What Is Hyperprolactinemia?

Hyperprolactinemia, also known as hyperprolactinemia, is a type of hypothalamic-pituitary axis reproductive endocrine disorder caused by elevated prolactin and related clinical manifestations caused by multiple causes. Syndrome is a general term for a group of clinically common diseases that can affect reproductive, endocrine and nervous systems. At present, the serum prolactin level is generally higher than 1.14 nmol / L (25 g / L) as the standard. Due to different detection methods, the normal value reference range of each unit is slightly different. Patients often present clinically with symptoms such as amenorrhea, lactation, frequent menstruation, rare menstruation, infertility, hyposexuality, headache, obesity and other symptoms. Patients can therefore be seen in obstetrics and gynecology, reproductive medicine, andrology, breast, Neurology and neurosurgery. Hyperprolactinemia is still mainly treated with drugs, supplemented by surgical treatment and radiotherapy, and treatment is selected according to the principle of individualization. Epidemiology currently reports large differences in the incidence of the population, most commonly in women of reproductive age. Generally speaking, it accounts for about 0.4% of women of childbearing age, 5% of women with menstrual disorders, and 17% of women with reproductive disorders.

Basic Information

nickname: Hyperprolactinemia
English name: Hyperprolactinemia
Visiting department: Endocrinology, Neurology
Multiple groups: Women of childbearing age

Common causes: Physiological, pathological, pharmacological and idiopathic, pathological is more common in hypothalamic and pituitary diseases, systemic diseases, ectopic prolactin production, etc.
Common symptoms: Amenorrhea, lactation, frequent menstruation, rare menstruation, infertility, hyposexuality, headache, obesity, etc.

Causes of hyperprolactinemia

Under physiological conditions, the regulation of prolactin is dominated by inhibitory regulation. Any factor that interferes with hypothalamic dopamine synthesis and delivery to the pituitary gland and the action of dopamine and its receptors can weaken the inhibitory regulation and cause hyperprolactinemia. The common causes can be summarized into four categories: physiological, pathological, pharmacological and idiopathic.

Physiological

Prolactin is a stress hormone that is secreted in pulses and is secreted at night rather than during the day. The luteal phase of women's menstrual cycle peaks and the follicular phase is low. Significantly increased at term pregnancy and after delivery. In addition, prolactin secretion is significantly increased under stress conditions. High-protein diets, exercise, stress and sexual activity, breastfeeding, nipple stimulation, and sleep disorders can all lead to elevated serum prolactin levels.

2. Pharmacology

Any drug that interferes with dopamine synthesis, metabolism, reabsorption, or blocks the binding of dopamine to the receptor can cause hyperprolactinemia, but is generally lower than 4.55nmol / L. Common drugs are estrogen, dopamine receptor blockers (such as antipsychotics, sedatives, antihypertensive drugs reserpine, monoamine oxidase inhibitors such as phenelzine, -methyldopa), and H2 receptor blocking Agents (such as gastric motility drugs, medicolin, metoclopramide and cimetidine, etc.), drugs that inhibit dopamine metabolism (such as opioids), etc.

3. pathological

Mainly found in hypothalamic-pituitary diseases, systemic diseases, ectopic prolactin production and other reasons.

Diaphragmatic hypothalamic lesions: such as craniopharyngioma, glioma, sarcoidosis, tuberculosis and other oppressive pituitary stems; hypothalamic function is impaired after craniocerebral radiation therapy.

Pituitary diseases: Prolactin-type pituitary microadenomas; pituitary somatotropin adenoma, adrenocorticotrophic adenoma; empty sphenoidal syndrome, sarcoidosis, granulomatosis, inflammatory lesions.

(3) Systemic diseases: primary hypothyroidism; chronic renal failure; severe liver disease, cirrhosis, and hepatic encephalopathy; certain tumors such as adrenal tumors, bronchial cancer, and ovarian cystic teratoma.

Neurogenic: chest wall lesions, shingles neuritis and breast surgery.

Others: polycystic ovary syndrome.

4. Idiopathic

Idiopathic hyperprolactinemia refers to an increase in serum prolactin, usually <4.55nmol / L, negative tests of the pituitary, central nervous system, and system, accompanied by symptoms such as lactation, thin menstruation, and amenorrhea. The onset may be related to the heterotypic structure of the prolactin molecule, and the course of the disease is self-limiting.

Clinical manifestations of hyperprolactinemia

Lactation

As the main clinical manifestation of hyperprolactinemia, about two-thirds of patients will lactate during non-pregnancy and non-lactation, and male patients may also develop breast development and lactation. The secreted milk is colostrum-like, water-like, serous-like, yellow or white. In most cases, the secretion amount is not much, usually only under squeeze. Milk can flow out on its own. Although lactation is closely related to an increase in blood prolactin levels, the amount of lactation has nothing to do with the degree of elevated prolactin levels. Lactation is more common in patients with pituitary microadenomas, accounting for about 70%; only 30% of non-tumorous hyperprolactinemia will lactate.

2. Menstrual disorders and amenorrhea

Patients can show menstrual disorders, secondary amenorrhea, decreased libido, and severe cases can have genital atrophy and osteoporosis. When the patient lactates, reduces menstrual flow, or even amenorrhea, it is called amenorrhea-galactorrhea syndrome. Patients with polycystic ovary syndrome are often accompanied by hyperprolactinemia. In addition to elevated prolactin, blood androgen levels also increase, as well as obesity, hairiness, acne, and thin menstruation.

3. Infertility and infertility

Most hyperprolactinemia is caused by pituitary microadenomas. Approximately 90% of patients present with amenorrhea or amenorrhea, and can also show infertility, accounting for about 70%. Men can show reduced libido, decreased sperm quality, and infertility.

4. Other

Patients with pituitary or intracranial neoplastic hyperprolactinemia may also have headaches, blurred vision or loss of vision, blindness, diplopia, and hypopituitarism; those with growth hormone adenoma may also develop giantness and acromegaly; Cushing disease can also occur in patients with adrenocorticotropic hormone adenomas; hyperthyroidism and nonfunctional tumors can also occur in patients with thyrotropin tumors.

Hyperprolactinemia test

Laboratory inspection

(1) Determination of serum prolactin at rest Normal range of prolactin and diagnostic criteria for hyperprolactinemia Normal prolactin level 1.14nmol / L (25g / L, 1g = 21.2mU / L), if it exceeds 1.14 nmol / L is hyperprolactinemia. Precautions When measuring serum prolactin, it is necessary to consider its pulsed release and food (especially high protein diet) to increase its secretion characteristics. Fasting should be performed on the day of each examination, and intercourse should be prohibited on the morning of the day; rest for 1 hour after admission, and take blood at about 9-11 am; blood can be collected for 3 consecutive days or 3 consecutive times on the same day to exclude pulse peaks, which is conducive to high prolactin secretion Judgment. For patients with a history of drug application, the drug can be stopped for 48 to 72 hours without affecting the treatment of the disease. For example, the prolactin value of drug-induced hyperprolactinemia will decrease after discontinuation. Etiological analysis: Prolactin rises but does not exceed 4.55nmol / L (about 2000mU / L), which may be caused by drugs, estrogen or idiopathic high prolactin; more than 6.83nmol / L (about 3000mU / L, higher than Prolactin adenoma may be present at 5 times the normal value; typical prolactin adenomas have prolactin in excess of 11.38nmol / L (about 5000mU / L), but prolactin adenomas can occur at various prolactin levels; non-prolactin Pituitary adenomas cause only a slight increase in prolactin levels.

(2) Prolactin dynamic test includes pituitary excitability test and inhibition test. Prolactin above 2.28nmol / L requires thyroid function check. Drugs that stimulate prolactin secretion (such as thyrotropin-releasing hormone, metoclopramide, and cimetidine) or drugs that inhibit prolactin secretion (levodopa) can be selectively used to observe the dynamic changes of prolactin. Except for the bromocriptine inhibition test, pituitary prolactin adenomas generally have no significant changes in prolactin secretion in stimulant and inhibitor experiments, which is helpful in distinguishing idiopathic hyperprolactinemia from pituitary adenomas.

1) Excitatory tests are commonly used in thyroid-stimulating hormone pituitary excitatory test and chlorpromazine test. Pituitary excitability test of thyrotropin-releasing hormone: Before applying thyrotropin-releasing hormone, collect blood to determine the basic value of prolactin. Thyrotropin-releasing hormone 500 g was injected intravenously, and blood thyroid-stimulating hormone and prolactin were measured after 30 minutes and 60 minutes of administration. After the application of thyrotropin-releasing hormone in normal women, thyroid-stimulating hormone increased by 2 to 4 times and prolactin increased by 4 times. In the case of prolactinoma, the prolactin-releasing effect of thyrotropin-releasing hormone is lower than normal. This experiment is suitable for patients with slightly increased prolactin (within 2.28nmol / L). Chlorpromazine test: 25-50 mg intramuscular injection of chlorpromazine, doubled for 60-90 minutes, lasting 3 hours. Because it inhibits the function of dopamine receptors and promotes the secretion of prolactin, it increases prolactin. Such as pituitary tumor prolactin does not increase.

2) Levodopa test and bromocriptine test are commonly used for inhibition test. L-dopa test: L-dopa 500 mg was orally administered, and prolactin decreased significantly to <0.18 nmol / L within 2 to 3 hours. L-dopa is a precursor substance of dopamine, and the prolactin is significantly reduced by the action of dopamine. There is no fluctuation of prolactin in pituitary tumors. Bromocriptine test: Bromocriptine 2.5 ~ 5mg orally. After 2 ~ 4 hours, prolactin decreases by more than 50% for 20 ~ 30 hours. When suffering from hyperprolactinemia and pituitary microadenomas, prolactin after taking the drug Obvious reduction.

(3) Macromolecular prolactin screening can use prolactin chromatography, polyethylene glycol immunoprecipitation, gel filtration chromatography and other methods to help rule out hyperprolactinemia caused by macromolecular prolactin isomers.

(4) Determination of reproductive endocrine hormones On the third day of menstruation, the serum reproductive hormones follicle-forming hormone (FSH), luteinizing hormone (LH), estradiol (E2), testosterone (T), pregnancy Ketone (P) to understand ovarian function. The normal serum FSH value is 3 to 10 U / L. If the FSH value exceeds 11 U / L, it indicates that the ovarian reserve capacity is low. When the FSH value exceeds 25U / L, it indicates premature ovarian failure, normal or low estrogen levels; sometimes accompanied by low LH and FSH or low E2 may be related to amenorrhea-galactorrhea syndrome. If the level of T is elevated or the ratio of LH / FSH is abnormal, it is helpful to diagnose polycystic ovary syndrome. If the T level rises, pay attention to ultrasound examination to exclude ovarian masculinized tumors and testicular feminized tumors.

(5) Examination of pituitary, thyroid, adrenal and other related endocrine functions. Elevated thyrotropin releasing hormone, thyroid stimulating hormone, and prolactin, suggesting primary hypothyroidism; prolactin may also increase when adrenal function is low; blood growth hormone 2. Determination of adrenocorticotropic hormone can suggest growth hormone adenoma and adrenocorticotrophic adenoma.

(6) Other pregnancy tests are excluded.

2. Imaging examination

It helps to identify the pituitary and saddle space occupying lesions. The main method is the imaging of the skull / saddle (MRI or CT). It is generally recommended that the above examinations should be completed for those who have prolactin> 4.55nmol / L and no clear cause; if the serum prolactin level continues to increase> 9.1nmol / L, the pituitary prolactinoma is highly likely. Dynamically enhanced pituitary and saddle MRI pairs have the advantages of high resolution, multi-directional imaging, no radiation damage, and can be repeated multiple times. It can diagnose small adenomas larger than 3 mm and even smaller; for larger lesions and lesions, calcification The changes in bone structure are more sensitive than MRI, which is helpful for distinguishing from craniopharyngioma and the choice of surgical approach.

3. Neuro-Ophthalmology Examination

For patients with suspected saddle tumors (such as those caused by pituitary tumors, craniopharyngiomas, etc.), especially those with larger lesions, the eyesight, visual field, and fundus conditions should be checked, the size and expansion of the tumor should be evaluated, and the optic nerve and cross-optic receptor influence level. For pituitary microadenomas within 1 cm, no visual field examination is generally required.

Hyperprolactinemia diagnosis

For the diagnosis of the etiology of hyperprolactinemia patients, a distinction should be made between functional and organic tumors. Clinicians should exclude physical and medicinal factors through careful medical history collection, physical examination, hormone level determination and imaging examination, clarify the source of high prolactin levels and whether there are pathological reasons and give corresponding treatment.

1. Medical history collection

Suspicious patients are asked for detailed medical history, especially to understand the possible related medical history of the patient from the three aspects of physiology, pathology and pharmacology of hyperprolactinemia. Ask in detail whether you have thin menstruation, amenorrhea and corpus luteum insufficiency. Learn about the time of lactation, menstrual history, history of childbirth and lactation, history of surgery and previous medical history. Gastric motility drugs, antihypertensive drugs, or contraceptives; history of thyroid, kidney, and chest wall diseases. Hormone determination for stress states such as hypoxic exercise, exercise, sexual intercourse, anesthesia, pain, hypoglycemia, surgery, nipple stimulation, psychiatric mood fluctuations, or pelvic examinations.

2. Examination

Squeeze the breast to understand the lactation situation, pay attention to changes in vision, visual field, whether there are hairy, obese, high blood pressure, chest wall lesions, etc. during the whole body examination.

Hyperprolactinemia treatment

Treatment principle

In addition to the physiological and pharmacological factors of hyperprolactinemia, the serum prolactin level, clinical symptoms, and fertility requirements should be selected based on pathological hyperprolactinemia. Ectopic prolactin secretion caused by ectopic pregnancy, malignant tumors, hypothyroidism, renal failure, etc. needs to be treated for the primary disease; if the prolactin is slightly elevated, menstrual regularity and those who do not want to give birth can be temporarily observed; With amenorrhea, low estrogen status, infertility and pituitary microadenomas, or with headaches, drug treatment should be preferred. For patients with compression symptoms caused by pituitary adenoma, visual field defects, headache and vomiting, or ineffective drug treatment or intolerance to drug treatment, surgery can be considered; those who are not suitable for surgery use radiotherapy.

2. Treatment goals

Inhibits prolactin secretion, restores normal menstruation and ovulation or conception, reduces milk secretion, and improves visual impairment.

3. Drug treatment

Hyperprolactinemia drug treatment mainly includes ergotine derivatives, the most commonly used are dopamine receptor agonists, as well as auxiliary ovulation-promoting drugs (for fertility patients) and hormone replacement therapy. The principle is to start with a small dose and gradually increase, taking oral administration as the main component. Those who cannot tolerate oral administration can use vaginal administration. Patients treated with medication should be closely monitored and followed up.

(1) Bromocriptine Bromocriptine is the first selective dopamine receptor agonist. It is still the most effective drug in the clinical treatment of hyperprolactinemia, and can also be used as an adjunct to acromegaly and Parkinson's disease treatment.

1) Side effects and side effects are common, but nausea, hallucinations, dizziness, headache, nasal congestion, constipation, etc. are the main ones, and severe side effects are orthostatic hypotension. Due to its bile excretion, hepatic and biliary function should be checked before medication.

2) There are long-acting intramuscular injection preparations and oral sustained-release preparations. It can be used once a month for injection, and it can be used quickly to treat large adenomas.

3) In general, the prolactin decreased significantly after 4 weeks of treatment, and 70% to 90% of patients treated for 7 to 8 weeks (average 5 to 7 weeks) could recover ovulation and stop lactation. Usually 3 months is a course of treatment.

4) Treatment of pituitary tumors For large pituitary adenomas, a large daily dose of bromocriptine can shrink the tumor quickly, but individual patients need long-term large doses. If the dose is increased to 10 mg / d, the tumor cannot be reduced (three treatments Months later), especially those who affect vision, should consider surgery. Large adenomas shrink in the first 3 months of treatment, and serum prolactin rises above 45.5 nmol / L. Local infiltration of the tumor should be considered, and long-term application of bromocriptine is still required even for surgical treatment.

5) Pregnancy is the drug of choice for pregnant patients . For patients who wish to conceive, use a small dose of bromocriptine until the pregnancy stops, or only use the drug during the follicular phase, and discontinue the drug after ovulation (B-ultrasound) to prevent overdose in early pregnancy.

6) At the time of withdrawal, pay attention to avoid recurrence of withdrawal. Generally, the drug should be maintained at the lowest dose. If the serum prolactin level is normal and the patient is asymptomatic for more than 2 years, try stopping the medicine or intermittently using dopamine agonists. The prolactin value is measured 3, 6, 12 or 6 months after stopping the drug. Patients should pay attention to seeing the doctor in time when symptoms recur.

(2) Cabergoline is a new type of specific dopamine D2 receptor agonist newly synthesized in recent years. It is administered orally and has a long half-life. It can be taken 1 to 2 times a week, which has a stronger effect, a lighter gastrointestinal reaction, and tolerance. Sex is better. Oral 1-2mg / w has the same effect as bromocriptine 5-10mg / d, and prolactin can be stabilized in the normal range for a long time after the former is discontinued. It can be used as a first-line for those who are not preparing for pregnancy or physiological breast milk and men. drug.

(3) Quegolide is a non-ergotamine dopamine receptor agonist, taken once a day, before bedtime. It is mainly used for those who are allergic to ergotine and resistant to bromocriptine.

(4) Medication for special circumstances

1) Infertility bromocriptine caused by hyperprolactinemia in women is the preferred treatment for hyperprolactinemia, and about 80% of patients with ovulation after 6 months of treatment. Lutein dysfunction is slightly elevated in 40% to 47% of prolactin, and luteal dysfunction in patients with normal secreted lactin levels may have "transient hyperprolactinemia", and bromocriptine treatment is also effective. Some recurrent miscarriages are caused by hyperprolactinemia or "recessive hyperprolactinemia" and can also be treated with bromocriptine.

2) Hyperprolactinemia caused by hyperprolactinemia in men is manifested by hyposexuality, ejaculation abnormalities, impotence, and spermatogenesis disorders, etc. The loss of sexual desire is more common, and some patients can recover after the serum prolactin level is corrected. Normal sexual desire. Infertile patients can adopt appropriate assisted reproductive technology to solve fertility problems according to the semen and spouse situation.

3) Drugs intended for pregnancy and during pregnancy. Unless there is a large adenoma, the risk of pregnancy induced by drug treatment to the mother and child is not great, and the abortion rate, fetal malformation rate, and twin rate do not increase significantly. Those with higher levels of prolactin during pregnancy should continue to take bromocriptine treatment until the placenta after pregnancy establishes the effect of replacing the corpus luteum of pregnancy (about 12 weeks or more). Regardless of the presence or absence of prolactinoma, it is usually reviewed 10 to 12 weeks after delivery. If a pituitary accident occurs suddenly during pregnancy, most patients can use bromocriptine to control symptoms, but sometimes still need surgery. In addition, pregnancy may also help patients with hyperprolactinemia return to normal.

4. Treatment of hyperprolactinemia due to saddle disease

(1) Purpose of treatment Control or remove tumors, lesions, eliminate or reduce compression, and promote functional recovery; Reduce high secretion hormones and correct metabolic disorders; Restore and protect the pituitary gland and surrounding sensitive structural functions; Properly handle comorbidities.

(2) The treatment method is based on the choice of treatment strategies such as drugs, surgery, radiosurgery, and chemotherapy.

(3) Treatment strategies for various types of lesions

1) Prolactin adenomas currently advocate drug therapy as the first choice; surgery is mainly applicable to large adenomas with symptoms of nerve compression, small adenomas with obvious endocrine symptoms, and prolactin glands that do not respond to or do not tolerate dopamine agonists. Tumor is also suitable for patients with systemic diseases such as mental illness, who need to take drugs that can cause hyperprolactinemia for a long time. In addition, X knives, gamma knives, and proton knives have also become effective treatments for prolactin adenomas.

2) Adrenocorticotrophic adenomas can show more severe systemic damage and have a high resistance to radiation therapy. Surgical treatment is preferred.

3) Non-functional adenomas are mostly diagnosed with compression symptoms, the tumor volume is relatively large, and there are many surgical treatments; patients who ignore the compression of the road can also be treated with radiosurgery.

4) Craniopharyngioma is mainly treated by surgery . The subfrontal , pterygoid, endplate, transsphenoidal, corpus callosum, and cortical approaches can be selected according to the specific site, growth direction, volume, and composition of the lesion. Microscopy is used during the operation. Surgery, endoscopy, and neuronavigation guidance can better protect the hypothalamus and peripheral nerve blood vessels, and remove tumors more thoroughly. For recurrent parenchymal tumors far from the nerve structure, radiosurgery can be used; those who are close to sensitive structures can choose stereotactic radiotherapy. Interstitial radiotherapy is suitable for a single cystic tumor without significant optic nerve compression or vision loss for many years, but it is not suitable for parenchymal, cystic, thin-walled and polycystic tumors. Intracystic chemotherapy for cystic tumors has a better effect.

5) Total resection of germ cell tumor in the saddle area can reduce the dose of radiotherapy and chemotherapy, reduce its side effects, and delay the tumor recurrence time. Because it is very sensitive to radiation therapy, most of the tumor fields and wider peri-tumor tumors are administered with a total dose of 50 Gy and divided radiation therapy for 5 to 6 weeks. Multiple radiation lesions, cerebrospinal fluid tumor cell positive, spinal cord, and ventricular metastasis are required. Total central nervous system radiation therapy. Ono radiation therapy for younger children has obvious complications and needs to be carefully selected. It is often combined with chemotherapy or delayed chemotherapy by chemotherapy.

6) Other saddle lesions such as meningioma, sarcomatoid disease, optic glioma, hamartoma, metastasis, sarcoidosis, granulomatous disease, cerebrovascular disease, empty saddle and inflammatory lesions, etc., high Prolactinemia is only a manifestation of damage to the hypothalamus or pituitary stalk, and the primary disease should be actively treated through surgical treatment; patients with residual tumors or malignant tumors need to be combined with radiation therapy, and young children must be combined with chemotherapy or postponed radiotherapy if necessary; Small tumors that are oppressed in the visual pathway, (AVM) can be treated with radiosurgery.