INFERTILITY
What
is infertility?
In general, infertility
is the reduced capacity to conceive compared
to the general population.
True infertility is rare – but
this occurs if:
• The male partner has no sperm.
• Both fallopian tubes are blocked or otherwise damaged.
• The patient does not ovulate.
Most of the time, it is really sub-fertility,
which is defined as:
• Failure to conceive after one year of unprotected intercourse
• When a woman has had 2 or more spontaneous abortions or stillbirths
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How
common is infertility or sub-fertility?
• At least 6 million American
couples (approximately 10% of reproductive-age population)
have difficulty conceiving.
• 25% of women experience an episode of infertility during their reproductive
life.
• 5-10% of normal fertile couples take more than 1-2 years to conceive.
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What
are the common causes of infertility?
• 10-15% Ovulation dysfunction
• 30-40% Pelvic factors (tubal, endometriosis, adhesions)
• 30-40% Male factor
• 15-20% Cervical factor
• 10-15% Idiopathic or unexplained
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Unexplained
infertility
When the woman is younger than 35,
failing to conceive after three years of unprotected
intercourse is considered unexplained infertility.
After this time, she must seek fertility care right
away.
In couples who are already seeking fertility care,
unexplained infertility (UI) means that the causes
of infertility are so subtle that they cannot be determined
using the tests and procedures that are currently available
to specialists. Therefore, all the tests performed
on the couple come back normal but they still fail
to conceive. UI can be more frustrating than infertility
with known causes.
The treatment and the prognosis for couples diagnosed
with UI depends primarily on the woman’s age.
Age
and infertility
The woman’s age is the most
critical factor in fertility treatment.
Age causes a progressive and irreversible decline in
fecundity (the chance of getting pregnant during a
normal cycle) compared to a woman’s peak reproductive
years, from puberty to age 24, as follows:
• At 25-29 – by 6%
• 30-34 – by 14%
• 35-39 – by 31%
• After 40 – Even with IVF, only 5% chance of pregnancy and live
birth
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What
are the usual chances for pregnancy
IF THERE ARE NO OBVIOUS FERTILITY
PROBLEMS?
Chances are better if :
• Woman is younger than 30
• Previous full-term pregnancy
• Trying less than 3 years
• BMI (body mass index)* 20-26
• Both partners don’t smoke
• Less than 2 cups coffee daily
• No use of recreational drugs
Chances are reduced if :
• Woman is older than 35
• Never conceived before
• Trying more than 3 years
• BMI <20 (underweight) or >27 (overweight/obese)
• One or both partners smoke
• More than 2 cups of coffee daily
• Regular or recent use of recreational drugs
*BMI is a standard way to determine
whether your weight is appropriate for your height.
You may consult a BMI chart from the National Institutes
of Health on
http://www.nhlbi.nih.gov/guidelines/obesity/bmi_tbl.htm
The chart will tell you whether you are underweight,
normal, overweight or obese.
Patients who are overweight or obese by BMI are encouraged
to lose at least 10% of their current weight to improve
chances of conceiving and before undertaking fertility
treatment.
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When
should you seek specialized fertility care?
Usually, patients start fertility
care with their gynecologist.
For a woman, however, age is a significant factor
for infertility.
Therefore , it is best to be practical about judging
when to seek specialized fertility care with a trained
infertility specialist.
The urgency increases with age.
For women who have regular cycles and whose partners
do not have a history that suggests a major sperm
problem, the following is a good guide:
• If you are younger than 35:
After one year of trying.
• Between 35-39: After six months of trying, whether on your own or through Clomid
and/or insemination.
• 40 and older: As soon as possible.
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What
is an Infertility Specialist (Reproductive
Endocrinologist)?
The infertility specialist is an
gynecologist who has had special training in infertility
and reproductive endocrinology and devotes his practice
to treating infertility.
Most gynecologists have basic training in infertility
during their 4-year residency.
• They are therefore able to perform basic infertility evaluation and
some forms of treatment.
• Some gynecologists perform IVF without specialty board certification,
if they belong to a practice that has a board-certified infertility
specialist.
Requirements
to become a Gynecologist
• A gynecologist must complete 2-3 additional years of fellowship training
in reproductive endocrinology and infertility (REI) at a
university hospital with an approved REI training program.
• Usually this done after passing the board examinations for Obstetrics
and Gynecology.
• Completion of fellowship in REI and passing the Ob/Gyn boards makes
the gynecologist eligible to take the board examinations
in REI.
• This is a two-step process that begins with a written examination.
• Once the written exam is passed, the candidate is required to undertake
an REI- related research project whose results can be
written up and accepted for publication in a medical or scientific
journal. - - This publication is a requirement before applying
for the second step of the REI boards - the oral examination, generally
given two years after the written exam.
• The other requirement is a case list of all surgeries performed
in the preceding two years, describing the patient’s
diagnosis and the procedures performed.
During the oral examinations, the candidate is questioned
by experts in three areas:
• General knowledge of REI;
• The surgical case list – Why certain procedures are done, how
these procedures are done, how complications are dealt with;
and
• The research paper – how the study was designed; scientific methods
used to carry out the study; how study results were reported
and analyzed; statistical methods used to interpret the results;
and interpretation and significance of the
results.
After passing the oral exams, the
gynecologist earns his second board qualification.
In addition to Obstetrics and Gynecology, he will now
be board-certified as well in Reproductive Endocrinology
and Infertility.
Dr. Brandeis was-board-certified
in REI in 1994.
An infertility specialist assures you of:
• Prompt and proper diagnosis of what is causing your fertility problem
• State-of-the-art treatment that addresses your diagnosis directly
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Age
and Infertility
In the past 4-5 decades, many working
women have postponed having children until after they
are 35. - Since natural fecundity [the chance of conceiving
in any given ovulatory month] declines rapidly in women
after age 37, they have a narrow window of 2 years
when their chances are still fairly good.
This decline in fertility potential is the natural
consequence of aging on a woman’s egg cells.
• No medication, reproductive
technology or lifestyle changes can stop, prevent, slow
down or reverse the effect of age on egg cells.
• A woman may look 30 or even 25 when she is 40, but her eggs will be
as old as her actual age. This is a biologic fact which an
older fertility patient must learn to face realistically.
It is even more difficult for some
women in their 20s who already show the same pattern
of poor fertility potential as a woman twice their
age.
Lower pregnancy rates and higher miscarriage rates
are both the consequences of the aging process, and
reflective of a decline in egg quality (Table 1).
| Age |
Pregnancy
Rates Natural Cycle |
*
Risk all Chromosomal Abnormalities |
*
Risk Trisomy 21 (Downs Syndrome) |
Miscarriage
Rates |
| 25 |
25
- 30 % |
|
1:1000 |
10% |
| 30 |
25
- 30 % |
1:300 |
1:700 |
10% |
| 35 |
18% |
1:134 |
1:300 |
25% |
| 40 |
5% |
1:40 |
1:90 |
40% |
| 45 |
1% |
1:11 |
1:22 |
50% |
*Risk of Chromosomal abnormalities at mid-trimester
(second trimester of pregnancy around time f genetic
testing)
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The
Physiology of egg aging
Each woman is born with a predetermined
number of eggs dormant (temporarily inactive) in her
ovaries.
• This number will never be replenished but continue to decline.
• When the ovaries are first formed between week 16-20 of pregnancy, a
female fetus will have about 6-7 million potential egg cells.
• By the time she is born, this number is down to about 2 million.
• By the time she reaches puberty (when she first menstruates) and able
to reproduce, she will only have about 300,000.
• The number of eggs will continue to decline as she grows older, and
will not be interrupted by birth control pills or pregnancy.
• Out of 300,000 eggs, fewer than 500 will be ovulated – at the
rate of one every 28 days, for women with regular cycles
- during the reproductive years.
• All the rest simply undergo atresia, in which the egg cells are permanently inactivated
and become part of the regular ovarian tissue
A woman ovulates her healthiest
eggs first, starting with her first period to her early
30s.
• By her mid-30s, the remaining eggs are poorer in quality.
• After age 37, the process of atresia accelerates – that is why
fertility potential shows a drastic decline at this point.
• After 40, only eggs with very low fertility potential are available
either to be ovulated or to be recruited with fertility medication.
• At menopause, the ovaries have no eggs left and no longer have ovulatory function.
Age therefore decreases both
• the number of eggs available for ovulation, and
• the quality of the eggs.
The term ovarian reserve refers to a woman's current
supply of eggs, therefore, it is a measure of reproductive
potential.
In general, the greater the number of remaining eggs,
the better the chance for conception. Conversely, low
ovarian reserve greatly diminishes a patient's chances
for conception.
Although ovarian reserve generally corresponds to age,
some women, even in their 20s, can have diminished
or low ovarian reserve, which, unfortunately, usually
goes with poor egg quality.
Poor egg quality, regardless of the woman’s age,
is generally associated with chromosome abnormalities
that develop when an egg cell is activated for ovulation.
At birth, all the egg cells that a woman has are in
a state of suspended development (at the prophase stage
of the cell cycle).
• They do not get activated for further development unless they are ‘selected’ for ovulation.
• As a woman grows older, her egg cells are more likely to develop chromosome abnormalities
when activated.
Before the start of each menstrual cycle, the body
naturally selects several follicles [the ovarian sacs
that contain one egg each) to develop during the first
half of the cycle, out of which one follicle will dominate
and produce the activated egg that is ovulated.
A healthy egg will have 1) normal
chromosomes, and 2) must be able to combine its chromosomes
with sperm chromosomes correctly at fertilization.
With age, the remaining egg cells are less likely to
fulfill both requirements.
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Cell
division in egg cells
http://www.emc.maricopa.edu/faculty/farabee/biobk/femrep1.gif
 
http://www.contexo.info/DNA_Basics/images/meiosisstep1.gif
http://www.contexo.info/DNA_Basics/images/meiosis2c.gif
http://www.contexo.info/DNA_Basics/images/meiosis3.gif
http://www.contexo.info/DNA_Basics/images/meiosis4.gif
As mentioned earlier,
egg cell development is suspended at a certain stage
of the cell cycle, which will not resume until the
egg is activated for ovulation.
• At this stage,
called prophase, the 23 chromosomes in the egg cell
have duplicated preparatory to cell
division, and the chromosomes in each pair are bound
to each other.
• In all other cells, including the sperm cell, this duplication is followed
almost instantaneously by the next step of cell division.
• But in the egg cell, these chromosomes will remain paired until the
egg is is penetrated by a sperm cell.
• This can mean for as short as 9 years (if the girl starts menstruating
at 9) to as long as 40-45 years, depending on when the woman
reaches menopause, which is simply the cessation of ovarian
function.
That’s a very
long time – but that’s how long the egg
can remain ‘suspended’ before it is activated.
• During that time, the chromosomes are susceptible to many influences
in the cell environment which could cause DNA damage.
• The longer the egg is in its ‘suspended state’, the more
likely that its chromosomes will incur DNA damage.
Furthermore, the cell
division that takes place on activation depends on
the proper functioning of a spindle that forms in the
cell at the time of cell division.
• The spindle
is a structure along which the paired chromosomes will
regroup – 23
on each end – after division.
• With age, a defective spindle mechanism is more likely, resulting in
abnormal chromosome separation and regrouping – more
chromosomes may be pulled to one spindle, and less to the
other.
• Even if the chromosomes have not suffered DNA damage, this unbalanced
division will result in abnormal chromosome number - more
than 23 or less than 23.
• Most chromosome abnormalities are due to such numeric errors, because
a normal sex cell (egg or sperm) should have only 23 chromosomes.
An egg cell with abnormal
chromosomes
• May not fertilize at all. .
• If it does, the embryo will not develop normally
• if it develops, it is not likely to survive very long.
• If it does survive and results in a pregnancy, this will often end up
in miscarriage.
This is a process of natural selection that will not
allow abnormal embryos to progress.
However, a few chromosomally abnormal embryos can result
in a birth defect like Downs syndrome (which results
from the presence of 3 #21 chromosomes instead of the
normal 2).
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FSH
And Ovarian Reserve
Ovarian reserve is a measure
of fertility potential.
However, we cannot measure it directly since we have
no way to count how many eggs there are in the ovary.
Currently, the two most common ways of measuring ovarian
reserve are by:
• FSH/E2 hormone levels in the early part of the cycle, preferably on
Day-3
• Antral follicle count at the start of the cycle
Studies have shown that the most predictive
value for pregnancy in a given cycle is basal FSH
and/or E2.
• Elevated FSH and/or estradiol (E2) generally indicate and confirm diminished ovarian
reserve (DOR).
• In most laboratories today, a baseline FSH value and an above 10 and
an E2 above 70 are above the normal values.
• An elevation of either hormone, or of both, indicates DOR and decreased
chance of pregnancy.
• Treatment, particularly ART, is not advisable when the baseline hormones
are elevated because it is not likely to work.
Before menopause, FSH and
E2 levels tend to vary in different cycles, and treatment
may be attempted in a cycle when these levels are
normal.
• But repeated elevation for
three successive months is an indication that perhaps
the patient should consider using
donated eggs.
• Normal baseline FSH and E2 in pre-menopausal women only mean that their chances
for pregnancy will be age-appropriate, i.e., having an FSH of 3 when you are
42 will not increase your pregnancy chances beyond the 3-5% in that age group.
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Antral
Follicle Count
Another indirect measure of ovarian
reserve is the antral follicle count.
• This refers to the number of follicles seen by ultrasound on Day-3 of
the cycle.
• These are the follicles ‘recruited’ for development during
this particular cycle.
• Patients with DOR will generally have less than 5 in both ovaries.
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Clomid
Challenge and other tests for DOR
A very sensitive test for assessing
ovarian reserve is the Clomid challenge.
• It is particularly useful in evaluating older patients who show normal
baseline FSH and E2.
• After baseline testing, the patient is given 100 mg (2 tablets) of clomiphene
citrate (marketed as Clomid or Serophene) daily from Day
5-9.
• On Day 10, FSH is measured. A value higher than 10 indicates DOR, even
if baseline FSH and E2 were both normal.
Another very good test for DOR, although it is not
practical, makes use of leuprolide acetate (generic
name for Lupron).
• This is administered daily starting on D2 of the cycle.
• E2 is measured on D2 and D3, D4 and D6.
• Four response patterns are possible:
1) Prompt E2 elevation on D3 then decrease by cycle day 4
2) Delayed E2 rise with fall by cycle day 6
3) Persistent E2 elevation
4) No E2 response after GnRH-a
• Studies showed that clinical pregnancy rates for women who underwent
IVF after showing these patterns were best for #1 (46%) with
a progressive decline through the 3 other responses.
• #4 patients had a 6% pregnancy rate.
DOR not only means decreased chances for pregnancy.
• It also means that if treatment is attempted – IVF is the most
direct option – the patient will respond poorly to
stimulation, even at high dose.
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Options
in case of DOR
Currently, the best alternative
available to women with DOR is donor-egg IVF.
The chance of pregnancy is at least 50% per cycle
It is currently allowed in the United States for women
up to age 50.
However, most patients usually want to try at least
one IVF cycle with their own eggs first.
There have been three strategies tested to
help women with DOR improve their chances of pregnancy
using their own eggs, but none has shown increased
pregnancy rates.
The first two also involve the use
of donated eggs:
• In cytoplasmic transfer, the cytoplasm (cell material other than the
nucleus) in the patient’s egg is replaced with the
cytoplasm, from a donated egg.
• In nuclear transfer, the nucleus of a donated egg is replaced with the
nucleus from the patient’s egg.
In both cases, the genetic material in the egg is the
patient’s, but the cost and effort involved have
not been justified by initial results.
The third strategy is egg freezing, for women who want
to delay motherhood but may freeze her eggs when she
is much younger (before 35, but the earlier the better).
• Although egg freezing is
now being done, there has been no conclusive study
about its pregnancy success rate
because most women who have frozen their eggs
in the past few years since the technique became feasible
have not yet used them.
If egg donation is unsuccessful,
the only other options are adoption or choosing to
live child-free.
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