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The PCOS Spectrum: What PCOS Is and Is Not

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TO CONFIRM A diagnosis of polycystic ovary syndrome (PCOS), clinicians must confirm the presence of two out of the three following conditions: hyperandrogenism, menstrual irregularities, and polycystic ovaries. Because some women will present with all three criteria and others will have only two, PCOS represents a spectrum of disease. The Rotterdam criteria recognized this continuum and grouped patients into four different phenotypes:

·Frank or classic polycystic ovary PCOS (chronic anovulation, hyperandrogenism, and polycystic ovaries—3 of 3 criteria)

·Classic non-polycystic ovary PCOS (chronic anovulation, hyperandrogenism, and normal ovaries—2 of 3 criteria)

·Nonclassic ovulatory PCOS (regular menstrual cycles, hyperandrogenism, and polycystic ovaries—2 of 3 criteria)

·Nonclassic, mild PCOS (chronic anovulation, normal androgens, and polycystic ovaries—2 of 3 criteria)

The frank phenotype represents the most severe disease and is associated with metabolic diseases like obesity and type 2 diabetes and with cardiovascular risk factors like high blood pressure and cholesterol. In contrast, women with nonclassic, mild PCOS are at the lowest risk of metabolic disease.¹ Why some women with PCOS present with hyperandrogenism as opposed to anovulatory cycles is unknown.

While women may have genetic or other factors that predispose them to PCOS, lifestyle—and particularly Body Mass Index—likely determines their position on the spectrum. Weight gain moves women toward the severe end of the spectrum.² Weight loss, in contrast, moves women toward the less severe end of the spectrum by improving fertility, ovulatory cycles, and hirsutism.³

MAKING THE DIAGNOSIS

Hyperandrogenism

Male sex hormones, called androgens, are normally present in both men and women, but the normal levels for men are far higher than for women. Testosterone is the best-known androgen and contributes to many of the physical factors that distinguish men from women. It is produced in the testes in men and in the ovaries in women. Small amounts are also produced in the adrenal glands that sit above the kidneys. Testosterone helps regulate sex drive, fat distribution, and bone mass. More than 80 percent of women who present with symptoms of hyperandrogenism will eventually be diagnosed with PCOS.⁴

Common features of hyperandrogenism include

·increased facial and body hair growth (hirsutism),

·male-pattern baldness,

·acne,

·lowered tone of voice,

·menstrual irregularities, and

·clitoral enlargement (in severe cases).

The feature most commonly associated with PCOS is hirsutism, which affects an estimated 70 percent of women with PCOS. Just as with men, more testosterone increases the growth of facial and body hair in certain areas, such as the face, legs, chest, back, and buttocks. At the same time, higher levels of testosterone can cause hair loss on the scalp, which leads to crown-pattern or male-pattern baldness. In women with hyperandrogenism, this hair gain and loss becomes very obvious.

An estimated 15 to 30 percent of PCOS patients develop acne, though it has only recently been recognized as a symptom of hyperandrogenism. Among women who complain of acne, 40 percent are eventually diagnosed with PCOS, so it is important to keep it in mind.⁵ Deepening of the voice and enlargement of the clitoris indicate severe hyperandrogenism.

Serum androgen levels can be measured through blood testing. The most useful blood tests for hyperandrogenism determine levels of serum testosterone and DHEA-S (dehydroepiandrosterone sulfate), another type of androgen. These hormones fluctuate throughout the day and throughout the menstrual cycle, making it harder to define normal and abnormal ranges. Nevertheless, 75 percent of women with PCOS will have an abnormal value, if you look hard enough. Because high testosterone levels are not part of the diagnostic criteria (only clinical manifestations of it are), most clinicians do not bother to administer these blood tests.

It is worth noting that androgens also act as precursors to female sex hormones (estrogens) in both men and women. Excess adipose (fat) tissue can convert testosterone into estrogen, causing breast enlargement in both men and women. This process accounts for the very obvious “man boob” phenomenon seen in some older and obese men; it is much less obvious in women. There are ethnic differences in sensitivities to androgens, with white people being the most sensitive and Asians being the least.

Menstrual irregularities

Dr. John Nestler from Virginia Commonwealth University estimates that “if a woman has fewer than eight menstrual periods a year on a chronic basis, she probably has a 50 to 80 percent chance of having polycystic ovary syndrome based on that single observation.”⁶ Irregular, absent, or rare menstrual cycles are all common symptoms of PCOS. An estimated 85 percent of women with PCOS suffer menstrual irregularities.⁷ During the normal menstrual cycle, the human egg develops from the primordial follicle. It grows during the first half of the menstrual cycle and then is released into one of the fallopian tubes to be carried to the uterus, where it awaits fertilization by the sperm. Ovulation is the release of the egg from the ovary. Irregular menstrual cycles are caused by the failure of ovulation. In PCOS, the main menstrual problems are anovulation and oligo-ovulation. Anovulation means a complete lack of ovulation and oligo-ovulation refers to a lower-than-normal rate of ovulation.

Figure 2.1. Follicle development in a normal menstrual cycle

When normal ovulation does not occur, then menstrual cycles may be completely absent (amenorrhea) or may last longer than usual (oligomenorrhea). But even having a regular cycle does not mean that ovulation has occurred normally, especially in women with other evidence of hyperandrogenism. Twenty to 50 percent of women with signs of excess testosterone and regular periods still have evidence of anovulation. This lack of ovulation will result in difficulty conceiving and infertility. PCOS is associated with recurrent miscarriages, and it is the most common cause of infertility in industrialized nations.

When I was trying to conceive, I often bought over-the-counter ovulation prediction kits that use urine strips to test for luteinizing hormone (LH). This hormone spikes just before a woman ovulates and indicates that it’s baby-making time! During many of my infertile months, I noticed the same thing as many of my infertile patients do. Even when I had a menstrual cycle, whether it was regular or not (much longer than 28 days), I did not have an LH surge. In other words, I was not ovulating.

Polycystic ovaries

Follicles are collections of cells in the ovary. During a normal menstrual cycle, many follicles begin to develop and one eventually becomes the human egg that is released into the uterus at the time of ovulation. The other follicles usually shrivel up and are reabsorbed into the body. When these follicles fail to shrivel up, they become cystic and show up on an ultrasound as ovarian cysts.

The Rotterdam criteria define polycystic ovaries as being the presence of 12 or more follicles measuring 2 to 9 mm in diameter in each ovary. Two main factors influence the number of cysts. Small (2–5 mm) follicles are related to the serum androgen level and larger (6–9 mm) follicles are related to both serum testosterone and fasting insulin levels. Because 20 to 30 percent of otherwise normal women may have multiple cysts on their ovaries, the mere presence of cysts is not enough to make the diagnosis of PCOS. And there is no correlation between the number of cysts and the severity of PCOS.

WHEN WHAT LOOKS LIKE PCOS IS NOT

DESPITE THE REASONABLY clear diagnostic criteria for PCOS, certain populations present with symptoms that fit the Rotterdam criteria but do not necessarily indicate PCOS. Certain conditions, too, can look a lot like PCOS but have completely different causes and associated treatments.

Misdiagnosis in adolescents

Making the diagnosis of PCOS in adolescents is particularly tricky because irregular cycles, hyperandrogenism, and polycystic ovaries can all be found during normal puberty.

When girls first begin to menstruate (called menarche), their cycles are commonly irregular and may not always be accompanied by ovulation. In the United States, the median age of menarche is 12.4 years. The period of irregular cycles often lasts for two years or more, and the cycle intervals typically range from 21 to 45 days (average of 32.2 days). This average is quite close to the 35-day cycle that is defined as oligomenorrhea, or infrequent menstrual cycles in women of childbearing age.

Normal puberty and the irregular cycles seen in PCOS overlap significantly. To avoid overtreatment and unnecessary worry, clinicians should generally wait until the third year after menarche to confirm a diagnosis of PCOS in teens. By that time, 60 to 80 percent of girls have cycles that are 21 to 34 days long, which is typical of a normal adult cycle.

Blood testing of androgens in adolescents does not distinguish unusually high levels, because normal levels are not well defined in this age group. During puberty, there is a normal physiological increase in testosterone levels that peaks a few years after menarche. This increased testosterone leads, for example, to the familiar problem of acne during teenage years that improves or disappears in later adult years. The presence and the severity of this temporary increase in acne do not predict a later diagnosis of PCOS.

Polycystic ovaries, too, are difficult to diagnose during adolescence. In adult women, a transvaginal ultrasound, in which the ultrasound probe is inserted into the vagina, provides the clearest images of the ovary. However, this technique is usually avoided in adolescent girls, which makes the radiological diagnosis more difficult. In studies where ultrasounds were performed, 26 to 54 percent of asymptomatic adolescent girls had polycystic ovaries by imaging.⁸

Special care must be taken in labeling a patient with PCOS during their teen years, and it is often prudent to wait until after adolescence to make the diagnosis since it is not an urgent condition. If there is evidence of obesity or type 2 diabetes, these associated conditions should be treated earlier. Obesity is known to be associated with increased insulin levels, and this effect is magnified during early puberty. Fasting insulin is more than three times higher in the obese group. This effect is also seen during late puberty and adulthood, but not with such a marked difference. Testosterone levels are also likely to be higher in overweight adolescents. For example, in one study, 93.8 percent of obese preteens were found to have elevated testosterone levels versus 0 percent of the non-obese group.⁹

Differential diagnoses

Hyperandrogenism and polycystic ovaries are not exclusive to PCOS, so other diseases that mimic PCOS must be excluded by history or by physical or laboratory examination before the diagnosis can be confirmed. While most of these conditions are rare, they may be serious and require entirely different treatments, which makes the distinction important. The list of similar conditions includes

·pregnancy,

·hyperprolactinemia (prolactin excess),

·thyroid disorders,

·nonclassic congenital adrenal hyperplasia (NCAH),

·Cushing’s Syndrome, and

·hyperandrogenemia (androgen excess, tumor/drug-induced) Let us consider some of these other conditions.

» Pregnancy

Pregnancy is by far the most common cause of menstrual irregularity. Obviously, a simple pregnancy test, either a home test or laboratory confirmation, is mandatory before confirming the diagnosis of PCOS. It would be very embarrassing to miss this simple diagnosis.

» Hyperprolactinemia

Prolactin is a hormone normally secreted by the pituitary gland in the brain that enables mammals, including humans, to produce milk. Prolactin levels normally increase toward the end of pregnancy for proper breast development in preparation for breastfeeding. Excessive prolactin in the blood when a woman is not pregnant is known as hyperprolactinemia.

A wide range of conditions may lead to hyperprolactinemia, including chronic kidney or liver disease, drug use, and thyroid disease. Another common cause is a small tumor (microadenoma) of the pituitary gland, which may oversecrete prolactin into the blood. The diagnosis of hyperprolactinemia is made by measuring the blood level of prolactin.

High prolactin levels may mimic PCOS by inhibiting estrogen and causing menstrual irregularities and difficulty with ovulation. Symptoms that may help differentiate the disease include breast enlargement and abnormal milk production.

» Thyroid disorders

The thyroid is a small gland at the front of the neck. It secretes thyroid hormone, which controls many aspects of metabolism. Too little thyroid in the body may cause weight gain, menstrual irregularities, infertility, and hair loss that may be confused with PCOS. The diagnosis of thyroid disorders is made by measuring the blood levels of the thyroid hormones (TSH, T3, T4) to rule out this easily treated condition.

» Nonclassic congenital adrenal hyperplasia

Androgens are normally produced in both the ovaries and the surface (cortex) of the adrenal glands. In rare situations, the adrenal glands overproduce androgens, resulting in a syndrome called nonclassic congenital adrenal hyperplasia (NCAH), which is reminiscent of PCOS, with irregular menstruation, hirsutism, and acne. It is a rare genetic disorder that can affect young girls and women, and there is no commonly used diagnostic test for it.

» Cushing’s Syndrome

Prolonged exposure to high levels of the hormone cortisol causes Cushing’s Syndrome. In some cases, tumors oversecrete cortisol. In other cases, this syndrome can be caused by synthetic cortisol (prednisone), which is used to treat autoimmune diseases (asthma, lupus) and to suppress the immune system during organ transplants. Elevated cortisol levels can cause weight gain, menstrual irregularities, and infertility, which may be confused with PCOS. While prolonged periods of stress or athletic overtraining may increase cortisol, these circumstances almost never do so to the degree that’s necessary to develop Cushing’s Syndrome.

Cushing’s Syndrome presents with some characteristic symptoms that can help to distinguish it from PCOS. These include a pocket of fat that develops below the nape of the neck (a buffalo hump), stretch marks (striae), thinning skin, muscle weakness and atrophy, sensitivity to infections, decreases in bone density, and severe psychiatric and cognitive dysfunction. The diagnosis of high cortisol levels is made by taking a small blood sample.

» Hyperandrogenemia

Tumors in the adrenal glands or ovaries may oversecrete androgens causing hirsutism, clitoral enlargement, deepening of the voice, and male-pattern baldness. These tumors are extremely rare but potentially life-threatening. The average age of diagnosis is 23.4 years, which overlaps significantly with the age range for PCOS. Tumors typically produce far higher levels of androgen than are found in PCOS, leading to far more severe symptoms. The diagnosis of these tumors is usually made by looking at an image from a computerized tomography (CT) scan of the abdomen.

Drug-induced androgen excess is usually associated with those surreptitiously taking testosterone, mostly to enhance athletic performance. Because patients may not always admit to the use of these drugs, a high index of suspicion is necessary to make the diagnosis.

When I was diagnosed with PCOS, I checked the boxes for all three of the diagnostic criteria, even though only two out of three are necessary for the diagnosis. I had frank PCOS, the most severe phenotype, and I was devastated by this news. Today, I know there is a natural way to reverse even the worst PCOS. By understanding the underlying root cause of the syndrome, we can treat it rationally and successfully.