Abstract
Objective
To explore the association of hypothalamic-pituitary-adrenal activity with ovarian functioning in women with and without chronic abdominal pain (CAP).
Design and Setting
A secondary data analysis was performed using data from female participants in a natural history protocol at the National Institutes of Health.
Participants
A total of 36 women (19 – 39 years, mean 27.11) were included in the study.
Methods
This pilot study was conducted using a subset of participants enrolled in a natural history protocol conducted in the Hatfield Clinical Research Center at the National Institutes of Health. The parent study included participants with and without CAP who provided a five hour urine sample for determination of cortisol levels and serum samples for determination of circulating levels of cortisol, luteinizing hormone, and follicle stimulating hormone. Chronic abdominal pain was defined as presence or absence of chronic pain for ≥ 6 months and was determined via self-report.
Results
Anti-Müllerian hormone (AMH) concentrations declined significantly with age as expected. When AMH levels were dichotomized as normal or abnormal (defined as higher or lower than age-specific normative ranges), there were significant associations between abnormal AMH levels and CAP and urine cortisol levels. Subjects with CAP or low urine cortisol levels were significantly more likely to have abnormal AMH levels.
Conclusion
Results suggest that chronic abdominal pain and hypothalamic-pituitary-adrenal dysregulation may be associated with abnormal AMH levels.
Key terms: ovarian reserve, AMH, chronic abdominal pain, reproductive health
Call-outs
Identifying factors that contribute to the decline of ovarian reserve may help detect and prevent follicular depletion, premature ovarian failure, and impaired fertility.
Hypothalamic-pituitary-adrenal dysregulation may contribute to ovarian dysfunction as expressed by abnormal anti-Müllerian hormone levels in women with chronic abdominal pain.
Anti-Müllerian hormone, as measure of ovarian reserve, may offer valuable insight into the enduring effects of hypothalamic-pituitary-adrenal activity on the reproductive system.
One in ten women faces early ovarian senescence, which meand that around 10% of women will experience fertility problems related to diminished ovarian reserve by their early to mid-thirties (Maheshwari, Bhattacharya, & Johnson, 2008). Ovarian reserve, the number of remaining follicles in the ovary, declines naturally with age; however, researchers recently demonstrated that age alone is not an accurate indicator of reproductive age and that other factors may be implicated in the depletion of the ovarian follicle pool (van Disseldorp et al., 2008). Thus, identifying factors that contribute to the decline of ovarian reserve may aid in the prevention and early detection of follicular depletion, premature ovarian failure, and importantly impaired fertility (Lie Fong et al., 2009).
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis accelerates biological aging and may contribute to ovarian senescence (Miller, Chen, & Parker, 2011; Révész et al., 2013). Chronic physiologic stress, such as chronic abdominal pain (CAP) can lead to HPA dysregulation (Révész et al., 2013). Women report CAP more frequently than men in the United States (2:1), and CAP is estimated to occur in 14% of women worldwide (Lovell & Ford, 2012; Peace et al., 2012). Individuals with chronic pain often exhibit HPA dysregulation (Simons, Elman, & Borsook, 2014; Vachon-Presseau et al., 2013), and for this reason, CAP is an ideal model for exploring the influence of HPA activity on ovarian function. In this pilot study, we explored the association between chronic pain, a model of HPA deregulation, and ovarian reserve.
Anti-Müllerian Hormone: A Measure of Ovarian Reserve
Anti-Müllerian hormone (AMH) is produced by the granulosa cells of growing ovarian follicles until they have reached the size and differentiation state at which they may be selected for dominance (La Marca et al., 2012). Kelsey et al. (2011) validated serum AMH as a biomarker of ovarian reserve and demonstrated changes in AMH levels throughout a female’s lifespan (Kelsey, Wright, Nelson, Anderson, & Wallace, 2011). AMH levels steadily increase from conception, reach their peak at 24.5 years of age and then steadily decline until menopause (Kelsey et al., 2011). Two properties of AMH make it particularly useful in the study of ovarian reserve; the decline of AMH levels in serum is the earliest indication of a decline in ovarian reserve and AMH levels remain stable throughout the menstrual cycle (Shaw et al., 2011).
AMH has been used to predict ovarian response to reproductive assistive technologies and to determine the effect of chemotherapy and radiation on ovarian functioning. More recent data supported the association between AMH and the onset of menopause, significantly expanding the potential application of this measure as a biomarker of ovarian function (van Disseldorp et al., 2008). Factors associated with lower serum concentrations are obesity (Malhotra, Bahadur, Singh, Kalaivani, & Mittal, 2013; Steiner, Stanczyk, Patel, & Edelman, 2010), oral contraceptive use, (Dewailly et al., 2014; Steiner et al., 2010), and pregnancy (Nelson, Stewart, Fleming, & Freeman, 2010). However, it is not known if chronic pain, or HPA dysregulation, affects ovarian reserve.
HPA Dysregulation, Stress and Ovarian Function
HPA dysregulation due to repeated or prolonged stressors, such as chronic pain, stimulates cortisol secretion, reducing pulsatile luteinizing hormone (LH) secretion and interrupting the follicular phase of the menstrual cycle (Breen & Mellon, 2014). At homeostatic levels, cortisol contributes to steroid biosynthesis and maintenance of gonadotropin release; elevated cortisol levels suppress gonadotropin releasing hormone (GnRH) secretion at the level of the pituitary and increases rates of follicle atresia (Whirledge & Cidlowski, 2010; Whirledge & Cidlowski, 2013).
Allsworth et al. (2001) were among the first to investigate the effect of chronic stress on ovarian reserve. They examined whether ovarian hormone levels (follicle stimulating hormone [FSH] and estradiol [E2]) indicative of menopausal changes were observed at an earlier age among 732 women (ages 36–44) who experienced physical or sexual violence compared with women who reported no exposure to violence. More extreme levels of both FSH and E2 in relation to abuse history among premenopausal women 41–45 years of age were observed, whereas little difference was seen for younger women. Allsworth et al. offered a potential biological explanation for the association between abuse history and ovarian function; stress activates the HPA axis and stimulates glucocorticoid secretion, which in turn inhibits the synthesis and release of GnRH, LH, and FSH. However, Allsworth et al. did not include a biomarker of stress in the study and as a result, were unable to examine this proposed biological mechanism (Allsworth, Zierler, Krieger, & Harlow, 2001).
Pal et al. (2010) expanded the work of Allsworth et al., examining associations between acute (serum cortisol) and chronic (history of abuse and/or drug use) psyho-social stress and biomarkers of ovarian reserve (FSH and Müllerian-Inhibiting-Substance [MIS], now referred to as AMH) in 89 pre-menopausal infertile women <42 years of age. Women were considered to have diminished ovarian reserve (DOR) if they either demonstrated early follicular phase (days 1–3) FSH levels >10 mIU/ml and/or poor ovarian response during attempts at ovarian hyperstimulation. Those with chronic stress demonstrated reduced ovarian reserve parameters: higher FSH (p = 0.051) and significantly lower MIS levels (p = 0.034), and were three times more likely to be diagnosed with DOR (p = 0.025). However, no association was observed between serum cortisol levels and DOR. Pal et al. concluded that chronic but not current stress was associated with DOR. They proposed inappropriate HPA activation as a plausible explanation for this association (Pal, Bevilacqua, & Santoro, 2010). Because a biomarker of chronic stress was not included in the study, they were unable to provide evidence supporting this theory.
While it is well established that psychological stress interrupts normal reproductive functioning (An, Sun, Li, Zhang, & Ji, 2013; Kalantaridou et al., 2010; O’Connor et al., 2011; Whirledge & Cidlowski, 2013), the biological mechanisms underlying this effect are poorly understood (Bleil et al., 2012; Lynch, Sundaram, Buck Louis, Lum, & Pyper, 2012). The purpose of this pilot study was to explore the association between HPA activity and ovarian reserve (AMH) in women with CAP. Because CAP is associated with HPA dysregulation, we hypothesized that women with CAP would exhibit abnormal AMH concentrations.
Theoretical Framework
The theoretical framework used to guide this study was life history (Whirledge & Cidlowski, 2013). Life history theory posits that the allocation of biological resources is a trade-off between survival and reproduction. The intrinsic and extrinsic environments of the organism influence the timing of puberty, fertility outcomes, and reproductive lifespan. The division of resources is mediated through HPA activation. HPA activation leads to an increase in glucocorticoids, directing resources to vital physiological activities such as energy mobilization, cardiac output, and cognition. At normal physiological levels, glucocorticoids promote reproductive function, but in circumstances of prolonged stress, such as chronic pain, prolonged exposure to increased levels of glucocorticoids suppresses gonadotropin release.
Methods
Study Population
The protocol was approved by the Institutional Review Board at the National Institutes of Health (Clinicaltrial.gov # NCT00824941). This pilot study was conducted using a subset of participants enrolled in a natural history protocol (Clinicaltrial.gov #NCT00824941) conducted in the Hatfield Clinical Research Center at the National Institutes of Health. The parent study included participants who completed the Socio-demographic Questionnaire developed by the Center for Research in Chronic Disorders, University of Pittsburgh School of Nursing (1999) and provided urine and serum samples. For this pilot study, only women between the ages of 19 and 39 years who had their menses for at least two years were included. Exclusion criteria were history of organic gastrointestinal disease, cardiac, pulmonary, neurologic, renal, endocrine, or gynecologic pathology; taking medications for gastrointestinal symptoms daily or other medications that would alter serotonin, catecholamines, or cortisol; work during the late evening and night shifts; severe co-morbid pain or psychiatric conditions; > 300 mg of caffeine containing beverages or food in the afternoon-evening or > 2 servings of alcohol containing beverages every day; unable to physically use the touch screen for the purpose of the study; visually impaired or institutionalized; or pregnant or lactating. A total of 36 women (33.3% Black or African American, 47.2% White, 19.4% Asian/Other) between the ages of 19 and 39 years with mean age 27.11 ± 5.03 were included in the study. All participants were between days 3 and 7 of their menstrual cycles.
Data Collection
Participants enrolled in the parent study completed the socio-demographic questionnaire electronically. Whole blood was collected between the hours of 0800 and 1000, and a 5 hour urine sample was collected between the hours of 1000 and 1500. Whole-body air displacement plethysmography, which is used to measure body fat percentage, was completed on all participants. Body fat of ≥ 30% was categorized as high body fat and less than 30% as low body fat. Urine cortisol was measured via liquid chromatography-tandem mass spectrometry. Cortisol secretion follows a diurnal pattern, and levels peak in the morning and steadily decrease throughout the day (Hannibal & Bishop, 2014). Thus, 5 hour urine cortisol reflects a time-averaged measure of adrenocortical function. Serum was analyzed for circulating levels of cortisol, FSH, and LH. CAP was defined as self-reported presence or absence of abdominal pain for ≥ 6 months and was confirmed during their clinical visit using the Gastrointestinal Pain Pointer (Henderson et al., 2015).
AMH
For this pilot study, in addition to the measures included in the parent study as descried above, the AMH Gen II ELISA (Beckman Coulter, Inc., Brea, CA) was used to measure AMH concentrations in stored serum samples of 36 women per manufacturer’s instructions. The AMH Gen II ELISA has a sensitivity of 0.57 pmol/l, and the intra-assay coefficient of variation was 4.5%. The validated model of serum anti-Müllerian hormone by Kelsey et al. (2011) and the nomogram with normative values for age published by La Marca et al. (2012) were used to interpret AMH levels. Continuous AMH levels were used to investigate associations between AMH, CAP, serum and urinary cortisol, and body fat. A dichotomous AMH variable (normal or abnormal) was also created for contingency analysis. Abnormal AMH values were defined as values which fell above or below the normative age-specific ranges published by La Marca et al.
Statistical Analysis
Descriptive analyses were performed for demographic variables using grouping factors: high (≥ 30%) and low (< 30%) body fat, presence or absence of CAP, oral contraceptive usage, and AMH category (normal or abnormal). Body fat (Freeman et al., 2007; Malhotra et al., 2013; Steiner et al., 2010) and oral contraceptive usage (La Marca et al., 2010; Shaw et al., 2011) were included as grouping factors in the descriptive analysis because of prior evidence of their association with abnormal AMH levels. CAP was included to explore differences between participants with and without chronic pain.
Multiple linear regression was used to explore associations between serum AMH concentration and serum and urine cortisol, FSH and LH, body fat, and CAP with and without adjusting for age as a covariate in the model. A contingency analysis was also conducted to evaluate the association between categorized AMH levels (normal or abnormal) and CAP (yes, no) and serum and urine cortisol respectively. All p-values ≤ 0.05 were considered statistically significant and no adjustment for multiplicity was made. Mean ± SD were used to report the average and dispersion, unless otherwise specified. Analysis was performed using SPSS 15 (SPSS Inc., Chicago, Illinois) and JMP 11 (SAS Inc. Cary, NC).
Results
There were significant differences in laboratory and demographic data between selected grouping factors (Table 1). Participants with CAP had lower urine cortisol levels (p = 0.02) and LH levels (p = 0.048) than those without CAP. Participants with high body fat were older than participants with low body fat (p = 0.03). Those who used oral contraceptives had significantly lower FSH (p = 0.002) and LH (p ≤ 0.001), and higher serum cortisol levels (p ≤ 0.001).
Table 1.
Overall (n = 36) | Pain (n = 17) | No Pain (n =19) | p-value | High Body Fat (n = 22) | Low Body Fat (n = 14) | p-value | |
---|---|---|---|---|---|---|---|
Age (years) | 27.11 ± 5.03 | 28 ± 3.82 | 26.32 ± 5.9 | 0.31 | 28.64 ± 4.87 | 24.71 ± 4.44 | 0.019* |
Body Fat (%) | 31.99 ± 8.85 | 33.83 ± 7.76 | 30.13 ± 9.77 | 0.22 | 37.68 ± 5.71 | 22.75 ± 4.05 | < 0.001*** |
FSH (U/L) | 4.50 ± 2.14 | 4.5 ± 2.44 | 4.51 ± 1.96 | 0.99 | 4.84 ± 2.2 | 3.99 ± 2.08 | 0.25 |
LH (U/L) | 3.64 ± 2.66 | 2.65 ± 2.25 | 4.38 ± 2.78 | 0.048* | 3.46 ± 2.42 | 3.72 ± 3.08 | 0.79 |
Serum cortisol (mcg/dL) | 11.06 ± 4.85 | 12.14 ± 5.27 | 10.26 ± 4.49 | 0.26 | 10.76 ± 4.59 | 11.75 ± 5.46 | 0.58 |
Urine Cortisol | 40.68 ± 46.92 | 29.59 ± 29.17 | 51.16 ± 57.99 | 0.022* | 31.92 ± 27.01 | 55.51 ± 67.69 | 0.09 |
AMH | 4.05 ± 3.11 | 4.31 ± 4.16 | 3.81 ± 1.81 | 0.504 | 3.9 ± 3.43 | 4.27 ± 2.64 | 0.29 |
| |||||||
Overall (n=36) | OC Use (n =12) | No OC Use (n = 24) | p-value | Abnormal AMH (n=5) | Normal AMH (n=31) | p-value | |
| |||||||
Age (years) | 27.11 ± 5.03 | 26.17 ± 3.76 | 27.58 ± 5.57 | 0.51 | 29 ± 2.92 | 26.81 ± 5.26 | 0.32 |
Body Fat (%) | 31.99 ± 8.85 | 29.6 ± 7.8 | 33.02 ± 9.43 | 0.37 | 34.68 ± 9.43 | 31.42 ± 8.95 | 0.41 |
FSH (U/L) | 4.50 ± 2.14 | 2.99 ± 1.93 | 5.26 ± 1.89 | 0.002** | 3.68 ± 1.68 | 4.64 ± 2.23 | 0.34 |
LH (U/L) | 3.64 ± 2.66 | 1.58 ± 2.34 | 4.56 ± 2.24 | <0.001*** | 3.87 ± 2.7 | 1.68 ± 1.29 | 0.12 |
Serum cortisol (mcg/dL) | 11.06 ± 4.85 | 16.28 ± 3.63 | 8.58 ± 3.09 | <0.001*** | 13.28 ± 5.37 | 10.8 ± 4.82 | 0.34 |
Urine Cortisol | 40.68 ± 46.92 | 32.88 ± 23.41 | 44.75 ± 55.48 | 0.87 | 16.64 ± 10.94 | 44.69 ± 49.48 | 0.04* |
AMH | 4.05 ± 3.11 | 4.47 ± 4.5 | 3.83 ± 2.21 | 0.81 | 5.88 ± 7.13 | 3.75 ± 1.97 | 0.49 |
Note. BMI = body mass index; FSH = follicle stimulating hormone; LH = luteinizing hormone; TSH; AMH = Anti-Müllerian hormone; OC = oral contraceptive
p < 0.05,
p < 0.01,
p < 0.001
CAP was negatively associated with urine cortisol levels (p = 0.02). Subjects with CAP also had significantly lower LH levels. As expected, OC use was associated with lower LH and FSH levels. OC use was also associated with higher serum cortisol levels. Previous studies have demonstrated this association; exogenous estrogens in oral contraceptive pills increase corticosteroid-binding globulin and total plasma cortisol concentrations (Jung et al., 2011).
Serum AMH concentrations were negatively correlated with age as expected (r = −.423, p = 0.01). Serum AMH, with and without adjusting for age, was not associated with CAP, urine and serum cortisol, and body fat. However, when AMH was categorized as normal or abnormal (La Marca et al., 2012) a contingency table analysis showed serum AMH was associated with CAP and 5 hour urinary cortisol. Participants with abnormal AMH levels (n = 5) were more likely to have CAP (100% vs 38% p = 0.01) than those with normal AMH levels (n = 31). Participants with abnormal AMH levels were also more likely to have a lower 5 hour urine cortisol (16 ± 11 vs 45 ± 49, p = 0.04) than those with normal AMH levels (Figure 1). AMH (normal or abnormal) was not associated with body fat percentage (p = 0.41) or serum cortisol (p = 0.34).
Discussion
We found that urine cortisol levels were lower in women with CAP. Others have reported that chronic stress, including chronic pain, is associated with lower or blunted cortisol levels (Generaal et al., 2014; Juster et al., 2011; Suzuki, Poon, Papadopoulos, Kumari, & Cleare, 2014; Voellmin et al., 2015). The lower levels of urine cortisol observed in subjects with CAP supports our premise that CAP leads to HPA dysregulation. CAP was also associated with lower LH levels. Others have shown that chronic stress suppresses LH levels, validating that CAP is a chronic stressor (Breen, Billings, Wagenmaker, Wessinger, & Karsch, 2005). Abnormal AMH levels were significantly associated with the presence of CAP and lower urine cortisol levels. These findings suggest that CAP may alter HPA activity, as expressed by lower urine cortisol levels in women with CAP. Hypothalamic-pituitary-adrenal dysregulation may contribute to ovarian dysfunction as expressed by abnormal anti-Müllerian hormone levels in women with chronic abdominal pain. Previous studies have demonstrated that cortisol has both stimulatory and inhibitory effects on the ovary (Whirledge & Cidlowski, 2013).
Further research is needed to clarify the association between chronic physiological and psychological stressors, such as chronic pain and ovarian function. Understanding the biobehevioral mechanism behind this association will improve the ability to identify and prevent a modifiable risk factor of premature ovarian aging. Several studies have demonstrated negative associations between daily/acute stress levels and reproductive function. Schliep et al. (2015) found that high daily stress was associated with lower E2 and LH, as well as higher FSH. Daily stress was also associated with lower luteal phase progesterone and higher odds of anovulation. Conversely, Bleil et al. (2012) found that psychological stress was related to higher antral follicle count (AFC), a measure of ovarian reserve, among younger women and greater AFC decline across women. They proposed a model by which high stress promotes reproductive readiness in the short term (i.e. increased number of developing follicles) at the cost of prematurely depleting the ovarian follicle pool over time (Bleil et al., 2012).
Within the context of in vitro fertilization, stress has been associated with reduced chances of achieving a successful pregnancy (Bleil et al., 2012; Ebbesen et al., 2009; Lynch, Sundaram, Maisog, Sweeney, & Buck Louis, 2014), and incorporating stress reduction interventions may improve fertility outcomes (Catherino, 2011). However, the majority of studies examining this association have been in infertile populations undergoing assistive reproductive treatments, and for this reason, it is unclear whether stress is a biobehavioral risk factor for the development of infertility, or secondary to an infertility diagnosis. Improved understanding of the effect of prolonged stress on ovarian function will increase our ability to counsel those for whom stress may lead to premature ovarian aging and an increased risk of infertility.
We also found that body fat and OC use were not associated with abnormal AMH levels. While these findings contradict the results of prior studies (Freeman et al., 2007; Steiner et al., 2010), this may be due to the relatively small sample size as well as the limited range in body fat percentages. In addition to these main findings, we demonstrated an innovative way to examine the relationship between AMH and other factors thought to affect ovarian function. Previous researchers have examined AMH as a continuous variable; however, any AMH value that falls outside the normative age-specific range (too high or too low) is considered abnormal in the clinical setting. This would suggest that predictors of abnormal AMH levels might be more accurately identified through an analysis of AMH as a categorical variable (normal, abnormal). Additional studies are warranted to confirm the usefulness of this novel statistical approach in future research and clinical practice.
Limitations
The study has several limitations. Because the study was an exploratory study using data collected from a subset of subjects who met specific inclusion/exclusion criteria, the sample size is small. Another limitation was that we relied on cross-sectional data. To achieve a more precise representation of the effect of chronic stress, such as CAP, on reproductive health, further studies will require the use of a longitudinal design in which AMH levels are measured at various intervals across the menstrual cycle and symptom experience. Finally, CAP was measured using self-report, which is subjective. However, because individuals with CAP do not have a consistent pain experience, we did not collect data on participants’ current level of pain at the time of enrollment in the study.
Conclusion
Because knowledge of factors affecting ovarian reserve is incomplete, AMH may be a useful tool to aid in assessment of ovarian functioning. Because this was a pilot study, we believe the data supports the idea that HPA dysregulation may affect ovarian function. Anti-Müllerian hormone, as measure of ovarian reserve, may offer valuable insight into the enduring effects of hypothalamic-pituitary-adrenal activity on the reproductive system. We can only conclude that more research is needed to answer pressing clinical questions to improve nursing practice for care of women experiencing reproductive health issues.
Acknowledgments
Supported by by the Division of Intramural Research, National Institute of Nursing Research (1ZIANR000018-01-04, Summer Internship Program, and Intramural Research Training Award). The authors thank Angela Martino, Drs. Joan K. Austin and Ann K. Cashion for their assistance.
The opinions expressed herein and the interpretation and reporting of these data are the responsibility of the author(s) and should not be seen as an official recommendation, interpretation, or policy of the National Institutes of Health or the United States Government.
Footnotes
Disclosure: The authors report no conflict of interest or relevant financial relationships.
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Contributor Information
Theresa M. Hardy, Doctoral student in the College of Nursing, Marquette University, Milwaukee, WI.
Donna McCarthy, Professor and Interim Dean of the College of Nursing, Marquette University, Milwaukee, WI.
Nicolaas Fourie, Research fellow in the Division of Intramural Research, National Institute of Nursing Research, Bethesda MD.
Wendy A. Henderson, Investigator in the Biobehavioral Branch and Chief of the Digestive Disorders Unit, Intramural Research Program, National Institute of Nursing Research, Bethesda, MD.
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