Introduction

Frohlich's Syndrome (FS), also known as adiposogenital dystrophy, is an acquired (not inherited) endocrine disorder caused by damage in the part of the brain called hypothalamus. The condition is characterised by overeating, growth retardation, and delayed development of sexual characteristics (and in some cases, intellectual disabilities). The hypothalamus controls our body’s autonomic functions — functions that occur without our knowledge like breathing, heart rate, temperature, and blood pressure. The hypothalamus also communicates the production and release of hormones in our body. This communication is achieved with the help of the pituitary gland — a hormone-secreting gland that tells other endocrine glands to release specific hormones in target organs for specific bodily functions. The pituitary gland is often referred to as the master gland because it controls virtually all of our body's physiological processes following the signal of the hypothalamus. This signalling communication constitutes the main link that ties the hypothalamus and the pituitary gland, which can be traced at the pituitary stalk, and together, the link is referred to as the hypothalamus-pituitary complex — your brain’s central control point. This central control point helps us regulate physiological processes such as stress response, growth, metabolism, lactation, reproduction, water balance, and labour. Therefore, any damage to your hypothalamus interferes with hypothalamic function, indirectly impacting the functions of your endocrine glands. Hence, the undesirable physiological changes and clinical characteristics associated with Frolic syndrome — short stature, delayed puberty, obesity, tiny testes.¹ 

Causes of Frohlich's Syndrome 

Damage to the hypothalamus mostly occurs when a head injury is sustained and disrupts the normal functioning of the hypothalamus and pituitary often from: 

• Surgical lesions (cuts during surgery)
• Tumour (overgrowth of abnormal cells can compromise the hypothalamus and pituitary) 
• Infections (infections can cause brain inflammation, which affects brain function, and in turn contributes to FS)
• Brain swelling 
• Pituitary apoplexy (bleeding or shortage of blood supply to the pituitary)
• Aneurysm 

Pathophysiology 

Frohlich's syndrome affects physiology because of the damage the hypothalamus sustains, particularly the regions controlling appetite and hormone regulation. Hypothalamus makes and produces its hormones which control many of our physiological processes. At the same time, it controls the pituitary by manipulating it to make and release hormones that maintain homeostasis and metabolism. Due to sustained hypothalamic damage, this functional process is disrupted, leading to undesirable outcomes that impact your body’s ability to regulate and maintain biological functions. This often leads to obesity, delayed puberty, hypogonadism, and other endocrine issues.

Underlying Mechanisms of Frohlich's Syndrome

At a glance, we have established that Frohlich's syndrome is caused mainly by damage to the hypothalamus, however, where exactly in the hypothalamus is affected, what hormones are affected and how do they impact biological activities? 

Where In The Hypothalamus Is Affected?

The regions that are affected include the arcuate nucleus and ventromedial nuclei.^1,2

The arcuate nucleus of hypothalamus (ARH): 

ARH is the integral region of the hypothalamus that consists of neurons of the brain and endocrine system (neuroendocrine neurons). These neuroendocrine neurons are responsible for releasing neuroactive substances such as neurotransmitters and neuropeptides to regulate metabolism, reproduction, and appetite/energy.^2,3 In FS, these substances include: 

• Dopamine 

This is a neurotransmitter that acts as a hormone. It is associated with the feeling of pleasure after any action as a reward, hence the title “feel-good hormone” or “dopamine rush”. Ultimately, it regulates the release of prolactin. It is also involved in regulating mood, behaviours, memory, movement, sleep, and arousal. In Frohlich's syndrome, dopamine’s functions are disrupted, leading to high concentrations of prolactin in the bloodstream. 

• Gonadotropin-releasing hormone (GRH)

This is a releasing hormone responsible for stimulating the production and release of sex hormones — Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) — in the pituitary gland. FSH helps the body to regulate the production of sperm in men and the growth of ovarian follicles in women, this causes the production of testosterone in men and progesterone in women respectively. LH  produces oestrogen which triggers ovulation in women. However, GRH levels are reduced as a result of the damaged hypothalamus in FS, which contributes to delayed development of sexual characteristics and infertility. 

• Growth hormone-releasing hormone (GHRH)

This hypothalamic peptide hormone helps to oversee the production and function of human growth hormone (HGR). It also helps to control metabolism in the body. When you sustain damage to the hypothalamus, it interrupts the production of GHRH, leading to decreased levels of GHRH, which can then affect the level of growth hormone. Consequently, this leads to growth impairment where you see stunted growth (short stature) in people with FS.

The ventromedial nuclei of the hypothalamus (VMH): 

This is the satiety centre of the brain that is involved in regulating appetite, thermogenesis, behavioural response, and energy.⁴ The hormones involved in this process include:

• Leptin

This is a hormone made by the body’s adipose tissue (fat cells). It helps to maintain body weight by sending signals to the brain when the body has had enough food intake—alerting satiety or fullness; It also stores fat energy. By doing so, it promotes the feeling of fullness thereby regulating hunger and balancing energy expenditure. When this process is disrupted, it can make you feel hungry, which can make you eat more and facilitate weight gain, which can lead to obesity. 

• Insulin

This is a hormone produced by the pancreas responsible for regulating blood glucose levels in the body by allowing cells to absorb glucose for energy. For example, when you eat carbohydrate-rich foods, they are broken down into smaller units of sugars—glucose—which is then absorbed into your bloodstream. Once absorbed, insulin receptors recognize the glucose and bind to it, giving access to entrances into cells. In turn, the cells get their energy to carry out their functions. If the insulin fails to bind to glucose, it results in high sugar levels in the blood—diabetes.

Others 

Although the arcuate and ventromedial nuclei of the hypothalamus are the key affected regions in FS, other parts of the hypothalamus can become compromised as a result. The hypothalamus generally consists of six hormones, three of which are contained in the arcuate nucleus of the hypothalamus (ARH) - dopamine, gonadotropin-releasing hormone, and growth hormone-releasing hormones. The remaining three are a part of the said compromised regions of the hypothalamus (along with the pituitary gland). These hormones are:

• Corticotropin-releasing hormone(CRH) — It is involved in stimulating the release of adrenocorticotropic hormone (ACTH) from the pituitary gland which in turn makes sure cortisol (stress hormone) is produced and secreted properly. It also plays a role in regulating the immune system. When CRH is disrupted, the ability to handle stress is reduced.
• Somatostatin — this is an inhibiting hormone: it helps to slow down the production of other hormones to prevent overproduction/oversecretion of those hormones that could affect their normal functions. These hormones include growth-releasing hormone, insulin, digestive enzymes, and glucagon. Damage to the hypothalamus may cause hormonal imbalance, which may lead to other health conditions.  
• Thyrotropin-releasing hormone — this key hormone is involved in making sure the thyroid-stimulating hormone (TSH) is formed and thyroid function is regulated. 

Influence of Hypothalamic Damage on Pituitary Gland’s Functions in Frohlich's Syndrome 

Through physiology, it is seen that the hypothalamus-pituitary axis is oftentimes impacted as a result of hypothalamic distress. This signifies that the pituitary gland, which is involved in overseeing the neuro-endocrine functions in the body, is significantly jeopardised in the case of Frohlich's syndrome. The pituitary gland is divided into two: the anterior pituitary gland and the posterior pituitary gland. These glands are accorded with distinctly, respective hormones, which carry out many different physiological functions that help in coordination with the hypothalamus to regulate homeostasis in the body.

The Anterior Pituitary Gland: 

This is the frontal lobe of the pituitary gland which is responsible for making and releasing six hormones responsible for regulating various physiological processes in the body such as growth, reproduction, and stress amongst others. Hormones of the pituitary gland and their functions include the following:

• Prolactin – a hormone that stimulates the production of breast milk in pregnant and lactating mothers
• Human Growth hormone (HGH)) – an important hormone that regulates growth and development in children, and helps in the maintenance of healthy bones and muscles in adults
• Adrenocorticotropic hormone (ACTH) – it stimulates the release of stress hormones (cortisol) from the adrenal gland
• Thyroid stimulating hormone (TSH) – controls the secretion of thyroid hormone in the body. As a result, ensuring a healthy metabolism
• Follicle stimulating hormone (FSH)  – this is a hormone that stimulates the production of sperm from the testes in males. In females, it regulates the making of eggs during ovulation; it also releases oestrogen
• Luteinizing hormone (LH) –  in women, LH stimulates the production of progesterone and conversely, testosterone in men

When the anterior pituitary gland becomes affected, metabolism, growth, stress, secondary sexual characteristics, and reproductive health are compromised. You may see emotional dysregulation, increased fear with aggression, irritability, apathy, etc in FS.

The posterior pituitary gland:

The posterior pituitary gland is the storage vessel for the hormones the hypothalamus produces — oxytocin and vasopressin. In addition to storing these hormones, its role is to release them into the bloodstream when necessary.⁵

Hormones of the posterior pituitary gland include: 

• Oxytocin (OT) – this is a type of hormone that is released during childbirth. It helps to stimulate the contractions of the uterus, making the cervix dilate to make room for the baby out of the womb. Oxytocin also facilitates the flow of breast milk in lactating women. It is also responsible for making the vas deferens contract to release semen during ejaculation in men. Commonly known as the “love hormone”, it is thought to be associated with lovey-dovey feelings during times of any form of closeness.
• Vasopressin (antidiuretic hormone, ADH) – this helps the kidney regulate fluid levels in the body in order to attain water reabsorption and prevent dehydration.

Low levels of oxytocin may cause uterine contraction to stop (leading to a difficult birth process), and stop breast milk production. It is linked with depressive episodes and autism spectrum disorders. Low levels of vasopressin may cause your kidneys to release more water, leading your body to be dehydrated and fall in blood pressure. 

Physiological Changes In Froelich's Syndrome

When the hypothalamus is damaged, hormones fail to properly activate their assigned functions, which results in the following physiological changes:

• Metabolic dysfunction 
• Deficient sex hormones; associated with disruption of gonadotropin-releasing hormone
• Lack of breast milk in lactating mothers; from low levels of prolactin
• Growth retardation; from growth hormone deficiency
• Heightened stress and anxiety levels due to dysregulation of cortisol 
• Affected menstrual cycle due to imbalance of luteinizing and follicle stimulating hormones
• Difficult childbirth in women from oxytocin dysfunction
• Infertility due to hormonal imbalance of gonadotropin-releasing hormone 
• Emotional dysregulation
• Delayed sexual development 

Summary

Frohlich's syndrome is a serious condition that is acquired through sustained injury to the hypothalamus, affecting the hypothalamus-pituitary axis in the brain (central control point of the brain). As a result, signal communication between the hypothalamus and endocrine system is cut short, causing neuroendocrine functions to fail, which brings about a variety of physiological changes such as hypothalamic dysfunction, metabolic problems, endocrine disorder, neurological manifestations characterised by clinical features including lack of satiety, weight gain, obesity, growth impairment, unregulated metabolism, emotional distress, reproductive problems such as infertility. Unfortunately, this condition cannot be cured yet. However, treatments such as hormone replacement therapy in cases of hormone deficiencies, surgical removal in cases of tumours, and antibacterial therapies for infections may be of help in the management of the condition.