Hyperprolactinaemia (also spelled hyperprolactinemia) is a condition characterized by abnormally high levels of

prolactin Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secr ...

in the blood. In women, normal prolactin levels average to about 13 ng/mL, while in men, they average 5 ng/mL. The upper normal limit of serum prolactin is typically between 15 and 25 ng/mL for both genders. Levels exceeding this range indicate hyperprolactinemia. Prolactin (PRL) is a

peptide hormone Peptide hormones are hormones composed of peptide molecules. These hormones influence the endocrine system of animals, including humans. Most hormones are classified as either amino-acid-based hormones (amines, peptides, or proteins) or steroid h ...

produced by lactotroph cells in the anterior

pituitary gland The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the human brain, brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus contr ...

. It plays a vital role in

lactation Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The process ...

and breast development. Hyperprolactinemia, characterized by abnormally high levels of prolactin, may cause

galactorrhea Galactorrhea ( also spelled galactorrhoea) ( galacto- + -rrhea) or lactorrhea ( lacto- + -rrhea) is the spontaneous flow of milk from the breast, unassociated with childbirth or nursing. Galactorrhea is reported to occur in 5–32% of females. ...

(production and spontaneous flow of breast milk), infertility, and menstrual disruptions in women. In men, it can lead to

hypogonadism Hypogonadism means diminished functional activity of the human gonad, gonads—the testicles or the ovary, ovaries—that may result in diminished biosynthesis, production of sex hormones. Low androgen (e.g., testosterone) levels are referred t ...

infertility In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...

and

erectile dysfunction Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...

. Prolactin is crucial for milk production during pregnancy and lactation. Together with

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

, insulin-like growth factor-1 (IGF-1), and hormones from the placenta, prolactin stimulates the proliferation of breast alveolar elements during pregnancy. However, lactation is inhibited during pregnancy due to elevated estrogen levels. After childbirth, the rapid decline in estrogen and progesterone levels allows lactation to begin. Unlike most tropic hormones released by the anterior pituitary gland, prolactin secretion is primarily regulated by hypothalamic inhibition rather than by negative feedback from peripheral hormones. Prolactin also self-regulates through a counter-current flow in the hypophyseal pituitary portal system, which triggers the release of hypothalamic dopamine. This process also inhibits the pulsatile secretion of

gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and rele ...

(GnRH), thereby negatively influencing the secretion of pituitary hormones that regulate gonadal function. Estrogen promotes the growth of pituitary lactotroph cells, particularly during pregnancy. However, lactation is hindered by the elevated levels of estrogen and progesterone during this period. The rapid decline in estrogen and progesterone after childbirth enables lactation to begin. While breastfeeding, prolactin suppresses gonadotropin secretion, potentially delaying ovulation. Ovulation may resume before the return of menstruation during this time. Although hyperprolactinemia can result from normal physiological changes during pregnancy and breastfeeding, it can also be caused by other etiologies. For example, high prolactin levels could result from diseases affecting the

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

and

. Other organs, such as the liver and kidneys, could affect prolactin clearance and consequently, prolactin levels in the serum. The disruption of prolactin regulation could also be attributed to external sources such as medications. In the general population, the prevalence of hyperprolactinemia is 0.4%. The prevalence increases to as high as 17% in women with reproductive diseases, such as

polycystic ovary syndrome Polycystic ovary syndrome, or polycystic ovarian syndrome, (PCOS) is the most common endocrine disorder in women of reproductive age. The name is a misnomer, as not all women with this condition develop cysts on their ovaries. The name origin ...

. In cases of tumor-related hyperprolactinemia, prolactinoma is the most common culprit of consistently high levels of prolactin as well as the most common type of pituitary tumor. For non-tumor related hyperprolactinemia, the most common cause is medication-induced prolactin secretion. Particularly,

antipsychotics Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizo ...

have been linked to a majority of non-tumor related hyperprolactinemia cases due to their prolactin-rising and prolactin-sparing mechanisms.

Typical antipsychotic Typical antipsychotics (also known as major tranquilizers, and first generation antipsychotics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia). Typical antipsychotics m ...

s have been shown to induce significant, dose-dependent increases in prolactin levels up to 10-fold the normal limit.

Atypical antipsychotic The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as tranquilizers and neurol ...

s vary in their ability to elevate prolactin levels; however, medications in this class, such as

risperidone Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder, as well as aggressive and self-injurious behaviors associated with autism spectrum disorder. It is t ...

and paliperidone, carry the highest potential to induce hyperprolactinemia in a dose-dependent manner similar to typical antipsychotics.

Signs and symptoms

In women, high blood levels of prolactin are typically associated with hypoestrogenism, anovulatory

, and changes in

menstruation Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and Mucous membrane, mucosal tissue from the endometrium, inner lining of the uterus through the vagina. The menstrual cycle is characterized ...

. Menstruation disturbances commonly manifests as

amenorrhea Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...

or oligomenorrhea. While mild hyperprolactinemia may not always result in menstrual disorders, it is uncommon for women to have normal menstrual cycles if their serum prolactin levels exceed 180 ng/ml (3,600 mU/L). In such cases, irregular menstrual flow may result in abnormally heavy and prolonged bleeding (

menorrhagia Heavy menstrual bleeding (HMB), previously known as menorrhagia or hematomunia, is a menstrual period with excessively heavy flow. It is a type of abnormal uterine bleeding (AUB). Abnormal uterine bleeding can be caused by structural abnorm ...

). Women who are not pregnant or nursing may also unexpectedly begin producing

breast milk Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by the mammary glands in the breasts of women. Breast milk is the primary source of nutrition for newborn infants, comprising fats, proteins, carbohydrates, and a var ...

(

), a condition that is not always associated with high prolactin levels. For instance, many pre-menopausal women experiencing hyperprolactinemia do not experience galactorrhea and only some women who experience galactorrhea will be diagnosed with hyperprolactinemia. Thus, galactorrhea may be observed in individuals with normal prolactin levels and does not necessarily indicate hyperprolactinemia. This phenomenon is likely due to galactorrhea requiring adequate levels of

to prepare the breast tissue. Additionally, some women may also experience loss of

libido In psychology, libido (; ) is psychic drive or energy, usually conceived of as sexual in nature, but sometimes conceived of as including other forms of desire. The term ''libido'' was originally developed by Sigmund Freud, the pioneering origin ...

and breast pain, particularly when prolactin levels rise initially, as the hormone promotes tissue changes in the breast. In men, the most common symptoms of hyperprolactinemia are decreased

sexual dysfunction Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction ...

, erectile dysfunction/impotence,

, and

gynecomastia Gynecomastia (also spelled gynaecomastia) is the non-cancerous enlargement of one or both breasts in men due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse (10 Novemb ...

. Unlike women, men do not experience reliable indicators of elevated prolactin such as

menstrual The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of egg ...

changes, to prompt immediate medical consultation. As a result, the early signs of hyperprolactinemia are generally more difficult to detect and may go unnoticed until more severe symptoms are present. For instance, symptoms such as loss of libido and sexual dysfunction are subtle, arise gradually, and may falsely indicate a different cause. Many men with pituitary tumor–associated hyperprolactinemia may forego clinical help until they begin to experience serious endocrine and vision complications, such as major

headaches A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Head ...

or eye problems. Men often present late in the course of hyperprolactinemia, typically with symptoms related to the expansion of their pituitary tumor, such as headaches, visual defects, and external ophthalmoplegia, or symptoms from secondary adrenal or thyroid failure. Despite experiencing sexual impairment for many years before receiving a diagnosis, it is unclear whether macroprolactinomas are more commonly seen in men due to delayed diagnosis or if the

pathogenesis In pathology, pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes . Descript ...

of prolactinomas differs between men and women. Unlike women, who most commonly have microprolactinomas, men usually present with macroprolactinomas, and their serum prolactin levels are generally much higher than those observed in women. Long-term hyperprolactinaemia can lead to detrimental changes in bone metabolism as a result of hypoestrogenism and hypoandrogenism. Studies have shown that chronically elevated prolactin levels lead to increased

bone resorption Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood. The osteoclasts are multi-nuclea ...

and suppress bone formation, resulting in reduced

bone density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although medicine#Clinical practice, clinically it is measured by ...

, increased risk of

fracture Fracture is the appearance of a crack or complete separation of an object or material into two or more pieces under the action of stress (mechanics), stress. The fracture of a solid usually occurs due to the development of certain displacemen ...

s, and increased risk of

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...

. In men, the chronic presence of hyperprolactinemia can lead to

and osteolysis. The prevalence of bone impairment is significantly higher in men with prolactinomas compared to women. Impaired

bone mineral density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to opti ...

(BMD) serves as an "end organ" marker, reflecting the full extent of the disease. It could potentially become a surrogate marker for the severity of long-term hyperprolactinemia and associated hypogonadism.

Causes

Prolactin secretion is regulated by both stimulatory and inhibitory mechanisms. Dopamine acts on pituitary lactotroph D₂ receptors to inhibit prolactin secretion while other peptides and hormones, such as thyrotropin releasing hormone (TRH), stimulate prolactin secretion. As a result, hyperprolactinemia may be caused by disinhibition (e.g., compression of the pituitary stalk or reduced dopamine levels) or excess production. The most common cause of hyperprolactinemia is prolactinoma (a type of

pituitary adenoma Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas. A blood serum prolactin level of 1000–5000 mIU/L (47–235 ng/mL) may arise from either mechanism, however levels >5000 mIU/L (>235 ng/mL) is likely due to the activity of an

adenoma An adenoma is a benign tumor of epithelium, epithelial tissue with glandular origin, glandular characteristics, or both. Adenomas can grow from many glandular organ (anatomy), organs, including the adrenal glands, pituitary gland, thyroid, prosta ...

. Prolactin blood levels are typically correlated with the size of the tumors. Pituitary tumors smaller than 10 mm in diameter, or microadenomas, tend to have prolactin levels <200 ng/mL. Macroadenomas larger than 10 mm in diameter possess prolactin >1000 ng/mL. Hyperprolactinemia inhibits the secretion of

(GnRH) from the

, which in turn inhibits the release of

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, puberty, pubertal maturat ...

(FSH) and

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (G ...

(LH) from the

and results in diminished

gonad A gonad, sex gland, or reproductive gland is a Heterocrine gland, mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gon ...

sex hormone Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...

production (termed

). This is the cause of many of the symptoms described below. In many people, elevated prolactin levels remain unexplained and may represent a form of

hypothalamic–pituitary–adrenal axis The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus (a part of the brain located below the thalamus), the pituitary gland ( ...

dysregulation.

Physiological causes

Physiological (i.e., non- pathological) causes that can increase prolactin levels include:

ovulation Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and ...

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

, chest wall injury, stress, stress-associated

REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...

, and exercise. During pregnancy, prolactin increases can range up to 600 ng/mL, depending on estrogen and progesterone concentrations. After delivery, progesterone concentrations decrease, and prolactin levels drop. Only during nipple stimulation will prolactin levels rise, allowing for milk production. At 6 weeks post-birth (postpartum), estradiol concentrations decrease, and prolactin concentrations return to normal even during breastfeeding. Fluctuations in prolactin levels during menstrual cycles and menopause are inconclusive. Stress-related factors include physical exercise,

hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

, and surgery. While aerobic and anaerobic activity increases prolactin, anaerobic activity has a greater effect. Coitus can also contribute to an increased prolactin release. Prolactin serum concentrations increase during nocturnal sleep, and increase transiently during daytime naps. After waking, prolactin levels return to daytime levels within 60–90 minutes.

Medications

Prolactin secretion in the pituitary lactotroph cells is normally suppressed by the brain chemical

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

, which binds to dopamine receptors. Drugs that block the effects of dopamine at the pituitary or deplete dopamine stores in the brain may cause the pituitary to secrete excess prolactin without an inhibitory effect. These drugs include the

typical antipsychotic Typical antipsychotics (also known as major tranquilizers, and first generation antipsychotics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia). Typical antipsychotics m ...

s: phenothiazines such as

chlorpromazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar d ...

, and

butyrophenone Butyrophenone is an organic compound with the formula C6H5C(O)C3H7. It is a colorless liquid. The butyrophenone structure—a ketone flanked by a phenyl ring and a butyl chain—forms the basis for many other chemicals containing various subst ...

s such as

haloperidol Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychos ...

;

atypical antipsychotic The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as tranquilizers and neurol ...

s such as

and paliperidone; gastroprokinetic drugs used to treat gastro-esophageal reflux and medication-induced nausea (such as that from

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

metoclopramide Metoclopramide is a medication used to treat nausea, vomiting, gastroparesis, and gastroesophageal reflux disease. It is also used to treat migraine headaches. Common side effects include feeling tired, diarrhea, akathisia, and tardive dyski ...

and

domperidone Domperidone, sold under the brand name Motilium among others, is a dopamine antagonist medication which is used to treat nausea and vomiting and certain gastrointestinal problems like gastroparesis (delayed gastric emptying). It raises the ...

; less often, alpha-methyldopa and

reserpine Reserpine is a drug that is used for the treatment of hypertension, high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diur ...

, used to control

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

; and TRH.

Aripiprazole Aripiprazole, sold under the brand name Abilify, among others, is an atypical antipsychotic primarily used in the treatment of schizophrenia, bipolar disorder, and irritability associated with autism spectrum disorder; other uses include as ...

, while an atypical antipsychotic, lowers prolactin levels as it is contains both agonistic and antagonistic dopamine-receptor activity. It is well known that estrogen stimulates prolactin secretion by upregulating the formation of lactotrophs. However, there is mixed evidence on whether estrogen-containing oral contraceptives significantly increase prolactin levels. Gender-affirming therapy for transgender women that includes estrogen and antiandrogens has been shown to increase prolactin levels, but it is unclear whether the cause is due to the estrogen or antiandrogen therapy. The melatonin receptor agonist

ramelteon Ramelteon, sold under the brand name Rozerem among others, is a melatonin agonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset. ...

also increases the risk of hyperprolactinemia, however, the mechanism is unclear.

Specific diseases

A common cause for hyperprolactinemia is prolactinomas and other tumors arising near the pituitary. These adjacent tumors, such as those that cause

acromegaly Acromegaly is a disorder that results in excess growth of certain parts of the human body. It is caused by excess growth hormone (GH) after the growth plates have closed. The initial symptom is typically enlargement of the hands and feet. There ...

, can physically compress the

pituitary stalk The pituitary stalk, also known as the infundibular stalk, infundibulum, or Fenderson's funnel, is the connection between the hypothalamus and the posterior pituitary, the posterior lobe of the pituitary gland. The floor of the third ventricle is ...

and block the flow of dopamine from the hypothalamus to the pituitary gland, causing prolactin levels to increase. Other causes include

chronic kidney failure Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...

hypothyroidism Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as cold intolerance, poor ability to tolerate cold, fatigue, extreme fatigue, muscle aches, co ...

liver cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...

bronchogenic carcinoma Lung cancer, also known as lung carcinoma, is a malignant tumor that begins in the lung. Lung cancer is caused by genetic damage to the DNA of cell (biology), cells in the airways, often caused by cigarette smoking or inhaling damaging chemi ...

and

sarcoidosis Sarcoidosis (; also known as Besnier–Boeck–Schaumann disease) is a disease involving abnormal collections of White blood cell, inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph n ...

. Hyperprolactinemia develops in one-third of individuals with chronic kidney disease due to impaired renal clearance and regulation. Some women with

may have mildly elevated prolactin levels.

Premenstrual dysphoric disorder Premenstrual dysphoric disorder (PMDD) is a mood disorder characterized by emotional, cognitive, and physical symptoms. PMDD causes significant distress or impairment in menstruating women during the luteal phase of the menstrual cycle. The symp ...

appears to be also correlated with elevated prolactin levels. In men, hyperprolactinemia leads to hypoactive sexual desire and, occasionally,

. However, the link between erectile dysfunction and prolactin levels is not conclusive. When prolactin levels return to normal in these individuals, sexual desire fully recovers; however, erectile dysfunction only partially recovers. Nonpuerperal mastitis may induce transient hyperprolactinemia (neurogenic hyperprolactinemia) of about three weeks' duration; conversely, hyperprolactinemia may contribute to nonpuerperal mastitis. Some inflammatory conditions, such as

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

and

systemic lupus erythematosus Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...

, are also linked to higher prolactin levels in certain regions. Apart from diagnosing hyperprolactinemia and hypopituitarism, prolactin levels are often checked by physicians in those who have had a

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

, when there is a need to differentiate between

epileptic seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

or a

non-epileptic seizure Non-epileptic seizures (NES) are paroxysmal events that resemble epileptic seizures but are not caused by abnormal electrical discharges in the brain. They are not a single condition, but a descriptive category encompassing multiple disorders th ...

. Shortly after epileptic seizures, prolactin levels often rise, whereas they are normal in

Diagnosis

An appropriate diagnosis of hyperprolactinemia starts with conducting a complete clinical history before performing any treatment. Physiological causes, systemic disorders, and the use of certain drugs must be ruled out before the condition is diagnosed. Screening is indicated for those who are asymptomatic and those with elevated prolactin without an associated cause. The most common causes of hyperprolactinemia are prolactinomas, drug-induced hyperprolactinemia, and macroprolactinemia. Individuals with hyperprolactinemia may present with symptoms including galactorrhea, hypogonadism effects, and/or infertility. The magnitude that prolactin is elevated can be used as an indicator of the etiology of the hyperprolactinemia diagnosis. Prolactin levels over 250 ng/mL may suggest prolactinoma. Prolactin levels less than 100 ng/mL may suggest drug-induced hyperprolactinemia, macroprolactinemia, nonfunctioning pituitary adenomas, or systemic disorders. Prolactin levels over 500 ng/mL usually indicates the presence of macroprolactinoma, however, in patients with elevated serum prolactin ( >250 ng/mL) without evidence of prolactinoma, some medications such as metoclopramide, a dopamine receptor antagonist, can result in elevation of prolactin ( >200 ng/mL) in patients with no evidence of pituitary adenomas. In patients with mildly elevated serum prolactin levels, secondary causes such as pituitary adenomas can be ruled out Elevated prolactin blood levels are typically assessed in women with unexplained breast milk secretion (

) or irregular

menses Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and Mucous membrane, mucosal tissue from the endometrium, inner lining of the uterus through the vagina. The menstrual cycle is characterized ...

, and in men with impaired sexual function and milk secretion. If high prolactin levels are present, all known conditions and medications which raises prolactin secretion must be assessed and excluded for diagnosis. After ruling out other causes and prolactin levels remain high, TSH levels are assessed. If TSH levels are elevated, hyperprolactinemia is secondary to hypothyroidism and treated accordingly. If TSH levels are normal, an MRI or CT scan is conducted to assess for any pituitary adenomas. Although hyperprolactinemia is often uncommon in postmenopausal women, prolactinomas detected after menopause are typically macroadenomas. While a plain

X-ray An X-ray (also known in many languages as Röntgen radiation) is a form of high-energy electromagnetic radiation with a wavelength shorter than those of ultraviolet rays and longer than those of gamma rays. Roughly, X-rays have a wavelength ran ...

of the bones surrounding the pituitary may reveal the presence of a large macroadenoma, small microadenomas will not be apparent. Magnetic resonance imaging (

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...

) is the most sensitive test for detecting pituitary tumors and determining their size.

scans may be repeated periodically to assess tumor progression and the effects of therapy.

Computed Tomography A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...

(CT scan) is another indicator of abnormalities in pituitary gland size; it also gives an image of the pituitary, but is less sensitive than the MRI. In addition to assessing the size of the pituitary tumor, physicians also look for damage to surrounding tissues, and perform tests to assess whether production of other pituitary hormones are normal. Depending on the size of the tumor, physicians may request an eye exam that includes the measurement of visual fields. In the rare cases that other causes of hyperprolactinaemia, such as surgery, medication usage, renal and hepatic diseases, and seizures, are ruled out and no evidence of existing adenomas, the hyperprolactinaemia is considered "idiopathic". When the cause of hyperprolactinaemia is concluded as idiopathic, standard of care is given to patients, and an MRI is expected to be repeated in 6–12 months. In diagnosing hyperprolactinaemia in men, some physical signs may indicate the onset of the condition. Increased prolactin can affect the inhibition of GnRH secretion, which is responsible for libido, and the release of FSH (Follicle-stimulating hormone), LH (Luteinizing hormone), and testosterone. FSH in men is responsible to stimulate sperm production and LH is responsible for the stimulation of testosterone; with the inhibition of GnRH, FSH, and LH, physical signs that show in men include reduced sex drive and infertility, these symptoms suggests the onset of hyperprolactinaemia. However, a high measurement of prolactin may also result from the presence of macroprolactin, otherwise known as 'big prolactin' or 'big-big prolactin', in the serum. Macroprolactin occurs when prolactin polymerizes together and can bind with IgG to form complexes. Although this can result in high prolactin levels in some assay tests, macroprolactin is biologically inactive and will not cause symptoms typical of hyperprolactinemia. In those who are asymptomatic or without obvious causes of hyperprolactinemia, macroprolactin should be assessed and ruled out. However, in patients with abnormally high levels of serum prolactin, false negative results that indicates a low level of prolactin may occur; this occurrence is due to a phenomenon called the "Hook effect". Antigen tests such as the pregnancy test shows positive line via the formation of a sandwich immune complex that allows the positive line to be visible, in the occurrence of Hook Effect, large amounts of analyte exists in the solution which saturates the antibodies, preventing normal binding and formation of the sandwich immune complex therefore showing a weak positive line. In the case of diagnosing hyperprolactinaemia, a weak positive line can often lead to a false negative result and increase the risk of misdiagnosis of the condition or a potential pituitary adenomas. If Hook Effect is suspected in the patient diagnosis, serial dilution of the analyte until the concentration of prolactin falls within the assay's analytical measurements is suggested. Ruling out the possibilities of false negatives is important to ensure patients receive necessary care for their conditions.

Treatment

The treatment for hyperprolactinemia is usually dependent upon its cause. There are many underlying factor that can cause hyperprolactinemia, some of them are hypothyroidism (disorder in which thyroid glands has a reduced thyroid hormone production), drug-induced hyperprolactinemia (such as antidepressant medication, antihypertensive medication and medication that can promotes bowel motility), hypothalamic disease(disorder caused by damage in the hypothalamus), idiopathic hyperprolactinemia (no recognized cause are present since there is no pituitary or central nervous disease present), macroprolactin (complex form of prolactin in the blood), or prolactinoma (non-cancerous tumor in the pituitary gland). Because there are so many underlying factors, to provide the proper management of hyperprolactinemia, the pathological form and physiological increase in prolactin levels are differentiated, and the correct cause of hyperprolactinemia must be identified before treatment. There are two types of functional hyperprolactinemia: symptomatic and asymptomatic. For functional asymptomatic hyperprolactinemia, the treatment of choice is removing the associated cause, including antipsychotic therapy. However, prolactin levels should be drawn and monitored both before any discontinuation or changes to therapy and afterwards. In contrast to functional asymptomatic hyperprolactinemia, the treatment for functional symptomatic hyperprolactinemia is different since stopping antipsychotic drugs for a short trial period is not recommended due to the risk of exacerbation or relapse of symptoms. A systematic review and meta-analysis have shown that options for the treatment of hyperprolactinemia in people with psychotic disorder include decreasing the dose of antipsychotics, adding aripiprazole as an adjunctive therapy, and switching antipsychotics as a last resort. On the other hand, the treatment of hyperprolactinemia in children and adolescents with antipsychotic medications has been studied to provide guidelines, as these medications may adversely affect child growth and development. Results have shown that aripiprazole significantly decreases prolactin levels compared to other medications such as olanzapine and risperidone, which result in increased prolactin levels. Pharmacologic hyperprolactinemia, the concerning drug can be switched to another treatment or discontinued entirely. ''Vitex agnus-castus'' extract may be tried in cases of mild hyperprolactinemia. No treatment is required in asymptomatic macroprolactin and instead, serial prolactin measurements and pituitary imaging are monitored in regular follow-up appointments. Medical therapy is the preferred treatment for prolactinomas. In most cases, medications that are dopamine agonists, such as cabergoline, quinagolide and bromocriptine (often preferred when pregnancy is possible), are the treatment of choice used to decrease prolactin levels and tumor size upon the presence of microadenomas or macroadenomas. A systematic review and meta-analysis has shown that cabergoline and quinagolide are more effective in the treatment of hyperprolactinemia compared to bromocriptine, this is because evidence had suggested fewer side effects, rapid titration and offers better dosing interval in medication like quinagolide compared to bromocriptine. Similar studies have been conducted regarding the safety and efficacy of dopamine agonists. According to SUCRA (Surface Under the Cumulative Ranking) and SMAA (Stochastic Multicriteria Acceptability Analysis), quinagolide was found to be the best treatment for women since it can help reduce menstrual irregularities, in addition bromocriptine was shown to be more effective in the treatment for galactorrhea (breast milk production unrelated to pregnancy), and cabergoline was the safest medication as it did not show any alarming side effects. Other dopamine agonists that have been used less commonly to suppress prolactin include dihydroergocryptine, ergoloid, lisuride, metergoline, pergolide, and terguride. If the prolactinoma does not initially respond to dopamine agonist therapy, such that prolactin levels are still high or the tumor is not shrinking as expected, the dose of the dopamine agonist can be increased in a stepwise fashion to the maximum tolerated dose. Another option is to consider switching between dopamine agonists. The prolactinoma can be resistant to bromocriptine but respond well to cabergoline or other dopamine agonists, and vice versa. It is crucial for people undergoing treatment with dopamine agonists to adhere to their medication and not stop it unless instructed by their medical provider. Meta-analysis and systematic reviews have shown that in many patients, hyperprolactinemia reemerges after withdrawal of the medication. For successful treatment with cabergoline, a duration of at least two years is recommended. Surgical therapy can be considered if pharmacologic options have been exhausted. There is evidence to support improvement in outcomes in hyperprolactinemic patients who have shown to be resistant to or intolerant of the most effective treatment with dopamine agonists; for those patients, radiotherapy and surgery are an alternative. Although some studies have tried to explain the consequences of untreated hyperprolactinemia, there are limited studies available. However, it has been shown that some consequences can lead to osteoporosis (low bone mass), increasing the risk of fracture. Further analysis might determine whether populations like high-risk men or post-menopausal women with no other indication for treatment should be on dopamine agonists.

References

External links

{{Prolactin receptor modulators Gynaecological endocrinology Pituitary disorders Syndromes