Lecture 12a - The Luteal Phase of the Estrous Cycle and the Menstrual Cycle

Reading

• Chapter 9
• Additional diagrams or pictures not found in text

Lecture 12a:

Luteal Phase (text figure 9-1)

• CL
  • corpus hemorrhagicum (ovulation till day 1 to 3)
  • CL becomes more recognizable by day 3 to 5
• production of progesterone
  • size of CL corresponds with its progesterone production
• luteolysis
  • regression of CL
  • change in structure as well as ability to secret progesterone
  • the CL becomes the corpus albicans

Corpus Luteum Formation (text figure 9-2, lecture uses older versions of these images)

• in response to LH surge, granulosa and theca cells of preovulatory follicle luteinize
• basement membrane disintergrates
• at ovulation the walls of the follicle collapse
• theca and granulosa cells mix
• basement membrane becomes the connective tissue network of CL
• breakage of small blood vessels leads to the blood clot seen in the corpus hemorrhagicum

CL structure and Function

• large luteal cells from granulosa
  • contain secretory granules
    • during estrous cycle contain oxytocin
    • during pregnancy contain relaxin
• small luteal cells from theca interna
  • do not contain secretory granules
• both small and large luteal cells make progesterone
• increase in CL size due to
  • large luteal cells increase in size (hypertrophy)
  • small cells increase in number (hyperplasia)
• vascularization of CL
• insufficient luteal function important factor in reproductive failure

Targets of Progesterone Action (text figure 9-7)

• hpothalamus
  • negative feedback on GnRH amplitude and frequency
  • prevents behavioral estrus
  • stops preovulatory LH surge
• uterus
  • endometrium
    • stimulates endometrial gland secretion which supports development of conceptus prior to implantation
  • myometrium
    • decreases muscle contraction (motility)
• mammary gland
  • stimulates development of alveoli

Progesterone Synthesis (text figure 9-8)

• Cholesterol ester is importated into the cell bound to LDL
• LH via its binding to its receptor increases cAMP and PKA
• PKA causes
  • increase internalization of the cholesterol-LDL molecule
  • activates cholesterol esterase
  • increased cholesterol uptake by mitochondria
  • probably a role in regulating pregnenolone conversion to progesterone in smooth ER

Luteolysis

• uterus required (text figure 9-9)
  • hysterectomy prevents luteolysis
  • partial hysterectomy
    • ipsilateral
      • prevents luteolysis
    • contralateral
      • no effect on luteolysis, occurs at normal time
  • transplant ovary to neck
    • prevents luteolysis
  • uterus needed for luteolysis and must be near ovary to have effect
• PGF is luteolysin
  • counter current exchange between uterine vein and ovarian artery (Figure 1)
    • present in cow, ewe, sow
      • important as PGF is destroyed in peripheral circulation as it passes through the lungs
    • not present in mare (Figure 2)
      • PGF gets to ovary after going through the general circulation
      • mare ovary is more sensitive to PGF than other species
  • sensitivity of CL to PGF (Figure 3)
    • cow, ewe only after day 5-6 of cycle
    • sow not until day 12-14 of cycle
• oxytocin (text figure 9-11, 9-12, Figure 4))
  • produced by CL (large luteal cells)
  • receptors in uterus decline after ovulation as progesterone increases
  • after 10-12 days progesterone, uterine oxytocin receptors again begin to increase
  • in response to oxytocin binding to its receptor in the uterine endometrium, PGF is released
  • PGF triggers release of oxytocin from CL to intiate a positive feedback loop
  • oxytocin can also come from posterior pituitary
• intracellular mechanisms of luteolysis
  • ischemia (decreased blood flow to CL)
  • apoptosis
    • increase in intracellular calcium
    • protein kinase C inhibits progesterone synthesis
• the immune system
  • macrophages and lymphocytes are present in luteal tissue and increase at the time of luteolysis
    • can perform phagocytosis of luteal cells
    • cytokines are released and cause
      • cell death
      • stop progesterone production
      • apoptosis

Menstrual Cycle in Human Females (Figure 5)

• Average cycle length is 28 days from start of menstruation until start of next menstruation
• Ovarian events
  • Follicular wave starts day 1 -2 with recruitment followed by selection and dominance
  • Ovulation occurs on day 14
  • luteal phase 14 days
• Luteolysis in Primate
  • Does not require the uterus
  • CL lifespan in the human is 12-14 days unless pregnancy occurs
    • In the absence of pregnancy, CL self destructs
    • Possible intra-ovarian oxytocin receptors and PGF2α production
• Menstruation
  • Drop in P4 and E2
  • Endometrial PGF2α, vasoconstriction, necrosis
  • Endometrial inflammation and tissue degeneration

Manipulation of Ovulation Time

• Hormonal induction of ovulation
  • PGF2α - regresses CL between days 5 - 17 bovine estrous cycle
  • Ovsync
    • day 0 - GnRH - eliminate current follicular wave
    • day 7 - PGF2α - regress CL, either induced by GnRH or natural CL
    • day 9 - GnRH (36 - 48 hr following PGF2) - induces ovulation of dominant follicle from
      wave initiated by GnRH on day 0
  • Progestins - prevents estrus and positive estrogen feedback as long as present. Give until natural CL
    regresses on its own. Stop giving progestin, estrogen now has positive feedback, estrus is stimulated,
    get GnRH and LH surge.
• Superovulation - drugs stimulate recruitment and selection so more follicles grow
  • FSH - must give multiple injections
  • eCG - only need 1 injection, limited use in US

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