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Polycystic Ovary Syndrome

An overview of the diagnosis, evaluation and treatment

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Approximately 6% to10% of women in the United States are affected by polycystic ovarian syndrome (PCOS) starting as early as age 11.1

PCOS is an endocrine disorder that predominantly affects women of reproductive age and is the result of a hormone imbalance. The major hormones involved in PCOS include estrogen, progesterone and androgen. Androgen, a male hormone, is produced in higher abundance in patients with PCOS, causing irregularities in the menstrual cycle, formation of ovarian cysts and high rates of infertility.

Women with PCOS also tend to experience obesity, hirsutism, alopecia, acne and hyperpigmented skin, and are at increased risk for developing diabetes, metabolic syndrome, heart disease and hypertension.2

Defining PCOS
In 1973, the World Health Organization provided the first biological definition of PCOS as a group 2 ovulatory dysfunction or anovulation.

Since this classification, the NIH, Rotterdam and Androgen Excess Society (AES) have published various inclusion criteria for PCOS (Table 1). The NIH considered hyperandrogenism and anovulation as the inclusion criteria for PCOS.

Rotterdam added ovarian morphology as a third inclusion criterion, whereas AES defined PCOS as hyperandrogenism and ovulatory dysfunction. Due to the differences in these inclusion criteria, there are various studies and research about risk stratifications and comorbidities related to PCOS.2,3

Pathophysiology of PCOS
Three key steps occur in the development of PCOS.

First is pituitary dysfunction, which causes an increase in GnRH pulse resulting in high levels of LH. An increased level of LH is a leading indicator of PCOS. The LH/FSH ratio, which is normally 1:1 in premenopausal women, is greater than 2 or 3 times the normal limit in obese women with PCOS.

SEE ALSO: Polycystic Ovarian Syndrome

Second is the effect of increased LH levels on ovarian thecal cells, which causes excess production of androgen in the ovaries. Lastly, patients with PCOS have increased insulin resistance due to a genetic coding defect for phosphorylation of its receptors.

A variety of other symptoms and conditions can be present in women with PCOS; thus the diagnosis largely made clinically. 1

Risk Factors
PCOS is a heritable disorder and is more prevalent among first-degree relatives. A higher incidence of PCOS occurs in monozygotic twins versus dizygotic twins, likely indicating a genetic component in its development.

According to Sirmans and Pate, the condition can be linked to chromosome 2 near the LHCGR and chromosome 9 near the obesity gene DEEND1A. However, the precise mechanism through which PCOS is inherited is still unknown.3

Insulin resistance plays a major role in PCOS. As a result, PCOS and diabetes are highly correlated. Both diabetes types 1 and 2, as well as gestational diabetes, increase the risk of PCOS.

In a study of 85 white women with type 1 diabetes, Escobar-Morreale et al found that 16 had PCOS (18.8%) based on the NIH/NICHD criteria. In a study by Codner et al, 42 women with type 1 diabetes were screened and 40.5% were found to have PCOS using the ESHRE/ASRM criteria. Eight-two percent of the women with type 2 diabetes had PCOS. 3

Weight gain is another risk factor for PCOS development. Patients often present to their providers complaining of weight gain along with other symptoms of PCOS. In addition, studies have shown that diet- and exercise-induced weight reduction can lead to a decrease in testosterone, causing a decrease in hirsutism and an increase in insulin sensitivity. By losing excess weight, patients are significantly less susceptible to the common symptoms of PCOS. 3

Epilepsy is also considered a risk factor for PCOS. Bilo et al based their research on the NIH criteria and found that 13 of 50 women who were screened with epilepsy also had PCOS (26%). These patients exhibited signs and symptoms of PCOS prior to treatment of epilepsy, establishing that the development of PCOS was independent of the treatment for epilepsy. 3

Clinical Presentation
Hyperandrogenicity is one of the more prevalent symptoms of PCOS; it affects the skin and hair, and thus many patients with PCOS present to dermatology with complaints of acne, hirsutism, alopecia, acanthosis nigricans and/or skin tags.

These women are often overweight and may report a history of irregular menses. It is not always the case that a patient will present with all of the manifestations of this disorder at once, so it is the job of the clinician to be aware that any pairing of these symptoms could be an indication of PCOS.2

The acne typically found in patients with PCOS is unlike other types of acne. It is mostly unresponsive to regular treatment or reoccurs soon after treatment. This prompt relapse of symptoms is another indicator of PCOS, and these patients often require extremely potent acne medications such as isotretinoin and/or hormonal therapy. 2

Patients can present with female pattern hair loss (FPHL); early onset of FPHL can indicate PCOS as an underlying cause. The patient's hair develops a vellus quality, making it appear that she is balding. On the other hand, hirsutism, or the excess growth of facial hair, may also occur in patients with PCOS. Hyperandrogenicity increases the growth rate, diameter and melanization of hair in androgen-sensitive areas, including the face. The pairing of both FPHL and excessive facial hair should trigger a high suspicion for PCOS.2

Hirsutism has a higher prevalence in PCOS than acne: Approximately 70% of women with PCOS present with hirsutism, while only 15% to 30% present with acne. The difference in the prevalence of these two presenting features is due to difference in expression of 5-alpha-reductase in the sebaceous gland and the hair follicle. For this reason, it is much more likely for a patient to present with excess facial hair rather than unresponsive acne.2

Acanthosis nigricans has a strong association with PCOS and typically presents as thickened, hyperpigmented skin of the neck, axillae, groin and other intertriginous areas. Skin tags can occasionally develop in these hyperpigmented areas as well. Acanthosis nigricans is caused by the stimulation of tyrosine kinase growth factor by insulin, and can be a sign of prediabetes, one of the complications of PCOS. Obese patients often present with thickened interiginous skin, which should raise concern for type 2 diabetes as well as PCOS. 2

Diagnosis & Evaluation
PCOS is considered a diagnosis of exclusion, and when untreated it is associated with multiple life-threatening comorbidities.

When making the diagnosis, it is important to rule out other androgen-excess disorders such as idiopathic hyperandrogenism or hirsutism, adrenal hyperplasia, Cushing syndrome, androgen-secreting tumor, tumors of the pituitary gland and thyroid disorders.

The medical provider should obtain a thorough history from the patient, including information about menstrual cycle, changes in weight, history of infertility, and signs and symptoms of hyperandrogenism.2,3

A full physical exam should follow, including evaluation of BMI, waist size and hair pattern. A pelvic exam is needed to check for enlarged ovaries due to cyst formation. The laboratory and diagnostic tests that need to be obtained following the pelvic exam are estrogen, FSH, LH, free testosterone, 17-ketosteroids, fasting blood glucose, thyroid function, prolactin level and a trans-vaginal ultrasound. 3 Early detection and treatment of comorbidities including dyslipidemia, hypertension and mental health disorders are essential to reduce mortality.

Hormonal evaluation should be performed on the fourteenth day, which is considered to be the pre-ovulatory phase of the menstrual cycle. However, since many patients with PCOS have ovulatory dysfunction with irregular menstrual cycles, the best time frame for examination is the second to fourth day after the onset of menses.

In patients unaffected by PCOS, the FSH level is found to be three to four times greater than LH at that time. In patients with PCOS, the opposite is seen: LH levels are two times greater than FSH levels, which is a sign of pituitary imbalance. When evaluating testosterone level, a rise that is three times the normal range usually suggests ovarian or adrenal neoplasm. These findings necessitate further evaluation with trans-vaginal ultrasound to exclude an ovarian neoplasm.4

After exclusion of other possible diagnoses, one must consider the inclusion criteria for the diagnosis of PCOS. A transvaginal ultrasound can be used to measure the number of follicles and ovarian volume with relatively good sensitivity and specificity. The difference in classification as defined by three organizations is shown in Table 1.2,3,7

Treatment Options
There is no single or definitive cure for PCOS Treatment is currently aimed at reducing hirsutism and hyperandrogenism, managing endocrine/metabolic imbalances and regulating menstruation in women of childbearing age who wish to have children.

Patients often require multiple pharmacologic and occasionally some nonpharmacologic treatments to combat the various conditions that can present concurrently in PCOS. Treatment is typically aimed either at infertility/anovulation or at reducing symptoms such as hyperandrogenism, hirsutism, obesity, menstrual disorders, etc.2,4,8,9  Table 2 lists pharmacologic treatment options, its mechanism of action (MOA) and common side effects.

Table 3 summarizes the most commonly used treatments according to the conditions they target most effectively.

Obesity & Insulin Desensitization: According to American College of Obstetricians and Gynecologists (ACOG), the gold standard in treating obesity and insulin-desensitization is lifestyle modifications, including weight loss, diet and exercise.

These modifications also help decrease the risk of PCOS comorbidities such as hypertension. Physical activity has been strongly linked with symptom and comorbidity improvement, since it helps increase weight loss, improves sensitivity to insulin, increases menstrual frequency and stimulates ovulation.5,8,13

Metformin and abdominal acupuncture are two other treatments used to combat obesity. Metformin improves insulin resistance and can increase weight loss in women with PCOS who are not at risk for diabetes. In women with PCOS who are at risk for development of diabetes, it is the first-line treatment for glucose intolerance. 12

Hyperandrogenism & Hirsutism: First-line pharmacologic treatment for PCOS is combined oral contraceptives (COC). These exist in varying concentrations, but low-dose COCs are usually preferred. COC is considered the standard of care and significantly reduces hyperandrogenism and hirsutism and increases menstrual frequency.

Other pharmacologic agents commonly used to treat hyperandrogenism are metformin, spironolactone and finasteride. Metformin lowers androgen levels and may be the most beneficial for long-term PCOS maintenance.  The evidence supporting spironolactone's efficacy is not overwhelming, but it is still used for this purpose. Finasteride has been used in postmenopausal women and in women with documented hyperandrogenicity to combat hirsutism, and its efficacy has been found to be similar to that of spironolactone.2,13

Menstrual Infrequency & Infertility: In combatting infertility, weight loss remains the first-line treatment; even a change in weight as small as 2% to 5% can help induce ovulation.13

Pharmacologically, the treatment of choice is clomiphene citrate, sometimes used in combination with thiazolidinediones. If these measures fail, aromatase inhibitors while still experimental in their use-can induce ovulation comparably to clomiphene citrate. They are being proposed as first- and second-line treatment for ovulation induction in PCOS due to their ease of administration, short half-life, seemingly higher implantation rates, reduced rate of multiple pregnancies due to monofollicular ovulation and positive effects on the endometrium. 2

Anti-androgens such as cyproterone acetate, drosperinone, levornogestril, norgestimate and desogestril can help prevent endometrial hyperplasia and the eventual development of carcinoma in patients with PCOS.2,8,

Ovarian surgery is a second-line treatment for infertility in women with PCOS and helps to reduce rates of multiple pregnancies post-procedure. Ovarian surgery does not improve metabolic abnormalities, however, and often requires adjuvant therapy with clomiphene citrate for continued fertility benefits after the procedure is completed.2

To effectively treat PCOS, the three main areas of dysfunction must be addressed: chronic anovulation, hyperandrogenism and infertility caused by polycystic ovaries.

Although the evaluation and final diagnosis of PCOS can be lengthy and difficult, it is critical to be aware of metabolic changes and assess for signs of hyperandrogenism early in the disease course. Earlier detection and management of these factors can lead to a significantly improved prognosis.

High-risk patients should be followed and routine lab work should be performed every 6 to 12 months. If this protocol is followed, the patient's diagnosis of PCOS should be prompt and treatment begun immediately. As a result, the incidence of complications and comorbidities will be reduced and the patient's overall care will be optimized.

Table 1: National Institute of Health vs. Rotterdam Criteria vs. Androgen Excess Society criteria for PCOS Diagnosis14

 

National Institute of Health

Rotterdam criteria

Androgen Excess Society

Clinical and/or biochemical signs of hyperandrogenism

?

?

 

Oligo-anovulation or chronic anovulation

?

?

 

Polycystic Ovaries

 

?

 

Hyperandrogenism and/or hirsutism

 

 

?

Oligo-anovulation and/or polycystic ovaries

 

 

?

Table 2: Pharmacologic Treatment Options MOA and Common Side Effects

Treatment

MOA

Common SE

Combined Oral Contraceptives

Works on HPG axis to suppress synthesis and secretion of FSH and LH thus inhibiting the development of ovarian follicles and ovulation

Increased risk of VTE development

Anti-androgens

Suppresses androgen and LH secretion, increases SHBG levels

Loss of libido, mood changes

Spironolactone

Antagonizes aldosterone, decreases Na and water reabsorption, increases K retention

Electrolyte imbalance, renal failure

Metformin

Decreases hepatic glucose production and glucose absorption in intestine, increases insulin sensitivity

GI disturbance, lactic acidosis

Finasteride

5-alpha reductase inhibitor

Teratogenicity and feminizing of male fetuses

Ornithine decarboxylase inhibitors

Ornithine decarboxylase inhibitor

Minimal; skin irritation

Clomiphene citrate

Anti-estrogen agent

Multiple pregnancies

 

Aromatase Inhibitors

Blocks enzyme aromatase which turns androgen into estrogen; only used in post-menopausal women

Joint pain, hot flashes

*Chart was created by authors

Table 3: Summary of PCOS-Associated Conditions and Commonly used Treatment Options

Condition

Treatment

Hirsutism

Hyper-androgenism

Endocrine-Metabolic Disorders

Menstrual Infrequency

Infertility- Anovulation

Obesity

Lifestyle Modification

 

 

?

?

?

?

Combined Oral Contraceptives

?

?

 

?

 

 

Spironolactone

?

?

 

?

 

 

Metformin

?

?

?

 

?

?

Abdominal Acupuncture

 

 

 

 

 

?

Finasteride

?

?

 

 

 

 

Ornithine decarboxylase inhibitors

?

 

 

 

 

 

Clomiphene Citrate

 

 

 

 

?

 

Armatase Inhibitors

 

 

 

 

?

 

Ovarian Surgery

 

 

 

 

?

 

*Chart was created by authors

Song Eie Choi is currently working in pediatric surgery at a hospital in Mali, Africa. Mary Elizabeth Kearney is currently working as a medicine physician assistant at Mount Sinai West in Manhattan. Alison Hazan is a recent graduate of the Pace University Physician Assistant program in New York City. Jean Covino, DHSc, MPA, PA-C is a clinical professor at Pace University-Lenox Hill Hospital in New York City.

References
1.     Fauser B, et al. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group.  Fertil Steril. 2012;97(1):0015-0282. doi:10.1016/j.fertnstert.2011.09.024  

2.     Madnani N, et al. Polycystic ovarian syndrome. Indian Journal of Dermatology, Venereology & Leprology. 2013;79:310-21.

3.     Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol. 2013;6:1-13. doi: 10.2147/CLEP.S37559.

4.     Groot PD, et al. PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis. Oxford Journals. 2011;17(4):496-500.

5.     Lo J, et al. Epidemiology and adverse cardiovascular risk profile of diagnosed polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91(4):1357-63

6.     Hadine J, et al. Editorial: polycystic ovarian syndrome-relationship to epilepsy and antiepileptic drug therapy. J Clin Endocrinol Metab. 2001;86(7):2946-9. doi: http://dx.doi.org/10.1210/jcem.86.7.7788

7.     Nandi A, et al.  Polycystic ovary syndrome. Endocrinology and Metabolism Clinics of North America. 2014;43:123-147.

8.     Aquino CI, Nori SL. Complementary therapy in polycystic ovary syndrome. Transl Med UniSa, 2014 Apr-Jun;9:56-65.

9.     Bird ST, et al. Polycystic ovary syndrome and combined oral contraceptive use: a comparison of clinical practice in the United States to treatment guidelines. Gynecol Endocrinol. 2013;29:365-269.

10.   Roe AH, Dokras A. The diagnosis of polycystic ovary syndrome in adolescents. Rev Obstet Gynecol. 2011;4:45-51.

11.   Studen KB, et al. Cardiovascular risk and subclinical cardiovascular disease in polycystic ovary syndrome. Novel Insights into Causes and Therapy, 2013;40:64-82.

12.   Zheng YH, et al. Effectiveness of abdominal acupuncture for patients with obesity-type polycystic ovary syndrome: a randomized controlled trial. J Altern Complement Med. 2013;19(9):740-5.

13. Nandi A, et al. Polycystic Ovarian Syndrome. Endocrinology and Metabolism Clinics of North America. 2014;43(1):123-147.

14. Sirmans SM, et al. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol. 2013;6:1-13. doi: 10.2147/CLEP.S37559.

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