Introduction 

Frohlich syndrome, also known as Adiposogenital Dystrophy, is a rare endocrine disorder caused by lesions in an area of the brain called the hypothalamus. This area is responsible for regulating body temperature, blood pressure, thirst, hunger, sleep and mood by stimulating the pituitary gland to release different types of hormones for growth and metabolism. This disorder is more prevalent in people assigned male at birth and is typically acquired before puberty. It is characterised by obesity, growth issues (short stature), hypogonadism (the under-production of hormones), visual impairment, polydipsia leading to polyuria (the excess production of urine), and pubertal delay.1 Metabolic disorders such as Frohlich syndrome are associated with cardiovascular disease (CVD), in part due to abdominal obesity, which gives rise to a group of conditions including dyslipidemia (abnormal lipid levels in the blood) and hypertension, which leads to cardiovascular morbidity and mortality.² 

In this article, we will discuss the causes, risks, symptoms, management and challenges of CVD in patients with Frohlich syndrome.

Understanding frohlich syndrome 

Frohlich syndrome is caused by the hormonal imbalance in the hypothalamic-pituitary-adrenal (HPA) axis, and a reduction in the secretion of gonadotropin hormone (GnRH).¹ The HPA axis is a neuroendocrine system that regulates the body’s stress response. It mainly works on the hypothalamus, pituitary gland, and adrenal glands. 

The HPA axis works by: 

• When a stressful situation occurs, the autonomic nervous system triggers the hypothalamus to release a hormone called corticotropin-releasing hormone (CHR)
• The CHR will trigger the pituitary gland to release adrenocorticotropic hormone (ACTH) 
• ACTH will then trigger the adrenal glands to release Cortisol 
• Cortisol triggers the hypothalamus to stop releasing CHR (this is a negative feedback loop) which terminates the stress response. 

Excess stress levels can lead to dysfunction of this axis. However, in Frohlich syndrome, the dysfunction arises from damage to the hypothalamus. This dysfunction will lead to various metabolic syndromes.^3,14

Cardiovascular disease in frohlich syndrome

Risk factors

Type 2 diabetes is a major risk factor. Insulin resistance commonly develops in response to high glucose levels, which are associated with type 2 diabetes and obesity. This happens when cells in target tissue in the liver, adipose tissue, and skeletal muscle stop responding to insulin, so are unable to take up glucose. Fatty acids and proinflammatory cytokines are involved in the development of insulin resistance, as they are involved in the increased production of adipose tissue.⁴ Changes in the signalling pathways of insulin mean that cardiovascular disease (CVD) and atherosclerosis become more prevalent.5 There are several other risk factors, including dyslipidemia, which causes atherosclerosis because of the lipid deposits on the walls of the arteries. This causes high levels of low-density lipoprotein (LDL) and triglycerides, and low levels of high-density lipoprotein (HDL) cholesterol.6 Obesity associated with Frohlich syndrome can also lead to hypertension (high blood pressure levels), which increases the risk of CVD as it can lead to hardened arteries, increased clotting and thinning of the heart muscles. Chronic inflammation also plays a huge role in aggregating the growth of plaque in arteries, which will cause blood clots. The dysfunction of the endothelium caused by high inflammation increases the transport of lipoproteins into the blood and elevates the expression of inflammatory cytokines.⁷

Diagnosis

Cardiovascular risk assessment is a tool used to determine the degree of risk of getting CVD. This assessment includes cholesterol level, family history, body mass index (BMI), alcohol consumption, and physical activities.⁸ Early detection of CVD can reduce life-threatening events and hospitalisation taking place. For dyslipidemia, lipid profile tests must be carried out to monitor the cholesterol levels.¹² Blood glucose levels and frequent blood pressure tests must be done to detect diabetes and hypertension. An ECG monitoring system can help in the early detection of heart disease.9 However, the cardiovascular risks of Frolish syndrome must be managed by specialists such as cardiologists, endocrinologists, and dietitians. 

Radiology examinations such as a CT scan, MRI or X-ray are typically used to detect the characteristic brain abnormalities associated with Frohlich syndrome, such as the lesions to the hypothalamus.¹³

Treatment 

Lifestyle changes can play a huge role in lowering cardiovascular risks in Frohlich syndrome; including weight loss through a healthy diet (reducing fat and sugar intake), regular exercise and stress management.

Pharmacological approaches are also available, including: 

• Statins: lower cholesterol levels (the ‘bad’ cholesterol- LDL levels¹⁰ 
• Antihypertensives: lower blood pressure associated with obesity, which might lead to cardiovascular disease⁹
• Hormone replacement therapy (HRT): to replace missing hormones¹¹
• Insulin-sensitizing agents: such as metformin might be beneficial for patients with type 2 diabetes

Challenges and future research directions

Due to its low prevalence, there is a lack of research on Frohlich syndrome and cardiovascular risks. Most research conducted focuses on either hypothalamic disorders or metabolic syndromes, but not the distinctive causal mechanisms associated with Frohlich syndrome. This means that treatment is not targeted to the unique causes of CVD associated with Frohlich syndrome. There must be a potential for future research on the long-term cardiovascular effect of patients with Frohlich syndrome. 

FAQs

What is frohlich syndrome?

• Endocrine disorder is caused by damage in an area of the brain called the hypothalamus 

What causes frohlich syndrome?

• Caused by damage to an area of the brain called the hypothalamus, which leads to hormonal imbalance/dysfunction of the HPA axis. 

What are the symptoms of frohlich syndrome?

• Obesity, short stature, delayed puberty and hypogonadism 

What is the treatment for frohlich syndrome?

• Hormone replacement therapy, pharmacological approaches (medications), and lifestyle changes (balanced diet and regular exercise)

Summary 

The link between Frohlich syndrome and cardiovascular disease (CVD) is due to a cluster of factors, including obesity, dyslipidemia, and HPA axis dysfunction. These lead to hormonal imbalances, hypertension, and insulin resistance. The specialist management of cardiovascular risk factors is essential for individuals with Frohlich syndrome, to improve quality of life. Treatment may involve lifestyle changes, pharmacological interventions such as medication and continual monitoring, which have proven to decrease the severity of symptoms. Improving and intensifying research will significantly assist in gathering more data about Frohlich syndrome and its linkage with CVD, which will improve patient outcomes.