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In women, a high blood level of prolactin often causes hypoestrogenism with anovulatory infertility and a decrease in menstruation. In some women, menstruation may disappear altogether (amenorrhoea). In others, menstruation may become irregular or menstrual flow may change. Women who are not pregnant or nursing may begin producing breast milk. Some women may experience a loss of libido (interest in sex) and breast pain, especially when prolactin levels begin to rise for the first time, as the hormone promotes tissue changes in the breast. Intercourse may become difficult or painful because of vaginal dryness.
In men, the most common symptoms of hyperprolactinaemia are decreased libido, sexual dysfunction (in both men and women), erectile dysfunction, infertility, and gynecomastia. Because men have no reliable indicator such as menstruation to signal a problem, many men with hyperprolactinaemia being caused by a pituitary adenoma may delay going to the doctor until they have headaches or eye problems caused by the enlarged pituitary pressing against the adjacent optic chiasm. They may not recognize a gradual loss of sexual function or libido. Only after treatment do some men realize they had a problem with sexual function.
Because of hypoestrogenism and hypoandrogenism, hyperprolactinaemia can lead to osteoporosis.
Galactorrhea can take place as a result of dysregulation of certain hormones. Hormonal causes most frequently associated with galactorrhea are hyperprolactinemia and thyroid conditions with elevated levels of thyroid-stimulating hormone (TSH) or thyrotropin-releasing hormone (TRH). No obvious cause is found in about 50% of cases.
Lactation requires the presence of prolactin, and the evaluation of galactorrhea includes eliciting a history for various medications or foods (methyldopa, opioids, antipsychotics, serotonin reuptake inhibitors, as well as licorice) and for behavioral causes (stress, and breast and chest wall stimulation), as well as evaluation for pregnancy, pituitary adenomas (with overproduction of prolactin or compression of the pituitary stalk), and hypothyroidism. Adenomas of the anterior pituitary are most often prolactinomas. Overproduction of prolactin leads to cessation of menstrual periods and infertility, which may be a diagnostic clue. Galactorrhea may also be caused by hormonal imbalances owing to birth control pills.
Galactorrhea is also a side effect associated with the use of the second-generation H receptor antagonist cimetidine (Tagamet). Galactorrhea can also be caused by antipsychotics that cause hyperprolactinemia by blocking dopamine receptors responsible for control of prolactin release. Of these, risperidone is the most notorious for causing this complication. Case reports suggest proton-pump inhibitors have been shown to cause galactorrhea.
Galactorrhea (also spelled galactorrhoea) ( + ) or lactorrhea ( + ) is the spontaneous flow of milk from the breast, unassociated with childbirth or nursing.
Galactorrhea is reported to occur in 5–32% of women. Much of the difference in reported incidence can be attributed to different definitions of galactorrhea. Although frequently benign, it may be caused by serious underlying conditions and should be properly investigated. Galactorrhea also occurs in males, newborn infants and adolescents of both sexes.
Hyperprolactinaemia or hyperprolactinemia is the presence of abnormally high levels of prolactin in the blood. Normal levels are less than 500 mIU/L [20 ng/mL or µg/L] for women, and less than 450 mIU/L for men.
Prolactin is a peptide hormone produced by the anterior pituitary gland that is primarily associated with lactation and plays a vital role in breast development during pregnancy. Hyperprolactinaemia may cause galactorrhea (production and spontaneous flow of breast milk) and disruptions in the normal menstrual period in women and hypogonadism, infertility and erectile dysfunction in men.
Hyperprolactinaemia can also be a part of normal body changes during pregnancy and breastfeeding. It can also be caused by diseases affecting the hypothalamus and pituitary gland. It can also be caused by disruption of the normal regulation of prolactin levels by drugs, medicinal herbs and heavy metals inside the body. Hyperprolactinaemia may also be the result of disease of other organs such as the liver, kidneys, ovaries and thyroid.
Symptoms of galactorrhea hyperprolactinemia include a high blood prolactin level, abnormal milk production in the breast, galactorrhea, menstrual abnormalities, reduced libido, reduced fertility, puberty problems, and headaches.
Galactorrhea hyperprolactinemia is increased blood prolactin levels associated with galactorrhea (abnormal milk secretion). It may be caused by such things as certain medications, pituitary disorders and thyroid disorders. The condition can occur in males as well as females. Relatively common etiologies include prolactinoma, medication effect, kidney failure, granulomatous diseases of the pituitary gland, and disorders which interfere with the hypothalamic inhibition of prolactin release. Ectopic (non-pituitary) production of prolactin may also occur. Galactorrhea hyperprolactinemia is listed as a “rare disease” by the Office of Rare Diseases of the National Institutes of Health. This means that it affects less than 200,000 people in the United States population.
The symptoms due to a prolactinoma are broadly divided into those that are caused by increased prolactin levels or mass effect.
Those that are caused by increased prolactin levels are:
- Amenorrhea (disappearance of ovulation periods)
- Galactorrhea (Milk production; infrequent in men)
- Loss of axillary and pubic hair
- Hypogonadism (Reduced function of the gonads.)
- Gynecomastia (an increase in male breast size)
- Erectile dysfunction (in males)
Those that are caused by mass effect are:
- Bitemporal hemianopsia (due to pressure on the optic chiasm)
- Vertigo
- Nausea, vomiting
A prolactinoma is a benign tumor (adenoma) of the pituitary gland that produces a hormone called prolactin. It is the most common type of functioning pituitary tumor. Symptoms of prolactinoma are too much prolactin in the blood (hyperprolactinemia), or those caused by pressure of the tumor on surrounding tissues.
Prolactin stimulates the breast to produce milk, and has many other functions such as regulation of mood. Hence prolactin levels are usually higher during pregnancy and after childbirth. After delivery of a baby, a mother's prolactin levels come down to normal a few weeks after breastfeeding is discontinued. Each time the milk is dispensed, prolactin levels rise; this process may cycle to maintain milk production. In males it is responsible for the sexual refractory period after orgasm and excess levels can lead to erectile dysfunction.
Based on size, a prolactinoma can be classified as a "microprolactinoma" (10 mm diameter).
Hyperprolactinemic SAHA syndrome is a cutaneous condition characterized by lateral hairiness, oligomenorrhea, and sometimes acne, seborrhea, FAGA I, and even galactorrhea.
Multiple endocrine neoplasia or MEN is part of a group of disorders that affect the body's network of hormone-producing glands (the endocrine system). Hormones are chemical messengers that travel through the bloodstream and regulate the function of cells and tissues throughout the body. Multiple endocrine neoplasia involves tumors in at least two endocrine glands; tumors can also develop in other organs and tissues. These growths can be noncancerous (benign) or cancerous (malignant). If the tumors become cancerous, some cases can be life-threatening.
The two major forms of multiple endocrine neoplasia are called type 1 and type 2. These two types are often confused because of their similar names. However, type 1 and type 2 are distinguished by the genes involved, the types of hormones made, and the characteristic signs and symptoms.
These disorders greatly increase the risk of developing multiple cancerous and noncancerous tumors in glands such as the parathyroid, pituitary, and pancreas. Multiple endocrine neoplasia occurs when tumors are found in at least two of the three main endocrine glands (parathyroid, pituitary, and pancreatico-duodenum). Tumors can also develop in organs and tissues other than endocrine glands. If the tumors become cancerous, some cases can be life-threatening. The disorder affects 1 in 30,000 people.
Although many different types of hormone-producing tumors are associated with multiple endocrine neoplasia, tumors of the parathyroid gland, pituitary gland, and pancreas are most frequent in multiple endocrine neoplasia type 1. MEN1-associated overactivity of these three endocrine organs are briefly described here:
- Overactivity of the parathyroid gland (hyperparathyroidism) is the most common sign of this disorder. Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of the bones (osteoporosis), high blood pressure (hypertension), loss of appetite, nausea, weakness, fatigue, and depression.
- Neoplasia in the pituitary gland can manifest as prolactinomas whereby too much prolactin is secreted, suppressing the release of gonadotropins, causing a decrease in sex hormones such as testosterone. Pituitary tumor in MEN1 can be large and cause signs by compressing adjacent tissues.
- Pancreatic tumors associated with MEN-1 usually form in the beta cells of the islets of Langerhans, causing over-secretion of insulin, resulting in low blood glucose levels (hypoglycemia). However, many other tumors of the pancreatic Islets of Langerhans can occur in MEN-1. One of these, involving the alpha cells, causes over-secretion of glucagon, resulting in a classic triad of high blood glucose levels (hyperglycemia), a rash called necrolytic migratory erythema, and weight loss. Another is a tumor of the non-beta islet cells, known as a gastrinoma, which causes the over-secretion of the hormone gastrin, resulting in the over-production of acid by the acid-producing cells of the stomach (parietal cells) and a constellation of sequelae known as Zollinger-Ellison syndrome. Zollinger-Ellison syndrome may include severe gastric ulcers, abdominal pain, loss of appetite, chronic diarrhea, malnutrition, and subsequent weight loss. Other non-beta islet cell tumors associated with MEN1 are discussed below.
Pituitary tumors occur in 15 to 42% of MEN 1 patients. From 25 to 90% are prolactinomas. About 25% of pituitary tumors secrete growth hormone or growth hormone and prolactin. Excess prolactin may cause galactorrhea (see Pituitary Disorders: Galactorrhea), and excess growth hormone causes acromegaly clinically indistinguishable from sporadically occurring acromegaly. About 3% of tumors secrete ACTH, producing Cushing's disease. Most of the remainder are nonfunctional. Local tumor expansion may cause visual disturbance, headache, and hypopituitarism. Pituitary tumors in MEN 1 patients appear to be larger and behave more aggressively than sporadic pituitary tumors.
They are classified by histology as benign; however, as with many brain tumors, their treatment can be difficult, and significant morbidities are associated with both the tumor and treatment.
- Headache (obstructive hydrocephalus)
- Hypersomnia
- Myxedema
- post surgical weight gain
- Polydipsia
- Polyuria (diabetes insipidus)
- Vision loss (bitemporal hemianopia)
- Vomiting
- often occurs post treatment
- Growth hormone (GH) insufficiency, caused by the reduction in growth hormone (GH) production. Symptoms include:
- Stunted growth and delayed puberty (in children)
- General fatigue, loss of muscle mass and tone (in adults)
- Pituitary insufficiency
- often occurs to some degree because craniopharyngiomas develop in the area of the pituitary stalk, which can affect the function of the pituitary gland.
- Reduction in prolactin production. This is very uncommon and occurs with severe pituitary insufficiency.
- Large pituitary tumors can paradoxically elevate blood prolactin levels due to the "stalk effect." This elevation occurs as a result of the compression of the pituitary stalk, which interferes with the brain's control of prolactin production.
- In premenopausal women, elevated prolactin can lead to reduction or loss of menstrual periods and/or breast milk production (galactorrhea).
- With stalk effect, prolactin levels are usually only slightly elevated, as opposed to prolactinomas in which the prolactin level is usually very high.
- Diabetes insipidus. This occurs due to the absence of a posterior pituitary hormone called antidiuretic hormone (ADH). Symptoms include:
- Excessive thirst
- Excessive urination
- Adrenal insufficiency. This occurs because of a reduction in ACTH production, a reduction in cortisol. In severe cases, it can be fatal. Symptoms include:
- Fatigue
- Low blood pressure
- Electrolyte abnormalities
Craniopharyngioma is a rare, usually suprasellar neoplasm, which may be cystic, that develops from nests of epithelium derived from Rathke's pouch. Rathke's pouch is an embryonic precursor of the anterior pituitary.
Craniopharyngiomas are typically very slow growing tumors. They arise from the cells along the pituitary stalk, specifically from nests of odontogenic (tooth-forming) epithelium within the suprasellar/diencephalic region and, therefore, contain deposits of calcium that are evident on an x-ray.
Eye involvement occurs in about 10–90% of cases. Manifestations in the eye include uveitis, uveoparotitis, and retinal inflammation, which may result in loss of visual acuity or blindness. The most common ophthalmologic manifestation of sarcoidosis is uveitis. The combination of anterior uveitis, parotitis, VII cranial nerve paralysis and fever is called uveoparotid fever or Heerfordt syndrome (). Development of scleral nodule associated with sarcoidosis has been observed.
Any of the components of the nervous system can be involved. Sarcoidosis affecting the nervous system is known as neurosarcoidosis. Cranial nerves are most commonly affected, accounting for about 5–30% of neurosarcoidosis cases, and peripheral facial nerve palsy, often bilateral, is the most common neurological manifestation of sarcoidosis. It occurs suddenly and is usually transient. The central nervous system involvement is present in 10–25% of sarcoidosis cases. Other common manifestations of neurosarcoidosis include optic nerve dysfunction, papilledema, palate dysfunction, neuroendocrine changes, hearing abnormalities, hypothalamic and pituitary abnormalities, chronic meningitis, and peripheral neuropathy. Myelopathy, that is spinal cord involvement, occurs in about 16–43% of neurosarcoidosis cases and is often associated with the poorest prognosis of the neurosarcoidosis subtypes. Whereas facial nerve palsies and acute meningitis due to sarcoidosis tends to have the most favourable prognosis. Another common finding in sarcoidosis with neurological involvement is autonomic or sensory small fiber neuropathy. Neuroendocrine sarcoidosis accounts for about 5–10% of neurosarcoidosis cases and can lead to diabetes insipidus, changes in menstrual cycle and hypothalamic dysfunction. The latter can lead to changes in body temperature, mood and prolactin (see the endocrine and exocrine section for details).
Chiasmal syndrome is the set of signs and symptoms that are associated with lesions of the optic chiasm, manifesting as various impairments of the sufferer's visual field according to the location of the lesion along the optic nerve. Pituitary adenomas are the most common cause; however, chiasmal syndrome may be caused by cancer, or associated with other medical conditions such as multiple sclerosis and neurofibromatosis.
Foroozen divides the causes of chiasmal syndromes into intrinsic and extrinsic causes. Intrinsic implies thickening of the chiasm itself and extrinsic implies compression by another structure. Other less common causes of chiasmal syndrome are metabolic, toxic, traumatic or infectious in nature.
Intrinsic etiologies include gliomas and multiple sclerosis. Gliomas of the optic chiasm are usually derived from astrocytes. These tumors are slow growing and more often found children. However, they have a worse prognosis, especially if they have extended into the hypothalamus. They are frequently associated with neurofibromatosis type 1 (NF-1). Their treatment involves the resection of the optic nerve. The supposed artifactual nature of Wilbrand's knee has implications for the degree of resection that can be obtained, namely by cutting the optic nerve immediately at the junction with the chiasm without fear of potentially resulting visual field deficits.
The vast majority of chiasmal syndromes are compressive. Ruben et al. describe several compressive etiologies, which are important to understand if they are to be successfully managed. The usual suspects are pituitary adenomas, craniopharyngiomas, and meningiomas.
Pituitary tumors are the most common cause of chiasmal syndromes. Visual field defects may be one of the first signs of non-functional pituitary tumor. These are much less frequent than functional adenomas. Systemic hormonal aberrations such as Cushing’s syndrome, galactorrhea and acromegaly usually predate the compressive signs. Pituitary tumors often encroach upon the middle chiasm from below. Pituitary apoplexy is one of the few acute chiasmal syndromes. It can lead to sudden visual loss as the hemorrhagic adenoma rapidly enlarges.
The embryonic remnants of Rathke’s pouch may undergo neoplastic change called a craniopharyngioma. These tumors may develop at any time but two age groups are most at risk. One peak occurs during the first twenty years of life and the other occurs between fifty and seventy years of age. Craniopharyngiomas generally approach the optic chiasm from behind and above. Extension of craniopharyngiomas into the third ventricle may cause hydrocephalus.
Meningiomas can develop from the arachnoid layer. Tuberculum sellae and sphenoid planum meningiomas usually compress the optic chiasm from below. If the meningioma arises from the diaphragma sellae the posterior chiasm is damaged. Medial sphenoid ridge types can push on the chiasm from the side. Olfactory groove subfrontal types can reach the chiasm from above. Meningiomas are also associated with neurofibromatosis type 1. Women are more prone to develop meningiomas.