Pharmaceutical & Non-Pharmaceutical Cortisol Decrease in Patients with Hypertension

Introduction

The heart is an intricate and vital organ since it is part of many organ systems that allow the body to function correctly. From endocrine hormone movement to something as simple as nutrient and oxygen distribution, the heart keeps the body alive. The heart involves two pumps, the ventricles, moving the blood in series. Blood pressure is the pressure of blood as it flows through the blood vessels. This pressure is required to ensure the blood reaches target tissues. Systolic blood pressure is known as the pressure of blood after the ventricles contract, and diastolic blood pressure is the pressure of blood after relaxation of the ventricle muscles. Hypertension is the incidence of elevated blood pressure over a period of time (Oparil et al., 2018). 48.1% of adults in the United States have hypertension or are taking medicine to treat hypertension. In 2021, hypertension contributed to 691,095 deaths in the United States (Centers for Disease Control and Prevention, 2023). The American Heart Association states that hypertension can lead to heart attacks, heart failure, kidney damage, strokes, and vision loss. A greater understanding of specific mechanisms that lead to hypertension is crucial for knowledge that may treat and prevent hypertension-related fatalities.

Hypertension is more specifically defined as a systolic blood pressure greater than 130 mmHg or a diastolic blood pressure greater than 80 mmHg (Centers for Disease Control and Prevention, 2023). Hypertension can lead to blood clots, which can travel to the brain and lead to a stroke. According to the American Heart Association, the clots can also travel to the coronary arteries and lead to a heart attack. Hypertension can occur mainly through two routes, one being the increased volume of blood traveling through the blood vessels. This can be done by impaired endocrine responses or by increased sodium intake in the diet (Denton et al., 1995). The second route is by arterial over-contraction, which increases the pressure by decreasing the space in which the blood volume can travel through (Brenner et al., 2000, Qiao et al., 2014). This may occur through the sympathetic system or other endocrine hormones (Furuhashi et al., 2000). The renin-angiotensin-aldosterone system is an endocrine system that can cause hypertension. Renin is released by the juxtaglomerular cells of the kidneys when baroreceptors sense low blood pressure in arterioles. Renin can also be released by the sympathetic nervous system. Renin then cleaves angiotensinogen released by the liver into angiotensin I. Angiotensin-converting enzyme (ACE) then converts angiotensin I to angiotensin II. Angiotensin II can then exert biological effects in various ways. Angiotensin II directly and indirectly (via aldosterone release) promotes sodium and chloride reabsorption in the kidneys, which draws water back into the body, increasing blood volume and thereby blood pressure. Angiotensin II also stimulates arteriolar vasoconstriction, directly increasing blood pressure (Ames et al., 2019). Other risk factors play a role in hypertension and mechanisms are not fully understood, such as obesity and exercise. Investigating one of these hormones, cortisol is essential to understanding its role in hypertension. Cortisol, the ‘stress hormone’, is a glucocorticoid released by the adrenal cortex in response to environmental stressors. Adrenocorticotropic hormone (ACTH) is released by the anterior pituitary gland in response to corticotropin-releasing hormone (CRH) from the hypothalamus and acts on the adrenal cortex to release cortisol and small amounts of aldosterone (Turkelson et al., 1981).

Cushing syndrome (CS) is a disorder which causes excess cortisol release, where hypertension is one of the many possible symptoms (Buliman, 2016). One medicinal treatment for hypertension is diuretics. These drugs work by increasing urine production, thereby decreasing blood volume and blood pressure (Ellison, 2019). ACE inhibitors work by inhibiting the conversion of angiotensin I to angiotensin II by ACE (Heran et al., 2008). This stops the increase in blood pressure caused by angiotensin II and aldosterone. Non-medicinal ways to prevent hypertension involve exercise to improve cardiovascular health and sodium reduction in the diet to decrease water retention and strain on kidney health. This review will be looking at various studies that decrease cortisol levels. Pharmaceutically, there are the drugs mifepristone, relacorilant, atenolol, and nebivolol. Mifepristone and relacorilant are glucocorticoid receptor antagonists, which block cortisol binding to its receptor. Nebivolol and atenolol are beta-blocker drugs. These drugs act by blocking beta receptors. Catecholamines, epinephrine, and norepinephrine bind beta receptors to cause decreased heart rate, blood pressure, and other outcomes (Poirier et al., 2014). Non-pharmaceutical studies use aromatherapy, qigong exercise, relaxation training, and forest therapy to observe a decrease in cortisol levels.

Therefore, the present study aims to see the barometric effects of pharmaceutical and non-pharmaceutical cortisol decrease in hypertensive patients. By doing this, a more in-depth understanding of the correlation between cortisol and hypertension can direct future research. Prospectively, further studies can improve the methods of care taken for patient-specific treatment.

Literature Review

In a 1983 study, Whitworth et al. administered ACTH to hypertensive and normotensive patients. They found that there was a significant increase in systolic blood pressure in both groups, except for patients with Addison’s disease (AD). AD is a deficiency of glucocorticoids and mineralocorticoids (Burton et al., 2015). By knowing this, Whitworth et al. indicated the blood pressure rise was adrenally dependent.

One year later, Whitworth et al. (1984) gave oral cortisol doses to six normal men every six hours for five days at variable doses. They also gave six other men cortisol paired with spironolactone, a drug that causes sodium and water secretion in the kidneys. They found that cortisol infusion in men led to a significant increase in systolic blood pressure, plasma sodium concentration, and blood glucose levels. They found that cortisol increased systolic blood pressure significantly in both groups. The group getting spironolactone did not see an increase in weight and a decrease in serum potassium, indicating that mineralocorticoid function is not the main mechanism by which cortisol increases blood pressure. Mineralocorticoids increase blood pressure by causing reuptake of sodium in the kidneys, thereby increasing blood volume in the blood vessels. Another study by Hamer and Steptoe (2022) took 479 participants who were healthy and did not have a history of cardiovascular disease or hypertension at the start of the study. They then measured their baseline salivary cortisol levels. Followed by tasks that induce mental stress, salivary cortisol and incident hypertension were then remeasured. They then did a follow-up three years later to assess which subjects had developed hypertension. There was a positive association between cortisol stress response and incident hypertension.

The studies conducted by Whitworth et al. and Hamer and Steptoe demonstrate a correlation between increasing cortisol and rising blood pressure. This article aims to examine whether reducing or inhibiting cortisol positively affects patients with hypertension.

Methodology

A systematic review was conducted within PubMed using the search terms “Cortisol AND Hypertension.” These were then filtered to be men and women over the age of 40 since the most significant jump in hypertension rates occurs in these age groups, according to the American Heart Association. The primary intervention will be decreasing cortisol levels in patients who already have hypertension. Refer to Figure 1 for a breakdown of how the studies were processed. Meditation, martial arts, or pharmaceuticals may cause this decrease in cortisol. The study must record baseline and cortisol levels after intervention if the method is not a pharmaceutical reduction of cortisol levels. There is no regional/continental bias for choosing studies; any ethnicity was considered. The patients would then compare their blood pressure values to a control group or baseline blood pressure values at the start of the experiment. By measuring the blood pressure, the outcome of the experiments would either show an increase, decrease, or no change in overall blood pressure in the patient population. Studies are omitted first by title, meaning if the title does not sound relevant to the research question, it will be excluded. Next, the reports are retrieved and abstracts are read. The abstract must show relevant information towards the target population and the intervention taken. Studies that do not follow the criteria such as: no cortisol change, patient age under 40, and non-hypertensive patients are excluded. Finally, the remaining reports were thoroughly checked for research methods, results and their relevant discussion Data was gathered on a Google Sheet and the studies were split into two groups: pharmaceutical and non-pharmaceutical. The results of the database screening is found in figure 1 below.

Results

Pharmaceutical Drug Experiments

Two experiments where there was a cortisol decrease via a pharmaceutical drug looked at patients with CS or patients with abnormally high cortisol levels. The study looking at relacorilant administration by Pivonello et al. (2021) saw an average 52.1% success rate for the patients who completed the study in both the low and high-dose groups. Success rate was defined as a decrease in mean systolic or diastolic blood pressure by 5mmHg or more, which indicated clinical significance. The low dose group received 100 mg per day, increasing by 50 mg every four weeks until 200 mg per day. The high dosage group started at 250 mg per day, also increasing by 50 mg every four weeks until 400 mg per day. The high dosage group had a higher success rate (63.6%) but a higher patient withdrawal rate as well. 10 of the 21 (47.6%) subjects starting in the high dosage group withdrew, with eight of these being due to an adverse event. Adverse events included back pain, headache, peripheral edema, pain at extremities, nausea, diarrhea, and dizziness. The low-dosage group had a 41.6% success rate and one of 13 (7.69%) starting patients withdrew due to an adverse event. The increase in median baseline urinary free cortisol and ACTH were 4.0 nmol/d and 3.7pmol/L respectively in the ACTH-dependent CS group. In the adrenal group, there was an increase of 7.0 nmol/d in urinary-free cortisol and 0.2 pmol/L in ACTH. Baseline levels of ACTH in the study population were 10.8 pmol/L, and 357.0 nmol/d in urinary-free cortisol. 

Figure 1 Overview of collecting, screening, and excluding reports on PubMed.

In the Fleseriu et al. (2012) study using mifepristone, they looked at patients with CS and broke them down into two groups: CS with type 2 diabetes mellitus and CS with hypertension. Seven of 21 (33.3%) withdrew in the hypertension group, with five of these due to an adverse event. Nine of 29 (31%) withdrew from the diabetes group, with two of these being due to an adverse event. 12 patients saw an elevation in blood pressure, with nine of these being prescribed spironolactone. An increase of ACTH of at least 2-fold was seen in 62.8% of patients, with a 7.92-fold increase in late-night salivary cortisol. At the six-week follow-up, ACTH and cortisol declined to near baseline levels.

Atenolol and nebivolol were administrated to patients with hypertension but without CS. Pesant et al. (1999) found a significant decrease in cortisol from baseline to treatment values only in the atenolol treatment. Table 1 below indicates specific hormone level changes and their associated significance levels. Atenolol treatment saw mean baseline levels of blood pressure of 160/99 mmHg to 145/88 mmHg. Nebivolol saw mean baseline levels of blood pressure of 150/98 mmHg to 141/90 mmHg. Both blood pressure decreases are statistically significant from baseline to treatment values. Both groups saw significant increases in atrial natriuretic factor (ANF). 

Figure 2 Hormone profile of (A) Cortisol, (B) ANF, (C) Aldosterone, and (D) ACTH after 3 months of nebivolol and atenolol treatment. The graphs were generated using GraphPad PRISM with data obtained from Pesant et al., 1999. * p < 0.05, ** p < 0.001

Non-Pharmaceutical Experiments

Systolic blood pressure is statistically significant when Lee et al. (2009) is comparing qigong to control levels, and when comparing qigong over the time interval. Diastolic blood pressure only shows statistical significance over the time interval, and not between groups. The researchers did not include specific values for their findings, but they provided graphs depicting results. The graphs showing changes in mean systolic and diastolic blood pressure are shown in Figures 3A and 3B below. Both mean epinephrine and norepinephrine levels decreased significantly compared to the control group.

The 1994 study by McGrady involving relaxation training saw 49% of 70 total patients have a decrease in mean arterial pressure of 5mmHg or more. Overall, the mean systolic blood pressure was 132.4 +/- 12.6 mmHg pretest, and 126.5 +/- 13.7 mmHg. This indicates a mean systolic blood pressure change of 5.9 mmHg. There was a significant decrease in urinary cortisol but also plasma aldosterone. There was no significant decrease in plasma cortisol. Forest therapy, a similar concept to relaxation training, saw a statistically significant decrease in salivary cortisol, but systolic blood pressure changes were not significant longitudinally between groups (p = .16). Both control and experimental groups saw a significant decrease in systolic blood pressure (Sung et al., 2012).

Aromatherapy was investigated by Hwang (2007) and showed statistically significant serum cortisol decline (p=.041) after the experiment completion, only in the experimental group. This decline was not seen in serum epinephrine or norepinephrine. There was a mean decrease of 19.32mmHg at week 4 from baseline levels in the experimental group. At 129.26 +/- 12.20 mmHg systolic pressure at week 4 in the experimental group, there was a significant difference between the controls (p=0.002). The controls at week 4 had a mean systolic pressure of 138.89 +/- 9.48mmHg and 141.67 +/- 16.51mmHg for control groups 1 and 2 respectively.

Overall, both the pharmaceutical and non-pharmaceutical methods have studies that show a statistically positive correlation between decreasing cortisol levels and decreasing blood pressure. 

Figure 3 (A) Systolic blood pressure and (B) Diastolic blood pressure vs. time in control and qigong groups (Lee et al., 2003).

Discussion

The present study is set out to view the effectiveness of decreasing cortisol levels in patients with hypertension. This is seen through pharmaceutical and non-pharmaceutical methods, where the two are descriptively compared. Relacorilant, by binding to the glucocorticoid receptor, antagonizes cortisol activity (Pivonello et al., 2021). Mifepristone acts the same as relacorilant at high doses, blocking the glucocorticoid receptor (Fleseriu et al., 2012). Both these drugs had a significant withdrawal rate, especially for adverse effects, which are concerning for use as an improvement to blood pressure. This also may lead to attrition bias, as many patients who may have not benefitted were removed from the study and their results omitted. Both the relacorilant and mifepristone studies were also looking at patients with CS, where high cortisol levels act as a risk factor for developing hypertension. These studies show a positive correlation between decreasing cortisol and decreasing blood pressure in patients with CS. These results may be different in patients who have normal levels of cortisol. These studies also have a small sample size, with no control group. The study looking at relacorilant had a low and high-dose treatment group. However, these had different durations and were completed sequentially, not in parallel, which limits the conclusions that can be drawn from a dose response. Mifepristone is not only a glucocorticoid receptor antagonist at high doses but also a progestin antagonist at low doses. This means it blocks progesterone binding to its intracellular receptor and exerts physiological effects on the body (Kawai et al., 1987). This raises many adverse effects for people using this drug as a way to reduce the effects of cortisol. This includes fetal death, hot flashes, and headaches (Autry & Wadhwa, 2022; Rodger & Baird, 1987). Furthermore, both studies saw increased cortisol levels due to the buildup of unbound cortisol in the blood. As stated earlier, cortisol does interact with mineralocorticoid receptors, but studies suggest it is not the primary mechanism that increases blood pressure. Even though not the primary mechanism, seeing such a substantial increase in cortisol levels when using mifepristone as a glucocorticoid antagonist explains the increase in blood pressure and hypokalemia of some patients. When taking into consideration the side effects of blocking progesterone and the large increase in cortisol levels from mifepristone, relacorilant is a safer option for glucocorticoid antagonism.

The study by Pesant et al. (1999) saw both drugs induced a decrease in ACTH levels, but only atenolol saw a decrease in cortisol levels. The mechanism by which cortisol levels decreased from these drugs is not well understood, as these drugs are known as beta blockers. The decrease in blood pressure can be explained by the decrease in action of epinephrine and norepinephrine, as these neurotransmitters/endocrine hormones are well known to act in the fight-or-flight response to increase blood pressure (Oliver & Schäfer, 1895, Persichini et al., 2012). Furthermore, an increase in ANF was also seen. This hormone is released by the right atrium, where it acts on the kidneys to promote sodium and water release, and decrease renin release from the juxtaglomerular cells of the kidney (Maack, 1996, Bełtowski, 2000). These two effects in tandem decrease blood volume and thereby decrease blood pressure. With this in mind, the effect of cortisol is not well understood in this study. While there was a decrease in blood pressure and cortisol, the conclusions that can be made between their correlations are limited. Another limitation of this study is the small sample size. With only 37 total patients, this makes it more difficult to extrapolate the statistical analysis to the general population (Faber & Fonseca, 2014). This limitation is even greater when looking at the further division of those 37 patients into two smaller groups. Moreover, some results as shown in figure 2 have large error bars, meaning the data is largely spread. This does complicate the strength of the paper’s findings, making it less likely that the paper’s findings will be externally valid. One benefit to this study is that it is looking at hypertensive patients without CS. This is a benefit as it can show the effect of decreasing cortisol in a patient without endogenous hypercortisolism. Overall, this study is not great at showing the effect of decreasing cortisol in hypertensive patients due to catecholamine decrease and ANF increase, which may be confounding variables.

Qigong exercise was found to decrease systolic and diastolic blood pressure significantly throughout a time interval (Lee et al., 2009). However, the contribution of cortisol to this decrease is unknown, this study does find a significant decrease in epinephrine and norepinephrine levels. These sympathetic suppression effects could be a reason why the decrease in blood pressure was seen since the sympathetic nervous system is known to directly affect blood pressure (Esler et al., 2006). While there is a correlation between decreasing cortisol levels and qigong exercise, this cannot be concluded as a causational relationship.

Relaxation training also shows a decrease in mean arterial pressure in 49% of hypertensive patients (McGrady, 1994). Yet, like the qigong findings, the direct effect of cortisol is still in question. This study also found a decrease in plasma aldosterone as well as urinary cortisol levels. As indicated before, aldosterone leads to sodium reuptake in the kidneys and increased fluid in the blood, increasing blood pressure. This decrease in plasma aldosterone can be a contributing factor to the decrease in blood pressure, once again making it difficult to imply a causational relationship between cortisol and blood pressure. Also, while this study found a significant decrease in urinary cortisol, there was no significant decrease in plasma cortisol levels. The researchers did point out that patient compliance with 24-hr urine tests were problematic so urinary cortisol measurements are somewhat unreliable. Forest therapy saw a decrease in systolic blood pressure in both the control and experimental group. This means that some variables that were not controlled caused a decrease in blood pressure in the negative control group. The researchers tried explaining this due to the many mechanisms that affect blood pressure, and that these mechanisms have a relative degree of contribution specific to each person. The forest therapy study was limited by many factors. Firstly, the study was not truly random, the patients were placed into groups based on their availability for the program. This introduces lifestyle bias, as one being more available means they have fewer stressors in their life (work, etc.). This could affect the decrease in cortisol in the experimental group. Furthermore, the desire or motivation to participate in the program or be healthy could be a strong ‘placebo’ effect (Sung et al., 2012). The study did not follow lifestyle changes (diet, exercise) in the experimental or control group. Finally, the researchers said their sample size was too small to draw statistical significance from the experiment.

The aromatherapy experiment by Hwang (2007) had many limitations to its study design. Firstly, the study measured hormone levels both before the intervention and after its completion, contrasting with blood pressure measurements, which were taken twice weekly throughout. This inconsistency makes it hard to draw conclusions that the plasma cortisol reduction was caused by this aromatherapy. Secondly, the study shows that significant decreases in blood pressure compared to the two control groups only occurred in the final week, as a slow and gradual decrease throughout the weeks. Also, the experiment had a small sample size, which made the study more variable and less likely to be representative of the population. Further research is needed to validate aromatherapy as a way to decrease cortisol and blood pressure in patients with hypertension.

Conclusions & Future Directions

Overall, the studies looking at non-pharmaceutical and alternative forms of medicine show a decrease in blood pressure. However, these studies are poorly controlled in study design to only view cortisol changes and cortisol level effects. The drugs mifepristone and relacorilant do show improvements in patients with CS and hypertension, and these studies do seem to be more controlled in knowing that blocking glucocorticoid receptors is what causes blood pressure to decrease. While there are many potential side effects of using pharmaceutical drugs as compared to the non-drug studies, the drug studies have a stronger causal relationship, since the mechanisms of action are known. Therefore, drug usage as a means of decreasing cortisol is recommended, especially with relacorilant since it does not have the progesterone-blocking effects of mifepristone.

Future directions of this research topic involve larger sample sizes in phase 3 clinical study, comparing it with other treatments. Furthermore, while these studies are promising, further research is needed to see if micro doses of these drugs can help patients without CS and only hypertension. Some limitations of this paper involve only using PubMed as a search engine. Only one search engine limits the studies found, not thoroughly explaining all scientific literature on this topic. Finally, not doing a meta-analysis limits the inferences that can be made between studies, being another limitation of this paper.

Incidents of hypertension and deaths from hypertension-related diseases are common in our society. With hypertension being a multi-factor medical condition, this is why a thorough understanding of how decreasing cortisol levels affects hypertensive patients is crucial. With a deeper knowledge of hypertensive mechanisms, medical professionals can provide personalized care, knowing all the factors affecting hypertension.

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