What is Frohlich syndrome?

Frohlich syndrome is a rare disorder primarily affecting individuals assigned male at birth (AMAB). It is characterised by growth retardation, underdevelopment of sexual organs (hypogonadism) and obesity caused by endocrine dysfunction due to damage or dysfunction of the hypothalamus.¹

What causes Frohlich syndrome?

Frohlich syndrome mainly results from damage or dysfunction of the hypothalamus.² The hypothalamus is an almond-sized structure situated deep within your brain which serves as a link between your endocrine and nervous system. The hypothalamus controls the pituitary gland (the master gland of the human body) which releases various hormones regulating vital body functions like growth, reproduction and metabolism. It maintains the body's internal balance by regulating body temperature, blood pressure, appetite, thirst, emotions, behaviour, sleep and digestion.

Below are some of the reasons behind hypothalamic dysfunction, which may lead to Frohlich’s syndrome:

• Brain trauma: Accidents or brain surgery can cause injury to the hypothalamus, resulting in disturbance of its functions³
• Infection of the brain: Brain infections like meningitis and encephalitis may damage the normal functioning of the hypothalamus⁴
• Tumour: A tumour of the hypothalamus, most commonly craniopharyngiomas, disrupts normal functions of the hypothalamus⁵
• Certain genetic disorders may predispose individuals to Frohlich syndrome

What key hormones get affected in Frohlich syndrome?

Several key hormones become imbalanced in Frohlich syndrome, including the primary ones listed below:

Growth hormone

Growth hormone (GH) is a hormone secreted by the pituitary gland. The pituitary gland is a pea-shaped gland situated at the base of the brain. Growth hormone as its name implies serves the major function of promoting the growth of all kinds of tissues in the body.

The secretion of growth hormone from the pituitary gland needs stimulation from another hormone known as growth hormone-releasing hormone (GHRH). GHRH is secreted from the hypothalamus. When there is damage or dysfunction of the hypothalamus it impairs the release of GHRH, which leads to reduced secretion of GH from the pituitary gland.

Gonadotropin-releasing hormone

The hypothalamus produces GnRH, which stimulates the pituitary gland to release luteinising hormone (LH) and follicle-stimulating hormone (FSH).⁶ LH and FSH are important hormones for the onset of puberty and normal sexual development. In Frohlich syndrome, there is a reduction in GnRH release.⁷ Due to reduced GnRH release in Frohlich syndrome, there is a delayed onset of puberty and the sexual organs remain underdeveloped due to reduced levels of LH and FSH.

Thyroid-stimulating hormone

Thyroid stimulating hormone (TSH) is a hormone produced by the pituitary gland. TSH stimulates the thyroid gland to produce two main hormones, thyroxine (T4) and triiodothyronine (T3). The hypothalamus releases the thyrotropin-releasing hormone (TRH), which stimulates the pituitary gland to release TSH. Any dysfunction of the hypothalamus in turn affects levels of TRH, TSH, and thyroid hormones, potentially resulting secondary hypothyroidism.⁸

What is the role of growth hormone in Frohlich syndrome?

 A deficiency of GHe in Frohlich syndrome results in the following manifestations:

Growth retardation

Growth hormone as its name implies serves the major function of promoting the growth of all kinds of tissues in the body. It stimulates the synthesis of proteins and breaks down fats to release energy for tissue growth. In children, the effect of GH increases height and overall growth of body structure.

After the growth phase is over, it maintains body structure and regulates blood sugar levels in adults. A reduced supply of GH in individuals with Frohlich Syndrome halts normal growth, preventing them from reaching typical height milestones and often resulting in short stature.⁹

Impaired sexual development

GH works alongside other hormones needed for normal sexual development. Therefore, a deficiency in GH has an indirect relationship with impaired sexual development (hypogonadism), which is a common characteristic of Frohlich’s syndrome.¹⁰

Obesity

GH also plays a role in metabolism by promoting the breakdown of fats, helping to maintain a lean body composition. In individuals with Frohlich Syndrome, a GH deficiency impairs the body's ability to metabolise fat, increasing the likelihood of central obesity.

Additionally, hypothalamic dysfunction can lead to an increased appetite and reduced energy expenditure, further contributing to obesity. This creates an imbalance between fat and muscle tissue in affected individuals.¹ 

Role of growth hormone replacement treatment in Frohlich syndrome

Hypothalamic dysfunction is the primary underlying cause of Frohlich syndrome, often caused by tumours, surgical damage, trauma, infection, or in rare cases, genetic reasons. Growth hormone deficiency is just one aspect of broader endocrine dysfunction occurring in Frohlich’s syndrome so growth hormone therapy is not the only and primary treatment for Frohlich syndrome.

The treatment for Frohlich’s syndrome involves addressing the root cause of hypothalamic dysfunction along with treatment for managing the symptoms. Growth hormone therapy is suggested when there is a confirmed deficiency of growth hormone. This is confirmed through endocrine testing.

How can growth hormone therapy help in Frohlich syndrome?

Improved growth and height

In cases of growth hormone deficiency, normal height milestones are not achieved, resulting in short stature. Growth hormone therapy can lead to improved growth and height.

Obesity reduction

GH can help to reduce obesity by promoting fat breakdown and increasing lean body mass by supporting muscle growth.

Improves bone health

GH helps with bone development, improves bone density and reduces the risk of osteopenia or osteoporosis.

What are the challenges in growth hormone therapy?

Although growth hormone replacement can help in Frohlich syndrome, all of the above functions require optimal balance and the functioning of other hormones as well. In Frohlich’s syndrome along with GH, there is a widespread imbalance of LH, FSH, and TSH as well. Accordingly, only growth hormone replacement is not sufficient to address the issue. It needs a multidisciplinary approach covering other areas as well.

What are the potential side effects and risks of growth hormone therapy?

• Hyperglycaemia: GH therapy can increase blood sugar levels (hyperglycaemia) as it reduces insulin sensitivity¹²
• Swelling on eyes, face and limbs: GH therapy may cause the body to retain excess fluid leading to swelling (oedema). If this swelling occurs around the nerves, it can lead to tingling, numbness, or pain in hands or wrists (carpel tunnel syndrome)
• Hyperlipidaemia: GH therapy can also increase cholesterol and lipid levels in the blood
• A Sudden increase in height and growth due to growth hormone therapy can cause muscle and joint pain
• It can also cause an increase in the pressure inside the skull (intracranial hypertension) causing headaches, nausea, and vision issues
• It can also cause overgrowth of tissues leading to problems like enlarged hands and feet or excess growth of internal organs (organomegaly) or gigantism

What precautions to take while taking GH therapy?

• Regular monitoring: It is important to regularly monitor blood glucose and insulin levels to detect any signs of hyperglycaemia or insulin resistance
• Lipid profile: Periodic checks of lipid levels should be conducted to identify any increases in cholesterol or other lipids that may occur during therapy
• Thyroid function tests: Thyroid function should be evaluated regularly, as growth hormone therapy can impact thyroid hormone levels
• Physical examinations: Routine physical examinations are essential to observe for any signs of oedema (swelling), excessive tissue growth, or other abnormal findings that may indicate complications

Summary

• Frohlich syndrome is a rare disorder primarily affecting individuals assigned male at birth, characterised by growth retardation, underdevelopment of sexual organs (hypogonadism) and obesity. Frohlich syndrome mainly results from damage or dysfunction of the hypothalamus
• The hypothalamus is an almond-sized structure situated deep within your brain. The hypothalamus controls the pituitary gland which releases various hormones regulating vital body functions like growth, reproduction and metabolism
• Growth hormone (GH) is a hormone secreted by the pituitary gland. The secretion of growth hormone from the pituitary gland needs stimulation from another hormone known as growth hormone-releasing hormone(GHRH)
• GHRH is secreted from the hypothalamus. When there is damage or dysfunction of the hypothalamus it impairs the release of GHRH, which leads to reduced secretion of GH from the pituitary gland
• GH as its name implies serves the major function of promoting the growth of all kinds of tissues in the body. Deficiency of GH along with widespread imbalance of other endocrine hormones developed due to damage or dysfunction of the hypothalamus leads to short stature due to growth retardation, central obesity and impaired sexual development
• Growth hormone therapy can help in improved height and growth, obesity reduction and improved bone health
• Although growth hormone replacement therapy can help to resolve some of the symptoms of Frohlich syndrome, the functions that are impaired in Frohlich’s syndrome require optimal balance and functioning of other hormones as well
• Accordingly, only growth hormone replacement is not sufficient to address the issue. It needs a multidisciplinary approach covering other aspects of Frohlich syndrome with other additional treatment options