Phoenixin-14 ameliorates ovarian morphology in a DHEA-induced rat model of PCOS.

Abstract: Polycystic ovary syndrome (PCOS) is a complex reproductive-endocrine disorder characterized by impaired folliculogenesis, anovulation, and hormonal imbalance. While PNX-14 is known as a hypothalamic peptide that modulates GnRH signaling, emerging evidence indicates its local ovarian expression, particularly in granulosa and luteal cells, suggesting potential peripheral roles in follicular development. This study aimed to evaluate the therapeutic potential of PNX-14 in a dehydroepiandrosterone (DHEA)-induced rat model of PCOS, with a focus on its potential peripheral effects on ovarian tissue. Female rats were divided into control, PCOS, and PCOS + PNX-14 (2.5, 5, or 30 nmol) groups. PCOS was induced by DHEA administration (60 mg/kg/day, s.c.) for 21 days. Vaginal cytology, hormone assays (FSH, LH, E2, P4, and testosterone), histological analysis, PCNA immunohistochemistry, and western blot were performed. DHEA-induced PCOS rats exhibited disrupted estrous cycles, suppressed gonadotropins and estradiol, and polycystic ovarian morphology with extensive follicular atresia and reduced PCNA expression. PNX-14 treatment, particularly at 5 nmol, significantly improved estrous cyclicity, restored primordial and antral follicle populations, reduced atretic and cystic follicles, and normalized PCNA levels in granulosa cells. Serum hormones showed trends toward recovery without consistent statistical significance after 3 days of treatment. This study provides the first in vivo evidence that peripheral administration of this peptide ameliorates key morphological and cellular features of PCOS in rats, primarily by enhancing granulosa cell proliferation and early folliculogenesis. These findings support further investigation into PNX-14 as a novel therapeutic candidate as a local ovarian modulator for PCOS, potentially offering disease-modifying effects beyond conventional symptom-targeted therapies. Lay summary: PCOS is a leading cause of infertility and affects millions of women worldwide. It disrupts normal egg development, causing hormonal imbalances and cyst formation in the ovaries. Current treatments mainly control symptoms but do not repair the ovary itself. We investigate PNX-14, a natural peptide present in the brain and ovary that supports early egg growth. We tested this peptide found in the brain and ovary that supports early egg growth, in a well-established rat model of PCOS. After three days of treatment, it improved ovarian structure and restored regular reproductive cycling. Importantly, it significantly reduced degenerating follicles, helping to preserve healthy early-stage follicles. These benefits occurred even though major blood hormone levels were largely unchanged, suggesting that this peptide acts locally within the ovary. This is the first in vivo evidence that it can directly counter key cellular and structural damage caused by PCOS. The findings highlight PNX-14 as a potential new therapy to protect ovarian health and improve fertility in people with PCOS.