Subclinical Hypothyroidism in Women with PCOS Needs More Research

Women with polycystic ovary syndrome appear at increased risk for comorbid thyroid disorders, yet a study by researchers from the Cleveland Clinic introduced more questions about pregnancy outcomes.

With James H. Liu, MD, and Lubna Pal, MBBS

Polycystic ovary syndrome (PCOS) is a common heterogenous endocrine disorder that is believed to affect between 8% to 20% of reproductive-aged women worldwide,1 including approximately 5 million women in the US.2 However, the prevalence varies depending upon which set of criteria for PCOS are used.1

An estimated 50% to 70% of women with PCOS have insulin resistance; as such, common comorbidities include metabolic syndrome, hypertension, dyslipidemia, glucose intolerance, and diabetes.1 Nearly half of women (40%) with PCOS are infertile, and PCOS is the most common cause of anovulatory infertility.1

Pregnant women with polycystic ovary syndrome may have hypothyroid disease.

Thyroid Conditions in Women with PCOS 

Thyroid disorders are also more common in women with PCOS, and an estimated 10% to 25% of women with PCOS have subclinical hypothyroidism (SCH).3 Numerous studies have examined the effect of SCH in patients with PCOS on cardiovascular risk factors; however, because the studies use different criteria to diagnose PCOS and varying TSH cut-off levels to define SCH, the findings are not clear-cut.3-5

Nevertheless, evidence suggests that SCH in PCOS may be associated with at least mild metabolic and cardiovascular abnormalities and may warrant additional clinical attention. There is, however, minimal evidence supporting an increased risk of cardiovascular events in this patient population.1

A recent cross-sectional study was initiated into a possible association between PCOS and subclinical hypothyroid disease by evaluating the clinical, hormonal, and metabolic parameters.6 The researcher team, led by James H. Liu, MD, professor, and chairman of obstetrics and gynecology at Case Western Reserve University in Cleveland, Ohio evaluated 137 women who were diagnosed with PCOS using Rotterdam criteria and attending a tertiary care infertility clinic over a three-year period.

Hypothyroidism is commonly defined as an elevated thyroid-stimulating hormone (TSH) level and normal free thyroxine (FT4) level; most endocrinologicy studies use a cutoff of TSH >5 mIU/L to diagnose hypothyroid, and subclinical hypothyroid (SCH) is often diagnosed as TSH >4.5 mIU/L.  However, because adverse pregnancy outcomes have been reported with TSH levels >2.5 mIU/L, this level is often selected to diagnose SCT in women with infertility concerns.6

Data was collected on mean age, body mass index (BMI), fasting plasma glucose (FPG), glucose tolerance test (GTT), hemoglobin A1c (HbA1c), fasting insulin, a 2 hours insulin level after 75g glucose load, cholesterol, LDL, HDL, and homeostatic model assessment (HOMA) for 137 women with (n=30) and without (n=107) SCH.6

A homeostatic model assessment was described as a fasting insulin mIU/mL X fasting glucose mM)/22.5; HOMA >2.5 was diagnosed as insulin resistance. Only five of the 30 women with SCH had a TSH value > 4.5 mIU/L.6 There were no significant differences between the SCH and euthyroid groups in mean age (29.5y and 28.5y, respectively) and mean BMI (31.3 and 31.5, respectively); similar mean values were observed in FPG, GTT, HbA1c, fasting insulin levels, insulin levels at two hours post 75 g glucose, lipid levels, and HOMA.  

However, even after adjusting for age and BMI, women with SCH had a significantly higher incidence of abnormal FPG (P=0.03) and HOMA (P=0.01) values compared with euthyroid women.6

Women with PCOS May Benefit from Screening for Subclinical Hypothyroid

Dr. Liu told EndocrineWeb, “the study findings suggest that clinicians should routinely screen patients who meet PCOS criteria for thyroid hormone levels to see if they have subclinical hypothyroidism (SCH).” Noting that while this screening is likely routinely performed in fertility clinics and endocrinology practices, it may not be part of the standard of care in OB/GYN practices, particularly among adolescent patients for whom fertility issues are not yet of concern.

Because this was a cross-sectional study of women diagnosed with PCOS,Dr. Lui acknowledged that the study did not include any interventions such as thyroid hormone treatment and did not track pregnancy outcomes of the participants.

As such, the study did not address whether or not women who were treated for SCH (TSH >2.5) had altered pregnancy outcomes if women with SCH were at greater risk for gestational diabetes, and if SCH affected neonatal outcomes. Similarly, the study did not provide evidence for different outcomes with TSH >2.5 versus TSH >4.5, as there were too few subjects in the latter group.

Study Introduces Many Intriguing Questions for these Women

Lubna Pal, MBBS, FRCOG (UK), FACOG, director of the Polycystic Ovarian Syndrome and Menopause Program at Yale School of Medicine in New Haven said, “the observed association between SCH and abnormal FPG reported by Dr. Liu’s group is intriguing and raises questions regarding the plausible mechanism (s) that may explain the observed associations between mildly elevated TSH level and abnormal FPG in women with PCOS.

However, there were no clear-cut criteria for entrance into the study other than a diagnosis of PCOS and attendance at this particular infertility clinic. It is confounding that it took three years to reach their enrollment number, and yet, when the results were provided, only P values were offered but no actual data was presented.

Therefore, there isn’t sufficient outcomes data or adequate context for their findings, and without any follow-up or any intervention, the study presents many intriguing questions for future investigation but no clinically relevant insights as yet.

Issues to Be Considered in Future Studies

While adding to the existing literature on the topic, Dr. Pal told EndocrineWeb, “the observations reported by Bedaiwy et al. underscore a need for appropriately designed future research endeavors that are powered to examine:

  • Confirm the prevalence of SCH in women with PCOS compared to women of normal reproductive physiology 
  • If mechanisms for SCH, such as autoimmunity, differ between PCOS and non-PCOS populations 
  • Whether insulin resistance or dysglycemia contribute to thyroid dysfunction or if SCH is a surrogate “bystander”  in women with PCOS  
  • Determine if the clinical relevance of the observed associations are in fact causal
  • If TSH level >2.5 is truly reflective of thyroid dysfunction."

While women who have subclinical hypothyroid may face a greater risk of infertility, further research is necessary to gain a clearer understanding of the clinical management needed to care for this subset of women, according to Dr. Pal.

Author disclosure statement: no competing financial interests exist.

Continue Reading:
Some Pregnant Women Should Be Treated for Subclinical Hypothyroidism
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