Infertility, General
Pharmacology Fertility; Clomiphene,
Question: My ob/gyn said that it
was okay for me to continue taking asthma medications (Singulair),
but that after I get pregnant, I should stop. My mom just
pointed me to the FDA page that says I should not be taking
it if I am trying to get pregnant or while pregnant. Is it
dangerous or just unknown? Also, are there any drugs I should
be avoiding while trying to get pregnant? I know this is stretching
- but are there any drugs that can cause temporary infertility?
We've been trying for 11 years. I was on Clomid for the past
6 months and I was off my Singulair during this time but everything
has been to no avail.
Comment: After 10 years, it would seem that a detailed evaluation
be performed and that there be a frank discussion with a specialist
about the etiology of your infertility and possible therapeutic
options. Most drugs used in the treatment of asthma are ok
during pregnancy. Still each should be looked at individually.
Singulair has been given a Category B rating for pregnancy,
indicating no adverse effects are known or suspected, but
the safety has not been fully established. At very high doses
fertility was reduced in rats, but there have been no human
studies. Generally this is considered a safe drug and if the
response to therapy is good, there is probably no reason to
change.
Question: My doctor has just told me that I have PCOS. He
wants to put me on the birth control patch. I have gained
30 pounds and cannot lose any of it. He thinks this will help
lose the weight along with the acne and other symptoms this
disorder has caused. Will the patch help or should I ask for
something else?
Comment: The patch, the "pill"? It's like shoes,
they all fit your feet, but each fits differently. The pill
and patch contain virtually the same hormones, work in the
same way, and mostly have the same side effects. The patch
is superior for those who cannot remember to take a pill.
Both should regulate your cycles, both should improve acne.
Scientific studies have failed to show that OCs cause weight
gain, although it is a very common complaint. It is very much
a personal choice, but recently I have been favoring a particular
pill called Yasmin. It contains a different type of progestin,
an agent that is especially good for skin and hair problems.
Studies have shown that most people do not gain weight on
this pill. Again, there are many options; you and your doctor
may have several tries to get the preparation that suits you
best. SST
Question: What are the
risks and side effects of taking Depo-Provera when you have
polycystic ovaries?
Comment: Depo-Provera
is a relatively good contraceptive agent. The most positive
aspect of Depo-Provera is that it will reduce the chance of
uterine cancer, which is higher in women with PCOS. There
is concern that its use in teens may increase the risk of
osteoporosis later in life. I know of no specific studies
that have addressed this issue Depo-Provera in PCOS. Sometimes
Depo-Provera is given to solve problems other than contraception;
it my opinion that it may cause more problems than it treats.
I am not convinced it is a very good drug for PCOS. The side
effect profile is quite long and may be of the same type,
but worse in severity compared with those who do not have
PCOS. Depending on the specific objectives of therapy there
may be better alternatives. SST
Question: My doctor has just told me that I have PCOS. He
wants to put me on the birth control patch. I have gained
30 pounds and cannot lose any of it. He thinks this will help
lose the weight along with the acne and other symptoms this
disorder has caused. Will the patch help or should I ask for
something else?
Comment: The patch, the "pill"? It's like shoes,
they all fit your feet, but each fits differently. The pill
and patch contain virtually the same hormones, work in the
same way and mostly have the same side effects. The patch
is superior for those who cannot remember to take a pill.
Both should regulate your cycles, both should improve acne.
It is very difficult to tell about weight loss. It is very
much a personal choice, but recently I have been favoring
a particular pill called Yasmin. It contains a different type
of progestin, an agent that is especially good for skin and
hair problems. Studies have shown that most people do not
gain weight on this pill. Again, there are many options; you
and your doctor may have several tries to get the preparation
that suits you best.
Question: I was diagnosed with hypothyroidism after the birth
of my son who is now 10 months old. I now take 100 mg of thyroxine
daily and blood tests show all is now normal. I got pregnant
very quickly first time. I am now trying to get pregnant again
but I am not ovulating. What do you suggest? Is this likely
to be due to hypothyroidism and is it treatable?
Comment: Patients with hypothyroidism, an underactive thyroid
gland, often have irregular bleeding and ovulation problems.
The primary screening tool for thyroid disease is measurement
of thyroid stimulating hormone (TSH). As the thyroid gland
produces less thyroid hormone (thyroxine, T4), TSH levels
rise to compensate. Low levels of TSH usually indicate too
much replacement, or hyperthyroidism, while high TSH levels
indicate under active thyroid, or too little replacement.
It takes 6 weeks after initiation of thyroid therapy or a
change in dosage for the TSH to equilibrate. The goal of replacement
therapy is to keep the TSH level straight in the middle of
the normal range, usually at 2-3. If you achieve normal thyroid
status with therapy, the next step is to look for other reasons
why ovulation may not be occurring. A link has been suggested,
but not yet proven, between hypothyroidism and polycystic
ovary syndrome (PCOS). Risk factors for PCOS include a family
history of diabetes, weight and skin problems. For PCOS, metformin
may be a possible therapy, but the typical first line therapy
for anovulation is clomiphene.
Question: What are the risks and side effects of taking Depo-Provera
when you have polycystic ovaries?
Comment: Depo-Provera is a relatively good contraceptive agent.
The most positive aspect of Depo-Provera is that it will reduce
the chance of uterine cancer, which is higher in women with
PCOS. There is concern that its use in teens may increase
the risk of osteoporosis later in life. I know of no specific
studies that have addressed this specific issue. Sometimes
Depo-Provera is given to solve problems and it may cause more
problems than it treats. I am not convinced it is a very good
drug for PCOS. The side effect profile is quite long and may
be of the same type, but worse in severity compared with those
who do not have PCOS. Depending on the specific objectives
of therapy there may be better alternatives.
Question: I am a 27-year-old female who has been trying for
almost five years to conceive. When we first tried, I got
pregnant immediately. Unfortunately, I miscarried after eight
weeks. I had a d&c and then had one shot of Depo thinking
we would wait. After the one shot we decided to try again.
We tried consistently over the years with no luck. As a result
of the Depo I did not have a period for a year and a half.
I was told this was normal and one of the side effects. When
I did begin my periods again they came every 28 days like
clockwork. Last year I had an HSG that was normal. My partner
does have two children of his own, so we believe he is fine.
We are both healthy, normal weight, and limit alcohol and
no smoking. I do have a problem with a high recurrence of
bacterial vaginosis. I am treated and it goes away, sometimes
for months and sometimes for weeks. Is this a reason why we
are not conceiving or did it have to do with the miscarriage,
d&c, or Depo shot? I would greatly appreciate any information
you could provide before we jump into any expensive tests
or treatments.
Comment: Your question encompasses the entire field of infertility
diagnosis and management and is very difficult to answer briefly.
I am not a big fan of Depo-Provera for the reasons stated
above. Most individuals with previously normal ovarian function
will resume normal menstruation within the first six months
after a single injection. The chance that the D&C has
caused adhesions in the uterus is slim, but not impossible.
We must look for a single cause that would combine the miscarriage,
prolonged time to resume menstruation and your present infertility
into a unified problem. This is probably ovarian dysfunction
and anovulation.
In terms of a general approach to infertility, I view investigation
and therapy in compartments: 1) ovulation/egg, 2) sperm, and
3) pelvic anatomy (tubes and uterus). The most common reason
not to conceive is disordered ovulation. Ovulation is suggested
with the clinical findings of cycle length not less than 26
or more than 35 days, mid-cycle pain and mucus changes. Ovulation
is further substantiated with and use of basal body temperature
tracking, ovulation detection kits, and blood tests for progesterone
7-8 days after ovulation. If ovulation is not occurring then
use of clomiphene citrate is probably in order. No more than
six cycles should ever be used and most pregnancies are achieved
in 4 or less. Before clomiphene is given an ultrasound scan
should be performed to make sure there are no easily identified
pelvic abnormalities. Many suggest monitoring follicular development
by mid-cycle vaginal ultrasound. In the initial stages of
an investigation a semen analysis should be performed. We
usually do this in conjunction with an insemination procedure
at the time of ovulation. If ovulation is occurring and the
semen parameters are normal, a laparoscopy and hysteroscopy
to evaluate pelvic anatomy is probably in order. The will
exclude problems such as scar tissue in the uterus and pelvis
as well as endometriosis.
Question: I am 28 and married. We have gone through two unsuccessful
IVF cycles, with no explanation. We are about to do a third
IVF, and I have been researching on the web and have found
a lot of information on taking baby aspirin during the cycle
to help blood flow to the uterus. Is it a good thing to try?
This is our last chance and we are willing to try anything.
Comment: It is unclear to me why you have not become pregnant.
Certainly, it can take more than 2 tries and thus far your
lack of success might be only chance. Still, a "sit down”
with your doctor is in order to review your case and discuss
possible therapy modification as well as estimation of success
for a repeat attempt. Use of aspirin is controversial. There
is one very good and well-publicized study that reports increased
success in IVF after aspirin use. Most successful programs
do not routinely use aspirin. The beneficial effect of aspirin
has not been unequivocally proven and its use needs further
validation. We know that large amounts of non-steroidal anti-inflammatory
agents such as aspirin, ibuprofen and naprosyn can block ovulation
and implantation. Probably small doses have no negative effects.
I do not stop patients from using low-dose aspirin, if they
wish.
Question: I am currently trying to conceive. I was recently
diagnosed with PCOS and tested for insulin resistance. I am
not insulin resistant. I know that some doctors put PCOS women
on metformin even if they are not insulin resistant. Is metformin
beneficial for these women, and should I ask my doctor about
putting me on it? I've heard that it can alleviate the symptoms
of PCOS, improve egg quality, and won't hurt you even if you
aren't insulin resistant.
Comment: The Internet abounds with testimonials about successful
therapy with metformin in women who have normal insulin levels.
About fifty percent of women with PCOS are insulin resistant.
Diagnosis of insulin resistance can be subjective based on
the type of testing. A fasting insulin level alone cannot
diagnose insulin resistance. Measuring insulin levels during
a glucose tolerance test adds reliability, but is not absolute.
Some women may have insulin levels that are in normal range,
but slightly higher than is needed for proper functioning
of the ovary. If there is associated obesity, signs of hyperglycemia
or a family history of diabetes, I often give metformin a
try on a "why not?" basis. If weight is lost, periods
improved and/or the patient feels better I am likely to continue
it; if not, it is stopped. Perhaps all women with menstrual
cycle irregularity should be given a short trial before progressing
to more invasive therapy such as gonadotropin injections or
IVF. Regardless, metformin is not approved for use in problems
other than diabetes and the decision for its use should be
individualized after close consultation with a physician.
Question: I have been diagnosed with PCOS and have been trying
to get pregnant for over a year. I do not have any weight
problems. My doctor is currently trying me on metformin and
Clomid. I have just been on Clomid at the 50-, 100-, and 150-mg
dose levels and it didn't work. Then I was on just the metformin,
even though no insulin problem was found. Metformin alone
has done nothing. As I said, right now I am on metformin and
Clomid. My doctor has hopes that "this is it," that
this will work. What is the next step if this does not work?
Comment: At this juncture, treatment protocols become much
more limited. It is a very difficult transition time for both
patient and physician because you are moving into the fast
lane of therapy — more aggressive, more expensive and
more risky. There are generally 3 pathways: (1) gonadotropin
injections, (2) laparoscopy with possible hysteroscopy to
exclude anatomic problems. This may be associated with the
ovarian drilling procedure to improve ovarian responsiveness.
(3) IVF. Some physicians will start by adding small doses
of injections to the clomiphene stimulation.
Question: My 14-year-old daughter has been put on Glucophage
to start menses. How will this help with PCOS? Is it a standard
therapy? She also has Hashimoto's disease.
Comment: I trust that a diagnosis of insulin resistance has
been made and a rationale for metformin use other than menstrual
induction alone has been given. A frequent cause of failure
to start menses by age 14 is PCOS, but this is not the only
cause. Metformin is an insulin sensitizer. It improves the
body's response to insulin so less insulin is required. Higher
levels of insulin can have adverse effects on the ovary, preventing
ovulation and increasing the production of male hormones (androgens).
By improving the body's response to insulin/glucose, ovarian
function and thus menstrual cycles are improved. Use of metformin
for any reason other than diabetes is not "standard"
therapy. Metformin use in teens is becoming increasingly common
with good safety and success. There should be specific reasons
for its use, and periodic monitoring to judge its success.
The issue becomes how long should it be used or when should
it be stopped? These questions have not been answered. PCOS
and thyroid disease share some common symptoms. Both are common
disorders. There is increasing evidence that links thyroid
disease with PCOS, but no proof that one causes the other.
Question: I recently read an article about a woman who had
PCOS and was given the drug Eulexin (commonly used to treat
prostate cancer). It apparently treated her PCOS, and she
lost 90 pounds eating low-glycemic foods. Is this drug therapy
something new? I have not read anything about this before;
could you give me some more information about it with regards
to helping with PCOS?
Comment: Eulexin (flutamide) is a potent anti-androgen that
blocks the action of male hormones on target tissues like
skin. There have been several trials investigating its use
in excessive hair growth, hirsutism. Results have been favorable,
but it is a relatively expensive drug and has a possibility
of liver damage. I do not favor its use when other agents,
such as oral contraceptives, spironolactone, Vaniqa (a cream
that blocks hair growth), and laser therapy are equally or
more effective. It does not cause weight loss and may cause
weight gain. I suspect the woman in the case above had success
not because of the flutamide, but due to her hard work and
weight loss.
Question: What is the current thinking on the best treatment
of PCO? The doctors I have seen always recommend either birth
control pills or Clomid (if I want to get pregnant). It seems
like there must be something else out there!
Comment: At least 50% of PCOS appears to have a component
of abnormal glucose tolerance, increased insulin, or insulin
resistance. In part by accident, it was stumbled on that insulin-altering
drugs generally used in the treatment of diabetes were successful
in regulating periods, promoting ovulation and increasing
fertility. These drugs have not received FDA approval for
this use, but have become widely employed. We now have a therapy
that actually treats the cause of PCOS rather than just overpowering
or suppressing it. The principle first line therapy is metformin
(Glucophage) which often has the benefit of weight loss, but
has GI side effects. The second group of drugs includes Actos
and Avandia and directly reduces insulin. The success of these
agents seems to be at least as a good a clomiphene and a sometimes
work when all else fails. Still, they are not perfect and
should be discussed in detail with your physician and best
used after appropriate lab testing.
Question: I have PCOS; however, I am not overweight nor do
I have a facial hair problem, so I went undiagnosed for years.
The only telltale sign was having no regular cycle (perhaps
1-3 periods a year). I conceived my daughter with metformin
(Clomid did nothing for me). Now I want to conceive again.
I'm sure I will have to use Metformin again. My question is,
IS there any way I can get regular fertile cycles back without
the pill or using metformin in the short term? If not, will
this mean that I will never have regular periods?
Comment: Unfortunately, PCOS is for life. The pattern of menstrual
cycles is very individualized and is impossible to predict.
We know that periods tend to become more regular after age
35. Periods often become more regular after pregnancy, but
this didn’t seem to work for you.
Generally, I believe it is better to have periods than not.
One direct and proven benefit of regular menstruation is a
reduction in uterine cancer. An alternative minimalist therapy
that usually does not impede fertility and may promote it
slightly is the periodic use of oral progesterone. This may
be preferred over Medroxyprogesterone acetate that you have
probably used in the past.
In at least one way, you are lucky that metformin did so well
for you. However, because it worked this may be an indication
of insulin resistance and therefore, you are at higher risk
for type 2 diabetes. Trials are underway to see if long-term
metformin may protect against development of diabetes. We
do not know the answer to this question. Perhaps, you should
not consider metformin only as a fertility agent. A good sit
down with your physician to discuss the options may be in
order.
Question: I have PCOS and my insulin level is 11. Is that
enough of a resistance to be
able to take metformin?
Comment: A fasting insulin level of 11 is not considered elevated
by most. While some use 10 as a cut off level, many individuals
have levels this high and are otherwise normal. Most who are
overweight will have levels over 10. Almost all experts consider
a level of over 20 as abnormal. I personally use 14, but there
is no hard fast rule. When the fasting insulin level is elevated,
that is called hyperinsulinemia. Hyperinsulinemia is a marker
of insulin resistance, but it is not the same as insulin resistance.
There are a variety of tests that are used to measure insulin
resistance. One test is the insulin level obtained during
a glucose tolerance test. Also, what is insulin resistance
anyway? Insulin resistance can be thought of as deafness.
The best way to explain insulin resistance is as the organs
that use insulin grow increasingly “hard of hearing”,
in order to compensate and keep the lines of communication
open the pancreas where insulin is made starts to “speak
loud and louder.” Insulin resistance is deafness, not
to sound, but to the action of glucose and insulin. Now as
to when to be treated. This is a very controversial topic.
Insulin resistance is clearly linked to increased risk of
developing of type 2 diabetes. Insulin resistance is also
clearly related to abnormal ovarian function and increased
levels of androgens. However insulin resistance is not a disease
as such. Some advocate a trial of insulin altering drugs in
almost all those who do not ovulate. Others reserve therapy
for those that have clearly been shown to be insulin resistant.
Pregnancies have been reported after use of insulin altering
drugs, such as metformin, when the insulin levels are completely
normal. This is a decision that is best made in cooperation
with an individual physician well versed in PCOS and insulin
altering drugs.
Question: I haven't been officially diagnosed with PCOS, and
I'm neither overweight nor
have excess hair or diabetes, but I've been prescribed metformin
and it made me have a normal cycle for the first time in 16
months (I did not respond to Clomid). My question is where
the metformin is working for me, do you think it's possible
that I have a mild case of PCOS?
Comment: The experts can’t agree with what PCOS is.
So sure, you could have it. The largest single cause of lack
of ovulation lies along the PCOS spectrum. It seems that about
50% of those with PCOS are insulin resistant and insulin resistance
leads to lack of ovulation. Often insulin resistance will
be missed on the routine lab testing for PCOS. I pay considerable
attention to the ultrasound appearance of the ovaries. I bet
there is an increase in small follicles (cysts) less than
10mm or an increase in the size of the ovary. The fact that
your cycles are regulated is great news. Hopefully a pregnancy
is not far behind.
Pharmacology Other:
Question: I am currently 8 months pregnant. I have PCO and
conceived while using
Metformin. I've been on it throughout my pregnancy and thankfully
I've had an uneventful pregnancy. I want to know if it is
ok to stay on the metformin while I breastfeed or should I
go off it until I stop breastfeeding. What are the dangers
to the baby of staying on Metformin while breastfeeding?
Comment: Metformin is released in breast milk. Most doctors
recommend not using Metformin while breastfeeding. Although
there is no specific research study that I know of indicating
that it would be of harm.
Question: Could you please tell me if there is any difference
between Metformin (Diabex)
and Metformin (Glucophage). I have read a lot about women
being told to try Glucophage to help them get pregnant. I
am on Diabex.
Comment: Diabex is another
brand of metformin. Glucophage is a brand of metformin. Generics
are on the way and will lower the cost of the medication use.Pharmacology
Other; Glucophage
Question: I just found
out that I am pregnant. I've been on Glucophage for 2 months.
I would rarely have periods, so I expected that the Glucophage
would help with periods. I was very surprised to find out
that I had conceived so soon. My question is do you think
it is safe to stay on the medication while pregnant?
Comment: There is very
limited information on this. One study has shown a decrease
in the rate of miscarriage in a relatively small group of
patients. Another also reported no problem when used during
pregnancy. In the future, Metformin may be widely used in
pregnancy but its use can not be universally recommended at
present. We just do not know the risks. Hopefully this issue
will be cleared up in the near future. A decision should be
made in conjunction with advice from your obstetrician.
Question: I was diagnosed with POCS several years ago. I have
many classic symptoms -
weight gain, excess hair, insulin resistance, anovulatory
periods etc. My OB suspects that I have always had it but
that the development of the symptoms was triggered by my first
pregnancy as until then I had no symptoms other than irregular
periods. I have three children, the last of which required
Clomid to induce ovulation. I have had less than a period
a year since the birth of my second son 5 years ago. With
each pregnancy my symptoms get worse. I guess I have several
questions - is it likely that my PCOS is indeed getting worse
with each pregnancy? Is there any alternative to drugs (e.g.
metformin) to control it? We are wishing to get pregnant with
our last child but I am reacting negatively to the Clomid
dose required to induce ovulation (50 mg). So are there alternatives
to this? I am now 33.We wish to conceive fairly quickly -
is there anything else we can do? And possibly most importantly
- my mother is into alternative medicine and has suggested
that I could restore my cycles with the use of natural progesterone
cream. What are your thoughts? I would appreciate any answers
you could give me.
Comment I would agree with your OB that you have always had
PCOS. It is a genetically based disorder. I am not sure about
whether it was your pregnancy, or that it was age and often
weight that brings PCOS to the surface. Since PCOS can be
altered by environment, I would strongly suggest that you
encourage the very healthiest lifestyle in your children.
They may not be able to escape the gene(s), but it is possible
to alter their consequences by the changing the environment.
Hopefully this indirectly answers a part of your questions.
I would concentrate on establishing and maintaining the healthiest
possible lifestyle. Maximize nutrition (without dieting);
increase physical activity without stressing yourself. Small
investments can pay major dividends. Metformin may be a good
alternative, especially since you state that you are insulin
resistant. I am very cautious about recommending supplements.
It is not that they may not work, but that I have too much
respect for them to idly prescribe herbs and supplements without
a firmer scientific basis of their positive actions, and most
importantly possible negative actions.
Question: I am 26 and have recently been diagnosed with PCOS.
I have a 16-month-old
daughter that was conceived with gonadotropins. I have been
having regular though light periods but have not ovulated.
I am taking 1500mg of Glucophage a day. How many cycles should
I wait before adding fertility treatment to the mix? My doctor
is in a hurry, but I would like to get my system in order
first and see if I ovulate on my own.
Comment: I usually will try clomiphene challenge in the 5th
or 6th month of metformin. Some individuals who have been
previously clomiphene resistant will ovulate and become pregnant
on the metformin-clomiphene regimen, when neither alone is
sufficient. It is usually the patient and not the physician
that is in a hurry. If you are making positive lifestyle alteration
and are feeling better, plus starting to have regular cycles,
what’s the rush? At 26 and with one successful pregnancy,
your chances for another pregnancy are very high. The drug
companies will make sure that there are plenty of gonadotropins
whenever you might need them.
Question: I would like
to know about metformin being used to help with fertility
in women with PCOS. I was told four years ago I had PCOS and
I am also a type two diabetic and have been told I will need
insulin injections instead of Metformin. I am on diabex (500mg)
three times a day. Any information you have would be a great
help.
Comment: I am not trying to evade the question. I do not like
to give contrary information and there are many right ways.
Having said this, I believe Metformin to be a foundation of
the treatment of type 2 diabetes regardless of pregnancy desires.
The first evidence that metformin was useful for infertility
came from the accidental finding that diabetics using metformin
began having regular menstrual cycles and subsequently got
pregnant. We are hopeful that diet, exercise, and insulin-altering
drugs will be able to keep the thousands off insulin. You
may also want to check out the American Diabetes Association
site that has good information.
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