The Good, the Bad and the Ugly
Most of us have likely heard about hydrocortisone. We can find it in creams and gels in the pharmacy in the skin care sections, the hemorrhoids section, and the first aid section. Hydrocortisone can be used on the skin to treat rashes, itches, bug bites and swelling. It is so ubiquitous that we may not be conscious of the miracles performed by this hormone.

A Little History and A Little Mystery
The story begins in the mid1930s when researchers at the Mayo Foundation for Medical Education and Research started to focus on the component hormones of the adrenal glands. (1) Dr. Philip Hench observed that patients under his care for rheumatoid arthritis would see improvements under circumstances such as pregnancy, surgery, estrogen and testosterone treatments, high fat diets or even starvation. He theorized that the functioning of the adrenal glands might have something to do with these disparities. Under the direction of Dr. Edward Kendall, adrenal hormones were extracted and crystallized and were named in order of their extractions as Compounds A,B,C,D and E and F. The first treated human patient suffered from rheumatoid arthritis. She received injections of Compound E. (Compound E later became “cortisone”.) Her treatment started on September 21, 1948 and within one week of treatments, her disease disappeared. Other patient treatments followed with similar success. This work was so ground breaking that Dr. Hench and his colleagues received the Nobel Prize in Medicine in 1950.(2)

Kendall’s Compound F became hydrocortisone or sometimes called cortisol. Although both cortisone and hydrocortisone are still used today, cortisone must be converted into the active form hydrocortisone to produce its effect. Hydrocortisone became the preferred treatment. These hormones are made in the cortex of the adrenal gland. Like the sex hormones, these adrenal hormones are in the family of hormones called “steroids”.

Too Much of a Good Thing
It was fortunate that these early researchers used large doses to witness the drama they did. However, trouble soon arrived with a whole host of unwanted effects. These included a “moon face” and thinning of the skin to the point of bruising or bleeding under the skin. Osteoporosis and bone fractures became apparent. Side effects such as weight gain, fluid retention, peptic ulcers and increased incidence of infection made a poor tradeoff for treatment success. A whole host of similar compounds such as prednisone, prednisolone, methyl prednisolone, and dexamethasone were created in hopes to minimize these complications. The synthetic compounds proved to be just as problematic. Medical practitioners soon became leery of using any kind of “cortisone” therapy.

Dr. William McK. Jefferies
Working at Case Western Reserve in Cleveland as an endocrinologist, Dr. William Jefferies (3) became convinced that the problems with using hydrocortisone and cortisone occurred when the dosing exceeded the amounts that the human body normally produced. He claimed that the benefits of these hormones were achieved and the alarming side effects avoided when the dosing was “physiologic”, that is, mimicking the amounts and timing as close as possible to that produced in the human body. He observed the best results using 20 to 30 mg of hydrocortisone daily in 4 divided doses. Hydrocortisone became the focus of his 45 year career.

Dr. Thierry Hertoghe
Writing in the January 2018 issue of the Townsend Letter, Dr. Thierry Hertoghe, (4) a Belgium physician takes up the torch from Dr. Jefferies. He points out that there were three therapy errors in the use of hydrocortisone that led to so many problems. First, he echoes Dr.Jefferies that the dosing was simply too high and actually produced effects associated with Cushing’s Disease. (Cushing Disease is the overproduction of hydrocortisone by the adrenal glands.) Secondly, hydrocortisone and derivatives caused tissue breakdown. Normally adrenal hormones like DHEA and other androgen hormones would balance this action of hydrocortisone but were not used. Hormones should be used with consideration to balance rather than using single hormones. Thirdly, tissue breakdown can be counterbalanced by appropriate amounts of protein in the diet and was not known earlier.

Functions of Hydrocortisone
Dr. Hertoghe summarizes the main functions of hydrocortisone and related hormones. The first is to increase energy and stress resistance. He notes that in adequately functioning adrenal glands, hydrocortisone naturally rises in 3 to 15 minutes when challenged with a stress. Energy is boosted by action upon glucose, the sugar molecule in the blood which is used to produce energy in the cells. Hydrocortisone increases release of glucose when needed and at rest directs glucose into its storage form, glycogen. Glycogen stores are maintained in the liver and muscles. Hydrocortisone can also direct conversion of protein to glucose when glucose levels are inadequate. Because hydrocortisone and related compounds direct blood glucose, they are also called “glucocorticoids”.

Hydrocortisone is an activator of dopamine in the brain by stimulating more receptor sites. Dopamine, a neurotransmitter hormone, increases energy and wellbeing.

Hydrocortisone increases blood, oxygen and nutrients to the brain and other tissues. Finally, energy is increased by directing the burning of fat stores.

Through various mechanisms, hydrocortisone is also anti-inflammatory. Swelling and pain may signify deficiencies. It prevents excessive production of collagen. Collagen excess leads to the creation of fibrotic tissue such as scars, keloids and scleroderma.

Tissue damaging molecules made from oxygen are called “free radicals”. These molecules are extremely disrupting to cell functions. Hydrocortisone can behave as an “antioxidant” and quench the dangerous free radicals.

Major Symptoms and Signs
Those with low hydrocortisone with have problems with fatigue, they will experience “adrenal burnout” with severe depletions. There is low resistance to stress (including infections). With infections there is a flu-like malaise that presents with low energy and achiness in the joints and muscles. Because of low blood pressure and low glucose levels, there is a feeling of light-headedness, dizziness, and “foggy brain”. There are sugar cravings, and allergies including skin reactions and asthma. Because of compensation for hydrocortisone by adrenaline from the adrenal glands, people can have sweaty hands, feet and armpits and be irritable and jittery. They can have trembling of the hands and rapid heart rate.

Dr, Hertoghe describes physical signs such as hollow checks, pigmented spots on the face and dark circles under the eyes. The hollowed cheeks may occur because those with low hydrocortisone have a diminished appetite. They may also have difficulties with nutrient absorption due to inflammation of the intestinal tract. Protein assimilation is particularly difficult. Hydrocortisone helps maintain body water so its lack can manifest as dehydration revealed in the shrunken features in the face.

ACTH (adrenocorticotropic hormone) is a hormone released by the pituitary gland. It is produced to stimulate hydrocortisone production by the adrenal gland. When the adrenals fail to make enough hydrocortisone ACTH becomes more and more elevated. High ACTH is responsible for dark spots on the face and body, darkening of the skin folds, and dark circles under the eyes.

The absence of enough hydrocortisone to protect against inflammation can manifest as many diseases. There are inflammations of the eyes, ears and nose. There can be skin rashes, eczema and psoriasis. Inflammation of the gastrointestinal tract results in colitis, gastritis and enteritis. (Note that all the “itis” endings of diagnoses words refer to inflammation.) Allergies and asthma are related to low hydrocortisone. Arthritis and autoimmune diseases such as lupus and even cancers have a component of inflammation due to low hydrocortisone.

Addison’s Disease showing hollowed checks and pigmentation of the face and hands and inflammation of the hands.

Causes of Mild Adrenal Deficiencies
Dr. Jefferies writes that the diminished production of hydrocortisone can be directly at the adrenal gland. It can be a secondary pituitary problem with not enough release of the signaling molecule ACTH. There is a third origin if the hypothalamus is involved and the hormone, corticotropin-releasing hormone (CRH), is not stimulating the pituitary. Confounding the situation further, there can be issues with receptors for hydrocortisone and with binding proteins. Dr. Hertoghe suggests testing for cortisol binding globulin (CBG). Levels can be elevated in women who have used birth control pills thus creating a block to hydrocortisone function. Mild adrenal deficiencies are very common.

Dr. Jefferies identified low hydrocortisone in his patients struggling with infertility. He mainly prescribed his low dose protocol of 20 mg in 4 divided doses. He theorized that low hydrocortisone produced excessive estrogen and androgen production by the adrenal glands that interfered with normal function of the ovaries. Acne and facial hair as in polycystic ovary disease would resolve with hydrocortisone treatment. Dosing was continued throughout the pregnancies without problem and often continued thereafter. Adrenal deficiencies can be behind multiple miscarriages. Dr. Jefferies also reported that sometimes whole thyroid hormone needed to be included. He worked with male patients with low sperm counts with success. Since sperm require 2 to 3 months to mature, he advised starting hydrocortisone treatment with that timing in mind.

Excessive amounts of the hormone histamine can exist in tissues and cause runny noses, watery eyes, rashes, hives and itches, asthma, food allergies, and even anaphylaxis. Those with low hydrocortisone lack enough of the enzyme histaminase to break down histamine. Additionally, hydrocortisone can also inhibit the enzyme responsible for creating more histamine. The small physiologic doses recommended by Dr. Jefferies can remedy excess histamine.

Autoimmune Disorders
Dr. Jefferies reported success in treating Grave’s disease including resolution of bulging eyes. Because of the intimate relationship of hydrocortisone and blood glucose, those with diabetes should be evaluated and treated for adrenal deficiencies. Inflammatory diseases of the gut are often treated with prednisone, but Dr. Jefferies suggested that low doses of hydrocortisone are warranted. He predicted that low dose hydrocortisone would also be beneficial in diseases such as multiple sclerosis.

One of the most important aspects of adequate hydrocortisone and adequate adrenal functioning is resilience to infection. Dr. Jefferies reported this routinely in his patients. In his later years, he demonstrated that there is a possible interference with the ACTH signaling from the pituitary to the adrenals by the viral infection.(5) This essentially causes a shutdown of the adrenal glands. Viral infections like influenza can be avoided if those who are deficient are already treated. If the infection does start, the course of the infection can be shortened and its intensity dampened with hydrocortisone. In these cases, Dr. Jefferies would advise his patients to adjust their hydrocortisone dosing to meet the challenge just as the body would do. He would have them increase to 20 mg four times daily until the symptoms stopped and then resume their normal low doses. Dr. Jefferies related that he had personally used twice that amount over three days to treat a shingles outbreak. The lesions healed rapidly and he experienced no pain. He then resumed his normal dosing. (6) In the case of bacterial infections, Dr. Jefferies recommended using antibiotics in conjunction with the hydrocortisone dosing.

And More!
There are many more issues that may have underlying hydrocortisone deficiencies. Dr. Jefferies reviewed some of these: hirsutism (inappropriate face and body hair), acne, even including the more severe cystic types, severe menstrual cramping, and PMS. There is a type of hypothyroidism that occurs with high levels of active thyroid in the blood but resistance to uptake by the cells. Using hydrocortisone can improve the utilization of thyroid hormone. In evaluating and treating low blood sugar, chronic fatigue, fibromyalgia and jet lag, hydrocortisone should be considered. In the case of breast and prostate cancer, Dr. Jefferies believed that high estrogen levels provoked by low hydrocortisone could be alieved as well as progress of these hormone related cancers. In fact, he felt that all cancer patients should be evaluated for low hydrocortisone.

Dr. Al Plechner
Dr. Al Plechner, DVM (7) observed these same problems in animals. He began to routinely test for deficiencies or dysfunctions of hydrocortisone. He documented excessive estrogen levels which he attributed to adrenal origin when hydrocortisone was lacking. At the same time he identified and tested for immune system deficiencies. He felt that here was an important nexus between the endocrine and immune systems. He successfully treated thousands of animals by restoring hydrocortisone, just as Dr. Jefferies recommended in physiologic dosing. He could document diminishment of estrogens and a restoration of immune functioning in a matter of weeks.

Mild adrenal deficiencies are widespread. Physicians easily identify and treat the worst case scenario known as Addison’s disease. They are failing to take into account that our bodies don’t have just an “on and off” switch but the degrees of hydrocortisone deficiencies range from mild to life threatening. Small doses of hydrocortisone as Dr. Jefferies recommended were life changing in his practice. He also taught his patients how to increase their dosing in response to exceptional stress or infection. Hydrocortisone treatments are inexpensive. It is magical but it takes determination and steadfastness to try to mimic the body’s hydrocortisone output. And unlike many other therapies and treatments, Dr. Jefferies points out, it is safe!

In Conclusion
The “good” is the exceptionally safe and effective use of the adrenal hormone hydrocortisone in physiologic dosing. The “bad” occurs when crippling side effects occur with large doses. Hydrocortisone has even been designated “the death hormone” because very high levels can be produced in response to unrelenting stress. This has the same effects as excessive dosing. But, eventually, the adrenal glands give up. Then deficiency problems then turn up. The “ugly” is that medical practitioners have been ignoring this very safe and effective treatment for decades. Happily, there is still research focused on Dr. Jefferies’ ideas of physiologic dosing. (8) Andrea Isidori and her group demonstrated success with a modified release dosage form, continuing to honor the principles of physiologic dosing and timing.

(1) Cooney, William “Compound F: The History of Hydrocortisone and Hand Surgery” JHS Vol 38A April 2013: 774-778
(3) Safe Uses of Cortisol, Second Edition by William McK Jefferies Charles C Thomas, Springfield IL, 1996
(4) Hertoghe, Thierry “Cortisol Deficiency: Frequent, Life Impairing, and How to Give Patients Their Lives Back by Correcting It” Townsend Letter 2018 Jan 52-59
(5) Jefferies WM et al, “Low plasma levels of adrenocorticotropic hormone in patients with acute influenza.” Clin Infect Dis. 1998 Mar;26(3):708-10.
(6) Personal communication
(7) (we could also link to the articles we published about Dr. Plechner’s work)
(8) Isidori, Andrea et al “Effect of once-daily, modified –release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomized controlled trial” Published online December 2017: 1-13

Written by Carol Petersen and published at