Defining polycystic ovary syndrome with an integrative lens

Photo Cred: Imani Clovis/Unsplash

By Gary Goldman

Over the years, I’ve had several patients come to me with polycystic ovary syndrome (PCOS). Some have seen several prior practitioners who have not been able to help her, much less explain the lost periods, excess hair growth, acne, and weight gain.

PCOS is a common and complex condition found in 8 to 13 percent of women. The condition is characterized by menstrual irregularities, infertility secondary to anovulation, virilization, metabolic syndrome, and obesity.

There is substantial variability in the severity of symptoms among affected individuals. Common presenting symptoms include menses that are irregular, infrequent, or even absent. This is caused by irregular or absent ovulation, which in turn can impair the ability to achieve a pregnancy.

Masculinizing changes in skin and hair are common. Known as virilization or hirsutism, the changes in underlying hormone production of androgens can cause acne, oily skin, and coarse hair growth in areas typically found in men. Some women will experience crown hair loss, or alopecia. Other skin changes indicative of associated insulin resistance are acanthosis nigrans, a darkly pigmented velvety skin around the neck, as well as numerous skin tags around the neck and under arms.  

Women with PCOS often have some or all the features of metabolic syndrome, which substantially increases the risk of cardiovascular disease. These include:

• Increased visceral adiposity, characterized by fat deposition predominantly in the waist
• Elevated triglycerides
• Lowered HDL cholesterol
• Elevated blood pressure
• Pre-diabetes or diabetes

The diagnostic criteria for PCOS have changed over time, but it has always been a diagnosis of exclusion; once other sources of pathology have been ruled out, we then consider PCOS. A 1990 National Institute of Health consensus paper required the presence of both chronic anovulation, and clinical or biochemical signs of increased androgens. 

The Rotterdam criteria are used far more commonly to diagnose PCOS. Proposed in 2003, they require irregular or absent ovulation, clinical, or biochemical signs of hyperandrogenism, and sonographic evidence of polycystic ovaries; two of the three criteria are needed.  The presence of PCOS type ovaries without concurrent ovulatory dysfunction or androgen excess is insufficient to make the diagnosis of PCOS.

The Rotterdam sonographic criteria consist of the presence of 12 or more follicles within each ovary, each with a diameter of two to nine millimeters, or an ovarian volume of 10 cubic centimeters or greater. Subsequent authors have suggested more stringent criteria of up to at least 26 follicles. Adolescents normally have many follicles; thus, sonography may not be used in establishing their diagnosis.

Due the wide variety in clinical presentation, four main phenotypes of PCOS have been described. Type 1 is the classic presentation, which includes hyperandrogenism, chronic anovulation and polycystic ovaries on sonogram. This is the most common sub-type and accounts for 70 percent of women with PCOS. Type 2 includes hyperandrogenism and chronic anovulation but does not have polycystic ovaries. Type 3 has hyperandrogenism and polycystic ovaries, though no anovulation. Type 4 includes chronic anovulation and polycystic ovaries but lacks evidence of hyperandrogenism.

Long-term sequela of PCOS can be multisystem and problematic. Obesity and metabolic syndrome substantially raise the risk of cardiovascular disease, adult-onset type II diabetes, sleep disordered breathing or obstructive sleep apnea, and liver injury in the form of nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD). Chronic anovulation, increased inflammation, and adiposity increase the risk of endometrial cancer by two- to six-fold. For those women who successful achieve a pregnancy, they are at an increased risk of pre-term delivery, pre-eclampsia and gestational diabetes. Depression is another common associated ailment.

Diagnostic lab studies should begin with thyroid stimulating hormone, prolactin, and early 17-hydroxy-progesterone to exclude disorders with similar phenotypic presentations.

The ovary is the main driver of hyperandrogenism in PCOS via thecal cell hyperplasia. Increased ovarian androgens can be reflected in elevations of testosterone via measurements of total, free or bioavailable levels. Liquid chromatography, mass spectrometry (LCMS), or extraction or chromatography immunoassays are the most accurate ways to measure total or free testosterone. Elevations in adrenal androgens can be found by evaluating DHEAS, as well as its precursor androstenedione. Sex hormone binding globulin (SHBG) levels should also be measured as this modifies the biologic activity of circulating androgens.

Anovulation can be confirmed by checking for progesterone levels that remain consistently low. Alternatively, this can be evaluated with static basal body temperatures. Erratic cycles should be followed with a menstrual diary.

Follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels are sometimes altered. Women with PCOS can make an insufficient amount of FSH in the granulosa cell and have a normal to high normal amount of LH, which is made in the theca cell. This can produce an increased LH to FSH ratio of greater than three when measured on day three of an ovulatory cycle. Elevated LH levels can give a false positive home urine ovulation test. These tests are designed to turn positive at a certain level indicative of the LH surge seen in normal ovulatory women, a level exceeded chronically without ovulation in some women with PCOS.

Anti-Mullerian hormone (AMH) is often elevated in women with PCOS. This compound is made by the granulosa cell and is overexpressed by the multitude of small follicles in arrested development through negative action of aromatase expression and FSH action.

The propensity toward metabolic syndrome should be evaluated in several ways. Fasting insulin and fasting glucose should be measured. The Homeostatic Index (HOMA) can be calculated from these values to estimate insulin sensitivity. A Hemoglobin A1c will provide information on long-term sugar control, while a Fructosamine level will reflect shorter term glucose control. A two-hour oral glucose tolerance test with a 75-gram glucose challenge can also be considered.

Serum lipids should be carefully monitored, including at a minimum fasting cholesterol, HDL, LDL, and triglycerides. As metabolic syndrome is a highly inflammatory state, elevated hs-CRP levels can be used to follow systemic inflammation, along with lowered high-molecular-weight adiponectin. Not usually obtained in a clinical setting, other inflammatory mediators are occasionally evaluated, including the cytokines IL-6, IL-8 and TNF.

A 2017 study found that prostate specific antigen (PSA) was highly correlated with PCOS. Both free and complex PSA were found to be useful predictors of PCOS.

In addition to lab studies, a good physical exam remains essential. In particular, the exam should note blood pressure, weight, body mass index (BMI), waist and hip circumferences, as well as the waist to hip ratio, and evaluation for hirsutism, which can be documented with the Ferriman-Gallaway score (abnormal is greater than six).

The etiology of PCOS remains enigmatic. It appears that almost any insult can contribute to the condition. A major insult is poor lifestyle, especially a lack of exercise, increased weight, and a highly inflammatory, high carbohydrate diet. This promotes increased insulin production and leads to insulin resistance. Increased circulating insulin is also associated with progressive oxidative stress and free radical production causing widespread DNA and cellular damage.

Family history is another contributor. Various genetic alterations in the form of single nucleotide polymorphisms (SNPs) have been reported, specific to particular populations. These SNPs can cause metabolic derangements in 3-beta- and 17-beta-hydroxysteroid dehydrogenase, which results in elevated androstenedione and testosterone production. Metabolic derangements of 17-hydroxylase and 17,20-lyase, induced by cytochrome P450c17 (CYP17) and encoded by CYP17A1, have also been reported.

When a woman with PCOS who is hyperandrogenic becomes pregnant, she may have increased levels of circulating androgens during crucial times of fetal development. Female offspring exposed to increased levels of excess maternal testosterone have a substantially increased risk of developing PCOS upon menarche.

Recently several researchers have proposed the origin of PCOS lies in neuroendocrine alterations, especially a decrease in GABA production. Increased GnRH pulse frequency in the hypothalamus, yielding an increase in LH secretion, has also been reported.

Other metabolic derangements may also contribute. Reduced hepatic production of SHBG, causing increased circulating physiologically active androgens. Vitamin D deficiency appears to be a potentially reversible contributor to PCOS. Altered microbiome with preponderance of pathologic flora has been reported in PCOS patients, raising the question if probiotic supplementation can help to restore a healthy metabolism. Autoimmune adrenal insufficiency may also be a cause, especially in lean PCOS patients with low adrenal androgens and cortisol, high AMH, and concurrent autoimmune diseases.

Lastly, a variety of toxins have been reported to produce a PCOS phenotype in animal models, including Bisphenol A, which inhibits aromatase in granulosa cells and can produce a hyperandrogenic state.

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Therapy for PCOS should be tailored to each patient’s concerns and goals. It should encompass all the metabolic issues that have been identified, seeking to improve the patient’s symptoms as well as address the potential long-term consequences of metabolic dysregulation.

The first step is evaluation by history, examination and lab evaluations. Exclude other reasons for hyperandrogenism such as excessively high ovarian or adrenal hormone levels that might indicate a hormone-secreting tumor, elevated prolactin, abnormal thyroid hormone levels, or elevations in 17-hydroxy-progesterone that might indicate adult-onset congenital adrenal hyperplasia.

Traditional first-line therapy is the oral contraceptive pill (OCP). OCPs increase SHBG, which binds free testosterone rending it physiologically inactive. They also reduce LH secretion, lowering the production of testosterone. No OCP has been demonstrated to have an advantage over others to treat hyperandrogenism. I usually recommend one with the least androgenic progestin, though this is of debatable biologic efficacy; higher levels of estrogen produce higher levels of SHBG.

Insulin-sensitizing agents result in lower insulin levels, lower oxidative stress, and decreased androgen production. Other benefits include improved glucose regulation and improved ovulation, thus attention to contraception is important. Doses range from 500 to 2,000 milligrams per day. Dosing should start low and go up slowly to avoid diarrhea. Rare concerns include lactic acidosis, hypoglycemia, and hyperkalemia.

Anti-androgens act primarily by blocking the ability of testosterone to bind to peripheral androgen receptors in the skin. Secondarily they also block ovarian and adrenal steroidogenesis via inhibition of 5-alpha-reductase, which is responsible for converting testosterone to the more potent androgen dihydrotestosterone (DHT). The usual dose ranges from 25 to 100 milligrams twice daily.

The value of lifestyle modifications cannot be overestimated. Multiple studies have demonstrated the wide-ranging benefits of weight loss, improved diet, and increased exercise in women with PCOS who are overweight. The most effective diet for PCOS is a low glycemic index, low carbohydrate, high fiber, high vegetable diet. Enlisting a nutritionist, an exercise trainer, or a health coach can provide the emotional support and expert instruction necessary to produce a sustained change in lifestyle. Improved metabolism specifically addresses the underlying biochemical dysregulation responsible for PCOS and its sequela.

Alternative therapies to hyperandrogenism center around compounds that increase sex hormone binding globulin, decrease androgen production, increase degradation of sex hormones, increase conversion of testosterone to estradiol, inhibit conversion of testosterone to DHT, lower oxidative stress, correct neuroendocrine and vitamin deficiencies, improve insulin sensitivity, and augment weight loss.

A functional approach to PCOS must start with a complete review of the person, her overall health and medical history. Pay attention to the potential contribution of thyroid and adrenal dysfunction. Adrenal overstimulation from chronic stress causes an outpouring of cortisol and DHEA, which can augment PCOS.

In addition to the testing discussed above, I recommend testing for TSH, T3, T4, rT3, antithyroid antibodies, DHEA, and 4-sample salivary cortisol. A complete metabolic profile with full lipid analysis is vital, along with Vitamin D levels. I often use a deeper analysis of sex hormone metabolism with the Dutch Complete test. Additional testing is performed per the clinical circumstances. Armed with these results we can recommend the following remedies:

Increase SHBG:

• Lower insulin via weight loss, proper diet, and exercise
• Resveratrol
• Coffee
• Metformin
• D-chiro-inositol
• Spironolactone
• Stinging nettle root
• Saw palmetto
• Pygeum
• Phytoestrogens, e.g. flaxseeds, soy, alfalfa sprouts
• Walnuts, almonds
• Reverse inflammation at its source, once identified
• Additional anti-inflammatories, e.g. curcumin, berberine
• Probiotics containing Lactobacillus and Bifidobacterium species

Decrease androgen production:

• Melatonin at 2 milligrams nightly decreases androgens, increases FSH and decreases AMH. It regulates steroidogenesis, folliculogenesis, and oocyte maturation. It also serves as an antioxidant.
• Phytoestrogens
• Peppermint tea; Spearmint tea or essential oils
• Licorice (glycyrrhizic acid)
• Chinese peony (Paeonia lactiflora)
• Isoflavanoids
• Metformin
• Myo-inositol 4 grams daily
• Berberine
• Vitamin D if deficient
• Probiotics containing Lactobacillus and Bifidobacterium species
• Green tea
• Decanoic acid from palm or coconut oil

Increase degradation of sex hormones

• DIM
• Indole-3-carbinol
• O3FO
• SAMe
• Methylated B12/Folate
• NAC/Glutathione

Increase conversion of testosterone to estradiol by induction of aromatase

• Red wine
• Resveratrol
• Green tea

Inhibit conversion of testosterone to dihydrotestosterone

• Green tea
• Pygeum
• Saw palmetto
• Stinging nettle root

Lower oxidative stress and inflammation

• Vitamins C, D, A
• NAC, glutathione
• Melatonin
• Quercetin
• Curcumin
• O3FO
• Probiotics containing Lactobacillus and Bifidobacterium species
• Avoid gluten, sugar and dairy

Correct neuroendocrine and vitamin deficiencies

• GABA supplements
• Valerian root
• Glutamine
• Passiflora
• L-theanine
• Vitamin D if deficient
• Zinc if deficient

Improve insulin sensitivity

• Weight loss, exercise, healthy diet
• Metformin
• Berberine
• Quercetin
• Cinnamon (cinnamomum verum)
• Myo-inositol
• Chromium
• Vitamin D if deficient
• Probiotics containing Lactobacillus and Bifidobacterium species
• Decanoic acid from coconut or palm oil

Augment weight loss

• Metformin
• Berberine
• Quercetin
• ALA 400 milligrams daily
• Tribulus terrestris

References

American College of Obstetricians and Gynecologists (2018). Polycystic Ovary Syndrome. Practice Bulletin Number 194.

Azziz, R., Carmina, E., and Dewailly, D. (2009) Task Force on the Phenotype of the Polycystic Ovary Syndrome of the Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertility and Sterility.

Crespo, P., Bachega, A., Mendonça, B., and Gomes, G. (2018). An update of genetic basis of PCOS pathogenesis. Archives of Endocrinology and Metabolism.

Dadachanji, R.Shaikh, N. and Mukherjee, S.. (2018). Genetic Variants Associated with Hyperandrogenemia in PCOS Pathophysiology. Genetics Research International.

Legro, R., Arslanian, S., Ehrmann, D., Hoeger, K., Murad, M., and Pasquali, R. (2013) Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism.

Rosenfield, R. and Ehrmann, D. (2016) The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited, Endocrine Reviews.

Rotterdam, E. (2003) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Fertility and Sterility.

Tabrizi, R. (2019) The Effects of Probiotic Supplementation on Clinical Symptom, Weight Loss, Glycemic Control, Lipid and Hormonal Profiles, Biomarkers of Inflammation, and Oxidative Stress in Women with Polycystic Ovary Syndrome: a Systematic Review and Meta-analysis of Randomized Controlled Trials. Probiotics and Antimicrobial Proteins. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/31165401

Teede, H., Misso, M., Costello, M., Dokras, A., Laven, J., Moran, L. Piltonen, T., and Norman, R. (2018) Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome, Human Reproduction.

Zawadsky J. and Dunaif, A. (1992) Diagnostic criteria for polycystic ovary syndrome. Blackwell Scientific.