Introduction

What is frohlich syndrome?

Frohlich syndrome, also known as adiposogenital dystrophy, is a rare endocrine disorder resulting from injury to a specific part of the brain, particularly the hypothalamus. The hypothalamus plays a crucial role in the release of several important hormones from the pituitary gland. 

Hormones play a significant role in this disorder. Hormones are substances that stimulate action in target organs. Both under- and over-secretion of hormones can cause serious health problems. In Frohlich syndrome, stimulating hormones like growth hormone and gonadotropin are under-secreted, leading to the characteristic features of the disorder: obesity due to excessive eating, delayed puberty, and the development of secondary sexual characteristics. 

Frohlich syndrome is an acquired disorder that affects males more than females.  It is most commonly caused by a tumour in the hypothalamic-pituitary area, just above the pituitary gland. 

Hormonal imbalances in frohlich syndrome

Pathophysiology of frohlich syndrome

Hypothalamic dysfunction

The hypothalamus, a structure located deep inside the brain, controls body functions such as heart rate, body temperature, and sleep cycle through hormone secretion. It regulates the pituitary gland, a pea-sized structure beneath it, by secreting hormones that trigger the pituitary to release stimulating hormones targeting specific organs. In Frohlich’s syndrome, injury or a tumour in the hypothalamus disrupts the release of gonadotropin-releasing hormone (GnRH) and growth hormone-releasing hormone (GHRH), leading to reduced secretion of gonadotropins and growth hormone from the pituitary gland to the testes and liver, respectively.

Growth hormone (GH) deficiency

Growth hormone is composed of proteins and targets the liver. It primarily influences height and the development of bones and muscles. Its role is particularly significant during childhood and puberty when its levels peak. Hypersecretion of growth hormone during childhood can cause excessive growth, while in adulthood, it may lead to increased body fat and decreased muscle mass. This explains why Frohlich’s syndrome patients often exhibit short stature and increased body fat. 

Gonadotropin deficiency

Luteinising hormone (LH) and follicle-stimulating hormone (FSH) are secreted from the pituitary gland when GnRH is released from the hypothalamus. These hormones work together to facilitate sexual development. FSH is responsible for estrogen production and the maturation of eggs in females, as well as sperm production in males.¹ A deficiency in FSH can lead to reduced bone density and loss of libido in females and a lower number and quality of sperm in males. LH regulates the menstrual cycle and triggers the release of an egg from the ovary in females. In males, it enables the production of testosterone, one of the most important hormones in male development. Therefore, LH deficiency can lead to loss of libido, infertility, and diminished masculinisation (such as reduced facial and body hair) in males, as well as sexual dysfunction and infertility in females.² The absence of gonadotropins results in hypogonadism in patients, as it prevents the full development of secondary sexual characteristics.

Insulin and glucose regulation

Hypothalamic dysfunction in Frohlich’s syndrome causes obesity, which significantly decreases the body's insulin sensitivity and disrupts glucose metabolism. There are several “energy centres” in the hypothalamus that regulate food intake. The main centre, the Arcuate Nucleus (ARC), consists of orexigenic neurons that produce signals promoting hunger and anorexigenic neurons that promote satiety.³ Multiple studies suggest that orexigenic neurons are overactive in metabolic disorders like Frohlich’s syndrome.⁴ This causes patients to feel hungrier and increase their food intake. Additionally, the deficiency of growth hormone also slows down the metabolic rate, so collectively, all of these dysfunctions contribute towards obesity in Frohlich’s syndrome patients.

As patients become more obese, fat builds up in tissues, leading to a decrease in adiponectin. Adiponectin,  a hormone produced by adipose tissue, helps maintain healthy insulin sensitivity. As patients become less sensitive to insulin, glucose metabolism is impaired.

Clinical manifestations

Obesity and adiposity

In addition to the over-reactivity of orexigenic neurones mentioned above, obesity also results in leptin resistance. The brain fails to recognise signals for satiety, leading to continued food consumption. Unfortunately, obese individuals with higher levels of circulating leptin are more prone to weight regain.⁵

Other associated symptoms

Literature has also shown that adiposity and metabolic dysfunction can affect working memory and increase anxiety and depressive-like behaviours. Factors contributing to these changes include oxidative stress, decreased neurogenesis, and central inflammation.⁶

The inability to process glucose can easily lead to type II diabetes. Additionally, high levels of fat are a risk factor for cardiovascular disease, as they are linked to high blood pressure. This results in a greater volume of blood passing through the blood vessels, thereby increasing pressure and resistance.

Treatment and management

If the hypothalamic dysfunction is caused by a brain tumour in the hypothalamus, the tumour should be surgically removed if possible. 

Hormone replacement therapy

In order for the child to return to a normal growth curve, growth hormone replacement therapy will be implemented as part of the treatment. A dose of man-made growth hormone, calculated based on the weight of the patient, is injected under the skin on a daily basis. However, this treatment does not work for everyone, but in most cases, children can reach normal adult height if the treatment is started early. 

Sex hormone replacement for gonadotropin deficiency

The absence of GnRH results in the failure to develop secondary sexual characteristics. For male patients, doses of testosterone or human chorionic gonadotropin (hCG) which aids the production of testosterone, are injected. For female patients, oestrogen and progestin are injected. Sex hormone replacement aims to stimulate spermatogenesis in males and folliculogenesis in females.  

Weight management

Appetite control due to insensitivity to satiety hormones can be more challenging than managing sex hormone deficiencies. Therefore, weight control relies on diet and exercise interventions. 

There are also diabetic drugs that can help control obesity, such as glucagon-like peptide-1 (GLP-1) agonists. GLP-1 agonists have a similar structure to GLP-1, which is responsible for increasing insulin levels and decreasing glucagon levels. Due to their molecular structure, the agonists can bind to GLP-1 receptors to mimic the action of GLP-1. GLP-1 limits food intake and maximises nutrient absorption, thereby limiting weight gain.  

Monitoring and long-term management

Following hormone therapy, patients need to attend regular follow-up appointments to assess whether the hormone dosage needs adjustment based on changes in height and weight. These check-ups will also monitor for any side effects from the treatment. As teenage patients grow older, they will transfer from a paediatric endocrinologist to an adult endocrinologist for lifelong monitoring. 

For GLP-1 agonist treatment, measurements are taken before and after the treatment to compare weight and assess whether diabetes has improved over the course of treatment.

FAQs

How is frohlich’s syndrome diagnosed?

Physicians will first examine the patient’s physical features to identify the characteristic signs of Frohlich’s syndrome. Then, blood tests will be conducted to determine the levels of pituitary hormones, such as FSH, LH, and GH. Low levels of these hormones may indicate a lesion or injury in the hypothalamus or pituitary gland. A CT scan or MRI of the brain may follow the blood tests to reveal any tumours in the hypothalamus or pituitary gland. 

How does frohlich’s syndrome affect quality of life?

Due to a deficiency of sex hormones, patients often have underdeveloped genitalia, which may cause distress and impair sexual quality of life. For male patients, unfortunately, there is a lack of literature demonstrating any treatment, other than phalloplasty, that can ensure the penis will reach a normal size. Patients may also be dissatisfied with their height due to the lack of growth hormone. Literature reviews suggest that psychological support should be available to patients whose quality of life is affected by these symptoms.⁷