Polycystic Ovarian Syndrome is common condition in women that wreaks havoc on hormones and causes physical and psychological damage. Polycystic ovarian syndrome (PCOS) is a complex hormonal disturbance that effects the entire body and has numerous implications for general health. Women with this syndrome have, over the course of their life, an increased risk of coronary disease, diabetes and endometrial cancer. PCOS was first diagnosed in 1935 as Stein-Leventhal syndrome. Between 5 and 30 percent of women have some characteristic of PCOS. The disorder is probably the most common hormonal abnormality in women of reproductive age and certainly is a leading cause of infertility. PCOS patients were once dismissed as"fat" women with no self control. Doctors still can often miss, or dismiss, the diagnosis because they fail to recognize the diverse set of symptoms as being part of one medical condition. There are three broad reasons why PCOS patients seek medical care: 1) menstrual cycle disturbance and infertility 2) problems of appearance and self esteem arising from obesity and excessive hair growth, and 3) metabolic derangements, including abnormalities in blood fat (lipid) levels, insulin/glucose (sugar), and elevated blood pressure (hypertension). Often gynecologists, the health care provider to whom may women turn for help, have concerned themselves with only the first of these concerns and have been relatively insensitive to the latter two.
Making the Diagnosis of PCOS
In no other gynecological condition is the general medical history more important than in PCOS. There are 3 different ways to make the diagnosis of PCOS: 1) by symptoms and physical findings, 2) hormonal testing, and 3) ultrasound. Probably most individuals will have abnormalities in all three, some only in two, and possibly only in one. Some may argue that findings in only a single category may not constitute PCOS. But, until we have PCOS better characterized, or find a different diagnosis for these patients, the diagnosis of PCOS should remain and provides a good starting point for communication. Even the most minor of apparent problems may have significant implications for future general health and well-being. The classic findings of PCOS are: menstrual cycle abnormalities, increased sexual hair growth and obesity.
Often in PCOS patients, the menarche occurs at the usual age of 12-13 years. Some PCOS patients may start menstruating earlier. Not uncommonly, PCOS patients may first be seen by a physician for lack of menses. Any female who has not had menses by age 16 should be evaluated. The menstrual cycle may at first be regular, but by high school, cycles start to lengthen and may be skipped. Often during this time, oral contraceptives are started. The "pill" usually regulates the menstrual cycle and may give the false impression that all is well. Usually in the teenage years, the other symptoms of skin and weight problems also start to be seen. Some PCOS patients easily establish a pregnancy in these early years. Occasionally, birth control pills may even increase the chance of pregnancy by suppressing abnormal hormonal production.
Often the PCOS patient is seen by a gynecologist when she is in her 20's after stopping the pill, and her periods. Some PCOS patients have quite regular 28 days cycles, but the diagnosis should be suspected in individuals with cycle length over 35 days. Some patients have no bleeding unless some form of medication, usually a progestin, is given. In some there is excessive bleeding, or long periods of spotting. It is thought that the age of menopause in individuals with PCOS is about the same, age 50, as other women.
While virtually never mentioned in medical publications, or recognized by physicians, it seems that chronic pelvic pain and premenstrual (PMS) symptoms are quite common. Given the chronically abnormal hormonal patterns, the capacity of hormones to alter body fluid and even the enlarged cystic ovaries, these findings should not be surprising.
Hair and Skin Problems
The skin manifestations associated with PCOS are possibly more common than either menstrual cycle irregularity, or obesity. Disorders of the skin in PCOS patients are related to an increase in level of male hormones (hyperandrogenism). This may be due to an absolute increase in androgen level, or an alteration in ratio of hormone levels. A third possibility is an exaggerated response of the skin to relative normal androgen levels. The end result of all three of these possibilities is the same and includes: acne, seborrhea, balding, hidradenitis suppurtiva (inflammation of the specialized sweat glands in the arm pit and groin), acanthosis nigricans (see below) and hirsutism.
Hirsutism is defined as an increase in amount and/or coarseness of hair distributed in the male pattern in a female. This is opposed to hypertrichosis which is excessive growth of non-sexual hair. The issue of facial hair is usually self-evident, but a good screening test is the amount of hair between the umbilicus and pubic hair line. Other areas of male pattern hair growth include 'sideburns,' lower neck, lower back and inner thighs. A faint moustache is quite common and may be more related to family trait and ethnic group than hormonal imbalance. The same can be said for occasional "stray" hair around the breasts. Outside hirsutism, other manifestations of hyperandrogenism are often dismissed, or not recorded in the gynecologist's evaluation.
Acne and seborrhea occur quickly as androgens rise. Androgens increase sebum which is a combination of skin oils and old skin tissue. Increased sebum causes plugging of skin pores. Bacteria that thrive on sebum are increased, resulting in inflammation. The inflamed skin pore is called a comedon. Closed comedones are "whiteheads," while "blackheads" are open comedones. The black color comes not from dirt, but from the breakdown of keratin, a natural skin product. Increased male hormone levels also cause seborrhea. A particularly common skin condition and one not usually associated with hormonal alterations is dandruff. Contrary to what is generally believed, dandruff is caused by oily, not dry skin and is a variety of seborrheic dermatitis.
Many women complain of skin problems that wax and wane during the menstrual cycle. In regularly cycling women, the second half of the menstrual cycle is characterized by increased progesterone levels. Progesterone is a weak androgen and may create a situation of relative hyperandrogenism. Around the time of menstruation estradiol is decreased. Low levels of estrogen (hypoestrogenism) also creates a situation of relative increase in androgens with resultant increased oiliness and inflammation of the skin. One of the most distressing of hyperandrogenic skin disorders is alopecia (balding). The most androgen sensitive area of the scalp is the vertex, the highest point of the head. Frontal balding and anterior hairline recession is seen only in the more severe cases of androgen excess. As can be imagined, the mechanism for hair growth (and loss) has been extensively studied, but no unified theory has emerged.
A search for acanthosis nigricans (AN) should be a part of every physical exam of the PCOS patient. AN is usually described as a velvety, raised, pigmented skin changes, most often seen on the back of the neck, axillae and beneath the breasts. AN is often seen in association with skin tags (acrochordons). Possibly the best description is that it looks like the affected area is 'dirty' and would benefit from scrubbing. Obviously this is not the case. There is an association of this finding with simple obesity as well as other endocrine disorders. AN should always alert the clinician to a risk of diabetes, major lipid abnormalities, and hypertension. Although less common, it may be a warning signal of cancer.
Elevated androgen levels may be only a part of the problem. For androgens to have an effect on the skin they must bind together with an androgen receptor in the skin. There may little, or no, physical evidence of hyperandrogenism despite very high androgen levels, if the androgen receptor is lacking or present in relatively low numbers. The number of androgen receptors varies among different ethnic groups and individuals. Northern European women with PCOS are more likely to be hairier than Asian women. A third requirement for androgen action in the skin, besides androgens and receptors, is a specific enzyme called 5-alpha-reductase. Testosterone must be converted to dihydrotestosterone (DHT) by this enzyme to exert its effect. Only sexual hair follicles contain the necessary enzymatic machinery for conversion of circulating androgens to DHT. A fair skinned individual may have little excess hair growth despite high levels of testosterone, due to absence of the specific androgen receptor, or enzyme converting capacity, in the hair follicles. Another individual may be quite hirsute with no apparent abnormality in circulating hormones.
Whether obesity is a cause of PCOS or obesity is a result of PCOS is unclear, but it seems that the latter is more likely. A distinction has been made between the "lean" and "obese" PCOS patient. The typical obesity of PCOS is described as "centripetal," related to fat distribution in the center of the body, as opposed to the thighs and hips. This "apple" opposed to a "pear" type of fat distribution clearly is associated with greater risk of hypertension, diabetes and lipid abnormalities. Certainly, many metabolic derangements improve with weight loss, but PCOS is not "cured" by weight reduction. Almost always, individuals with PCOS gain weight very easily and lose it only with great effort. Everyone knows that some individuals consume large quantities of food and never gain weight while others work hard just to stay "fat" instead of severely obese. Vanity keeps some from weighing much more than they might, if only they were less vigilant. When seeking medical help for weight control, too often, the obese patient has been told to exercise more, or to eat less.
Clearly, this over-simplification fails to take into account the high likelihood that individuals vary in the way their body utilizes calories. Some use calories less effectively, or store fat more easily. A key to the way the body uses energy is insulin. Insulin is a hormone released by the pancreas in response to the breakdown of food into sugars, proteins and fats by the digestive system. Insulin promotes the storage of fat to ensure a constant source of fuel, calories, ensuring the body's most efficient operation. PCOS increasingly has been linked to abnormalities of insulin and glucose metabolism. In the past, this may have been an adaptive advantage allowing survival against cold, or famine. Now, in part a response to today's sedentary lifestyle, obesity has become a genetically related disease which may treated, but only with great personal conviction and effort. Certainly, weight loss can only be achieved when caloric expenditure exceeds caloric intake, but genetic, metabolic and environmental alterations make this a much more complex equation. Hopefully in the future, there will be relief which is both more effective and less painful than our present treatment strategies. Obesity may be the single most important health issue in the United States today. Obese individuals have greater risk of hypertension, high blood pressure, diabetes, cancer, stroke, gall bladder disease, and uterine cancer. But obesity alone does not explain everything, possibly not anything.
Virtually all patients with PCOS will have at least subtle laboratory abnormalities. The reported results may be only on the upper limits of the 'normal range,' showing only a tendency, not a discrete abnormality. Often a pattern will emerge after considering a group of tests together. These subtleties may reveal dysfunction in the control mechanisms of the hypothalamus, pituitary, ovary and adrenal (HPOA axis) working collectively. In distinction, serious pathology may be more evident by a marked elevation, or suppression of a single test. Though the value of repeated blood testing for the same hormones could be questioned, it is recommended that each PCOS patient have an initial, relatively comprehensive evaluation and interpretation by an individual familiar with this testing. Any level that is twice the upper or lower limit of normal, is particularly important and may indicate a serious problem. The marginally elevated test is almost always dysfunctional, rather than pathologic. As a rule, endocrine testing, other than a pregnancy test, is probably best performed in the morning, soon after a spontaneous, or induced menses. The days around ovulation or mid-cycle should be avoided. Hormonal evaluation in patients on oral contraceptive will often give misleading results with suppression of gonadotropin, ovarian steroid and SHBG levels. It is of limited value to determine these hormone levels in patients on the pill. Glucose and lipid evaluation should be in the morning after fasting (no food or drink after midnight the night before). Fasting insulin levels and a glucose tolerance test can be very important in the diagnosis of insulin resistance.
Sonography of the pelvis is warranted in virtually every potential PCOS patient. Evaluation should be performed by individuals experienced in judging ovarian and endometrial function. The finding of greater than ten cystic structures less than 10 mm in either ovary, meets the generally established ultrasound criteria of PCOS. Often cysts of PCOS are located in a peripheral subcortical ring leading to the reference of a "string of pearls." The PCOS ovaries are typically 1.5 to three times normal size. In some cases the ovary is virtually filled with small cysts. In other cases, it is heterogeneously dense with hardly detectable microcystic changes. It must be remembered that any hyperandrogenic state may be manifested by the PCO-appearing ovary. Diffusely enlarged ovaries without discrete mass on ultrasound, in the absence of adrenal findings, are consistent with the diagnosis of hyperthecosis which is probably a less common variant in the PCOS spectrum.
The cause of PCOS is unknown. However, the story is starting to unravel and several important lines of evidence have emerged that offer clues about a central mechanism. Is there only one, or are there many causes of PCOS? PCOS is a "final common pathway" of a variety of disorders and the diagnosis PCOS itself remains one of exclusion. It is a near universal finding that PCOS is genetic, but the heritage is complex. This genetic predisposition is not as simple as brown eyes or blue, but has a complex heritage. The tendency to develop PCOS may be inherited from either the mother's side, (maternal origin), from the father's side (paternal origin), or from both sides. A paternal origin is equally likely, but often is overlooked. Also, various characteristic traits of PCOS may be passed down with varying degrees of severity. Insulin resistance may be a key player. Women with PCOS produce too much insulin, which in turn signals their bodies to release the male hormone testosterone. Too much testosterone creates facial hair, acne, weight gain and multiple cysts on the ovaries. Doctors believe the same insulin and testosterone overload that may cause PCOS in women may also be responsible for premature male-pattern balding in men. Several medications are on the market and clinical trials are now underway testing new medications that control the release of insulin.
Therapy for PCOS
With weight loss there is often an improvement in endocrine parameters and sometimes return of menses. Clearly important, but always much easier said than done.
A progestin is a medication that mimics the action of progesterone. While progestins may be used to regulate the menstrual cycle and blood levels of LH may be reduced by progestins, they appear to be of little use in reduction of hair growth, or possibly metabolic derangements. Examples are Provera, Aygestin, Cycrin.
Oral contraceptives (OC's) are a mainstay of treatment of PCOS in women who do not want to become pregnant. They increase the SHBG which "traps" circulating androgens. The pill also reduces LH. Menses are often regulated and overall there are numerous positive health benefits.
Steroids have the ability to suppress adrenal androgen production and may be useful in treatment of PCOS with an adrenal component. Overall, their use is better in theory than practice and they are often discontinued by patients because of unwanted side effects.
This group of medications can be used only when not attempting a pregnancy or without some form of adequate birth control. There is, at least a theoretical, risk of feminizing the genitals of a male fetus. The value of the agents for PCOS patients is to improve the skin problems that occur with PCOS. None of these medications are approved for treatment of hirsutism or PCOS. Some may have potentially serious side effects. Examples are spironolactone (Aldactone), Flutamide, cyproterone acetate, and Finasteride.
Gonadotropin releasing hormone (GnRH) is a hormone that is released from the hypothalamus and promotes production and release of the gonadotropins (LH and FSH) from the pituitary gland. While quite a good therapy for suppression of the ovary and its abnormal hormonal production of PCOS, the high cost and undesirable side-effects limits GnRH use.
In PCOS, the normal mechanisms of hypothalamic-pituitary-ovarian (HPO) axis and therefore, follicle growth and ovulation are disturbed. "Fertility drugs" are commonly used in an attempt to temporarily override the problem and facilitate ovulation. Clomiphene (Clomid) is an oral fertility agent. There are also several injectable gonadotropin preparations that can be used when clomiphene fails.
In the past, ovarian wedge resection, a procedure whereby a portion of the ovary is removed and the ovary sewn back together, resulted in a significant reduction in LH and androgen production, reestablishment of regular menses in over 75% of patients and a pregnancy rate of about 60%. However, pelvic adhesive disease, which was often severe, occurred in about 30% of patients. There is probably no longer an indication for wedge resection by laparotomy, although electrosurgical incisions, or "ovarian drilling," has become relatively common place. Success rates of microcautery vary by operator and, while adhesion formation may be considerably less, it is still common.
By treating the insulin resistance, PCOS may be also treated, possibly reversed. It is still very unsettled which PCOS patient may derive benefit from these medications. With some PCOS patients these medications have successfully restored normal menstruation and fertility, even the absence of the insulin resistance. They may be a useful alternative when other therapies have failed, or benefit appears to exceed risk. These agent are:
An FDA advisory subcommittee voted unaminously in March 1994 that Metformin be approved for the treatment of insulin resistance and type 2 (insulin resistant) diabetes that cannot be controlled by diet alone. It had the strong endorsement of the American Diabetes Association and is presently used in over 80 countries. By September 1996 over one million U.S. patients had been prescribed the medication. Use is predicted to sharply rise. Metformin enhances the body's sensitivity to insulin and inhibits glucose production from the liver without the risk of hypoglycemia. It does not lower blood glucose levels, but acts to improve the body's sensitivity to insulin without affecting insulin secretion. Some patients have shown weight loss, improved lipid profiles, lowering of blood pressure, return of menstruation, and pregnancy.
Metformin appears to have an excellent safety profile and is generally well tolerated. Gastrointestinal upset and a tendency toward looser stools, or more frequent bowel movements, are the most frequent side effects. These are common in the first month and can be reduced by starting at lower doses and increasing. These side-effects are also more commonly experienced after a fatty meal, or dessert. Lactic acidosis, a rare and potentially fatal condition, has been associated with Metformin use. The reported incidence of lactic acidosis is 3 /100,000 patients using the drug for 1 year. Almost all cases occurred in older patients with other significant diseases and risk factors. A relative disadvantage of Metformin therapy may be the postponement of more aggressive fertility therapy. The usual dose is 500 mg. three times daily.
Troglitazone is an anti-diabetic agent not related to either the sulfonylureas (Diabeta, Diabenase, Tolinase), or Metformin. It was introduced in 1997 for treatment of type 2 diabetes and it was recently reported that there were over one million users. Justification for its use is the same as described above for Metformin. In contrast to Metformin, troglitazone appears to work by directly affecting insulin production. Blood glucose is lowered by improving the body's response to insulin. Troglitazone appears to be clearly better tolerated than Metformin, i.e. less GI distress. A repeated warning has been issued by the FDA regarding the potential of serious liver damage. Liver function testing should be followed monthly for the first eight months, then every two months. The usual dose is 400 to 600 mg once daily.