REFERENCES

• Infertility, 2nd 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

Causes of the age-related decrease in reproductive potential

• Intrinsic aging• Weatheringฎendometriosis, pelvic

infection, smoking, DM and obesity• Socioeconomic factors ฎpoor nutrition,

poor health, delay in marriage

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)

M.Dorland et al., 1998

There might be a relationship between ageing and ovarian ageing

(Maturitas 1998; 30: 113-8)

EFFECT OF AGE ON THE COMPONENTS OF

THE FEMALE REPRODUCTIVE SYSTEM

• OVARYovarian function

- the quality and quantity of oocytes released- the hormonal milieu of the

preovulatory follicle and postovulatory corpus luteum and

its progesterone production

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)

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)

EFFECT OF AGE ON OVARY

-ฎoocyte reservoir- ฎoocyte quality - ฎovarian responsive to gonadotropic sti

mulation - ฎovarian blood flow - shorter and irregular menstrual cycle

3-9 yrs before menopause- ฎFSH- LH levels remains unchanged

SIGNS OF OVARIAN AGING-ฎfollicular inhibin ฎtheearliest sign-ฎearly follicular serum FSH- FSH > 15 IU/L ฎpredictive value for poor reproductive potential and decrease in the number of oocytes

ฎฎfertility rate- FSH>25 IU/L ฎa zero pregnancy rate- quality of the oocytes correlates negatively

with age, particularly for women older than 38 years

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 ฎฎovarian 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

GnRH agonist stimulation test

-leuprolide acetate (1.0 mg/ml) on D2- measure estradiol 24 hr later

- change in estradiol < 15 pg/ml ฎpregnancy rate < 5%- change in estradiol > 100 pg/ml ฎ pregnancy rate of 35%

Factors that may be used to predict faster oocyte depletion

• early menarche• age at last pregnancy• poor nutrition• smoking• family Hx of early menopause

Older women

• Non growing follicles enter the growing pool at an accelerated rate• ฎquality of the oocytes

chromosomal anomalies • ฎimplantation rate

Uterus

• some studies suggest a decrease in uterine receptivity with age, but most studies do not• age does not seem to affect the endometria

l thickness • leiomyomas, endometrial hyperplasia & p

olyps which increases with age ฎmay influence implantation

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 gonadotro

pins may change with age less than that of younger women

• ฎfibrosis of the pituitary gland after 4th decade of life

Cervix

• endocervical cells height • the stroma of the cervix changes from reti

cular connective tissue to collagen connective tissue• produces noncyclic secretions

Fallopian tubes • tubal motility is influenced by age and me

nopause• transportation of an ovum

- muscular wall contractility

- ciliary activity ฎnot contain estrogen & progesterone receptors

- secretion of the oviduct- diameter of the lumen

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

Fertility rate

• is the probability of conceiving within 1 year within a given population• the number of livebirths in 1 year and divi

ding it by the total population of women in the reproductive age group.

0

100

200

300

400

500

600

20-24 25-29 30-34 35-39 40-44 45-49

US 1981

Iranian Village 20th century

French Village 17th century

Hutterites 20th century

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

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

0

5

10

15

20

25

30

35

20-24 25-29 30-34 35-39 40-41 42-44

TID

GIFT

IVF

TID

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 probabl

y is a matter of very early fetal loss rather than subfertility per se

(Maturitas 1998; 30: 103-4)

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

Results of IVF in women aged > 40 yr

Preg rateLive birth rate

• < 25 yr 21.2 % 17.2 %• 40-44 yr 9.5 % 6.3%• > 45 yr 3.1 % 2.3 %

Human Fertilisation and Embryology Authority, 1995

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

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• ฎserum LH and FSH concentration• ฎLH pulse frequency and duration, ฎฎamplitude• ฎspermatogenesis, total sperm count,

sperm motility and morphology