Weekly Osteopathic Manipulative Treatment to Improve Measures of Sympathetic Tone in Women With Polycystic Ovary Syndrome: A Randomized, Controlled Pilot Study

Participant Recruitment and Consent

Study participants were recruited from the Erie, Pennsylvania, area by direct advertising through radio, billboard, website, newspaper, and magazine advertisements. Physician referrals from Medical Associates of Erie physicians were also used to recruit potential participants. Recruitment lasted 4 months, from October 2016 through January 2017. Potential participants signed a consent form to have relevant medical records released to confirm PCOS diagnosis, as well as informed consent to participate in the study. All protocols were approved by the Lake Erie College of Osteopathic Medicine institutional review board (protocol No.23-156). (ClinicalTrials.gov No. NCT03383484)

Participant Inclusion and Exclusion Criteria

A questionnaire was given to each participant at the time of consent to supplement the medical records to determine eligibility. Participants were women between the ages of 22 and 43 years, with a body mass index (BMI) of 20 to 48, who had a confirmed diagnosis of PCOS and exhibited the 2003 Rotterdam criteria for PCOS diagnosis, defined as at least 2 of the following 3 features: clinical or biochemical hyperandrogenism (moderate acne or a modified Ferriman-Gallwey score ≥8 or free testosterone >5 pg/mL), polycystic ovaries (≥12 cysts on 1 ovary by ultrasonography or ovarian volume >10 mL for 1 ovary), and menstrual irregularity (defined as ≤8 menstrual periods per year or cycles averaging >35 days).¹¹ Exclusion criteria included smoking, use of hormone-based medications within the past 3 months (hormonal contraception, ovulation inducers, antiandrogens) or insulin-sensitizing agents, presence of another endocrine disorder diagnosis, pregnancy or breastfeeding within the past 6 months, and/or diagnosis of a major psychiatric disorder or use of antipsychotic medication. None of the participants had received OMT, chiropractic treatment, or acupuncture within the 6 months before the study. Participants who did not complete the 3-month measurements or who were in the OMT intervention group and did not complete at least 10 weeks of OMT were excluded from data analysis.

Study Design and Data Collection

Participants were enrolled in the study after confirming eligibility according to inclusion and exclusion criteria. All participants were randomly assigned a unique, sequential number to allow for random assignment to a group: the no intervention (control) or the OMT intervention group (Figure 1). As part of this study on nonpharmacologic interventions for women with PCOS, a third group undergoing yoga intervention for 3 months was also formed, and results are reported separately.⁴⁴ More participants were assigned to the intervention group in anticipation of some attrition because of the time commitment involved in participating in a weekly intervention for 3 months. Investigators collecting clinical and physiologic data were blinded to the intervention group (C.M., S.B., H.M., V.P., C.A.B.S.). Deidentified participant data were stored in a secure database.

Figure 1.

Study design and timeline. Participants with polycystic ovary syndrome (PCOS) were recruited from the Erie, PA, region. Participants were randomly assigned to either the osteopathic manipulative treatment (OMT) intervention or no intervention (control) group. Physiologic, endocrine, metabolic, reproductive, and psychological measurements were made before and on completion of the 3-month OMT intervention period for women in both groups. Nineteen women completed the study. Twenty others were assigned to a separate study arm evaluating the effect of yoga on PCOS.⁴⁴

Clinical Assessment of Metabolic, Reproductive, and Endocrine Parameters

In January 2017, a gynecologist (C.A.B.S.) who was blinded to the assigned intervention group assessed participants' weight, height, BMI, blood pressure, HR, waist and hip circumference, hirsutism (modified Ferriman-Gallwey score), and acne (face, chest, and back). Patients were asked about their menstrual cycle history and pattern (<25, 25-35, or >35 days), pregnancies, and any medications that they had taken within the last 6 months. Clinical assessments and measurements were repeated in April 2017 for participants in both the control group and the OMT intervention group (≥10 weeks of treatment), within 1 week after the conclusion of the 3-month OMT intervention.

Serum Analysis of Hormones and Metabolic Parameters

All participants had a fasting venous blood collection before the beginning of the intervention period, as well as on completion of the 3-month intervention period. All whole blood samples were collected by Associated Clinical Laboratories and analyzed by Associated Clinical Laboratories or Quest Diagnostics. Fasting blood glucose was measured by spectrophotometry; free testosterone was calculated from a mathematical model using sex hormone-binding globulin, albumin, and total testosterone (quantified by liquid chromatography-mass spectrometry); androstenedione and dehydroepiandrosterone (DHEA) were quantified by liquid chromatography-mass spectrometry; and serum insulin, DHEA sulfate (DHEA-S), luteinizing hormone, follicle-stimulating hormone, prolactin, thyroid-stimulating hormone, and serum human chorionic gonadotropin levels were determined by immunoassay.

Physiologic Assessment of Sympathetic Tone

For each participant, resting HR (measured by pulse oximeter) and blood pressure (standard method, using the antecubital artery) were recorded while the participant was seated and quiet. Heart rate variability was determined from a continuous 5-minute electrocardiogram recording while the participant was lying quietly in a supine position. Next, participants exercised on a stationary bike for 15 minutes at 70% effort, during which time HR was recorded at 5 minutes, 10 minutes, and 15 minutes, as well as 1 min after completion of the exercise.^45-47 Heart rate recovery after exercise was calculated as the difference between HR at 15 minutes while exercising and at rest 1 minute after exercise. Blood pressure was also recorded within 1 minute of exercise completion. Measurements were made by an investigator (C.M., H.M., S.B., and V.P.) blinded to each participant's group and taken in the same temperature- and humidity-controlled room for each participant.

HRV Analysis

Length of adjacent QRS complexes (normal-normal [NN] intervals) were quantified from a continuous 5-minute electrocardiogram recording for each participant. Recordings were analyzed for mean interval length between adjacent QRS complexes (mean NN), mean (SD) NN, and percentage of differences between adjacent NN intervals that were greater than 50 milliseconds (pNN50).⁴⁸

Assessment of Anxiety and Depression

All participants were provided unique web links to complete the Beck Anxiety Index (BAI) and the Beck Depression Index II (BDI-II; Pearson Clinical) before the 3-month OMT intervention and within 1 week of the completion of the OMT intervention period. Surveys were automatically scored online. The BAI scores were reported on a range of 0 to 63, with total scores interpreted as follows: 0 to 7, minimal anxiety; 8 to 15, mild anxiety; 16 to 25, moderate anxiety; and 26 to 63, severe anxiety. The BDI-II scores were reported on a range of 0 to 63, with total scores interpreted as follows: 0 to 13, minimal depression; 14 to 19, mild depression; 20 to 28, moderate depression; and 29 to 63, severe depression.

Osteopathic Manipulative Treatment

As in the earlier and separate arm of this study, all participants were evaluated by an osteopathic physician (S.E.D. or J.H.) for the presence of anterior and posterior CPs related to the heart, adrenal glands, and ovaries, and for VSRs in spinal regions segmentally related to the heart (T1-5), adrenal glands (T8-10) and ovaries (T10-11).² These regions were selected because PCOS pathophysiology involves overproduction of androgens by the ovaries, and the adrenal glands have also been implicated in contributing to excessive androgen production in some patients. Increased ovarian sympathetic tone has been reported in women as well as in animal models of PCOS, and the adrenal glands and heart are additional proxies for detecting increased sympathetic tone.^{2,14-18,26-31}

The OMT group was evaluated and treated for 12 consecutive weeks. Participants received OMT for positive CPs, which consisted of a firm yet gentle rotatory motion applied by fingerpad over each positive CP for heart, adrenal glands, and ovaries until dissolution of edema and lessening of tension, which indicated the end point. Treatment of positive CPs was followed by treatment of VSRs, consisting of rib-raising and paraspinal inhibition in the regions of the heart (T1-5), adrenal glands (T8-10), and ovaries (T10-11).⁴⁹

Data Analysis

Power analysis was conducted with the Statistical Decision Tree Power Calculator (QFAB Bioinformatics) to determine the sample size needed to detect a Pearson correlation coefficient of 0.6 with a power of at least .80, with a significance level of .05 (n=8 per group). GraphPad Prism 7.03 software was used for data analysis. Mean values of initial parameters (age, BMI, waist-to-hip ratio) for women in each group were analyzed by unpaired t tests to ensure that the groups of women were comparable. Paired t tests (for normally distributed data) or Wilcoxon matched-pairs signed rank tests (for data that were not normally distributed) were used to compare participants' initial measurements (0 months, January 2017) with their postintervention measurements (3 months, April 2017). Statistical significance was set at P<.05, with P values between .05 and .10 considered trending.

Postexercise Systolic Blood Pressure

Pre- and postintervention period measurements were compared for each individual (paired t test or Wilcoxon matched-pairs rank test; Table 2). A significant decrease was found in postexercise systolic blood pressure for participants in the OMT group (135.8 vs 129.1 mm Hg, P=.0002), with no change in this parameter for participants in the control group (Figure 2). Postintervention resting blood pressure was lower in the OMT group participants (124.2 vs. 120.7 mm Hg), but did not reach significance.

Figure 2.

Systolic blood pressure (BP) after exercise in OMT group. Postexercise BP results. Women in the osteopathic manipulative treatment (OMT) intervention group were treated weekly with manipulation of Chapman points, followed by rib-raising and paraspinal inhibition for viscerosomatic reflexes, for regions associated with the heart, ovaries, and adrenal glands. For this test, systolic BP after exercise was assessed within 1 minute of completing 15 minutes of 70% effort on a stationary bike. Compared with their test results before the 3-month intervention period, participants had a significantly lower systolic BP after exercise after the 3-month OMT intervention. ^aPaired t test, P<.005, n=10.

Heart Rate Recovery

There was no significant improvement in either group for resting HR after the intervention in women with PCOS (Table 2), although there was a trend toward improved HRR for the OMT group participants (23.2 vs 29.4 seconds; P=.099).

Heart Rate Variability

The mean participant values for resting blood pressure and measures of HRV (mean [SD] NN) were slightly outside of reported normal values for both groups,^45-47 indicating increased sympathetic tone in this study population and consistent with previous reports.^{2,14,21,50-53} No significant changes were detected in any of the measured parameters for HRV in either group after the 3-month intervention period (Table 2), although the mean NN value trended lower after the OMT intervention.

Metabolic, Endocrine, and Reproductive Parameters

No significant changes were observed in either group for endocrine parameters (free testosterone, DHEA, androstenedione, modified Ferriman-Gallwey score) or in menstrual cycle length (Table 3). Free testosterone was elevated in both groups of participants, as expected for women with PCOS. While the free testosterone was slightly lower in participants in the OMT group after the 3-month intervention compared with their initial values, this change did not reach statistical significance (5.69 vs 4.64 pg/mL). In the control group, the DHEA-S level was higher after the 3-month period (P=.0038). No significant changes were noted in either group for metabolic parameters (Table 3).

Anxiety and Depression Scores

Scores on the BAI indicated mild anxiety in most participants, with a few scores indicating minimal or moderate anxiety. Similarly, the BDI-II scores indicated minimal to mild depression in most participants, with some reporting moderate depression. No significant change in individual participants' pre- and postintervention scores were found in either group (Table 3), although both groups demonstrated a trend toward improved BDI-II scores after the 3-month intervention period (P=.06 for no intervention and P=.09 for OMT intervention).

Somatic Dysfunction and Spinal Facilitation

Somatic dysfunction caused by visceral pathology will result in a segmental response that can then affect the segmentally related viscera due to spinal facilitation.^49,54 With spinal facilitation, a population of neurons remain in a state of subthreshold excitation, which may be caused by chronically elevated afferent input, altered patterns of afferent input, or changes to the cells' microenvironment. Because of this relationship, treating somatic dysfunction as a result of VSRs provides a therapeutic effect on the segmentally related viscera. Inhibitory OMT techniques, such as paraspinal inhibition with rib raising and treatment of CPs, aim to disrupt the facilitated state. This disruption allows attenuation of the hypersympathetic response and balance of autonomic tone, thereby providing a therapeutic intervention to the involved viscera.^{41,42,49,55-57}

SNS and PCOS

The SNS plays a role in several disease processes, including the pathogenesis and presentation of PCOS.^14-18 Systemically, sympathetic hyperactivity can promote hypertension and reduce HRV, thereby contributing to the risk of developing cardiovascular sequelae.⁵⁸ Obesity, common in women with PCOS, can further activate the SNS and contribute to the development cardiometabolic disease.^22-25 Improving some aspects of sympathetic tone in women with PCOS may help to reduce the risk of cardiovascular sequelae. In addition to systemic effects, there appears to be a link between sympathetic hyperactivity and the production of ovarian androgens, as well as ovulation regularity,^26,31 further underscoring the importance of recognizing the role of the SNS in PCOS pathogenesis and identifying methods to improve sympathetic tone in this population. In our study, there appeared to be a decrease in serum testosterone levels with weekly OMT, suggesting that improvements in sympathetic tone may lead to improvements in androgen profile as well. Further studies are needed to investigate the potential for OMT to significantly improve the androgenic and reproductive profiles of women with PCOS, including larger clinical trials, longer intervention periods, and alternate OMT protocols.

Limitations and Future Studies

Limitations of this study included the small sample size, the lack of a sham procedure group, and use of a limited set of CPs. Expanding this type of study to a larger population of women with PCOS will help to elucidate whether the trends observed in serum testosterone levels, as well as other physiologic measures of sympathetic tone, such as HRR, are consistent and significant. The possibility that serum testosterone may be responsive to OMT is particularly appealing, as this would represent a nonpharmacologic approach to improve serum androgen levels in women with PCOS and potentially improve the associated clinical features, acne, and hirsutism. Women with PCOS have expressed interest in the availability of adjunctive therapies for managing PCOS-associated symptoms, citing the desire for effective, safe modalities with fewer side effects as a major reason³³; OMT could be such a modality. Research with a larger population will also allow for the inclusion of a sham group to help distinguish between the effects of manipulation compared with light touch. Future studies should investigate which combination of CP manipulation and rib raising are most effective in improving sympathetic tone, as our study focused on manipulation of points associated with the ovaries, adrenal glands, and heart in combination with rib raising for VSRs of the same. Given the prevalence of hyperinsulinemia and insulin resistance in women with PCOS,^7,9,10,13 manipulation of CPs and VSRs associated with the pancreas could be a beneficial adjunct treatment modality.⁵⁷

Persistent Sympathetic Hyperactivity

Over the course of the 3-month intervention period, some women in the OMT group had a decrease in the number of CPs or VSRs (not shown). However, some had a decrease in CPs but an increase in VSRs or vice versa, and 1 participant had an increase in both CPs and VSRs. These findings suggest that, although manipulation of CPs and rib raising improved some aspects of sympathetic tone in our study population, sympathetic hyperactivity and visceral dysfunction still existed. The majority of our participants, and women with PCOS in general, are overweight or obese, which has been shown to activate the SNS.^22-25 Therefore, given the role of the SNS in PCOS pathogenesis,^18,26-30 it is unlikely that sympathetic hyperactivity can be completely ameliorated in women with PCOS. However, any improvements in sympathetic tone are likely to confer some benefit in terms of reducing PCOS-associated symptom severity and cardiovascular risk.^21,22,24,59

Anxiety and Depression

In addition to the impact on endocrine and reproductive parameters, sympathetic tone, and metabolic health, studies^9,10,60-62 have also indicated that women with PCOS are more likely to have psychological disorders, including anxiety and depression. We did not find a significant improvement in depression scores after the 3-month intervention period, although both groups trended lower. This finding may reflect a seasonal improvement in feelings of depression, an improvement related to participating in a research study on PCOS, or a perceived increase in attention to the individual with respect to her PCOS diagnosis. The exact causes of depression and anxiety in women with PCOS are likely complex, as they may relate to clinical signs of hyperandrogenism, obesity, subfertility, sympathetic hyperactivity, or other physiological and psychological influences.^9,10 Regarding anxiety, there is a relationship between anxiety and sympathetic activation, although the direction of this relationship is debated and may differ depending on the underlying causes of anxiety. In the current study, most participants scored in the mild range for anxiety level, with a few scoring in the minimal and moderate ranges. We found no significant difference in either group between pre- and postintervention BAI scores. Our findings suggest that OMT alone may not be effective in addressing these psychological disorders, rather, it should be a component of a comprehensive care plan for women with PCOS. These results are consistent with other studies reporting anxiety in this population and highlight the need to consider this aspect of patient health when providing care and resources for women with PCOS.