Polycystic Ovary Syndrome (PCOS)

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Introduction

Polycystic Ovary Syndrome (PCOS) is primarily characterized by ovulatory dysfunction and hyperandrogenism.  Adolescent girls with PCOS have increased risk of infertility, metabolic syndrome, type 2 diabetes, and cardiovascular disease.  It is one of the leading causes of infertility in women, and the most common cause of hyperandrogenism/anovulatory symptoms in teenagers. PCOS is a syndrome with multiple clinical presentations, therefore any of the above clinical signs should cause concern for PCOS.

It is a spectrum disorder comprising the following features:

• Cutaneous hyperandrogenism (hirsutism, acne, pattern balding)
• Menstrual irregularity
• Polycystic ovary
• Obesity and insulin resistance
             

Early identification and treatment of PCOS is key to preventing more severe long-term sequelae including infertility, type 2 diabetes, and potential endometrial carcinoma.
  

Pathophysiology:

The exact cause of PCOS remains unknown, with debate as to whether it is primarily a disorder of pituitary gonadotropin secretion or a disorder of downstream ovarian and/or adrenal steroidogenesis.

It has been established, however, that the major pathophysiologic abnormality in PCOS is excessive ovarian androgen secretion. Both insulin and luteinizing hormone (LH) have been shown to play a role in this hyperandrogenemia. 

Nearly 1/3 of sisters of PCOS patients have elevated testosterone levels and ½ of those patients will later develop symptoms meeting PCOS diagnosis by NIH criteria. Over 1/3 of PCOS patients also had a parent with metabolic syndrome or diabetes mellitus.  No specific genes have been identified that cause PCOS.  Proposed genes likely regulate the hypothalamic-pituitary-ovarian axis. Due to this high frequency of PCOS and metabolic syndrome in family members it is recommended that family be screened for PCOS and metabolic syndrome, especially those who are obese.

Diagnosis:

Three sets of diagnostic criteria exist for PCOS (NIH, Rotterdam, and AES), however, the 1990 NIH criteria remain the gold standard. Clinical diagnosis that requires evidence of both:
           

• Hyperandrogenism (hirsutism, severe acne, pattern alopecia, or biochemical evidence of hyperandrogenemia)
     
• Anovulation symptoms (anovulation or oligoovulation)
                  

Additionally, both of these criteria must not be attributable to any disorder the patient may have. Furthermore, since in adolescents oligo-ovulation can be normal in the years following menarche, it is important to remain vigilant of potential ongoing anovulation through followup/monitoring deverloping of menstrual cycle regularity over time.

Differential Diagnosis:

1. Congenital Adrenal Hyperplasia
2. Ovarian Steroidogenic Block
3. Cushing Syndrome/Cortisol Resistance
4. Hyperprolactinemia
5. Acromegaly
6. Insulin Resistance Disorders
7. Virilizing Tumors
8. Thyroid Dysfunction
9. Drugs (Anabolic Steroids, Valproic Acid)

Clinical Features:       

• Hirsutism
  • ​​Hirsutism is usually insidious in onset in PCOS. Rapid development of hirsutism would be concerning for an adrenal/ovarian tumor.
• Anovulatory Symptoms:
                              
  • Observed in two-thirds of adolescents with PCOS, however, it is clinically indistinguishable from the oligo-ovulation that typically follows menarche. If these problems persist over 2 years post-menarche, PCOS should be considered.
                           
  • Anovulatory Symptoms in adolescents may include:
    • Primary amenorrhea: lack of menarche by age 15
    • Secondary amenorrhea: > 90 days without a menstrual cycle, following onset on menarche
    • Oligomenorrhea: missing over 4 menstrual cycles per year

It is important to notes that since menstrual cycles often are anovulatory in the first 1-2 years post-menarche, normal cycles of bleeding does not indicate that ovulation is still occurring. Clinical workup for PCOS is still required if other clinical features point to this diagnosis.
                

• Polycystic Ovaries:
                       
  • Due to many small ovarian follicles develop during the follicular phase of the attempted menstrual cycle, but not to the pre-ovulatory size, hence resulting in failure to ovulate since no dominant follicle is selected for ovulation.
                   
  • A polycystic ovary is one in which 12 or more follicles measuring 2-9 mm in diameter. A polycystic ovary is found in the majority of adolescents with PCOS, however it may not develop until years after menarche. Additionally, polycystic ovaries can also be found in adolescents without PCOS as a normal pubertal variant.
                          
  • Therefore, Abdominal Ultrasound in adolescents with PCOS can be conducted to exclude other diagnoses, however this imaging does not necessarily to confirm PCOS. 
                   

• Obesity:
               
  • The majority of adolescents with PCOS are either overweight or obese, with this often being the presenting symptom of the syndrome. Even normal-weight females with PCOS are reported to have a body fat content that is 50 percent greater than normal. Generally, these adolescents have an android fat distribution (significant abdominal fat).
                   
  • These patients’ excess adipose tissue has been shown to be associated with increased insulin resistance, another cardinal feature of PCOS.
                            

• Diabetes/Insulin Resistance:
                    
  • In addition to the contribution that PCOS patients’ increases adipose tissue already add to insulin resistance, adolescents with PCOS have decreased insulin sensitivity compared with BMI (body mass index)-matched controls. These patients also often have external signs of insulin resistance, such as acanthosis nigricans.
                 
  • A long-term major sequelae of PCOS is the development of Type II Diabetes if ongoing insulin resistance is not controlled.

Lab Evaluation and Imaging:

Since PCOS is a spectrum disorder, the evaluation and treatment varies. The following table summarizes various lab testing.  Laboratory samples measuring androgen level must be drawn early in the morning, at peak time of androgen production, about 8 am.

Treatment:

Since PCOS has such variable presentation, the syndrome’s management is individual tailored based on the patient’s clinical features. However, some of the major pillars of general PCOS management includes:
        

Weight Loss                  

• Weight loss has been shown to be effective in prolonging the transition from increased insulin resistance to meeting clinical criteria for Type 2 Diabetes Mellitus.
                          

• Weight loss of at least 5% has also been associated with improvements in other clinical features of PCOS, including reduced hirsutism and increasing normalization menstrual cycles.
   

Oral Hypoglycemics (Metformin)       

• Metformin is an antidiabetic drug that reduces hepatic glucose production and improves insulin sensitivity, which thereby results in reduced androgen and LH levels.
                  
• In adolescents with PCOS, metformin is used as an adjunct agent to lifestyle changes (weight loss, healthy eating) in the management of obesity and the related insulin-resistant metabolic abnormalities in PCOS.
           
• Clinical trials have also shown that that metformin significantly increases the frequency of menses and ovulation (by about 50 percent), and lowers testosterone levels (by about 20 percent). Its effectiveness is minimized in the absence of weight control.

 Oral contraceptive pills (OCPs)

• Considered first-line therapy for treatment of adolescents with PCOS. OCPs play the dual role of normalizing the menstrual cycle and reducing androgen level.
       
• Combination OCPs (estrogen and progestin) are most typically used. Estrogen inhibits activity of the hypothalamic-pituitary-gonadal axis via negative feedback, thereby reducing LH spikes and ovarian androgen production, as well as increasing serum sex hormone binding globulin (SHBG) levels. This results in decreased levels of unbound testosterone. OCP therapy will typically normalize androgen levels in 18-21 days.

 Antiandrogens (Spironolactone)

• Antiandrogenic therapy, which inhibits binding of androgen to its receptor, is primarily for symptomatic relief of hirsutism, but has not been shown to play a significant role in correcting underlying PCOS abnormalities.
      
• The 2008 Endocrine Society Clinical Guidelines suggest adding antiandrogen therapy in patients taking OCPs for at least six months who desire additional hirsutism reduction.
      
• Spironolactone probably is the antiandrogenic drug of choice due to its potency and relatively insignificant side effect profile. It has been shown to reduce hirsutism by approximately 33% on average in patients with PCOS.

References:

1. Ehrmann, D.A. (2005). Polycystic ovary syndrome. NEJM, 352(12), 1223-36.
2. Gray, S.H. (2013). Menstrual disorders. Pediatrics in Review, 34(1), 6-18. 
3. Nestler, J.E. (2008). Metformin for the treatment of polycystic ovary syndrome. NEJM, 358(1), 47-54.
4. Nurman, M.M., et. al. (2009). Glucose metabolism in overweight hispanic adolescents with and without polycystic ovary syndrome. Pediatrics, 124(3), 496-504.
5. Rosenfield, R. L. (2007). Polycystic ovary syndrome in adolescence associated with obesity. AAP News, 28(4), 20.