Aging and Female Fertility

Fertility peaks when a woman is in her late teens and early twenties

begins to decline at age thirty

dropping more rapidly after age 35 years

Fertility plummets after age 40 and pregnancy After age 45 is rare botros et.al infertility and assisted reproduction - 2008

infertility rate :

overall : 2.4%after age 34 : 11%after age 40 : 33% by the age 45 : 87% Speroff et.al Clinical Gynecologic Endocrinology & Infertility, 7th Edition -2005

↓fertility rates :25- 29 age : 4% to 8% ↓30 -34 age : 15% to 19% ↓35- 39 age : 26% to% 46%↓ 40-45 age : 95%↓

Factors Involved in Female Fertility Loss

• Egg QuantityEgg quantity refers to the number of eggs that you have in your ovaries

Germ cells in the female are not replenished during life

the number of oocytes and follicles is determined in utero and declines following an exponential curve from the second trimester to menopause

Speroff et.al Clinical Gynecologic Endocrinology & Infertility, 7th Edition -2005

During fetal life , germ cells rapidly proliferate by mitosis to yield approximately 6 to 7 million oogonia by 16-20 weeks of pregnancy

Transformed to oocytes after entering the first meiotic division, the number of germ cells falls to between 1 and 2 million at birth and to about 300,000 to 500,000 by the onset of puberty

Over the next 35-40 years of reproductive life, only about 400 to 500 oocytes will ovulate

Until age 37-38 : approximately 25,000 oocytes remain

At the time of menopause , fewer than 1,000 follicles remain


2. Egg QualityEgg Quality refers to how ready and able your eggs are to become fertilized.

Every woman carries a certain number of eggs in her ovaries ready to be released for fertilization

These eggs need to have the right shape, health, and

chromosomes in order to be able to develop into an embryo and, eventually, a baby.

Unfortunately, egg quality also changes over time

As you age, your eggs become weaker, and less able to form a healthy embryo

Your eggs also begin to decrease in number, leaving fewer and fewer quality eggs available for fertilization. A woman of 40 typically has lower egg quality than a woman of 20

Complications of Poor Egg Quality

Poor egg quality can lead to a vareity of complications, including: 1. IVF or IUI failure 2. repeated miscarriages 3. chromosomal abnormalities

Female Age and Egg Quality

Age is one issue, but the real fertility issue is egg quality and quantity and not the number in a woman's age.

Egg quantity and quality in an individual woman can be average for her age, better than average, or worse than average. We know that egg quantity and quality tends to decline significantly in the mid to late 30s and fall faster in the late thirties and early 40s.

Testing Fertility Loss as You AgeThe following ovarian reserve screening tests are used by fertility specialists to predict the "remaining egg supply" and the ability (reserve) of the ovaries to respond to stimulation with drugs. These tests are helpful. However, they predict the quantity of eggs

remaining - rather than the quality of those eggs.

Do ovarian reserve tests check egg quantity, quality, or both?

Ovarian reserve testing can tell us quite a lot about the remaining quantity of eggs a woman has, but it tells us little about the quality of those eggs.

1.Day 3 FSH testing2.AMH levels3.Antral follicle counts

http://www.advancedfertility.com/testovar.htm

Age is the best "test" that we have at this time for egg qualityIf your FSH levels were run using a different assay, you can not compare your results to those shown below with confidence. For example, with some assays an FSH of 12 is normal.

Day 3 FSH level FSH interpretation for DPC Immulite assay

Less than 9 Normal FSH level. Expect a good response to ovarian stimulation

9 - 11 Fair. Response is between normal and somewhat reduced

(response varies widely). Overall, a slightly reduced live birth rate

11- 15 Reduced ovarian reserve. Expect a reduced response to

stimulation and some reduction in embryo quality with IVF. Reduced live birth rates on the average

15 - 20 Expect a more marked reduction in response to stimulation and

usually a further reduction in embryo quality. Low live birth rates. Antral follicle count is an important variable

Over 20 This is pretty much a "no go" level in our center. Very poor (or no) response to stimulation. "No go" levels should be individualized

for the particular lab assay and IVF center.

http://www.advancedfertility.com/antralfollicles.htm

What is AMH?

AMH production is highest in the preantral and small antral stages (less than 4mm diameter) of follicle development. Production decreases and then stops as the follicles grow larger.There is almost no AMH made in human follicles over 8mm in size. Because of this, the levels are quite constant and the AMH test can be done on any day of a woman's cycle.

How can AMH hormone levels be a fertility test?

Since AMH is produced only in small ovarian follicles, blood levels of this substance have been used to attempt to measure the size of the pool of growing follicles in women.Research shows that the size of the pool of growing follicles is heavily influenced by the size of the pool of remaining primordial follicles (microscopic follicles in "deep sleep").Therefore, AMH blood levels are thought to reflect the size of the remaining egg supply - or ovarian reserve

With increasing female age, the size of their pool of remaining microscopic follicles decreases. Likewise, their blood AMH levels and the number of ovarian antral follicles visible on ultrasound also decreases. Women with many small follicles, such as those with polycystic ovaries have high AMH hormone values and women that have few remaining follicles and those that are close to menopause have low anti-mullerian hormone levels

AMH levels and pregnancy chances with in vitro fertilization

AMH levels probably do not reflect egg quality, but having more eggs at egg retrieval gives us more to work with - so we are more likely to have at least one high quality embryo available for transfer back to the female partner's uterus.

Ovarian reserve testing methods

Anti mullerian hormone is one potential test of ovarian reserve.

What Are Antral Follicles?

Antral follicles are small follicles (about 2-8 mm in diameter) Vaginal ultrasound is the best way to accurately assess and

count these small structures. In my opinion, the antral follicle counts (in conjunction with

female age) are by far the best tool that we currently have forestimating ovarian reserve and/or chances for pregnancy with in

vitro fertilization

1. When there are an average (or high) number of antral follicles, we tend to get a "good" response with many mature follicles.

Pregnancy rates are higher than average.2. When there are few antral follicles, we tend to get a poor

response with few mature follicles.3. When the number of antral follicles is intermediate, the

response is not as predictable.

IVF live birth rates are reduced with low antral follicle countsThe average antral follicle count in the under 35 age group was 21

Antrals and IVF Success - Female age under 35 IVF

From our own observations and experience, here are some general guidelines:

Antrals and IVF Success - Female age 35-37

The average antral follicle count in this group was 16


The average antral follicle count at age 38 to 40 was 13


the average antral count in this group was only 11

Advanced Fertility Center of Chicago

Menstural characteristicMenstrual characteristics in older women correlate with the number of follicles remaining

The ovaries of regularly menstruating older women contain 10-fold more follicles than those of perimenopausal women having irregular and infrequent menses

the interval from loss of menstrual regularity to menopause is approximately 5 years

As age increases and FSH levels rise, the follicular phas becomes shorter, LH levels and luteal phase duration remain unchanged

Cycles remain regular, but overall cycle length and cycle variability decrease

Over the subsequent 8 - 10 years preceding the menopause , average cycle length and variability steadily increase as ovulations become less regular and frequent

Circulating follicular phase inhibin-B levels decrease as or even before FSH concentrations begin to increase

serum follicle-stimulating hormone (FSH) levels begin to increase; luteinizing hormone (LH) concentrations remain unchanged

rise in circulating FSH concentrations : 1. age-related changes in the pattern of pulsatile gonadotropin-

releasing hormone (GnRH) secretion 2. progressive follicular depletion and lower levels of feedback

inhibition on pituitary FSH secretion by ovarian hormones

Later, luteal phase serum inhibin-A levels decline as well


The initial rise in FSH levels precedes any measurable decrease in estradiol levels, by several years

Follicular phase estradiol levels in older cycling women are generally similar to those in younger women and often even higher

However, careful studies have shown that the earlier acute rise in estradiol levels results not from accelerated follicle growth but from advanced follicular development at the beginning of the cycle and earlier selection of the dominant follicle

Luteal phase progesterone levels in older and younger cycling women are also similar


Female Age and Miscarriage and Fertility

Numerous studies have documented the increased risk for miscarriage and increase in infertility as women age

Maternal Age and Pregnancy Loss Rate

botros et.al infertility and assisted reproduction - 2008

Miscarriages

The main reason for the increased risk for miscarriage in "older" women is due to the increase in chromosomal abnormalities (abnormal karyotype) in their eggs

Chromosomal Problems in Aging Eggs Many studies have documented the increased rate of chromosomal abnormalities in women of advanced reproductive age.

● The meiotic spindle is a critical component of eggs that is involved in organizing the chromosome pairs so that proper division of pairs can occur as the egg is developing

● When the chromosomes line up in a straight line on the spindle, the division process should proceed normally

● However, with a disordered arrangement on an abnormal spindle, the division process may be uneven with an unbalanced chromosomal situation resulting

Older eggs are significantly more likely to have abnormalspindles and an abnormal spindle predisposes to development of chromosomally abnormal eggs.

There are 2 general types of chromosomal abnormalities: ● Numerical abnormalities where there is an abnormal number of chromosomes This situation is called aneuploidy Such as a missing (monosomy) or an extra chromosome (trisomy) An example of monosomy is Turner Syndrome and a well known example of trisomy is Down Syndrome ● Structural abnormalities where there is a problem with the structure of a chromosome Examples include translocations, duplications and deletions of part of a chromosome

17% of the eggs studied from women 20-25 years old were found to have an abnormal spindle appearance and at least one chromosome displaced from proper alignment. 79% of the eggs studied from women 40-45 years old were found to have an abnormal spindle appearance and at least one chromosome displaced from proper alignment.

Maternal age Aneuploidy

<35 10

40 30

43 50

>45 100

Recipient Age

Summary

There is a significant reduction in implantation rates in egg donor recipients 45-50 years of ageThere is a significant increase in miscarriage rates in egg donor recipients 45-50 years of age

Discussion

Uterine receptivity might decline with advanced age due to unknown biochemical and/or molecular aberrations of the endometriumThis decline could also be the result of a higher incidence of other pathological conditions in the uterus such as myomas, synechiae or polypsHypertension and other systemic disorders are more common in older women and could be contributing to the reduced potential for implantation and successful pregnancy outcome

Aging and female fertility1. Fertility Drugs

For women 40 and older, success rates with this form of infertility treatment are very low, and IVF should be considered relatively soon

2. ART egg freezing for preservation of fertility

This study involved 40 cycles in women (average age 35.5)

The ongoing pregnancy rate (beyond 12 weeks of pregnancy) with vitrified eggs was 30% per cycle.

■ Study by L Rienzi, et al, Human Reproduction; January 2010

● A 2009 study of 23 IVF cycles using frozen eggs (average age 31.5)

There were 14 pregnancies, 1 miscarriage and 13 ongoing

pregnancies (57% per transfer)

■ Study by J Grifo and N Noyes, Fertility and Sterility; May 2009

Clinical Applications of Egg Freezing

Oocyte cryopreservation could be a clinical tool for:Oocyte cryopreservation could be a clinical tool for:

Women at risk of losing ovarian functionWomen at risk of losing ovarian function

Women desiring fertility preservationWomen desiring fertility preservation (e.g. delayed maternity)(e.g. delayed maternity)

Eliminating ethical concerns of embryo Eliminating ethical concerns of embryo cryopreservationcryopreservation

Future considerationsFuture considerations

Oocyte cryopreservationOocyte cryopreservation““Pausing the biological clock”Pausing the biological clock”

Cytoplasmic transferCytoplasmic transferDonation of enucleated oocytesDonation of enucleated oocytes

Reproduction without gametesReproduction without gametesUse of nuclear material from somatic Use of nuclear material from somatic cellscellsDonated or synthetic cytoplasmDonated or synthetic cytoplasmReconstituted oocytesReconstituted oocytes

ovum donation in older women

pregnancy outcome after ovum donation in older women :

Pregnancy in advanced maternal age women after ovum donation carrying twins is associated with significant maternal and fetal complications, with increased risks of prematurity and lower birthweight. Possibly, the aged uterus is less suitable for

carrying a multifetal pregnancy than a younger uterus.

Therefore, the alternative of transferring a single, good-quality embryo should be the preferred option.

Human Reproduction 2009 24(10):2500-2503

Who are candidates for egg donation ?Who are candidates for egg donation ?

Premature ovarian failurePremature ovarian failure

Ovarian insufficiency (e.g. FSH>15 )Ovarian insufficiency (e.g. FSH>15 )

Physiologic menopause : Maternal age over 43Physiologic menopause : Maternal age over 43

History of poor egg/embryo quality or multipleHistory of poor egg/embryo quality or multiple

IVF failuresIVF failures


How old is too old ?How old is too old ?

Danger to motherDanger to mother

Decreased life expectancy of parentsDecreased life expectancy of parents

Is 55 a “physiological limit”Is 55 a “physiological limit”


Pregnancy in the Sixth Decade of Life:Pregnancy in the Sixth Decade of Life:

Obstetric ComplicationsObstetric Complications

Pre-eclampsia : 35%Pre-eclampsia : 35%

Background Incidence : 3-10% Background Incidence : 3-10%

Gestational Diabetes : 20%Gestational Diabetes : 20%

Background Incidence : 5%Background Incidence : 5%


Pregnancy in the 6th decade of life : Pregnancy in the 6th decade of life :

ConclusionConclusion

There does not appear to be any definitive medical There does not appear to be any definitive medical

reason for excluding these women from attemptingreason for excluding these women from attempting

pregnancy on the basis of age alonepregnancy on the basis of age alone


Genetic TestingGenetic Testing

PreconceptionPreconception

PreimplantationPreimplantation

PrenatalPrenatal

PostnatalPostnatal

In the general population, the risk for a live birth with a chromosomal abnormality is about:

The published studies on IVF with PGD success rates thus far have generally shown:

● No improvement in clinical pregnancy rates with PGD - it appears at this time that PGD actually results inlower pregnancy rates● No improvement in live birth success rates with PGD - it appears at this time that PGD actually results in lower live birth rates● Questionable improvement in implantation rates with PGD - and the possibility of actually having lower implantation rates. Not uncommonly, fewer embryos are transferred after PGD"Implantation rate" is the percentage of transferred embryos that implant in the uterus and are seen with early pregnancy ultrasound● Some studies are showing a somewhat lower rate of miscarriage after PGD, other studies are not showing any difference (see details of studies discussed above on this page)

Are PGD test results reliable?

PGD test results are not always correct

● Sometimes the embryo has abnormal chromosomes, but PGD testing shows a normal result

● Sometimes the embryo has normal chromosomes, but PGD testing shows an abnormal result

● Therefore, some chromosomally normal embryos will be discarded, and some chromosomally abnormal embryos will be transferred after PGD

PGD – Clinical IndicationsPGD – Clinical Indications

Single gene defectsSingle gene defectsBalanced translocationsBalanced translocationsAdvanced maternal age (aneuploidy)Advanced maternal age (aneuploidy)Repetitive IVF failureRepetitive IVF failureRecurrent pregnancy lossRecurrent pregnancy lossEmbryo selectionEmbryo selection

IVF with preimplantation genetic diagnosis for reasons of

advanced maternal age or in couples with unexplained

recurrent pregnancy loss can increase implantation rates and

decrease miscarriage risk

but the modest improvements in live birth rates achieved thus

far cannot justify the associated costs in couples without

other specific indications for IVF.


Thank youThank you

Aging and Female Fertility

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