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Slide 1
This review focuses on a common ovulation dysfunction that is often referred to as polycystic ovarian syndrome or PCOS. PCOS is a
complex disorder that usually involves several different hormone systems that in turn affect many different parts (or organs) of the
body. Over the years, and after a great deal of effort, the disorder of PCOS remains poorly understood within the medical community
and there is significant controversy even with respect to its defining characteristics.
The initial medical description of PCOS is associated with two physicians, Stein and Leventhal, who characterized PCOS in 1935. They
identified women with amenorrhea (an absence of menstrual intervals), obesity (especially around the waist rather than around the hips),
and hirsutism (excessive male pattern hair growth). They also noted an association with infertility and enlarged ovaries that contain
many cysts (polycystic ovaries).
This review presents the most common current medical definitions of PCOS, the diagnostic tests that are thought to be useful in the
clinical evaluation of PCOS, and treatment alternatives for women with polycystic ovarian syndrome.
A general discussion of ovulation disorders including PCOS is made available by The NJ Center for Fertility and Reproductive Medicine
on their website. The location of this website is available at the lower right hand corner of each slide in this presentation.
Slide 2
It is believed that as many as 10% of all reproductive age women (or as many as 1 in 10 reproductive age women) suffer from PCOS.
PCOS is clinically characterized by irregular or absent menstrual intervals, signs of elevated male hormones such as excessive male
pattern hair growth or acne and oily skin, and many small to mid sized cysts containing eggs within the ovaries that have been arrested
in their maturation (or development).
Slide 3
The National Institutes of Health (the NIH) held a conference in 1990 where medical experts discussed, debated and eventually proposed
a set of minimal criteria to be used for the diagnosis of PCOS. According to the consensus, the diagnosis of PCOS requires that the
woman have (1) irregular or absent menstrual intervals, (2) evidence of elevated male hormones (hyperandrogenemia), and (3) no other
identifiable cause for the menstrual irregularity and elevated male hormones.
Slide 4
The NIH panel of experts identified menstrual irregularity due to an ovulation dysfunction as either (1) fewer than 9 menstrual cycles
per year, or (2) an absence of menstrual cycles for 3 or more consecutive months (3 months in a row). Other identifiable causes for
ovulation disorders should be excluded, such as hormonal imbalances that result in ovulation dysfunctions, trauma, medications or
stress. A detailed review of the potential causes for ovulation disorders is presented in another presentation that is also available
through the NJ Center for Fertility and Reproductive Medicine website (linked at the lower right hand corner of each slide in this
presentation)
Slide 5
The NIH panel of experts also identified evidence of elevated male androgenic hormones as either (1) clinical signs such as excessive
male pattern hair growth (hirsutism) or acne and oily skin, or (2) abnormal bloodwork for androgenic hormones such as testosterone,
androstenedione, or dihydroepiandosterone sulfate or DHEAS. Other causes of elevated male hormones need to be excluded including
congenital adrenal hyperplasia or CAH, Cushing's syndrome, androgen producing tumors, and androgenic medications.
Slide 6
Experts from the European Society of Human Reproduction and Embryology and the American Society of Reproductive Medicine convened as a
consensus workshop group in Rotterdam (within the Netherlands) in 2003 to further explore the definition of PCOS. The diagnostic
criteria that were proposed as a result of this conference were a revision of the 1990 NIH criteria and they included a broader
range of women. The 2003 Rotterdam criteria require any 2 of 3 conditions to define PCOS. The three conditions include the two
criteria identified at the NIH conference in 1990 and also a third condition: polycystic ovaries on ultrasound examination.
Slide 7
The Rotterdam group specified that in order to identify polycystic ovaries on ultrasound examination there must be either (1) more than
12 follicles in each ovary that measure 2-9 mm in diameter, or (2) the calculated total ovarian volume must be over 10 cubic centimeters
or mL.
Slide 8
The clinical evaluation of a woman who may have PCOS includes a complete medical history and a thorough menstrual history. Initial
laboratory tests for a woman with irregular or absent menses includes a pregnancy test, basal hormone concentrations assessing ovarian
reserve (including FSH, LH and estradiol concentrations on the 2nd to 4th day of the cycle), thyroid stimulating hormone or TSH and
prolactin hormone concentrations. Further tests are directed according to the history, physical examination and initial bloodwork.
The classic history obtained from women with PCOS includes an early age of onset for menstrual irregularity (around puberty) or immediately
following a rapid increase in weight, slowly progressive appearance of thick dark hair in a male pattern distribution (such as under
the belly button, on the face, on the back), inflammatory acne that is unusually aggressive and difficult to treat, android rather than
gynecoid obesity (that is, excess weight around the waist rather than around the hips), and dark velvety irregular raised patches of
skin (called acanthosis nigricans) especially in moist locations (such as the back of the neck, the armpit, or under the breasts)
For women who may have PCOS, additional androgenic bloodwork may be obtained (including total or free testosterone, androstenedione,
and DHEAS) along with an ultrasound looking for polycystic ovaries. Once a woman is defined with PCOS, additional testing for insulin
resistance is often suggested.
Slide 9
The treatment of PCOS is directly related to the desired goal. Fertility, protection of the endometrium from endometrial hyperplasia
and carcinoma, treatment of excessive male pattern hair growth or acne, and overall protection of health if the metabolic syndrome or
syndrome X coexists are all common and reasonable treatment goals.
When the ultimate goal is fertility then ovulation induction to produce a mature fertilization capable egg is the immediate goal.
Simply put, women with 12 ovulation cycles per year have more eggs that may result in a pregnancy per year than women with fewer cycles
per year.
For overweight women with PCOS ovulation induction has been shown to be significantly more successful following a 5-10% weight loss.
If a PCOS patient also has insulin resistance then insulin-sensitizing medications such as glucophage are sometimes suggested since
ovulation induction may be significantly easier.
The entry-level ovulation inducing medication for PCOS is clomiphene citrate. This medication induces ovulation in 60-85% of PCOS
patients, is generally less expensive than injectable medication, has few complications (the twinning rate is about 8-10% and ovarian
cysts are relatively uncommon), and the side effects are often mild. When clomiphene citrate is ineffective or the woman is intolerant
to the side effects, then injectable medications like menotropins are considered.
Injectable menotropins medications contain FSH as the primary active ingredient, are relatively expensive, usually result in the
maturation of multiple eggs simultaneously which then increases the incidence of complications (such as multiple pregnancies
including higher order multiples like triplets and ovarian hyperstimulation syndrome), and require frequent monitoring with
bloodwork and ultrasounds by a qualified fertility physician. However, these medications are usually highly effective in PCOS
patients.
Surgery designed to remove or destroy part of the outer ovary has been used over the years with mixed success. At present, most
fertility specialists believe that the scar tissue resulting from this type of surgery is often very damaging.
Slide 10
A hormonally active and dynamic tissue called endometrium lines the cavity of the uterus. Estrogen stimulates the endometrium to grow
thicker and progesterone stabilizes the lining to allow for embryo implantation and development of a normal pregnancy.
With PCOS, there are irregular menstrual intervals with fewer than the normal number of menstrual flows per year. In these situations,
the estrogen hormone that is active prior to ovulation stimulates a greater than normal amount of endometrial growth and in fact the
endometrium may become overgrown (a condition called endometrial hyperplasia) and may deteriorate into a malignancy (called endometrial
carcinoma or endometrial cancer).
In order to limit exposure to the risk of endometrial overgrowth or cancer a progesterone or progesterone like medication should be
administered regularly to those women with less than 1 cycle every other month.
Oral contraceptive pills are a common and effective way of providing protection since all contraceptive pills are predominantly
progestagenic. The oral contraceptives also reduce ovarian androgen production by reducing excess LH so they may help with excess
male pattern hair growth or acne. Note that the progestagen contained in the pills can also have some androgenic side effects.
There are several pills with low androgenic side effects some of which, but by no means all, are listed here. Ortho tri cyclen is
FDA approved for treatment of acne and is thought to have few androgenic side effects. Yasmin contains a progestagen with
antimineralocorticoid and antiandrogenic actions similar to the popular medication for excess male pattern hair growth, Spironolactone.
Demulen 1/50 may be used if there is persistent break through bleeding on a low dose estrogen pill and additional estrogen is
desireable.
If a woman is not a candidate for the pill or is intolerant to the side effects of the pill, then intermittent use of progesterone
can be useful. A common regimen is provera 10mg x 7-10 days every 1-2 months. Many gynecologists are more comfortable with just
giving provera 10mg x 10 days every month on calandar days 1-10 (January 1-10, February 1-10, etc). If a woman is also intolerant
to the side effects of provera then natural progesterone like prometrium usually has fewer side effects.
Slide 11
The physical signs of elevated androgens disturb many women with PCOS. These include acne and oily skin, excessive male pattern hair
growth or male pattern balding, obesity with a distribution that is mainly around the waist rather than the hips, or dark velvet-like
discolorations of the skin in small patches. Excess male pattern hair growth may be a minor cosmetic issue for some women and an
emotionally challenging problem with significant psychological impact for others.
The treatments that are designed to reduce the effect of androgen hormones should not be used during pregnancy since a male fetus may
not develop normally when the androgenic hormones are blocked.
Oral contraceptive pills are often effective and are considered a first line therapy when PCOS presents with signs of hyperandrogenemia
since the hormones in the pill will reduce LH concentrations and this will in turn reduce ovarian androgen production and there is some
reduction in adrenal androgen secretion. Corticosteroid medications may reduce the adrenal gland's production of androgenic hormones
(such as DHEAS) but chronic steroid use has some potentially serious risks such as weight gain, osteoporosis, impaired glucose
tolerance and adrenal suppression so it is not currently recommended for this purpose at this time.
Any treatment for excessive hair growth takes 3 to 6 months to see an effect since the half life of a particular hair in a follicle is
about 6 months. When oral contraceptives alone are not effective then the addition of a second medication may be suggested.
Spironolactone inhibits the binding of testosterone and its derivatives to their receptors (for example in hair follicles) and this
then reduces the action of excess androgenic hormones. Spironolactone is considered one of the safest medications for the treatment
of hyperandrogenemia and is often recommended in addition to oral contraceptive pills. Flutamide inhibits the binding of testosterone
to its receptors but it is very expensive, it is not FDA approved for treatment of excess hair growth, and it can be toxic to the liver
and result in very serious complications. Therefore, Flutamide is not recommended for this purpose. Finasteride inhibits the
conversion of testosterone to its more potent bioactive derivatives but is not as effective as Spironolactone and also has some
potentially very serious complications, so it is also not recommended for this purpose at this time. Cyproterone acetate is a
progestin with antiandrogen activity and it has been shown to be effective in combination with oral contraceptive pills in European
and Canadian studies, but this medication is not available in the USA at this time (2006).
Slide 12
PCOS is associated with obesity (especially android obesity with most excess weight around the waist rather than hips) and insulin
resistance, both of which are risk factors for type 2 diabetes.
A syndrome known as the "metabolic syndrome" or "syndrome X" has been defined by the World Health Organization as elevated insulin or
elevated glucose concentrations in the blood along with at least two of the following conditions: (1) abdominal obesity, (2) abnormal
lipid concentrations with either elevated cholesterol or elevated triglycerides, and (3) high blood pressure. This syndrome is
recognized by many other prominent health organizations including the American Heart Association and the International Diabetes
Federation. There is a significant risk for subsequent development of Diabetes, Heart Disease, fatty liver disease, chronic kidney
disease and sleep disordered breathing including sleep apnea.
Whenever there is a suspicion of metabolic syndrome I suggest an internal medicine consultation and aggressive management to reduce
future morbidity and mortality.
Slide 13
The ultimate goal in the treatment of polycystic ovarian syndrome or PCOS is to employ modern medical knowledge and treatments to help
women and couples enjoy a happy and healthy family.
It was a pleasure to be able to present this information to you and I thank you for your attention. If you are interested in similar
presentations, you can check the website for the NJ Center for Fertility and Reproductive Medicine regularly since new topics will be
posted as they become available.
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