Hyperprolactinemia

Psychotropic drugs involving dopamine must consider the problem of high prolactin, but not limited to antipsychotics. It is very necessary to routinely check this item after medication. If hyperprolactinemia is found with treatment, the first step is to check the pituitary magnetic resonance imaging, especially for the elevation above 100 units. We can't just consider the dopamine blocking effect of drugs in the funnel area It would be safer to come back after empty sella syndrome to consider drug causes. Specifically, when considering the drugs, we should not only consider the dopamine blocking effect, but also consider the high TSH and antihistamine effects of drugs that lead to polycystic ovary and hypothyroidism, which are also the causes of hyperprolactinemia in psychotropic drugs.

The medical project declared by the multidisciplinary clinical diagnosis and treatment team composed of the Laboratory Medicine Department, Endocrinology Department and Neurosurgery Department of Huashan Hospital: to establish a prolactin monomer detection method and specific reference interval to enhance the ability to identify megaprolactinemia, which stood out from many medical institutions around the world and won the "UNIVATS Excellence Medical Award", Become the only Chinese team to win the award in 2024. The "UNIVATS Excellence Award" was jointly selected and awarded by seven leading global healthcare organizations (IFCC, ADLM, EHMC, Modern Healthcare, HIMSS, NAHQ, IHE). The jury selected the excellent project team to achieve quantifiable performance improvement from five aspects of uniqueness, accessibility, scalability, standardized processes and laboratory intelligence. So far, the award has attracted more than 175 countries and hundreds of projects every year. Previously, the prolactin monomer detection project has won many honors, including the third prize of the 10th Shanghai medical staff scientific and technological innovation "Starlight Plan" in 2020, the second prize of the first National Endocrine Disease Test and Clinical Thinking Case Competition in 2021, and the silver prize of the 34th Shanghai Excellent Invention Selection Competition in 2022. Hyperprolactinemia is a common clinical disease caused by many reasons, and the serum prolactin level is continuously higher than the normal range. Although hyperprolactinemia will not endanger life, it will lead to serious complications, including irregular menstruation, infertility, decreased libido, breast hyperplasia, milk secretion and other problems. Hyperprolactinemia may also lead to male infertility, decreased libido, breast enlargement and other problems. Therefore, timely identification and treatment of hyperprolactinemia is crucial to improve the quality of life of patients. When more than 60% of prolactin in the peripheral blood circulation is composed of macroprolactin, this disease is also called macroprolactinemia. The latest meta-analysis results show that macroprolactin blood is an inactive isomer of prolactin, which will interfere with the immunoassay for prolactin detection. If the concentration of macroprolactin is too high, that is, when more than 60% of circulating prolactin is composed of macroprolactin blood, it may lead to the wrong diagnosis of hyperprolactinemia, which may result in unnecessary examination and/or drug treatment. According to statistics, among the global hyperprolactinemia, the incidence of macroprolactinemia is 18.9% (95% CI 15.8%, 22.1%). Therefore, early screening of macroprolactin blood is helpful to avoid misdiagnosis and unnecessary treatment. The Laboratory Medicine Department of Huashan Hospital cooperated with the Endocrinology Department and the neurosurgery "Golden Pituitary" multidisciplinary, through case discussion, understanding of clinical needs, establishing a giant prolactin blood screening plan, especially adopting the standardized laboratory operating procedures of polyethylene glycol precipitation, and building a prolactin monomer detection method based on the chemiluminescence immune detection, The reference interval of prolactin monomer was established, which was verified by clinical samples and confirmed that the method could be used to identify macroprolactinemia. The prolactin monomer detection method and the use of gender specific reference intervals established by the team can help clinicians diagnose hyperprolactinemia and pituitary tumors more accurately, and avoid unnecessary drug treatment. Zhao Yao, chief physician of neurosurgery department of Huashan Hospital, said that prolactin monomer detection can greatly alleviate the anxiety of patients and their families. Compared with the original method based on imaging, prolactin monomer detection can help clinicians to make a clear diagnosis six months earlier. Ye Hongying, chief physician of the Endocrinology Department of Huashan Hospital, said that prolactin monomer detection has the role of making a clear diagnosis and shortening the course of treatment in the diagnosis and treatment of hyperprolactinemia, which can significantly shorten the treatment process of patients and reduce the cost of patient care. The multidisciplinary clinical diagnosis and treatment team of Huashan Hospital affiliated to Fudan University starts from subtlety and creates outstanding clinical value with innovative thinking. The giant prolactin screening project is a model of collaboration between different disciplines to solve clinical and patient needs, and has fully implemented the concept of taking disease as the chain and patients as the center. (Transferred from the subscription number of Huashan Hospital Affiliated to Fudan University, Department of Laboratory Medicine)

High prolactin is not necessarily a pituitary tumor. There are many factors that cause prolactin increase, and pituitary tumor is only one of them. Reasons for high prolactin: 1. Physiological factors: mental stress, exercise, eating and other stress conditions may lead to high physiological prolactin. 2. Drug factors: Taking anti anxiety and antipsychotic drugs, as well as antiemetics, estrogen drugs, contraceptives, etc., may lead to high prolactin. 3. Tumors: Tumors in the intracranial sellar region, such as craniopharyngioma, hamartoma, vacuolar sella, etc., may also cause high prolactin. 4. Idiopathic increase: prolactin is high due to imbalance of prolactin, prolactin or hormone inhibiting prolactin secreted by hypothalamic pituitary.

How to manage hyperprolactinemia (prolactinoma) during pregnancy? Prolactin (PRL) is an anterior pituitary hormone, whose main function is to induce and maintain breast milk secretion. The serum prolactin level of women of normal childbearing age is generally<25ng/ml. Hyperprolactinemia is an increase in serum prolactin caused by various factors, mainly manifested as amenorrhea, galactorrhea, rare menstruation, infertility and tumor compression symptoms, which is an important cause of female fertility disorders. The pregnant period of women with hyperprolactinemia is dominated by drug therapy, dynamic monitoring and evaluation, multidisciplinary cooperation, and refined and individualized comprehensive management to obtain a good pregnancy outcome. Hyperprolactinemia is defined as the state in which the PRL level in peripheral blood continuously increases due to various reasons, which is called hyperprolactinemia. According to the serum prolactin level, hyperprolactinemia can be divided into the following categories: ≮ mild 25~50ng/ml;  Moderate 50~100ng/ml;  Severe degree ＞ 100ng/ml. Hyperprolactinemia tends to occur in women aged 20-50 years, with an incidence rate of about 1/10000. The peak incidence is around 30 years old, and 40% of hyperprolactinemia is idiopathic. The etiology of hyperprolactinemia hyperprolactinemia is caused by a variety of physiological, pharmaceutical and pathological reasons.  The biological factors include: pregnancy, lactation, stress, exercise, etc; ▄ Drug factors mainly include drugs that antagonize hypothalamic dopamine or enhance the stimulation of prolactin releasing factor and cause hyperpRLemia, such as phenothiazine, methyldopa, morphine, cocaine, estrogen, oral contraceptives, isoniazid, etc;  Pathogenic factors mainly include hypothalamic or adjacent lesions and pituitary diseases, primary hypothyroidism, chronic renal insufficiency, cirrhosis, chest wall diseases, and chronic stimulation of the breast. 20%~30% of hyperpRLemia have pituitary adenoma, the most common is prolactinoma. Pituitary prolactinoma accounts for 30%~50% of all pituitary neuroendocrine tumors. Treatment of hyperprolactinemia High level PRL causes ovulation disorder and luteal insufficiency by inhibiting GnRH pulse, thus causing fertility disorder. The incidence of hyperprolactinemia in infertile women ranges from 9% to 17%, and the incidence of recurrent abortion is 2% to 5%. Therefore, the treatment principle for hyperprolactinemia with fertility requirements is to aim at the cause, restore the PRL level to normal, reduce the size of pituitary tumor, restore normal menstruation and ovulation, reduce complications and prevent recurrence. Drug therapy is the first choice for treatment. Dopamine receptor agonists (DAs) are the main treatment for almost all pituitary prolactinomas, including microadenomas, macroadenomas or giant adenomas. DAs, such as bromocriptine, cabergoline, and quingolide, have therapeutic effects related to individual sensitivity, which can effectively inhibit PRL secretion and reduce tumor size; Long acting DA (cabergoline) is also commonly used in clinical treatment. Small doses are administered at intervals (0.25~0.5mg, once a week), with mild side effects and high compliance, but the price is expensive. After 2 years or more of DAs treatment, if the PRL is normal and the pituitary tumor disappears, the dosage should be reduced or the drug should be stopped. The indications for surgical treatment include drug resistance or intolerance to DAs, or large doses of DAs cannot reduce PRL or tumor volume, or pituitary apoplexy occurs. If patients with mild PRL elevation have regular menstruation and ovulation, there may be macromolecular PRL. Regular reexamination is not necessary. PRL is slightly elevated and accompanied with clinical symptoms. Active treatment should be taken to restore PRL to normal level. The blood PRL of drug-induced hyperprolactinemia was rechecked 3 days after drug withdrawal. If there was no significant increase, no treatment was generally needed. Pretreatment of pregnancy with hyperprolactinemia Pregnancy timing After treatment of hyperprolactinemia, the serum PRL maintained at a normal level for 10 to 12 months, which was conducive to improving infertility. In patients with pituitary microadenoma before pregnancy, the PRL level drops to normal, and pregnancy can be achieved after regular menstruation. For women with large adenomas who have a birth plan, they need to be treated with bromocriptine to shrink the adenomas before pregnancy; For huge PRL tumor, tumor reduction surgery can be considered to relieve the compression symptoms of the tumor and retain the pituitary function. For patients with extrasellar tumors, pregnancy can be achieved only after the tumor shrinks to the boundary of the sellar region. If ovulation still fails to resume after PRL returns to normal, DAs can be combined with ovulation induction therapy. DAs can reduce the level of luteinizing hormone (LH), increase the sensitivity of the ovary to drugs, and increase the pregnancy rate; If the ovarian reserve function is poor or the hypothalamic pituitary function is low, exogenous hormones can be used to assist fertility. During pregnancy preparation, DAs bind to D2 receptors in the anterior pituitary to reduce the proliferation of PRL cells, thereby reducing the synthesis of PRL and reducing tumor volume. The visual field defect was mostly improved within 2 weeks, and the tumor volume was significantly reduced after 3-6 months. Although bromocriptine and cabergoline are both Class B drugs of the US Food and Drug Administration, bromocriptine has a shorter half-life than cabergoline, and bromocriptine has a higher safety. Therefore, bromocriptine is the first choice for patients with fertility requirements. Quigolide is not safe, so it is not recommended for female patients who are preparing for childbirth. The common side effects of DAs include nausea, headache, somnolence and postural hypotension. Therefore, the drug should be administered from a small dose, gradually increased, and maintained at the lowest effective dose. The initial dose is 1.25 mg/d, taken with meals, increased to 2.5 mg/d after one week, and increased to 1.25 mg/d every week until menstruation and ovulation resume. The effective dose is usually 5~7.5 mg/d. During the gradual dose process, attention should be paid to monitoring side effects, and the drug should be stopped as soon as possible after confirming pregnancy. If pregnancy is unexpected during the medication, it is not recommended to terminate pregnancy due to medication. Patients with pituitary microadenoma before pregnancy should stop taking the drug after 12 weeks of pregnancy because of the need to maintain luteal function; In patients with large adenomas before pregnancy, pituitary magnetic resonance imaging (MRI) examination showed that the tumor size was reduced, which could be reduced by 1.25mg/d every 1 to 2 months, and the lowest effective dose was used to maintain the normal level of PRL. It was recommended to use drugs throughout pregnancy. Pituitary adenoma will recur after drug withdrawal. After DAs2 is used for more than two years, the recurrence rate after drug withdrawal is significantly lower than that of patients with short-term application. One year after drug withdrawal is a high-risk time for recurrence. After drug withdrawal, the PRL level is monitored monthly. After three months, the PRL level is reviewed every six months, and then every year. In case of recurrence, the lowest effective dose should be maintained. The indications of surgery or radiotherapy before pregnancy can be considered for those who cannot tolerate drug treatment, have poor drug treatment effect (PRL is normal but the tumor does not shrink), and have giant adenoma with compression symptoms (severe headache and visual field defect). In most cases, transsphenoidal surgery will not damage the gonadal axis, and the surgical effect depends on the skill and experience of the surgeon; Radiotherapy is only used for patients who have failed surgery or considered malignant tumors. After treatment, 30% of the patients' PRL can return to the normal level, but the treatment cycle is long and may be accompanied by hypopituitarism. Evaluation and management of pregnancy The monitoring of blood PRL level during pregnancy is not recommended for routine monitoring during pregnancy. The increase of estrogen level during pregnancy in healthy women leads to the proliferation of pituitary prolactinoma. The PRL level starts to increase in 5-8 weeks of pregnancy, which is related to the increase of the size and number of PRL cells. The response of PRL to normal stimuli (such as sleep, diet, and lactation) remains unchanged throughout pregnancy. Therefore, PRL is not a monitoring indicator of the progress of pituitary prolactinoma during pregnancy. Women with macromolecular hyperprolactinemia (bioactive macromolecules) will produce normal amounts of bioactive prolactin during pregnancy and lactation. MRI examination during pregnancy is not recommended for routine examination during pregnancy, but the evaluation of clinical symptoms should be emphasized. Microadenoma patients have less tumor growth after pregnancy, while large adenoma patients have more than 25% probability of tumor growth after pregnancy. Patients with pituitary microadenoma and macroadenoma were evaluated every 3 months during pregnancy, excluding the monitoring of serum PRL level; For patients with large adenomas without surgical treatment, the number of prenatal examinations and visual examinations can be increased. In case of tumor compression symptoms such as headache or visual field defect, gadolinium free MRI examination and neurology and ophthalmology evaluation are required. The drug maintenance treatment for patients with giant adenoma should be decided by the clinician. There are relatively more reports of bromocriptine continued to be used during pregnancy than other DAs, and there is no clear adverse drug reaction report. Carmergoline can be used for patients who cannot tolerate bromocriptine. It is recommended to conduct clinical evaluation and visual evaluation every 3 months during the medication period. If compression symptoms occur, MRI scanning without gadolinium should be selected; If MRI examination results indicate tumor growth related to clinical manifestations, drug treatment needs to be reassessed, and the symptoms of pituitary tumor growth still cannot be controlled by readjusting the use of DAs. If the drug treatment effect is poor, surgical treatment is preferred in the middle of pregnancy. If it is nearly term, termination of pregnancy can be considered. The basic principle of medication in pregnancy is to limit the exposure of the fetus to drugs in as little time as possible. DAs have no inhibitory effect on placental PRL. In 6272 pregnancies using bromocriptine or 1061 pregnancies using cabergoline, the maternal and fetal outcomes were not significantly abnormal. Although bromocriptine and cabergoline have been proved to have no adverse effects on the pregnancy process or the fetus, they should be stopped in principle if pregnancy occurs during drug treatment; If the pregnant woman has a history of taking DAs, it is not recommended to terminate the pregnancy. Since withdrawal of drugs during pregnancy may lead to tumor growth, clinical symptoms such as headache, visual field defect and diabetes insipidus should be carefully monitored. Postpartum treatment has been observed that postpartum serum PRL level may be lower than that before pregnancy. In some patients, hyperprolactinemia can heal itself after delivery. There is no evidence to support that breast-feeding will stimulate tumor growth. For women who are willing to breast feed, unless the tumor growth induced by pregnancy needs treatment, they will generally review the PRL level after finishing breast-feeding before starting to use DAs. Because DAs inhibit lactation, women who need medication and plan to breastfeed can have MRI reexamination to assess the tumor 4-6 weeks after delivery to weigh the advantages and disadvantages. With the development of monitoring and diagnosis and treatment methods, more and more women with hyperprolactinemia are facing fertility problems. We should pay attention to the reasonable monitoring of the perinatal period and in-depth research on the impact of DAs drug treatment on pregnancy. For women suffering from pituitary adenoma, the perinatal period should be jointly managed by obstetricians and neurosurgeons to minimize complications, so as to obtain a good pregnancy outcome. Source MediEndo Weekly News

How to diagnose and treat hyperprolactinemia? Hyperprolactinemia (HPRL) is a syndrome caused by internal and external environmental factors, characterized by elevated serum prolactin (PRL) levels (≥ 25ng/ml), amenorrhea, galactorrhea, anovulation and infertility. The physiological function of prolactin and its regulation PRL is a polypeptide hormone secreted by the anterior pituitary gland. There are four molecular structures in blood, including monomer, dimer, macroprolactin and macroprolactin. The structural form of PRL determines that it has different biological activities and immune reactivity. Among them, the proportion of monomer small molecule prolactin is the largest, and its biological activity is the highest; Megaprolactin is a high molecular weight "PRL-IgG immune complex" formed by monomer and autoantibody. It has large molecular weight and is difficult to clear, which is easy to create the false appearance of hyperpRLemia, but most of them have no clinical manifestations of amenorrhea and lactation. Physiological functions of PRL: including promoting the maturation of mammary gland vesicle system and the generation of milk, controlling the balance of water and electrolyte in vertebrates, participating in immune regulation, regulating the composition and volume of amniotic fluid, and promoting bone metabolism. The PRL in blood of women with premenstrual tension syndrome is significantly increased before menstruation, which is involved in the occurrence of edema and other symptoms. The secretion of PRL is regulated by hypothalamic PRL releasing factor (PRF) and PRL releasing inhibitory factor (PIF). Normally, the PIF inhibitory regulation represented by dopamine (DA) is dominant. Any factor that interferes with the synthesis of DA in the hypothalamus, the delivery of DA to the pituitary, and the role of DA receptors in DA and PRL cells can weaken the inhibitory regulation and cause HPRL. In addition, the secretion of pituitary PRL can regulate itself through short loop feedback (Figure 1). Figure 1. Definition of short negative feedback loop HPRL for dopamine regulating prolactin secretion HPRL is a state of continuous increase in the level of prolactin in peripheral blood caused by various reasons, not a disease. HPRL is the most common pituitary hypothalamic axis endocrine disorder in young women. The incidence of HPRL varies among different testing populations. The normal reference range of most laboratories is PRL<30ng/ml. The guidelines recommend that in women of normal childbearing age, blood sampling and testing should be carried out in strict accordance with the specifications, and dynamic monitoring is not recommended. Diagnosis and etiological differentiation of HPRL Clinically, HPRL should be suspected for those who have clinical manifestations indicating HPRL or have abnormal elevated blood PRL levels during examination. The diagnosis of HPRL is generally divided into two steps: first, comprehensive analysis of clinical manifestations and blood PRL levels to determine whether there is HPRL; Secondly, through detailed inquiry of medical history, laboratory examination and imaging examination, physiological or pharmaceutical factors were excluded to cause the increase of PRL level, and pathological factors were actively searched. Pituitary prolactinoma is the most common cause of pathological HPRL. There are some clinical manifestations that are inconsistent with the blood PRL level. Special attention should be paid to: when the blood PRL level is significantly elevated without the clinical manifestation of HPRL, the differential diagnosis can be made by polyethylene glycol (PEG) precipitation before measurement to exclude macroprolactinemia. When the proportion of serum macroprolactin level to total PRL is higher than 60%, macroprolactinemia can be diagnosed; When the clinical symptoms of HPRL (such as amenorrhea and galactorrhea) are obvious, but the laboratory PRL measurement value is very low or normal, the serum PRL level can be repeatedly measured by multiple dilution method; In addition, giant PRL tumor (PRL significantly increased) with hypopituitarism of the anterior pituitary (with estrogen deficiency) may not have galactorrhea. Figure 2. The diagnosis process of HPRL The etiology of HPRL can be divided into physiological, pharmacological and pathological conditions (Figure 3). Figure 3. Etiology identification of HPRL The therapeutic objectives of HPRL are to inhibit PRL secretion, shrink tumors, improve compression symptoms and restore menstruation, ovulation and fertility. Treatment plan: drugs, surgery, radiotherapy and other means should be comprehensively applied according to the clinical manifestations and needs of patients. Dopamine receptor agonists (DAs) are the first choice. Surgical treatment can be selected for patients with poor drug treatment effect, intolerance and refusal to take drugs. Both drugs and radiotherapy can be used for the continued treatment of some patients after surgery. Common DAs include bromocriptine, cabergoline and quingolide. Bromocriptine is the first dopamine receptor agonist clinically used to treat HPRL (1975), and is also the most widely used drug in China. "Reynolds" phenomenon and arrhythmia may occur at large doses. A few patients may have postural hypotension at the beginning of treatment, and some patients may even have transient loss of consciousness. Bromocriptine is recommended to be taken before bed, and activities that can reduce blood pressure, such as hot showers or baths, should not be taken during the period of taking bromocriptine. Bromocriptine is effective in 70%~90% cases. As the coenzyme of dopamine decarboxylase, vitamin B6 can promote the endogenous dopamine to become dopamine in the hypothalamus, which is conducive to reducing the secretion of PRL. It is often used in combination with bromocriptine clinically, which can enhance the efficacy and reduce the adverse reactions of bromocriptine on the digestive tract [2]. About 10% of the patients are not sensitive to bromocriptine, are not satisfied with the efficacy or cannot tolerate the treatment dose of bromocriptine, and can be replaced with other drugs or surgery. The American Endocrine Society (ENDO) believes that: during the treatment of pituitary PRL tumors, patients should be regularly followed up for changes in clinical symptoms and serum PRL; The drug reduction or withdrawal should be at least 2 years after the continuous treatment. In addition to the patient's serum PRL level stable in the normal range, it should also be emphasized that there is no pituitary tumor visible on the pituitary MRI. Carergoline and quingolide are highly selective dopamine D2 receptor agonists, which have stronger inhibitory effect on PRL, relatively fewer side effects and longer action time. More than 50% of patients with PRL adenoma who are resistant to bromocriptine (15mg of bromocriptine per day is still unsatisfactory) or intolerant are effective when they switch to new dopamine receptor agonists. It is recommended to use cabergoline for patients with invasive adenoma with impaired vision who expect drug treatment [3]. The use of cabergoline may be related to cardiac valve fibrosis, and tricuspid regurgitation is common. Especially for male patients with prolactinoma, if the dosage of cabergoline is large, echocardiography (UCG) follow-up can be considered. When bromocriptine/cabergoline resistance occurs, it may be considered to add somatostatin analogues such as octreotide, or the new somatostatin receptor ligand paretide, which may have some improvement effect. HPRL considers surgical procedures, including: patients with poor drug treatment effect and intolerance to drug treatment; Patients with sudden tumor hemorrhage that may lead to acute pituitary apoplexy; Some pituitary adenoma patients with mental symptoms should also consider surgery if DA agonist aggravates mental symptoms; Recently, some scholars believe that surgery is also an alternative first-line treatment for microadenomas in the high-throughput pituitary center. The operative methods include transnasal transsphenoidal approach, craniotomy for pituitary adenoma resection and combined approach. Radiotherapy can be considered for patients with large invasive tumors, postoperative residual or recurrent tumors, ineffective drug therapy or intolerant side effects of drug therapy, patients with surgical contraindications or refusing surgery, and some patients who are unwilling to take drugs for a long time. Treatment of HPRL complicated with pregnancy First, pituitary MRI should be performed during pregnancy preparation to assess the increased risk of prolactinoma during pregnancy. Patients with large adenomas can be operated first or tumor reduction surgery. Patients with microadenoma should stop bromocriptine or cabergoline and continue pregnancy after pregnancy is confirmed. During pregnancy, patients do not need routine follow-up blood PRL, visual field examination and MRI. When patients have headache and visual field changes, visual field examination and pituitary MRI plain scan are recommended. If the tumor increases during pregnancy and affects the visual field, bromocriptine is recommended to be given continuously throughout the pregnancy (the safety of pregnancy drugs is Grade B) for large adenoma before pregnancy, and transsphenoidal surgery can be performed in the second trimester if necessary. Source International Diabetes

Patients often ask nervously with the results of sex hormone tests: What if prolactin is high? First, let's understand what prolactin is. Prolactin (PRL) is a peptide hormone secreted by anterior pituitary cells. Its main function is to promote the development and growth of mammary gland, stimulate and maintain lactation, and play an important role in gonadal function and menstrual cycle in combination with other hormones. During pregnancy and lactation, the level of prolactin will increase significantly to promote breast development and lactation. However, if there is a sustained increase in prolactin in other periods, especially in the preparatory period, we should be alert. Because too high prolactin will interfere with ovarian ovulation and follicular development, thereby affecting fertility. Precautions for prolactin inspection Since prolactin will be affected by many factors such as eating, emotional excitement and exercise, there are strict requirements for blood collection in order to ensure the accuracy of the inspection results. It is generally required to have an empty stomach at about 9:00 in the morning. After 15 minutes of sitting in silence, draw blood to see prolactin for 0 minutes, and then sit in silence for half an hour to see prolactin for 30 minutes. Note: Different hospitals use different kits, and the reference values are also different. The interpretation results must be combined with clinical practice. The causes of prolactin increase can be caused by a variety of physiological, pharmacological and pathological factors, which should be carefully identified. Physiological reasons Many physiological factors can affect the level of prolactin. The level of serum prolactin changes in different physiological periods, and it may also increase temporarily under stress, such as exercise, eating, mental factors, sleep, hypoglycemia, and various physiological phenomena such as pregnancy and lactation, which can lead to a temporary increase in the level of prolactin. 02 Pharmacological reasons Taking certain drugs may also cause the increase of prolactin, including antipsychotics, antidepressants, gastrointestinal antiemetics, antihypertensive drugs, analgesics, estrogen drugs, etc. It is necessary to exclude the influence of drugs when making a clear diagnosis. Pathological causes mainly include pituitary diseases, such as prolactinoma, vacuolar sella syndrome, etc; Hypothyroidism; Polycystic ovary syndrome; Chronic renal insufficiency; Liver cirrhosis and hepatic encephalopathy can lead to the increase of prolactin level. Among them, pituitary prolactinoma is the most common cause. In addition, some patients have slightly increased blood PRL level with symptoms, but no reason for the increase of blood PRL level has been found, which may be caused by diffuse proliferation of PRL secretory cells. How to do if prolactin rises? The treatment methods for prolactin increase caused by different factors are also different: 1. For prolactin increase caused by physiological factors, no treatment is needed, only recheck after eliminating the factor. 2. For patients with prolactin elevation after taking certain drugs: if it is only slightly elevated, there is no need for treatment when there is no abnormal menstruation, ovulation disorder, galactorrhea and other symptoms. Regular reexamination is enough to observe the changes of clinical manifestations and PRL. If there are clinical symptoms, professional doctors can guide whether to stop or use other drugs that do not affect prolactin according to the condition. 3. For the increase of prolactin caused by pathological factors, drug intervention or surgical treatment is usually required for specific causes.

A male, 35 years old. From September to 19, prolactin 36.76 was checked and treated with traditional Chinese medicine. From December to 10, prolactin 12.38 was checked and returned to normal! [Zeng Shi's advice]: Soothing the liver, regulating the qi, tonifying the spleen and kidney, reuse 45g of stir fried malt, 45g of red peony! The effect is remarkable! Professor Zeng and his disciples

Prolactin, also called prolactin, is a polypeptide hormone secreted by the anterior lobe of the pituitary gland. Its physiological role is mainly to promote the growth and development of the breast and lactation. The most common one on the six sex hormone report sheet is the increase of prolactin, which is clinically called hyperprolactinemia. 1. What is the clinical manifestation of hyperprolactinemia? The main symptoms were amenorrhea, galactorrhea, infrequent menstruation, infertility and tumor compression. 2. Diagnostic criteria for hyperprolactinemia? The serum PRL value detected more than twice is greater than 1.14nmol/L (25 μ g/L, 1 μ g/L=21.2mU/L), which can be diagnosed. 3. What is the cause of hyperprolactinemia? Physiological factors such as: mental factors, exercise, eating, sleep, sexual intercourse; Nipple stimulation can cause temporary increase of PRL; A variety of physiological phenomena lead to a long-term increase in PRL, such as late follicular and luteal periods, pregnancy, and lactation. Drug factors, many drugs can cause HPRL, such as: oral dopamine receptor antagonists (chlorpromazine, perphenazine, metoclopramide, haloperidol, etc.); Antihypertensive drugs (reserpine, verapamil, etc.); H receptor antagonists (cimetidine, ranitidine, etc.); Opioid preparations; Monoamine oxidase inhibitor, etc. Pathological factors: such as hypothalamic disease, craniopharyngioma, glioma, etc; Pituitary diseases Pituitary microadenoma, empty sella syndrome, etc; Systemic disease hypothyroidism, renal failure, severe liver disease, ovarian cystic teratoma, etc; Neurogenic: Herpes zoster neuritis, breast surgery, etc; Others: polycystic ovary syndrome. Idiopathic: The pathogenesis may be related to the heteromorphic structure of prolactin molecules, and the course of disease is self limited. 4. Precautions for prolactin serological determination? Have an empty stomach or a pure carbohydrate breakfast in the morning. Do not have sexual intercourse that morning. Take blood at about 9~11 a.m., sit sober for half an hour, and then take blood. Try to "hit the nail on the head" and minimize stress. 5. Treatment of hyperprolactinemia? Physiological, pharmaceutical and idiopathic hyperprolactinemia generally do not need special treatment. Drug treatment: Bromocriptine, a dopamine receptor agonist, is the first choice for the treatment of pathological hyperprolactinemia. Starting from a small dosage and gradually adding the dosage can significantly reduce the adverse reactions. Surgical treatment: it is applicable to patients with ineffective drug treatment or poor effect, large drug treatment response that can not be tolerated, giant pituitary adenoma with obvious visual field obstacle, no obvious improvement after drug treatment for a period of time, invasive pituitary adenoma with cerebrospinal fluid rhinorrhea, and those who refuse to take drug treatment for a long time. Radiotherapy: generally used as adjuvant therapy, it is mainly used for patients with poor drug or surgical treatment effect, or for preventing recurrence after surgical treatment. Psychotherapy: HPRL patients usually have trouble and psychological burden in their daily life. In clinical treatment, simple and understandable language can be used to clarify the etiology and pathological mechanism of the disease to patients, reduce the psychological burden of patients, and improve the treatment effect. 6. Monitoring and follow-up of hyperprolactinemia? Lifelong monitoring and follow-up are required after drug treatment. Regular and standardized monitoring and follow-up can find the recurrence of HPRL as early as possible, so as to facilitate timely treatment. It is generally recommended to gradually reduce the drug dose after the serum PRL level returns to normal 2 to 3 years after drug treatment. The drug can be stopped if the serum PRL level remains normal 1 year after low-dose treatment. During the treatment period, the serum PRL level should be rechecked every month, and the cranial MRI should be rechecked every year. The serum PRL should be rechecked monthly within three months after drug withdrawal, once every three months within one year, and then once every six months, and the brain MRI should be rechecked every 1-2 years. Follow up after surgery: Serum PRL level and cranial MRI should be rechecked 1~2 weeks after surgery. Three months later, the serum PRL and cranial MRI were rechecked. Thereafter, the serum PRL level was rechecked once every six months, and the cranial MRI was rechecked every 1-2 years.

1. Mechanism: Antipsychotic drugs block D2 receptor on hypothalamic funnel pathway, which can cause hyperprolactinemia (defined as plasma prolactin concentration>20 μ g/L) Frequency: The incidence of hyperprolactinemia was 91% for risperidone, 48% for typical antipsychotics, 40% for olanzapine, 22% for ziprasidone, 22% for quetiapine, 11% for clozapine, and 1.8% for aripiprazole Degree: The study points out that the blood concentration of prolactin taken by risperidone is 102 μ g/L, and that of olanzapine is 18.7 ～ 24.1 μ g/L; The administration of ziprasidone 40 mg/d did not increase prolactin, while 160 mg/d temporarily increased prolactin, and continued administration restored normal prolactin; Quetiapine or clozapine did not increase or transiently increase serum prolactin level, while aripiprazole reduced prolactin by 57%. The severity of hyperprolactinemia is probably risperidone>haloperidol=chlorpromazine>olanzapine=ziprasidone>quetiapine=clozapine>aripiprazole. 3 Common consequences ⑴ Breast: The breast overflow rate caused by risperidone through hyperprolactinemia is 2.4% in women, and the feminization rate of male breast is 0.4%. Hyperprolactinemia can worsen breast cancer, while aripiprazole reduces the level of prolactin. When schizophrenia is accompanied by breast cancer, aripiprazole is the best choice. ⑵ Menstrual disorders: Hyperprolactinemia can be asymptomatic. When there are symptoms, menstrual disorders are the most common. For example, the amount of menstruation is small within a few months of taking the medicine, the menstrual cycle is prolonged or amenorrhea (no menstruation lasts for more than three months), and the menstrual disorder rate is 1/2 when taking risperidone, which increases in a dose-dependent manner; Taking typical antipsychotics is 1/4. Prolonged menstrual cycle indicates delayed ovulation, amenorrhea indicates no ovulation, and no ovulation will cause infertility. ⑶ Sexual dysfunction: hyperprolactinemia inhibits androgen and reduces sexual desire; Inhibit estrogen, dry vagina, and cause pain in copulation. The rate of sexual dysfunction was 43% when taking risperidone and 33% when taking typical antipsychotics. Clozapine, olanzapine and quetiapine do not increase the level of prolactin, so the rate of sexual dysfunction is low, and the rate of sexual dysfunction of quetiapine is lower than that of olanzapine Rare consequences (1) Pregnancy delusion: Ahuja et al. (2008) described 12 patients with hyperprolactinemia caused by taking antipsychotic drugs, which may be due to prolonged menstruation. Six patients thought they were pregnant (4 delusions, 2 non delusions). When the prolactin level dropped to normal, this delusion disappeared. (2) Promote tumor occurrence: The prevalence rate of pituitary tumor taking risperidone is higher than taking haloperidol or other atypical antipsychotics. Among 307 patients with pituitary tumors, 64 (21%) were taking antipsychotic drugs, and 44 (69%) of 64 patients were taking risperidone. Two explanations: First, the number of patients taking risperidone is large, and the position of risperidone has ranked first in the world for many years; Second, risperidone is more prone to hyperprolactinemia than other antipsychotics, which promotes them to check MRI frequently, thus increasing the detection rate of benign pituitary tumors. ⑶ Reduced bone density: Becker et al. (2003) treated premenopausal schizophrenic women with risperidone or olanzapine for at least 2 years. The results showed that the bone density of the risperidone group was significantly lower than that of the olanzapine group. Diphosphates (such as alendronate and risedronate) can be used to treat osteoporosis. ⑷ Promote children's growth: sexual precocity can inhibit growth. Hyperprolactinemia inhibits sexual development, which can certainly inhibit sexual precocity and promote its growth. 700 children aged 5 to 15 years with disruptive behavior disorder were treated with risperidone for 11 to 12 months. Prolactin increased and promoted their growth Examination (1) Check prolactin: Hyperprolactinemia and amenorrhea can occur with the treatment amount of risperidone, so the patients taking risperidone should actively ask whether their menstruation and sexual function are normal or not. If they are normal, there is no need to check serum prolactin; If it is abnormal, check the serum prolactin. ⑵ Further examination: when the serum prolactin of female patients is higher than normal, they should ① ask whether they are taking hormonal contraceptives; ② Do pregnancy test to exclude pregnancy; ③ Check serum thyroid stimulating hormone to exclude hypothyroidism; ④ Check serum creatinine to exclude renal failure. Because these four conditions can increase the level of prolactin. 6 According to the time relationship between the onset of antipsychotic drugs and the onset of hyperprolactinemia and menstrual disorders, the diagnosis can determine whether it is hyperprolactinemia caused by antipsychotic drugs, but it is still uncertain. The pituitary gland can be closely scanned by MRI to exclude pituitary tumors Treatment (1) Prolactin<200 μ g/L: If hyperprolactinemia has no symptoms, it is often not treated. If only the menstrual cycle is prolonged, such as once every 6-8 weeks, it is unnecessary to deal with it. If it is amenorrhea, it can be treated in the following order: ⑴ Change dressing: change to antipsychotic drugs that increase prolactin effect less (such as clozapine, olanzapine, quetiapine, ziprasidone or aripiprazole); ⑵ Drug reduction: reduce the amount of antipsychotic drugs, but prone to disease; ⑶ Substitution: estrogen contraceptives are used to supplement insufficient estrogen, but tend to thrombosis. Smoking women over 35 years old are prohibited. In case of sexual dysfunction, the method of ⑴ or ⑵ can be selected. ⑵ Prolactin ≥ 200 μ g/L. If the scan is normal, you can take dopamine agonists such as bromocriptine or amantadine, which can partially improve hyperprolactinemia, but can cause gastrointestinal reactions, and sometimes worsen psychosis.

Guide: Women secrete prolactin only after giving birth to children and feeding them. How can big men have prolactin? If there are men diagnosed with hyperprolactinemia, what is the situation? Prolactin is related to male sexual function and sperm production, so the serum prolactin level should also be checked for male infertility and sexual dysfunction. Clinically, patients with high prolactin are often encountered. Faced with such a situation, many doctors think of prolactinoma of the pituitary gland, and then suggest that patients do further examinations to diagnose or eliminate it, so as to ensure safety. However, most of them had normal results after reexamination or further examination. Where is the problem? 1、 What is prolactin? Let's first understand what is prolactin. Prolactin, also known as prolactin, is a polypeptide protein hormone composed of 199 amino acids secreted by the anterior pituitary gland. Its main physiological function is to promote the development of female mammary glands during pregnancy and induce lactation, but its physiological effect on men is still unknown. Some studies have pointed out that prolactin receptors are mainly distributed in the surface epithelium of seminiferous tubules in the male reproductive system, which suggests that prolactin may participate in male spermatogenesis and testosterone formation. 2、 Mechanism of prolactin secretion prolactin, also known as "prolactin, PRL", is a hormone secreted by the human hypothalamic pituitary gland. The secretion of PRL is regulated by the hypothalamic prolactin releasing factor (PRF) and prolactin releasing inhibitory factor (PIF), and is transmitted through the hypothalamic pituitary portal vein circulation. Dopamine (DA) is the main physiological prolactin inhibitor (PIF); In most cases, PIF is dominant, which mainly inhibits the release of PRL mediated by dopamine. PRF promotes the release of PRL mediated by hypothalamic thyrotropin releasing hormone. Other PRFs include gonadotropin releasing hormone (GnRH), serotonin, opioid peptide μ receptor, etc. The balance between PRF and PIF determines the amount of prolactin. Any pathological and physiological changes that destroy the above balance will lead to hyperprolactinemia. Elevated PRL is the main clinical manifestation of hyperprolactinemia (HPRL). 3、 Why do men have prolactin? Male prolactin mainly comes from the pituitary gland and is an important reproductive hormone. For mammals and humans, PRL has a wide range of functions, including regulating the balance of water and electrolyte, growth and development, endocrine and metabolism, spirit and behavior, regulating reproductive function, immune regulation and immune protection. Take three examples: (1) prolactin participates in the stress response of the human body. PRL, together with adrenocorticotropic hormone and reproductive hormone, is known as the three "stress hormones" secreted by the pituitary stress response. For example, under the stress conditions of anesthesia, surgery, shock and strenuous exercise, the concentration of PRL increases. (2) Prolactin can enhance human immune regulation, accelerate lymphocyte proliferation and increase antibody production. (3) Prolactin affects reproductive and sexual activities. PRL participates in regulating the synthesis of FSH and LH, and can stimulate spermatogenesis; However, high levels of PRL can inhibit the secretion of LH and FSH, resulting in ovulation or spermatogenesis diseases. 4、 If you want to detect prolactin accurately, you need to tell the patient about these precautions: you need to know the characteristics of prolactin first; The secretion of prolactin is regulated by the hypothalamic prolactin release inhibiting factor (mainly dopamine) and prolactin release promoting factor. It has the characteristics of circadian rhythm changes. It gradually increases after falling asleep. Before waking up in the morning (4 and 5 o'clock in the morning), it can reach the peak value of the day. After waking up, it rapidly drops, and falls to the valley value of the day from 10 a.m. to 2 p.m, This period of time is the best time for us to draw blood to test the level of prolactin in peripheral blood. In addition to circadian rhythm changes, prolactin secretion is also affected by many external factors, such as stress (surgery, hypoglycemia, myocardial infarction, syncope, trauma, etc.), high protein diet, exercise, eating, tension, sexual intercourse, sleep disorders, etc. In order to eliminate the interference of the above factors, the correct detection method is: 1) Avoid taking sedatives, hypnotics, stomach motility drugs (such as motiline) and other drugs that affect prolactin secretion a few days before blood drawing. 2) Do not sleep together and stimulate the nipple in the night before the test to ensure good sleep. Try not to be active before blood collection, and have a quiet rest for at least half an hour. 3) The blood should be drawn at the low point of prolactin secretion in the day (9~11 a.m.). 4) Testing prolactin does not require an empty stomach, but it is not advisable to overeat. A small amount of carbohydrate is enough. 5) For those with slightly elevated prolactin test results, do not make a diagnosis of hyperprolactinemia (or prolactinoma) easily, and must recheck in strict accordance with the test requirements. In addition, it is better to test five items of thyroid function (FT3, FT4, TSH, TPOAb, TGAb) at the same time to exclude the increase of prolactin caused by primary hypothyroidism. 6) There are three forms of human prolactin in serum: the content of single prolactin with biological and immune activity is the most, accounting for 60-90%, which has the greatest impact on endocrine system; 15-30% are dimers without biological activity; In addition, less than 10% are tetramers with relatively high molecular weight and low biological activity, as well as polymers of immunoglobulin and monomer prolactin, which are called macroprolactin. Therefore, the blood PRL level will be inconsistent with the clinical manifestations. This kind of pseudo hyperprolactinemia is different from true hyperprolactinemia. The patient has no clinical symptoms and does not need special treatment, but only needs regular follow-up. 25% polyethylene glycol pretreated serum can precipitate macroprolactin and oligomeric prolactin, which can distinguish between patients with true hyperprolactinemia (increased bioactive monomer prolactin) and patients with macroprolactinemia (normal monomer prolactin concentration). 5、 When hyperprolactinemia (HPRL) is mentioned as a possible reason for the increase of male prolactin, many people will think of women's irregular menstruation and galactorrhea, but few people know that men will also suffer from this disease. Hyperprolactinomia may lead to male fertility decline and infertility, which is easily ignored in the diagnosis and treatment of male infertility. It is reported that its incidence is 36/100000, only about 1/10 of that of women. The incidence of HPRL in male infertility patients is about 4%, and only some of them show abnormal semen quality. It has been reported that only 1.4% of male HPRL caused by pituitary microadenoma has infertility, and most male infertility patients with increased PRL have slightly increased hormone levels. So in the male population, what factors will lead to the increase of prolactin? We summarized the possible reasons for the increase of male prolactin by consulting relevant data. 1. Physiological factor prolactin is a stress hormone, which is secreted in a pulse manner, and the secretion at night is higher than that at daytime. The secretion of prolactin increases significantly under stress conditions, and is greatly stressed by the outside world, such as surgery, hypoglycemia, syncope, trauma, high protein diet, exercise (especially blood sampling immediately after intense exercise to detect prolactin), eating, tension, sleep disorders, etc. can all lead to the increase of serum prolactin level. 2. If the level of prolactin increases due to pathological factors, male comrades should consider the following issues: first, whether there is a common prolactinoma, we can conduct prolactin level detection and pituitary MRI, and judge whether there is hyperproteinemia and prolactinoma. Secondly, in some other cases, the level of male prolactin may also increase, such as hypothyroidism, which will lead to the increase of TSH level. However, TSH and prolactin may co secrete, which will lead to the increase of prolactin level at the same time. Finally, when the level of liver function and kidney function is low, the metabolism in the body is slowed down, and the level of male prolactin can also rise at this time. Pathology is mainly found in hypothalamic pituitary diseases, systemic diseases, neurogenic and ectopic PRL generation. 2.1 Hypothalamic lesions Any reason that blocks DA from entering the anterior pituitary cells through the pituitary stalk can lead to the inability of DA that inhibits the synthesis and release of PRL to enter the portal vein system and make PRL increase. For example, craniopharyngioma, glioma, sarcoidosis, tuberculosis, etc. can distort and compress the pituitary stalk, making DA transmitted to the pituitary gland decrease; Hypothalamus function is damaged after brain radiotherapy, which may affect DA synthesis. 2.2 Pituitary disease Pituitary tumor is the most common cause of HPRL, and PRL adenoma is the most common. Growth hormone tumor and adrenocorticotropic hormone tumor can increase TRH and stimulate PRL secretion. Empty sella syndrome, sarcoidosis, granulomatosis, inflammatory diseases, etc. can squeeze the normal pituitary, affect the portal blood flow, reduce the DA concentration in the anterior pituitary, and cause an increase in PRL. 2.3 The level of T3 and T4 in peripheral blood of patients with primary hypothyroidism of systemic diseases decreases, leading to the increase of TRH secretion in hypothalamus and the increase of PRL synthesis and secretion in pituitary; TRH may also increase PRL by inhibiting DA secretion. The increase of PRL in patients with chronic renal failure is related to the decrease of renal metabolic clearance rate of PRL and the excessive production of PRL; At the same time, renal failure can not metabolize and inactivate hormones normally. Hyperazotemia also changes the sensitivity of pituitary PRL cells to DA, reducing the inhibition of PRL secretion. Severe liver disease, cirrhosis, etc. can also affect the metabolism of DA and cause the increase of PRL; The formation of pseudoneurotransmitters increases in hepatic encephalopathy, and the decrease of PIF can lead to the increase of PRL. 2.4 Neurogenic chest wall lesions, chest wall trauma, herpes zoster neuritis, etc. promote PRL secretion through autonomic nerve stimulation and interference with central nervous pathways. 2.5 Ectopic secretion of certain tumors, such as bronchial carcinoma, adrenal adenoma and renal carcinoma, etc. Mutant tumor cells can cause the transcription of PRL gene to start, and secrete a large amount of PRL. 3. Drug related factors2 Any drug that interferes with the synthesis, metabolism, reabsorption of dopamine or blocks the binding of dopamine and its receptor can cause hyperprolactinemia, but generally less than 4.55 nmol/L. 3.1 Promote the synthesis and release of PRL. Long term use of estrogen can directly act on pituitary PRL cells and promote the synthesis and release of PRL. 3.2 DA receptor or H2 receptor blockers antipsychotic drugs, gastric motility drugs such as motiline, metoclopramide, cimetidine and other H2 receptor blockers can block the DAR of pituitary PRL cells, leading to the weakening of DA's inhibitory effect on PRL release. 3.3 The central nervous system DA consumer sedatives, antihypertensive drugs reserpine, α - methyldopa, monoamine oxidase inhibitors, etc. can reduce the central nervous system DA content, leading to HPRL. 3.4 Inhibition of DA metabolism Opioids stimulate hypothalamic opioid receptors to inhibit DA metabolism, thereby promoting PRL secretion. 6、 Cause and mechanism of male infertility and sexual dysfunction caused by HPRL 1. Prolactin, also called prolactin (PRL), is a spherical protein composed of 199 amino acids (23kD) secreted by anterior pituitary cells. PRL is a stress hormone, which is secreted in pulse mode and has circadian rhythm. With the increase of age, the serum PRL decreases, and the average PRL level of elderly men is about 50% lower than that of young people. The secretion of PRL is mainly regulated by the balance between hypothalamic afferent inhibition and stimulation signals and peripheral blood hormones. PRL can affect hypothalamic pituitary gonadal axis and fertility. In the cycle, 85% of PRL exists in the form of monomer, and there are also bimolecules and larger molecules bound by covalent bonds. PRL receptors are distributed in the surface epithelium of seminiferous tubules, Leydig cells and prostate in the male reproductive system, suggesting that PRL may have a regulatory effect on spermatogenesis and testosterone production. At the pituitary level, PRL has a synergistic effect with gonadotropin to regulate hypothalamic gonadotropin releasing hormone; At gonadal level, PRL can enhance the concentration of LH receptor in Leydig cells to maintain testosterone synthesis in testes, and promote the growth and normal function of prostate and seminal vesicle in the presence of testosterone; PRL may be important for maintaining normal sexual desire. 2. HPRL interferes with the effect of gonadotropin releasing hormone by destroying the pulse release of gonadotropin, which can lead to hypogonadism, sexual dysfunction, histological changes of testes and decreased spermatogenesis, thus affecting male fertility. Low PRL level does not necessarily have pathological significance. No gene mutation of PRL gene or its receptor has been found in humans. In addition, anterior pituitary cells secrete adrenocorticotropic hormone (ACTH), growth hormone (GH), thyroid stimulating hormone (TSH) and other glycoprotein hormones. When pituitary lesions that cause HPRL affect the cells that secrete these hormones, they will also have a negative impact on male reproductive function. It has been observed that FSH and LH are closely related to spermatogenic function between azoospermia and oligospermia in male infertile patients with HPRL, but there is no difference in the level of PRL, indicating that HPRL has more influence on testes through pituitary gonadal axis than direct effect. 3. There are many reasons for male HPRL stress induced HPRL: the "stress state" of physiology or psychology may cause a slight increase in PRL. Drugs that interfere with dopamine synthesis or dopamine receptor blockers can cause HPRL, such as antipsychotics such as phenothiazines, tricyclic antidepressants and monoamine oxidase inhibitors; Gastrointestinal drugs such as metoclopramide, domperidone, etc; Antihypertensive drugs such as verapamil and reserpine; It has also been reported that angiotensin converting enzyme inhibitors, such as enalapril, may promote the release of PRL. In pathological HPRL, prolactinoma is the most common cause. Most prolactinomas are sporadic benign tumors, and there are also reports of family onset. Malignant prolactinomas are quite rare. The microadenoma is smaller than 10mm in diameter, the large adenoma is larger than 10mm in diameter, and the giant adenoma is larger than 40mm in diameter. Large adenomas and giant adenomas grow rapidly and are large in size, which can cause erosion and damage to surrounding tissues (such as the optic nerve), and even destroy the gonadotropin cells of the pituitary, leading to the reduction of FSH and LH. Other pathological reasons include hypothalamic disorder, pituitary or ectopic prolactinoma, pituitary tumor secreting other hormones, primary hypothyroidism, liver and kidney dysfunction, etc. Some patients were classified as idiopathic if no clear reason was found. 7、 The clinical manifestation of hyperprolactinemia (HPRL) is a hypothalamic pituitary gonadal axis dysfunction disease. The prevalence rate of the general population is 0.4%, and that of reproductive dysfunction patients is 9%~17%, and women are higher than men. The main manifestations of men are hypolibido, erectile dysfunction, sperm reduction, infertility, osteoporosis, etc., which have seriously affected people's health and quality of life. Hyperprolactinemia (HPRL) is characterized by the continuous increase of serum prolactin (PRL), which leads to the syndrome of hypothalamic pituitary gonadal axis dysfunction. 1. Sexual dysfunction: PRL elevation shows that PRL elevation can interfere with GnRH release and pituitary response to GnRH, reduce follicle stimulating hormone (FSH) and LH secretion, and reduce testosterone synthesis and secretion; Excessive PRL can also destroy the synergistic effect of PRL with FSH and LH, directly affect the reaction ability of gonads and accessory glands to FSH and LH, resulting in hypogonadism, decreased libido and erectile dysfunction. 2. Male infertility: testicular spermatogenesis disorder, spermatogenic cells blocked in the primary spermatocyte and sperm cell stage, unable to develop into mature sperm, resulting in a decrease in the number of sperm and ejaculation, which can be expressed as male infertility. There is even mild testicular atrophy, which is more obvious when the testicles become soft than small. Testicular biopsy can show normal, thickened or fibrotic seminiferous tubules in different patients; The spermatogenic function was normal, or decreased, or blocked; The testis of patients with hypogonadism may present the pre pubertal tissue morphology and lose the function of spermatogenesis. 3. Decreased male secondary sexual characteristics: slow growth of beard, sparse pubic hair, soft testis, muscle relaxation, etc; Lower androgen level will also cause osteoporosis; Due to excessive estrogen and relatively insufficient androgen, the normal glandular epithelium "residues" in the male breast proliferate, resulting in male breast development; Male lactation symptoms are rare. 4. Symptoms and signs of nervous system: Male PRL adenomas often fail to see a doctor in time due to mild symptoms, and the diagnosis is not made until central nervous system compression symptoms appear. Patients may have severe headache, visual impairment, nervous system diseases, hypophysis dysfunction, cerebral hemorrhage and other symptoms. According to the location and size of the primary focus, tumors in the sellar region can cause headache or visual field loss to varying degrees. 5. Other pituitary or intracranial neoplastic hyperprolactinemia patients may also have blurred vision or visual field loss, blindness, diplopia, and hypopituitarism; Gigantism and acromegaly may also occur in patients with growth hormone adenoma; Cushing disease may also occur in patients with adrenocorticotropic hormone adenoma; Hyperthyroidism and nonfunctional tumors may also occur in patients with thyrotropin tumor. 8、 Diagnosed patients often seek medical treatment due to decreased libido, sexual dysfunction, infertility or central nervous system compression symptoms caused by large PRL tumors. Diagnosis can be made through medical history inquiry, physical examination and serum hormone detection. Imaging examination can find whether there is central nervous system disease. 9、 The goal of treating prolactin elevation is to control prolactin, restore male sexual function, fertility function and improve other symptoms (such as headache and visual impairment). After determining the increase of prolactin, it is necessary to decide whether treatment is needed. Reconstruct the balance of hypothalamus pituitary gonad axis, mainly improve symptoms, and do not emphasize the change of single index. If the compression of the central nervous system or other symptoms are caused by the tumor, surgery should be performed to relieve the compression symptoms, and DAR agonists should be taken orally; If it is caused by drugs, the pros and cons should be weighed to decide whether to stop the drug; Patients with hypothyroidism may take thyroxine orally. 1. It is unnecessary to treat stress induced HPRL. Asymptomatic HPRL patients can be closely observed, and do not need to rush to medication, and regularly review the blood hormone levels. Those who take drugs to increase PRL should stop taking drugs. One third of patients with idiopathic HPRL can obtain remission without treatment. The lower the blood PRL level is, the greater the possibility of spontaneous remission. The remission rate of<1.820nmol/L is 2/3. For symptomatic patients, you can choose to take drugs to reduce PRL. 2. Drugs to reduce HPRL. Prolactin is synthesized and secreted by prolactin cells in the anterior lobe of the pituitary gland. It is regulated by the hypothalamic dopaminergic pathway. Dopamine acts on the dopamine D2 receptor on the surface of prolactin cells and inhibits the production and secretion of prolactin. Any physiological and pathological process that reduces the effect of dopamine on the dopamine D2 receptor on the surface of prolactin cells will lead to the increase of serum prolactin level. During HPRL, dopamine receptor agonists can reverse this process. The drug treatment of hyperprolactinemia mainly includes ergot derivatives, and the most commonly used is dopamine receptor agonist. The principle is to start from a small dose and gradually increase it, mainly by oral administration. Drug users should be closely monitored and followed up. (1) Bromocriptine is the first choice drug, and has experienced a long period of clinical application. Bromocriptine, a semi synthetic ergot alkaloid, is a powerful dopamine D2 like receptor agonist and a partial dopamine D1 like receptor agonist. It inhibits the secretion of PRL and has no effect on other pituitary hormones. Bromocriptine treatment can make 70%~90% of the patients obtain good curative effect, which is manifested by the reduction of serum prolactin level to normal, the disappearance or reduction of lactation, the reduction of pituitary adenoma, and the restoration of sexual desire and spermatogenic ability and correction of male infertility in men. 1) Side effects and side effects are common, but generally nausea, hallucination, dizziness, headache, nasal congestion, constipation, etc. are the main side effects. The serious side effects are postural hypotension. Because it is excreted through bile, the liver and gallbladder function should be checked before use. 2) Dosage form and usage: At present, there are long-term intramuscular injection preparations and oral sustained-release preparations. The injection can be used once a month. It has a quick effect and can be used to treat large adenomas. Since bromocriptine has hypotensive side effects, it should be administered at a small dose (1.25 mg/d), starting at night before bedtime, and gradually increasing the dose, which will be distributed in the morning, middle and late in the next day, until the serum PRL level is normal and stable. The maximum dose is 20~30mg/d. After reaching the maximum efficacy, the dose of bromocriptine can be gradually reduced, and it can be maintained for a long time after reaching the minimum effective dose. The decrease of PRL level will be accompanied by the shrink of prolactinoma. 3) The course of treatment is generally 4 weeks, the blood prolactin drops significantly, and 70%~90% patients can recover after 7-8 weeks of treatment (5-7 weeks on average). Usually, 3 months is a course of treatment. 4) Pituitary tumor treatment For large pituitary adenoma, generally a large daily dose of bromocriptine can rapidly shrink the tumor, but some patients need a long-term large dose. If the dose increases to 10mg/d, the tumor cannot shrink (after 3 months of treatment). Especially for those who affect vision, surgery should be considered. In the first three months of treatment, the large adenoma shrinks, while the serum prolactin increases ≥ 45.5nmol/L. It should be considered that the local invasion of the tumor, even if the surgical treatment still needs the long-term use of bromocriptine. 5) At the time of drug withdrawal, attention should be paid to avoid relapse caused by withdrawal. Generally, the drug should be maintained at the lowest dose. If the serum prolactin level is normal and the patient has no symptoms for more than 2 years, the drug can be stopped or treated with dopamine agonists intermittently. The blood prolactin value should be measured 3, 6, 12 months or every 6 months after drug withdrawal. The patient should pay attention to seeing a doctor in time when the symptoms reoccur. (2) Carergoline is a specific dopamine D2 receptor agonist newly synthesized in recent years. It has a long half-life after oral administration and can be taken once or twice a week. It has stronger curative effect, less gastrointestinal reaction and better tolerance. The treatment starts from 0.25-0.5mg, once or twice a week, and increases month by month until the PRL level is normal. The course of treatment should generally last for 12 to 24 months. Oral administration of 1~2mg/w is equivalent to bromocriptine 5~10mg/d, and the prolactin of the former can be stabilized in the normal range for a long time after withdrawal. For pregnant women who need to control the recurrence of pituitary prolactinoma or pituitary macroadenoma, bromocriptine is safer for embryo safety. (3) Quigolide is a non ergot dopamine receptor agonist, which is taken once a day before sleep, mainly for those allergic to ergot drugs and those resistant to bromocriptine. 3. Treatment of male sexual dysfunction Male HPRL patients with sexual dysfunction is due to HPRL acting on the central nervous system to some extent, which inhibits sexual desire and erectile function, and sexual function can be improved after PRL decreases. For those with gonadotropin cell dysfunction caused by PRL tumor compression, testosterone level cannot return to normal after PRL level drops, androgen can be supplemented to restore and maintain the male secondary sexual characteristics. Sexual dysfunction with serious symptoms, especially those who have been ill for a long time and have changed their behavior patterns such as anxiety and depression, is necessary to carry out sexual counseling and treatment, carry out sexual rehabilitation according to the strategy of sexual dysfunction treatment, and appropriately use drugs for erectile dysfunction. In addition to androgen supplementation, thyroid hormone and cortisol replacement therapy are also necessary for patients with complete loss of pituitary function caused by surgery or radiotherapy. 4. Bromocriptine can significantly reduce the level of PRL, but semen parameters and pregnancy rate have no significant improvement. Gonadotropin treatment can be used together to restore fertility function, or appropriate assisted reproductive technology can be adopted according to semen analysis results and spouse conditions to solve the fertility problems of patients. For men with fertility needs, the use of exogenous androgen in treatment should be cautious. Long term and large dose use of exogenous androgen may be detrimental to testicular spermatogenesis, and it is best to use HCG plus FSH. In patients with hypogonadotropic dysplasia, bromocriptine alone could not increase the release of gonadotropin, but the combination of bromocriptine and gonadotropin might receive a better response. 5. For surgery and radiotherapy, transsphenoidal prolactinoma resection is only selected when giant adenoma has compression symptoms or drug treatment is ineffective. Surgical treatment accounts for less than 10% of patients. Operation indications: (1) ineffective or ineffective drug treatment; (2) Those who can not tolerate the drug treatment reaction; (3) Giant pituitary adenoma with obvious vision and visual field disorders, and no obvious improvement after drug treatment for a period of time; (4) Invasive pituitary adenoma with cerebrospinal fluid rhinorrhea; (5) Those who refuse to take medication for a long time. The use of bromocriptine before and after operation can improve the curative effect. The main indications of surgery or neuroradiotherapy also include other tumors causing HPRL. Due to the effectiveness of drug and surgical treatment and the side effects of hypopituitarism of radiotherapy, radiotherapy is only used as an auxiliary treatment for male PRL tumors. Radiotherapy can be considered for poor surgical effect or residual or recurrent tumor after operation. Deep X-ray, 60Co, alpha particle and proton radiation can often be used. Treatment of Pituitary Tumor with Male Sexual Dysfunction The "Golden Pituitary" team of Huashan Hospital affiliated to Fudan University is one of the first demonstration units in China to carry out multidisciplinary cooperation in the diagnosis and treatment of pituitary tumors. Many well-known experts are from neurosurgery, endocrinology, andrology, gynecology and obstetrics, imaging, radiotherapy and other national key disciplines. Professor Zhao Yao, the chief expert, pointed out that for patients with pituitary adenoma complicated with male sexual dysfunction, individualized treatment should be taken according to the objective condition and the patient's requirements for sexual life quality. The serum prolactin level of patients usually drops to normal 1~12 weeks after surgery, which is very important for maintaining male sexual function. If the serum prolactin returns to normal, but the testosterone is still low, and the male sexual dysfunction has not been improved, the type 5 phosphodiesterase inhibitor can be added at the same time of testosterone supplementation; If the serum prolactin level cannot be reduced to normal, even testosterone supplementation is still difficult to improve the sexual function of patients. In addition, some patients can also improve sexual function through non-specific treatment such as sexual counseling, sexual behavior therapy, psychotherapy, etc.