Home Health & Wellness Study Highlights FSH and Glutamine’s Role in Ovulation Regulation

Study Highlights FSH and Glutamine’s Role in Ovulation Regulation

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A recent study published in Protein & Cell sheds light on the mechanisms underlying ovulation and the implications for polycystic ovary syndrome (PCOS). The research indicates that follicle-stimulating hormone (FSH) regulates the synthesis of glutamine in granulosa cells (GCs), which is critical for ovulation. This discovery not only provides new insights into ovulation but also suggests potential therapeutic targets for PCOS.

Polycystic ovary syndrome (PCOS) is a leading cause of anovulatory infertility, affecting a significant number of women globally. Despite extensive research, the aetiology and pathophysiology of PCOS remain incompletely understood. The study identifies elevated glutamine levels in the follicular fluid (FF) of PCOS patients as a key factor disrupting normal ovulation.

In normal ovarian physiology, glutamine levels decrease before ovulation, facilitating the apoptosis of GCs and subsequent follicle rupture. However, in PCOS patients, glutamine levels remain high, inhibiting GC apoptosis and preventing ovulation. Comparing FF metabolites from PCOS patients and healthy controls led to this discovery. The PCOS patients had significantly higher glutamine levels than the healthy controls.

The study delved into the cellular and molecular mechanisms by which FSH regulates glutamine synthesis in GCs. It was found that FSH promotes the expression of glutamine synthetase (GS), an enzyme responsible for glutamine production from glutamate. The activation of the epidermal growth factor receptor (EGFR), which connects hormone signalling to glutamine synthesis, mediates this process.

High levels of GS were found in granulosa cells, which line the follicle and are important for oocyte maturation. This was especially true for GCs that were exposed to FF. The study showed that FSH, by activating EGFR, keeps GS expression high in GCs, which keeps glutamine production going while the follicle grows. This mechanism ensures the integrity of the follicle wall by preventing premature GC apoptosis.

The role of glutamine in regulating GC apoptosis was further explored through in vitro experiments. Glutamine deprivation induced apoptosis in cultured human granulosa cells, while glutamine supplementation inhibited it. This apoptotic regulation was linked to the ASK1-JNK signalling pathway. Specifically, glutamine inhibited the activation of ASK1, a key player in the extrinsic apoptotic pathway, thereby preventing GC apoptosis.

In mouse models, high-glutamine diets replicated PCOS traits, including disrupted estrous cycles and reduced ovulation rates. Conversely, glutamine deprivation in these models restored normal ovarian function, promoting follicle rupture and regular estrous cycles.

The study’s findings suggest that targeting the glutamine synthesis pathway could offer new therapeutic strategies for PCOS. Interventions that reduce glutamine levels or inhibit its synthesis might restore normal ovulation in PCOS patients. The research highlighted the potential of using metformin, an existing diabetes medication known to induce apoptosis via the ASK1-JNK pathway, to promote ovulation in PCOS.

Moreover, the study explored the use of AT-101, a compound that activates the ASK1-JNK pathway, in mouse models. Treatment with AT-101 induced GC apoptosis, restored regular ovulation cycles, and alleviated PCOS-like symptoms. These findings show that changing apoptotic pathways could be a useful way to treat anovulatory infertility that is linked to PCOS.

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