The health of the entire hypothalamic-pituitary-adrenal (HPA) axis is critically important for maintaining proper health primarily because of cortisol’s role in the body.
Cortisol is known as a glucocorticosteroid because of its effects on blood sugar regulation (gluco), it is made in the cortex of the adrenal glands (cortico) and of course, its action as a potent steroid hormone with effects that are far reaching systemically. Released primarily in response to perceived low blood sugar in order to directly stimulate glucuoneogenesis and indirectly, glycogenolysis, cortisol helps to counter inflammation through certain cytokines in the immune system and increases to prepare the body for “fight or flight” as part of the normal, healthy stress response. Like all things, balance is key as high levels can result in inflammatory tissue damage, bone loss, blood sugar dysregulation, memory loss via the hippocampus and insomnia.
Low levels may worsen depression and fatigue, result in more inflammation throughout the body, reduce gastric-acid secretion in the stomach and affect proper blood sugar regulation. While there are well-known adrenal gland conditions such as Addison’s and Cushing’s disease, other conditions and symptoms seem to fall on a broadly categorised HPA axis dysfunction spectrum.
This is where proper testing comes into play as someone may have low cortisol production causing symptoms such as fatigue and a weakened immune system, however their results are not low enough to diagnose ‘Addison’s Disease’ or warrant cortisol replacement. Alternatively, someone may have high cortisol production causing symptoms like weight gain or insomnia yet it does not fall into the ‘Cushing’s Disease’ category.
How is HPA axis dysfunction best tested in order to properly identify problems and treatment when there are many parts to evaluating cortisol through the day such as total production, cortisol clearance, free cortisol values, and the diurnal pattern?
By the middle of the end of the 1950’s there were reasonable solutions to both Addison’s and Cushing ’s diseases. (Contreres, 1986) About the same time, although in relative independence, Hans Selye and others were dramatically increasing our understanding of the stress response. Until the 1980’s lab testing for cortisol was limited primarily to serum cortisol and 24-hour urine testing of free cortisol.
In 1981 salivary cortisol testing was first reported. In 2006, Jerjes showed similar patterns of free cortisol in saliva and urine using “spot” urine collections serially throughout the day. (Jerjes, 2005, 2006) They also looked at the metabolites of cortisol. Their research showed that while free cortisol is lower in patients with Chronic Fatigue Syndrome, levels of cortisol metabolites are not. They showed equivalent results when looking at cortisol’s end metabolites in one study.
In a separate study, they showed slightly increased metabolites of cortisol in patients with CFS. If free cortisol results are lower and cortisol metabolites are equivalent or higher in patients with CFS, cortisol metabolism/clearance may be up-regulated. Increased clearance of cortisol may ultimately lead to hypocortisol conditions even if the patient’s cortisol production is “normal.” (Jerjes, 2006).
The importance of cortisol clearance – using Anorexia as a case study
Elevations in hormone levels are often assumed to be due to increased hormonal production. In some scenarios, however, elevations may be due decreased metabolism or clearance of a hormone. Such is the case with elevated free cortisol (and DHEA) in anorexia nervosa. In 2012, Oskis published that patients with anorexia nervosa may have “hypersecretion of both cortisol and DHEA.” They concluded this after finding higher levels of both hormones in the saliva of patients with anorexia.
However, in 2011 levels of cortisol and DHEA metabolites were published showing dramatically lower levels in patients with anorexia. High levels of free hormone and reduced levels of metabolites implies that the elevation in free hormones may be caused by slow metabolism/clearance of these hormones. (Wassif, 2011)
More than 30 years before the two studies referenced above, Boyar showed that cortisol’s metabolic clearance rate was indeed twice as slow in anorexic patients. (Boyar, 1977) This study also showed that levels of T3 were more than 2.5 times lower in the anorexia patients (more on the role of hypothyroidism later).
As we characterise anorexia as a condition with respect to cortisol, higher levels of free cortisol (which may lead patients to be more at risk for depression and other conditions seen in hypercortisolism) and lower levels of cortisol metabolites are both relevant observations. Knowing both the free and metabolised hormone levels gives insight into situations where clearance/metabolism rates may be abnormal.
Common conditions where cortisol clearance rates may be abnormal:
Hypo/Hyperthyroidism – In a 1993 publication, Taniyama published data correlating thyroid status with the excretion rates of cortisol metabolites (also confirmed by Hoshiro, 2006). They measured 17-hydroxycorticosteroid (total of cortisol metabolites, 17-OHCS) levels in urine along with the ratio of cortisol metabolites (THF) to cortisone metabolites (THE). As you can see in the graph below, excretion of cortisol metabolites (17OHCS) generally parallels thyroid status.
Patients with higher thyroid levels also show a preference for cortisone metabolites, meaning cortisol tends to spend more time in its inactive form. Conversely, a hypothyroid patient tends to hold on to their cortisol. It is not as readily deactivated to cortisone nor is it cleared as rapidly as 17OHCS cortisol end products. (Taniyama, 1993).
- Contreras, L. N., S. Hane and J. B. Tyrrell (1986). “Urinary cortisol in the assessment of pituitary-adrenal function: utility of 24-hour and spot determinations.” J Clin Endocrinol Metab 62(5): 965-969.
- Cook, M. R., C. Graham, R. Kavet, R. G. Stevens, S. Davis and L. Kheifets (2000). “Morning urinary assessment of nocturnal melatonin secretion in older women.” J Pineal Res 28(1): 41-47.
- Denari, J. H., Z. Farinati, P. R. Casas and A. Oliva (1981). “Determination of ovarian function using first morning urine steroid assays.” Obstet Gynecol 58(1): 5-9.
- Hoshiro, Y. Ohno, H. Masaki, H. Iwase and N. Aoki (2006) “Comprehensive study of urinary cortisol metabolites in hyperthyroid and hypothyroid patients” Clinical Endocrinology 64: 37-45
- Iranmanesh, A, Lizarralde, G, Johnson, M, and Veldhuis, J, (1990) “Dynamics of 24-Hour Endogenous Cortisol Secretion and Clearance in Primary Hypothyroidism Assessed before and after Partial Thyroid Hormone Replacement*” Journal of Clinical Endocrinology and Metabolism 70(1): 155-161
- Jerjes, W. K., A. J. Cleare, S. Wessely, P. J. Wood and N. F. Taylor (2005). “Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome.” J Affect Disord 87(2-3): 299-304.
- Jerjes, W. K., T. J. Peters, N. F. Taylor, P. J. Wood, S. Wessely and A. J. Cleare (2006). “Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome.” J Psychosom Res60(2): 145-153.
- C. Vantyghem, A. Ghulam, C. Hober, C. Schoonberg, M. D’Herbomez, A. Racodot, A. Boersma and J. Lefebvre (1998) “Urinary cortisol metabolites in the assessment of peripheral thyroid hormone action: Overt and subclinical hypothyroidism.” J.Endocrinol. Invest. 21:21-225
- Miro, F., J. Coley, M. M. Gani, P. W. Perry, D. Talbot and L. J. Aspinall (2004). “Comparison between creatinine and pregnanediol adjustments in the retrospective analysis of urinary hormone profiles during the human menstrual cycle.” Clin Chem Lab Med 42(9): 1043-1050.
- Mistry, H. D., N. Eisele, G. Escher, B. Dick, D. Surbek, C. Delles, G. Currie, D. Schlembach, M. G. Mohaupt and C. Gennari-Moser (2015). “Gestation-specific reference intervals for comprehensive spot urinary steroid hormone metabolite analysis in normal singleton pregnancy and 6 weeks postpartum.” Reprod Biol Endocrinol 13: 101.
- Munro, C. J., G. H. Stabenfeldt, J. R. Cragun, L. A. Addiego, J. W. Overstreet and B. L. Lasley (1991). “Relationship of serum estradiol and progesterone concentrations to the excretion profiles of their major urinary metabolites as measured by enzyme immunoassay and radioimmunoassay.” Clin Chem 37(6): 838-844.
- Probst-Hensch, N. M., S. A. Ingles, A. T. Diep, R. W. Haile, F. Z. Stanczyk, L. N. Kolonel and B. E. Henderson (1999). “Aromatase and breast cancer susceptibility.” Endocr Relat Cancer 6(2): 165-173.
- Roos, J., S. Johnson, S. Weddell, E. Godehardt, J. Schiffner, G. Freundl and C. Gnoth (2015). “Monitoring the menstrual cycle: Comparison of urinary and serum reproductive hormones referenced to true ovulation.” Eur J Contracept Reprod Health Care 20(6): 438-450.
- Taioli, E., A. Im, X. Xu, T. D. Veenstra, G. Ahrendt and S. Garte (2010). “Comparison of estrogens and estrogen metabolites in human breast tissue and urine.” Reprod Biol Endocrinol 8: 93.
- Taniyama, M, Keiko Honma, K and Ban, Y (1993) “Urinary Cortisol Metabolites in the Assessment of Peripheral Thyroid Hormone Action: Application for Diagnosis of Resistance to Thyroid Hormone” Thyroid 3(3): 229-233
- Waller, K., S. H. Swan, G. C. Windham, L. Fenster, E. P. Elkin and B. L. Lasley (1998). “Use of urine biomarkers to evaluate menstrual function in healthy premenopausal women.” Am J Epidemiol 147(11): 1071-1080.
- Oskis, A., C. Loveday, F. Hucklebridge, L. Thorn, and A. Clow (2012) “Diurnal patterns of salivary cortisol and DHEA in adolescent anorexia nervosa” Stress 15(6): 601-607
- Wassif, S. W., D. M. McLoughlin, R. P. Vincent, S. Conroy, G. F. M. Russell, and N. F. Taylor (2011) “Steroid metabolism and excretion in severe anorexia nervosa: effects of refeeding” The American Journal of Clinical Nutrition 93: 911-917
- Boyar, R. M., L. D. Hellman, H. Roffwarg, J. Katz, B. Zumoff, J. O’Connor, H. L. Bradlow, D. K. Fukushima (1977) “Cortisol secretion and metabolism in anorexia nervosa” New England Journal of Medicine296(4): 190-193
- Abraham, S. B., Rubino, N. Sinaii, S. Ramsey, L. K. Nieman (2013) “Cortisol, obesity and the metabolic syndrome: A cross-sectional study of obese subjects and review of the literature” Obesity (Silver Spring)21(1): E105-E117
- Tomlinson, J. W., J. Finney, B. A. Hughes, S. V. Hughes, P. M. Stewart (2008) “Reduced Glucocorticoid Production Rate, Decreased 5?-Reductase Activity, and Adipose Tissue Insulin Sensitization After Weight Loss” Diabetes 57: 1536-1543
ABOUT THE AUTHORS:
Dr Carrie Jones, ND, MPH, Medical Director for Precision Analytical
Dr. Carrie Jones’ passion and expertise lies in the areas of hormonal, adrenal, and thyroid health. She recognises that imbalance can occur at any age and believes it is important to look at the big picture such as the appropriate use of lab testing. Dr. Jones graduated from the National University of Natural Medicine (NUNM) in Portland, Oregon then went on to complete her residency in women’s health, endocrinology and hormones. Later she graduated from Grand Canyon University’s Master of Public Health program with a goal of doing more international work and health empowerment. Dr. Jones is an adjunct professor at NUNM and regularly consults, lectures, and writes on the topic of hormones, thyroid, adrenals, autoimmune and more.
As the Medical Director for Precision Analytical, Inc., her goals are to provide ongoing cutting edge integrative clinical education to the large network of providers paving the way of healthcare with functional medicine.
Mark Newman, Owner and President of Precision Analytical
Mark is a recognised expert and international speaker in the field of hormone testing. He has assisted many laboratories in developing novel tests to create world-class laboratory testing. He has also educated thousands of providers about hormone monitoring best practices.
Precision Analytical (dutch testing) was established by Mark to address the need for better clinical accuracy, subsequently developing one of the most advanced and comprehensive models for testing a patients steroid and adrenal hormones.
Dr Joseph Mercola, Dr Sara Gottfried, and Chris Kresser are just a few of the international experts that have found the dutch model to be the most advanced test for hormone testing.