November 17, 2008

Nov ’08 Research: Treatments, Causes, Risks

Posted in RESEARCH tagged cause, cysts, Dr Nestler, Insulin Resistance, PCOS, research, risk at 12:41 am by PCOSLady

New Studies Examine Treatments, Causes and Risks for
Women with PCOS
~
Toronto, Canada, June 21, 2000 – New
research presented today on treatments, causes and risks
associated with Polycystic Ovary Syndrome(PCOS), a disease
that effects between five and 10 percent of reproductive aged
women, offers a glimmer of hope to the millions of women who
suffer from the disease. The research was presented today in
a panel at ENDO 2000, The Endocrine Society’s 82nd Annual
Meeting, which is taking place in Toronto from June 21-24.
The new studies examine several areas of PCOS, including a
possible gene that triggers PCOS, new treatments for the
disease, the relationship between diet and PCOS and the risk
of heart disease in women with PCOS….
~
http://www.emergen.com/pages/research/pcos.html
~
Two of the studies that were presented examined new treatments
for women with PCOS. One study found that women with PCOS
who reduced their dietary fat might improve some of their
reproductive parameters. Another study of adolescent girls with
PCOS found that treatment with metformin, a medicine that
decreases the body’s requirement for insulin, improves irregular
or absent periods, a symptom of PCOS in young girls; lessens
body hair and acne; and promotes weight loss…. “We have
shown that metformin, which is typically a diabetes treatment,
is effective in treating young women with PCOS,” said Dr. Ken
Lee Jones, an endocrinologist at the University of California,
San Diego who presented the research on metformin. “The new
information that is presented today will help improve the quality
of life for the women throughout the world who suffer from this
disease.” … Dr. Walter Futterweit and Dr. Yaron Tomer,
endocrinologists at Mount Sinai Medical Center in New York,
presented a study that found an association between a
marker near the insulin receptor gene and PCOS. Previous
research has found that PCOS is hereditary. The new research
discovered evidence that the insulin receptor gene, or a nearby
gene, may cause the tendency for women to inherit PCOS….
“This type of research will ultimately lead to better diagnosis and
treatment for women with PCOS,” said Dr. Tomer….
~
Additionally, the research suggests that the inheritance of
PCOS is caused by subtle changes in the insulin receptor
gene, which may alter its function in the ovaries…. “We hope
that these findings will enable us to better understand the
mechanisms leading to PCOS,” said Dr. Futterweit…. Two
of the other studies examined risk factors for women with
PCOS, including insulin resistance and heart disease. One
study, which was presented by Dr. David Ehrmann, an
endocrinologist at the University of Chicago, found that
women with PCOS function near their maximum ability to
secrete insulin in response to glucose. According to this
new research, any further reductions in insulin sensitivity
would be met with inadequate compensation in insulin
secretion…. Dr. Rose Christian, a clinical research fellow
at the Mayo Clinic, reported on additional research that points
to an increased risk of coronary heart disease for women with
PCOS. Researchers found that coronary artery calcium,
a marker for atherosclerosis, is more common and extensive
in women with PCOS than in ovulatory women of similar age,
weight and risk factors…. “Our research showed that women
with PCOS are as likely to develop coronary calcium as men
of the same age,” said Dr. Christian. “Normally, coronary
calcium and heart disease are three to four times more
common in young men than in women of the same age.” …
“PCOS is a common yet, silent disease that affects thousands
of women,” said Dr. Lisa Fish, an endocrinologist at Park
Nicollett Medical Center in Minneapolis, Minnesota. “These
studies provide new options to women with PCOS in treating
their illness and also offer new information on risks that are
associated with the it, such as heart disease. In addition,
this research looks into the genes that may cause PCOS
and its relationship to diabetes.” … Based in Bethesda,
Maryland, The Endocrine Society consists of over 9,000
scientists and physicians in more than 80 countries. Founded
in 1916, The Endocrine Society is the world’s oldest, largest,
and most active organization devoted to research on hormones,
and the clinical practice of endocrinology. Together, these
physicians, scientists, educators, nurses, and students who
make up the organization’s membership, represent all basic,
applied, and clinical interests in endocrinology. To learn more
about The Endocrine Society, and thefield of endocrinology,
visit our web site at www.endo-society.org…. New Directions
in the Treatment of Polycystic Ovarian Syndrome by Ellen
Friedman Bender … Polycystic Ovarian Syndrome (PCOS)
is a hormonal disorder affecting between 5 percent and
10 percent of women of reproductive age. Although many
people correctly associate PCOS with impaired fertility
- chronic anovulation and hyperandrogenism (elevated
male hormones) are two of its cardinal symptoms, it is more
than an infertility disorder. Increasingly, PCOS is being
recognized as a major women’s health problem because
of the havoc it wreaks on the endocrine system. Many
women with PCOS suffer from endocrine abnormalities including
insulin resistance which affects the bodies ability to metabolize
sugar and fat….Significantly, according to a research study,
premenopausal women who have the disorder are seven
times more likely to suffer from adult onset diabetes than
women without PCOS. In addition, over time, many women
with PCOS develop elevated levels of cholesterol and
triglycerides so that here is a greater risk of heart attack and
stroke for women in their forties and fifties. Moreover,
because of their irregular menstrual cycles, women with PCOS
are at greater risk for endometrial cancer. Women with PCOS
also frequently encounter self- esteem and body-image issues
arising from other frequent symptoms of the disorder including
hirsutism (excess facial and body hair),obesity, acne and
male-pattern baldness… Traditionally, treatment for PCOS
has focused on individual symptoms instead of the syndrome
as a whole. Thus, a woman with PCOS who was trying to
get pregnant might be given fertility drugs such as clomid
or pergonal. A woman in her twenties might be given oral
contraceptives to regulate her menstrual cycle or provera to
periodically shed the lining of her uterus. Another woman
might be given spironolactone to inhibit hair growth. But
recent research suggests that there may be lifestyle changes
and medications that by attacking the insulin resistance,
actually treat the syndrome as a whole…. At the very least,
some doctors recommend that their PCOS patients follow
a carbohydrate-restricted diet and increase their exercise
level. But the cutting edge research in PCOS is in the area
of insulin sensitizing drugs. Recent studies have found that
insulin sensitizing drugs given to type 2 diabetics, such as
metformin, may also benefit women with PCOS. In one
study, recently reported in the New England Journal of
Medicine, an insulin sensitizing drug called INS-1 not only
induced ovulation in 86% of the PCOS patients in the study,
it also reduced their triglyceride and blood pressure levels,
lowering their risk for cardiovascular disease. At the moment,
however, none of these insulin sensitizing agents are FDA
approved for the treatment of PCOS and some of them have
unpleasant side effects…. Ellen Friedman Bender co-chaired
the American Infertility Association’s recent conference on
PCOS, “Understanding Polycystic Ovarian Syndrome: A
Reproductive and Metabolic Disorder.” A version of this
article appeared in the November 1999 issue of the
Women’s O.W.N. of NYU Medical Center newsletter….
~
Treatment Options For PCOS
This information is provided for informational purposes only
and is in no way meant to replace advice from a qualified
medical professional…. Until recently, only the symptoms of
PCOS – hirsutism, acne, infertility – could be treated.
In the past few years, however, there has been a great
deal of research pointing to excess production of insulin
and resulting insulin resistance as the root of the problem….
Treatment With Insulin-Sensitizing Medications – The
Newest Option A number of recent studies have shown
that treating women with PCOS with insulin-lowering
medications such as metformin (also known as
Glucophage), Avandia (rosiglitazone) and Actos
(pioglitazone), used to treat adult-onset diabetes,
can not only reduce the risks of heart disease and
diabetes in women with PCOS by treating the underlying
problems with insulin production and usage, but also
relieve many of the bothersome symptoms and even
make weight loss possible.1, 2
~
(Please note that these are not weight-loss drugs; women whose
weight problems stemmed from insulin resistance may lose weight
when the problem is corrected.)
~
These drugs do not lower blood sugar and so are generally
safe even for those with hypoglycemia3, but there may be
side effects. Metformin often causes diarrhea and/or nausea,
especially for the first few weeks and when the dosage is
increased. This is most problematic if it’s taken without food;
these problems may be minimized by taking it halfway through
a meal. A rare side effect is lactic acidosis, which may be fatal
if not detected. Rezulin (troglitazone) was also used for this
purpose until recently, but has been taken off the market
after reports of liver abnormalities and even a handful of
deaths in some people who were taking it. Avandia and
Actos are chemically related to Rezulin, but the effective
dosages are far lower (4-8 mg/day of Avandia or 45 mg/day
of Actos vs. 200-400 mg/day of Rezulin), making liver
complications less likely. In
clinical trials involving over 4500 patients, there have been no
reports of Avandia-related liver toxicity or related problems4, 5;
there have also been no reports of such complications from
Actos4, 6 Even so, the FDA has recommended that patients
who already have elevated liver enzyme levels be monitored
regularly. Some people who take Avandia or Actos experience
a slight weight gain. (This hasn’t been my experience, though
– I’ve actually lost several pounds in the last few months.) It
is important to be aware that all of these medications are
currently only approved by the FDA (in the US – I’m not entirely
sure of their approval status in other countries) for the treatment
of diabetes. There is a lot of convincing research showing that
most if not all cases of PCOS can be improved by treating
insulin resistance, and these drugs treat diabetes by treating
insulin resistance. So, they’re likely to be helpful to many
women with PCOS, and doctors are allowed to prescribe an
approved drug for any purpose they wish, but some (especially
those who aren’t up to date on the new research) may not be
willing to do this. I’m working on writing up some information
about d-chiro-inositol, the first medication being studied specifically
to treat PCOS-related insulin resistance, but I want to do more
research before I post anything here. In the meantime, check
out Ovulatory and Metabolic Effects of d-Chiro-Inositol in
the Polycystic Ovary Syndrome. This is an abstract of an
article that appeared last year in the New England Journal
of Medicine summarizing the findings of a study of this drug
in women with PCOS….
~
Birth Control Pills
Birth control pills treat a few of the symptoms of PCOS.
They usually bring on a period each month (though some
women with PCOS do not have regular periods even while
taking birth control pills) which is important for women who
do not have regular cycles because lack ofmenstruation
puts a woman at higher risk for endometrial cancer. Some
women find that hair problems either lessen or stop getting
worse while on the pill, particularly with Diane-35 or Dianette
(which contains cyproterone acetate, an anti-androgen), which
is available in some countries in Europe and also in Ausralia and
New Zealand but has not been approved in the United States.
Acne may improve as well. Weight gain is highly variable –
for some women weight gain may stabilize while on the pill;
for others it may get worse. Changing brands may help if
you find yourself gaining weight or having other unpleasant
side effects. The triphasic birth control pills, such as
Ortho Tri-Cyclen, may be problematic in that the estrogen
dose they provide in the early part of the cycle may be too
low to prevent women with PCOS from developing follicles,
possibly resulting in a greater number of cysts on the ovaries.1 …
~
Treating Hirsutism
Hirsutism can an extremely difficult and emotional issue in a
society where women are expected to be smooth and hairless.
Shaving, plucking, waxing, electrolysis and laser hair removal
treatments may work in many cases but can be, depending
on the method, time-consuming, messy, painful and/or very
expensive. Spironolactone (brand name Aldactone),
if taken over a period of time, will stop new hair growth
in many women with hirsutism and may possibly decrease
existing growth for some. In countries where Diane-35
has been approved, it may be prescribed help with hair
problems….
~
Provera
Provera or other forms of synthetic progesterone are
often prescribed to women experiencing amenhorrea
(lack of periods). It’s common for a Provera-induced
period to be more heavy or painful than usual, but it’s
important that something be done to cause regualar
menstruation because prolonged amenhorrea may
increase a woman’s risk for endometrial cancer.
This doesn’t mean that if you haven’t had a period
for a very long time that you are destined to get cancer,
but it does introduce a higher than usual risk. Some
women have had success using progesterone cream
as an alternative to Provera….
~
1. Kidson, Warren. Polycystic ovary syndrome: a new
direction in treatment. MJA 1998; 169: 537-540.
2. Hopkinson, Zoe E. C. et al. Polycystic ovarian
syndrome: the metabolic syndrome comes to
gynaecology, BMJ 1998;317:329-332
3. Perloe, Mark. Polycystic Ovarian Syndrome:
Treatment With Insulin-Lowering Medications.
4. Fonseca, Vivian A. Overcoming Insulin
Resistance and Preventing Cardiovascular Disease
in Diabetes: The Contributions of the
Thiazolidinediones.
5. Avandia Shows Promising Results in Combination
Therapy
6. Actos Approved By FDA For Type II Diabetes
~
April 28, 1999
~
New Drug May Help Women With Infertility Syndrome
An investigational drug that helps insulin to function more
efficiently appears to combat infertility in women with polycystic
ovary syndrome (PCOS), the most common cause of female infertility,
according to a research team funded in part by the National Institute
of Child Health and Human Development (NICHD). The drug, D-chiro-
inositol, occurs naturally in fruits and vegetables and appears to
have no side effects in the comparatively small number of PCOS
patients who took part in this preliminary trial….
~
The study, conducted by researchers at Virginia Commonwealth
University (VCU) in Richmond, appears in the April 29 issue of The New
England Journal of Medicine….
~
“These early results show a lot of promise,” said Dr. Donna Vogel,
Associate Chief for Clinical Research in NICHD’s Reproductive Sciences
Branch and NICHD program officer for the study. “Dr. Nestler and his
colleagues have shown that a substance naturally produced by the body
to assist in insulin action promotes ovulation in the majority of PCOS
patients who take it.” …
~
PCOS affects from 5 to 10 percent of American women of reproductive
age (as many as 5 million in all), explained the study’s principal
investigator, John E. Nestler, M.D., chairman of endocrinology at
VCU’s Medical College of Virginia. The ovaries of women with PCOS
appear to be filled with numerous small cysts. The cyst-like
appearance results from an accumulation of immature ovarian follicles,
the bubble-like structures which, upon maturation, rupture and give
rise to the egg cell….
~
The features of PCOS may include failure to ovulate or menstruate,
abnormally high levels of insulin, obesity, high blood pressure,
hardening of the arteries, and high triglyceride levels.
(Triglycerides are fatty substances used for energy storage, and high
triglyceride levels may increase the risk for coronary artery
disease.) PCOS patients also have high levels of the male hormone
testosterone, which may cause them to grow excess facial or body hair….
~
* “PCOS is not just a reproductive disorder; it’s a major health concern
for women who are affected,” Dr. Nestler said. “This is a promising
new drug because not only does it dramatically improve ovulation, it
improves a woman’s overall health.” …
~
Dr. Nestler added that, traditionally, physicians have been able to
treat only the symptoms of PCOS, and not eliminate its cause. For
example, antiandrogens were prescribed to block the action of
testosterone and reduce excessive hair growth. Birth control pills
were used to regulate the menstrual cycle, and when the women sought
to have children, they were treated with fertility drugs–either alone
or in combination with in vitro fertililzation….
~
Roughly two years ago, however, Dr. Nestler and his colleagues were
successful in reducing the PCOS symptoms of a group patients by
treating them with the drug metformin, used to treat insulin
resistance in patients with adult onset (type II) diabetes. (Insulin
resistance is the failure of cells to respond to insulin properly).
Metformin increases the body’s sensitivity to insulin and allows the
body to use insulin more efficiently. Troglitazone, another insulin-
sensitizing agent, has similar effects in PCOS patients. * …
~
Although both drugs do restore ovulation, both have a number of side
effects. Metformin, for example, may cause diarrhea, nausea, and loss
of appetite, and Troglitazone may be toxic to the liver….
~
The current findings strongly suggest that PCOS results from a failure
to use insulin properly. Presumably, Dr. Nestler said, this failure
causes insulin levels to rise. The high insulin levels, in turn, cause
a variety of other effects, such as high blood pressure, hardening of
the arteries, and high triglyceride levels. Insulin also appears to
have an effect on the ovaries, causing them to produce high levels of
testosterone and similar compounds, which halt egg maturation and
interfere with the menstrual cycle….
~
In the current study, the researchers followed 44 obese women with
PCOS; half received D-chiro-inositol, and half received a placebo. Of
the 22 women who received the study drug, 86 percent ovulated,
compared with only 27 percent of the women in the placebo group. Women
who received D-chiro-inositol also saw improvements in insulin, blood
sugar, blood pressure, testosterone and triglyceride levels. No side
effects were reported….
~
Dr. Nestler explained that the body uses D-chiro-inositol to
manufacture the D-chiro-inositol mediator, which allows the cell to
process glucose after insulin binds to the cell’s surface. According
to Dr. Nestler, the research offers insight into the possible cause of
insulin resistance in women with PCOS, which previously had been
unknown. A PCOS patient’s insulin resistance could be due, in part, to
a D-chiro-inositol deficiency….
~
NICHD is currently funding a trial of D-chiro-inositol in a large
number of patients to further ascertain its safety and effectiveness.
The drug is also being tested in patients with type II diabetes.
~
The study drug is manufactured by INSMED Pharmaceuticals, Inc., which
develops products to detect and treat insulin resistance. The research
is funded by an NIH Small Business Innovation Research Grant. These
grants are given to independently owned and operated U.S. companies
that have fewer than 500 employees….
~
Polycystic Ovarian Syndrome
New Thought on an Old Disease
Polycystic Ovarian Syndrome (PCOS) has been a subject of intense
interest and research since it’s initial description by Drs. Stein and
Levinthal in the 1930′s. However, it was not until the 1980′s that an
association between this syndrome and insulin resistance was
discovered, and only in the last several years that the benefit of
insulin sensitize therapy in treating this condition has become known.
Hence, the recent flurry of articles appearing not only in scientific
journals but also in the lay press….
~
Why all the fuss? Probably because virtually everyone has a friend,
relative or acquaintance who is affected with this disease. It is seen
in 5-9% of reproductive age women, making it arguably the most common
endocrine abnormality in this age group….
~
In spite of decades of research and volumes of material written on
PCOS, there is not a universally agreed upon definition. The reasons
for this is that the condition is a syndrome rather than a single
specific disease intensity. In other words, there are many discreet
abnormalities, which may cause women to develop this syndrome, and
each has certain unique features. However, although most of the
“classic” signs or symptoms of PCOS are present in little more than
half of women with this disease, irregular cycles with absent of
infrequent ovulation is a prerequisite for labeling a patient with
this diagnosis. Hair growth, acne, obesity, and the various hormonal
and biochemical abnormalities associated with this condition are
usually absent in at least a third of patients diagnosed with this
condition….
~
Traditional therapies for Polycystic Ovarian Syndrome include
bilateral ovarian wedge resection (now largely replaced by medical
therapy or laparoscopic ovarian diathermy) contraception if patient
does not wish to conceive, and clomiphene citrate if the patient is
desirous of conception….
~
For patients who desire cycle control or relief from acne or
hirsutism, oral contraceptives are the first line of management.
Clomiphene citrate, which is an antiestrogen, can induce ovulation in
PCOS patients by altering the natural secretion of ovulation enhancing
hormones. However, only 60-80% of women with Polycystic Ovarian
Syndrome will achieve regular spontaneous ovulation with this drug,
and only about half of that number will ultimately conceive. The
reason for this discrepancy between ovulation and pregnancy rates is
not fully understood….
~
More recently, the role of insulin resistance in this condition has
become better understood. In some individuals, insulin resistance is
probably responsible for the development of PCOS. In others, it is
merely an association, linked either to obesity or genetic factors.
There is a tremendous amount of research presently being conducted in
this arena….
~
Of most significance to our patients with this condition, the role of
insulin sensitizer therapy has become well known. There are three such
medicines in used today, the common names of which are Actos, Avandia,
and Glucophage. These medications allow the cells to respond more
normally to the body’s insulin secretion which leads to a decrease in
insulin production by the pancreas. The resulting decline in insulin
levels affect a number of other pathways, ultimately improving a
woman’s overall hormone balance and helping her to achieve ovulation
more readily. In some women, insulin sensitizer therapy alone will
allow women with PCOS to ovulate and conceive. In others, medicines
such as clomiphene citrate are still necessary. However, we now can
help such women to ovulate with lower doses of clomiphene, and some
women who could not previously ovulate even with high and prolonged
doses of Clomiphene can now conceive without having to resort to
expensive injectable medications. Therefore, the extreme usefulness of
these medications in the treatment of this condition have become
recognized as the first major medical advance in many years….
~
Not all women with PCOS have insulin resistance, and many who do have
only a mild problem, which would probably not benefit from use of
insulin sensitizer therapy. Often, these women may achieve similar or
better results using other methods such as weight loss and exercise.
Adjunctive medications such as Tamoxifen or Decadron, or injectable
menotropins may also be used with excellent results. Finally, ovarian
diathermy, in which the ovaries are treated with electrical energy
during an outpatient laparoscopic procedure, produces excellent
ovulation and pregnancy rates. It is beyond the scope of this article
to delineate the situations which would favor one treatment modality
over another….
~
We have also become increasingly aware that there are sufficient long-
term complications of insulin resistance and polycystic ovarian
syndrome. During pregnancy, these patients display a higher incidence
of gestational diabetes, a potentially serious condition for the
mother and fetus. Further on down the road it appears that women with
PCOS are at significantly increased risk for hypertension, Type II
diabetes, and cardiovascular disease. There is currently much interest
and research in this area, but as yet little information on how these
potential complications are best avoided….
~
If you have or think you may have polycystic ovarian syndrome or
insulin resistance, see your physician, or your infertility specialist
for testing. Further details may be found on our web site, or through
national organizations such as Resolve or American Society for
Reproductive Medicine…..
~
Future Research
——————————————————————————–
The role of insulin sensitizers in the long-term treatment of PCOS is
still relatively new and hotly debated. More research is being
conducted to determine the safety and efficacy of these treatments
[3]….http://pbl.cc.gatech.edu/mindy/952

It has also been found that PCOS is highly genetic. By studying
families where PCOS is seen in several women, studies will hopefully
be able to identify the gene(s) contributing to this disease. Dr.
Andrea Dunaif, Chief of the Division of Endocrinology, Metabolism, and
Molecular Medicine at Northwestern University Medical School and a
member of the Advisory Board for the Polycystic Ovary Syndrome
Association, is the Principal Investigator of an ongoing National
Institutes of Health-funded study examining the genetics of PCOS. She
is recruiting women with PCOS (diagnosed or undiagnosed) and their
family members to study the genetics of this syndrome….
~
http://hsc.virginia.edu/medcntr/centers/crr/

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