The Luteal Phase of the Estrous and Menstrual Cycle John Parrish • present 1-3 days following ovulation • blood vessels in follicle wall rupture • steroid synthesis • walls collapse – progesterone • collagenase • cells intermix – theca interna • old basement membrane becomes connective tissue of CL • increases in size – papilla forms Luteal Tissue • composed of cells • Large cells from granulosa from the granulosa and theca interna • Small cells from the theca interna • progesterone production increases • a small cavity may be present where the folliclular antrum was present Mitochondria Secretory Granules - Oxytocin - Relaxin Blocks Estrus Negative Feedback Progesterone Targets Functional Capability of CL Aveolar • the number of luteal cells Development – large cells undergo hypertrophy (3 fold) – small cells undergo hyperplasia (5 fold) and hypertrophy – vascularization of CL – Initiated by angiogenic factors from follicle – Vascularity effects CL steroid synthesis and delivery of hormones • Insufficient CL function – Failure to maintain pregnancy – Important in domestic animals Molecular Mechanism of LH on Luteal Cell Molecular Mechanism of LH on Luteal Cell (cAMP second messenger) (cAMP second messenger) Chol LH LH LDL Receptor G Plasma Membrane Receptor G Plasma Membrane Adenylate Cyclase Adenylate Cyclase cAMP cAMP Progesterone PKA Progesterone PKA Chol R R ATP cAMP ATP cAMP LDL S-ER C S-ER C Chol-Ester Steroid Synthesis Steroid Synthesis (+ PO4) (+ PO4) LDL Mitochondria Mitochondria Chol Pregnenolone Cholesterol Pregnenolone Cholesterol Esterase Histones Cholesterol Cholesterol Nucleus DNA Protein Protein R-SynthesisER R-SynthesisER mRNA Protein Synthesis(Enzymes) Protein Synthesis(Enzymes) LH receptor location Luteolysis • Small luteal cells • Uterus – LH receptors • PGF2a – Progesterone production driven by LH • Oxytocin • Large luteal cells – Very few LH receptors – Progesterone production mostly independent of LH Luteolysis in Cows, Luteolysis Ewes, Normal Total Uterus Hysterectomy Sows CL • Uterus CL Lifespan CL Normal Lifespan Longer • PGF2a Similar to Gestation Length • Oxytocin Contralateral Ipsilateral Hysterectomy Hysterectomy CL Lifespan CL Normal Lifespan Longer >35 days Prostaglandin F2a Control of Luteolysis Uterine Horn Progesterone from Prostaglandin synthesis CL stimulates Normal Total by uterine endometrium production of CL is released into the uterine PGF2a after Uterus Hysterectomy uterine vein. day 15 in cow CL Normal Corpus CL Maintained Oviduct Lifespan Luteum Luteolysis Mare Ovary Uterine Vein Ovarian Pedicle PGF Contralateral Ipsilateral PGF2a is picked up by Hysterectomy Hysterectomy ovarian artery through PGF into Artery 50% of CL’s 50% of CL’s counter current exchange Uterine Artery Maintained Maintained and delivered back to the ovary where it causes lysis of the CL Blood Supply to Uterus and Ovary in the Mare PGF Not Effective (Sow) PGF Not Effective (Cow, Ewe, Mare) Luteolysis • Uterus • PGF2a • Oxytocin Relationship of Oxytocin and PGF2a Posterior Anterior Pituitary Pituitary CL Oxytocin PGF2a Ovary Uterus Molecular Mechanism of PGF 2+ Luteolysis (Ca Second Messenger) Ca2+ PGF Plasma DAG • decreased blood flow PIP2 Membrane G-protein Receptor PLC • cellular response IP3 Protein Kinase C – apoptosis 2+ R Ca – progesterone synthesis Cholesterol Ca2+ • Immune response Endoplasmic Reticulum – Lymphocytes Apoptosis – Macrophages Progesterone Plasma Membrane Luteolysis PGF action in CL • decreased blood flow • Small luteal cells – PGF receptors few • cellular response • Large luteal cells – apoptosis – PGF receptors numerous – progesterone synthesis – Unsure what molecules come from large • Immune response luteal cells but they do trigger regression of small luteal cells – Lymphocytes – Macrophages Anterior LH Pituitary FSH Menstrual Cycle Hormones Progesterone Ovarian Hormones Estradiol Ovulation Corpus Follicle Corpus Luteum Albicans Ovary Recruitment Dominance Selection Recruitment Uterine Endo- metrium 2 4 6 8 10 12 14 16 18 20 22 24 26 28 2 Luteolysis in the Primate • Does not require the uterus Luteolysis in the Primate (cont.) • CL lifespan in the human is 12-14 days unless pregnancy occurs • Menstruation – In the absence of pregnancy, CL self destructs – Drop in P4 and E2 – Primate CL dependent on LH – Endometrial PGF2a, vasoconstriction, – Luteal cells start to die in absence of LH, then necrosis – Endometrial inflammation and tissue produce intra-ovarian PGF2a (oxytocin?) and luteal regression. degeneration.