Testosterone-associated blood pressure dysregulation in women with androgen excess polycystic ovary syndrome

Abstract

We tested the hypothesis that hyperandrogenemia in androgen excess polycystic ovary syndrome (AE-PCOS) is a primary driver in blood pressure (BP) dysregulation via altered sympathetic nervous system activity (SNSA), reduced integrated baroreflex gain and increased renin-angiotensin system (RAS) activation. We measured resting SNSA (microneurography), integrated baroreflex gain, and RAS with lower body negative pressure in obese insulin-resistant (IR) women with AE-PCOS [n = 8, 23 ± 4 yr; body mass index (BMI) = 36.3 ± 6.4 kg/m²] and obese IR controls (n = 7, control, 29 ± 7 yr; BMI = 34.9 ± 6.8 kg/m²), at baseline (BSL), after 4 days of gonadotropin-releasing hormone antagonist (ANT, 250 μg/day) and 4 days of ANT + testosterone (ANT + T, 5 mg/day) administration. Resting BP was similar between groups for systolic blood pressure (SBP; 137 ± 14 vs. 135 ± 14 mmHg, AE-PCOS, control) and diastolic BP (89 ± 21 vs. 76 ± 10 mmHg, AE-PCOS, control). BSL integrated baroreflex gain was similar between groups [1.4 ± 0.9 vs. 1.0 ± 1.3 forearm vascular resistance (FVR) U/mmHg], but AE-PCOS had lower SNSA (10.3 ± 2.0 vs. 14.4 ± 4.4 burst/100 heartbeats, P = 0.04). In AE-PCOS, T suppression increased integrated baroreflex gain, which was restored to BSL with ANT + T (4.3 ± 6.5 vs. 1.5 ± 0.8 FVR U/mmHg, ANT, and ANT + T, P = 0.04), with no effect in control. ANT increased SNSA in AE-PCOS (11.2 ± 2.4, P = 0.04). Serum aldosterone was greater in AE-PCOS versus control (136.5 ± 60.2 vs. 75.7 ± 41.4 pg/mL, AE-PCOS, control, P = 0.04) at BSL but was unaffected by intervention. Serum angiotensin-converting enzyme was greater in AE-PCOS versus control (101.9 ± 93.4 vs. 38.2 ± 14.7 pg/mL, P = 0.04) and reduced by ANT in AE-PCOS (77.7 ± 76.5 vs. 43.4 ± 27.3 µg/L, ANT, and ANT + T, P = 0.04) with no impact on control. Obese, IR women with AE-PCOS showed decreased integrated baroreflex gain and increased RAS activation compared with control.NEW & NOTEWORTHY Here we present evidence for an important role of testosterone in baroreflex control of blood pressure and renal responses to baroreceptor unloading in women with a common, high-risk androgen excess polycystic ovary syndrome (AE-PCOS) phenotype. These data indicate a direct effect of testosterone on the vascular system of women with AE-PCOS independent of body mass index (BMI) and insulin-resistant (IR). Our study indicates that hyperandrogenemia is a central underlining mechanism of heightened cardiovascular risk in women with PCOS.

Keywords: angiotensin-converting enzyme; baroreflex gain; blood pressure; muscle sympathetic nerve activity; renal angiotensin system.

Figure 1.

Protocol for gonadotropin releasing hormone (GnRH) antagonist and hormone administration.

Figure 2.

Total (Total_[T]) and free testosterone (Free_[T]) changes during gonadotropin releasing hormone suppression (ANT) and testosterone addback (ANT + T). Groups: androgen excess polycystic ovary syndrome (AE-PCOS), n = 8, n = 7 at baseline (BSL); control, n = 7. n = 7 for T in PCOS. Please note the different scales on the y-axis between AE-PCOS and control. Data were analyzed with two-way repeated-measures ANOVA followed by planned comparisons within each group. Bars in the graphs represent means.

Figure 3.

Serum hormone concentrations before and over hormone treatments. Data are concentration levels in androgen excess polycystic ovary syndrome (AE-PCOS) at baseline, during hormone suppression (ANT), and with testosterone administration (ANT + T). Groups: AE-PCOS, n = 8, n = 7 at baseline (BSL); control, n = 7. *Overall effect of group, AE-PCOS vs. control, P = 0.0016; **AE-PCOS vs. control, P = 0.04. S_[T], total testosterone; S_[E2], serum 17β-estradiol; Free_[T], free testosterone (calculated from S_[T]/S_[SHBG]). Free E₂ index (FEI) is calculated by dividing the serum S_[E2]/S_[SHBG] × 100 pmol/L. Data were analyzed with two-way repeated-measures ANOVA followed by planned comparisons within each group. Bars in the graphs represent means.

Figure 4.

Resting muscle sympathetic burst frequency and incidence (MSNA) at rest. Groups: androgen excess polycystic ovary syndrome (AE-PCOS), n = 8; insulin resistant (IR) obese/overweight control, n = 7. Groups: AE-PCOS, n = 8, n = 7 at baseline (BSL); control, n = 7. Data were analyzed with repeated-measures ANOVA followed by planned comparisons within each group (see Table 4). Data are presented as means ± SE.

Figure 5.

Stroke volume (SV) changes in women with androgen excess polycystic ovary syndrome (AE-PCOS) and control during lower body negative pressure (LBNP). Data are shown as a function of LBNP preceded by 7° head-down tilt. Groups: AE-PCOS, n = 8, n = 7 at baseline (BSL); control, n = 7. Women were tested during gonadotropin releasing hormone suppression (ANT) and testosterone addback (ANT + T). Groups: AE-PCOS, n = 8; control, n = 7. Data were analyzed with repeated-measures ANOVA followed by planned comparisons within each group. Data are presented as means ± SE.

Figure 6.

Integrated baroreflex gain (iBR) in women with androgen excess polycystic ovary syndrome (AE-PCOS) and control during lower body negative pressure (LBNP). iBR gain is calculated as forearm vascular resistance (FVR)/mmHg as function of LBNP preceded by 7° head-down tilt. Groups: AE-PCOS, n = 8; control, n = 7. Women were tested during gonadotropin releasing hormone suppression (ANT) and testosterone addback (ANT + T). Groups: AE-PCOS, n = 8; control, n = 7. Data were analyzed with repeated-measures ANOVA followed by planned comparisons within each group. Bars in the graphs represent means.