Endocrine Dysfunction in Anorexia Nervosa Patients
Endocrine Abnormalities of Anorexia Nervosa
Anorexia nervosa and its correlated malnutrition and overexercise can cause a variety of endocrine abnormalities. Prolonged starvation can greatly impact the pituitary gland, thyroid gland, adrenal glands, gonads and bones. While most complications resolve with weight restoration, others don’t fully normalize even with weight restoration. Many of these hormonal changes are appropriate physiologic adaptations to help conserve energy, but they come at the cost of bone health and other physiologic abnormalities.
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) in a pulsatile manner, 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.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 circulating androgens (male sex hormones). Adipocytes, or fat cells, contain enzymes that help to convert the androgens to estrogen but these adipocytes 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.
In Males
Prolonged calorie restriction can cause a disruption in the male gonadal axis as well. 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
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 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 starvation, insulin levels are also low. However, anorexia nervosa is also associated with increased insulin sensitivity, meaning the insulin that is present is able to 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 (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. Insulin also likely impacts development of edema that can develop upon re-introduction of nutrition.
Thyroid Hormones
The hypothalamic-pituitary-thyroid 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 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—the laboratory abnormalities normalize with weight restoration.
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 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 and 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 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 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 (“orexigenic”), fat deposition and growth hormone. It is elevated in anorexia nervosa.
Symptoms of Endocrine Complications
Physical exam findings such as hypotension (low blood pressure), bradycardia, and hypothermia may be attributed to endocrine dysfunction, although malnutrition itself is generally the cause of these findings. It is, therefore, unsurprising that patients with anorexia nervosa are often referred to endocrinologists for evaluation.
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.
Endocrine Testing
There are numerous tests that can be ordered to assess thyroid, pituitary and adrenal gland function.
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 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.
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 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
In general, the hormonal dysregulation will normalize through refeeding and weight restoration, but they may lag behind nutritional rehabilitation.
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 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
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 accordingly.
Supplemental Testosterone
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.
Supplemental Estrogen
Oral hormone replacement therapy/oral contraceptives do not appear to be beneficial for bone health in anorexia nervosa. Transdermal estrogen, on the other hand, is likely beneficial in this regard.
Resources
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- Kano, M., Muratsubaki, T., van Oudenhove, L., et al. (2017). Altered brain and gut responses to corticotropin-releasing hormone (CRH) in patients with irritable bowel syndrome. Scientific Reports, 7(1).
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- Singhal, V., Nimmala, S., Slattery, M., et al. (2022). Physiologic transdermal estradiol replacement mimics effects of endogenous estrogen on bone outcomes in hypoestrogenic women with anorexia nervosa. Nutrients, 14, 2257.
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- Wong, H. K., Hoermann, R., & Grossmann, M. (2019). Reversible male hypogonadotropic hypogonadism due to energy deficit. Clinical Endocrinology. https://doi.org/10.1111/cen.1397
Last Reviewed: November 2023 by Dennis Gibson, MD, FACP, CEDS
