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.

How Does Anorexia Nervosa Affect the Endocrine System?

Anorexia nervosa, along with its associated malnutrition and overexercise, can lead to various endocrinological abnormalities. Prolonged starvation affects the entire endocrine system, impairing the body’s ability to use hormones to regulate metabolism, reproduction, growth and development.

Many of these hormonal changes are adaptations to conserve energy during periods of malnutrition, but they have a cost. While most complications resolve with weight restoration, some don’t fully normalize even after gaining weight, underscoring the importance of early identification and treatment of eating disorders.¹

Endocrine Abnormalities of Anorexia Nervosa

Sex hormones

In both males and females, overexercise and food restriction disrupt the hypothalamic-pituitary-gonadal axis, leading to hypothalamic hypogonadism – a condition in which the testes or ovaries produce little or no sex hormones.¹

Normally, the hypothalamus secretes gonadotropin-releasing hormone (GnRH), which increases the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland to signal the testes or ovaries to produce sex hormones like testosterone and estrogen.¹

Female sex hormones

In female patients with anorexia nervosa, not only does reduced GnRH cause decreased production of estrogen from the ovaries, but it also reduces production of estrogen in other tissue, such as body fat.

Ultimately, this compromises the body’s ability to convert androgens (male sex hormones) into estrogen and disrupts ovulation in pre-menopausal women.¹

Male sex hormones

Prolonged calorie restriction in men with eating disorders can disrupt the male gonadal axis.² Reduced LH fails to stimulate Leydig cells in the testes to produce testosterone, resulting in low testosterone levels, decreased sex drive and diminished sexual function.

Growth hormone

Patients with anorexia often have increased GH levels and decreased IGF-1 levels, indicating a state of GH resistance and diminished effects of this hormone.¹ Most of GH's effects are mediated through IGF-1, which is an anabolic hormone with many metabolic effects.

Long-term inability of this hormone to function properly may lead to:

• Permanently reduced growth
• Short stature

Cortisol

Cortisol, the primary stress hormone in the body, is elevated in patients with anorexia nervosa.¹Anorexia nervosa can lead to dysregulation of the hypothalamic-pituitary-adrenal axis. There also appears to be increased levels of corticotropin-releasing hormone (CRH), which stimulates cortisol production.¹

When malnourished, cortisol helps regulate metabolism by increasing glucose production to maintain blood sugar levels, but it also:

• Contributes to gastritis development
• Promotes bone breakdown
• Impacts the immune response
• Influences mood, cognition and neural health
• Affects gastrointestinal function

Insulin

Due to low blood glucose levels and a low BMI caused by extreme malnutrition, insulin levels are also reduced in patients with anorexia nervosa.³ However, anorexia nervosa is also linked to increased insulin sensitivity, meaning the insulin present can have a stronger impact despite being low.³

One of the main effects of insulin is to help the body use blood sugars for energy; therefore, other sources of energy are used when insulin levels are low, like breaking down fats to produce glucose or by breaking down glycogen.

However, glycogen stores in the liver are only a short-term backup for blood sugar, and with minimal fat stores, the body cannot compensate for low glucose. This puts patients at high risk for hypoglycemia, which can lead to coma and death.¹

Thyroid hormones

Thyroid function is also disrupted in individuals with anorexia nervosa.^1,4 Patients with anorexia may experience many of the features of hypothyroidism, including:

• Bradycardia
• Hypothermia
• Hypotension
• Dry skin
• Reduced metabolic rate

The abnormalities most often resemble those seen in euthyroid sick syndrome or nonthyroidal illness syndrome, where triiodothyronine (T3) levels are low, but thyroxine (T4) and thyroid-stimulating hormone (TSH) tend to be in the low to normal range.⁴

T4 is converted to inactive reverse T3, rather than the active T3 hormone, in the peripheral tissues to help conserve energy.⁴ Use of thyroid supplements should be avoided, as these changes are physiologic, and these patients are not considered hypothyroid; laboratory abnormalities return to normal with weight restoration.

Cholesterol

High blood cholesterol is common in patients with anorexia nervosa. Cholesterol is a waxy substance found in cell membranes that acts as a precursor in the production of the body's hormones. Typically, high cholesterol in patients with anorexia nervosa results from increased levels of:⁵

• Total cholesterol
• Protective high-density lipoprotein (HDL)
• Low-density lipoprotein (LDL)

Leptin

Leptin levels are diminished in patients with anorexia nervosa. Leptin plays an import role in energy balance.⁴ Leptin helps the body maintain its weight over the long term, circulating at levels proportional to fat stores. Due to reduced body weight and fat mass in patients with anorexia, leptin levels are low.⁴

Low leptin can lead to issues with:

• Energy regulation
• Satiety cues
• Bone health
• Reproductive function

Ghrelin

Ghrelin is elevated in those with anorexia nervosa. Ghrelin plays a crucial role in energy balance, often called the “hunger hormone.”⁴ It is produced in the stomach, and its most notable effects are:

• Increasing hunger and appetite
• Promoting fat storage
• Stimulating growth hormone levels

Because individuals with anorexia nervosa often have an energy deficit, the stomach releases more ghrelin to stimulate hunger and promote eating.⁴

Symptoms of Endocrine Complications

Osteopenia & osteoporosis

Osteopenia and osteoporosis are two conditions that endocrinologists should watch for, as they can indicate anorexia nervosa. Changes in gonadal hormones, growth hormone, cortisol, adipokines and gut hormones in anorexia nervosa all negatively affect bone health, which may already be poor due to low BMI and decreased skeletal muscle mass.⁴

Patients with anorexia nervosa often experience severe and persistent bone mineral loss and may have a history of fractures. Patients who develop anorexia nervosa at a young age also may have never reached peak bone mass.

Amenorrhea & oligomenorrhea

Amenorrhea and oligomenorrhea are common features in women and girls with anorexia nervosa, even early in their disorder.⁶ This can make conception and family planning more challenging for women while the disease is active.

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 Endocrine Abnormalities

Nutritional rehabilitation

In general, hormonal dysregulation normalizes through nutritional rehabilitation, but endocrinological problems may lag behind. Refeeding and weight restoration establishes the foundation for sustained recovery and long-term clinical improvement.

Supplemental estrogen

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.⁷

Supplemental testosterone

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.⁸

Should Patients With Anorexia Nervosa Receive 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.

Getting Help for a Severe Eating Disorder

Endocrine complications from a severe eating disorder can disrupt hormones and lead to long-term complications, like decreased bone mass. With nutrition therapy and evidence-based treatment, recovery is possible.

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References

1. Haines, M. S. (2023). Endocrine complications of anorexia nervosa. Journal of Eating Disorders, 11(1). https://doi.org/10.1186/s40337-023-00744-9
2. Wong, H. K., Hoermann, R., & Grossmann, M. (2019). Reversible male hypogonadotropic hypogonadism due to energy deficit. Clinical Endocrinology, 91(1), 3–9. https://doi.org/10.1111/cen.13973
3.  Fukushima, M., Nakai, Y., Taniguchi, A., Imura, H., Nagata, I., & Tokuyama, K. (1993). Insulin sensitivity, insulin secretion, and glucose effectiveness in anorexia nervosa: A minimal model analysis. Metabolism, 42(9), 1164–1168. https://doi.org/10.1016/0026-0495(93)90275-s
4. Usdan, L. S., Khaodhiar, L., & Apovian, C. M. (2008). The endocrinopathies of anorexia nervosa. Endocrine Practice, 14(8), 1055–1063. https://doi.org/10.4158/ep.14.8.1055
5. Ohwada, R., Hotta, M., Oikawa, S., & Takano, K. (2006). Etiology of hypercholesterolemia in patients with anorexia nervosa. International Journal of Eating Disorders, 39(7), 598–601. https://doi.org/10.1002/eat.20298
6. Ante, Z., Luu, T. M., Healy‐Profitós, J., He, S., Taddeo, D., Lo, E., & Auger, N. (2020). Pregnancy outcomes in women with anorexia nervosa. International Journal of Eating Disorders, 53(5), 673–682. https://doi.org/10.1002/eat.23251
7. Pedreira, C. C., Maya, J., & Misra, M. (2022). Functional hypothalamic amenorrhea: Impact on bone and neuropsychiatric outcomes. Frontiers in Endocrinology, 13. https://doi.org/10.3389/fendo.2022.953180
8. Mehler, P. S., & Andersen, A. E. (2022). Eating Disorders: A comprehensive guide to medical care and complications (Fourth Edition). Johns Hopkins University Press.