormonal rhythms.

5. Cautions in special populations

NMN use in women with hormone-sensitive tumors, such as breast or endometrial cancer, should be approached with caution. Its potential effects on estrogen biosynthesis and oocyte metabolism warrant exclusion or careful monitoring of these populations in clinical studies. Furthermore, NMN use during pregnancy or lactation remains untested and is currently not recommended.

Conclusion and future directions

NMN represents a promising intervention at the intersection of aging, metabolism, and reproductive health. Preclinical data across multiple animal models consistently demonstrate that NMN improves mitochondrial function, reduces oxidative stress, and enhances ovarian endocrine and reproductive capacity. These findings provide a strong mechanistic and phenotypic rationale for clinical translation.

However, the transition from bench to bedside remains incomplete. Although NMN has shown a favorable safety profile in general adult populations, its effects on reproductive health, particularly in women of reproductive age, remain insufficiently explored. The absence of clinical trials targeting ovarian endpoints, hormonal balance, and long-term fertility outcomes highlights a significant research gap.

Future research must prioritize:

(1) Longitudinal RCTs examining NMN in women with age-related infertility, POI, or PCOS.
(2) Dose–response studies defining optimal therapeutic windows without endocrine disruption.
(3) Fertility-focused biomarker analyses, including AMH, follicle-stimulating hormone, oocyte yield, and embryo quality.
(4) Safety surveillance in pregnancy and multigenerational reproductive models.

If validated in humans, NMN could shift the paradigm of fertility preservation from reactive interventions, such as cryopreservation, to proactive metabolic modulation. Furthermore, its potential applications in reproductive longevity and the menopausal transition have broader implications for women’s healthspan. Integrating NMN into reproductive medicine may ultimately not only extend reproductive years but also improve quality of life during aging.

Conflict of interest

No potential conflict of interest relevant to this article was reported.

Acknowledgments

To improve the clarity and fluency of the manuscript, the authors used ChatGPT (OpenAI, San Francisco, CA, USA) for English-language editing. The authors reviewed and verified all content to ensure its accuracy and originality.

Author contributions

Conceptualization: IK, JL. Writing-original draft: IK, JL. Writing-review & editing: IK, JL. Approval of final manuscript: IK, JL.

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