Endocrine Dysfunction in Anorexia Nervosa Patients

Endocrine Abnormalities of Anorexia Nervosa

Anorexia nervosa and its associated malnutrition and overexercise, can cause a variety of endocrine abnormalities. Prolonged starvation greatly impacts the pituitary gland, thyroid gland, adrenal glands, gonads and bones. While most complications resolve with weight restoration, others can be enduring or permanent. Many of these hormonal changes are appropriate physiologic adaptations to help conserve energy but come at the detriment of bone health and other physiologic abnormalities.

Sex Hormones

In both males and females, overexercise and/or caloric restriction causes a disruption in the hypothalamic-pituitary-gonadal axis, resulting in hypothalamic hypogonadism. Normally, the hypothalamus secretes gonatropin-releasing hormone (GnRH) in a pulsatile manner, causing increased secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary gland, which causes production of various hormones from the ovaries (or testes) that ultimately result in increased levels of progesterone and estradiol (or, in males, testosterone). With anorexia nervosa and a disrupted axis, low levels of estrogen and testosterone are produced due to reduced pulses of GnRH from the hypothalamus.^1,2,4,5 Generally, one must achieve a minimum of 90% ideal body weight in order normalize this axis.

In Females

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 androgens (male sex hormones)—enzymes that convert androgens to estrogen are present in fat cells, which are severely depleted due to the extreme weight loss. Ovulation also fails to occur as a certain amount of estrogen is required for the LH surge that results in the release of the oocyte (egg).  

Amenorrhea, primary and secondary, is a common characteristic of women and girls with anorexia, even early into their disorder.This can also cause infertility and problems conceiving in women while the disease is active.¹

In Males

Excessive exercise, particularly when it occurs alongside prolonged calorie restriction 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.^4,5

Growth Hormone

Severe malnutrition can alter secretion of growth hormone (GH) and insulin-like growth factor (IGF-1). GH levels are increased, while levels of IGF-1 are decreased in patients with anorexia, indicative of a state of GH resistance an reduced physiologic effects of this hormone.  IGF-1 is important for growth and metabolism . Long-term inability of this hormone to act appropriately may cause permanently reduced growth and stature.^1,2

Cortisol

The hypothalamic-pituitary-adrenal axis is also dysregulated in those with anorexia nervosa. Cortisol, the main stress hormone of the body, is up-regulated in starvation. 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 effects the immune response. CRH also has many deleterious effects within the brain as well as the gut.⁶

Insulin

Due to the low levels of blood glucose and low BMI resulting from extreme starvation, insulin levels are also low.² 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 can be appropriately 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 (stored polymers of glucose). 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 reduced adipose (fat) tissue.

Thyroid

The hypothalamic-pituitary-thyroid axis is dysregulated in those with anorexia nervosa. The abnormalities 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) in the low to normal range.⁴ T4 is appropriately converted to the inactive reverse T3 in the periphery instead of the active T3 hormone 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.

Cholesterol

Cholesterol is a waxy substance found in cells 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. Typically, it is caused by elevated total cholesterol, cardioprotective high-density lipoprotein (HDL) and elevated low-density lipoprotein (LDL), with these findings likely effectuated through changes in metabolism.⁷ 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 adipose tissue and helps the body maintain its weight long-term, circulating at levels that are in proportion to adipose tissue stores. Leptin acts to limit the production of anabolic hormones (those that act to “build-up” our body’s tissues), inhibits hunger, and likely regulates some of the above mentioned hormonal adaptations to starvation. Due to the reduced body weight and fat mass in patients with anorexia, leptin concentrations are low.^1,2

Ghrelin, colloquially known as the “hunger hormone,” is mainly produced within the stomach. It has many effects within the body but its effects can generally be regarded as opposite those of leptin, acting to increase hunger/appetite, fat deposition and growth hormone release (overall, ghrelin is an anabolic hormone). It is elevated in anorexia nervosa.^2,3

Symptoms of Endocrine Complications

Pseudo-hypothyroidism

Many of the symptoms found in the physical examination of patients with anorexia nervosa that might indicate endocrine dysfunction are similar to those seen in hypothyroidism, including:

• Cold intolerance
• Bradycardia (low heart rate)
• Hypothermia
• Light-headedness
• Abnormal reflexes
• Dizziness

It is unsurprising that patients with anorexia may be referred to an endocrinologist for evaluation,² therefore endocrinologists should be aware of the symptoms and consequences of the disease while evaluating patients. As stated above, individuals should no be treated with thyroid replacement but instead of nutritional rehabilitation.

Osteopenia and Osteoporosis

Osteopenia and osteoporosis are two conditions endocrinologists can look out for that may indicate anorexia nervosa. Patients with anorexia nervosa can often have severe and enduring bone mineral loss and a history of bone fractures. 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. In addition to pseudo-hypothyroid symptoms, physicians can also look out for:

• Chronic pain associated with bone fractures
• Reduced strength and mobility
• Emotional suffering associated with a chronic illness

Endocrine Testing

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 as a diagnosis of anorexia nervosa can be made clinically and neither measurement effects therapy.²

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 turnover, but no testing has been done on its efficacy on weight gain or bone metabolism. Because of the lack of research there is currently no role for IGF-1 or GH in the treatment of anorexia nervosa.²

CortisolHypercortisolemia 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 Complications

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

Nutritional Rehabilitation

Amenorrhea, low testosterone and estrogen, hypoglycemia, hypercholesterolemia, low leptin and elevated ghrelin levels will all normalize through refeeding and weight restoration, but they may lag behind nutritional rehabilitation.²

Thyroid Hormone 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. The risks of unnecessary thyroid hormone are twofold. First, thyroid hormone replacement therapy can negatively impact on bone mineral density, which is already compromised in anorexic patients. Second, it may increase metabolic rate and counter weight gain, which should be considered the primary medicine.⁴

Patients with suspected primary hypothyroidism, whose abnormal test results do not resolve with nutritional rehabilitation should have further evaluation of their pituitary function and may require treatment from a specialist.⁴ Findings suggestive of hyperthyroidism should be treated accordingly.

Supplemental Testosterone

Testosterone supplementation is optional and can be supplemented for men with anorexia nervosa. However, there have been no definitive studies that demonstrate either testosterone replacement or a natural return of levels being more beneficial than the other. 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.²

Testosterone levels should be reassessed after a month, and if low levels persist it may indicate inadequate weight gain or a primary testicular disorder.²

References

1. 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
2. Mehler, P. S., & Andersen, A. E. (2017). Eating Disorders: A Guide to Medical Care and Complications (third edition). Johns Hopkins University Press.
3. Dostálová, I., & Haluzík, M. (2009). The role of ghrelin in the regulation of food intake in patients with obesity and anorexia nervosa. Physiological Research, 159–170. https://doi.org/10.33549/physiolres.931448
4. Mehler, P. S., & Brown, C. (2015). Anorexia nervosa – medical complications. Journal of Eating Disorders, 3(1). https://doi.org/10.1186/s40337-015-0040-8
5. Wong, H. K., Hoermann, R., & Grossmann, M. (2019). Reversible male hypogonadotropic hypogonadism due to energy deficit. Clinical Endocrinology. https://doi.org/10.1111/cen.13973
6. Kano, M., Muratsubaki, T., Van Oudenhove, L., Morishita, J., Yoshizawa, M., Kohno, K., Yagihashi, M., Tanaka, Y., Mugikura, S., Dupont, P., Ly, H. G., Takase, K., Kanazawa, M., & Fukudo, S. (2017). Altered brain and gut responses to corticotropin-releasing hormone (CRH) in patients with irritable bowel syndrome. Scientific Reports, 7(1). https://doi.org/10.1038/s41598-017-09635-x
7. 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