Introduction

Fröhlich syndrome (FS) is a rare condition affecting the endocrine system. This condition, also known as adiposogenital dystrophy (AD), leads to high-fat deposition, obesity and genital abnormalities¹, and is mainly prevalent in people assigned male at birth (AMAB). Men with this condition were often referred to as feminine due to growth retardation and fat deposition resembling that of a typical person assigned female at birth (AFAB). The endocrine system is affected due to damage to the hypothalamus.² FS is linked to sleep disorders, with the most common disorders being insomnia, hypersomnia and sleep apnea. The hypothalamus, which is damaged in FS, regulates sleep patterns and cycles. Therefore, FS is associated with sleeping disturbances.³ It is important to study the relationship between FS and sleep disturbances; since sleep affects lipid deposition, studying the condition allows researchers to determine whether the initial fat deposition affects sleep, or whether sleep affects the fat levels.⁴ The link between FS and sleep disturbances will be explored in this article

Pathophysiology of fröhlich syndrome

FS is mainly caused by the hypothalamus incorrectly regulating growth and causing obesity.⁷ Three key factors lead to the presentation of FS: hypothalamic function, hormonal imbalances, and circadian rhythm disruption, which affects sleeping patterns. The hypothalamus is located at the base of the brain and controls the homeostasis of energy by controlling the production of hormones, therefore regulating body weight and metabolism. Hypothalamic dysfunction, such as temperature dysregulation, leads to hypogonadism and metabolic syndrome. As neurons in the hypothalamus undergo apoptosis, lipid metabolism becomes less strictly regulated, causing individuals with FS to become overweight or obese.⁵ This leads to the body becoming more resistant to hormones in the endocrine system, such as to leptin, the main hormone that regulates hunger,⁶ and is released from adipose tissues when the hypothalamus signals to adipocytes.

Issues with the hypothalamus also disrupt pituitary gland function. This gland produces different hormones, one of them being the human growth hormone (HGH). Dysregulation of HGH and leptin are among many endocrine factors contributing to FH. In addition, the production of gonadotropin-releasing hormone by the pituitary gland is also reduced due to hypothalamic dysfunction, which leads to smaller and abnormal genitalia.⁸

Hypothalamic dysfunction also affects the circadian rhythm and disrupts sleep patterns. The suprachiasmatic nucleus (SCN) in the hypothalamus is involved in regulating the circadian rhythm and prevents neurotransmission via vasopressin and neurotensin. These hormones control the circadian rhythm, driven by the hypothalamus.⁹

Common sleep disorders in fröhlich syndrome

Insomnia, sleep apnea and hypersomnia are all common in FS.

The hypothalamic-pituitary-adrenal (HPA) axis is situated between the hypothalamus, the.adrenal and pituitary glands. This axis is constantly active during insomnia. Hypothalamic dysfunction leads to dysregulation of the HPA axis, causing insomnia.¹⁰ Increased cortisol levels lead to over-activation of the HPA axis, causing insomnia and limited REM sleep.  However, as FS is a relatively rare condition, there are few recently-reported cases.

Obstructive sleep apnea (OSA) is caused by obstructions in the respiratory tract, leading to hypoxia during sleep. This is due to obesity in many cases and there is a positive feedback loop in which OSA causes obesity.¹¹ This is because fat deposits lead to upper airway obstruction and chest capacity reduction. Less oxygen is supplied to these tissues as a result. Heavier breathing may force carbon dioxide out of the airways, however, less oxygen is entering these tissues, thus breathing difficulties make it harder to sleep.¹² 

Hypersomnia is a condition where people sleep for excessive periods of time during the day. This is likely due to obesity causing leptin resistance, causing lower cocaine- and amphetamine-regulated transcript (CART) levels. CART levels regulate physical activity, therefore a reduced CART level leads to less physical activity and more sleep. Lower levels of α-melanocyte-stimulating hormone (aMSH) lead to lower metabolism, which causes individuals to be more fatigued and have hypersomniac tendencies.¹³

Clinical presentation and diagnosis

There are many signs of sleep disorders in FS. Some patients tend to sleep in the day for long periods of time which demonstrates a disruption to the circadian rhythm.¹⁶ Symptoms of sleep apnea include fatigue and heavy breathing, as well as snoring due to breathing being obstructed in FS instances.¹⁷ Patients may gasp for air during sleep and wake up with headaches because of OSA. Nocturia can also (night-time urination) disturb sleep. This is largely due to the obesity that is associated with FS.¹⁸ Hypothalamic dysfunction may also cause restless leg syndrome (RLS), where patients move the legs during rest periods, due to the HPA axis being overactive.¹⁹ 

Different methods are used to diagnose sleeping disorders. Polysomnographs analyse blood oxygen levels alongside metrics such as heart rate, and patients who differ in these metrics compared to the norm are more likely to have sleeping disorders.¹⁹ 

Urine sampling detects levels of lipocalin-type prostaglandin D synthase (L-PGDS). L-PGDS levels are higher in individuals with OSA, therefore polysomnographs and urine sampling are the main ways to detect sleeping disorders.²⁰ There is a risk of false positives, as there are other conditions with similar symptoms, such as hyperthyroidism and polycystic ovary syndrome (PCOS) in patients with AFAB. Attention deficit hyperactivity disorder (ADHD) also presents some similar symptoms, as well as neurodegenerative conditions that are typically in older age patients, such as Parkinson’s disease.

Management and treatment

There are multiple ways to treat and manage FS. Hypothalamic dysfunction can be addressed by targeting the paraventricular nucleus (PVN) of the hypothalamus for treatments such as lesion removal. However, the link between the PVN and FS needs to be further established.²¹ Hormones can be replaced by taking drugs, such as vasopressin, to improve the circadian rhythm. Melatonin is a common drug for sleep disorders. The main way to treat obesity-related sleep disorders is to make lifestyle changes, such as increasing the frequency of exercise and having a better diet, which will improve airway circulation. Continuous positive airway pressure (CPAP) machines are used to produce constant airway pressure, despite the reduction in chest capacity, and have been shown to reduce snoring and daytime sleep caused by OSA.²³ Therapies such as cognitive behavioural therapy (CBT) may also reduce sleep disturbance and insomnia.²⁴ It is also important to make lifestyle changes to reduce common FS symptoms such as obesity, as this is a major cause of sleep issues. 

A combinatorial approach may be needed in FS individuals, by taking medications, undergoing therapy and having other treatments in some cases such as CPAP. Multidisciplinary care is needed to manage FS as sleep specialists help with therapies specifically tailored to sleep disorders. Endocrinologists can analyse hormone differences exhibited in FS patients. Other healthcare providers such as GPs can help prescribe drugs that are needed for FS management. Melatonin and other hormone-related therapies are usually recommended by endocrinologists.

Prognosis and long-term outcomes

FS has many long-term effects on the quality of life of those affected. Sleep disturbances cause many health problems including hypertension and cardiovascular disease in the long-term. Patients may eventually develop type 2 diabetes and colorectal cancer, in addition to many other medical conditions that can develop due to FS.²⁵ Sleep disorders have major cardiovascular implications, especially due to the hypoxaemia that occurs during OSA.²⁶ These symptoms must be monitored in FS patients. Daytime sleeping and fatigue should also be closely monitored. Preventing OSA and other sleep disruptions through medicines, lifestyle changes and technology such as CPAP machines alongside counselling is crucial in FS instances. The short-term effects of FS are very inconvenient and lead to individuals feeling isolated; there are also long-term effects which can be irreversible if not treated.

Future research directions

As FS is a rare condition, there are few studies on the effects of FS on sleep. There are also not many studies that differentiate between the effects on people with AMAB or AFAB as people with AMAB are more commonly affected. Whilst treatments are available, there needs to be more clinical trials on the treatments utilised for this condition. More clinical trials should be designed to assess the effects of treatments on obesity, and whether this is directly linked to sleeping disorders such as OSA. Polysomnographic data can help determine whether sleep quality improves significantly with early intervention. Different treatment strategies and lifestyle changes should be monitored and evaluated to further understand the relationship between FS and sleep. This will help ascertain what the most effective treatment options are.

Summary

FS has many effects on sleep and causes issues such as OSA, hypersomnia and insomnia due to hormonal interactions, issues with the HPA axis and other factors such as obesity. There are few studies regarding FS and its effects on sleep; however, there are well-known symptoms that must be managed. This can be done through medications, lifestyle alterations as well as counselling and other treatments. Early management strategies are paramount in preventing long-term health implications. Detecting these symptoms earlier and understanding the pathophysiology of this rare disease will improve many lives.