Endocrine Dysfunction in Anorexia Nervosa

Anorexia nervosa can lead to endocrine abnormalities, such as hormonal imbalances, affecting metabolism, menstruation and bone health. Malnutrition disrupts hormone production, which can result in issues like infertility, osteoporosis and delayed puberty. Treating the eating disorder is essential to restoring hormonal balance and preventing long-term health complications.

Endocrine abnormalities of anorexia nervosa

Anorexia nervosa and its associated malnutrition and overexercise can cause a range of endocrinological abnormalities. Prolonged starvation impacts the entire endocrine system, impacting the body’s ability to use hormones to control its metabolism, reproduction, growth and development.

Many of these hormonal changes are adaptations to help conserve energy during periods of malnutrition, but they come at a cost. While most complications resolve with weight restoration, others don’t fully normalize even after weight restoration.

How anorexia nervosa impacts the endocrine system

Although few patients will be referred to an endocrinologist with a diagnosis of anorexia nervosa, endocrinologists should be aware of symptoms and consequences of the disease when examining patients.

Sex hormones

In both males and females, overexercise and caloric restriction cause a disruption in the hypothalamic-pituitary-gonadal axis, resulting in hypothalamic hypogonadism. Normally, the hypothalamus secretes gonatropin-releasing hormone (GnRH), causing increased secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary gland, that ultimately result in increased levels of progesterone and estradiol in females and testosterone in males. However, with anorexia nervosa and a disrupted axis, low levels of estrogen and testosterone are produced due to reduced pulses of GnRH from the hypothalamus.

Female sex hormones

In female patients with anorexia nervosa, not only does reduced GnRH cause decreased production of estrogen from the ovaries, but there is less peripheral production of estrogen from the normally present circulating androgens (male sex hormones). Fat cells contain enzymes that help to convert the androgens to estrogen, but these cells are severely depleted due to the extreme weight loss. Ovulation also fails to occur because there isn’t enough estrogen for the LH to trigger the release of an egg.

Male sex hormones

The prolonged calorie restriction seen in men with eating disorders can cause a disruption in the male gonadal axis. Diminished LH fails to stimulate Leydig cells in the testes to produce testosterone, causing low testosterone levels, lowered sex drive and reduced sexual function.

Growth Hormone

Severe malnutrition can alter secretion of growth hormone (GH) and insulin-like growth factor (IGF-1). GH levels are increased, and levels of IGF-1 are decreased in patients with anorexia, indicative of a state of GH resistance and reduced physiologic effects of this hormone.  Most of the effects of GH are mediated through IGF-1, which is an anabolic hormone having many effects on metabolism. Long-term inability of this hormone to act appropriately may cause permanently reduced growth and stature.

Cortisol

Cortisol, the main stress hormone of the body, is also up-regulated in starvation. Anorexia nervosa can cause a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. There also appears to be increased levels of corticotropin-releasing hormone (CRH), which is a hormone secreted from the hypothalamus and acts to increase production of cortisol. In this state of starvation, cortisol is important to help regulate metabolism (acts to increase glucose production, thus helping to maintain blood sugars) but also contributes toward the development of gastritis, increases bone breakdown, and affects the immune response. CRH also has many deleterious effects within the brain as well as the gut.

Insulin

Due to the low levels of blood glucose and low BMI resulting from extreme malnutrition, insulin levels are also low. However, anorexia nervosa is also associated with increased insulin sensitivity, meaning the insulin that is present can have a stronger effect.

One of the main effects of insulin is to help the body utilize blood sugars, the body’s main energy substrate, for metabolism; therefore, other metabolic pathways are utilized due to the reduced levels of insulin. The purpose of these other metabolic pathways is to help increase blood glucose levels through the breakdown of fatty acids to allow increased production of glucose and breakdown of glycogen. However, the body remains at high risk for hypoglycemia, which can result in coma and death, due to the depletion of hepatic glycogen stores and a lack of fat.

Thyroid hormones

Thyroid hormones are also impacted by eating disorders. The HPA axis is dysregulated in those with anorexia nervosa. The abnormalities most commonly resemble those found with euthyroid sick syndrome or nonthyroidal illness syndrome, in which triiodothyronine (T3) levels are low but thyroxine (T4) and thyroid stimulating hormone (TSH) tends to be in the low to normal range.

T4 is appropriately converted to the inactive reverse T3, instead of the active T3 hormone, in the peripheral tissues as a means to help conserve energy. Use of thyroid supplement should be avoided, as these changes are physiologic, and these patients are not considered hypothyroid — the laboratory abnormalities normalize with weight restoration.

Cholesterol

Cholesterol is a waxy substance found in cell membranes that acts as a substrate in the creation of the hormones of the body. High blood cholesterol, or hypercholesterolemia, is common in patients with anorexia nervosa. Typically, it is caused by elevated total cholesterol, cardioprotective high-density lipoprotein (HDL) and elevated low-density lipoprotein (LDL), with these findings likely effectuated by changes in metabolism. These changes do not require treatment, aside from weight restoration, as they do not appear to increase the risk for cardiovascular disease.

Leptin & ghrelin

Leptin and ghrelin play important roles in energy balance. Leptin is produced primarily in white fat and helps the body maintain its weight long-term, circulating at levels that are in proportion to adipose tissue stores. Leptin has numerous effects on energy homeostasis, inhibits hunger, and interacts with numerous other hormonal axes. Due to the reduced body weight and fat mass in patients with anorexia, leptin concentrations are low.

Ghrelin, colloquially known as the “hunger hormone,” is elevated in those with anorexia nervosa. It is produced in the stomach and its most notable effect is increasing hunger/appetite, fat deposition and growth hormone.

Symptoms of endocrine complications

Physical exam findings such as hypotension (low blood pressure), bradycardia and hypothermia may be attributed to endocrine dysfunction. Although malnutrition is the real cause, many patients with anorexia nervosa are often referred to endocrinologists for evaluation and treatment of their psuedoendocrine issues.

Osteopenia & osteoporosis

Osteopenia and osteoporosis are two conditions endocrinologists can look out for that can indicate anorexia nervosa. Patients with AN often have severe and enduring bone mineral loss and a history of bone fractures, and patients that develop anorexia nervosa young also may never achieve peak bone mass.

The changes in gonadal hormones, growth hormone, cortisol, adipokines and gut hormones in anorexia nervosa all have a negative impact on bone health. This is exacerbated by low BMI and reduced mass of skeletal muscle.

Amenorrhea

Amenorrhea is a common characteristic of women and girls with anorexia, even early into their disorder. This can make conception and family planning more difficult in women while the disease is active.

Testing & treating pseudoendocrine abnormalities

Endocrine testing for anorexia nervosa patients

There are numerous tests that can be ordered to assess thyroid, pituitary and adrenal gland function. Most patients with anorexia nervosa do not have primary endocrine disorders, but these tests can help guide treatment when it’s unknown whether a patient has an underlying endocrinological problem.

Thyroid panel

Thyroid function should be tested through the measurement of TSH and T4. While T3 and reverse results indicate euthyroid sick syndrome, testing them is unnecessary. A very low TSH can be suggestive of hyperthyroidism, but the findings need to be interpreted carefully, and repeating thyroid hormone levels with weight restoration may be a good consideration.

GH & IGF-1

There is no value in measuring GH or IGF-1 levels in individuals with anorexia, as replacement therapy is unlikely to be effective. Administration of IGF-1 to patients has been shown to increase markers of bone formation, but no testing has been done on its efficacy on weight gain or bone mineral density. Because of the lack of research there is currently no role for IGF-1 or GH in the treatment of anorexia nervosa.

Cortisol

Hypercortisolemia is an expected abnormality in anorexia nervosa, but adrenal insufficiency/cortisol deficiency may need to be ruled out in some instances. If cortisol is low to normal, a cosyntropin stimulation test should be sought to make sure the individual does not also have adrenal insufficiency.

Treatment of pseudoendocrine complications

Most of the endocrine abnormalities seen in patients with anorexia nervosa resolve after nutritional rehabilitation, but other hormone therapies may be beneficial for some patients.

Nutritional Rehabilitation

In general, hormonal dysregulation normalizes through refeeding and weight restoration, but endocrinological problems may lag nutritional rehabilitation.

Thyroid replacement hormone

It is important to avoid unnecessary and potentially dangerous thyroid hormone replacement therapy for low-weight anorexic patients since abnormal test results typically normalize with nutritional rehabilitation.

Thyroid hormone replacement therapy can negatively impact bone mineral density, which is already compromised in anorexic patients. It may also increase metabolic rate and lessen weight gain, which should be considered the primary treatment.

Patients with suspected primary hypothyroidism, whose abnormal test results do not resolve with nutritional rehabilitation, should have further evaluation of their pituitary and thyroid function and may require treatment from a specialist. Findings suggestive of hyperthyroidism should be treated by an endocrinologist accordingly.

Supplemental estrogen or testosterone

For females, oral hormone replacement therapy and oral contraceptives do not appear to be beneficial for bone health in anorexia nervosa. However, studies suggest that transdermal estrogen benefits bone mineral density.

For males, testosterone supplementation is optional and can be supplemented for men with anorexia nervosa. In theory, testosterone replacement should be beneficial for bone health, although this has not been directly studied. Extreme caution should be exercised in the use of testosterone replacement in males who are not close to full height or maximal bone growth, as it can cause premature closure of the bony growth plates.

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