Optimal DX Supplement Series: Adrenal Hyperfunction/Adrenal Stress

Adrenal hyperfunction or overactive adrenals occur when the adrenal glands produce excessive amounts of hormones, including cortisol.

All stress, good or bad, activates the hypothalamic-pituitary-adrenal (HPA) axis and the release of associated stress hormones (Anderson 2008). This is commonly known as the “fight or flight” response. The hormones (e.g., cortisol) released in this process have numerous effects on the body that are intended to provide a burst of energy and heighten alertness to deal with acute threats. For example, the body’s energy stores are mobilized; non-essential bodily functions, like digestion and reproduction, are suppressed; and the delivery of oxygen and nutrients to vital organs and muscles via the cardiovascular system is improved (Todorova 2021). When activation of the HPA axis and release of adrenal hormones becomes constant or chronic, health problems develop (Anderson 2008).

The HPA axis organs may become desensitized and damaged, leading to a “kink” in the system and an overproduction of cortisol (Anderson 2008). Chronically elevated cortisol levels have been shown to affect reproduction, growth hormone, and thyroid function (Anderson 2008). Excess cortisol can be a cause of and a result of oxidative stress, which adversely affects adrenal function. Endogenous antioxidants, including glutathione, glutathione peroxidase, catalase, and superoxide dismutase, and exogenous antioxidants, including vitamins C, E, carotenoids, selenium, and zinc, help counteract oxidative stress and protect adrenals (Patani 2023).

Source: Patani, Anil et al. “Harnessing the power of nutritional antioxidants against adrenal hormone imbalance-associated oxidative stress.” Frontiers in endocrinology vol. 14 1271521. 30 Nov. 2023, doi:10.3389/fendo.2023.1271521 This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

Supportive Supplements

Adaptogens

Adaptogen is a term applied to herbs that normalize physiology and encourage non-specific resistance to stressors (Anderson 2008). They are associated with improving the body’s ability to adapt to stress and normalizing metabolic functions (Todorova 2021). The following adaptogens are recommended:

Ashwagandha (Withania somnifera)

250 mg of standardized extract once or twice daily (Stengler 2016)

• Extract doses can range from 225 to 1,250 mg per day for 6 to 8 weeks to reduce feelings of stress and anxiety and to decrease fatigue, sleeplessness, and stress hormone levels (ODS 2023; Abedon 2008; Lopresti 2019).
• Whole root granules of 12,000 mg/day (equivalent to 6,000 mg of root powder) have also been used (ODS 2023).

Siberian ginseng (Eleutherococcus senticosus)

• Demonstrated effects on stress-induced fatigue, immune changes, and corticosterone elevations in an animal model of stress (Kimura 2004).
• Improvements in mental health and social functioning in the elderly after 4 weeks of 300 mg dried extract per day (Cicero 2004).

Holy basil (Ocimum tenuiflorum)

125 mg of a standardized extract twice daily (Lopresti 2022)

• Supplementation associated with improvements in Perceived Stress Scale and Profile of Mood States, Athens Insomnia Scale scores; buffered stress response to Maastricht Acute Stress Test; lower salivary cortisol, amylase, blood pressure, and subjective stress ratings (Lopresti 2022).

Rhodiola rosea

200 mg/d of a standardized extract (Anghelescu 2018)

• A standardized extract (200 mg per day for 12 weeks) improved performance speed and task accuracy in situations of simulated multi-tasking (Heldmann 2016).
• Supplementation of 170 mg/d of extract containing approximately 4.5 mg salidroside for 14 days reduced fatigue in under stressful conditions (Darbinyan 2000).
• A literature review found that 200 mg/d of a standardized extract helps normalize the release of stress hormones while boosting energy metabolism (Anghelescu 2018).

Magnesium

350 to 500 mg/d (Schutten 2020)

• Has a role in enzymes that inactivate cortisol. After 24 weeks, urinary cortisol excretion decreased in the magnesium group compared to the placebo group (Schutten 2020).
• Supplementation of 500 mg/d for 4 weeks downregulated the HPA axis, altered the typical pattern of ACTH and cortisol change, and reduced immune response activation in Mg-supplemented rugby players (Dmitrašinović 2016)

Omega-3 Fatty Acids

1 to 2 g/d (Jahangard 2019, Kiecolt-Glaser 2011)

• Daily 1,000 mg omega-3 supplementation for 8 consecutive weeks positively influenced psychological and physiological markers of occupational burnout, including lowering morning cortisol (Jahangard 2019).
• Medical students taking 2.5 g/d omega-3 for 12 weeks showed a 14% decrease in lipopolysaccharide-stimulated interleukin 6 production and a 20% reduction in anxiety symptoms (Kiecolt-Glaser 2011).

Vitamin C

1,000 mg two to three times daily (Stengler 2016)

• 1000 mg per day of ascorbic acid for two months reduced cortisol in women with functional hypercortisolemia (Begyarlan 2023)

Dehydroepiandrosterone (DHEA)

25 to 200 mg/d (Kroboth 2003; Genazzi 2006; Chen 2021)

• DHEA administration, 200 mg for 29 days, resulted in lower cortisol levels in aging men and women, with a more pronounced effect in women (Kroboth 2003).
• Chronic DHEA administration (25 mg/d) modified circulating levels of androgens and progestins in both early and late postmenopausal women by modulating the age-related changes in adrenal function (Genazzani 2006).
• A meta-analysis of randomized, controlled trials found that DHEA supplementation significantly decreased cortisol levels (Chen 2021).
• Note: Monitoring of estrone, estradiol, estriol, and testosterone should be performed with chronic DHEA use.

Phosphatidylserine

400 to 800 mg/d (Monteleone 1992, Hellhammer 2004)

• Administration of 800 mg/d for 10 days significantly blunted the ACTH and cortisol responses to physical exercise, suggesting that chronic oral administration of phosphatidylserine may counteract stress-induced activation of the HPA axis (Monteleone 1992).
• Researchers observed a selective stress-dampening effect of phosphatidylserine (400 mg for 4 weeks) on the pituitary-adrenal axis, including a substantial reduction in the increase in serum cortisol concentration, suggesting the potential for the treatment of stress-related disorders (Hellhammer 2004)

References

Abedon, Bruce et al. "A standardized Withania somnifera extract significantly reduces stress-related parameters in chronically stressed humans: a double-blind, randomized, placebo-controlled study." JANA 11 (2008): 50-56.

Anderson, D. “Assessment and nutraceutical management of stress-induced adrenal dysfunction.” Integrative Medicine 7.5 (2008): 18-25.

Anghelescu, Ion-George, et al. "Stress management and the role of Rhodiola rosea: a review." International Journal of Psychiatry in Clinical Practice 22.4 (2018): 242-252.

Beglaryan, Narine, Gagik Hakobyan, and Eduard Nazaretyan. "Vitamin C supplementation alleviates hypercortisolemia caused by chronic stress." Stress and Health 40.3 (2024): e3347.

Chen, Hu et al. “Effects of dehydroepiandrosterone (DHEA) supplementation on cortisol, leptin, adiponectin, and liver enzyme levels: A systematic review and meta-analysis of randomised clinical trials.” International Journal of Clinical Practice vol. 75,11 (2021): e14698. doi:10.1111/ijcp.14698

Cicero, Arrigo Francesco Giuseppe, et al. "Effects of Siberian ginseng (Eleutherococcus senticosus maxim.) on elderly quality of life: a randomized clinical trial." Archives of Gerontology and Geriatrics 38 (2004): 69-74.

Darbinyan, V., et al. "Rhodiola rosea in stress induced fatigue—a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty." Phytomedicine 7.5 (2000): 365-371.

Dmitrašinović, Gordana et al. “ACTH, Cortisol and IL-6 Levels in Athletes following Magnesium Supplementation.” Journal of medical biochemistry vol. 35,4 375-384. 2 Nov. 2016, doi:10.1515/jomb-2016-0021

Gaffney, Ben T., Helmut M. Hügel, and Peter A. Rich. "The effects of Eleutherococcus senticosus and Panax ginseng on steroidal hormone indices of stress and lymphocyte subset numbers in endurance athletes." Life sciences 70.4 (2001): 431-442.

Genazzani, A. R. et al. “Long-term low-dose oral administration of dehydroepiandrosterone modulates adrenal response to adrenocorticotropic hormone in early and late postmenopausal women.” Gynecological Endocrinology, 22.11 (2006):627–635. doi: 10.1080/09513590601024681.

Heldmann, M., et al. "EP 116. Impact of Rhodiola Rosea extract WS1375 on electrophysiological correlates of attention allocation in a dual task paradigm." Clinical Neurophysiology 127.9 (2016): e290.

Hellhammer, J., et al. "Effects of soy lecithin phosphatidic acid and phosphatidylserine complex (PAS) on the endocrine and psychological responses to mental stress." Stress 7.2 (2004): 119-126.

Jahangard, Leila, et al. "Omega-3-polyunsatured fatty acids (O3PUFAs), compared to placebo, reduced symptoms of occupational burnout and lowered morning cortisol secretion." Psychoneuroendocrinology 109 (2019): 104384.

Kiecolt-Glaser, Janice K et al. “Omega-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial.” Brain, behavior, and immunity vol. 25,8 (2011): 1725-34. doi:10.1016/j.bbi.2011.07.229

Kimura, Yoshiyuki, and Maho Sumiyoshi. "Effects of various Eleutherococcus senticosus cortex on swimming time, natural killer activity and corticosterone level in forced swimming stressed mice." Journal of Ethnopharmacology 95.2-3 (2004): 447-453.

Kroboth, Patricia D., et al. "Influence of DHEA administration on 24-hour cortisol concentrations." Journal of Clinical Psychopharmacology 23.1 (2003): 96-99.

Lopresti, Adrian L et al. “A randomized, double-blind, placebo-controlled trial investigating the effects of an Ocimum tenuiflorum (Holy Basil) extract (Holixer™) on stress, mood, and sleep in adults experiencing stress.” Frontiers in Nutrition vol. 9 965130. 2 Sep. 2022, doi:10.3389/fnut.2022.965130

Lopresti, Adrian L et al. “An investigation into the stress-relieving and pharmacological actions of an ashwagandha (Withania somnifera) extract: A randomized, double-blind, placebo-controlled study.” Medicine vol. 98,37 (2019): e17186. doi:10.1097/MD.0000000000017186

Monteleone, P et al. “Blunting by chronic phosphatidylserine administration of the stress-induced activation of the hypothalamo-pituitary-adrenal axis in healthy men.” European journal of clinical pharmacology vol. 42,4 (1992): 385-8. doi:10.1007/BF00280123

ODS Fact sheet for health professionals. Ashwagandha: Is it helpful for stress, anxiety, or sleep? National Institutes of Health Office of Dietary Supplements. Accessed June 18, 2024. https://ods.od.nih.gov/factsheets/Ashwagandha-HealthProfessional/

Patani, Anil et al. “Harnessing the power of nutritional antioxidants against adrenal hormone imbalance-associated oxidative stress.” Frontiers in Endocrinology vol. 14 1271521. 30 Nov. 2023, doi:10.3389/fendo.2023.1271521

Schutten, Joëlle C et al. “Long-term magnesium supplementation improves glucocorticoid metabolism: A post-hoc analysis of an intervention trial.” Clinical endocrinology vol. 94,2 (2021): 150-157. doi:10.1111/cen.14350

Stengler M, et al. Prescription for Natural Cures: A Self-care Guide for Treating Health Problems With Natural Remedies Including Diet, Nutrition, Supplements, and Other Holistic Methods. Third ed. Turner Publishing Co, 2016.

Todorova, Velislava et al. "Plant adaptogens—History and future perspectives." Nutrients, 13.8 (2021): 2861.

van Niekerk, Jan K., Felicia A. Huppert, and Joseph Herbert. "Salivary cortisol and DHEA: association with measures of cognition and well-being in normal older men, and effects of three months of DHEA supplementation." Psychoneuroendocrinology 26.6 (2001): 591-612.