“The Luteal phase”

1. “The Luteal phase” • Human M.Fatemi, MD, PhD • Centre for Reproductive Medicine • Brussels, Belgium

2. The luteal phase 2 titel

3. Early History of the Corpus Luteum • Coiter (1573) described the presence of cavities filled with a yellow solid in the ovary, • Malpighi (1689) provided an accurate microscopic description of these structures and was the first to apply the name corpus luteum, literally the yellow body. • Beard (1897) postulated that corpora lutea were responsible for the suppression of ovulation and estrus during pregnancy, • Prenant (1898) suggested that the corpus luteum might be a gland of internal secretion directly benefiting the egg with which it appeared to be associated. • Fraenkel (1903) who demonstrated that corpora lutea were necessary for implantation and the subsequent maintenance of pregnancy in the rabbit. • Corner and Allen (1929) and Allen and Corner (1930) prepared a relatively pure alcoholic extract of corpora lutea from sows and showed that this extract maintained pregnancy in ovariectomized rabbits. • A few years later, the isolation of the pure crystalline hormone was reported simultaneously by four groups (Butenandt et al., 1934, Hartmann and Wettstein, 1934, Slotta et al., 1934, Wintersteiner and Allen, 1934). • Slotta et al. (1934) named the compound progesterone and suggested a structural formula, and in the same year, the compound was synthesized by Butenandt and Westphal (1934). • De Graaf (1943) who gave the first definitive description of these structures. 3 titel

4. The luteal phase • The most significant event in the early development of the corpus luteum: • Capillaries of the theca interna penetrate the basal membrane in response to secretion of angiogenic factors such as vascular endothelial growth factor (Anasti et al., 1998) • Granulosa becomes vasularized. • This angiogenic response allows large amounts of luteal hormones to enter the systemic circulation. • The granulosa cells remaining in the follicle begin to take up lipids causing the characteristic yellowish aspect. • These cells are active secretory structures that produce progesterone, estrogen and inhibine A. 4 titel

5. The role of progesterone • Induces secretory transformation of the endometrium in the luteal phase (Bourgain et al. 1990) • Progesterone deficiency delays endometrial maturation (Dallenbach-Hellweg G,1984) • Removal of CL prior to 7 weeks of gestation leads to pregnancy loss (Csapo et al.,1972) • Normal pregnancy was sustained when progesterone was given after removal CL (Csapo et al., 1973) 5 titel

6. Luteal phase defect: effect on endometrium Rogers et al, 1986 6 titel

7. Follicular phase: two cell two gonadotropin theory 7 titel

8. Steroid biosynthesis by theca and luteinized granulosa cells • 30% of luteal cells are steroidogenic (Sanders and Stouffer, 1997) • Small luteal cells are derived from the theca interna (TI), while large luteal cells are originated from granulosa cell lineage(GC) • P4 and E2 production are generally grater in GC than in TC, due to aromatase activity (Devoto et al., 2001) • TC produce the androgen precursors and 17@OHP that are aromatized by GC • The Two cell model is preserved also in he Luteal phase (Kohen et al., 2003) 8 titel

9. What is the cause of the luteal phase defect in stimulated cycles? 9 titel

10. Endocrine profile of a spontaneous pregnancy Jaervelae et al., 2008 10 titel

11. The “real” corpus luteum function Jaervelae et al., 2008 11 titel

12. The role of progesterone 12 titel

13. Histological findings- Fatemi et al., 2007 13

14. Histological findings Fatemi et al., 2007 14 titel

15. Progesterone and uterine contractions 15 titel

16. Luteal phase defect? • As early as 1949, the premature onset of menses was recognized as indicative of a luteal phase deficiency of progesterone production, which was shown to be correctable by exogenous progesterone administration (Jones G., 1979). 16 titel

17. Causes of the LPD in unstimulated cycles • The prevalence of a luteal phase defect in natural cycles in normo-ovulatory patients with primary or secondary infertility was demonstrated to be about 8.1% (Rosenberg et al., 1980). • Pathophysiologic alterations of the complex reproductive process that lead to delayed endometrial maturation characteristic of LPD include • disordered folliculogenesis, • defective corpus luteum function (LH) • abnormal luteal rescue by the early pregnancy. • A variety of clinical conditions, such as • hyperprolactinemia, • hyperandrogenic states • weight loss • stress, • athletic training • may result not in oligo- or anovulation, OR may be manifest as LPD (Ginsburg , 1992). • The three main causes of luteal phase defect in unstimulated cycles include • poor follicle production • premature demise of the corpus luteum, • failure of the uterine lining to respond to normal levels of progesterone. 17 titel

18. Luteal phase defect: The importance of StAR 18 titel

19. How to define a luteal phase defect? • Although LPD has been clearly described in research settings, the clinical diagnosis remains controversial (Jordan et al., 1994). • A defective luteal phase in natural cycle has been defined when the serum midluteal progesterone levels are less than 10ng/ml (Jordan et al.,1994). • However, mid luteal P levels do not always reflect the endometrial maturation (Batista et al., 1994). • Therefore, in the literature the most reasonable consensus of a defective luteal phase is a lag of more than two days in endometrial histological development compared to the expected day of the cycle (Jones, 1991, Dawood, 1994). • in phase or out of phase endometrium (Noyes, 1950!) 19 titel

20. The use of progesterone in IVF Nosarka et al., 2005 20 titel

21. Means of progesterone administration 21 titel

22. Patients Prefer vaginal over IM progesterone Levin et al., 2000 22 titel

23. IM Progesterone • Vaginal and intramuscular progesterone has comparable implantation and clinical PRs (Penzias,2002, Nosarka, 2005, n=1675 cycles) • Levin et al., 2000 in a multicenter U.S. study involving almost 2,000 women, found that, pregnancy rates were comparable between women who had used i.m. progesterone and those who had used vaginal gel 23 titel

24. IM Progesterone • Effective • Physiological serum levels • Painful (long, thick needles) • Occasional sterile abscess • Occasional allergic reaction (oil vehicle) • Needs to be administered by nurse, husband • Acute eosinophilic pneumonia associated with IM administration of progesterone as luteal phase support after IVF: 4 case report 24 titel

25. Vaginal Progesterone • Effective • Convenient (self-administration) • First uterine pass effect /targeted delivery • Might require multiple dosing /day (suppositories) 25 titel

26. How to correct a luteal phase defect? • Vaginal progesterone,Yes, but what dose??? • Chanson et al., 1996? 26 titel

27. Conclusions • An adequate luteal phase is imperative for a pregnancy • Prevalence of LPD in natural cycles is 8% • however, the diagnosis remains difficult • The main hormone of he luteal phase is progesterone • LH is the main hormone, controlling he corpus Luteum • Rescue of the corpus Luteum: vaginal progesterone (7 weeks), but cave! 27 titel