Polycystic Ovary Syndrome

Common and Misunderstood

Polycystic ovary syndrome affects at least 1 in 6 women struggling with infertility. Its effects are felt beyond fertility, from birth throughout a lifetime.

Polycystic ovary syndrome is really a misnamed medical condition. Our patients often comment that the name conjures ideas of large cysts on the ovaries raising concerns of big tumors, possible cancer and need for surgery. This couldn’t be further from reality. A better way to think of this condition is: a genetically based disorder of metabolism impairing the body’s ability to manage sugars, cholesterol and other chemistry that may impair the body in many ways, including a woman’s reproductive balance, function of the ovary, eggs and fertility potential.

There is a collective worldwide movement in the medical community to rename this condition in more appropriate terms, such as Metabolism and Ovary Dysfunction Syndrome.

How Does a Normal Ovary Work?

An ovary is a solid organ that contains eggs and other cells that make hormones such as estrogen, progesterone and testosterone. A cyst is a fluid filled sac lined by cells. A follicle is a special cyst within the ovary containing cells including an egg. So as you can see, an ovary normally contains cysts referred to as follicles. A fertile woman usually has about 5 to 10 resting follicles within each ovary at any given time. The resting follicles are very small. Each follicle measures about 6 mm in size. These follicles compete for dominance, and only one is the winner and will grow to about one inch (26 mm) before it ruptures and ovulates, releasing the egg. A new batch of follicles is activated to compete for dominance each month until menopause.

How Was the Term Polycystic Ovary Syndrome Chosen for This Condition of Ill Health?

The prefix ‘poly’ is derived from the Greek word ‘polus’ which means ‘many’. Ovaries containing an excessive number of small resting follicles might be described as ‘poly-follicle’ ovaries. Since follicles are special cysts, a more catchy term, ‘poly-cystic ovary’, was coined.

The History of Polycystic Ovary Syndrome

1935

Two American physicians, Irving Stein Sr. and Michael Levanthal, wrote a landmark medical journal article describing seven women having an abnormal condition excess body hair, and infrequent or absent menstrual periods. Only three of the seven women were described as overweight.  Initially, the condition was called ‘Stein-Levanthal Syndrome’. Due to the excess hair growth and discovery that male type hormones called androgens were present in the ovary, surgery was performed entering the abdomen to inspect the ovaries. They observed the ovaries were larger than normal, smooth and glistening on the surface, rather than having normal narrow small ridges, and thus appearing as though they were inflated. There were many very small clear fluid filled bead-like bumps scattered beneath the surface. They removed some of these bumps and looked at them under a microscope. They discovered each bump contained an egg and was in fact a follicle.

1950s -1960s

Ultrasound technology reveals more of the PCOS mystery.
Ultrasound technology emerged as a useful diagnostic tool to peer into the abdomen without performing surgery. The appearance of ultrasound images are on a gray scale from black, representing fluid-like substance such as water, to white, representing solid-like substance such as bone. Within an ovary, the solid portions are more in the center core and look gray, while small resting follicles reside on the outer perimeter of the ovary just beneath the surface, contain fluid, and appear black. You can imagine that in ovaries with excessive small follicles, they may appear as a strand of small, black circles often said to look like a string of (black) pearls lining the perimeter of the ovary. I prefer to view the ovaries as chocolate chip cookies with follicles being the chocolate chips. The term ‘Polycystic Ovaries’ came into vogue during this era based on this ultrasound appearance.

Through basic science animal research, it was discovered that the solid tissue in the ovary was the source of male type hormones, androgens. In an effort to reduce excessive hair growth in areas of a woman’s body where usually only observed in men, surgery to remove some of the solid portion of the ovaries was performed. This is called a ‘Wedge Resection’ of the ovary. This treatment would often result in temporary resumption of more regular menstrual cycles, ovulation and improved fertility, but was less effective in reducing the excess hair growth. A deeper understanding of the hormone disorder causing PCOS would have to wait until the 1970s.

1970s

Directly measuring blood hormone levels comes of age.
In the early 1970s, a technology called ‘radioimmunoassay’ (RIA) was refined, making it possible to directly measure key hormone levels in the bloodstream that effect the reproductive system by obtaining a simple blood sample. These hormones are substances that travel through the blood stream providing signals between the brain, ovary and uterus that command and influence their function as well as the function of other tissues in the body.

Brain

• Follicle Stimulating Hormone (FSH)
• Luteinizing Hormone (LH)
• Prolactin
• Thyroid Stimulating Hormone (TSH)

Ovary

• Estradiol (E2)
• Progesterone (P4)
• Testosterone

Another source of male type hormones called androgens is the adrenal gland located on top of each kidney. Genetic abnormalities can cause the adrenal gland to go ‘rogue’ and produce an excess of androgen hormone, a root cause of polycystic ovary syndrome.

Adrenal Gland

• 17-Hydroxyprogesterone (17-OHP)
• Dehydroepiandrosterone Sulfate (DHEAS)

The RIA technology provided us with a new lens through which we could see deeper into the process and cause of polycystic ovary syndrome. Research with the RIA tool enabled us to learn and appreciate the normal patterns of human hormone release with interplay like the sound of beautiful symphonic music. Comparing normal hormone patterns to hormone patterns of women with PCOS launched our appreciation for orchestral instruments playing unique, erratic, abnormal dissonant sounds of PCOS.

In the 1970’s, obesity was thought to be a key diagnostic feature in the profile of women having PCOS. Therefore, only obese women were tested to develop the hormone profiles that defined the disorder in that era. We now know that obesity may affect over 50% of women with PCOS, but it is by no means necessary women be obese to have PCOS. Recall that Stein and Levanthal’s 1935 article described only three of the seven women  presented overweight.  Thus, the hormone profiles of the 1970s actually apply only to a limited proportion of women having PCOS: those who were overweight.

We now know the blood hormone profiles listed below, defining PCOS in the 1970s and 1980s, need not be present to make the diagnosis:

• Blood LH to FSH hormone level ratio of 3:1
• Excess blood testosterone hormone level

1980s

The insulin resistance story is discovered.
We all recognized that obesity is related to problems controlling our blood sugar levels leading to abnormally low blood sugar known as ‘hypoglycemia’ and abnormally high blood sugar known as ‘hyperglycemia’, better known as ‘Diabetes Mellitus’. Later age onset of diabetes mellitus, often worsened by obesity, is known as ‘type 2’ diabetes mellitus.

Let’s look at the nuts and bolts of sugar metabolism as it relates to diabetes mellitus. Food can be divided into three main categories based on its content: carbohydrates, proteins and fats. Carbohydrates include starchy foods such as potatoes, breads, pasta, rice and pure sugar. Once eaten, carbohydrates are absorbed into the blood stream through the surface of our mouth and small intestines. The carbohydrates are converted to a usable sugar known as ‘glucose’. The pancreas is an organ in the abdomen that maintains normal blood sugar levels. Special cells in the pancreas respond to the rise in blood sugar level by releasing insulin. Insulin is a hormone that travels through the bloodstream, picks up the glucose, and actively carries the glucose out of the blood stream through special gates and into our body tissues such as the liver, muscle and brain to be used as energy immediately or stored for future energy needs. Here’s the glitch. Caused by a root program error in genetics, some of us have gates that are vulnerable to having rusty hinges making them hard to open and close. This creates ‘resistance’ to the function of insulin intended to carry glucose out of the blood stream. Insulin resistance results in a tendency for excess levels of glucose to accumulate in the blood and a genetically created vulnerability or risk of developing diabetes in our lifetime. The gates may rust out over time as we age and may also rust out more quickly if there is an increase in the proportion of our body composition made of  fat cells- obesity. The pancreas will compensate and release extra insulin in order to control blood sugar levels. If the gates rust out too much, then even the extra insulin is not enough to keep blood sugars down resulting in diabetes mellitus. This is the connection between obesity and type 2 diabetes mellitus.

The excess insulin released in the bloodstream, called ‘hyper-insulinemia’, has unintended consequences.

• It stimulates the skin to become thicker and darker, particularly at our natural skin folds on the neck, arm pits, groin and breast line. This darkening and thickening of skin is called ‘acanthosis nigracans’- a sign of abnormally elevated insulin levels due to insulin resistance.
• It stimulates cells in the solid part of the ovary to produce excess testosterone, thereby promoting ovulation dysfunction and polycystic ovary syndrome.

In 1982, the ‘Eureka!’ moment came. Young obese women known to have PCOS were developing type 2 diabetes mellitus, for example, by 30 years of age. At that time, it was presumed their obesity was the cause of diabetes as explained above.

Their treatment included three main parts:

• Low carbohydrate/high protein diet
• Exercise
• Metformin

The diet and exercise optimize use of efficient fuel for the body. Metformin lubricates the rusty gates enabling insulin to work more effectively. That’s why metformin is often termed an ‘insulin sensitizer’. It doesn’t promote release of extra insulin to push harder against the rusty gates, it oils the gates so the insulin already produced can pass glucose through them easier. Metformin also assists the body in managing glucose storage and release from the liver more efficiently. This allows for better overall blood glucose control, avoiding the hills and valleys of blood sugar levels.

As women with PCOS and type 2 diabetes mellitus were treated with diet, exercise and metformin, they were losing weight and feeling more energetic, but something unexpected happened: some started having very regular menstrual cycles, began ovulating and when intending, became pregnant! This was observed in about 1 of 5 women, not everyone. It was a clue… a big clue: the connection between insulin resistance and reproduction. Further studies in the 1980’s and 1990’s demonstrated consistent health benefit of diet, exercise and metformin. The genetic vulnerability to insulin resistance induced diabetes mellitus was discovered to be related to lipid metabolism, cardiovascular disease and is now known as ‘metabolic syndrome’.

We now know that women with PCOS inherently have a vulnerability to insulin resistance and metabolic syndrome irrespective of obesity. By the year 2000, studies showed low carbohydrate/high protein diet, exercise and metformin benefit to fertility not only for obese women, but also for women of normal weight and body composition.

1990s

Redefining Polycystic Ovary Syndrome.
By 1990, the collective medical community recognized that PCOS was not a disorder limited to women who were overweight or had hormone profiles as defined in the 1970s. In 1990, a consensus workshop of medical experts sponsored by the National Institutes of Health/National Institute of Childhood Diseases (NIH/NICHD) suggested that a person has PCOS if she has all of the following:

• Prolonged menstrual cycle intervals (35 days or greater interval) described as infrequent ovulation known as ‘oligo-ovulation’.
• Signs of androgen excess (physical signs or blood chemistry).
  1. Physical signs
     1. Excess hair growth known as ‘hirsutism’,
     2. Acne on face, chest or back,
     3. Enlarged clitoris, muscle mass and deepening of voice known as ‘virilization’.
  2. Blood chemistry- abnormally elevated testosterone level. The ovary is the major source of testosterone androgen hormone.
• Exclusion of other disorders that can result in menstrual irregularity and androgen hormone excess.
  1. Thyroid gland disorders, (TSH hormone screening test),
  2. Abnormally elevated blood prolactin levels,
  3. Adrenal gland disorders (abnormally elevated 17-OHP, DHEAS).

2000s to Present Time

Further refinement in understanding of PCOS: diagnosis, causes, and vigilance from birth though a lifetime.
In 2003, the collective medical community recognized that some women with PCOS managed a very healthy lifestyle and lacked the more obvious signs and symptoms defined in the 1990 consensus workshop. The more ‘stealth’ presentation of PCOS would manifest itself through weight gain, dietary changes, infertility, pregnancy and aging. Therefore in 2003 a follow up international consensus workshop convened, sponsored by the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM)  in Rotterdam, Netherlands.

The criteria to diagnose PCOS were modified to better account for women with a more subtle presentation of PCOS. PCOS is present if any 2 out of 3 criteria are met in the absence of other disorders that might cause these findings:

Any 2 out of 3 Inclusive findings:

• Oligo-ovulation (see definition above) or complete absence of ovulation known as ‘anovulation’,
• Excess androgen activity (physical signs or blood chemistry),
• Pelvic ultrasound evidence of polycystic ovaries (new addition from 1990).

Exclusion of other disorders that may cause these findings:

• Thyroid gland disorders, (TSH hormone screening test),
• Abnormally elevated blood prolactin levels,
• Adrenal gland disorders, (17-OHP, DHEAS).

Luteal Phase Deficiency- Demystified!

In the 1970s, the concept of ‘luteal phase deficiency’ was introduced, and we now understand that it does not exist as a separate disorder. Rather, it is likely a more subtle presentation of hormone imbalances, including polycystic ovary syndrome. Here is the reasoning from the 1970s through the 1990s. The luteal phase of a menstrual cycle is the second half of a 28-day menstrual cycle: after ovulation has occurred and the remnant follicle known as a ‘corpus luteum’ produces progesterone under the direction of luteinizing hormone released from the brain. Progesterone prepares the uterine lining known as the ‘endometrium’ to be receptive to an embryo implanting and growing into a fully developed newborn infant. The luteal phase should be about 10 to 14 days- the time between ovulation and the first day of the following menstrual flow. A luteal phase deficiency was confirmed if the luteal phase time was abnormally short, or blood progesterone level was abnormally low or an endometrial tissue sampling known as a ‘biopsy’ taken about a week after ovulation showed a delay in maturity compared to the time of the menstrual cycle. It was thought that a luteal phase deficiency could be the cause of infertility, either impairing the ability to become pregnant or increasing the risk of miscarriage early in pregnancy.

What Do We Now Know?

• Blood progesterone levels rise and fall every 90 minutes. Such variation has led to a consensus that a progesterone value of at least 2 ng/ml is sufficient to confirm ovulation has occurred with few exceptions. Although the urban legend is often quoted that 10 ng/ml is the minimal progesterone level to confirm ovulation, this is not supported in fact within the world medical literature.
• Endometrial biopsy to assess for luteal phase defect cannot distinguish between fertile and infertile women. This procedure and test has been abandoned and is no longer part of mainstream medical practice for fertility assessment.
• Abnormally short luteal phase, less than 10 days, is more likely due to PCOS or other hormonal imbalances.
• Bottom Line: Luteal phase deficiency is now considered in the same category as a fever: it is a sign of a problem, but not a problem as an independent disease.

In Conclusion:

• Metabolic syndrome is an epidemic in the United States.
• PCOS is an expression of metabolic syndrome that includes the families of genes that contribute to type 2 diabetes mellitus and cardiovascular disease, including hypertension and lipid disorders. Women with PCOS are at risk for these disorders in their lifetime and during pregnancy as gestational diabetes and pre-eclampsia. To reduce these risks, low carbohydrate diet and exercise are essential. Use of metformin may be considered depending on desire for fertility or the manifestations of metabolic syndrome.
• Women and men carry the genes that cause metabolic syndrome. It turns out that a woman’s reproductive system, with its cyclic variation in timing for proper fertility, is more vulnerable to the effects of metabolic syndrome than a man’s reproductive system.
• How well a woman maintains good diet, weight and metabolism during pregnancy will have an effect on her unborn child known as ‘imprinting’ by way of ‘epigenetics’. The environment in which the fetus develops including the food you eat will have an impact on your child’s risks for obesity, sugar metabolism disorders, lipid metabolism disorders starting in childhood throughout their lives. Just as cigarette smoking and alcohol consumption during pregnancy can have an impact on the baby, so too excess carbohydrate diet, poorly controlled metabolic syndrome and obesity during pregnancy can have adverse effects.

There is good hope to live a full and fertile life with polycystic ovary syndrome. Understanding the cause and how it can affect one’s health empowers us to enact a smart and successful treatment strategy.

Call 248-593-6990 or make an appointment with one of MRM’s expert physicians to learn more about PCOS and how you can take control of your reproductive health and your overall health for a lifetime!