Ovarian Hypertension: Polycystic Ovary Syndrome

Introduction

Polycystic ovary syndrome (PCOS) was originally described by Stein and Leventhal in 1935 as a reproductive disorder characterized by oligo-amenorrhea, hirsutism, and polycystic ovary morphology.¹ Thirty years ago, it was first reported that women with PCOS had hyperinsulinemia.² Subsequent research indicated that PCOS was associated with a unique disorder of insulin action, as well as defects in insulin secretion, and together these abnormalities conferred a substantially increased risk of glucose intolerance.³ Although the clinical manifestations of PCOS are heterogeneous, the hallmarks of the syndrome remain anovulation, androgen excess, and insulin resistance. Moreover, each of these features of the syndrome is responsible for the promotion of hypertension in this population. Therefore, therapy for hypertension should be targeted at treatment of these underlying abnormalities.

Diagnostic Criteria

The diagnostic criteria for PCOS have been a source of controversy. Outside the US, the diagnosis has been based on the presence of polycystic ovary morphology (PCO) by ovarian ultrasound examination; affected women are then further stratified based on ovulatory status. However, the finding that approximately 25% of normal women in many series can have PCO led investigators in the US to focus on the biochemical features of the syndrome for diagnostic criteria.^4-5 The 1990 NIH-NICHD conference on PCOS proposed what have become known as the NIH diagnostic criteria: hyperandrogenism (clinical and/or biochemical) and chronic anovulation with the exclusion of specific disorders of the ovary, adrenal and pituitary (Table 1).⁴ PCO by ultrasound was not included as a criterion because of the lack of diagnostic specificity of this finding.⁶ Ultrasonographically detected polycystic ovaries can be present in women with normal ovulation and sex hormone levels, whereas women with all the endocrine features of PCOS can have normal ovarian morphology by ultrasound exam.^6-7 The NIH criteria have been used to diagnose PCOS in the majority of the studies of hypertension in affected women.

Table 1.

Diagnostic Criteria for PCOS^a

NIH Criteriab	Hyperandrogenism/Hyperandrogenemia Chronic anovulation
Rotterdam Criteria	Two of the following: hyperandrogenism/hyperandrogenemia, chronic anovulation, polycystic ovaries
Androgen Excess Society criteria	Hyperandrogenism/Hyperandrogenemia Infrequent or irregular ovulation OR regular ovulation and polycystic ovaries

^aAll criteria include the exclusion of other medical conditions, including thyroid or pituitary dysfunction, androgen–secreting tumors, Cushing’s syndrome, or congenital adrenal hyperplasia

^bNIH criteria developed with National Institute of Child Health and Human Development

In 2003, an international conference in Rotterdam reassessed the diagnostic criteria for PCOS and proposed revised criteria that included PCO.⁸ The Rotterdam criteria require two of three of the following findings: hyperandrogenism, chronic anovulation, PCO (Table 1). Thus, these criteria would include all those women with PCOS by NIH criteria. However, the Rotterdam criteria also include women with hyperandrogenism and ovulatory cycles who would not be considered to have PCOS by NIH criteria. Since most ovulatory women with PCO have hyperandrogenism and increased LH levels, this additional group of women with PCOS according to Rotterdam criteria are analogous to the ovulatory PCO women identified by non-US investigators on the basis of ovarian ultrasound morphology. There are studies to suggest that ovulatory women with PCO are not insulin resistant compared to anovulatory women with PCO,⁹ although recent studies suggest they may have milder metabolic abnormalities.¹⁰ Therefore, it is unclear whether these women should be grouped with those with the classic anovulatory form of the disorder. Recently, the Androgen Excess Society (AES) developed diagnostic criteria for PCOS based on the feature of androgen excess, endorsing the NIH criteria but also recommending that women with regular ovulation and polycystic ovaries on ultrasound be included as a PCOS phenotype.¹¹

Epidemiology

PCOS is one of the most common endocrine disorders affecting women of reproductive age.¹² A recent Australian study examined the prevalence of PCOS in a retrospective birth cohort employing the NIH, Rotterdam, and AES diagnostic criteria.¹³ These data revealed prevalence based on NIH diagnostic criteria of 8.7 ± 2.0%, less than the 11.9 ± 2.4% and 10.2 ± 2.2% using Rotterdam and AES criteria, respectively. Prevalence estimates of PCOS among populations worldwide employing the NIH diagnostic criteria have been reported as approximately 6% in the Southeastern U.S.,¹⁴ Spain,¹⁵ the Mediterranean,¹⁶ and Mexico.¹⁷ Although studies have reported no statistically significant differences in the PCOS prevalence between black and white women,^{14, 18} there are data suggesting an increased prevalence of PCOS among Hispanic¹⁹ and Mexican-American¹⁷ women compared to other racial and ethnic groups. Nonetheless, PCOS is likely underdiagnosed in clinical practice so the use of chart based data in prevalence estimate derivations is problematic.

Pathophysiology

The biochemical reproductive phenotype in PCOS consists of increased LH relative to FSH secretion and hyperandrogenism.^4-5 (Figure 1). There is increased frequency of LH pulsatile release indicating that the frequency of GnRH secretion is increased. There is also increased amplitude of LH pulses that is secondary, in part, to increased pituitary sensitivity to GnRH, which appears to be estrogen-mediated. It is possible that there is also an increased amount of GnRH secreted per pulse. FSH release is relatively suppressed and the late luteal and early follicular phase increases that are essential for normal follicular development are absent. One explanation for these FSH abnormalities is the increased frequency of GnRH secretion, which results in a selective suppression of FSH relative to LH release.²⁰ The elevated circulating androgens feedback on the hypothalamic-pituitary axis, both directly by decreasing sensitivity to the normal actions of estrogen and progesterone to slow the frequency of pulsatile GnRH release²¹ and by extragonadal aromatization to estrogen, to increase LH relative to FSH release producing a self-sustaining syndrome.⁴

Figure 1.

Schema for the pathophysiology of PCOS. Increased GnRH pulsatility leads to a selective increase in LH pulsatility while suppressing FSH secretion. These gonadotropin secretory changes result in arrested follicular development and increased LH-dependent ovarian androgen production, increased theca cell androgen secretion, and decreased conversion of androgens to estrogens by the immature granulosa cells. These changes lead to increased ovarian androgen production, which feedback on the hypothalamic-pituitary axis, both directly by decreasing sensitivity to the normal actions of estrogen and progesterone to slow the frequency of pulsatile GnRH release and by extragonadal aromatization to estrogen, to increase LH relative to FSH release producing a self-sustaining syndrome. This figure is used with the permission of Andrea Dunaif.

Under normal circumstances, the theca cells of the ovarian follicles produce androgens under the control of LH. These androgens are then aromatized into estrogens, primarily estradiol, by the adjacent granulosa cells.²² FSH stimulates the granulosa cell growth and aromatase capacity. In PCOS, elevated LH levels stimulate enhanced theca cell androgen production. PCOS theca cells also have increased activity of multiple steroidogenic enzymes and produce increased amounts of androgens under basal circumstances as well as in response to LH.^22-23 Because of the acyclic FSH levels, there is arrested ovarian follicular development and decreased granulosa cell aromatase capacity resulting in decreased conversion of androgens to estrogens. Increased adrenal androgen secretion in a common finding is PCOS, most likely due to a shared defect in the steroid biosynthetic pathways common to the ovary and adrenals. The primary defect that initiates the reproductive features of PCOS remains unknown since it can be shown experimentally that either increasing androgen levels⁴ or GnRH release²⁴ can produce features of PCOS. However, the intrinsic abnormalities in thecal steroidogenesis taken together with recent family and genetic studies suggest that abnormalities in androgen biosynthesis may be a primary defect in many cases.²⁵

An additional biochemical hallmark of PCOS is increased ovarian and, frequently, adrenal androgen production.²⁶ There is increased activity of multiple steroidogenic enzymes common to the ovaries and the adrenal glands. This abnormality is accounted for in part by increased transcription of genes encoding for steroidogenic enzymes, including 3-β-hydroxysteroid dehydrogenase (3β-HSD), cytochrome P450 enzyme 17α-hydroxylase (P450c17), and 20α-hydroxysteroid dehydrogenase (20α-HSD), as well as increased mRNA accumulation of cholesterol side-chain cleavage enzyme (P450scc), 3β-HSD, P450c17, and 20α-HSD.

Insulin Resistance and Pancreatic β-cell Dysfunction

Although insulin resistance is a common feature of PCOS, not all women with PCOS are insulin resistant.²⁷ The insulin resistance in PCOS has been characterized in adipocytes by a post-binding defect in the insulin receptor-mediated signal transduction, which has also been confirmed in clinical studies of skeletal muscle action.²⁸ In addition, skin fibroblasts were used to demonstrate that defects in insulin signaling resulted from impaired insulin receptor tyrosine kinase activity.²⁷ This impairment has been determined to be secondary to increased receptor serine phosphorylation due to a serine kinase extrinsic to the receptor, which leads to selective resistance to the metabolic actions of insulin.²⁹

In addition to insulin resistance, beta cell dysfunction is present in PCOS and it is the combination of these two derangements that contributes to the development of T2DM.³⁰ The beta cell dysfunction seen in women with PCOS has been evidenced by several methods demonstrating impaired insulin secretion response to glucose and exists independently of impairment in glucose tolerance. Notably, the impaired insulin secretory response was observed most convincingly among the women who had first degree family members with T2DM.

Impaired glucose tolerance (IGT) and T2DM are both increased in women with PCOS compared to women of similar BMI with regular menses.³¹ In fact, in a large study of glucose intolerance among women with PCOS, 38.6% of the PCOS women had either IGT (31.1%) or diabetes (7.5%) by WHO criteria. Notably, when examining the non-obese women with PCOS, 10.3% had IGT and 1.5% had diabetes.³¹

Obesity

Obesity is present in 30-70% of women with PCOS, depending on PCOS diagnostic criteria used and race/ethnicity of the population.^{14, 22} Conversely, one study showed that 30% of morbidly obese women met criteria for PCOS compared to 5% of the lean population.³² The role of obesity in the development of PCOS has been supported by a prospective study revealing that abdominal obesity and weight gain after puberty were associated with the development of PCOS.³³ Obesity has also been shown to exacerbate the clinical complications of PCOS, including insulin resistance,²⁷ hirsutism,³⁴ and the prevalence of infertility.³⁵ Notably, bariatric surgery and correction of obesity have been shown to result in resolution of PCOS characteristics.³²

Genetic Susceptibility

The etiology of PCOS is unknown; however, several possible mechanisms have been postulated. In addition to the abnormal gonadotropin secretion and androgen excess previously discussed, the high heritability of PCOS characteristics suggests a genetic susceptibility to the disorder.^{25, 36-37} Candidate gene studies were initiated which examined genes associated with steroid hormone biosynthesis, gonadotropin, obesity, energy regulation, and insulin action.^38-39 However, the only susceptibility locus that has been replicated is a dinucleotide repeat polymorphism within an intron of the fibrillin-3 gene on chromosome 19.^40-41

Associated Metabolic Disorders

PCOS is characterized by multiple metabolic derangements, which may contribute to the development of hypertension and cardiovascular disease seen in this condition. However, it is important to note that, although women with PCOS manifest several cardiovascular disease risk factors, there have been no long-term prospective studies in women with PCOS that confirm the presence of increased cardiovascular disease events.⁴² One study employed menstrual irregularity as a proxy for PCOS in a prospective cohort study of 82,439 female nurses ages 20-35 years old.⁴³ During a fourteen-year follow-up, women with “usually irregular” or “very irregular” menstrual cycles had an increased risk for nonfatal or fatal coronary heart disease compared to women with “very regular” menstrual cycles [age-adjusted relative risks (RR), 1.25 and 1.67, respectively; 95% confidence intervals (CI), 1.07-1.47 and 1.35-2.06, respectively]; a finding that was still significant after adjusting for BMI. There was also an insignificant increase in overall stroke risk (RR, 1.30; 95% CI, 0.97-1.74) and in ischemic stroke risk (RR, 1.40; 95% CI, 0.97-2.04) associated with “very irregular” menstrual cycles.

Metabolic syndrome

Metabolic syndrome has been variably defined by several international organizations^44-49. However, all of the definitions include measures of central obesity, glucose intolerance, dyslipidemia, and high blood pressure. The prevalence of the metabolic syndrome in PCOS has been reported to be 43-47%, which is twice as high as the prevalence in the general population of comparable age, even after adjusting for BMI.⁵⁰ The components of the metabolic syndrome most commonly present in PCOS are central obesity and low serum high-density lipoprotein cholesterol (HDL); however, elevated blood pressure, impaired fasting glucose, and glucose intolerance are commonly present.⁵⁰ There is also an increased prevalence of metabolic syndrome among the sisters of women with PCOS.⁵¹

Dyslipidemia

The dyslipidemia in PCOS is similar to that seen in metabolic syndrome,⁵² characterized by low levels of HDL, small particle size of low-density lipoprotein cholesterol (LDL), and high triglyceride cholesterol levels.⁵³ This pattern is more often seen in obese than in lean PCOS, likely secondary to the presence of greater insulin resistance in obesity.⁴ The level of LDL cholesterol is also increased in women with PCOS and is less dependent on obesity than are HDL and triglyceride levels.⁵⁴ There is also evidence for heritability of dyslipidemia, so these lipid patterns can be seen not only in women with PCOS but also in their family members.⁵¹

Hypertension

Several studies suggest an increased prevalence of hypertension in women with PCOS compared to the general population^55-62 However, a factor complicating the interpretation of the studies is that obesity, which is common in PCOS, is itself a significant risk factor for hypertension and this variable was not consistently considered many studies. Moreover, in the studies which did adjust the analyses for BMI, either statistically or by study design involving matching control women by BMI, the association between hypertension and PCOS is not always clear.

Several studies demonstrated an association between PCOS and hypertension, but did not adjust for an elevated BMI. A Dutch study of PCOS women demonstrated a higher prevalence of hypertension among premenopausal women with PCOS compared to women without PCOS; however, the PCOS population was significantly more obese and the obesity could be responsible for the greater prevalence of hypertension in this population.⁵⁹ Additionally, hypertension was examined in menopausal women with PCOS who had undergone ovarian wedge resection.⁶³ This surgical procedure was the first established treatment for women with PCOS⁶⁴ and was commonly performed prior to the 1970s; however, it was discontinued due to the ovarian adhesions often following this procedure.⁶⁵ This study revealed that menopausal women post-ovarian wedge resection had a three-fold increased likelihood of being hypertensive compared to non-PCOS women.⁶³ These women with PCOS were also more obese than controls and this comparison was not adjusted for BMI. Although this study examines a postmenopausal population, the full burden of hypertension in PCOS has not been assessed since women with PCOS have not been followed prospectively beyond their reproductive years. One study which attempted to address this question was Wild et al. who conducted a retrospective examination of women with PCOS diagnosed an average of 31 years previously and found an increased prevalence of hypertension compared to a cohort of control women.⁶² However, given the study design, BMI was not considered in the statistical analysis and differences in BMI may explain the association with hypertension.

Additional studies demonstrated an association between PCOS and hypertension controlling for the influence of BMI. In one study, women with PCOS were 40% more likely to have elevated blood pressure than the non-PCOS women, independent of age, BMI, diabetes or dyslipidemia, (OR 1.41, 95% CI 1.31-1.51).¹⁹ Another population study from Brazil demonstrated similar findings in 69 women with PCOS when divided by BMI into normal, overweight, and obese categories and revealed a hypertension prevalence of 20.3%,;78.6% of these were obese and 21.4% were overweight.⁶⁶ An examination of a Czech population of PCOS women in their early 30s compared to non-PCOS women revealed that, after adjusting for BMI, PCOS women had higher blood pressure.⁵⁸ In a population of Dutch women with PCOS aged 45-54 yrs old, the prevalence of hypertension was 2.5 times greater than that of an age-matched Dutch female population.⁵⁹ Notably, the proportion of obese women with PCOS in this age group did not differ significantly from the control population.

Additionally, an investigation of daytime ambulatory blood pressure monitoring (ABPM) among young (mean age approximately 26 yrs) overweight women (mean BMI approximately 26 kg/m²) revealed women with PCOS had higher blood pressures compared to regularly-menstruating control women. The women with PCOS compared to controls, although all normotensive, had systolic blood pressures in the prehypertensive range (mean ± SD, 126 ± 11 vs. 119 ± 12 mmHg, p < 0.05) and was independent of BMI.⁶⁰

In addition to BMI, hypertension among women with PCOS may be affected by other background characteristics of the individual, such as race and ethnicity.¹⁹ The investigation by Lo et al. demonstrated that, among women with PCOS, the prevalence of hypertension or elevated blood pressure was lowest among Asians and Hispanics and highest among Blacks. Even after adjusting for age, BMI, and diabetes status, Blacks had the highest (OR 1.32, 95% CI 1.19-1.38) and Hispanics had the lowest (OR 0.68, 95% CI 0.62-0.75) prevalence of blood pressure elevation compared to the White population.¹⁹

There are data to suggest that the nocturnal decrease in blood pressure characteristic of healthy vasculature is absent in women with PCOS, both in adolescent⁶⁷ and adult⁶⁸ women. In the study examining adolescent women with PCOS, there was no difference in BMI between the women who had normal glucose tolerance (NGT) compared to IGT. However, all of the women with NGT manifested normal systolic blood pressure nocturnal dipping, whereas only 40% of those PCOS women with IGT demonstrated this normal blood pressure response.⁶⁷ In adult women with PCOS, ABPM was found to be increased in 30% of women with PCOS, a finding largely explained by the increased prevalence of obesity in affected women.⁶⁸

Other studies controlling for BMI have not revealed an association between PCOS and hypertension. A small study of 14 women with PCOS and 18 control obese women demonstrated no difference in blood pressures.⁶⁹ Another study of young lean PCOS compared to age-matched control women did not reveal an increased blood pressure among the PCOS women.⁷⁰ Conversely, a study of similarly overweight PCOS and control women did demonstrate a blood pressure discrepancy; however, the 50% prevalence of hypertension among PCOS women compared to 39% among control women did not reach statistical significance.⁷¹ One study demonstrated that obese women with PCOS were hypertensive compared to lean PCOS and lean control women. However, the lean PCOS women were not hypertensive compared to the lean control women.⁵⁶ Similarly, in a study of 244 PCOS and an equal number of control women, BMI was a significant predictor of both systolic and diastolic blood pressure among women with PCOS.⁵⁷ Additionally, there was no difference observed in ambulatory blood pressure in women with PCOS compared to control women with adjustment for BMI.⁷²

Hypertension in Pregnancy

Pregnant women with PCOS have a greater risk of perinatal morbidity from pregnancy-induced hypertension (PIH) and preeclampsia (PE) than non-PCOS pregnancies as demonstrated in a meta-analysis of pregnancy outcomes in women with PCOS compared to controls.⁷³ The studies included in the meta-analysis defined PIH as blood pressure ≥ 140/90 mmHg without proteinuria at a gestational age of >20 weeks) and defined PE as blood pressure ≥ 140/90 mmHg with proteinuria, either >0.3 g/24h urine or ≥ 2 + albustick at a gestational age of >20 weeks. The meta-analysis revealed an increased odds ratio of nearly 3.5-fold for both PIH (odds ratio, OR 3.67; 95% CI: 1.98-6.81), and PE (OR 3.47; 95% CI: 1.95-6.17). All of the women with PCOS in the preeclampsia studies included in the meta-analysis had higher BMI than controls. However, of the eight PIH studies included in the metanalysis, four studies matched PCOS and control women on BMI, while the other four studies had PCOS women with significantly higher BMI than the control women. In addition, the control groups were mainly spontaneous conceptions as opposed to the variable assisted reproductive therapies used among the PCOS women, which may⁷⁴ or may not⁷⁵ also increase the risk of preeclampsia.

Cardiovascular Disease Risk Factors

In studies that have examined more non-traditional risk factors for coronary heart disease, including inflammatory biomarkers,^76-77 impaired vascular function,⁷⁸ and arterial stiffness,⁷⁹ derangements were not observed in the PCOS populations independent of obesity. Adiponectin, an adipokine inversely associated with atherosclerosis⁸⁰ was also examined in PCOS and was found to be associated with insulin resistance and BMI, not with PCOS or testosterone levels.⁸¹ An examination of plasminogen activator inhibitor 1 (PAI-1) activity and tissue plasminogen activator (tPA) mass concentration between patients with PCOS and control women demonstrated that obese women with PCOS had increased levels of PAI-1 and tPA compared to controls; however, the lean PCOS levels of these two factors did not differ compared to the levels seen among the control women.⁸²

However, age-matched populations of women with PCOS have been found to have increased carotid intima media thickness (cIMT) compared to control women, even after adjusting for BMI.^83-85 Another study observed that cIMT was increased and brachial artery flow-mediated dilation was decreased in women with PCOS compared to age- and BMI-matched control women.⁸⁶ Coronary artery calcification has also been observed to be greater among women with PCOS compared control women, even after adjusting for age and BMI.^87-89

Pathophysiology of Hypertension in PCOS

Although the pathogenesis of PCOS has not yet been fully elucidated,⁹⁰ there are several mechanisms potentially responsible for the development of hypertension in PCOS (Box 1). Thus, the etiology of hypertension that occurs in the setting of PCOS is also multifactorial, including factors such as hyperandrogenemia, insulin resistance, obesity, and increased sympathetic nervous system activity.

Box 1. Potential Causes of Hypertension in Women with PCOS.

• Hyperandrogenism

• Insulin resistance

• Obesity

• Increased Sympathetic Nervous System Activity

Androgen Excess

There are data demonstrating that the hyperandrogenemia in PCOS women is associated with systolic and diastolic blood pressures in women with PCOS, independent of obesity or insulin resistance.⁹¹ Androgen excess has also been associated with an increase in cIMT in women with PCOS.⁸⁵ Increased cIMT has been widely used as a reflection of preclinical atherosclerotic disease, a contributor to the development of hypertension.⁹² A small study explored the relative impact of insulin resistance, another proposed etiology of hypertension in this population, compared to hyperandrogenism by studying PCOS women treated with an oral contraceptive containing 35 mcg of ethinyl estradiol and 2 mg of the antiandrogen cyproterone acetate (CPA-EE), to the insulin-sensitizer, metformin, then measuring ABPM and cIMT. The study revealed that CPA-EE use resulted in an increase in systolic, diastolic and mean arterial blood pressures during the day whereas metformin decreased all of these measures. No differences were observed in the nighttime parameters in response to either of these therapies. In addition, there was no statistically significant change in cIMT, although there was a tendency towards reduction in PCOS women treated with either CPA-EE or metformin. This study suggests that insulin resistance is more responsible than androgen levels for the hypertension seen in women with PCOS. However, the increase in blood pressure seen with the CPA-EE relative to the metformin group may have been due to the estrogen component and may not reflect the antiandrogenic effect.

Insulin Resistance

Hypertension may be secondary to enhanced sodium retention occurring in the setting of hyperinsulinemia.⁹³ High insulin levels have been associated with a subsequent increase in intracellular sodium and calcium.⁹⁴ as well as an increased insulin-like growth factor-1 (IGF-1) which may be associated with vascular smooth muscle hypertrophy. In support of the role of insulin resistance in mediating hypertension in women with PCOS, the beneficial effects of metformin on blood pressure have been reported.⁹⁵ Additionally, the insulin sensitizing effects of metformin lead to a decrease in serum advanced glycated end products (AGEs),⁹⁶ molecules that permit the proliferation and migration of smooth muscles cells to the vascular intima.⁹⁷ Subsequently, the decrease in AGEs seen in the setting of insulin sensitizer therapy may lead to a decrease in cIMT. Moreover, other investigators have found an improvement in cIMT in response to metformin therapy on women with PCOS.⁹⁸

Obesity

Obesity is a well-established risk factor for hypertension⁹⁹ and it has been considered the primary etiology implicated in the increased blood pressure in women with PCOS.⁶⁸ Current estimates internationally report greater than 60% of women with PCOS are overweight or obese.^100-102 One population study demonstrated that women with PCOS were more than four times more likely to be obese (body mass index ≥ 30 kg/m2) than non-PCOS women. Additionally, blood pressure was more likely to be elevated among women who were obese compared to those who were non-obese (43.1% vs. 12.4%, p< 0.001).

Sympathetic Nervous System

In addition, the sympathetic nervous system has been implicated in the etiology of hypertension in this population. Greater sympathetic nerve activity was found in a study of 20 women with PCOS who were compared to 18 weight- and age-matched control women.¹⁰³ The sympathetic nerve activity to the muscle vascular bed among women with PCOS was increased and highly correlated with testosterone level and to a lesser degree the cholesterol level. In addition, androgen excess¹⁰⁴ as well as insulin resistance¹⁰⁵ and obesity¹⁰⁶ have been implicated in stimulating the autonomic nervous system, thereby, each serving as a potential mediator of the hypertension observed in PCOS.

Therapeutic Considerations

Therapy for PCOS is targeted towards ameliorating or eliminating the symptoms for each individual woman. Consequently, given the association of hypertension with all of the common PCOS manifestations, treating the manifestations of PCOS may treat concomitant hypertension or the risk for hypertension as well. In addition, one needs to assess hypertension in the context of assessing other CV risk factors as well.¹⁰⁷

Treatment of hyperandrogenism revolves around the use of combination oral contraceptives (COC) or antiandrogens. However, the response to oral contraceptives has been inconsistent. The use of drospirenone, an antimineralocorticoid progestin, in combination with ethinyl estradiol compared to the vaginal contraceptive ring was associated with a minimal but statistically significant increase of diurnal and 24-hour systolic blood pressure in women with PCOS (drospirenone, 5 mmHg for both time periods, p = 0.001; and contraceptive ring, 6 mmHg for both time periods).¹⁰⁸ Another study demonstrated a more convincing decrease in systolic blood pressure in response to a drospirenone containing COC of 1.9 mmHg compared to a 1.7 mmHg increase in systolic blood pressure in the desogestrel-containing COC group of women with PCOS.¹⁰⁹ However, other investigations in PCOS demonstrated no change in blood pressure with a drospirenone-containing COC.^110-111

Another antiandrogenic therapy used in women with PCOS is spironolactone. This aldosterone antagonist has been used as a potassium-sparing diuretic in the setting of hypertension since the 1950s. It was serendipity that associated its use with improvement in hirsutism in a woman with PCOS undergoing treatment of hypertension¹¹² and it has since become the most widely used antiandrogen for female pattern hair loss in the US.¹¹³ Studies have demonstrated the efficacy in the treatment of hirsutism in women with PCOS¹¹⁴ so its use for this indication exceeds that for hypertension among women with PCOS. In studies examining the effect of spironolactone on blood pressure, one Indian study of spironolactone vs. metformin, no change in blood pressure was evident with either drug.¹¹⁵ In another investigation of PCOS women treated with spironolactone 100 mg daily for 2 months, mean blood pressure decreased significantly from 118 ± 5/82 ± 4 mmHg to 113 ± 4/72 ± 5 mmHg (p< 0.05).¹¹⁶

Lifestyle modifications, including diet and physical activity, are critical for women with PCOS who are overweight or obese in preventing hypertension.¹¹⁷ In addition, other methods of weight loss have shown promise for improving hypertension in the PCOS population. In a retrospective analysis of PCOS women who underwent a Roux-en-Y gastric bypass, normalization of blood pressure was observed in 78% of the previously hypertensive population.¹¹⁸

Conclusions

Hypertension is a significant contributor to the risk for cardiovascular disease. The increased prevalence of hypertension in women with PCOS may contribute to the increased risk of cardiovascular disease in women with PCOS. Thus, the Androgen Excess and Polycystic Ovarian Societies recommend that blood pressure be obtained in women with PCOS at every visit and that prehypertension be detected and treated given the potential benefit of lowering blood pressure for the prevention of CVD.¹⁰⁷ Whether hypertension is associated with PCOS independent of obesity remains controversial. Nevertheless, detection and subsequent treatment of hypertension in this population should decrease the adverse sequelae from hypertensive cardiovascular disease. Moreover, treatment of the risk factors inherent to PCOS, such as hyperandrogenism, insulin resistance, and obesity, may minimize the risk not only for the development of hypertension but also for incident cardiovascular disease independent of hypertension.¹⁰⁷ Treatment of hypertension in the PCOS population may take the form of lifestyle modification or pharmacotherapy.