The effect of oral contraceptive pill use on sympathetic nerve activity in patients with polycystic ovarian syndrome

Objective: Polycystic ovarian syndrome is a complex endocrine disorder. In addition to hyperandrogenism and ovarian dysfunction, obesity is associated with increased cardiovascular risk factors such as lipid abnormalities. High sympathetic nerve activity, is thought to be another cardiovascular risk factor, has been shown to correlate with circulating high testosterone levels. However its role on the pathophysiology of the polycystic ovarian syndrome has not been clearly established. Oral contraceptive pills are considered as first line therapy for women with polycystic ovarian syndrome who do not desire fertility. The aim of our study is to compare the sympathetic nerve activity between polycystic ovarian syndrome and control group and to evaluate whether oral contraceptive pill therapy has any effect on sympathetic nerve activity at the end of 1 month follow-up period of oral contraceptive pill users with or without polycystic ovary syndrome . Materials and Methods: Our study has designed as a prospective, case – control study including patients diagnosed with polycystic ovarian syndrome according to the Rotterdam criteria (n=41), in Department of Obstetrics and Gynecology at Dokuz Eylul University, Izmir, Turkey, between October 2017 and March 2018. The cases are compared with the same number of healthy controls. Healty women, who have regular menstrual cycles and no fertility problems in history was defined as control group. Body mass index, waist-hip ratio, Ferriman–Gallwey score, systolic – diastolic blood pressure measurements (mm/Hg) were calculated before starting oral contraceptive pill therapy and at the end of one month follow up. For oral contraceptive pill treatment, we prescribed a monophasic oral contraceptive pill, containing 30 mcg ethinyl estradiol plus 2 mg dienogest (Dienille, Exeltis, Sariyer, Istanbul), 21 film-coated tablets for one month. Follicule stimulating hormone, luteinizing hormone, estradiol, total testosteron, dehydroepiandrosterone sulfate, sex hormone binding globuline, prolactin, tiroid stimulating hormone were measured and free androgen index was calculated by using the total testosteron and sex hormone binding globuline levels ; Insulin resistance and glucose tolerance were assessed by baseline 75 g oral glucose tolerance test (OGTT) according to World Health Organization criteria, before starting oral contraceptive pill therapy and at the end of one month treatment follow up, in early follicular phase (days between D1-D5 of the menstrual cycle). In addition, sympathetic skin response and heart rate variability measurements were performed in the neurology / neuropsychology / electromyography laboratory to assess sympathetic activity for all participants before starting oral contraceptive pill therapy and follow up evaluations were made one month later in all participants. The study protocol was approved by our Institutional Review Board and Turkish Health Ministry Drug and Medical Device Foundation.RESULTS: The mean value of age of all participants (n=82) included the study was 28.34 ± 5.63 years and the mean value of age in PCOS group was significantly lower than control group (26.44±4.57 vs 30.24 ± 5.99, p=0,002). The mean value of arterial pressure (87.65±7.89 mmHg vs 82.69±6.65 mmHg, p=0.003), Ferriman- Gallwey score (9.12±2.77 vs 5.24±1.49, p<0.001), ovarian volume (p=0.001 vs p<0.001), number of follicles (the mean value of right ovaries 12.12±2.81 vs 7.73±1.94, p <0.001); the mean value of left ovaries 12.80±3.60 ile 7.75±1.86, p <0.001 )were significantly higher in PCOS group as compared to healthy controls. Similarly, the prevalence of hirsutism (FGS>8)( p<0.001) and acne were significantly higher in PCOS group (p=0.027). In the baseline condition the LH/FSH ratio (p=0.026), LH (p=0.044), DHEAS(p=0.023) and total testosterone levels(p=0.040) were significantly higher in women with PCOS as compared to healthy controls. After one month of treatment, reductions in Ferriman- Gallwey score (p=0.011), ovarian volumes (of both ovaries p<0.001), number of follicles (of both ovaries p<0.001), the LH/FSH ratio (p=0.003), LH (p=0.011) and androgen hormone levels were statistically significant (of DHEAS p=0.001; of total testosterone p=0.011); while their SHBG levels were significantly increased (p=0.007) as compared to baseline measurements.Sympathetic skin response (SSR latency, SSR amplitude) and R-R analysis parameters (Valsalva test, Standup test) were evaluated before starting oral contraceptive pill therapy and at the end of one month treatment follow up in PCOS and control group. The mean values of SSR amplitude and R-R analysis- valsalva test were higher in PCOS group as compared to the control group. However, these differences were not statistically significant. Similarly, no statistically significant difference in SSR latency and R-R analysis-standup test were demonstrated between PCOS and control groups.When evaluating the changes before and after treatment, the mean value of SSR amplitude was lower as compared to baseline conditions in one month treatment follow up in PCOS patients, even the decrease was not statistically significant. In control group, there was no significant difference in the mean values of SSR amplitude and R-R Valsalva test; while SSR latency and R-R standup test were found to be significantly lower when comparing the baseline to one month follow up. CONCLUSION: Although there is no statistically significant difference, our observations demonstrated increased SSR amplitude and decreased SSR latency in PCOS group as compared to healthy controls. In conclusion our study supports the increased sympatovagal activity in patients with polycystic ovarian syndrome.