Disorders Associated with Diabetes

Polycystic Ovarian Syndrome (PCOS)
Also referred to (but considered outdated) as
Stein-Levinthal Syndrome, Polycystic Ovary Disease

Cysts are a normally seen on ovaries when each month a follicle matures and an egg is released.
Women with PCOS do not release the egg each month because of abnormal hormone levels.
 This can lead to infertility and amenorrhea (absent monthly period cycle)

What is Polycystic Ovarian Syndrome (PCOS)?

Polycystic ovary syndrome (PCOS), originally known as Stein-Levinthal Syndrome for the doctors that first identified this disorder in 1935, is an endocrine disorder that affects 5–10% of women. It occurs in all races and nationalities, is the most common hormonal disorder among women of reproductive age, and is a leading cause of infertility.

Because of the common problems associated with ovulatory functions (egg follicles mature, but hormonal imbalances keeps them from releasing, thus creating multiple cysts on the ovaries), the syndrome is now referred to as PCOS. However, PCOS it is not a gynecological disorder, but a complex endocrine disorder affecting many systems and functions of the body.

The symptoms and severity of the syndrome vary greatly between women. While the causes are unknown, insulin resistance (often secondary to obesity) is heavily associated with PCOS.

Other names for this disorder include:

• Polycystic ovary disease (incorrect, as PCOS is characterised as a syndrome rather than a disease)
• Sclerocystic disease of the ovary
• Functional ovarian hyperandrogenism
• Hyperandrogenic chronic annovulation
• Ovarian dysmetabolic syndrome
• Ovarian androgen excess
• Stein-Levinthal Syndrome
• Syndrome "O"

PCOS is an endocrine disorder classified as a syndrome.  It is NOT a gynecological disease.   A syndrome is a disorder in which a person may have some but not all of the symptoms.  For a person to be classified as having a disease, they must have all the symptoms.  

Genetically Transmitted

A family history of thyroid disease, diabetes, insulin resistance, or Syndrome X is often found on the immediate and extended biological family members of women with PCOS.  The syndrome has a strong genetic component although, as with diabetes, environmental factors can affect the degree and nature of  symptoms.  Paternal transmission with PCOS occurs over 80% of the time when the father is affected with the gene.  Males carrying the gene that causes PCOS in women may have hypothyroid, Syndrome X, diabetes (especially type 2), heart problems, poor lipid profile, inability to grow a full beard, or premature balding.  Maternal transmission occurs approximately 45% of the time.  Either parent can transmit the gene, without showing any symptoms of PCOS (in men, usually referred to as Metabolic Syndrome).  However, any female sibling of a person diagnosed with PCOS or Syndrome X should be tested for PCOS.  Even when no outward sign of PCOS is present, studies show that upon physical inspection of the ovaries more than 50% of all female siblings of a person already diagnosed with PCOS will also have some degree of PCOS.  It should be noted that PCOS is occasionally associated with epilepsy without genetic transmission.

Signs and symptoms

Women with PCOS may have any of the following signs, symptoms, and problems:

Gynecological disorders

Including:

• Irregular or absent menses (periods) due to annovulation (lack of ovulation).  Women with PCOS may have few, or no periods, and many have infrequent, very heavy periods that may required a D&C procedure. However, some women with this disorder do have normal, regular periods.  Women with PCOS may also experience spotting.  This is usually not considered having a period but may be the result of excessive uterine lining building (it literally begins to slough and overflow, causing "spotting."
   
• Pre-menstrual Syndrome (PMS).  Prolonged, or profound PMS symptoms including pelvic and back pain, bloating, carbohydrate cravings, depression or moodiness, and sleep disturbances.  (Women that are overweight may also experience sleep apnea.)
   
• Numerous cysts on the ovaries.  These may cause pain, and become quite large as multiple cysts develop.  Anytime excessive pain or fever are present see your doctor immediately.  Ruptured or twisted ovaries can present a life-threatening situation and usually requires surgery.  An ultrasound of the pelvis (and sometimes uterus) is typically done as part of diagnosis of PCOS.  The ovaries often appear thickened, with a pearl white outer surface.
   
• Infertility in some women due to annovulation.  Weight loss, insulin sensitizing drugs or infertility drugs may help overcome infertility.  Women with PCOS may suffer from either primary or secondary infertility.
   
• Higher rate of miscarriage.  There is a higher rate of miscarriage in women with PCOS that become pregnant either naturally, or with the aid of fertility drugs.  This may be due to the quality of an egg, but can also be caused from low progesterone levels in women with PCOS.  Progesterone is one of the important hormones during the first trimester of pregnancy that cause and "hold" the implantation of the fetus.  Women with PCOS that become pregnant should have their progesterone levels monitored.  Many studies also suggest that women on Glucophage who become pregnant have a lower incidence of miscarriage if they stay on the drug at least during the firs trimester of pregnancy.  The safety of Glucophage during pregnancy and nursing has not been fully evaluated.  

Metabolic problems and symptoms

These include:

• Hyperinsulinemia.  Elevated insulin levels (despite normal blood glucose on GTT).  For this reason, women with PCOS should have their insulin levels checked in addition to their blood glucose.  Hyperinsulinemia may be an indication of insulin resistance or pre-diabetes)
   
• Insulin resistance, Metabolic Syndrome (formerly called Syndrome X), or diabetes, especially type 2 diabetes.
  
  
• Weight problems and carbohydrate sensitivity.  Weight gain may be both rapid and significant.  This may be due in part to elevated insulin levels, insulin resistance, or type 2 diabetes, and carbohydrate sensitivity.  Women with PCOS typically need to follow a special diet, low in simple carbohydrates, high in fiber, low in fat, with healthy protein choices, and low to moderate intake of low-glycemic carbohydrates.
   
• Hashimoto's Thyroiditis - as many as 4 times more common in women with PCOS than in the general population, this autoimmune disorder causes hypothyroid (low) levels of TSH.  It is possible for persons in the early stages with Hashimoto's to have normal thyroid levels so it is important to have a test done for specific antibodies for Hashimoto's.  Low thyroid may cause mental confusion, depression, sleep disorders, weight gain, skin conditions, and hair loss.  

Other disorders associated with PCOS

Other problems women with PCOS experience more frequently than the general population include:

• Hashimoto's Thyroiditis
• Irritable Bowel Syndrome (IBS)
• Depression
• Chronic Fatigue Syndrome (CFS)
• Fibromyalgia Syndrome (FMS)
• Insomnia (often alleviate when elevated insulin levels are corrected)
• Sleep apnea (most typically associated with excess weight)

Cosmetic complaints

Usually benign in nature, cosmetic issues associated with PCOS can be emotionally distressing and include:

• Acne and oil skin
• Acanthosis nigricans(AN)
• Acrochordons (skin tags)
• Hirsutism(excess facial and body hair)
• Seborrhea
• Thinning scalp hair (alopecia areata), and/or loss of body hair
• Viralization (enlargement of the clitoris)

Medical problems

Include:

• Increased levels of the male hormone testosterone.
• Decreased levels of sex hormone binding globulin
• Decreased levels of progesterone
• Increased levels of estrogen (particularly in women that are also overweight)
• High blood pressure
• Increased risk of cardiovascular problems
• Increased risk of certain types of cancer including ovarian and uterine cancers
• Increased rate of developing diabetes (especially type 2 diabetes)
• Elevated serum (blood) levels of androgens (male hormones), specifically testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS), causing hirsutism and occasionally masculinization or viralization (enlargement of the clitoris).
• The ratio of LH (Luteinizing hormone) to FSH (follicle stimulating hormone) is 2:1 or more, particularly in the early phase of the menstrual cycle.  

Diagnosing PCOS

Diagnosis of PCOS should include consideration of family history and diagnostic tests to rule out other possibilities such as Cushing’s syndrome.  A pelvic ultrasound of the ovaries, as well as blood tests should be performed.  Women with PCOS should consult with an endocrinologist for treatment, and a reproductive endocrinologist if infertility is an issue.  Although the syndrome is called polycystic ovarian, it is not a gynecological disorder, nor a disease of the ovaries.  PCOS affects the ovaries but the ovaries are not the source of PCOS.  Having an oopherectomy (removal of the ovaries) will not cure PCOS, in fact, there is no cure.  

According to Wikipedia.com, the definition and diagnosis should include the following considerations:

Definition of PCOS

"There are two definitions that are commonly used:

1. In 1990 a consensus workshop sponsored by the NIH/NICHD suggested that a patient has PCOS if she has (1) signs of androgen excess (clinical or biochemical), (2) oligoovulation, and (3) other entities are excluded that would cause polycystic ovaries.
    
2. In 2003 a consensus workshop sponsored by ESHRE/ASRM in Rotterdam indicated PCOS to be present if 2 out of 3 criteria are met: (1) oligoovulation and/or annovulation, (2) excess androgen activity, (3) polycystic ovaries (by gynecologic ultrasonography), and other causes of PCOS are excluded.

"The Rotterdam definition is wider, including many more patients, notably patients without androgen excess, while in the NIH/NICHD definition androgen excess is a prerequisite. Critics maintain that findings obtained from the study of patients with androgen excess cannot be necessarily extrapolated to patients without androgen excess.

"It is important to note that not all women with PCOS have polycystic ovaries, nor do all women with ovarian cysts have PCOS; although a pelvic ultrasound is a major diagnostic tool, it is not the only one. Diagnosis can be difficult, particularly because of the wide range of symptoms, and the variability of how they present themselves in individuals (which is why this disorder is characterized as a syndrome rather than a disease). There is a lot of controversy about the appropriate testing:

• gynecologic ultrasonography
• testosterone: free more sensitive than total
• Fasting biochemical screen and lipid profile
• 2-hour oral glucose tolerance test (GTT) in patients with risk factors (obesity, family history, history of gestational diabetes) and may indicate impaired glucose tolerance in 15-30% of obese women with PCOS. Frank diabetes can be seen in 6-8% of women with this condition.
• For exclusion purpose:
  • Prolactin
  • TSH
  • 17-hydroxyprogesterone

"The role of other tests is more controversial, including:

• fasting insulin level or GTT with insulin levels (also called IGTT). Elevated insulin levels have been helpful to predict response to medication and may indicate women who will require either higher doses of metformin or the use of a second medication to significantly lower insulin levels. Elevated blood sugar and insulin values do not predict who responds to an insulin lowering medication, low glycemic diet and exercise. Many women with normal levels may benefit from combination therapy. A hypoglycemic response where the two hour insulin level is higher and the blood sugar lower than fasting, is consistent with insulin resistance.
• LH:FSH ratio
• DHEAS
• SHBG
• Androstenedione

Before making a diagnosis of PCOS other causes of irregular/absent menstruation and hirsutism such as congenital adrenal hyperplasia, Cushing's syndrome, hyperprolactinemia and other pituitary and/or adrenal disorders, should be ruled out."

Treatment Options

Treatment includes lifestyle changes; diet modifications, weight and stress management, and an exercise program.  Medications are usually prescribed for insulin resistance (insulin sensitizing drugs such as Glucophage), to help restore the menstrual cycle (birth control pills and/or insulin sensitizing drugs), to address cosmetic issues (Aldactone and/or Vaniqa for hirsutism) and possible acne and/or weight loss drugs.  

When infertility is an issue various courses of action may be necessary to achieve pregnancy.  Infertility treatment needs to be tailored for each individual woman with PCOS but often begins with trying a combination of Glucophage and clomid, (a fertility drug) aimed at inducing ovulation, as the first step.

Medical treatment for PCOS include:

• Oral contraceptives to induce regular periods.  Women with PCOS that do not have naturally occurring cycles should use birth control pills, or, take progesterone to induce at least 4-6 periods each year. This may help protect fertility and reduce the risk of endometrial cancer.
   
• Spironolactone (see note below) or finasteride.  The drugs have an anti-androgen therapy effect, and block the effects of male hormones (they do not reduce testosterone, but block to effects).  Anti-androgens may help reduce  excessive hair growth (hirsutism), and may also improve acne.
  
  It may take up to 6 months on anti-androgens to see positive effects.  The typical dose of Aldactone for women with PCOS is high; usually 100 mg daily for this drug to be effective.  It may cause dizziness and because it is a potassium-sparing diuretic you should not take potassium supplements while on this drug unless your physician specifically tells you to, otherwise, a dangerous build-up of potassium (if taking supplements) can occur.
   
• Clomiphene citrate and/or human chorionic gonadotropin or dexamethasone to induce ovulation.  The dose for each women varies.  However, these fertility drugs are known to be more effective in women of normal weight, or, who lose 10-15% of excess weight.  Obese women may require higher doses (there are many side effects to fertility drugs) or be less sensitive to the effects of the medication.

Note:  Aldactone (spironolactone) is a diuretic sometimes used in treating heart patients.  It has an androgen blocking property when prescribed to women.  It is often administered to women with PCOS to help regulate high levels of testosterone which aggravates cosmetic issues associated with PCOS.  Caution:  Aldactone is a category X drug and may cause severe birth defects or miscarriage and should not be taken while trying to become, or already pregnant.  Recent studies indicate that there may be an increased risk for developing cancer for those taking Aldactone.

The following treatment protocol is excerpted from Wikipedia.com:

• Recent research suggests that the insulin resistance and over-release of insulin may be at the root of PCOS. Many women find insulin-lowering medications such as metformin hydrochloride (Glucophage®), pioglitazone hydrochloride (Actos®), and rosiglitazone maleate (Avandia®) helpful to them, and indeed ovulation may resume when using these drugs.
   
• Many women report that metformin use is associated with upset stomach, diarrhea and weight-loss. Both symptoms and weight-loss appear to be less with the extended release versions. Most published studies use either generic metformin or the regular, non-extended release version. Starting with a lower dose and gradually increasing the dosage over 2-3 weeks and taking the medication towards the end of a meal may reduce side effects. The use of basal body temperature charts or BBT charts is an effective way to follow progress. It may take up to six months to see results, but when combined with exercise and a low-glycemic diet up to 85% will improve menstrual cycle regularity and ovulation.
   
• Low-carbohydrate diets and sustained regular exercise are also beneficial. As well, initial research suggests that the risk of miscarriage is significantly reduced when Metformin is taken throughout pregnancy (9% as opposed to as much as 45%); however, further research needs to be done in this area.
  

For patients that do not respond to these and related medications/procedures, the polycystic ovaries can be treated with surgical procedures such as:

• laparoscopy electrocauterization or laser cauterization
• ovarian wedge resection (rarely done now, because it is more invasive and has a 30% risk of adhesions, sometimes very severe, which can obstruct fertility)
• ovarian drilling  

Complications and Risks Associated with PCOS

Women with PCOS are at risk for the following:

• Endometrial hyperplasia and endometrial cancer (cancer of the uterine lining) are possible, due to excessive accumulation of uterine lining, and also lack of progesterone resulting in prolonged stimulation of uterine cells by estrogen
• Infertility (primary and secondary)
• Increased rate of miscarriage (early supplementation of progesterone may be required to maintain the pregnancy)
• Women with PCOS have a higher rate of having an eating disorder than the general population
• Insulin resistance
• Type 2 diabetes, generally thought to be caused by hyperinsulinemia
• High blood pressure
• Dyslipidemiadisorders of lipid metabolism - cholesterol and triglycerides)
• Cardiovascular (heart) disease

References & Sources

The Jewish Hospital Cholesterol Center
Some content has been inserted into this article directly from Wikipedia.com (see, Polycystic Ovarian Syndrome)
Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:1223-36. PMID 15788499.