amenorrhea galactorrhea syndrome
Introduction
Introduction to amenorrhea and edema syndrome Non-pregnant and lactating women, or women who have stopped breast-feeding for 1 year, have persistent galactorrhea with amenorrhea, called amenorrheagalactorrheasyndrome, including different etiology and pathology. It should be noted that amenorrhea-galactorrhea syndrome is often a symptom of pituitary prolactinoma, and this symptom can be seen 10 years before the tumor is confirmed on the radiograph. Amenorrhea - galactorrhea syndrome with hyperprolactinemia was 79% to 97%. basic knowledge The proportion of sickness: 0.01% Susceptible population: non-pregnant and lactating women Mode of infection: non-infectious Complications: Obesity Osteoporosis
Cause
Causes of amenorrhea and galactorrhea syndrome
Physiological factors (30%):
During the sleep, plasma prolactin is elevated, and the increase of PRL secretion begins after sleep and continues throughout the sleep process. The secretion of PRL increases during pregnancy, which is more than 10 times higher than that of non-pregnant period. Sucking can temporarily increase the secretion of PRL. However, after 3 months of breastfeeding, the rate of increase gradually declines. In the long-term lactation, the normal range of prolactin levels can cause milk secretion; physical activity, stress, mental stimulation and stimulation of the nipple, menstrual luteal phase can increase prolactin Secretion.
Pathological factors (20%):
(1) Forbes-Albright syndrome: caused by a hypothalamic-pituitary system tumor, it is reported that this type of high PRL blood accounts for 71.6% of all patients with hyperprolactinemia, including lactation The tumor accounts for 33% to 76.9% of amenorrhea-galactorrhea syndrome, most of which are microadenomas (diameter <1cm, 66%), and a few are giant adenomas, accounting for 30%. Tumor cells are not inhibited by hypothalamic PIF. Sexual secretion of large prolactin, growth hormone (GH) tumor, GH/PRL mixed tumor, ACIH tumor and chromoblastoma can also cause hyperprolactinemia, tumor enlargement and compression of pituitary stalk, pituitary LH and FSH secreting cells Or when the PIF and GnRH transport in the hypothalamus is blocked, the prolactin is elevated with abnormal secretion of LH and FSH, amenorrhea-galactorrhea syndrome, gastrointestinal carcinoid or gastrinoma occasionally combined with hyperglycemia and high PRL Blood, patients with amenorrhea - galactorrhea, pituitary can be enlarged, imaging findings of pituitary tumors, pituitary tumors also disappear after removal of gastrointestinal carcinoids, the cause is unknown, pituitary gonadotropin (LH / FSH) secretion Tumors are rare, the average age of onset of male patients is over 50 years old, and blood FSH is elevated; The patient's blood FSH / LH also increased, but due to menopause and other reasons, it is often difficult to think of the disease, the determination of serum -subunit levels can help early diagnosis, high-resolution MRI can be clearly diagnosed, when the postmenopausal women have galactorrhea (menopausal), when the blood PRL is elevated, it is necessary to think about the pituitary gonadotropin-secreting tumor. For example, the patient's response to dopaminergic agonist treatment is poor, the curative effect is not obvious, the pituitary tumor is not reduced, the symptoms are not improved, or Although the blood PRL decreased during the treatment, but cortisol and ACTH increased, it should be thought that pituitary prolactinoma may be derived into ACTH tumor. Very few patients with PRL tumor may develop Cushing syndrome (not PRL/ACTH mixed tumor, tumor cell PRL immunohistochemical staining is negative and ACTH staining is positive), this phenomenon can occur when the pituitary stalk is compressed or due to the secretion of hypothalamic regulatory factors (such as galanin), except for PRL tumors and GH tumors, LH/FSH tumors, TSH Tumors, alpha-subunit tumors coexist, can also be combined with central diabetes insipidus.
In addition, vacuolar sella syndrome, hypothalamus and its adjacent tumors, compression of the pituitary gland reduces PIF and leads to elevated prolactin, craniocerebral trauma, pituitary accidental tumor, craniopharyngioma, pituitary cyst, meningioma, third Ventricular hematoma, arachnoid cyst, Rathke cyst, multiple radiculitis neuritis, multiple endocrine neoplasia syndrome (MEN) may also be associated with intrinsic.
(2) Postpartum hyperprolactinemia (Chiafi-Frommel syndrome): accounting for about 30% of all hyperprolactinemia, secondary to pregnancy, childbirth, miscarriage or induction of labor, once prolactin is elevated Decline, the PRL of this disease is only mildly elevated, the symptoms are mild, and the prognosis is good.
(3) idiopathic hyperprolactinemia (Ahumada-Argonzdel Castillo syndrome): rare, unexplained, mostly traumatic, caused by stress factors, partly caused by very small adenoma or macromolecular hyperprolactin of.
(4) Other diseases: hypothyroidism and high PRL may be caused by TRH-stimulated PRL release. In addition, Addison disease, chronic renal failure can also cause PRL secretion, and certain tumors (such as bronchial lung cancer, adrenal cancer, embryonic cancer) ) can also secrete ectopic PRL.
Primary hypothyroidism with amenorrhea-galactorrhea syndrome is mostly manifested by hypothyroidism itself, but it may also be associated with pituitary PRL tumors. After thyroid hormone replacement therapy, high PRL and even pituitary PRL tumors can disappear. The incidence of postpartum thyroiditis (prevalence rate of about 5.5%) has a certain genetic background, and is also related to environmental factors such as high iodine intake. The thyroid tissue sees plasma cells/lymphocyte infiltration, early with hyperthyroidism, and hypothyroidism occurs several months later. Performance, and may be accompanied by menstrual disorders, amenorrhea - galactorrhea and goiter, amenorrhea - galactorrhea symptoms are mild, most of them with the recovery of hypothyroidism and relieve themselves.
(5) iatrogenic hyperprolactinemia: some drugs can inhibit the synthesis of dopamine in the hypothalamus for a long time or affect its effect and cause prolactin secretion, which can be naturally recovered after stopping the drug.
Antipsychotic drugs, especially diazepam, can inhibit the release of central dopamine neurotransmitters, cause high PRL and amenorrhea-galactorrhea syndrome, long-term use and even lead to PRL tumors, generally advocate the addition of dopamine agonists, but bromocriptine It can also antagonize the action of diazepam, making the patient's psychiatric symptoms difficult to control. Melkersson et al. advocate the use of tranquilizers (such as clozapine, Clozapine) plus quinarbarbitone, which is beneficial to mental symptoms. Control, and prevent the rise of PRL.
Reflective factor (20%):
Stimulating nipples, chest surgery or chest lesions can stimulate prolactin secretion through nerve reflexes. Prolactin is mild to moderately elevated, often accompanied by galactorrhea, but not necessarily with amenorrhea. After removal of the cause, blood prolactin returns to normal.
In a recent case-control study, continuous use of contraceptives did not show pituitary tumor growth, and prospective studies showed that hormone replacement therapy had no adverse effects on hyperprolactinemia due to pituitary microadenomas.
Pathogenesis
1. Inhibition of hypothalamic-pituitary function: Hyperprolactinemia inhibits the secretion of dopamine (DA) in the hypothalamus, inhibits the synthesis and release of GnRH, and causes the positive feedback response of E2 and the LH-induced ovulation peak to disappear.
2. Inhibition of ovarian function: reduce the number of FSH, LH, PRL receptors in sinusoid follicles, accelerate follicular atresia, inhibit FSH-mediated aromatase activity of granulosa cells, reduce estrogen secretion, and cause luteal insufficiency, such as PRL100g /ml, progesterone synthesis completely stopped, Yoshimura et al found in rabbit in vitro granulosa cell culture, after adding PRL to the culture medium, follicular development was blocked, ovarian steroid hormone and progesterone synthesis stopped, follicle plasminogen The activity decreased, so that the follicular epithelial cells and follicular wall could not be decomposed. Even if the follicles matured and ovulated, the cleavage and fertilization ability of the eggs were significantly reduced, indicating that high levels of PRL can directly inhibit follicular maturation and ovulation, and reduce The quality of the egg.
3. The role of the mammary gland: prolactin affects the milk secretion of the mammary gland through its corresponding receptor action on the breast tissue, promotes the formation of lactoprotein and lactoprotein, and high prolactin can cause hyperplasia of the breast lobes, large breasts and galactorrhea, The galactorrhea can be autonomous (dominant) or occult (appearing when squeezing the breast), which can be serous, fatty or milky. In recent years, people have noticed that PRL plays an important role in the development of breast cancer. Some people think that it is high. Prolactinemia is a reliable indicator of poor prognosis in breast cancer.
Prevention
Amenorrhea syndrome
Non-pregnant and lactating women, or women who have had lactation for 1 year, have persistent galactorrhea with amenorrhea. Treatment of primary diseases (pituitary tumors, hypothyroidism, and Cushing's syndrome), to avoid adverse mental stimulation, reduce or avoid the use of elevated prolactin drugs. For patients with pituitary microadenomas, MRI should be actively treated. The cause of this disease is not clear, so early detection, early diagnosis, early treatment for complications prevention.
Complication
Complications of amenorrhea and diarrhea syndrome Complications obesity osteoporosis
Patients with hyperprolactinemia who are untreated often have obesity and are associated with insulin resistance and osteoporosis. Osteoporosis is mainly associated with estrogen deficiency and elevated PRL itself.
Symptom
Symptoms of amenorrhea and edema syndrome common symptoms galactorrhea
Mainly manifested as amenorrhea, galactorrhea, increased blood prolactin and infertility, most of which are secondary amenorrhea (89%), but there are also reports of primary amenorrhea (4%) and delayed puberty with hyperprolactinemia. There are many menstrual periods before amenorrhea, 2/3 patients have galactorrhea, bilateral or unilateral, breasts are normal or with lobular hyperplasia, usually amenorrhea occurs first, and galactorrhea is often found by doctors, there are also galactorrhea Later, menstrual disorders and even amenorrhea, high prolactinemia, ovarian corpus luteum function, sparse ovulation or no ovulation causes infertility, mildly elevated prolactin, may be ovulatory menstruation, but the luteal phase shortened, sometimes There may be progesterone withdrawal bleeding, some women with hyperprolactinemia do not appear galactorrhea, may be related to the lack of estrogen at the same time, there are a few galactorrhea women with normal prolactin levels, high prolactinemia with ovulatory menstrual cycle can be Secretion of macromolecular prolactin (macroprolactin).
Long-term amenorrhea may have estrogen deficiency, such as flushing, palpitations, sweating, vaginal dryness, painful intercourse, loss of libido, headache, acromegaly, decreased vision, reduced visual field and hypothyroidism, mostly PRL tumors or Due to hypothalamic pituitary lesions, most of the prolactinomas grow slowly, rarely a large adenoma, and the clinical symptoms and imaging of some patients can be spontaneously improved, or even self-resolved.
Patients with hyperprolactinemia who are untreated often have obesity and are associated with insulin resistance and osteoporosis. Osteoporosis is mainly associated with estrogen deficiency and elevated PRL itself.
Fiedeleff et al. carefully observed the evolution of a group of pubertal PRL tumors (40 cases, 29 women, ll cases). The age of onset of female patients was 8-16 years old, and most of them were small PRL tumors. The performance is mainly caused by menstrual disorders, galactorrhea, etc. The age of onset of men is 8 to 17 years old, and most of them are large PRL adenomas. The clinical manifestations are characterized by local symptoms caused by the tumor itself. Therefore, the PRL tumors of prepubertal women The performance of patients with growth is not the same, drug treatment can make the gonadotropin secretion of most patients normal.
Kleinberg et al analyzed the clinical data of 235 patients (5.5% male) with galactorrhea. 34% of women with amenorrhea had pituitary tumors, and their serum PRL was also high. About 1/3 of patients had only galactorrhea without amenorrhea. Among them, 86% of blood PRL is normal, 5 cases are associated with vacuolar sella syndrome, and some people still have galactorrhea and/or amenorrhea after drug, surgery or even radiation therapy, bromocriptine or ergotrile mesylate It can stop the galactorrhea in half of the cases and restore 70% of patients to menstruation.
1. History: focus on understanding the causes of amenorrhea, galactorrhea, systemic diseases and history of drugs related to hyperproliferemia, such as whether the patient's bra is suitable, whether there is nipple itching, frequent friction and other irritations, whether there is cold resistance, lethargy, edema, etc. The history of hypothyroidism and headache, visual acuity and other symptoms associated with hypothalamic-pituitary lesions. For drugs that may cause hyperprolactinemia, such as contraceptives, antihistamines, and dopamine antagonists, the usage and dosage should be well understood. The relationship with the intrinsic.
2. Physical examination: Any person with amenorrhea, whether with or without galactorrhea, should check whether there is galactorrhea in both breasts (the breasts are squeezed gently with both hands). If there is lactation, the diagnosis of amenorrhea-galactorrhea syndrome can be diagnosed. , with or without lumps, nipples with or without wrinkles, traits and amount of spillage, etc., while paying attention to systemic examination, with or without acromegaly, mucinous edema and other signs related to the thyroid and hypothalamus, pituitary, pay attention to check vision, Vision, gynaecological examination needs to understand the signs related to sexual organs and secondary sexual characteristics.
3. Ophthalmic examination: including vision, visual field, intraocular pressure, fundus examination to determine the presence or absence of intracranial tumor compression signs.
Examine
Examination of amenorrhea and galactorrhea syndrome
1. Pituitary function:
(1) PRL: The blood PRL of women in normal growth period is <20g/L. It is suggested that PRL2030g/L should be examined by imaging. The incidence of PRL50100g/L prolactinoma is 20%; >100g/L lactation The incidence of tumors is 50%: the incidence of PRL100300g is higher; PRL>300g/L, if no pregnancy is almost all caused by pituitary tumors, the larger the tumor, the higher the PRL, such as diameter 5mm, PRL is 171±38g /L; 5 ~ 10mm, PRL is 206 ± 29g / L; 10mm, PRL is 485 ± 158g / L, PRL may not increase when hemorrhagic necrosis of giant adenoma.
Drug-induced, blood PRL is generally within 80g / L, after 36h of withdrawal can be reduced to normal, estrogen-induced, PRL can be significantly reduced after a few months of withdrawal, Imai et al concluded Chiari-Frommel syndrome (3 cases), Argonzdel Castillo syndrome (5 cases), clinical characteristics of drug-induced amenorrhea-galactorrhea syndrome (12 cases): 1 The proportion of patients with normal blood-PRL amenorrhea and galactorrhea syndrome is quite high, of which Chiari-Frommel syndrome accounts for 66.7%, Argonz-del Castillo syndrome accounted for 40%, drug-oriented accounted for 33.3%; 2 many amenorrhea-galactorrhea syndrome blood PRL, normal, no responsiveness to TRH stimulation, its mechanism is unknown; 3 menstruation The main cause of disturbance and amenorrhea is not caused by decreased secretion or abnormal secretion of LH/FSH.
Due to the large fluctuation of PRL secretion, multiple blood tests should be taken. Currently, the PRL radiotherapy kit used in clinical practice only measures small molecule PRL (2500), but cannot measure macromolecules and macromolecules (50,000 to 100,000) PRL. Patients with obvious clinical symptoms and normal PRL cannot rule out the so-called occult hyperprolactinemia, ie, macromolecules and macromolecular RL antibodies, or HPLC analysis and quantification of different components of PRL.
(2) FSH, LH is often lowered, and the ratio of LH/FSH is increased.
(3) GH, TSH, ACTH are determined according to the condition.
2. Ovarian function test: blood E2, progesterone reduction, determination of E2 can accurately determine the patient's estrogen secretion status, progesterone determination only for patients with amenorrhea, but not for amenorrhea - galactorrhea, for high prolactin Testosterone can be elevated in patients with blood and hairy.
3. Thyroid function test: When combined with hypothyroidism, T3, T4 decreased, and TSH increased.
4. Prolactin dynamic test:
(1) TRH stimulation test: In addition to stimulating the release of TSH from the pituitary, TRH also stimulates the secretion of PRL. In normal women, one intravenous injection of TRH is 100-400 g, 15 to 30 minutes PRL is 5 to 10 times higher than that before injection, and TSH is increased by 2 Times, pituitary tumors do not rise, or PRL levels are less than 1.5 times higher than the base value, which is helpful for the diagnosis of prolactinoma. All drugs that interfere with PRL secretion should be stopped before the test. Drinking and smoking The results had no significant effect, but licorice or licorice preparations (most of the traditional Chinese medicine prescriptions contained licorice) inhibited the basal secretion of PRL and the maximum secretion after TRH stimulation.
(2) Chlorpromazine test: Chlorpromazine inhibits norepinephrine absorption, transformation and dopamine function through receptors, thereby promoting PRL secretion. After taking blood in the basal state, taking chlorpromazine 25~ 50mg, 60min and 120min after taking the blood were taken to measure PRL. After normal women were excited by chlorpromazine, the peak value of PRL increased by 2-5 times compared with the baseline value, and the pituitary tumor did not increase.
(3) Metoclopramide test (Metoclopramide test): This drug is a dopamine receptor antagonist, which can promote the synthesis and release of PRL, and is injected with metoclopramide after fasting blood sampling. 10 mg of chlorpyrifos was taken at 20, 30 and 60 min after injection, and PRL was taken after normal injection of metoclopramide (gastric ampoules). The peak of PRL appeared at 20-30 min, and the peak value of PRL increased compared with the baseline value. 7 to 16 times, and functional galactorrhea, PRL increased to 2 to 3 times the baseline value, prolactinoma is not significantly elevated, PRL peak should be at least 3 times the baseline value, can be considered normal, lower than above Standards, suggesting that there may be prolactinoma.
(4) Verapamil excitatory test: Verapamil is a calcium channel blocker. After intravenous verapamil (isopidine), it can not stimulate normal human secretion of PRL but idiopathic high PRL. The serum PRL of the patients with blood increased significantly, while the patients with pituitary PRL tumors did not respond. Barbaro et al. considered that there was no overlap between the two groups of patients, which is a good test for identifying idiopathic hyper-PRL and PRL tumors, but for the basic PRL. Already higher, the net increase in PRL may not be apparent, and the verapamil (expiratory) test does not distinguish pseudo-PRL tumors (ie, dopaminergic impulses are attenuated).
(5) Prolactin inhibition test: levodopa is a dopamine precursor, which produces DA by decarboxylase and inhibits PRL secretion. After normal oral administration of 500mg, 2~3hPRL is significantly decreased, pituitary tumors are not reduced, and bromocriptine is dopamine. Receptor agonists can strongly inhibit the synthesis and release of PRL. In normal women, after 2.5-5.0 mg orally, 2 to 4 h PRL decreased by 50% for 20-30 h, and the function of hyperprolactinemia and PRL adenoma decreased significantly. The decrease in GH and ACTH is lower than that of the former.
5. Sella X-ray tomography: It is of great value in the diagnosis of pituitary tumors, but micro adenomas can not be found. Normal women have a anteroposterior diameter of <17mm, a deep diameter of <13mm, an area of <130mm2, and a volume of <1100mm3. CT examination: 1 balloon-like ballooning; 2 double saddle bottom or double floor; 3 saddles in high/low density areas or density inhomogeneity; 4 plate-like deformation; 5 saddle-up ossification ( Hyperostosis); 6 anterior and posterior bed osteoporosis or saddle vacuolization; 7 bone destruction (erosion).
6. CT and MRI: Accurate localization and radiometric determination of intracranial lesions.
7. Contrast examination: including cavernous sinus angiography, gas cerebral angiography, cerebral angiography and sub-sinus sampling and angiography.
Diagnosis
Diagnosis and differential diagnosis of amenorrhea and galactorrhea
Diagnostic criteria
According to the medical history, physical examination and laboratory examination, it is generally diagnosed that amenorrhea-galactorrhea syndrome, and identify and distinguish the causes of amenorrhea-galactorrhea syndrome to guide treatment.
1. First ask about the history of medication, because chlorpromazine, methyldopa, piperazine, perphenazine, haloperidol (fluoperidol), blood and blood can cause prolactin increase, after stopping the majority Symptoms gradually disappear, except for breast and chest wall disorders (such as surgery, trauma, herpes zoster, etc.), as well as nipple irritation, long-term sucking and so on.
2. If the disease occurs after childbirth, it may be "chiari-Frommel syndrome".
3. X-ray saddle examination indicates that there are pituitary tumors, belonging to Forbes-Albright syndrome.
4. Primary hypothyroidism, accompanied by systemic symptoms, determination of hypothyroidism, effective treatment with thyroid hormone.
5. Empty Sella Syndrome, through gas cerebral angiography, can be found that gas freely enters the saddle, sometimes visible liquid level.
Patients with primary hypothyroidism may have only galactorrhea-menopausal syndrome, and the PRL concentration in the blood does not increase.
