Leptin Contributes to the Development of the Corpus Luteum.

The mechanistic events of female infertility have been investigated for over 50 years and despite progress many causes of infertility remain elusive. However, over half of idiopathic infertility issues have been attributed to a defective ovarian tissue responsible for the maintenance of a conceptus, the corpus luteum (CL). Many CL defects are attributed, in part, to abnormal vascularization (angiogenesis), which occurs primarily during the developmental stage of the luteal lifespan. A few well-established angiogenic growth promotants have been implicated in luteal angiogenic processes but the mechanisms of the process are still under investigation. Recent evidence supports a role for the adipokine hormone leptin as a probable component in the angiogenic and developmental processes of a CL. Leptin expression is present during the developmental and maturation stages of the luteal lifespan and stimulates the expression of angiogenic hormones in the CL. Induced leptin deficient CL have a higher occurrence of abnormal, underdeveloped gross morphology and an increase in the number of large diameter vessels and large luteal cells. Leptin replacement therapy in leptin deficient CL accelerates tissue development, increasing overall tissue mass and forming a structure that resembled a mature CL during the early stages of development. Collectively, the evidence supports the supposition that leptin is involved in the angiogenic and developmental processes of luteal tissue.

The effect of leptin on luteal angiogenic factors during the luteal phase of the estrous cycle in goats.

Fibroblast growth factor 2 (FGF2), angiopoietin 1 (Ang1), and vascular endothelial growth factor (VEGF) are angiogenic factors implicated in the vascular development of the corpus luteum (CL). Each factor is regulated or influenced by leptin in non-ovarian tissues. Moreover, leptin and its receptor, ObRb, have been identified in luteal tissue throughout the luteal phase. Therefore, leptin is hypothesized to influence luteal vasculature through the regulation of FGF2, Ang1, and VEGF. Multiparous, cycling crossbred female goats (does) were allocated to early (n=12), mid (n=8), and late (n=11) stages of the luteal phase for CL collection. Luteal tissue was harvested and either snap frozen in liquid N2, paraffin embedded, or cultured with leptin (0, 10(-12), 10(-11), 10(-10), 10(-9), 10(-8)M). Tissue was analyzed for FGF2, Ang1, VEGF, ObRb, and leptin expression. Angiopoietin 1, FGF2, VEGF expression was higher (P≤0.001) in the mid-luteal stage than the early stage. Expression decreased (P≤0.001) during the late luteal stage with the exception of VEGF, which remained elevated. In contrast, leptin and ObRb were lowest (P≤0.003) during the mid-luteal stage compared to the early and late stages. All factors were detected in and/or around vessels in early stage tissue compared to mid and late stages. Leptin stimulated (P≤0.02) Ang1, FGF2, and VEGF expression only in early stage luteal cultures. Collectively, these data provide evidence that leptin may be involved in the luteal angiogenic process during the early stage of CL formation.