Diagnosis and treatment of polycystic ovary syndrome (PCOS) using virtual health

Author

Caitlin Dunne, MD, FRCSC (biography and disclosures)

Disclosures: I intend to make recommendations for the off-label use of letrozole and I am co-director of the Pacific Centre for Reproductive Medicine.

What I did before

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age.¹ PCOS affects 8%–13% of young women and its symptoms are some of the most prevalent concerns that community physicians encounter.¹ As its name suggests, polycystic ovary syndrome comprises a variable constellation of symptoms, which can include menstrual irregularity, androgen excess, obesity, insulin resistance, and infertility. However, despite its prevalence, PCOS remains underdiagnosed and misunderstood, leaving patients at risk of long-term health consequences like endometrial cancer and diabetes.

PCOS was originally known as Stein-Leventhal Syndrome, published in 1935 as a series of patients with amenorrhea and bilateral polycystic ovaries.² Since then, there have been a few iterations of diagnostic criteria but the most widely accepted were the Rotterdam Consensus Criteria (2003).³ This guideline required that a patient demonstrate two out of three things⁴:

• Oligo or anovulation
• Clinical and/or biochemical signs of hyperandrogenism
• Polycystic ovaries
  *and exclusion of other aetiologies e.g., Cushing’s syndrome, androgen-secreting neoplasms, and congenital adrenal hyperplasia

In order to make the diagnosis, Rotterdam (2003) recommended a set of clinical, laboratory, and ultrasound investigations including:

1. History taking for menstrual cycles and hyperandrogenism (hirsutism, acne, alopecia)
2. 17-hydroxyprogesterone
   • To rule out late-onset congenital adrenal hyperplasia
3. Thyroid-stimulating hormone (TSH)
4. Prolactin
   • To rule out an alternate endocrinopathy causing oligomenorrhea
5. Follicle-stimulating hormone (FSH) and estradiol (E2)
   • To rule out hypogonadotropic hypogonadism (low FSH, low E2) or premature ovarian failure (high FSH, low E2)
6. Testosterone (ideally free testosterone) +/- sex hormone binding globulin (SHBG)
7. Androstenedione
   • To establish hyperandrogenemia and rule out androgen-secreting neoplasms
8. Dihydroepiandrosteronesulfate (DHEA-S)
   • To rule out an adrenal androgen-secreting neoplasm
9. Insulin resistance testing (fasting glucose and/or 2-hour 75 g oral glucose tolerance test)
10. Transvaginal pelvic ultrasound (≥ 12 follicles 2–9 mm or ovarian volume > 10 ml)
    • To assess for polycystic ovary morphology

What changed my practice

In 2018 a new guideline was published in collaboration with 37 societies and organizations covering 71 countries. The International evidence-based guideline for the assessment and management of polycystic ovary syndrome 2018⁵ contains some key changes: refinement of diagnostic criteria; reduction of unnecessary testing; increased focus on education, lifestyle, and quality of life; and evidence-based medical therapy and fertility management.¹

In addition to the new guideline, my practice was influenced by the COVID-19 pandemic. Virtual medicine became my primary form of patient consultation and COVID-19 precautions further established the need for judicious use of invasive testing and in-person examination.

The 2018 guideline presents a more clinical approach to diagnosis of PCOS. Laboratory and ultrasound investigations are limited and the primary focus is on appropriate diagnosis and management. I find the algorithm amenable to a virtual health diagnosis in most cases of PCOS.

Figure: Algorithm for screening, diagnostic assessment, risk assessment, and life-stage:

I also find it very helpful to order serum Anti-Müllerian Hormone (AMH) when assessing for PCOS in a virtual health setting. AMH is produced by granulosa cells, which surround each small follicle in the ovary. Hence, a high AMH value indicates the presence of a high number of ovarian follicles. AMH is not yet considered a substitute for polycystic ovary morphology on ultrasound¹ (i.e., you cannot establish that there are ≥ 20 follicles per ovary using this single test). However, there is increasing evidence that high, age-specific AMH levels can be used as diagnostic markers.⁶ I order AMH testing on most patients, especially if there is limited access to transvaginal ultrasound.  For example, AMH can quickly differentiate between PCOS (high AMH) and perimenopause (low AMH, < 8 pmol/L) as causes of oligomenorrhea. Community physicians can order AMH, it is private-pay (~$70) and can be drawn on any day of the menstrual cycle. In one study,⁶ the cut-off levels for the prediction of PCOS were:  20–27 years = 40.7 pmol/L,  27–35 = 32.5 pmol/L, and 35–40 = 26.4 pmol/L.

What I do now

My main consideration in managing a patient with possible PCOS is to establish the goal of treatment. Making the diagnosis of PCOS can be helpful, but it is more important to address the patient’s symptoms and reduce the risk of long-term comorbidities.

If the goal is to manage irregular bleeding and/or hirsutism:

• Combined oral contraceptive pill (OCP) is first-line (e.g., 20 mcg ethinyl estradiol + norethindrone)
• Cosmetic therapy can be utilized for hirsutism (e.g., waxing, laser, plucking)
• Due to the hair growth cycle, 6–12 months of treatment is required to evaluate response
• Antiandrogens (e.g., spironolactone, cyproterone acetate, finasteride, flutamide)⁷ should only be considered for hirsutism if 6 months of OCP and cosmetic therapy have failed to achieve the treatment goal (the guideline does not recommend any specific types or doses of antiandrogens)³
• Antiandrogens must be used with contraception to avoid accidental male fetal undervirilization

If the patient declines combined hormonal contraceptives, manage the risk of endometrial hyperplasia by inducing regular withdrawal bleeds:

• Women with PCOS have a 2–6 times increased risk of endometrial cancer as a result of chronic exposure to unopposed estrogen
• Medroxyprogesterone acetate 10 mg PO x 10–14 days every 1–3 months is one method of inducing endometrial shedding. I ask the patient to confirm a negative urine pregnancy test before starting each course
• Routine ultrasound screening for endometrial thickness is not recommended
• Maintain a low threshold for endometrial biopsy in cases of persistent irregular bleeding or thickened endometrium

If the goal is pregnancy, prescribe ovulation induction agents⁹:

• Letrozole (off-label) is first-line e.g., 2.5 mg PO daily x 5 days from cycle days 3–7
• Mid-luteal (day 21–23) progesterone > 10 nmol indicates ovulation
• Dose increases (e.g., letrozole 5 mg or 7.5 mg) are indicated for anovulation, not for lack of conception
• Clomiphene citrate is another option, in 50 mg, 100 mg, or 150 mg daily doses for 5 days from cycle days 3–7. Clomiphene can be compounded, but manufacturing of the tablets has been discontinued
• Metformin is not used alone for ovulation induction but can be combined with letrozole or clomiphene to treat anovulation for patients in high metabolic risk groups

Many patients with PCOS are obese and at risk for diabetes¹⁰:

• Assess body mass index (BMI) and cardiovascular risk factors every 6–12 months
• Counsel on healthy eating, no specific diet is recommended¹¹
• 5%–10% bodyweight loss¹
• Exercise prescription (150–250 minutes/week + 2 muscle-strengthening activities)
• Establish baseline glucose testing and retest every 1–3 years based on risk factors
• Bariatric surgery is considered an experimental fertility therapy in women with PCOS. Pregnancy should be avoided for at least 12 months after surgery, during rapid weight loss

Additional screening considerations:

• Blood pressure check at least annually
• Fasting lipid profile at diagnosis (cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride level) then reassessment as indicated by the patient’s cardiovascular disease risk factors (i.e., smoking, obesity, dyslipidemia, hypertension, lack of physical activity, glucose intolerance)
• Obstructive sleep apnea screening using the Berlin tool if indicated to relieve symptoms or determine the need for specialist referral
• Assessment of depression and anxiety symptoms at diagnosis is recommended, the optimal interval for reassessment is unclear and should be based on individual patient profile
• Health professionals should be aware of the increased incidence of disordered eating, psychosexual dysfunction, and body image issues

Conclusion

PCOS is a common endocrine condition that can hinder the quality of life and long-term health of young women. In many cases, diagnosis and management can be carried out in a virtual health setting using clinical criteria and judicious use of laboratory investigations. The International evidence-based guideline for the assessment and management of polycystic ovary syndrome 2018⁵ may assist community physicians in making a timely diagnosis. Early initiation of treatment for PCOS-related oligomenorrhea or infertility can improve patient satisfaction¹² and reduce the risk of comorbidities.

References

1. Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110(3):364-379. doi:10.1016/j.fertnstert.2018.05.004 (View)
2. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 1935;29(2):181-191. doi:10.1016/s0002-9378(15)30642-6 (Request with CPSBC or UBC or view the first page)
3. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long‐term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41-47. doi:10.1093/humrep/deh098 (View)
4. Lujan ME, Chizen DR, Pierson RA. Diagnostic criteria for polycystic ovary syndrome: pitfalls and controversies. J Obstetrics Gynaecol Can. 2008;30(8):671-679. doi:10.1016/s1701-2163(16)32915-2 (View)
5. Teede H, Misso M, Costello M, et al. International evidence-based guideline for the assessment and management of polycystic ovary syndrome 2018. Monash University, Australia, NHMRC, Centre for Research Excellence in PCOS and the Australian PCOS Alliance 2018. Published 2011. Updated February 2018. (View) Accessed August 6, 2022
6. Tehrani FR, Rahmati M, Mahboobifard F, Firouzi F, Hashemi N, Azizi F. Age-specific cut-off levels of anti-Müllerian hormone can be used as diagnostic markers for polycystic ovary syndrome. Reprod Biol Endocrin. 2021;19(1):76. doi:10.1186/s12958-021-00755-8 (View)
7. Badawy A, Elnashar A. Treatment options for polycystic ovary syndrome. Int J Women’s Heal. 2011;3:25-35. doi:10.2147/ijwh.s11304 (View)
8. McCormick BA, Wilburn RD, Thomas MA, Williams DB, Maxwell R, Aubuchon M. Endometrial thickness predicts endometrial hyperplasia in patients with polycystic ovary syndrome. Fertil Steril. 2011;95(8):2625-2627. doi:10.1016/j.fertnstert.2011.04.022 (View with CPSBC or UBC)
9. Smithson DS, Vause TDR, Cheung AP. No. 362-ovulation induction in polycystic ovary syndrome. J Obstetrics Gynaecol Can. 2018;40(7):978-987. doi:10.1016/j.jogc.2017.12.004 (View with CPSBC or UBC)
10. Yildiz BO, Knochenhauer ES, Azziz R. Impact of obesity on the risk for polycystic ovary syndrome. J Clin Endocrinol Metabolism. 2008;93(1):162-168. doi:10.1210/jc.2007-1834 (View)
11. Johnston BC, Kanters S, Bandayrel K, et al. Comparison of weight loss among named diet programs in overweight and obese adults: a meta-analysis. Jama. 2014;312(9):923-933. doi:10.1001/jama.2014.10397 (View)
12. Ismayilova M, Yaya S. “I felt like she didn’t take me seriously”: a multi-methods study examining patient satisfaction and experiences with polycystic ovary syndrome (PCOS) in Canada. Bmc Women’s Heal. 2022;22(1):47. doi:10.1186/s12905-022-01630-3 (View)

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