What Is Considered an Abnormal Prolactin Level?

Prolactin is a peptide hormone, also called prolactin (PRL), which is one of the hormones secreted by the pituitary gland. Prolactin secretion is strong in women during late pregnancy and lactation to promote breast development and lactation. Non-pregnant women's serum prolactin levels generally do not exceed 20 ng / ml ^[1] .

Prolactin is secreted by specialized cells concentrated on the two sides of the pituitary gland, and is derived from the same cell as growth hormone. Prolactin is elevated, which is medically called hyperprolactinemia. This is a hypothalamic-pituitary-gonadal axis dysfunction disease. Its main symptoms are a marked decrease in menstrual flow, thin menstruation and even amenorrhea, infertility, and galactorrhea. , Menopausal symptoms, etc. ^[1] .

Excessive prolactin will also cause the ovaries to lose their responsiveness to gonadotropins. As a result, the synthesis of estrogen and progesterone will be significantly reduced, which will cause the low level of estrogen that plays an important role in conception, which will directly affect the fertility function. When the large amount of sex hormones is reduced to a certain extent, patients will also have many symptoms similar to women's menopause ^[2] .

Chinese name: Prolactin
Foreign name: PRL
nickname: Prolactin

Classification: Peptide hormone
Secretory organ: Pituitary
Physiological effect: Promote breast development and lactation

Prolactin structure information

Prolactin was first found in the anterior lobe of the pituitary gland in 1928, human prolactin was isolated from the human pituitary gland in 1970, and Friesen used radioimmunoassay to detect prolactin in human blood ^[1] .

Prolactin is a protein hormone secreted by prolactin cells located on the posterior side of the pituitary gland. It is a single-chain protein with three disulfide bonds consisting of 199 amino acid residues. -helix structure. Prolactin can also be produced in multiple organs of the human body. Different types of prolactin-producing cells all express prolactin receptors. Prolactin receptors are expressed in many tissues, among which the liver, breast, adrenal, and hypothalamus are the most expressed. Receptor expression is affected by prolactin and steroid hormones in circulating blood. Human prolactin cDNA consists of 914 nucleotides, including an open reading frame of 681 nucleotides, encoding a 227 amino acid prolactin hormone. After removing a single peptide containing 28 amino acids, It becomes human mature prolactin ^[1] .

Prolactin has four different molecular structures in circulating blood: small molecule prolactin, glycosylated prolactin, large molecule prolactin and large molecule prolactin. The relative molecular mass of small molecule prolactin is 23,000, which accounts for 80% to 90% of human blood circulation, with the highest biological and immune activity. The macromolecular prolactin is a multimeric type with a relative molecular mass of 105 and the lowest biological immune activity, accounting for 1% to 5% of prolactin in circulating blood ^[1] .

Prolactin regulation mechanism

Prolactin secretion is pulsed and circadian. Under normal circumstances, when the human body is asleep, PRL secretion from the pituitary cells begins to increase, reaching a peak 1 to 2 hours before waking up, and PRL decreases quickly 1 hour after waking up. During the day, human prolactin content is highest from 5 to 7 in the morning and lowest from 9 to 11 am.

Prolactin secretion is mainly regulated by neuroendocrine. Prolactin secreted by the pituitary prolactin cells is regulated by the balance between the suppression of hypothalamic afferent and stimulus signals and the regulation of peripheral blood hormones. It is regulated by prolactin release inhibitors (PIFs) and prolactin release factors (PRFs) . Hypothalamic prolactin release inhibitors include dopamine, gonadotropin-combined peptide, and melanocyte stimulating hormone. As the major inhibitor of prolactin, dopamine exerts a variety of inhibitory effects by binding to the cell surface type 2 dopamine receptors, including reducing intracellular calcium and cAMP levels, inhibiting the expression of prolactin genes, and releasing the proliferation of prolactin cells. . Prolactin releasing factors (PRFs) include thyroid-stimulating hormone-releasing hormone (TRH), gonadotropin-releasing hormone, angiotensin II, and vasoactive peptides. Thyrotropin-releasing hormone acts on the pituitary prolactin-releasing hormone receptors and stimulates the expression of prolactin mRNA, thereby promoting the synthesis and secretion of prolactin. Prolactin can also affect the dopamine system through negative feedback regulation ^[1] .

In addition, several neuropeptides, thyrotropin-releasing hormone, and vasoactive intestinal peptide can strongly stimulate the release of prolactin in some cases. Several growth factors, such as estrogen, can provide long-lasting regulation. Among the growth factors, Insulin and epithelial growth factor can promote its release, while transforming growth factor can inhibit its growth. In addition, strenuous exercise, trauma, surgery, sexual intercourse, and high dietary protein can all promote the secretion of pituitary prolactin. Human mood changes, including depression or irritability, panic, stress, etc., can directly cause increased secretion of prolactin ^[1] .

Prolactin physiological function

Prolactin has more than 300 different biological functions, and it has two forms of action: circulating hormones and cytokines. Prolactin's function is triggered by binding to specific high-affinity receptors located in the plasma membrane and some tissues. Prolactin is combined with its receptor to form a trimer that causes prolactin to be activated. After prolactin receptor activation, it passes through two signaling molecule families, namely tyrosine kinase 2 (JAK2) and signaling and transcription activation factor family (STAT). The signal transduction function of the cell transmits information to the nucleus, causing the transcription and expression of target genes (such as interferon regulatory factor 1), thereby exerting its functions such as lactation, gonadal development, and regulation of immunity ^[1] .

Effects of Prolactin on the Mammary Gland

Prolactin has a physiological activity that promotes milk production from the breast. Under normal circumstances, lactating women secrete a large amount of prolactin, which promotes breast milk production. Shiu et al. First discovered prolactin receptors in breast tissue. In mammals, prolactin can act as a cytokine through autocrine and paracrine to regulate breast development, promote milk production, initiate and maintain lactation. During pregnancy, due to the high concentrations of estrogen and progesterone in the blood, it competes with prolactin for breast cell receptors and inhibits the lactation of prolactin. After childbirth, the concentration of estrogen and progesterone in blood decreases, and prolactin plays a role in initiating and maintaining lactation. However, if various factors lead to a pathological increase in the prolactin value in human serum, abnormal lactation will occur, which is clinically referred to as galactorrhea ^[1] .

Effects of prolactin on the endocrine system

Prolactin plays an important role in the human endocrine system, mainly affecting the function of the gonads. Low doses of prolactin promote the synthesis of ovarian estrogen and progesterone in women, and normal levels of prolactin are necessary to maintain luteal function. For men, in the presence of testosterone, prolactin can promote the growth of the prostate and seminal vesicles. It can also enhance the effect of luteinizing hormone on interstitial cells and increase testosterone synthesis. However, large amounts of prolactin are inhibited. Generally, in non-lactating women, high prolactin levels can interfere with gonad function. If the prolactin level is too high, the hypothalamus level will weaken the pulsatile secretion of luteinizing hormone, inhibit the positive feedback effect of estrogen on the hypothalamus, thereby hindering the occurrence of luteinizing hormone peak before ovulation and affecting ovulation; It can inhibit the synthesis of progesterone by granulocytes, reduce the secretion of progesterone, and cause symptoms such as sexual dysfunction, galactorrhea, amenorrhea and infertility ^[1] .

Effects of prolactin on the immune system

Studies have found that prolactin is an important neuroendocrine factor with immunoregulatory effects and has regulatory effects on cellular and humoral immunity. Prolactin can act as a mitogen to promote the proliferation of immune cells, protect lymphocytes by antagonizing the induction of apoptosis of glucocorticoids, and kill macrophages to kill pathogenic microorganisms. It can also include IgG and IgM The formation of antibodies promotes cellular and humoral immunity. Lymphocytes are capable of synthesizing and secreting prolactin, and by combining with prolactin receptors distributed on the lymphocyte membrane, they activate transmembrane signal transduction pathways, regulate the transcription of nuclear genes, and achieve regulation of immunity. Prolactin can also cooperate with other cytokines or hormones to promote helper T cell proliferation, cytotoxic activity of natural killer cells, activate B cell proliferation, and produce antibodies. These effects of prolactin are achieved through the expression of prolactin receptors on immune cells, and prolactin receptors are widely expressed on immune cell membranes such as T cells, B cells, and natural killer cells. In addition, prolactin is the same as adrenocorticotropic hormone and growth hormone. When the human body is in a stress state, the content of blood will increase. It can be seen that prolactin will participate in the human body's stress response ^[1] .

Prolactin content range

The normal reference range for prolactin is as follows:

Male <20 g / L; female follicular phase <23 g / L; luteal phase 5.0 ~ 40.0 g / L; 3 months before pregnancy <80 g / L; 3 months during pregnancy <160 g / L; 3 at the end of pregnancy Months <400 g / L (dual antibody radioimmunoassay) ^[3] .

WHO reports the PRL reference intervals as follows:

Females under 11 years of age (527.00 ± 15.89) mU / L; males (404.00 ± 15.28) mU / L. Adolescent females (436.00 ± 3.76) mU / L; males (392.00 ± 29.91) mU / L: adult female vesicular period (366.80 ± 48.9) mU / L; ovulation period (687.00 ± 269.60) mU / L; luteal phase 449.00 ± 69.80 mU / L ^[3] .

Prolactin influencing factors

1. Nerve stimulation: Some areas, especially the skin of the chest, are stimulated, including severe pain caused by peripheral nerve damage, which can be transmitted to the hypothalamus through the nerves and cause prolactin to increase. Such as chest surgery, burns, shingles on the chest and back, etc. ^[4] .

2, pituitary disorders: mainly various tumors of the pituitary area. In addition, some vacuolar saddle syndromes and hyperpituitarism can also cause galactorrhea and amenorrhea ^[4] .

3. Drug factors: Sedatives acting on the central nervous system, such as chlorpromazine and morphine, can reduce the content of catecholamines in the hypothalamus, thereby reducing the activity of prolactin-releasing factors produced by the hypothalamus. Antihypertensive drugs methyldopa and reserpine can inhibit the release of prolactin inhibitors. Metronidazole can stimulate the excessive secretion of pituitary prolactin ^[4] .

4. Primary hypothyroidism: When hypothyroidism occurs, the information of insufficient thyroid secretion is fed back into the hypothalamus, which causes the hypothalamus to produce a large number of thyroid-stimulating hormone-releasing factors, which stimulates the pituitary to secrete thyroid-stimulating hormone. It can also stimulate the excessive secretion of pituitary prolactin and cause galactorrhea ^[4] .

5. Hypothalamic disorders: Diseases in the hypothalamus and adjacent parts, such as encephalitis, craniopharyngioma, pineal tumor, partial hypothalamus infarction, pseudo-brain tumor, pituitary stem mutilation, etc., can cause hypothalamus. The prolactin inhibitory factor is reduced, or the prolactin-releasing factor and thyroid-stimulating hormone-releasing factor are increased. The former can blindly produce prolactin due to loss of inhibition, while the latter two directly promote prolactin production ^[4] .

Clinical significance of prolactin

Prolactin is synthesized and intermittently secreted by the anterior pituitary gland, and the target organ is the mammary gland, which is responsible for its maturation and differentiation. High concentrations of prolactin have an inhibitory effect on ovarian steroid production and pituitary gonadotropin production and secretion. It is used for research of pituitary microtumor, reproductive biology, and high lactation caused by various drugs ^[5] .

Increased prolactin is commonly found in pituitary tumors, hypothalamic lesions, primary hypothyroidism, bronchial cancer, gastric cancer, renal failure, craniopharyngioma, mental illness, polycystic ovary, drugs (such as antihypertensive drugs, stability, contraception Drugs, analgesics, etc.); pregnant and lactating women can also increase. Reduction is common in anterior pituitary hypofunction, monolactin deficiency, post-ovary resection, kidney cancer, etc. ^[5] . More specific clinical significance is as follows:

1. Physiological increase is seen in exercise, pregnancy, postpartum, breastfeeding, night sleep, stress state and menstrual secretion ^[3] .

2. Pathological increase seen in hypothalamic lesions (such as pituitary prolactinoma, hypothalamic tumor), pituitary growth hormone tumors (such as Cushing's syndrome). Ectopic tumor growth (such as pituitary tumor lung metastasis, breast tumors), endocrine organ diseases (such as Cushing's syndrome, acromegaly, adrenal hypofunction, primary hypothyroidism with increased TRH), gonadal diseases (such as Primary sexual dysfunction, gynecomastia, amenorrhea, and collateral syndrome) and liver and kidney diseases ^[3] .

3 Pathological reduction is seen in anterior pituitary hypofunction, such as Shear syndrome, breast cancer after pituitary resection, but incomplete pituitary resection can increase serum PRL ^[3] .

4 The drug affects oral contraceptives, cimetidine, chlorpromazine and other phenothiazines, certain antihistamines, alpha-methyldopa, synthetic thyrotropin-releasing hormone (TRH), general anesthetics, Arginine and insulin-induced hypoglycemia increase blood PRL levels. After treatment with L -dopa, calcitonin, norepinephrine, etc., it directly or indirectly inhibits the secretion and release of PRL, which reduces the level of PRL in the blood ^[3] .

Prolactin- related diseases

High prolactin can cause the following symptoms:

1. Irregular menstruation: 4% of primary amenorrhea, 89% of secondary amenorrhea, rare menstruation, 7% less. Dysfunction, corpus luteum function is 23% to 77%. Ovulation dysfunction and corpus luteum insufficiency are: rare menstruation, amenorrhea, infertility are more common, and related habitual abortion, hyposexuality, hairiness, acne, etc. Gynecological examination showed symptoms of estrogen deficiency such as dry vaginal mucosa and decreased secretion ^[6] .

2. Breast milk: milk can be seen on both sides of the breast, and fat droplets can be seen under the microscope. Among non-tumor types, it was 20.84%. The tumor type was 70.52%. Pure galactorrhea is 63 to 83.55%. The breasts are usually normal or with lobular hyperplasia or large breasts ^[6] .

3. Bone loss: Long-term decline in estrogen levels caused by HP can cause a decrease in bone density ^[6] .

4. Higher levels of prolactin may cause diseases such as visual impairment, nervous system disorders, hypopituitarism, cerebral hemorrhage, and cerebrospinal fluid rhinorrhea. ^[6]

Prolactin treatment

Prolactin western medicine treatment

Clinically, hyperprolactinemia is currently being treated. Most patients with hyperprolactinemia have pituitary prolactin adenomas, which are treated clinically by different means, including chemical drugs, surgery, and stereotactic radiotherapy. For pituitary prolactin microadenomas, chemotherapy is the first choice. The main chemical drugs are bromocriptine, cabergoline, and pergolide. They all act on the dopamine receptors in the pituitary prolactin cell membrane and combine to produce a dopamine-like effect, which inhibits PRL synthesis and release, thereby reducing serum PRL levels and improving patients Clinical symptoms, recovery of women's menstruation and fertility. Therefore, it has been widely used in the treatment of hyperprolactinemia, but has adverse reactions such as nausea, vomiting, mild headache, peripheral vasospasm, and orthostatic hypotension, etc., and is easy to relapse and expensive.

For non-invasive large adenomas, transsphenoidal or transcranial surgery is preferred; for aggressive pituitary tumors, dopamine agonists such as bromocriptine, surgery, and gamma knife are used in combination. Among them, -knife treatment has been shown as a new treatment, which can improve symptoms, control tumor growth and plasma PRL levels, and can be used as an adjunct. ^[7] For prolactinemia caused by drugs or physiological reasons, clinical use of bromocriptine and other drugs is mainly used to treat patients. At the same time, patients are required to adjust their living habits and avoid taking drugs such as chlorpromazine and contraceptives that cause elevated PRL. . ^[8]

Prolactin TCM Treatment

The symptoms caused by abnormally high prolactin are mainly explored in terms of galactorrhea and menstrual diseases. Some people think that the lack of kidney water, liver failure to support, spleen and stomach dysfunction caused the disease, and some people think that liver depression and kidney deficiency, mostly due to depression, anger, emotional disorder and qi and blood disorder, caused by imbalance. Traditional Chinese medicine is mainly treated by relieving liver and stagnation, regulating liver and kidney, promoting blood circulation and removing blood stasis. It is mainly based on traditional Chinese medicine and acupuncture, and has significant effects.

After the treatment of hyperplasia of mammary glands, such as traditional Chinese medicine compound Rupixiao and Yiru Granules, the patient's PRL level decreased, and symptoms improved significantly. It may achieve therapeutic effects by reducing the PRL level in the blood. Acupuncture may restore ovarian function by regulating the level of prolactin, reducing its antagonistic effect on follicle-stimulating hormone, and adjusting the secretory function of the pituitary-ovarian axis to achieve the purpose of treating breast hyperplasia. ^[1] ^[9]