2. REFERENCES Infertility, 2 nd ed 1997 : Machelle M.Seibel Human Reprod Update 1996;2:459-460 Maturitus 1998;30:103-4 Maturitus 1998;30:105-11 Maturitus 1998;30:113-18 Maturitus 1998;30:127-36 Maturitus 1998;30:137-42

3. Causes of the age-related decrease in reproductive potential Intrinsic aging Weathering ฎ  endometriosis, pelvic infection, smoking, DM and obesity Socioeconomic factors ฎ  poor nutrition, poor health, delay in marriage

4. T.B.L. Kirkwood, 1998 Mechanisms of aging - oxidative damage free radicals - accumulation of aberrant proteins - defective mitochondria accumulate in cells - DNA damage - mutations (Maturitas 1998; 30: 105-11)

5. M.Dorland et al., 1998 There might be a relationship between ageing and ovarian ageing (Maturitas 1998; 30: 113-8)

6. EFFECT OF AGE ON THE COMPONENTS OF THE FEMALE REPRODUCTIVE SYSTEM

7. OVARY ovarian function - the quality and quantity of oocytes released - the hormonal milieu of the preovulatory follicle and postovulatory corpus luteum and its progesterone production

8. Kathleen A. O’Connor et al, 1998 The inactive phase of the menstrual cycle - no follicles are growing or matured to the point of producing estradiol - loss of feed back control on LH and FSH - the younger age, this phase is effectively of leugth zero (Maturitas 1998; 30: 127-36)

9. Alain Gougeon, 1998 - the numbers of growing follicles decrease with ageing, especially in women over the age of 40 - selective follicles exhibit a mitotic activity of their granulosa cell higher in women older than 40 years than in younger women (Maturitas 1998; 30: 137-42)

10. EFFECT OF AGE ON OVARY -  ฏ  oocyte reservoir - ฏ  oocyte quality - ฏ  ovarian responsive to gonadotropic stimulation - ฏ  ovarian blood flow - shorter and irregular menstrual cycle 3-9 yrs before menopause - ญ  FSH - LH levels remains unchanged

11. SIGNS OF OVARIAN AGING -  ฏ  follicular inhibin ฎ  the  earliest sign -  ญ  early follicular serum FSH - FSH > 15 IU/L ฎ  predictive value for poor reproductive potential and decrease in the number of oocytes ฎ  ฏ  fertility rate - FSH>25 IU/L ฎ  a zero pregnancy rate - quality of the oocytes correlates negatively with age, particularly for women older than 38 years

12. Clomiphene citrate challenge test (CCET) -  intake of 100 mg of clomiphene citrate D5-9 - measure serum FSH D10 - FSH < 20IU/L ฎ  normal response - FSH > 20IU/L ฎ  ฏ  ovarian reserve - 3% before age of 30 years - 7% at 30-34 years of age - 10% at 35-39 years of age - 26% at 40 years of age and after

13. GnRH agonist stimulation test -  leuprolide acetate (1.0 mg/ml) on D2 - measure estradiol 24 hr later - change in estradiol < 15 pg/ml ฎ  pregnancy rate < 5% - change in estradiol > 100 pg/ml ฎ pregnancy rate of 35%

14. Factors that may be used to predict faster oocyte depletion early menarche age at last pregnancy poor nutrition smoking family Hx of early menopause

15. Older women Non growing follicles enter the growing pool at an accelerated rate ฏ  quality of the oocytes chromosomal anomalies ฏ  implantation rate

16. Uterus some studies suggest a decrease in uterine receptivity with age, but most studies do not age does not seem to affect the endometrial thickness leiomyomas, endometrial hyperplasia & polyps which increases with age ฎ  may influence implantation

17. Hypothalamus has not been adequately studied among human positive and negative feedback mechanism seems to remain intact with advancing age biologic activity of the secreted gonadotropins may change with age less than that of younger women ญ  fibrosis of the pituitary gland after 4th decade of life

18. Cervix endocervical cells height the stroma of the cervix changes from reticular connective tissue to collagen connective tissue produces noncyclic secretions

19. Fallopian tubes tubal motility is influenced by age and menopause transportation of an ovum - muscular wall contractility - ciliary activity ฎ  not contain estrogen & progesterone receptors - secretion of the oviduct - diameter of the lumen

20. Fecundability rate is the probability of conceiving during one menstrual cycle the observed conceptions during a number of cycles and dividing it by the total number of menstrual cycles of women who engage in sexual intercourse and do not practice contraception

21. Fertility rate is the probability of conceiving within 1 year within a given population the number of livebirths in 1 year and dividing it by the total population of women in the reproductive age group.

22. Figure 1. Fertility rate among natural populations and a U.S population

23. Figure 2. Pregnancy rate per cycle among infertile patients undergoing various treatments.

24. E.R. te Velde, 1998 Until age 30 fecundity is optimal, starting to decrease thereafter the monthly fecundity rate at age 35 = 50% of age 30, has dropped to 25% at 38 and 0% at about age 41-42 age-dependent decline of fecundity probably is a matter of very early fetal loss rather than subfertility per se (Maturitas 1998; 30: 103-4)

25. Samuel F. Marcus at al, 1996 fertility does not depend merely on oocyte age and quality but also on uterine age although ovarian reserve declines with age, it is a biological and not just a chronological function

26. Results of IVF in women aged > 40 yr Preg rateLive birth rate < 25 yr21.2 %17.2 % 40-44 yr9.5 %6.3% > 45 yr3.1 %2.3 % Human Fertilisation and Embryology Authority, 1995

27. Age is associated with poor IVF outcome poor responsiveness to ovarian stimulation drugs rate of cycle cancellation egg and embryo quality implantation rate rate of abortion

28. EFFECT OF AGE ON MALE FERTILITY the role of the age of the male partner in fertility is not known by the age of 65 years the fertility rate of men had dropped to 36% of that among men between 20-24 years ญ  serum LH and FSH concentration ญ  LH pulse frequency and duration,  ฏ  amplitude ฏ  spermatogenesis, total sperm count, sperm motility and morphology