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Pharmacological Approaches to Controlling Cardiometabolic Risk in Women with PCOS
Andrea Cignarella, Roberto Mioni, Chiara Sabbadin, Francesca Dassie, Matteo Parolin, Roberto Vettor, Mattia Barbot, and Carla Scaroni
Abstract: Polycystic ovary syndrome (PCOS) is characterized by elevated androgen production and subclinical changes in cardiovascular and metabolic risk markers. Total cholesterol, high-density lipoprotein (HDL) cholesterol, fasting glucose, and fasting insulin appear to increase specifically in PCOS compared with fertile women. PCOS also confers an increased risk of cardiometabolic disease in later life. Novel biomarkers such as serum’s cholesterol efflux capacity and blood-derived macrophage activation profile may assist in more accurately defining the cardiometabolic risk profile in these women. Aldosterone antagonists, androgen receptor antagonists, 5α-reductase inhibitors, and synthetic progestogens are used to reduce hyperandrogenism. Because increased insulin secretion enhances ovarian androgen production, short-term treatment with metformin and other hypoglycemic agents results in significant weight loss, favorable metabolic changes, and testosterone reduction. The naturally occurring inositols display insulin-sensitizing effects and may be also used in this context because of their safety profile. Combined oral contraceptives represent the drug of choice for correction of androgen-related symptoms. Overall, PCOS management remains focused on specific targets including assessment and treatment of cardiometabolic risk, according to disease phenotypes. While new options are adding to established therapeutic approaches, a sometimes difficult balance between the efficacy and safety of available medications has to be found in individual women.
1. Introduction
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women in their reproductive age. PCOS is a clinically heterogeneous condition defined by oligo- or anovulation, elevated androgen production, and polycystic ovary changes as per the Rotterdam criteria [1]. Apart from classic symptoms, including acne, hirsutism, and infertility, PCOS carries important cardiovascular comorbidities such as insulin resistance (IR), dyslipidemia, obesity, and hypertension [2,3]. Despite the lack of solid longitudinal studies, epidemiological data confirmed an increased prevalence of cardiovascular (CV) events in post-menopausal women with a clinical history of irregular menstrual cycles [4]. It is therefore paramount to promptly recognize and revert subtle cardiometabolic impairment to reduce future CV events. Although PCOS is a multifactorial disease with unknown pathophysiology, IR and compensatory hyperinsulinemia play a central role in the development and maintenance of both gynecological and metabolic disorders [5]. IR is indeed a common finding in PCOS, even though it is not found among diagnostic criteria, and represents a well-known predictor for the future development of type 2 diabetes (T2DM). One of the main causes of IR is overweight and obesity, whose prevalence can reach 80% in PCOS, but even lean patients often display relative hyperinsulinemia with a consequent increased likelihood of further developing T2DM [6]. Besides glucose metabolism impairment, hyperinsulinemia favors other classical CV risk factors such as hypertension, resulting from vascular smooth muscle cell hypertrophy and endothelial dysfunction through endothelin-1, and dyslipidemia [7]. Insulin has a gonadotropin-like action and may increase androgen production, which contributes to worsening both metabolic impairment and clinical picture [8]. In this regard, IR is an appealing target for PCOS management, and several insulin-sensitizing drugs have been used to treat patients with PCOS. However, it should be recalled that lifestyle changes should be the basis of any treatment because, if effective, they could significantly reduce cardiometabolic risk in later life [9].
The pathophysiology of PCOS is complex and several treatment options are currently available. In this comprehensive review, we set out to discuss the integration of novel biomarkers with pharmacological intervention to improve PCOS management. We summarize current treatment strategies, including discussion about disagreements in the field, and suggest future clinical trajectories.
3. Emerging Cardiometabolic Risk Biomarkers
4. Antiandrogen Therapy
4.1. Flutamide
4.2. Bicalutamide
4.3. Spironolactone
4.4. Ketoconazole
4.5. Finasteride
5. Antidiabetic Medications
5.1. Metformin
5.2. Inositols
5.3. Acarbose
5.4. Thiazolidinediones
5.5. Incretin Mimetics
5.6. SGLT2 Inhibitors
6. Metabolic Impact of Combined Oral Contraceptives
7. Statins
8. Conclusions
Hyperandrogenism is a hallmark of PCOS. Androgens in women play an unfavorable role in the CV system and, together with hyperinsulinemia and/or obesity, can cause high blood pressure, an increase of inflammatory markers, dyslipidemia, and CV events in PCOS patients. As these pathologic alterations or diseases usually begin in later periods of life, such as the third or fourth decade, when there may already be irreversible damage, overweight, obesity, hyperinsulinemia, IR, and dyslipidemia should represent the first step of therapeutic approach in PCOS subjects. However, these conditions represent co-morbidities that are not always present, especially in adolescence, while hyperandrogenism is the most frequent and one of the earliest causes of disease in PCOS. Thus, early correction of hyperandrogenism, already in youth, could improve or even prevent the aforementioned co-morbidities in later life. COCs represent for many scientific societies the drug of choice for the correction of hyperandrogenism in PCOS. However, COC intake can be accompanied by thromboembolic events, weight gain, and possibly additional, yet less frequent adverse effects. Thus, COC treatment needs to be personalized considering the metabolic and cardiovascular risk profile and family history of individual patients [182,183]. Furthermore, metabolic abnormalities impact global cardiovascular risk and mortality rate in the adult age of patients affected by PCOS [184,185]. Therefore, medications that can be taken for long periods with an acceptable safety profile should be considered. Antiandrogens, oral hypoglycemic agents, and possibly statins represent additional therapeutic options for the treatment of symptoms of androgen excess in PCOS and control of cardiometabolic risk factors. A sometimes-difficult balance between efficacy and safety of available medications according to disease phenotypes has to be found in individual women.
Andrea Cignarella, Roberto Mioni, Chiara Sabbadin, Francesca Dassie, Matteo Parolin, Roberto Vettor, Mattia Barbot, and Carla Scaroni
Abstract: Polycystic ovary syndrome (PCOS) is characterized by elevated androgen production and subclinical changes in cardiovascular and metabolic risk markers. Total cholesterol, high-density lipoprotein (HDL) cholesterol, fasting glucose, and fasting insulin appear to increase specifically in PCOS compared with fertile women. PCOS also confers an increased risk of cardiometabolic disease in later life. Novel biomarkers such as serum’s cholesterol efflux capacity and blood-derived macrophage activation profile may assist in more accurately defining the cardiometabolic risk profile in these women. Aldosterone antagonists, androgen receptor antagonists, 5α-reductase inhibitors, and synthetic progestogens are used to reduce hyperandrogenism. Because increased insulin secretion enhances ovarian androgen production, short-term treatment with metformin and other hypoglycemic agents results in significant weight loss, favorable metabolic changes, and testosterone reduction. The naturally occurring inositols display insulin-sensitizing effects and may be also used in this context because of their safety profile. Combined oral contraceptives represent the drug of choice for correction of androgen-related symptoms. Overall, PCOS management remains focused on specific targets including assessment and treatment of cardiometabolic risk, according to disease phenotypes. While new options are adding to established therapeutic approaches, a sometimes difficult balance between the efficacy and safety of available medications has to be found in individual women.
1. Introduction
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women in their reproductive age. PCOS is a clinically heterogeneous condition defined by oligo- or anovulation, elevated androgen production, and polycystic ovary changes as per the Rotterdam criteria [1]. Apart from classic symptoms, including acne, hirsutism, and infertility, PCOS carries important cardiovascular comorbidities such as insulin resistance (IR), dyslipidemia, obesity, and hypertension [2,3]. Despite the lack of solid longitudinal studies, epidemiological data confirmed an increased prevalence of cardiovascular (CV) events in post-menopausal women with a clinical history of irregular menstrual cycles [4]. It is therefore paramount to promptly recognize and revert subtle cardiometabolic impairment to reduce future CV events. Although PCOS is a multifactorial disease with unknown pathophysiology, IR and compensatory hyperinsulinemia play a central role in the development and maintenance of both gynecological and metabolic disorders [5]. IR is indeed a common finding in PCOS, even though it is not found among diagnostic criteria, and represents a well-known predictor for the future development of type 2 diabetes (T2DM). One of the main causes of IR is overweight and obesity, whose prevalence can reach 80% in PCOS, but even lean patients often display relative hyperinsulinemia with a consequent increased likelihood of further developing T2DM [6]. Besides glucose metabolism impairment, hyperinsulinemia favors other classical CV risk factors such as hypertension, resulting from vascular smooth muscle cell hypertrophy and endothelial dysfunction through endothelin-1, and dyslipidemia [7]. Insulin has a gonadotropin-like action and may increase androgen production, which contributes to worsening both metabolic impairment and clinical picture [8]. In this regard, IR is an appealing target for PCOS management, and several insulin-sensitizing drugs have been used to treat patients with PCOS. However, it should be recalled that lifestyle changes should be the basis of any treatment because, if effective, they could significantly reduce cardiometabolic risk in later life [9].
The pathophysiology of PCOS is complex and several treatment options are currently available. In this comprehensive review, we set out to discuss the integration of novel biomarkers with pharmacological intervention to improve PCOS management. We summarize current treatment strategies, including discussion about disagreements in the field, and suggest future clinical trajectories.
3. Emerging Cardiometabolic Risk Biomarkers
4. Antiandrogen Therapy
4.1. Flutamide
4.2. Bicalutamide
4.3. Spironolactone
4.4. Ketoconazole
4.5. Finasteride
5. Antidiabetic Medications
5.1. Metformin
5.2. Inositols
5.3. Acarbose
5.4. Thiazolidinediones
5.5. Incretin Mimetics
5.6. SGLT2 Inhibitors
6. Metabolic Impact of Combined Oral Contraceptives
7. Statins
8. Conclusions
Hyperandrogenism is a hallmark of PCOS. Androgens in women play an unfavorable role in the CV system and, together with hyperinsulinemia and/or obesity, can cause high blood pressure, an increase of inflammatory markers, dyslipidemia, and CV events in PCOS patients. As these pathologic alterations or diseases usually begin in later periods of life, such as the third or fourth decade, when there may already be irreversible damage, overweight, obesity, hyperinsulinemia, IR, and dyslipidemia should represent the first step of therapeutic approach in PCOS subjects. However, these conditions represent co-morbidities that are not always present, especially in adolescence, while hyperandrogenism is the most frequent and one of the earliest causes of disease in PCOS. Thus, early correction of hyperandrogenism, already in youth, could improve or even prevent the aforementioned co-morbidities in later life. COCs represent for many scientific societies the drug of choice for the correction of hyperandrogenism in PCOS. However, COC intake can be accompanied by thromboembolic events, weight gain, and possibly additional, yet less frequent adverse effects. Thus, COC treatment needs to be personalized considering the metabolic and cardiovascular risk profile and family history of individual patients [182,183]. Furthermore, metabolic abnormalities impact global cardiovascular risk and mortality rate in the adult age of patients affected by PCOS [184,185]. Therefore, medications that can be taken for long periods with an acceptable safety profile should be considered. Antiandrogens, oral hypoglycemic agents, and possibly statins represent additional therapeutic options for the treatment of symptoms of androgen excess in PCOS and control of cardiometabolic risk factors. A sometimes-difficult balance between efficacy and safety of available medications according to disease phenotypes has to be found in individual women.
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