Introduction 

Frohlich syndrome is a rare endocrine disorder, where the pituitary gland's dysfunction disrupts the delicate balance of hormone production, leading to significant consequences for growth, sexual development, and metabolism. At the heart of this syndrome lies hypopituitarism, where the pituitary gland doesn’t produce enough hormones. The condition underscores the critical role of the pituitary gland in maintaining hormonal harmony and overall health.

Anatomy and physiology of the pituitary gland 

Overview of pituitary gland function 

With the pseudonym “the master gland," the pituitary is an endocrine gland attached to the brain base in the bony sella turcica of the sphenoid bone. It has a uniquely complex connection with the hypothalamus. It is an essential structure of the human body, performing vital functions for sustaining life. It contains several major lobes, which are the source of various hormones, primarily of two anatomically and functionally distinct regions, the anterior lobe (adenohypophysis) and the posterior lobe (neurohypophysis).¹

Between them lies the intermediate lobe, a thin endocrine cellular layer producing melanocyte-stimulating hormone (MSH) and releasing β-endorphin.² The anterior pituitary secretes five endocrine hormones, whose release is regulated by releasing inhibitory hypothalamic hormones, which, in response to neural activity, release hypothalamic hormones, which are then carried down to the anterior pituitary in the veins.

The hormones secreted by the anterior pituitary are: growth hormone, follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone, and adrenocorticotropic hormone. On the other hand, the posterior pituitary is directly connected to the hypothalamus and secretes two hormones: oxytocin and antidiuretic hormone, ending in nerve terminals within the posterior pituitary. 

The condition causes rapid growth from birth to adulthood, resulting in a notable weight difference between females and males.

Mechanism of hypopituitarism

Hypopituitarism is a chronic endocrine disorder that refers to deficiency of one or more anterior or posterior pituitary hormones. It is associated with excess mortality, mainly attributable to respiratory and cardiovascular diseases.³ It may be due to loss, dysfunction or damage of the pituitary-secreting cells, also referred to as primary hypopituitarism. Secondary hypopituitarism is the result of affection of the hypothalamus or pituitary stalk, which interrupts the vascular connections to the pituitary, reducing the hormonal secretion.⁴

It can be diagnosed by blood test results of basal pituitary and target hormone levels, except growth hormone and adrenocorticotropic hormone deficiency, in the case in which dynamic stimulation tests are used. The diagnosis is made by measuring basal hormonal levels and target pituitary hormones, or by performing stimulation tests, and immunoassay techniques allow measurements of six pituitary hormones. In some cases, genetic testing may be diagnostic.⁵

Therefore, the diagnostic technique involves several combined pituitary function tests. Several variables are taken into consideration when assessing hypopituitarism because they significantly influence the clinical manifestation, including: 

• The cause of the hypopituitarism
• Age of onset 
• Speed and degree of hormone secretion deficiency 

Symptoms of Frohlich syndrome 

The clinical symptoms and signs depend on the affected pituitary hormone, overall significantly affecting patients quality of life and general manifestations. For example, if the cause is a tumour, or space-occupying lesion, the main symptoms are migraines, visual impairment, and even psychological manifestations such as personality changes.

However, the most common symptoms include:⁶

• Fatigue, weakness, dizziness, nausea, slow cognition
• Hypotension and hypoglycemia 
• Weight gain or weight loss
• Impaired sex function, infertility, inability to breastfeed, amenorrhea in women
• Polyuria, polydipsia, nocturia
• Decreased muscle mass and strength, premature atherosclerosis

Pathophysiology of Frohlich syndrome 

Frohlich Syndrome (FS), also known as adiposodysgenesis or adiposogenital dystrophy, is a rare acquired endocrine disorder, caused by hypothalamus lesions, first described in 1900 by Babinski in the case of a child assigned female at birth with obesity and failure of sexual maturity, accompanied by an intracranial damage in the sella turcica region. One year later, Frohlich described a child assigned male at birth with a similar clinical picture, starting to establish the hypopituitary etiology of this syndrome, contributing to the concept of studying the connection between the brain and the pituitary, namely the term neuroendocrinology.⁷

Unlike similar diseases, FS is acquired, not inherited, often associated with hypothalamic tumors after surgical treatment or lesions, and people assigned male at birth are more affected than females.⁸

FS can be caused by organic basal hypothalamic lesions, specifically of the infundibulo-tuberal region in the floor of the third ventricle and the tuber cinereum.⁹ Caused mainly by craniopharyngiomas, encephalitis, demyelinating diseases or Friedreich Ataxia. The neuroanatomical lesions are located in the tuberoinfundibular region; the route through dopamine is delivered from the hypothalamic arcuate nucleus to the pituitary gland.¹⁰

Etiology of Frohlich syndrome 

Characterized by endocrine dysfunction of the hypothalamic gland, it is caused by tertiary hypogonadism arising from decreased gonadotropin-releasing hormone (GnRH). This hormone secreted by the hypothalamus plays a crucial role in reproductive system regulation, stimulating the pituitary gland to release two key gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH).¹¹

Hence, it is vital to sexual maturity, mediating the central control of reproduction. The main physiological impairment in FS is the disruption in the hormonal axis that links the hypothalamus, the pituitary gland, and the gonads, also known as the hypothalamic-pituitary-gonadal (HPG) axis.¹²

Clinical manifestations and the link with hypopituitarism 

Because the GnRH neurons present in the hypothalamus release GnRH, damage disrupts its normal production and release; hence, the pituitary gland is not properly stimulated. The lack of sufficient GnRH leads to reduced FSH and LH production from the anterior pituitary, these hormones being essential for stimulating the gonads to produce sex hormones like estrogen, progesterone, and testosterone. 

Therefore, the clinical manifestation of FS typically involves: 

• Delayed or absent puberty, also known as hypogonadism, manifests as a lack of secondary sexual characteristics and may lead to infertility
• Underdeveloped gonads, due to the lack of necessary hormonal signals from FSH and LH, resulting in a failure to produce sufficient levels of sex hormones 

Another aspect that should be discussed is the hypothalamic role in appetite regulation, which is impaired in FS. Crucial in controlling appetite and energy balance, damage to the hypothalamus leads to dysregulation of hunger signals, causing hyperphagia (extreme hunger) leading to obesity. A hallmark of Frohlich syndrome is central obesity, predominant on the trunk and abdomen.

The neuroanatomical areas mentioned above are involved in controlling hunger and satiety, especially the arcuate nucleus of the hypothalamus, allowing entry of peripheral proteins and peptides that interact with its neurons to stimulate food intake and weight gain, which is disrupted in FS, characterized by increased or excessive eating that leads to obesity. 

Other related metabolic symptoms include: 

• Uncontrolled hyperphagia 
• Diurnal hypersomnolence (excessive sleepiness during the day)

Diagnosis, management and treatment 

Based on the clinical and biochemical characteristics (such as low levels of serum gonadotropins and a positive vasopressin test indicating polyuria- excessive urine production-in diabetes), radiologic imaging (X-ray, CT scan or MRI scan) may reveal delayed bone development, suprasellar calcifications, or damage, depending on the underlying cause.⁹

If possible, the hypothalamic tumors can be removed with surgery or radiation therapy, or hormone replacement therapy can be administered using pituitary hormone derivatives. For people assigned male at birth, human chorionic gonadotropin is administered until reaching puberty, followed by testosterone. People assigned female at birth usually receive a combination of estrogen and progesterone. Regarding hypothalamic obesity, gastric bypass surgery has been found useful in managing constant hunger, alongside calorie restriction and increased energy expenditure through physical activity.¹³

Summary

Frohlich syndrome, characterized by hypothalamic damage and resulting hypopituitarism, leads to impaired hormone production, affecting growth, sexual development, and metabolism. The disruption in the hypothalamic-pituitary-gonadal axis causes significant clinical manifestations, including delayed puberty, obesity, and other endocrine dysfunctions. Understanding and addressing the underlying pituitary gland dysfunction is crucial for effective management of this condition.