What is pituitary adenoma, what are its causes, symptoms, diagnosis?

The pituitary gland is a small, bean-shaped gland located at the base of the brain behind the nasal cavity. Anatomically, it is located just behind the optic nerve junction (called the chiasma opticum), in the depression of the cuneiform bone called the sella turcica.

This characteristic position of the pituitary gland determines the appearance of some clinical symptoms when it enlarges.

The gland has two parts, an anterior segment (adenohypophysis) and a posterior segment (neurohypophysis).

In the adenohypophysis there are cells that produce hormones, namely somatotropin, prolactin, thyrotropic hormone, follicle stimulating hormone, luteinizing hormone and adrenocorticotropic hormone.

The neurohypophysis does not produce hormones but contains granules. These store some of the hormones produced by the hypothalamus. These are oxytocin and antidiuretic hormone.

Although it is a small gland, it is the master organ for all the other endocrine organs of the body.

The hormones it produces help regulate important functions. They are:

• somatotropin - growth hormone, increases protein synthesis, mobilizes energy from adipose tissue and increases glycogen output from the liver as another efficient source of energy
• prolactin - stimulates mammary gland growth and breast milk production
• thyreotropic hormone - stimulates the secretion of thyroid hormones, namely triiodothyronine and thyroxinefollicle stimulating hormone - the hormone promotes follicle growth in the ovaries in women and sperm production in men
• luteinizing hormone - stimulates the production of estrogens and progesterone, triggering ovulation in women and testosterone production in men
• adrenocorticotropic hormone - affects the secretion of hormones from the adrenal cortex, specifically glucocorticoids, i.e. cortisol

A pituitary adenoma is a tumour that arises from the anterior part of the pituitary gland, i.e. the adenohypophysis. It is a benign 'growth', i.e. a tumour that is not malignant. It does not spread by metastasis or overgrow other structures.

However, it can grow expansively and press on its surroundings, hence its symptoms.

Pituitary adenomas account for about 80% of tumours occurring in the Turkish saddle. The remainder are craniopharyngeomas, meningiomas, germinative tumours and cysts.

They are divided according to size into microadenomas, which are less than 10 mm in size, and macroadenomas, which are more than 1 cm in size.

According to whether the adenoma produces hormones, they are divided into:

• functional adenomas, which show hormonal activity of a pituitary hormone
• affunctional adenomas, which are hormone mute and therefore do not secrete any hormone

The incidence of pituitary adenomas is relatively common, with an estimated 20-40 new cases per 100,000 population.

The majority of patients are female, with a peak incidence in the 30-40s.

In women, a functional microadenoma that produces prolactin or corticotropic hormone is more common. In men, larger adenomas, macroadenomas with large production of hormones - for example, also prolactin - are more common.

Younger patients under 30 years of age are at greater risk of more aggressive tumours, which can re-grow even after treatment.

Pituitary adenoma can occur sporadically, so that a random person starts to have uncontrolled growth of adenohypophysis cells. Why these cells start to grow uncontrollably is not yet known.

However, long-term follow-up and study have revealed an increased incidence in families, which may predict a certain genetic predisposition for pituitary adenoma.

There are several familial inherited syndromes that have an increased risk of pituitary adenoma.

The most common include the following:

• Familial isolated pituitary adenomas (FIPA) - This is a mutation of the AIP gene in which hereditary pituitary adenomas occur.
• Multiple Endocrine Neoplasia Type I (MEN1) - An inherited syndrome with a mutation in the MEN1 gene that results in endocrine tumors.
• Multiple endocrine neoplasia type II (MEN2) - Mutation of the RAT gene results in medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperfunction and pituitary adenoma.
• Multiple endocrine neoplasia type IV - Also referred to as MEN1-like syndrome, a syndrome similar to MEN1 but without the MEN1 gene mutation.
• Carney complex - A syndrome with a broad spectrum of symptoms that include characteristic skin patches, breast and testicular tumors, thyroid tumors, myxoma of the heart or bone, in addition to pituitary adenoma.
• Tuberous sclerosis - TSC1 and TSC2 gene mutations include a syndrome characterised by hamartoma formation, epilepsy, mental retardation and pituitary adenoma.

Pituitary adenomas do not always show visible or noticeable symptoms. Sometimes they are detected quite incidentally during an imaging test such as an MRI or CT scan, which is performed for a completely different reason.

Functional pituitary adenomas, which produce hormones, can cause symptoms depending on the hormone they produce.

Symptoms of pituitary tumors that are affunctional (do not produce hormones) are related to their expansive growth. This puts pressure on surrounding structures located in close proximity to the pituitary gland.

Symptoms from the compression are caused by macroadenomas, tumors larger than 10 mm. A typical symptom for macroadenoma growth is the so-called bitemporal hemianopsia, i.e. loss of peripheral visual field in both eyes.

This is caused by optic chiasm opticum oppression, in which the optic nerves cross conducting information from the peripheral halves of the retina.

If the macroadenoma affects the cavernous sinuses, paresis of the orbicularis oculi muscles from damage to the orbital nerves may be associated.

Sometimes pituitary apoplexy, which is acute bleeding from the adenoma, may occur. All the oculomotor nerves may be affected. The condition is called ophthalmoplegia. In addition, there is visual disturbance, headache and impaired consciousness.

If the macroadenoma reaches a large size, so-called obstructive hydrocephalus may develop. This is caused by a build-up of fluid which cannot circulate freely through the fluid pathways because the macroadenoma has created an obstruction in them.

An affunctional macroadenoma can even cause hypofunction of the pituitary gland, i.e. its reduced activity. Pressure on the adenohypophysis itself causes it to stop secreting its hormones, especially growth hormone.

It may be the absence of one hormone or more. If the production of all the pituitary hormones is reduced, the condition is called panhypopituitarism.

The absence of important hormones will manifest as:

• Nausea and vomiting
• Weakness
• Feeling cold
• Disturbance of the menstrual cycle or complete omission of menstruation
• Sexual dysfunction
• Increased urine production and frequent urination
• Weight loss or weight gain
• Excessive activity and agitation

Functional pituitary tumors cause hyperfunction of the adenohypophysis and therefore overproduction of its hormones.

Depending on what cells the adenoma is made of, it will also secrete hormones. It may be a single hormone and symptoms from its overproduction, or a combination of multiple hormones.

Prolactinoma

The most common tumour that produces prolactin is called a prolactinoma.

Overproduction of the hormone prolactin from a pituitary adenoma causes a reduction in normal sex hormone levels. In women, this is a reduction in estrogen and in men, a reduced secretion of testosterone.

Therefore, men and women have different symptoms of prolactinoma.

In women, the following symptoms are present:

• Irregular menstrual cycle
• Omission of menstrual bleeding
• Milk discharge from the breasts

In men, elevated prolactin causes what is called male hypogonadism. Symptoms include:

• Erectile dysfunction
• Decreased sperm count (azoospermia)
• Loss of libido
• Breast growth (gynecomastia)

Adrenocorticotropic hormone secreting tumor (ACTH)

The adenoma produces excessive amounts of the hormone adrenocorticotropin (ACTH), which stimulates the adrenal cortex. This starts an extreme production of the hormone cortisol.

If there is too much cortisol in the body, it will manifest itself in a set of symptoms that have the common name of Cushing's syndrome.

These symptoms include:

• Centripetal type obesity, that is, the accumulation of fat around the belly button and upper back
• A moon-like face, or a pronounced rounding of the face
• Muscle atrophy and weakness
• High blood pressure
• Elevated blood sugar
• Acne
• Bone thinning
• Increased bruising
• Numerous stretch marks on the skin
• Anxiety, irritability or depression

Tumor secreting growth hormone (STH)

Such a tumor produces an excess of growth hormone. If the disease is present in adulthood, after growth has ceased, the condition is called acromegaly.

If growth hormone is secreted while still in childhood or adolescence, before growth has ceased, the disease is called gigantism.

Symptoms of acromegaly:

• Constricted facial features
• Enlarged hands and feet
• Excessive sweating
• High blood sugar
• Enlarged heart and heart disease
• Joint pain
• Dental problems
• Increased body hair

Children and adolescents grow too fast and reach extreme heights.

Tumor secreting thyroid stimulating hormone (TSH)

An adenoma that overproduces thyroid-stimulating hormone is the cause of an overactive thyroid gland. The thyroid gland produces too much of the hormone thyroxine. This condition is called hyperthyroidism.

Thyroxine is a hormone that mainly affects metabolism. Therefore, when there is an excess of it, metabolism will be accelerated.

The symptoms of hyperthyroidism are as follows:

• Weight loss
• Tachycardia (rapid heartbeat)
• Arrhythmia
• Nervousness and irritability
• Diarrhoea, caused by overactive bowels
• Increased sweating

Symptoms from oppression of the neurohypophysis

Even if the adenoma does not affect the posterior segment of the pituitary gland (neurohypophysis), in gigantic adenomas this part can be oppressed and therefore its function impaired.

The neurohypophysis does not produce hormones. It serves as a reservoir for hormones that are produced in the hypothalamic nuclei.

From the hypothalamus, they are transported by axonal transport via the peduncle (infundibulum) to the neurohypophysis, where they are stored in granules. From the neurohypophysis, hormones are secreted into the bloodstream.

When the neurohypophysis is depressed, the secretion of antidiuretic hormone, called vasopressin, is impaired. This hormone is responsible for the proper management of water and salt content in the body. Its deficiency manifests itself as diabetes insipidus.

Symptoms of vasopressin deficiency:

• Polyuria is the excretion of a large amount of urine, but which is hypotonic, i.e. contains little salts.
• Polydipsia is a condition where a person drinks excessive amounts of fluids because of unquenchable thirst.
• If the patient does not drink enough water, dehydration occurs, which can be fatal.

Diagnosis of pituitary adenoma involves a history of trouble and a characteristic clinical picture, either from oppression of brain structures or from overproduction of pituitary hormones.

Sometimes these tumors go undiagnosed because their symptoms are similar to many other diseases. Conversely, a large number of adenomas are detected as an incidental finding on MRI imaging that was performed for other reasons.

Abnormalities may be detected from blood draws and urinalysis that are indicative of hormone overproduction or deficiency.

The most important diagnostic test is an MRI of the brain, or a CT scan of the brain. It shows an enlarged pituitary gland or an inhomogeneous image of the pituitary gland, which indicates the growth of a benign tumour.

In addition, the scan is used to assess the location and size of the tumor before surgery or radiation.

The eye examination may diagnose peripheral vision disturbance caused by tumor pressure on the optic nerve junction.

The overall hormonal profile is assessed by an endocrinologist or, in women, by a gynaecologist.

The course of the disease depends on the type of adenoma. Some patients live for years with a pituitary adenoma that they are unaware of because it causes no symptoms or problems.

However, if the adenoma is causing serious problems, limiting the patient's life or directly threatening it, immediate treatment of the tumour is undertaken. The treatment either stops its growth or shrinks or removes the tumour.