Pituitary microadenoma: causes, symptoms, what is dangerous, prognosis

The neoplasms of a benign nature arising in the endocrine glands are called adenomas, and the pituitary microadenoma is a small tumor of its anterior lobe, which produces a number of important hormones.

Epidemiology

The incidence of pituitary tumors is estimated at 10-23%, and pituitary adenomas, which can be of various shapes and sizes, are the most common (16%). [1]

Up to 20-25% of people can have small pituitary tumors - microadenomas, without even knowing it, and such tumors are discovered in about half of the cases by chance during brain imaging.

Prolactin-secreting microadenoma account for 45-75% of these tumors; the share of ACTH-producing formations accounts for no more than 14% of cases, and the frequency of STH-producing microadenoma does not exceed 2%.

Pituitary microadenoma in children and adolescents is detected in 10.7-28% of cases, and at least half of them are hormonally inactive. [2]

Causes of the pituitary microadenomas

Specialists do not know the exact causes of the appearance of a microadenoma in the  pituitary gland  - the endocrine gland of the brain, the cells of which produce:

• corticotropin or ACTH -  adrenocorticotropic hormone , which causes the secretion of steroid hormones by the adrenal cortex;
• growth hormone STH -  somatotropic hormone ;
• gonadotropins FSH -  follicle-stimulating hormone  and LH -  luteinizing hormone , on which the production of female sex hormones in the ovaries and male sex hormones in the testes depends;
• lactogenic hormone  prolactin  (PRL);
• thyrotropin or thyroid-stimulating hormone (TSH), which stimulates the synthesis of thyroid hormones.

It is assumed that craniocerebral injuries can lead to the occurrence of these neoplasms; insufficient supply of pituitary gland with blood; cerebral infections or exposure to toxins (causing edema and intracranial hypertension). 

Risk factors

It is known that pituitary adenomas and microadenomas often occur in the presence of a family history of MEN 1 syndrome -  multiple endocrine adenomatosis  type 1, which is hereditary. Thus, there are genetically determined risk factors associated with certain changes in DNA. [3]

Multiple endocrine neoplasia type 4 (MEN4): MEN 4 has a mutation in the cyclin-dependent kinase inhibitor 1 B (CDKN1B) gene, which causes pituitary tumors, hyperparathyroidism, testicular and cervical neuroendocrine tumors. [4]

Carney complex (CNC): There is a germline mutation in the tumor suppressor gene PRKAR1A in Carney complex leading to primary pigmentary nodular adrenocortical disease (PPNAD), testicular tumors, thyroid nodules, patchy hyperpigmentation of the skin, and acromegaly. [5]

The clinical form of familial isolated pituitary adenomas (FIPA) is characterized by genetic defects in the aryl hydrocarbon receptor interacting protein (AIP) gene in approximately 15% of all related and 50% of homogeneous somatotropin families.[6]

Familial isolated pituitary adenomas (FIPA): A mutation in the aryl hydrocarbon receptor interacting protein (AIP) is detected in adolescence or early adulthood in approximately 15% of all FIPA cases. These tumors are usually aggressive and most often secrete growth hormone, causing acromegaly.[7]

The possibility of the occurrence of this type of tumor due to functional disorders of other endocrine glands and cerebral structures, in particular, changes in the vascular system of the  hypothalamus , which, within the neuroendocrine hypothalamic-pituitary system, regulates the work of the pituitary gland and its anterior lobe - adenohypophysis, with its releasing hormones, cannot be ruled out.

Pathogenesis

According to its histology , pituitary adenoma  refers to benign tumors; depending on the size, these neoplasias are divided into microadenomas (up to 10 mm in size at the widest point), macroadenomas (10-40 mm) and giant adenomas (40 mm or more).

Studying the pathogenesis of tumor formation in the pituitary gland, it has not yet been possible to elucidate the mechanisms of hyperplastic transformation of the cells of its anterior lobe into a tumor.

Experts believe that one of the most convincing versions is the connection with the deregulation of the metabolism of the neurotransmitter and the hormone dopamine (which is the main inhibitor of prolactin secretion) and / or the dysfunction of the transmembrane dopamine receptors of the pituitary cells that secrete PRL (lactotrophs).

Most pituitary microadenomas are sporadic, but some occur as part of genetically determined  neuroendocrine syndromes such as MEN 1 syndrome, McCune-Albright syndrome, Werner syndrome, Carney syndrome (or Carney complex). In the latter case, there is an increased risk of developing benign tumors in the hormonal (endocrine) glands, including the pituitary, adrenals, thyroid, ovaries, and testicles.

Symptoms of the pituitary microadenomas

A pituitary microadenoma may not manifest itself for a very long time. Symptoms vary by location and usually result from endocrine dysfunction. This is the most common finding in cases of hormonal imbalance associated with excessive production of one or more hormones. In most cases, according to the location, this is a microadenoma of the anterior pituitary gland.

There are types of pituitary microadenoma according to their hormonal activity. So, the most common type is considered to be a non-functioning adenoma - a hormonally inactive pituitary microadenoma, which - until it reaches a certain size - does not give any symptoms. But a growing hormonally inactive pituitary microadenoma can compress nearby brain structures or cranial nerves, so a pituitary microadenoma and a headache in the frontal and temporal regions can be combined,  [8]and vision problems are also possible. [9]However, according to researchers, non-functioning (hormonally inactive) pituitary tumors in 96.5% of cases are macroadenomas. [10]

A hormonally active pituitary microadenoma (its anterior lobe) may also occur with increased secretion of the hormone prolactin -  pituitary prolactinoma . Increased production of PRL by lactotropic cells of the adenohypophysis is defined as hyperprolactinemia in pituitary microadenoma.

How does such a microadenoma of the pituitary gland manifest itself in women? A pathologically high level of this hormone inhibits the production of estrogens, and the first signs are manifested by menstrual irregularities - with the absence of menstruation (amenorrhea) and / or their ovulatory phase. As a result, persistent galactorrhea-amenorrhea syndrome develops   and the possibility of conception and pregnancy is lost.

A prolactin-secreting pituitary microadenoma in men can lead to  hyperprolactinemic hypogonadism  with decreased libido, erectile dysfunction, breast enlargement (gynecomastia), and reduced facial and body hair.

An active microadema secreting corticotropin (ACTH) leads to an excess of steroid hormones (glucocorticoids) produced by the adrenal cortex, which can cause  Itsenko-Cushing's disease of  pituitary etiology.

In children, such a microadenoma can manifest itself with symptoms  of hypercortisolism  (Cushing's syndrome), including headaches, general weakness, excessive deposition of adipose tissue on the trunk, a decrease in bone mineral density and muscle strength, band-like skin atrophy (in the form of purple striae), etc.

With an active somatotropin-producing microadenoma, the level of growth hormone in the body increases. In childhood, its excessive anabolic effect stimulates the growth of almost all the bones of the body and can lead to gigantism; adults may develop  acromegaly  with increased growth of the bones of the facial skull (causing a distortion of appearance) and cartilage in the joints of the extremities (which leads to a violation of their proportions and thickening of the fingers), with joint pain, excessive sweating and secretion of sebum, impaired glucose tolerance.

Very rarely (in 1-1.5% of cases) there is a pituitary microadenoma that produces thyrotropin, and since this hormone has a stimulating effect on the thyroid gland, patients have clinical signs of pituitary hyperthyroidism in the form of sinus tachycardia and atrial fibrillation, increased blood pressure, weight loss (with increased appetite), as well as increased nervous excitability and irritability. 

The so-called intrasellar pituitary microadenoma, a synonym - endosellar pituitary microadenoma, like the entire pituitary gland, is localized within the Turkish saddle (sella turcica) - inside the anatomical saddle-shaped depression in the sphenoid bone of the base of the skull. In this case, the pituitary gland is located at the bottom of this recess - in the pituitary fossa (intrasellar region). And the whole difference of terms is that "inside" in lat. - intra, and in Greek. – endom.

But a pituitary microadenoma with suprasellar growth means that the neoplasm grows upward from the bottom of the pituitary fossa.

Cystic pituitary microadenoma has a closed sac-like structure and is asymptomatic.

Pituitary microadenoma with hemorrhage may be the result of apoplexy or hemorrhagic infarction associated with enlargement of the gland and damage to the sinusoidal capillaries of the parenchyma of its anterior lobe, neurohemal synapses and / or portal vessels.

Pituitary microadenoma and pregnancy

As already noted, women with prolactin-producing pituitary microadenoma - due to estrogen deficiency and suppression of the pulsatile secretion of GnRH (gonadotropin-releasing hormone) - are usually infertile. For the onset of pregnancy, it is necessary to normalize the level of prolactin, otherwise conception does not occur, or the pregnancy is terminated at the very beginning.

• Is it possible to give birth with a pituitary microadenoma?

In women with clinically functioning microadenomas who are treated with dopamine agonists (Cabergoline or Dostinex), prolactin levels may return to normal and menstrual cycle and fertility may be restored.

Is breastfeeding possible with pituitary microadenoma?

In the postpartum period, breastfeeding is allowed in the absence of symptoms of the tumor, but it is necessary to monitor its size (using magnetic resonance imaging of the brain). And if the neoplasm grows, breastfeeding is stopped.

• Pituitary microadenoma and IVF

In vitro fertilization requires treatment of hyperprolactinemia, and the procedure itself can be started if normal prolactin levels are stable for 12 months and there are no abnormalities in serum levels of other pituitary hormones.

Complications and consequences

Why is a pituitary microadenoma dangerous? Although this tumor is benign, its presence can lead to complications and consequences, in particular:

• lead to dysfunction of the hypothalamic-pituitary-adrenal system with the development of Itsenko-Cushing's disease;
• disrupt the hormonal regulation of the menstrual cycle  in women and lead to erectile dysfunction in men;
• cause growth retardation and pituitary dwarfism (hypopituitarism) in children;
• provoke the development of osteoporosis.

In cases of compression by a growing tumor of the fibers of the optic nerves in the area of their intersection (which in 80% of people is located directly above the pituitary gland), there is a violation of the mobility of the eyes (ophthalmoplegia) and a gradual deterioration in peripheral vision. Although microadenomas are usually too small to exert such pressure.

Can a pituitary microadenoma resolve? It cannot resolve, but over time, a hormonally inactive tumor in children can significantly decrease. But in about 10% of patients, microadenomas can enlarge.

Diagnostics of the pituitary microadenomas

To diagnose a pituitary microadenoma, a complete patient history and laboratory tests are required: blood tests for hormone levels (produced by the pituitary gland), including a radioimmunoassay of blood serum for prolactin levels.

If prolactin is normal with a pituitary microadenoma, then this tumor is hormonally inactive. But if there are symptoms of prolactinoma, then such a false negative result may be the result of either a laboratory error, or the patient has a macroadenoma that compresses the pituitary stalk.

In addition, additional tests may be required, for example, for the level of thyroid hormones (T3 and T4), immunoglobulins, interleukin-6 in the blood serum.

Only instrumental diagnostics using  magnetic resonance imaging (MRI) of the brain can detect a microadenoma . And MRI in microadenoma is considered the standard of imaging, with contrast-enhanced MRI having a sensitivity of 90%.

MR signs of a pituitary microadenoma include: volume of the gland on the side of the microadenoma; an increase in the size of the Turkish saddle; thinning and changing the contour of its bottom (lower wall); lateral deviation of the funnel of the pituitary gland; isointensity of the rounded area compared to gray matter on T1- and T2-weighted images; slight hyperintensity on T2-weighted images.  [11]

Differential diagnosis

Differential diagnosis is carried out with craniopharyngioma, granular cell tumor (choristoma) of the pituitary gland, Rathke's pocket cyst, dermoidoma formation, inflammation of the pituitary gland - autoimmune or lymphocytic hypophysitis, pheochromocytoma, thyroid diseases, etc.

In women with an anovulatory cycle, pituitary microadenoma and polycystic ovaries are differentiated, since 75-90% of cases of lack of ovulation are a consequence  of polycystic ovary syndrome .

Treatment of the pituitary microadenomas

With adenomas and microadenomas of the pituitary gland, treatment can be medical and surgical. At the same time, if the tumors are asymptomatic, it is recommended to monitor them, that is, periodically conduct MRI, so as not to miss the beginning of their increase. 

The purpose of this or that drug is determined by what type of neoplasm the patient has.

Pharmacotherapy of PRL-secreting tumors is carried out with drugs of the group of stimulators of dopamine D2 receptors of the hypothalamus (selective dopamine agonists), and the most commonly used are Bromocriptine (Parlodel, Bromergol), Norprolac and an ergot derivative - Cabergoline or Dostinex with pituitary microadenoma with increased secretion of prolactin.

Side effects of Dostinex (Cabergoline) may include an allergic reaction; headache and dizziness; nausea, vomiting and abdominal pain; constipation; feeling weak or tired; sleep disorders. And among the side effects of Bromocriptine (except for an allergic reaction), chest pain is noted; rapid heartbeat and breathing with a feeling of lack of air; coughing up blood; deterioration in coordination of movements, etc. 

The drugs Okreotide (Sandostatin), Lanreotide (Somatulin), Pegvisomant, used for micro- and macroadenomas that secrete growth hormone, belong to STH inhibitors and antagonists of its receptors.

And with ACTH-secreting neoplasms of the adenohypophysis with Itsenko-Cushing's syndrome, Metyrapone (Metopirone) or Mitotan (Lizodren) is used.

Surgical treatment should be considered for functioning (hormonally active) microadenomas. In cases where conservative treatment is ineffective, and the tumor is characterized by a slight suprasellar expansion within the Turkish saddle, a  pituitary adenomectomy may be prescribed  - an operation to remove the pituitary microadenoma. Currently, a transnasal or transsphenoidal microdissection is being performed, that is, the removal of a pituitary microadenoma through the nose. 

Possible complications and consequences of removal of a pituitary microadenoma include postoperative bleeding and leakage of cerebrospinal fluid (often with the need for a second operation), as well as inflammation of the meninges, visual disturbances, hematoma formation, transient diabetes insipidus, recurrence of the microadenoma.

Homeopathy for pituitary microadenoma with hyperprolactinemia uses drugs whose action can help to partially relieve symptoms. For example, with irregular menstruation and amenorrhea, a remedy from cuttlefish ink Sepia and a preparation from the meadow backache plant - Pulsatilla are prescribed, and for galactorrhea - a remedy based on European cyclamen root.

Obviously, one should not hope that alternative treatment for pituitary microadenoma can be more effective. And not only because, with this diagnosis, herbalists are guided only by the complaints of patients (not knowing about their true etiology), but also because of the unreliability of many "folk remedies". You don't have to look far for examples.

Some online sources recommend using a mixture of spring primrose, ginger root and sesame seed to reduce prolactin levels. But primrose helps well with prolonged dry cough, thinning sputum, and ginger roots, like sesame seeds, exhibit lactogenic properties.

You can also find advice to take a tincture of a field bug. But, in fact, this remedy is used internally for flatulence, and externally for rheumatic joint pains. In all likelihood, the bedbug was confused with the roots of black cohosh used against hot flashes during menopause (its other names are cimicifuga and black cohosh).

Nutrition for pituitary microadenoma should be balanced - with a decrease in sugar and salt intake. This is not a special diet, but simply a lower calorie diet.

Alcohol is excluded with pituitary microadenoma.

Which doctor should I contact with pituitary microadenoma? Endocrinologists, gynecologists, and neurosurgeons deal with the problems that arise with this type of tumor.

Prevention

Since the causes of pituitary tumors related to the environment or lifestyle are unknown, it will simply not be possible to prevent the development of a pituitary microadenoma.

Forecast

Most pituitary tumors are curable. If a hormonally active pituitary microadenoma is diagnosed on time, the chances of recovery are great and the prognosis is favorable.

Disability and pituitary microadenoma: Disability may be associated with tumor growth and damage to the optic nerve, as well as other consequences of this pathology, the severity of which is individual. And the recognition of a patient as a disabled person depends on the existing health disorders and the level of functional disorders, which must comply with legally approved criteria.

Pituitary microadenoma and the army: Patients with this tumor (even if successfully removed) should not overheat, stay in the sun for a long time and physically overexert. So, they are unsuitable for military service.

How long do people live with a pituitary microadenoma? This tumor is not cancer, so there is no life expectancy limit. Although with an active GH-producing microadenoma, patients may develop hypertension and increase in heart size, and this can significantly reduce their life expectancy. An increased risk of death in patients older than 45 years is noted with Itsenko-Cushing's disease and acromegaly.