Stress hormones and ovarian cancer prognosis

Relation

Veneris JT, Darcy KM, Mhawech-Fauceglia P, et al. High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer [published online ahead of print April 26, 2017].Gynecological oncology. 2017.

Study design

Retrospective review

Learning objectives

To determine the association between tumor glucocorticoid receptor (GR) expression and clinical characteristics, progression-free survival (PFS), and overall survival (OS) in patients with ovarian cancer.

Participant

The patient population consisted of 481 women with ovarian cancer treated between 1995 and 2010 and 4 patients with benign ovarian diseases. Glucocorticoid receptor expression was analyzed using tissue microarrays of ovarian samples collected at the time of cytoreductive surgery. Of these cases, the analysis focused on 341 samples from patients who underwent debulking surgery before starting chemotherapy and had complete clinical follow-up data. The median age was 59 years (range, 24–89 years), and the majority of tumors (70.9%) were serous carcinomas. Most (91.2%) tumors were high grade (grade 2 or 3) and advanced stage (International Federation of Gynecology and Obstetrics [FIGO] III or IV) (71.8%).

Target parameters

GR expression was correlated with tumor histology, tumor grade, tumor stage, PFS and OS.

Key insights

High GR expression (defined as over 1% tumor cells with 2+ or 3+ intensity staining) was present in 39% of tumors; the highest prevalence was in serous tumors and the lowest in endometrioid tumors. Furthermore, high GR expression correlated with higher grade (P<0.001) and advanced stage at diagnosis (P=0.037 early vs. advanced). High GR expression was associated with a 66% increased risk of disease progression (hazard ratio [HR]=1.66; 95% confidence interval [CI]=1.29-2.14) and 15 months shorter median PFS compared to tumors with low GR expression (20.4 vs. 36.0 months,P<0.001). There was no significant difference in OS after GR expression.

The lack of association with OS may have been obscured by the fact that there was only a weak association between GR expression and advanced high-grade serous cancer – the most predominant subgroup in the study. Finally, in a multivariate analysis, high GR expression was an independent predictor of PFS (HR = 1.41; 95% CI 1.08-1.84,P=0.012).

Practice implications

This study provides further evidence of a link between glucocorticoids and ovarian cancer prognosis. In this study, GR expression was positively correlated with attributes of aggressive tumor behavior (grade and stage) and, not surprisingly, with PFS. The GR is a nuclear hormone receptor activated by endogenous cortisol and synthetic glucocorticoids. Tumor cells with greater GR expression are therefore more susceptible to the effects of hypercortisolemia, a physiological condition associated with prolonged and/or severe physical and psychosocial stress. The implication of this association suggests that stress may drive more aggressive subtypes of ovarian cancer.

Simply put, elevated stress hormones are linked to aggressive ovarian cancer.

The connection between stress and ovarian cancer prognosis is not new. Previous work by Guillermo and colleagues found that norepinephrine, a stress-induced catecholamine, activates the Src survival pathway in ovarian cancer cells.¹Catecholamines have also been found to increase prostaglandin E2 levels in ovarian cancer cells, leading to inflammation, which in turn drives tumor proliferation and metastasis.²

Furthermore, Lutgendorf et al. found that patients with depression, chronic stress, and low social support have increased matrix metalloproteinase-9 (MMP-9) in tumor-associated macrophages.³Expression of MMP-9 is associated with increased tumor proliferation and metastasis. Furthermore, norepinephrine and cortisol directly enhance macrophage production of MMP-9. Sood et al. demonstrated that norepinephrine, at concentrations compatible with those observed in situations of psychosocial stress, increased the in vitro invasiveness of ovarian cancer cells by 89% to 198%.⁴Blocking of b-adrenergic receptors by the b-adrenergic antagonist propranolol abolishes this effect, recently demonstrated clinically with perioperative use of propranolol, resulting in reduced tumor burden (as measured by cancer antigen [CA] 125).⁵

While the mechanisms underlying the association between stress hormones and ovarian cancer prognosis are now well elucidated, the clinical implications of this association remain to be fully understood. Simply put, elevated stress hormones are linked to aggressive ovarian cancer. Most women diagnosed with ovarian cancer respond to first-line surgery and chemotherapy; however, subsequent recurrence compromises survival. Therefore, it is essential to assess ongoing psychosocial stress in women diagnosed with ovarian cancer. In addition to direct queries, objective cortisol measurement with a 4-point cortisol test or a one-time cortisol sample before bedtime is indicated. Altered circadian rhythms, particularly elevated nocturnal cortisol, flattened diurnal cortisol, and reduced cortisol variability are each associated with poorer overall survival in women with ovarian cancer.⁶

Additionally, in women with ovarian cancer, higher nocturnal cortisol levels are associated with fatigue and autonomic depression (low energy, apathy, social withdrawal, and hypersomnia).⁷Therefore, the presence of these physical and psychological symptoms should trigger an investigation into the impaired hypothalamic-pituitary-adrenal (HPA) axis and, in particular, nocturnal cortisol.

Of note, diurnal cortisol dysregulation in cancer patients is not necessarily due to increased stress sensitivity per se, but may be due to impaired HPA axis feedback inhibition, affecting resilience rather than responsiveness. Furthermore, sleep disruption due to cortisol dysregulation can lead to upregulation of many inflammatory pathways, leading to disease progression.⁸

Assessment is most relevant when it leads to specific treatment interventions. If elevated cortisol levels and/or HPA axis dysfunction are identified in a patient with ovarian cancer, interventions to help restore HPA circadian rhythms are well warranted. Naturally, the focus of naturopathic practice is the use of herbal adaptogens. Most adaptogens increase adrenocorticotropic hormone (ACTH) and cortisol with single, high-dose administration and normalize ACTH and cortisol with longer-term administration and when administered before stressors.^9.10A key mechanism of adaptogens is to restore the sensitivity of the hypothalamus and pituitary gland to the negative feedback of cortisol, thereby reducing nighttime cortisol.¹¹Adaptogenic plants such asEleutherococcus senticosus(Siberian ginseng),Roseroot(Rhodiola),Withania somnifera(Ashwaganda) andOcimum Sanctuary(Holy Basil) are a few of many to consider.

Social support is also crucial for lowering stress catecholamines. Low social support accompanied by depressive symptoms is associated with increased intratumoral norepinephrine levels. Conversely, ovarian cancer patients with higher levels of perceived social support have lower inflammatory cytokines, including interleukin (IL)-6, lower MMP-9, and increased tumor-infiltrating lymphocytes.¹²Not surprisingly, greater social connection is associated with a lower likelihood of death (HR: 0.87; 95% CI: 0.77-0.98;P=.018) in patients with ovarian cancer.¹³

An exciting finding associated with norepinephrine tumor reduction in patients with epithelial ovarian cancer concerns eudaimonic well-being. Eudaimonic well-being describes experiencing a deeper meaning in life, a feeling of fulfillment of one's potential and a deep self-acceptance. In an observational study by Davis et al. Eudaimonic well-being was associated with lower tumor norepinephrine independent of positive affect and psychological distress.¹⁴These results suggest that a deeper sense of well-being may be more physiologically protective in patients with ovarian cancer than being positive or simply stress-free. Interventions that specifically support eudaimonic well-being, such as mindfulness interventions, positive psychology, and gratitude practices, can have profound physiological effects.

Finally, restoring optimal diurnal rhythmicity of the HPA axis to reduce elevated nocturnal cortisol levels is a direct route to modulating the effects of stress hormones and ovarian cancer prognosis. The main regulator of circadian rhythm is melatonin, which itself is influenced by the light-dark cycle. Night light and the resulting disruption of melatonin production therefore have a profound uncoupling effect on circadian timing.^fifteenIn addition to darkening the nighttime environment, exogenous supplementation of melatonin at night may facilitate the restoration of circadian timing.¹⁶

[See the article in this issue on camping as a way to reset melatonin production.]

Overall, evidence supporting a link between elevated stress hormones and a poorer prognosis for ovarian cancer is becoming clearer. Interventions to reduce norepinephrine and cortisol deserve a place in the integrative standard of care for women diagnosed with ovarian cancer.