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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 3  |  Page : 303-308

Polycystic ovarian syndrome and diabetes mellitus: What's new?


Department of Internal Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia

Date of Submission09-Nov-2020
Date of Decision24-Jan-2021
Date of Acceptance14-Feb-2021
Date of Web Publication26-Jul-2021

Correspondence Address:
Riad A Sulimani
Department of Internal Medicine, College of Medicine, King Saud University, Riyadh
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jnsm.jnsm_140_20

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  Abstract 


Polycystic ovarian syndrome (PCOS) is an important public health problem. In addition to its gynecologic and hyperandrogenic manifestations, it has been associated with an increased incidence of prediabetic state, gestational diabetes mellitus (GDM), and diabetes mellitus. The pathogenesis of PCOS, as well as its metabolic consequences, is complex. The two main causative factors are intrinsic insulin resistance and impaired β cell function. Obesity has frequently been reported in PCOS; however, it is not entirely responsible for the insulin resistance in this population. PCOS should be managed with lifestyle modifications and appropriate dietary measures. In addition, treatment with insulin sensitizers is usually needed. PCOS provides a unique opportunity for the screening and early diagnosis of diabetes and its management.

Keywords: Diabetes, insulin resistance, obesity, polycystic ovarian syndrome, prediabetes, β cell dysfunction


How to cite this article:
Nasr MY, Alhuqayl TA, Alshammari HA, Alkhudhayri HH, Alzin MB, Sulimani RA. Polycystic ovarian syndrome and diabetes mellitus: What's new?. J Nat Sci Med 2021;4:303-8

How to cite this URL:
Nasr MY, Alhuqayl TA, Alshammari HA, Alkhudhayri HH, Alzin MB, Sulimani RA. Polycystic ovarian syndrome and diabetes mellitus: What's new?. J Nat Sci Med [serial online] 2021 [cited 2021 Oct 19];4:303-8. Available from: https://www.jnsmonline.org/text.asp?2021/4/3/303/322320




  Introduction Top


Polycystic ovarian syndrome (PCOS) is a major public health problem and a global health burden.[1],[2],[3],[4],[5],[6] It is a common endocrine abnormality affecting at least 1 in 15 women of reproductive age[3] and has no single feature sufficient for its clinical diagnosis.[7],[8] Patients with PCOS usually present with different features–such as acne, obesity, hirsutism, acanthosis nigricans, menstrual disturbance, and rarely, baldness.[2],[4],[5],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16] Biochemical and radiological abnormalities have been linked to PCOS in various degrees–including dyslipidemia, hyperandrogenism, hyperprolactinemia, insulin resistance with prediabetes or diabetes, enlarged ovaries with multiple cysts, and nonalcoholic fatty liver disease.[7],[9],[11],[12],[13],[14],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21]

There are several criteria for the diagnosis of patients with PCOS,[22] but the most common is the presence of at least two of the following three clinical or biochemical features of the 2003 Rotterdam ESHRE/ASRM criteria—namely, hyperandrogenism, oligo-ovulation or anovulation, and polycystic ovaries.[8] PCOS has been recognized as an important nonmodifiable risk factor for prediabetes and diabetes by the International Diabetes Federation.[23] Patients with PCOS are usually diagnosed late because of a lack of specific characteristics that mark the syndrome.[24],[25],[26],[27] Thus, early diagnosis of diabetes and prompt treatment are crucial to prevent long-term consequences related to obesity, diabetes, and cardiovascular complications.[1],[4],[10],[15]


  Discussion Top


The role of obesity

Obesity is a common feature in patients with PCOS.[9],[10],[12],[16] However, there are some inconsistencies regarding the relationship between obesity and PCOS. In the US, a study discovered that the prevalence of PCOS in women with body mass index (BMI) <25 kg/m2 is not different from that in women with a BMI of 35/kgm2 or higher,[28] whereas in Spain, another study revealed that the prevalence of PCOS among people with obesity was 28.3%.[29]

Dahan and Reaven postulated that a BMI of at least 30-‰kg/m2 is the primary predictor of insulin resistance of sufficient magnitude to place patients with PCOS at increased risk of metabolic abnormalities.[30] Although there is no genetic predisposition for obesity among patients with PCOS, it is possible that obesity or insulin resistance develops in patients with PCOS in response to various gene alterations in insulin receptor substrates.[31],[32] In addition, it is possible that poor diet and physical inactivity could contribute to obesity in this population.[33],[34]

Insulin resistance and β cell dysfunction

Regardless of the role of obesity in PCOS, insulin resistance among women with PCOS appears to occur with high frequency.[35] On the other hand, insulin resistance and hyperinsulinemia have also been documented among women with PCOS who may be lean or obese, compared to age-matched controls.[36] Consequently, it has been proposed that a synergistic deleterious effect can occur in patients with coexistent PCOS and obesity, inducing glucose intolerance in these individuals.[32] If a genetic or ethnic predisposition is present, then a great surge in glucose intolerance or frank diabetes could occur.[37] There has been some debate on how frequently insulin resistance develops in PCOS. In general, this has been estimated to be between 50% and 70% in some series and 10%–22% in others.[35],[36],[37] These differences have been partly attributed to the way insulin resistance is defined and whether obesity is present in the population studied.[38],[39],[40] Some data have revealed that the mean effect of lower insulin sensitivity in these individuals when compared to controls is about 27% regardless of the criteria used to diagnose PCOS and independent of the BMI.[41]

PCOS has been classified into four different phenotypes, depending on their clinical presentations.[42] Phenotypes A and B (the classic type) are more prone to metabolic complications.[43] This group of PCOS patients displays a discrete preponderance for insulin resistance, aggravated by obesity.[44] These observations have been documented in different ethnic populations.[45],[46] Regarding the prevalence of type 2 diabetes in PCOS, β cell dysfunction has been demonstrated in PCOS patients.[47],[48] It has been postulated that with continued insulin resistance and hyperinsulinemia, a stage of β cell exhaustion develops.[48] However, other investigators have reported that the insulin secretion in response to glucose is not commensurate with the changes in insulin sensitivity, raising the possibility of a β cell defect.[49] Oxidative stress has been observed to contribute to the pathogenesis of some aspects of PCOS.[50] Malin et al. demonstrated that in PCOS, mononuclear cell (MNC)-derived oxidative stress of obesity may independently aggravate the β cell function deterioration.[51] The authors also found that in women with PCOS who are obese, first- and second-phase β cell function was reduced compared to lean and obese controls, and hyperglycemia-induced NF-kB activation from MNC and systemic inflammation was associated with deteriorated β cell function.[52] Hyperandrogenemia has been noted to contribute to the pathogenesis of oxidative stress, inflammation, and insulin resistance. Glucose-stimulated release of tumor necrosis factor-alpha has been found to be linked to insulin resistance in PCOS.[53] Activation of the MNC in the fasting state by hyperandrogenemia was found to increase MNC sensitivity to glucose, probably causing diet-induced inflammation in these patients.[53]

The true prevalence of diabetes in PCOS has been quite variable in the different international studies depending on the ethnic groups studied, the method of diagnosing diabetes, and the age and weight of the patients.[54],[55],[56],[57],[58],[59],[60],[61] The risk of developing diabetes in PCOS was estimated to be between five and ten times that of the general population.[40],[62] A large population-based study revealed that prediabetes and diabetes rates in PCOS did not increase in elderly women during long-term follow-up.[63] Thus, it suggested that routine screening for diabetes may be unnecessary for patients with PCOS in their late reproductive ages if they have not developed glucose intolerance by that time.[63]

Is polycystic ovarian syndrome a risk factor for gestational diabetes mellitus?

GDM, defined as carbohydrate intolerance during pregnancy, is a frequent complication affecting 4%–7% of all pregnancies.[64],[65],[66] There is good evidence that PCOS increases the risk of GDM.[67],[68],[69] This may be associated with the risk factors discussed above. However, according to Mikola et al., the increased risk for gestational diabetes is primarily related to obesity than to PCOS itself.[70] In addition to obesity, increased maternal age has also been suggested to contribute to the pathogenesis of GDM in this population.[71]

Whether the use of metformin before conception or throughout pregnancy can prevent GDM is a matter of debate. A metanalysis by Zhao et al. demonstrated that the use of metformin was associated with a reduced incidence of GDM.[72] Another recent metanalysis found that when the bias caused by the observational studies was eliminated, the prevalence of GDM among women with PCOS treated using metformin from before conception to the end of pregnancy did not differ from those treated only before conception.[73] Similar findings of the lack of effect on metformin on PCOS have been reported in other recent studies.[74],[75],[76]

Due to possible discrepancies between the results of the methods used to diagnose diabetes, the use of an oral glucose tolerance test (OGTT) to screen for diabetes in this population, whether obesity is present or not, has been suggested.[77],[78] OGTT has also been used to monitor the progression of diabetes in patients with PCOS over the years with reasonable accuracy and reproducibility.[78] However, Kim et al. noted that glycated hemoglobin (HbA1c) was superior in detecting prediabetes and diabetes to both OGTT and fasting blood glucose.[46] It has been recommended to screen for diabetes every 1–3 years regardless of BMI or age, with frequency influenced by the presence or absence of other risk factors.[79]

Treatment of glucose intolerance and diabetes in polycystic ovarian syndrome

Currently, there are plenty of therapeutic options for tackling the underlying pathogenic mechanisms—namely, obesity, insulin resistance, and β cell failure.[80],[81],[82] However, particular attention should be paid first to lifestyle modification, including dietary management and physical activity.[83],[84],[85] Weight reduction has been known to be associated with improvement in insulin resistance, ovulatory status, and cardiovascular risk.[85],[86] Different dietary regimens have been instituted to achieve weight loss—including, low energy intake, low dietary glycemic index,[87],[88] and ketogenic diets.[89],[90] However, according to Moran et al., weight loss improves the presentation of PCOS regardless of dietary composition in the majority of studies.[91] Even a modest weight loss of 5% has been noted to improve insulin resistance, menstrual function, and fertility.[92] Physical activity has also been found to be associated with reduced insulin resistance, improved ovulation, and weight loss.[93],[94]

Traditionally, pharmacologic treatment includes the use of insulin sensitizers to prevent the development of insulin resistance, and metformin commonly serves this purpose.[5] Metformin is recommended in lean adolescent patients from as low as 850 mg daily to 1.5–2.5 g in overweight and obese adolescents.[5] Its use has been associated with weight improvement and low conversion rate to diabetes.[95] In addition, it has been proven to decrease visceral fat.[96] Metformin was found to improve energy metabolism by upregulating adaptive thermogenesis.[97],[98] It has also been discovered that it reduces inflammation in adipose tissue, which contributes to its ability to improve obesity-associated metabolic dysregulation.[99]

Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, has been shown to improve insulin sensitivity, ovulation, and hyperandrogenism.[100],[101] However, its use has been associated with undesirable side effects, especially weight gain and fluid retention. Furthermore, glucagon-like peptide receptor agonists and dipeptidyl peptidase-4 inhibitors have been used in patients with PCOS and have shown variable degrees of improvement in insulin sensitivity and weight reduction in these patients.[102],[103],[104] Of the dipeptidyl peptidase-4 inhibitors, sitagliptin has been proven to improve insulin sensitivity and cell function in patients intolerant to metformin therapy.[105] Recently, sodium-glucose co-transporter-2 inhibitors, such as empagliflozin, have been utilized in patients with PCOS. Treatment with empagliflozin produced improvement in anthropometric parameters and body composition in overweight and obese women with PCOS after 12 weeks of treatment compared to metformin, although no changes were detected in hormonal or metabolic parameters.[106] In addition to pharmacologic therapy, bariatric surgery has been implemented in obese PCOS patients.[107],[108],[109],[110] Bariatric surgery was associated with improvement of clinical parameters, menstrual irregularities, fertility as well as reduction of insulin resistance in morbidly obese patients.[111] More studies are needed to confirm the utilization of this surgery in PCOS especially in less morbidly obese patients.

In conclusion, PCOS is considered a state of insulin resistance and β cell dysfunction with a propensity to advance to type 2 diabetes. It represents a situation suitable for early screening and diagnosis of diabetes. This is important for the early detection and prevention of diabetes-related complications in this population.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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