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Spring 2003 

Endocrine Causes of Chronic Fatigue: A Review of Symptoms, Treatments
By Theodore C. Friedman, MD, PhD and Camille Kimball

Diagnosing chronic fatigue and immune dysfunction syndrome (CFIDS) can be a time-consuming and complex process. Numerous diseases and disorders cause long-term fatigue — and doctors must eliminate all of them before arriving at a diagnosis of CFIDS.

Diseases of the endocrine system are among the most common causes of non-CFIDS fatigue, and in some cases can closely mimic CFIDS. The endocrine system includes a number of glands that produce hormones controlling metabolism, growth, sexual development and other body processes. In this article, Dr. Theodore Friedman discusses several key endocrine causes of fatigue — and ways to differentiate them from CFIDS and treat them.

Although fatigue may be the earliest manifestation of endocrine diseases, patients usually will have other symptoms as well. These endocrine symptoms differ from the classic infectious symptoms associated with CFIDS such as fever, sore throat and swollen joints. Symptoms suggestive of an endocrine cause of fatigue as opposed to an infectious cause or immunological cause are listed in Table 1. If the patient has some of the symptoms listed in the table, an endocrine cause of chronic fatigue may be suspected.

Some of the more common endocrine diseases that often cause chronic fatigue include the following:

Thyroid disease
Impaired conversion of the thyroid hormone T4 to T3
Adult growth hormone deficiency
Adrenal insufficiency
Mineralocorticoid insufficiency
Metabolic syndrome (Insulin resistance)
Diabetes
Hypoglycemia
Vitamin D deficiency
Cushing’s Syndrome
Androgen deficiency
Estrogen deficiency

A quick reference guide to several major endocrine causes of fatigue is provided below. Because these diseases can be tricky to diagnose, a primary care physician should carefully consider a specialist who is current on the latest developments in endocrinology and is experienced in its many subtleties. These endocrine diseases, unlike CFIDS, are often very treatable.

Hypothyroidism
This condition, marked by a reduced production of thyroid hormone, is probably the most common endocrine cause of chronic fatigue. Besides fatigue, patients may also have weight gain, sluggishness, decreased memory, coarse, dry skin, heavy periods and fluid accumulation, and also may feel cold. They could have an enlarged thyroid (goiter).

There is growing realization that patients with mild (often called subclinical) hypothyroidism may show only mildly elevated thyroid stimulating hormone (TSH, a marker for the condition) and the symptom of fatigue. Patients with a goiter found by an experienced endocrinologist, or with positive anti-TPO antibodies, are more likely to benefit from thyroid hormone replacement.

It is also noteworthy that patients with pituitary causes of hypothyroidism may have low-but-normal levels of TSH and the thyroid hormone T4. Some endocrinolgists are finding that treatment with levothyroxine (synthetic T4) alone is not enough in patients with hypothyroidism and that some patients need treatment with liothyronine (synthetic T3) in addition to T4.

Cushing’s syndrome
Cushing’s syndrome is often due to a tumor of the pituitary gland. This tumor will cause the adrenal glands to make too much of the stress-related hormone cortisol. Fatigue may be the earliest presentation of Cushing’s syndrome. Weight gain, trouble sleeping, irregular periods, extra hair growth (hirsuitism) and depression are other common symptoms. Many doctors, who have only seen textbook, severe cases of Cushing’s syndrome, may not recognize milder cases.

Cushing’s syndrome may be very difficult to diagnose. Early in the disease progression, some of the screening tests may be normal. Patients should be sent to an endocrinologist who may collect urine for cortisol (urinary free cortisol (UFC) and 17-hydroxysteroids) or collect nighttime salivary cortisol samples. Surgery to remove the tumor is often the treatment for Cushing’s syndrome.

The metabolic syndrome
The metabolic syndrome (also called Syndrome X or insulin resistance) is a newly identified syndrome associated with fatigue. These patients have elevated insulin levels and central (abdominal) obesity. They often have high blood pressure and hyperlipidemia (high cholesterol and triglycerides). Men may have gout or balding, and women may have extra hair growth and irregular periods. A high carbohydrate diet may be involved in this disease. These patients are at risk for having heart disease. In addition to weight loss and exercise, these patients may also benefit from a low carbohydrate diet or treatment with agents that improve insulin action, such as metformin (Glucophage).

Your endocrinologist may want to measure fasting insulin and glucose levels to make the diagnosis. A simple blood glucose level or even a glucose tolerance test may not be sufficient to detect insulin resistance.

Growth hormone deficiency
Adults with growth hormone deficiency have severe fatigue, weight gain (especially around the abdomen), are often depressed and have poor quality of life. Children, but not adults, with growth hormone deficiency are short. Most cases of adult growth hormone deficiency are due to damage to the pituitary gland, often due to a tumor (usually not malignant).

Symptoms of growth hormone deficiency may be the first manifestation of a pituitary tumor. However, a tumor is not always present even though a patient is truly growth hormone deficient.

Growth hormone therapy is effective only for patients who are truly GH deficient. Patients with other causes of chronic fatigue will not be helped by growth hormone therapy and some may be harmed by it. It is very important to be correctly diagnosed. You should not take growth hormone unless you are found to be growth hormone deficient.

Growth hormone is secreted in pulses so a single measurement of blood levels is not helpful. Rather than measuring a random growth hormone, your endocrinologist will probably screen you by measuring a plasma IGF-1 level. If it is low, your doctor may do sophisticated tests that stimulate growth hormone secretion and measure its levels. These tests should only be performed by personnel experienced with GH testing.

Estrogen deficiency
Many female patients develop fatigue around the time of menopause. This could be due the drop in estrogen at that time, although decreases in testosterone may also play a role.

Hormone replacement therapy has been a common treatment for this condition. Recently, however, many women have been told by their doctors not to take estrogen due to two recent studies that showed a slight increase in risk of breast cancer and heart disease in patients taking a synthetic estrogen, called Premarin, and a synthetic progestin, called Provera.

But there have not been any studies showing increased risk in breast cancer and heart disease in women taking just estrogen or more natural forms of estrogen plus progesterone. In fact, many women note an improvement in their fatigue when their low levels of estrogens are increased by being placed on estrogen supplementation.

Estrogen replacement is a complex subject as estrogens can interact with many other hormonal systems. Even the form of the estrogen is important. Oral estrogen can alter thyroid requirements and actions of growth hormone. Yet estrogen delivered by patch or by a gel does not interfere in the same way. The effects of different preparations of estrogen even vary from patient to patient. The body itself makes different estrogens, including estradiol and estriol.

The symptom of fatigue may be relieved with more specific estrogen preparations. Relying solely on the common but rather generic Premarin, which is a broad preparation from the urine of pregnant horses, may not be the best course for many women.

Testosterone deficiency
Low levels of testosterone may be due to a pituitary, adrenal or ovary/testis problem. If either men or women have fatigue and low libido (interest in sex), their doctor may want to measure their testosterone levels. If low levels are found, measurement of the pituitary hormones, LH and FSH, may help find the source of the problem. There are many good products for testosterone replacement in men, including gels and patches.

There are fewer options for testosterone replacement in women, although taking DHEA, which gets converted to testosterone, may be one option. (Editor’s note: Dr. Friedman is currently performing a study of testosterone replacement in women with pituitary problems. For more information see his Web site at http://goodhormonehealth.com/trials/clinical_trials.html.)                                                                                                

Addison’s disease
Adrenal insufficiency (Addison’s disease), like Hashimoto’s thyroiditis, is an autoimmune disease. Patients with one autoimmune disease often develop another. Patients with adrenal insufficiency can have severe fatigue, weight loss, abdominal pain and diarrhea, increased skin pigmentation and salt craving. They often have low blood pressure when they stand (orthostatic hypotension).

The adrenal gland makes two important hormones, cortisol and aldosterone. Cortisol, the glucocorticoid hormone, is the hormone involved in the stress system, while aldosterone, the mineralocorticoid hormone, regulates salt and water retention. It has recently been found that some patients with Addison’s disease may have deficiencies of only cortisol, only aldosterone, or both and that deficiencies of either hormone may give patients the symptoms of fatigue. Aldosterone deficiency may lead to lightheadedness, dizziness on standing, salt-craving and palpitations. Cortisol deficiency may lead to abdominal pain, diarrhea, weight loss or fever.

Your endocrinologist may want to measure hormones such as cortisol, ACTH, DHEAS, renin and aldosterone. You may be treated with replacement hormones including hydrocortisone, fludrocortisone (Florinef) and DHEA.

Finding out more
More information about the endocrine causes of fatigue can be found at http://www.goodhormonehealth.com. The Web site includes an easily readable table of symptoms associated with excesses and deficiencies of various hormones. It is hoped that a treatable endocrine cause for debilitating fatigue can be found for some patients.

Dr. Friedman is an associate professor in the Division of Endocrinology at the CharlesR.DrewUniversity of Medicine & Sciences-UCLASchool of Medicine in Los Angeles. He can be reached at (310) 335-0327, or by e-mail at mail@goodhormonehealth.com.