Spermidine and Fertility: What The Research Suggests

Spermidine, a naturally occurring polyamine, has drawn growing scientific interest for its potential role in reproductive health. Found in every living cell and in foods such as wheat germ, soybeans, aged cheese, and mushrooms, spermidine is involved in essential cellular processes, including growth, proliferation, and autophagy [1]. As the average age of first-time parents continues to rise worldwide, understanding age-related fertility decline, and whether it can be supported, has become increasingly relevant. Below, we look at the emerging research on spermidine and both female and male fertility. For a primer, see what spermidine is.

In short: Spermidine is a naturally occurring polyamine found in foods like wheat germ, soybeans, and aged cheese. Early research, largely in animal models, has explored its association with cellular processes tied to reproductive aging, including autophagy and antioxidant activity. 

Female Fertility and Spermidine

Female fertility declines with age as both egg quantity and quality fall, driven partly by mitochondrial dysfunction and oxidative stress. In animal studies, spermidine has been associated with improved egg quality through enhanced autophagy and antioxidant activity.

Female Reproductive Aging

Women are born with a finite number of oocytes (eggs), which decline in both quantity and quality with age. This natural process, known as ovarian reserve depletion, begins before birth and continues throughout a woman's reproductive lifespan.

At birth, a female has approximately 1 to 2 million eggs, which decreases to about 300,000 to 500,000 by puberty. By age 30, only about 12% of the original egg pool remains. This decline is associated with reduced fertility, particularly after age 35, with a more marked decrease by 37 and the onset of the menopausal transition typically occurring between 45 and 50 years [2]. The rate of this decline in both quality and quantity is influenced by various factors, including genetics, environment, lifestyle choices, and the biological hallmarks of aging.

Metabolic Regulation and Egg Quality

As women age, not only does the quantity of eggs decrease, but their quality may also diminish [4]. A key determinant of female fertility is metabolic regulation, particularly mitochondrial function in eggs. Mitochondria provide the energy necessary for optimal egg quality during embryonic development, maturation, and fertilization. They play a role in cellular energy production, calcium regulation, and the recycling of egg cell components. Aging, however, is associated with progressive mitochondrial dysfunction, primarily due to oxidative stress, which can affect egg quality and fertility.

Spermidine's potential to influence cellular processes related to aging and metabolism has led researchers to investigate its effects on reproductive function. Recent studies have looked at how this compound might relate to some of the changes associated with egg aging, including mitochondrial dysfunction and oxidative stress. The research below explores those associations.

Spermidine Levels and Egg Quality

Given the link between fertility and metabolism, the role of polyamines in supporting mitochondrial function is one avenue researchers are exploring in the context of preserving fertility.

Autophagy and Mitophagy

Building on this, a study published in Nature reported that spermidine was associated with improved egg quality in aged mice, in part through enhanced removal of damaged mitochondria via autophagy [5]. Using untargeted metabolomics, this research group identified spermidine as a metabolite of interest in the ovaries and its possible role in protecting eggs against aging. Notably, they reported that spermidine levels were lower in the ovaries of older mice, and that supplementation with spermidine was associated with:

• Follicle development
• Egg maturation
• Early embryonic development
• Improved measures of female fertility in aged mice

Antioxidant Properties

Polyamines have been shown to have antioxidant properties, which may help protect eggs from oxidative damage. Research indicates that spermine and spermidine can act as free radical scavengers, protecting cellular components from oxidative damage [6]. In one study, spermidine supplementation in mice was reported to increase the activities of several antioxidant enzymes and total antioxidant capacity in ovarian tissue [7]. That study also reported that spermidine reduced malondialdehyde (MDA) content in ovarian tissue, a marker associated with lipid peroxidation.

Benefits for Female Fertility

Because mitochondrial dysfunction and oxidative stress are considered major contributors to age-related changes in egg quality, spermidine's antioxidant and autophagy-related properties are of interest for reproductive research. By reducing oxidative stress, spermidine may help preserve the integrity of egg DNA, proteins, and lipids, which are important for fertilization and embryo development [8]. Through enhanced mitophagy, spermidine may support the removal of damaged mitochondria in eggs, which could relate to overall egg energy metabolism and quality. These remain research-stage associations rather than established outcomes.

Male Fertility and Spermidine

Male fertility declines gradually with age through reduced testosterone and sperm quality. In animal models, spermidine supplementation has been associated with improved sperm motility, morphology, and antioxidant protection. Research on spermidine and age-related sperm decline in humans has not yet been conducted directly, so conclusions remain preliminary.

Male Reproductive Aging

Unlike women, men do not experience a complete cessation of fertility with age. Male reproductive aging is instead characterized by a gradual decline in testicular function and sperm quality. This process typically begins around age 35 to 40, with more pronounced effects after 50 [9]. The decline is marked by decreasing testosterone levels and reduced sperm production, along with diminished sperm quality, including lower motility, decreased normal morphology, and increased DNA fragmentation [9]. These changes can lead to reduced fertility, a longer time to conception, and an increased risk of genetic abnormalities in offspring. The rate and extent of this decline vary among individuals and are influenced by genetics, lifestyle, environmental exposures, and overall health status. (For a related question, see whether spermidine is found in sperm.)

Spermatogenesis and Testicular Function

A key determinant of male fertility is the continuous process of spermatogenesis, which relies on the proper function of Sertoli and Leydig cells in the testes. Sertoli cells provide structural and nutritional support to developing sperm cells, while Leydig cells produce testosterone, which is essential for sperm production and maturation. With age, there is a gradual decrease in Leydig cell numbers and function, leading to reduced testosterone production. This hormonal change, together with a decline in Sertoli cell efficiency, is associated with decreased sperm production and quality. Aging is also associated with increased oxidative stress and DNA damage in sperm cells, which can affect fertilization potential and embryo development.

In animal research, spermidine has shown associations with several aspects of sperm quality, including motility, viability, and morphology.

Spermidine and Sperm Quality

Some research has reported that spermidine supplementation was associated with improved sperm motility and overall sperm health in animal models [10]. Motility matters because it relates to the sperm's ability to move through the female reproductive tract, which affects the likelihood of successful fertilization. Reported effects of spermidine on sperm quality extend beyond motility, with research pointing to a role in supporting normal sperm morphology and enhancing superoxide dismutase activity, which helps protect sperm from oxidative damage [11]. In a separate study, the addition of L-arginine (a polyamine precursor) to sperm samples from diabetic patients was associated with improved sperm motility [12].

Testicular Function

Research has also looked at spermidine's effects on testicular function. A study in mice reported that spermidine could help offset testicular dysfunction induced by triptolide, a compound known to impair male fertility in that model [13]. It was associated with increased expression of genes related to spermatogenesis and with improved offspring numbers. Spermidine has also been studied for a possible role in the timing of the acrosome reaction, a step that is essential for fertilization [10]. This suggests spermidine may be involved in the complex processes of sperm capacitation and the acrosome reaction.

Antioxidant Properties

As with female reproductive aging, oxidative stress is a significant factor in male infertility, affecting sperm function and DNA integrity [14]. Spermidine's antioxidant properties may help reduce this oxidative stress, offering some protection to sperm cells. This is relevant because oxidative stress can affect sperm production in the testes, contributing to a reduced sperm count (a condition known as oligozoospermia). Spermidine may help preserve sperm DNA integrity, which is important for fertilization and embryo development [15]. 

Clinical Relevance

Some clinical observations are consistent with a role for polyamines in male fertility. For example, the seminal plasma of infertile men has been reported to contain markedly lower levels of polyamines such as spermine and spermidine compared with normospermic controls. This suggests that maintaining adequate levels of these polyamines may be relevant to male fertility [10, 12].

If you would like to understand the compound itself in more depth, you can read more about food-derived spermidine, such as Primeadine, here.

This article is for educational purposes only and is not intended as medical advice. Oxford Healthspan products are not intended to diagnose, treat, cure, or prevent any disease or medical condition, including infertility. If you are trying to conceive or have concerns about your fertility, please consult a qualified healthcare provider before making changes to your diet or supplement routine.

References

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[2] American College of Obstetricians and Gynecologists Committee on Gynecologic Practice and Practice Committee. Female age-related fertility decline. Fertil Steril. 2014;101(3):633-4.

[3] Pan H, Ma P, Zhu W, Schultz RM. Age-associated increase in aneuploidy and changes in gene expression in mouse eggs. Dev Biol. 2008 Apr 15;316(2):397-407. doi: 10.1016/j.ydbio.2008.01.048. Epub 2008 Feb 15. PMID: 18342300; PMCID: PMC2374949.

[4] ESHRE Capri Workshop Group, Fertility and ageing, Human Reproduction Update, Volume 11, Issue 3, May/June 2005, Pages 261–276, https://doi.org/10.1093/humupd/dmi006

[5] Zhang, Y., Bai, J., Cui, Z. et al. Polyamine metabolite spermidine rejuvenates oocyte quality by enhancing mitophagy during female reproductive aging. Nat Aging 3, 1372–1386 (2023). https://doi.org/10.1038/s43587-023-00498-8

[6] Ha HC, Sirisoma NS, Kuppusamy P, Zweier JL, Woster PM, Casero RA Jr. The natural polyamine spermine functions directly as a free radical scavenger. Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11140-5. doi: 10.1073/pnas.95.19.11140. PMID: 9736703; PMCID: PMC21609.

[7] Jiang D, Guo Y, Niu C, Long S, Jiang Y, Wang Z, Wang X, Sun Q, Ling W, An X, et al. Exploration of the Antioxidant Effect of Spermidine on the Ovary and Screening and Identification of Differentially Expressed Proteins. International Journal of Molecular Sciences. 2023; 24(6):5793. https://doi.org/10.3390/ijms24065793

[8] Agarwal, A., Aponte-Mellado, A., Premkumar, B.J. et al. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol 10, 49 (2012). https://doi.org/10.1186/1477-7827-10-49

[9] Harris ID, Fronczak C, Roth L, Meacham RB. Fertility and the aging male. Rev Urol. 2011;13(4):e184-90. PMID: 22232567; PMCID: PMC3253726.

[10] Lefèvre PL, Palin MF, Murphy BD. Polyamines on the reproductive landscape. Endocr Rev. 2011 Oct;32(5):694-712. doi: 10.1210/er.2011-0012. Epub 2011 Jul 26. PMID: 21791568.

[11] Srivastava S, Desai P, Coutinho E, Govil G. Mechanism of action of L-arginine on the vitality of spermatozoa is primarily through increased biosynthesis of nitric oxide. Biol Reprod. 2006 May;74(5):954-8. doi: 10.1095/biolreprod.105.046896. Epub 2006 Jan 25. PMID: 16436531.

[12] Morales ME, Rico G, Bravo C, Tapia R, Alvarez C, Méndez JD. Aumento de movilidad progresiva por L-arginina y poliaminas en espermatozoides de pacientes con astenozoospermia idiopática y diabética [Progressive motility increase caused by L-arginine and polyamines in sperm from patients with idiopathic and diabetic asthenozoospermia]. Ginecol Obstet Mex. 2003 Jun;71:297-303. Spanish. PMID: 14515660.

[13] Wang JY, Ma D, Luo M, Tan YP, Ou Zhong, Tian G, Lv YT, Li MX, Chen X, Tang ZH, Hu LL, Lei XC. Effect of spermidine on ameliorating spermatogenic disorders in diabetic mice via regulating glycolysis pathway. Reprod Biol Endocrinol. 2022 Mar 7;20(1):45. doi: 10.1186/s12958-022-00890-w. PMID: 35255928; PMCID: PMC8900360.

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[15] Beygi Z, Forouhari S, Mahmoudi E, Hayat SMG, Nourimand F. Role of Oxidative Stress and Antioxidant Supplementation in Male Fertility. Curr Mol Med. 2021;21(4):265-282. doi: 10.2174/1566524020999200831123553. PMID: 32867638.