Dysglycemia, Not Altered Sex Steroid Hormones, Affects Cognitive Function in Polycystic Ovary Syndrome

Brittany Y. Jarrett; Natalie Vantman; Reid J. Mergler; Eric D. Brooks; Roger A. Pierson; Donna R. Chizen; Marla E. Lujan

Disclosures

J Endo Soc. 2019;3(10):1858-1868. 

In This Article

Abstract and Introduction

Abstract

Context: Polycystic ovary syndrome (PCOS) is a complex endocrine condition characterized by multiple reproductive and metabolic abnormalities. Because individual reproductive and metabolic abnormalities modulate working memory in the general population, there is growing interest in whether cognitive function is dually and negatively affected in PCOS.

Objective: To examine the association of reproductive and metabolic features with cognitive function in women with and without PCOS.

Design: An observational, cross-sectional study was conducted at an academic clinical research center in North America between 2006 and 2009. Common tests of working memory (i.e., manual dexterity, perceptual speed, and visuospatial ability) were performed by women with PCOS (n = 40) and control subjects (n = 40). Markers of sex steroid hormones, ovulatory function, and cardiometabolic health were also assessed.

Results: Reduced visuospatial ability was observed in women with PCOS compared with control subjects (P < 0.01). Reduced visuospatial ability was linked to higher levels of hemoglobin A1c in the entire study cohort, independent of body mass index or PCOS status. No associations were observed between visuospatial ability and reproductive features, after controlling for confounding variables.

Conclusion: Our findings support a role for glycemic control, and not PCOS per se, in cognitive dysfunction in women of reproductive age. Additional studies are needed to understand the short- and long-term effects of dysglycemia on brain health in women with PCOS, given their increased propensity for metabolic comorbidities, compared with control subjects.

Introduction

Polycystic ovary syndrome (PCOS) is characterized by reproductive and metabolic disturbances, including altered concentrations of sex steroid hormones, ovulatory dysfunction, obesity, dysglycemia, insulin resistance, hypertension, dyslipidemia, and inflammation.[1–6] Reproductive and metabolic disturbances individually modulate cognitive function in the general population. Therefore, there is growing interest in whether the abnormal endocrine milieu can uniquely influence cognitive outcomes in women with PCOS.[7–13]

There is reasonable evidence to suggest that sex steroid hormones exert activational effects on cognitive function.[14] Androgen and estrogen receptors are abundant in the hippocampus, a region of the brain closely involved with working memory.[15,16] Observational studies have demonstrated that women perform better than men on tests of manual dexterity and perceptual speed but worse on tests of visuospatial ability.[17] Sex-specific advantages have been linked to higher circulating concentrations of estradiol in women, compared with testosterone in men.[14] Changes in cognitive function have also been detected with physiologic[18,19] and pathologic variations in sex steroid hormones,[20] as well as during interventional studies of hormone replacement[21] and gender reassignment.[22] Such findings have led to the notion that hyperandrogenism and hyperestrogenism might enable male- and female-advantage cognitive task performance in PCOS.[7,8,11,13]

Previous studies have reported mixed evidence regarding sex steroid hormones and cognitive function in women with PCOS. Barry et al.[11] have described increased visuospatial ability in hyperandrogenic phenotypes compared with control subjects and associated male-advantage performance with elevations in total testosterone. However, other groups have found similar visuospatial ability, but reduced verbal memory and manual dexterity, in women with PCOS.[7,8] Deficits have been linked to androgen status,[7] albeit antiandrogen therapy has not yielded consistent improvements in female-advantage performance.[10,23] Some authors have responded to the conflicting data with an appreciation that sex steroid hormones may represent one of many factors contributing to cognitive differences in PCOS and that additional studies are needed to understand any potential relationships.[7,8,13]

Studies that focus on metabolic risk factors may be especially important. There is accumulating epidemiological and experimental evidence that insulin resistance contributes to the development of dementia in aging adults.[24] Insulin receptors and transporters are widely expressed in the brain, owing to the hormone's critical roles in energy balance, reproduction, and cognition.[25] Peripheral insulin resistance impairs neural insulin dynamics and leads to cerebral glucose hypometabolism,[26] neuroinflammation,[27] white matter abnormalities,[28] brain atrophy,[29] and cognitive decline.[24] Obesity, hypertension, dyslipidemia, and inflammation have also been linked to poor working memory, but the effects independent of insulin resistance remain unknown.[30–32] Interestingly, previous studies have described both cerebral glucose hypometabolism[12] and altered white matter microstructure in women with PCOS;[9] however, relationships between systemic metabolic disturbances and cognitive outcomes have not been explored.

Ultimately, the extent to which the spectrum of reproductive and metabolic disturbances in PCOS can influence cognitive outcomes is unclear. Such investigations are critical to inform patients about the long-term consequences of PCOS and to guide the selection of adequate therapies across the lifespan. Our objective for the current study was to examine the association of reproductive and metabolic features with cognitive function in women with and without PCOS. We hypothesized that the dual burden of reproductive and metabolic abnormalities would be linked to deficits in cognitive function in PCOS.

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