Review uncovers how tryptophan metabolism affects female reproductive health

In recent years, issues concerning female reproductive health have become a global challenge that cannot be ignored. Recently, a review published in the Chinese Medical Journal titled “Tryptophan metabolism: A hidden regulator of female reproductive health beyond fertility” revealed the profound impact of tryptophan metabolism on female reproductive health. This review comprehensively summarizes current understanding of how tryptophan influences ovarian function, fertility, and maternal-fetal health through its complex metabolic pathways.

Tryptophan is an essential amino acid. It is also the only amino acid with an indole ring structure. It has three major metabolic pathways in the body: the kynurenine (Kyn) pathway, the 5‑hydroxytryptamine (serotonin) pathway, and the indole pathway. Through these three pathways, tryptophan is converted into many bioactive molecules. These metabolites play key roles in many physiological aspects, including inflammation regulation, immune response, metabolic homeostasis, and neural function.

On the one hand, tryptophan metabolites indirectly affect the reproductive axis by regulating systemic abnormalities in the body’s internal environment, such as inflammation, oxidative stress, metabolic disorders, and aging. On the other hand, they act directly on the ovarian microenvironment to affect follicular development and hormone secretion. The serotonin pathway of tryptophan generally shows protective effects, while the kynurenine pathway has a double‑edged sword effect, and the indole pathway regulates the maternal internal environment by mediating the gut‑reproductive axis. Therefore, the imbalance of the main tryptophan metabolic pathways is a key driver of reproductive dysfunction.

In the regulation of ovarian function, serotonin and its derivative melatonin can protect oocytes and granulosa cells from oxidative damage and promote follicular development and hormone secretion. Kyn is associated with ovarian oxidative stress, metabolic disorders, and aging. However, nicotinamide adenine dinucleotide (NAD⁺), one of the final products of the Kyn pathway, has anti‑aging effects and can protect ovarian reserve. In metabolomic studies of ovarian dysfunction, the levels of tryptophan and its indole metabolites in the follicular fluid of patients with diminished ovarian reserve (DOR) are significantly decreased. In addition, the kynurenine pathway is abnormally activated in patients with polycystic ovary syndrome (PCOS).

Beyond ovarian function, tryptophan metabolism is also crucial during pregnancy. It affects embryo implantation, maternal health, and neonatal development. It helps establish immune tolerance between the mother and fetus, and its dysregulation is linked to pregnancy complications such as preeclampsia. A pregnant woman’s tryptophan intake also influences her mental health during pregnancy and affects fetal brain development and immune function.

Based on tryptophan metabolism, the review proposes several promising therapeutic strategies. These include dietary supplementation, modulation of the gut microbiota, therapies targeting key enzymes (such as indoleamine 2,3-dioxygenase (IDO)), and melatonin antioxidant therapy. However, these approaches currently rely on theoretical frameworks and animal studies. Future research needs more precise molecular mechanisms and cell-specific targets to develop more accurate and effective interventions.

This review, based on the framework of “three major metabolic pathways – ovarian function – maternal internal environment – maternal and infant health”, systematically expounds the specific mechanisms by which tryptophan metabolism regulates female reproduction. It highlights the multifaceted impact of tryptophan metabolism on female reproductive health. It lays the groundwork for future research and for developing novel, targeted therapeutic strategies for various reproductive disorders.