Hyperprolactinemia _ hyperprolactinemia symptoms, treatment and prevention

Introduction:

Hyperprolactinemia(hyperprolactimia) is the most common pituitary disease, which is characterized by galactorrhea and hypogonadism. If the patient has both galactorrhea and amenorrhea, it is called galactorrhea-abated syndrome, such as Chiari-Fromeel syndrome in postpartum; Forbes-Albright syndrome with pituitary tumors; non-postpartum without pituitary tumors It is called del Castillo syndrome. The main difference between the above syndromes is that there are two kinds of pituitary tumors and no pituitary tumors, and the other differences are only in the time of illness. Therefore, the names of these syndromes have recently been mentioned less frequently.

Cause:

(1) Causes of the disease

1. Physiological hyperprolactinemia In normal healthy women, plasma prolactin is elevated during nighttime and sleep (2-6am), late follicular and luteal phase. Plasma prolactin is increased 5 to 10 times during pregnancy. The concentration of prolactin in amniotic fluid is higher than that in plasma after the second trimester. In lactating women, plasma prolactin concentrations are 1 times higher than non-pregnant women. Fetal and neonatal (≥ 28 weeks gestation - 2 to 3 weeks postpartum) plasma prolactin corresponds to maternal levels. Massage the breast and sucking the nipple to reflexively promote prolactin secretion. Plasma prolactin remained at a high level during the puerperium (within 4 weeks). Prolactin in non-breastfeeding women fell to non-pregnancy levels within 3 months. Prolactin is significantly elevated in fasting, insulin-induced hypoglycemia, exercise, stress, and sexual intercourse.

2. Pathological hyperprolactinemia

(1) Hypothalamic-pituitary lesions:

1 hypothalamic non-functional tumors: including craniopharyngioma, invasive hypothalamic lesions sarcomatoid disease, histiocytosis, glioma and leukemia.

2 pituitary functional tumors: including pituitary adenomas (80% secretory prolactin), prolactinoma (prolactinoma),Acromegaly(25% with hyperprolactinemia),Cushing syndrome(Adrenal ACTH adenoma, 10% with hyperprolactinemia), prolactin cell hyperplasia (80% with hyperprolactinemia).

3 Functional hyperprolactinemia: caused by inhibition of dopamine function, including primary vacuolar sella syndrome (5% with amenorrhea and galactorrhea) and secondary vacuolar sellar syndrome (10% with Hyperprolactinemia).

4 Inflammatory and destructive lesions: including meningitis, tuberculosis, syphilis, actinomycosis, injury, surgery, arteriovenous malformation, granulomatosis; pituitary stalk lesions, injury or tumor compression.

5 trauma, stress andParkinson's Disease.

(2) thyroid and adrenal diseases: including primary and secondary hypothyroidism, pseudohypoparathyroidism, Hashimoto's thyroiditis. Adrenal diseases, including chronic kidney disease, Addison's disease, and chronic renal failure may have hyperprolactinemia.

(3) ectopic prolactin secretion syndrome: including undifferentiated bronchogenic lung cancer, adrenal cancer and embryonal cancer.

(4) Polycystic ovary syndrome.

(5) Obstetrics and gynecology surgery and local irritation: including induced abortion, erosive hydatidiform mole or stillbirth, postpartum, hysterectomy, tubal ligation, oophorectomy. Local breast irritation, including papillitis, cleft palate, chest wall trauma, herpes zoster, tuberculosis, and chest wall surgery can also cause hyperprolactinemia.

(6) Drugs that promote prolactin secretion:

1 anesthetic drugs: including morphine, methadone, methionine enkephalin.

2 psychiatric drugs: including phenothiazines, including haloperidol, fluphenazine, chlorpromazine, tricyclic antidepressants, alpha peptides, chlordiazepines, amphetamines and diazepam.

3 hormone drugs: including estrogen, oral contraceptives, thyroid stimulating hormone releasing hormone (TSH-RH).

4 antihypertensive drugs: including methyldopa, reserpine, verapamil (icopidine).

5 affecting dopamine metabolism and functional drugs: including: A. dopamine receptor antagonists, including phenothiazine,Haloperidol, metoclopramide, morphine, piperazine (pimozide); B. dopamine reuptake blocker: nomifensine (benziquinium); C. dopamine degrading agent, including blood Ping, methyldopa; D. dopamine conversion inhibitor: apeptide.

6 monoamine oxidase inhibitor.

7 benzodiazepine derivatives: including dibenzoxazole nitrogen leather, carbamoyl chloride, thiophene, imipramine, amitriptyline, phenytoin,Diazepam,Clonazepam.

8 histamine and histamine H1, H2 receptor antagonists: includingSerotonin, amphetamine and so on. H1 receptor antagonists, including meclizine, pyripramine. H2 receptor antagonist cyanoguanidine.

9 antiemetic drugs: including sulpiride, promethazine (purazine), perphenazine.

10 other: cyproheptadine.

(two) pathogenesis

The secretion of pituitary prolactin (PRL) is strongly controlled by dopaminergic neurons in the hypothalamic nodules-funnel, so any damage to the hypothalamic lesions such as tumors, radiation damage and inflammation may increase the secretion of pituitary PRL, resulting in High PRL. Some pituitary diseases (such as inflammation), if damaged by the pituitary stalk, can reduce the dopamine transported by the hypothalamus to the pituitary PRL cells and cause high PRL. Certain non-PRL pituitary tumors such as GH tumors, ACTH tumors, etc. can compress the pituitary stalk and cause high PRL. TRH has a strong effect on the secretion of PRL, while thyroid hormone can slightly inhibit the response of PRL cells to TRH, so high PRL can occur in primary hypothyroidism. 30% to 80% of patients with end-stage renal failure have mild to moderate high PRL, which may be due to accelerated dopamine metabolism in these patients. In cirrhosis, high PRL can be caused by abnormal metabolism of neurotransmitters. Some chest and breast diseases such as thoracic surgery, chest herpes, mastitis, etc. can also cause high PRL. Some non-endocrine gland tumors such as bronchial carcinoma can also secrete PRL, which produces high PRL, but is extremely rare.

symptom:

1. General performance

(1) menstrual disorders: primary amenorrhea accounted for 4%, secondary amenorrhea accounted for 89%, menstrual thin hair, menstruation less 7%, dysfunctional bleeding and luteal insufficiency accounted for 23% to 77%.

(2) The typical amenorrhea-galactorrhea syndrome of galactorrhea is 20.84% in non-tumor hyperprolactinemia, 70.6% in tumor type, and 63%-83.5% in simple galactorrhea. The galactorrhea appears as a dominant or extruded breast, as a water sample, as a serum, or as a milk. More normal breasts.

(3) The incidence of infertility is 70.7%, which may be primary or secondary infertility, and is associated with anovulation, luteal insufficiency or luteinized non-ruptured follicular syndrome (LUFS).

(4) low estrogenemia and hyperandrogenism: decreased estrogen causes flushing, palpitations, spontaneous sweating, vaginal dryness, sexual pain, loss of libido, etc. Elevated androgen causes moderate obesity, seborrheic, acne and hirsutism.

(5) visual acuity and visual field changes: pituitary tumors involving the optic nerve cross, can cause vision loss, headache, dizziness, hemianopia and blindness, as well as brain nerve II, III, IV dysfunction, fundus edema and exudation.

(6) Acromegaly: When seen in PRL-GH adenoma, mucinous edema is seen in patients with hypothyroidism, and some patients have type 2 diabetes and osteoporosis.

2. Clinical classification

(1) Tumor-type hyperprolactinemia: 71.61% of hyperprolactinemia, of which prolactin adenomas account for 46%, microadenomas account for 66%, giant adenomas account for 34%, and a few are prolactin-growth Hormone adenomas and suspected cell tumors. Most pituitary adenomas have a PRL ≥ 200 ng/ml, and some pituitary adenomas can naturally resolve.

(2) Postpartum hyperprolactinemia: 30% of hyperprolactinemia occurs in pregnancy, childbirth, abortion, and 3 years after induction of labor. Plasma prolactin is slightly elevated, and patients with menstrual thinning, menstrual disorders, galactorrhea, and prognosis are better.

(3) special hyperprolactinemia: rare, mostly related to trauma, stress factors, and some are extremely small adenomas.

(4) iatrogenic hyperprolactinemia is caused by iatrogenic factors or drugs, mostly caused by other diseases (such as hypothyroidism), which can be naturally recovered after the cause is removed.

(5) Potential hyperprolactinemia (OHP), also known as occult hyperprolactinemia,

(1) Causes of the disease

2. Pathological hyperprolactinemia

(1) Hypothalamic-pituitary lesions:

1 hypothalamic non-functional tumors: including craniopharyngioma, invasive hypothalamic lesions sarcomatoid disease, histiocytosis, glioma and leukemia.

2 pituitary functional tumors: including pituitary adenomas (80% secretory prolactin), prolactinoma (prolactinoma), acromegaly (25% with hyperprolactinemia), Cushing syndrome (adrenal ACTH gland) Tumor, 10% with hyperprolactinemia, prolactin cell hyperplasia (80% with hyperprolactinemia).

5 trauma, stress and Parkinson's disease.

(3) ectopic prolactin secretion syndrome: including undifferentiated bronchogenic lung cancer, adrenal cancer and embryonal cancer.

(4) Polycystic ovary syndrome.

diagnosis:

For patients with galactorrhea and hypogonadism, the possibility of high PRL should be considered, and the diagnosis can be confirmed by measuring blood PRL. Normal male blood PRL generally does not exceed 0.68nmol / L (15ng / ml), and women generally range from 0.23 to 0.91nmol / L (5 ~ 20ng / ml). Since PRL is pulsed and is affected by many factors, it is best to repeat the assay. It is worth noting that a small number of people have normal PRL in the morning but elevated PRL at night. These patients need to measure the level of nighttime blood PRL and perform an excitation test. Commonly used excitation tests are the TRH test and the metoclopramide (gastric ampoules) test.

The TRH stimulation test was performed by intraperitoneal injection of TRH 400-500 ug, and PRL was measured at 0, 15, 30, 45, 60, 90, and 12 min. In normal people, PRL increased after injection of TRH, and the peak appeared at 15 to 30 minutes after injection, and the peak value was about 5 times of the base value (3 to 5 times for males and 5 to 8 times for females). The metoclopramide test dose is 10 mg and can be administered orally or intravenously or intramuscularly. The peak of PRL in oral administration occurred 60 to 120 minutes after taking the drug. The peak value of intravenous or intramuscular injection occurred 20 to 60 minutes after administration, and the peak value of normal people was more than 3 times of the baseline value. Patients with PRL tumors were slow to respond to TRH and metoclopramide. The fold of PRL after administration was less than that of normal people, but the absolute value of the increase was higher than that of normal people.

Identification

1. Prolactin normal galactorrhea Some women have galactorrhea but normal blood PRL levels, called prolactin normal lactorrhea (normoprolactinaemic lactorrhea). Prolactin normal galactorrhea is not uncommon. According to foreign data, 28% to 55% of female galactorrhea has normal blood PRL levels. Prolactin normal galactorrhea occurs in women of childbearing age, with less menstrual disorders (about 1/3). In some patients, galactorrhea is associated with normal pregnancy and breastfeeding. These women stop breastfeeding after normal breastfeeding and maintain it for a long time. Others are related to oral contraceptives, while others are unclear. At present, the mechanism of the production of galactorrhea with normal prolactin is still unclear. It has been suggested that there is a variant PRL in the patient, which has normal biological activity but cannot be measured by the usual radioimmunoassay, so the patient has galactorrhea but The level of blood PRL is normal; others believe that it may be caused by elevated levels of other prolactin-producing hormones (such as hGH) in the body. However, the above viewpoint has not been confirmed so far. At present, most scholars believe that the sensitivity of patients to PRL is increased. The reason for the increased sensitivity of the body to PRL is unclear and may be related to an increase in the level of PRL receptors. Johnston et al. believe that normal women have a physiological increase in PRL receptor levels during pregnancy and lactation. After stopping breastfeeding, blood PRL and breast PRL receptor levels return to normal, but a few patients stop PRL after breastfeeding due to certain defects. The receptor is still maintained at a high level, so the blood PRL level is normal but there is still galactorrhea (the formation mechanism of oral contraceptives is similar). Some people use small doses of bromocriptine (although blood PRL levels are normal), lowering blood PRL levels to normal lower limits, and improving galactorrhea symptoms.

Prolactin normal galactorrhea is characterized by normal secretion of PRL. Patients not only have normal basal PRL levels, but also normal hypoglycemia and TRH responses, which can be differentiated from galactorrhea caused by high PRL.

2. Identification of the cause of high PRLemia After the determination of the presence of high PRL, the cause should be further diagnosed. First, the medical history should be asked in detail to determine whether high PRL is caused by drugs. Second, liver and kidney function should be measured to determine whether high PRL is caused by cirrhosis or renal failure. Determination of TSH, T3, T4 is necessary, such as TSH, T3, T4 are significantly increased, may be high PRL caused by pituitary TSH tumor; such as increased TSH and decreased T3, T4, may be primary Hyperplasia caused by hypothyroidism. At the same time, blood GH, ACTH and cortisol levels should be measured to determine the presence of GH tumors and ACTH tumors, as they all cause high PRL. The determination of FSH/LH and alpha subunits contributes to the diagnosis of gonadotropinoma and non-functioning pituitary adenomas, which is also valuable in identifying the causes of high PRL.

Pituitary CT, MRI and blood PRL are important for the diagnosis of etiologies. In general, if CT and MRI have positive findings and blood PRL levels exceed 9.1 nmol/L (200 ng/ml), the diagnosis of PRL tumors can be established. The level of blood PRL is closely related to tumor size. The PRL level of large adenoma is more than 11.38nmol/L (250ng/ml), while the microadenomas are mostly below 9.1nmol/L (200ng/ml). If the blood PRL level is only mild to moderately elevated (less than 9.1 nmol/L) and CT and MRI show large adenomas, the tumor is often not a true PRL tumor and belongs to the so-called pseudo PRL tumor.

In recent years, the use of 11C-labeled dopamine D2 receptor antagonists methyl spiperone and rallopride for PET imaging is not only diagnostic, but also predicts the efficacy of dopamine agonists. In general, the responder responds well to dopamine receptor agonists.

complication:

High PRL can also cause significant osteoporosis, possibly due to a decrease in estrogen levels, but it is also believed that PRL itself has a negative impact on bone density. Some patients are accompanied by breast lobular hyperplasia or large breasts.

treatment:

Western medicine treatment

medical treatement:

1. Anti-prolactin anti-prolactin includesBromocriptineLong-acting bromocriptine, thioproperin,Cameron, ergosone, ergoline, quinalin (nogonine) and ergoacetone.

(1) Bromocriptine therapy: Bromocriptine is a semi-synthetic ergoline derivative, a dopamine receptor agonist. Ao Yinting promotes the production and secretion of PRI-IH in the hypothalamus by enhancing the function of dopamine receptors and inhibits PRI production in pituitary. Bromocriptine also directly inhibits pituitary tumor growth and inhibits pituitary PRI, GH, TSH and ACTH secretion.

Bromocriptine therapy is suitable for all types of hyperprolactinemia and is the drug of choice for the treatment of pituitary adenomas. The oral dose is 2.5 to 5.0 mg/d. 1 to 3 hours after oral administration of bromocriptine, the blood drug concentration reached a peak, and the prolactin secretion was inhibited for 14 hours. One oral administration of bromocriptine 2.5mg, about 90% of patients with prolactin decreased, and 1/3 of patients with prolactin dropped to normal. Vaginal medication can be used for those who cannot tolerate oral administration.

The purpose of bromocriptine treatment is to inhibit galactorrhea, restore menstruation, promote ovulation and pregnancy. The average treatment time for non-tumor hyperprolactinemia was 12 months, with neoplastic prolactinemia and an average treatment time of bromocriptine for 47 months. Univariate and multivariate analysis found that there was a correlation between treatment outcome and age, gender, starting dose of bromocriptine, length of treatment, tumor size, pregnancy during treatment, and previous radiation therapy.

After treatment with neoplastic prolactinemia, bromocriptine treatment, 80% to 90% of pituitary microadenomas shrink, 10% to 20% of permanent regression, more often in the first few weeks of treatment. After discontinuation of bromocriptine, the tumor recurrence rate was 35%. Although there is no evidence that bromocriptine has teratogenic effects and does not affect pregnancy outcomes, treatment should be discontinued once during pregnancy.

Bromocriptine treatment for 1 year, 11% of women with microadenomas, prolactin and menstrual function permanently returned to normal. After 2 years of treatment, the permanent regression rate of pituitary tumors was 22%. Although high-dose bromocriptine (10 mg/d) is superior to low-dose, the side-reaction rate is difficult to tolerate. Bromocriptine (5 ~ 12.5mg / d) can cause 50% pituitary giant adenoma shrinkage, of which 2 / 3 occurred within 6 weeks before treatment, and 1/3 decreased after 6 months of treatment. The ovulation rate, pregnancy rate, dose and efficacy of bromocriptine treatment are detailed in the anti-prolactin section.

(2) cabergoline: a long-acting, high-efficiency anti-prolactin preparation with good clinical efficacy and tolerance. Cabergoline has a high affinity with dopamine receptor D2, directly inhibits pituitary prolactin-secreting cells and reduces prolactin secretion. The therapeutic dose ranges from 0.25 to 1.0 mg per week. Start with a small dose of 0.25 mg twice a week, and after 4 weeks, change to 1 mg twice a week. 2 to 3 hours after taking the drug, the blood drug concentration reached a peak, and the plasma half-life was 65 hours. After treatment with cabergoline, 80% of patients had prolactin down to normal, ovulation rate was 72%, and galactorrhea cessation rate was 90%. Plasma prolactin levels returned to normal after 6 months and gradually discontinued. Clinical observations show that cabergoline is superior to bromocriptine in efficacy and tolerability, and is the first-generation, safe and effective drug for the treatment of hyperprolactinemia.

Cabergoline significantly shrinks pituitary tumors or even completely disappears, and can be used to treat giant adenomas of pituitary gland that are resistant to bromocriptine. Clinical data show that although cabergoline has no adverse effects on pregnancy, once ovulation is resumed during treatment, treatment should be stopped one month before pregnancy.

(3) Quinula sinensis (Nuoguoning): a non-ergoline dopaminergic agonist, a new generation of specific, highly effective, long-acting anti-PRL drugs. The plasma half-life is 22 h. CV205-502 acts as a potent dopamine receptor (D1, D2) agonist, inhibiting PRL by enhancing dopamine receptor function at the level of hypothalamic-pituitary axis PRL cells. It is strong, long-lasting, well tolerated, and mild in side effects. Headache, dizziness, nausea, vomiting, etc. can occur at high doses. No adverse effects on heart, lung, liver, kidney, and blood function. The patient was well tolerated to the Quinna horn forest, and the probability of discontinuation due to adverse reactions was 7%, which was superior to bromocriptine.

Quinna sylvestre is used for the treatment of bromocriptine intolerance, treatment ineffective and relapse, the dose range is 0.04 ~ 0.1mg / d, the treatment effect is dose-related, such as oral 0.04mg / d, PRL decreased > 50%, For 8 hours; oral 0.06mg / d, PRL decreased by 66%, continued for 24h, 36h still decreased by 47%, sleep PRL peak disappeared. Quinna sinensis inhibits TSH synthesis and release, but does not affect FSH, LH, T. And adrenal axis function. Quinna horn increased the release of GH-RH and inhibited the release of GH-IH. Plasma GH was temporarily elevated after administration, but GH was still normal at night.

The treatment of quinalin should start from a small dose, 0.025 mg per day for the first 3 days, 0.050 mg/d for the next 3 days, and later changed to 0.075 mg/d, and then adjust the dose according to the treatment response, reaching 0.1 mg/d at 3 months. In most patients, prolactin began to decrease after 1 month of treatment, and the patient was well tolerated.

After treatment with quinalin, the volume of giant adenoma of the pituitary was reduced by 324 mm3 (46%), the adenoma was reduced by 73 mm3 (57%), and the plasma prolactin of giant adenoma was reduced by 163 μg/L (65%). Reduced by 113 μg/L (73%). In 27 medical centers in France, 107 cases were found to have obvious clinical effects after 2 years of treatment. Schultz (2000) treatment observation (50 cases, dose 100μg / d, average treatment 31.6 months), prolactin recovery normal rate, non-neoplastic hyperprolactinemia was 82%, micro adenoma was 73%, giant gland The tumor was 67%. The tumor volume reduction rate was 55% for microadenomas and 75% for giant adenomas, and vision improved or returned to normal. The pregnancy rate is 26%. Nobels (2000) found that high doses of quinalin did not effectively inhibit the growth of pituitary non-functional tumors, which may be related to the presence of dopamine receptors in tumors.

Di Sarno (2000) first applied quinalin (0.075 ~ 0.6mg / d, 12 months), followed by cabergoline (0.5 ~ 1.5mg / time, twice a week, 12 months). Prolactin returned to normal rate, 100% for microadenomas and 87.5% for giant adenomas. The tumor volume reduction rate was 80% or more, the microadenomas were 21.7%, and the giant adenomas were 25%. All patients developed hyperprolactinemia 15 to 60 days after discontinuation of quinalin. Both drugs are well tolerated. Some patients in the first week of quinalin treatment may have nausea and orthostatic hypotension, but the symptoms disappear naturally in the third week of treatment.

(4) thioproperin: a new generation of safe, inexpensive, well-tolerated antiprolactin drugs, is the drug of choice for the treatment of giant adenomas of the pituitary, the dose is 0.05 ~ 0.5mg / d. 12 months (3 to 36 months), PRL decreased by 88%, pituitary tumors decreased by 25%, 86%, reduced by more than 50%, 77%, and reduced by more than 75%, 45%, most patients returned to normal vision (Orrego, 2000).

2. Ovulation induction therapy is suitable for hyperprolactinemia, anovulatory infertility, simple bromocriptine treatment can not successfully ovulate and pregnancy. That is to use bromocriptine-based, combined with other ovulation-promoting drugs:

(1) Bromocriptine-CC-hCG.

(2) Bromocriptine-hMG-hCG.

(3) GnRH. Pulse therapy - bromocriptine and the like. Comprehensive therapy can save anti-prolactin drugs, shorten treatment cycles and increase ovulation rate and pregnancy rate.

Surgical treatment: suitable for the symptoms of intracranial compression of giant adenoma, bromocriptine treatment, giant adenoma, suspected cell tumor, a variety of pituitary hormone secretion. The current transsphenoidal microsurgery is safe, convenient, and easy to perform, and its efficacy is similar to bromocriptine therapy. The use of bromocriptine before and after surgery can improve the efficacy. The shortcoming of surgery is that the pituitary tumor has no obvious capsule, the boundary is unclear, the operation is not easy to be thorough or damaged, causing cerebrospinal fluid nasal cavity and postoperative pituitary dysfunction. It is worth noting that the preoperative application of bromocriptine can reduce the tumor, but it can cause tumor fibrosis, sclerotherapy and adhesion of surrounding tissues, which is not conducive to surgical separation and resection. Therefore, if surgery is performed, no drugs can be used before surgery. Then add medication or radiation therapy.

Microsurgical resection of pituitary prolactin adenoma mortality was less than 0.5%, postoperative temporary diabetes was 10% to 40%, permanent diabetes and iatrogenic hypothyroidism was less than 2%. Prolactin and ovulation return to normal after microadenomas are 65% to 85%, macroadenomas are 20% to 40%, and visual field recovery is 85%.

Chemotherapy (radiotherapy): for non-functional tumors in the hypothalamic-pituitary system, as well as ineffective drugs and surgical treatment. At present, advanced stereotactic radiotherapy methods are used: deep X-ray, γ, 60Co, alpha particle and proton beam, nuclide 90Y, 198Au pituitary implantation.

The above content is for reference only, please consult the relevant physician or relevant medical institution if necessary.

prevention:

Treatment of primary diseases (pituitary tumors, hypothyroidism, and Cushing's syndrome); avoiding bad mental stimulation as much as possible; reducing or avoiding the use of elevated prolactin drugs.

Introduction to hyperprolactinemia

Published by on January 29, 2019January 29, 2019