I. Physiology of prolactin
1. Secretion and regulation of prolactin: Prolactin is synthesized and secreted by prolactin cells in the anterior pituitary gland. Its synthesis and secretion are regulated by the dopaminergic pathway of the hypothalamus. Dopamine acts on dopamine D2 receptors on the surface of prolactin cells to inhibit the production and secretion of prolactin. Any physiological or pathological process that reduces the action of dopamine on dopamine D2 receptors on prolactin cells will lead to an increase in serum prolactin levels, a process that is reversed by dopamine receptor agonists in HPRL.
The physiological function of prolactin: The physiological role of prolactin is extremely broad and complex. In humans, it mainly promotes the development and growth of mammary gland secretory tissue, initiates and maintains lactation, and increases protein synthesis in mammary gland cells. Prolactin can affect gonadal function. In men, prolactin enhances testosterone synthesis by Leydig cells, and in the presence of testosterone, prolactin disorders promote prostate and seminal vesicle growth; however, chronic HPRL can lead to hypogonadism, reduced spermatogenesis, impotence and male infertility. In women, prolactin levels in follicular fluid change significantly during follicular development; however, HPRL not only inhibits the pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary follicular estrogen (FSH) and luteinizing disorder (LH). Moreover, it can directly inhibit the synthesis of luteinizing hormone and estrogen by ovaries, resulting in impaired follicular development and ovulation, which is clinically manifested as menstrual disorders or amenorrhea. In addition, prolactin is associated with autoimmunity. Human B and T lymphocytes, splenocytes and natural killer cells have prolactin receptors, and prolactin binds to these receptors to regulate cellular functions.J. Prolactin also plays an important role in the regulation of osmotic pressure.
3. Changes in PRL under physiological conditions.
(1) Circadian changes: Prolactin secretion has a circadian rhythm, rising gradually after sleep, reaching a 24h peak in the morning before waking up, falling rapidly after waking up, and dropping to a mid-day trough between 10am and 2pm.
(2) Changes in age and sex: Due to the influence of maternal estrogen, serum prolactin levels are as high as about 4.55 nmoL/L in newborn infants, and then gradually decline to normal levels by 3 months of age. Prolactin levels rise mildly during puberty to adult levels. Blood prolactin levels are consistently higher in adult women than in men of the same age. During the 18 months after menopause, a woman’s prolactin
levels gradually decline by 50% over the 18 months following menopause, but more slowly in women treated with estrogen supplementation. In women with HPRL, the application of estrogen replacement therapy did not cause changes in prolactin levels. The average serum prolactin level decreases by approximately 50% in older men compared to younger men L4J.
(3) Changes in the menstrual cycle: Prolactin levels do not change significantly with the menstrual cycle. In some women, prolactin levels increase in the middle of the menstrual cycle and decrease in the follicular phase. A mild increase in prolactin during ovulation may cause infertility in some women.
(4) Changes during pregnancy: Elevated estrogen levels during pregnancy stimulate prolactin cell proliferation and hypertrophy in the pituitary gland, resulting in an enlarged pituitary gland and increased prolactin secretion. At the end of pregnancy, serum prolactin levels can increase 10-fold, exceeding 9.10 nmoVL. After delivery, the enlarged pituitary gland returns to its normal size and serum prolactin levels decrease. Under normal physiological conditions, prolactin-secreting cells account for 15%-20% of pituitary cells, which can increase to 70% at the end of pregnancy.
(5) Changes in the postpartum prolactin process: If you do not breastfeed, the serum prolactin level drops to normal 4 weeks after delivery. During breastfeeding, nipple sucking can trigger rapid release of pituitary prolactin, and the basal serum prolactin level continues to rise in lactating women for 4-6 weeks after delivery. The basal prolactin level gradually decreases to normal in the following 4 to 12 weeks, and the magnitude of prolactin increase decreases with each breastfeeding. In the case of basal and lactation stimulation at 3-6 months postpartum, the decrease in prolactin levels is mainly due to the reduction in lactation caused by the addition of complementary foods. If strict lactation is maintained, basal prolactin levels will continue to rise with postpartum amenorrhea. In healthy women, stimulation of the breast in a non-lactating state can also lead to an increase in prolactin levels.
(6) Changes in prolactin due to stress: Stress hormones released by the pituitary gland during stress (e.g., emotional stress, cold, exercise, etc.) include: prolactin, adrenocorticotropic hormone (ACTH), and growth hormone (GH). Stress can increase prolactin levels several-fold, usually for less than lh.
HPRL
1. Definition of HPRL: A state in which peripheral serum prolactin levels are consistently higher than normal for various reasons is called HPRL. prolactin levels in normal women of childbearing age do not exceed 1.14 to 1.37 nmol/L (each laboratory has its own normal value). Standardized blood specimen collection and accurate and reliable laboratory measurements are essential to determine whether HPBL is present, especially if the prolactin level is mildly elevated, repeated measurements are needed to confirm the diagnosis.
2. Standardization of laboratory determination of blood prolactin: Since the diagnosis of HPBL is based on the measurement value of serum prolactin, accurate and reliable laboratory techniques are needed first. Due to the differences in the methods and kits used by different laboratories there may be large differences in the detection values, which exist whether the application of radioimmunoassay technology or the more widely used solid phase, sandwich method chemiluminescent immunometric assay (solidphase, two-sidechemoluminescentimmunometricassay). Serum samples for the assay must be determined to be fully agglutinated prior to centrifugation to remove fibrin interference, and ultracentrifugation to remove lipids is desirable. Each laboratory should have strict quality control to maximize the reliability of the serum prolactin assay and should establish criteria for defining high serum prolactin in their laboratory as suggested by the normal range of values in their laboratory and the parameters provided by the reference kit∞J.
In addition, because serum prolactin levels are influenced by its pulsatile secretion and diurnal wakefulness, blood collection should be done at the nadir phase of the day, i.e., 10 a.m. to ll. Stressful situations such as nervousness, cold, and strenuous exercise can cause prolactin levels to rise several times, but the duration will not exceed lh, so quietness should be advised for lh before blood collection.
3. Epidemiology of HPRL: HPRL is a common endocrine disorder of the hypothalamus-pituitary axis in young women. The incidence of hyperprolactinemia varies among the tested populations. In the unselected normal population, about 0.4% have HPRL; in the family planning clinic population, the incidence of HPRL is 5%. HPRL is present in about 15% of patients with simple amenorrhea and in 70% of patients with amenorrhea with overflowing breast. 15% of anovulatory women have HPRL and 43% of anovulatory women with overflowing breast have HPRL.
HPRL is present in 3-10% of patients with anovulatory polycystic ovary syndrome, and the incidence of HPRL in patients with infertility is rarely reported. Pituitary adenomas account for 10%-15% of all intracranial tumors. Prolactin adenoma is the most common functional pituitary adenoma, accounting for approximately 45% of all pituitary adenomas, and is the most common cause of clinically pathologic high HPRL. Prolactin adenomas are mostly benign tumors and can be divided into microadenomas (≤10mm) and macroadenomas (>10am) according to tumor size. Overall, the annual incidence of prolactin adenoma is about 6-10 per million and the prevalence is about 60-100 per million. Recent studies suggest that the prevalence of prolactin adenoma may be much higher than this, to increase 3-5 times on top of this.
4, the causes of HPRL: HPRL causes can be summarized into four categories: physiological, pharmacological, pathological and idiopathic.
(1) Physiological HPRL: Many physiological factors affect serum prolactin levels. Serum prolactin levels change at different physiological periods, even on an hourly basis every day. Many daily activities, such as physical exercise, trauma, hypoglycemia, nighttime, sleep, eating, stressful stimuli, sexual intercourse, and various physiological phenomena such as late follicular and luteal phases, pregnancy, breastfeeding, puerperium, nipple stimulation, and neonatal period can lead to temporary elevation of prolactin levels, but the elevation will not be too great, will not last too long, and will not cause relevant pathological symptoms.
(2) Pharmacological HPRL: Many drugs can cause PRL, most of these drugs are caused by antagonizing hypothalamic prolactin release inhibitory factor (PIF, dopamine is the typical endogenous PIF) or enhancing excitatory prolactin release factor (PRF), a few drugs may also have a direct effect on prolactin cells. Common drugs that may cause elevated prolactin levels include: dopamine depleting agents: methyldopa, reserpine; dopamine conversion inhibitors: opioid peptides, morphine, cocaine and other narcotics; dopamine reuptake blockers: nomifensine; diphenylazine derivatives: phenytoin, valium, etc.; histamine and histamine H1 and H2 receptor antagonists: 5 hydroxytryptamine, amphetamines, hallucinogenic drugs, meclizine, etc;
Monoamine oxidase inhibitors: phenelzine, etc.; angiotensin-converting enzyme inhibitors: enalapril, etc. Hormonal drugs: estrogen, oral contraceptives, anti-androgen drugs, thyroid hormone-releasing hormone, etc.; Chinese herbal medicines (especially those with tranquilizing and anti-stunning effects): Six-bit Dihuang Pills, Angong Niuhuang Pills, etc.; others: isoniazid, danazol, etc. Most people with drug-induced HPRL have serum prolactin levels <4.55 nmol/L, but there are reports of long-term use of some drugs that make serum prolactin levels as high as 22.75 nmol/L, which in turn causes massive lactation and amenorrhea.
(3) Pathologic HPRL: Frequently
The pathological causes of HPRL seen are.
(1) Hypothalamic PIF deficiency or obstruction of the pathway down to the pituitary gland, commonly due to hypothalamic or pituitary stalk lesions, such as skull base meningitis, tuberculosis, syphilis, actinomycosis, craniopharyngioma, sarcoidosis-like disease, glioblastoma, vacuolar pterygoid saddle syndrome, trauma, surgery, arteriovenous malformations, Parkinson’s disease, and psychological trauma.
(ii) Primary and/or secondary hypothyroidism, such as pseudohypoparathyroidism and Hashimoto’s thyroiditis.
③Autonomous high-functioning monoclonal strains of prolactin-secreting cells, as seen in pituitary prolactin adenomas, GH adenomas, ACTH adenomas, etc., and ectopic prolactin secretion (e.g., undifferentiated bronchopulmonary carcinoma, adrenal-like tumors, embryonal carcinoma, endometriosis, etc.).
④Enhanced afferent nerve stimulation enhances PRF action, as seen in various types of inflammatory chest wall diseases such as papillitis, chancre, chest wall trauma, herpes zoster, tuberculosis, traumatic and neoplastic diseases.
⑤ In chronic renal failure, prolactin is abnormally degraded in the kidneys; or in cirrhosis, hepatic encephalopathy, pseudoneurotransmitter formation, antagonizing the effect of PIF.
(6) Obstetrical and gynecological surgery: such as abortion, induction of labor, stillbirth, hysterectomy, tubal ligation, ovariectomy, etc.
(4) Idiopathic HPRL: These patients are not related to pregnancy, medication, pituitary tumors or other organic lesions, but are mostly due to dysfunction of the hypothalamus and pituitary gland, which leads to increased prolactin secretion. Most of them have mild elevation of prolactin, which may return to normal with long-term observation. However, in some cases with menstrual disorders and prolactin above 4.55 nmol/L, the patient should be alerted to the possibility of latent pituitary microadenoma.
The patient should be closely followed up. Some of the patients with idiopathic HPRL with markedly elevated serum prolactin levels without symptoms may have macroprolactinemia, which is immunoreactive but not biologically active|.
Diagnosis
The diagnosis of HPRL involves clarifying the presence of HPRL and determining the etiology of the cause of HPRL.
I. Confirmation of HPRL diagnosis
Since prolactin is not a routine screening test, the diagnosis of HPRL is usually confirmed by a combination of clinical manifestations and blood prolactin levels in patients with suspicions identified by specific clinical manifestations or by checking prolactin levels during examination for other diseases.
1. Women.
(1) Menstrual changes and infertility: HPRL can cause menstrual disorders and reproductive dysfunction in women. When prolactin is mildly elevated (<4.55-6.83nmol/L), recurrent spontaneous abortions can occur due to luteal insufficiency; and with further elevation of serum prolactin level, ovulation disorders can occur, with clinical manifestations of dysfunctional uterine bleeding, menstrual scarcity or amenorrhea and infertility.
(2) Overflow of breast milk: 27.9% of patients with HPRL had overflow of breast milk during non-pregnancy and non-lactation, and 75.4% had both amenorrhea and overflow of breast milk. Serum prolactin levels are generally significantly elevated in these patients.
(3) Other: Weight gain is usually associated with HPRL. Chronic HPRL can lead to progressive bone pain, decreased bone mineral density, and osteoporosis due to low estrogen levels. A few patients may develop hirsutism, seborrhea and acne, and these patients may be accompanied by other abnormalities such as polycystic ovary syndrome.
2. Males.
(1) Erectile dysfunction in men: HPRL is one of the common causes of erectile dysfunction in men. Conversely, erectile dysfunction is often one of the earliest clinical manifestations of HPRL. The mechanism leading to erectile dysfunction in men has not been fully elucidated, and it is currently believed that reduced blood testosterone levels are one of the causes. However, many patients with completely normal blood testosterone levels still exhibit significant erectile dysfunction.
In addition, if the blood prolactin level is not reduced to normal, the effect of testosterone supplementation therapy alone is not obvious, indicating that HPRL may have a direct effect on penile erectile function. Inability to ejaculate and orgasmic disorders are also common manifestations of sexual dysfunction in HPRL.
(2) Decreased libido: The frequency and amplitude of GnRH secretion by the hypothalamus are significantly reduced in HPRL, which causes the frequency and amplitude of LH and FSH secretion by the pituitary gland to decrease, and the amount of androgen synthesis by the testes to decrease significantly, resulting in decreased libido, which is manifested by decreased interest in sexual behavior or even disappearance.
(3) Hypospermatogenesis and male infertility: HPRL can cause hypospermatogenesis. When the frequency and magnitude of LH and FSH secretion by the pituitary gland is reduced, the function of spermatogenesis decreases significantly.
(4) Diminished secondary sexual characteristics: Long-term significant HPRL can lead to diminished secondary sexual characteristics in men. This can be manifested as slower growth of the beard, forward movement of the hairline, thinning of pubic hair, softening of the testicles, and muscle relaxation. In addition, there are still many patients with male breast development.
(5) Other: long-term HPRLemia leading to reduced androgen levels may cause osteoporosis.
(3) Compression symptoms of pituitary adenoma: Prolactin adenoma is pathological HPRL. I clinical manifestations of tumor occupancy include: headache, vision loss, visual field defects and other cranial nerve compression symptoms, seizures, cerebral fluid nasal leakage, etc. Spontaneous hemorrhage within pituitary adenoma exists in 15% to 20% of patients, and acute pituitary stroke occurs in a few patients, manifesting as sudden severe headache, vomiting, vision loss, actinic nerve In a few patients, acute pituitary strokes occur, manifesting as sudden severe headache, vomiting, loss of vision, articulatory nerve palsy and other neurological symptoms, and even subarachnoid hemorrhage and coma. In male patients with pituitary prolactin adenoma, symptoms caused by elevated blood prolactin levels are often mild and fail to be seen in time, resulting in a prolonged course of disease. The diagnosis is not made until the tumor is large enough to compress the optic cross and cause visual field disturbance or pituitary tumor stroke with severe headache.
4.Abnormally elevated blood prolactin: Since blood prolactin level is affected by many physiological factors and stress, there are strict blood collection requirements for measuring blood prolactin level (blood should be taken in a quiet and awake state at 10:11 a.m.). It is important to note that there are some inconsistencies between the clinical presentation and the prolactin level.
Some patients with elevated serum prolactin levels without associated clinical symptoms or symptoms that do not explain the degree of elevation need to be considered for the presence of macroprolactinemia. In contrast, individual patients with typical HPRL and pituitary adenoma manifestations but low or normal laboratory prolactin measurements may be due to a hook (HOOK) phenomenon caused by too high prolactin levels. This situation is the opposite of the previous one and requires repeated determination of the patient’s serum prolactin level by means of a multiplicative dilution.
II. Diagnosis of the etiology of HPRL
A detailed history, laboratory tests, and imaging tests are needed to rule out physiological or pharmacological causes of elevated prolactin levels and to determine whether there is a pathological cause. The most common cause is pituitary prolactin adenoma.
1. Medical history taking: The patient’s medical history needs to be targeted from 3 aspects: physiological, pathological and pharmacological causes of HPRL (see previous section). Patients should be asked about their menstrual history, childbirth history, surgical history, past medical history, history of taking relevant medications, and whether there was any stress during blood collection (e.g., exercise, sexual intercourse, mental and emotional fluctuations, or pelvic examination).
2.Laboratory tests; including pregnancy test, pituitary and its target gland function, kidney function and liver function, etc., which are selected according to the medical history.
3.Imaging examinations: After the above examinations, it is confirmed that mild HPRL and no clear cause is found or blood prolactin >4.55nmol/L should be subjected to imaging examinations of the saddle area (MRI or CT) to exclude or determine whether there are intracranial tumors that compress the pituitary stalk or secrete prolactin cords and empty butterfly saddle syndrome, etc. MRI is the imaging modality of choice for saddle lesions because of its high soft tissue resolution and multi-directional imaging, which is significantly better than CT in various aspects such as detection of pituitary micro tumors, characterization and localization of saddle lesions, and there is no radiation damage and can be repeated many times.
MRI should routinely include thin, small-scan field (FOV) sagittal and coronal T1WI sequences, and at least 1 plane of T2WI (sagittal or coronal) is required. Although some lesions can be diagnosed with certainty on MRI scan, it is recommended to perform an enhanced MRI of the saddle area at the same time for a higher detection rate of the lesion and, if necessary, a dynamic enhanced MRI of the saddle area.
Treatment
The goals of treatment for HPRL are to control HPRL, restore normal menstruation and ovulation in women or restore sexual function in men, reduce lactation and improve other symptoms (e.g., headaches and visual dysfunction). After HPRL is determined, the first step is to decide whether treatment is needed.
Pituitary prolactin macroadenomas and microadenomas with manifestations such as amenorrhea, lactation, infertility, headache, and osteoporosis require treatment; those with only increased blood prolactin levels without the above manifestations can be followed up and observed. The next step is to decide the treatment plan and which treatment method to choose. In pituitary prolactin adenomas, whether they are microadenomas or macroadenomas, dopamine agonist therapy can be preferred; due to the development of minimally invasive techniques, the efficacy of surgical treatment of pituitary prolactin adenomas, especially pituitary prolactin microadenomas, has been significantly improved and can be the first treatment option for some patients. Surgery should be the treatment of choice for patients with poor drug efficacy, intolerance of adverse drug reactions, and refusal of drug therapy.
Regarding the choice of treatment, doctors should fully respect the patient’s opinion and help the patient make an appropriate choice based on the patient’s own situation, such as age, fertility status and requirements, while fully informing the patient of the advantages and shortcomings of various treatment methods.
I. Drug therapy
Indications for dopamine agonist drug therapy. Dopamine agonist therapy is indicated for all HPRL patients with menstrual disorders, infertility, lactation, osteoporosis, and headache, optic cross or other cranial nerve compression symptoms, including pituitary prolactin adenomas. Commonly used drugs are bromocriptine, cabergoline and quinagolide.
1, bromocriptine: Bromocriptine is the first dopamine agonist in clinical application. In order to reduce adverse drug reactions, bromocriptine treatment is increased gradually from a small dose, i.e. from 1.25 mg at bedtime and incrementally to the required therapeutic dose. If the reaction is not significant, it can be increased to the therapeutic dose within a few days. The usual dose is 2.5-10.0mg per day, divided into 2-3 doses. 5.0-7.5mg per day has been shown to be effective in most cases. Dose adjustment is based on blood prolactin levels. Bromocriptine treatment can achieve good results in 70%-90% of patients.
Bromocriptine treatment can achieve better results in 70%-90% of patients, as shown by the reduction of blood prolactin to normal, disappearance or reduction of lactation, reduction of pituitary adenoma, restoration of regular menstruation and fertility, and in men, restoration of libido and spermatogenesis, and correction of male infertility. It should be noted that bromocriptine only causes reversible shrinkage of pituitary prolactin adenomas and inhibits tumor cell growth, and the tumor becomes fibrotic after long-term treatment. However, after stopping the treatment, the pituitary prolactin adenoma will grow back and cause HPRL to reappear, so long-term treatment is needed.
Only a small number of patients achieve clinical cure after long-term treatment. The main adverse effects of bromocriptine are nausea, vomiting, dizziness, headache, and constipation, which disappear within a short period of time in most cases. A gradual dosing method starting with small doses may reduce adverse reactions, and incremental doses may be reduced if intolerance becomes apparent at increasing doses. Raynaud’s phenomenon and abnormal heart rhythm may occur with high doses of the drug.
The most serious adverse effect of the drug is postural hypotension in a small number of patients at the initial dose, and loss of consciousness may occur in some patients, so the dose must be small at the beginning of treatment, and do not do activities that can lower the blood pressure when taking the drug, such as sudden rising, hot shower or bath. Do not use drugs that increase blood prolactin during bromocriptine treatment. Retroperitoneal fibrosis may occur in individual patients on long-term doses higher than 30ms/d. About 10% of patients who are not sensitive to bromocriptine, have unsatisfactory efficacy, or have severe headache, dizziness, gastrointestinal reaction, constipation, etc. that persistently do not disappear and cannot tolerate therapeutic doses of bromocriptine, may be replaced by other drugs or surgical treatment.
2. Other drugs: Cartegolide and quinagolide are highly selective dopamine D2 receptor agonists, which are substitutes of bromocriptine, with more powerful effect of prolactin inhibition and relatively less adverse effects and longer duration of action. Patients with prolactin adenoma who are bromocriptine-resistant (unsatisfactory with 15 mg of bromocriptine daily) or intolerant to bromocriptine therapy are still more than 50% effective when switched to these new dopamine agonists. Quinagolide is taken once a day at 75-300 “g; cartegolide is taken only once or twice a week at the usual dose of 0.5-2.0nag, with better patient compliance than bromocriptine.
3.Follow up after drug treatment: When dopamine agonists are applied to treat HPRL and pituitary prolactin adenoma, the effect of reducing blood prolactin level or tumor volume reduction is reversible, so long-term drug maintenance treatment is needed. After the dose is gradually increased to bring the blood prolactin level to normal and menstruation resumes, treatment should be continued at this dose for 3-6 months.
After that, patients with microadenoma can start to reduce the dose; while patients with macroadenoma can also start to reduce the dose after confirming that the prolactin tumor has shrunk significantly (usually the larger the tumor, the more significant the shrinkage) according to the MRI review results. The dose reduction should be carried out slowly (once every 2 months or so), usually 1.25 mg per dose, and preferably at the lowest dose that can maintain normal blood prolactin levels as a maintenance dose. Follow up at least 2 times a year to ensure that prolactin levels are normal.
The blood prolactin level should be checked at least 2 times a year to ensure that the blood prolactin level is normal. If menstrual disorders or elevated prolactin reappear during maintenance treatment, the cause should be investigated, such as the effect of the drug, pregnancy, etc., and if necessary, MR! For those who can maintain normal prolactin level by applying small dose of bromocriptine, and the tumor basically disappears by MRI, the drug can be discontinued after 5 years of drug treatment on a trial basis.
If the blood prolactin level increases again after discontinuation, long-term drug treatment is still required. In patients with prolactin macroadenoma, although the blood prolactin level is normal after dopamine agonist treatment, but the tumor volume is not reduced, the diagnosis of prolactin adenoma should be re-examined whether it is correct, whether it is a non-prolactin adenoma or a mixed pituitary adenoma, and whether it needs surgical treatment. Patients who already have visual field defects before treatment should have their visual fields reviewed at the beginning of treatment. If the visual field defect is severe, the visual field should be checked twice a week to observe the improvement of the visual field (the visual field of the corresponding area with existing optic nerve atrophy will be permanently defective). When drug treatment is satisfactory, visual field improvement is usually observed within 2 weeks. For visual field defects after pharmacological treatment
For patients with no improvement or only partial improvement after drug treatment, MRI should be repeated within 1 to 3 weeks after bromocriptine treatment to observe tumor changes to determine whether surgical treatment is needed to relieve the compression of the optic nerve by the tumor on the optic cross.
II. Surgical treatment
Due to the anatomical position of pituitary gland and its important role in endocrine, pituitary adenoma can cause local or systemic systemic dysfunction due to tumor compression and dysfunction of hypothalamus-pituitary axis, which is difficult to treat. In recent years, with the development of neuronavigation and endoscopic devices and the improvement of minimally invasive surgical techniques, trans-pituitary sinus surgery has become more precise, safer, with less damage and fewer complications. Therefore, transsphenoidal sinus surgery is also another option for patients with pituitary prolactin adenoma in addition to drug treatment.
1. Indications for surgery.
(1) Those with ineffective drug therapy or poor results.
(2) Those who cannot tolerate the large response to drug treatment.
(3) Giant pituitary adenoma with obvious visual field disorder, no significant improvement after a period of drug treatment.
(4) Invasive pituitary adenoma with cerebrospinal fluid nasal leakage.
(5) Those who refuse to take long-term medication. Surgery can also be used to treat recurrent pituitary adenomas. Surgery may also be used before or after drug therapy. There are almost no absolute contraindications to surgery, and the vast majority of relative contraindications are related to poor general status and organ dysfunction. In these patients, treatment should be performed prior to surgical treatment to improve the general systemic condition. It has also been suggested that dopamine agonists may increase the difficulty and risk of surgery due to their ability to cause tumor fibrosis.
The success of surgery depends on the experience of the surgeon and the size of the tumor. The surgical outcome of microadenomas is better than that of larger adenomas. In most large pituitary treatment centers, 60% to 90% of patients with microadenomas achieve normal postoperative prolactin levels, while a lower percentage of patients with macroadenomas achieve normal, about 50%. In addition, among patients with normal prolactin levels after surgery, recurrence is observed in 10% to 20% of patients over time.
The mortality and disability rates for transsphenoidal sinus surgery are 0.5% and 2.2%, respectively. Complications include 3 main areas: endocrine function, local anatomy, and medical origin. Endocrine complications include emerging hypopituitarism and transient or persistent uremia and symptoms of disorders of antidiuretic hormone (ADH) secretion, and persistent postoperative anterior hypopituitarism associated with the primary tumor volume.
Anatomic complications include injury to the optic nerve, injury to the peripheral neurovascular, cerebrospinal fluid nasal leak, nasal septal perforation, sinusitis, and skull base fracture, with injury to the cavernous sinus segment of the carotid artery being the most serious and often life-threatening complication. Other complications associated with surgery include deep vein thrombosis and pneumonia, all of which have a low incidence. However, some endocrinologists also believe that the incidence of postoperative hypopituitarism should be higher than the above-mentioned levels.
2. Follow-up and management after surgical treatment: A comprehensive pituitary function assessment is required after surgery. Patients with hypopituitarism need to be given appropriate endocrine hormone replacement therapy. Imaging should be performed 3 months after surgery, combined with endocrinological changes, to understand the extent of tumor resection. The fenestrated condition should be reexamined every 6 months or 1 year. Patients who still have tumor remnants after surgery need further drug or radiation therapy.
3.Radiation therapy
1.Status of radiation therapy: Due to the development of surgery and drug therapy, the number of radiation therapy cases of various pituitary adenomas has become less and less. With the development of stereotactic radiosurgery (1-knife, X-knife, proton radiation), there are increasing reports in the literature on the use of stereotactic radiation therapy for patients with partially selective prolactin adenomas. Comprehensive literature reports that radiation therapy is mainly applied to large invasive tumors, postoperative residual or recurrent tumors; patients who are ineffective in drug therapy or cannot tolerate the side effects of drug therapy; patients who have contraindications to surgery or refuse surgery and some patients who do not want to take long-term medication.
2.Radiotherapy methods: divided into traditional radiotherapy (including general radiotherapy, conformal radiotherapy and IMRI) and stereotactic radiosurgery. Traditional radiation therapy is prone to complications such as delayed hypopituitarism due to the relatively large irradiation field, and is currently only used for postoperative treatment of tumors with extensive invasion. Stereotactic radiosurgery is suitable for small to medium-sized tumors with clear borders. Tumors with a distance greater than 3-5 epistaxis from the optic pathway are preferred, and a one-time treatment dose of 18-30 Gy may be required. studies have found that dopamine agonists may have a radioprotective effect. Therefore, it is advisable to discontinue dopamine agonists while treating urothelial tumors.
3. Efficacy evaluation: It should include local control of the tumor as well as the decrease of abnormally increased prolactin. Usually the rate of local control of the tumor is high, while the return of prolactin to normal is slower. The literature reports that even after stereotactic radiosurgery, only 25%-29% of patients have normalized their prolactin within 2 years, and the rest of patients may need longer follow-up or additional medication.
4, complications: 2-10 years after conventional radiation therapy, 12% to 100% of patients have hypopituitarism, in addition, l% to 2% of patients may have visual impairment or radiolucent temporal lobe necrosis. Visual impairment and hypopituitarism are also possible after radiosurgery. Special attention should be paid to the possible effects of radiation therapy on fertility.
IV. Management of Pregnancy in HPRL Patients
The basic principle is to limit fetal exposure to the drug to as little time as possible. In untreated patients, optic cross-compression occurs in approximately 5% of pregnancies in patients with prolactin microadenomas, while the likelihood of this risk in patients with macroadenomas after pregnancy is over 25%¨ cited. Treatment with bromocriptine should be discontinued in patients with pituitary microadenomas after definite pregnancy, as the risk of tumor enlargement is less. Blood prolactin levels and visual field examinations should be measured regularly after discontinuation of the drug.
Prolactin levels can increase about 10-fold in normal individuals after pregnancy. Patients with blood prolactin levels significantly exceeding pre-treatment prolactin levels should be monitored closely and visual field examinations should be increased in frequency. Once visual field defects or cavernous sinus syndrome are detected, immediate administration of bromocriptine is expected to improve remission within one week. If remission does not occur, surgical treatment should be considered.
For women with pituitary macroadenomas with childbearing requirements, pregnancy should be allowed only after bromocriptine treatment for adenoma reduction; all pregnant patients with pituitary prolactin adenomas need to be evaluated every 2 months during pregnancy. Bromocriptine can still inhibit tumor growth if the tumor re-increases during pregnancy, but the drug must be continued throughout pregnancy until delivery. The effect of the drug on the mother and fetus may be less than that of surgery. Drug therapy requires close monitoring. Failure to respond to bromocriptine and progressive deterioration of the visual field should be treated by pterygoid surgery and termination of pregnancy as early as possible (near term).
The incidence of spontaneous abortion, intrauterine death, and fetal malformations after pregnancy in women with HPRL and pituitary PRL adenomas treated with bromocriptine is about 14%, which is similar to the obstetric anomalies of pregnancy in normal women. There is no evidence to support that breastfeeding stimulates tumor growth. In women who wish to breastfeed, DA agonists are generally used until the patient wants to end breastfeeding, unless pregnancy-induced tumor growth requires treatment.
Although pre-pregnancy radiotherapy (followed by bromocriptine) reduces the risk of tumor enlargement to only 4.5%, radiotherapy is rarely curative. Radiotherapy can also lead to long-term hypopituitarism, so this treatment is less acceptable and is not recommended.
V. Infertility-related treatment for female HPRL patients
Clomiphene is used to promote ovulation in women with HPRL after normal HPRL: more than 90% of women with HPRL can have their blood prolactin levels reduced to normal and resume ovulation after treatment with dopamine agonists. If prolactin levels fall and ovulation still does not resume, ovulation can be induced by a combination of ovulation-inducing definitions of other pituitary hormone levels helactin levels are mildly elevated and/or other pituitary hormone-changing ovulatory drugs, such as clomiphene citrate (CC).
CC is a nonsteroidal anti-estrogen with a structure similar to estrogen and has both anti-estrogenic and weak estrogenic activity. By inhibiting the negative feedback effect of endogenous estrogen on the hypothalamus, it indirectly promotes the release of hypothalamic GnRH, stimulates the secretion of pituitary gonadotropins, stimulates the ovaries, and promotes follicle development.CC also has weak estrogenic effects, acting directly on the pituitary and ovaries, improving their sensitivity and responsiveness, and promoting the activity of the ovarian sex hormone synthesis system, increasing the synthesis and secretion of sex hormones, and promoting positive feedback effect of estradiol. As a result of the peak in blood estradiol before ovulation, the positive feedback effect on the hypothalamic-pituitary? Ovarian axis (HPOA), which stimulates the pituitary LH peak and promotes ovulation.
CC ovulation promotion is only suitable for patients with certain function of hypothalamus-pituitary axis. If pituitary macroadenoma or surgery destroys pituitary tissue more seriously, CC ovulation promotion is not effective.
2. Post-operative hypogonadotrophic patients should be treated with sex hormones for ovulation.
If CC ovulation promotion is ineffective or if the pituitary gland tissue is destroyed after pituitary adenoma surgery and its function is impaired, exogenous human gonadotropin (Gn) can be used to promote ovulation, which is divided into human pituitary gonadotropin and human chorionic gonadotropin (hCG). Postoperative pituitary tumor patients with low Gn should be treated with human postmenopausal urinary gonadotropin (HMG, 75 IU of FSH and 75 IULH per dose) to promote follicular maturation and induce ovulation with HCG.
Due to individual differences in ovarian sensitivity to gonadotropins, it should be started with a low dose of HMG, usually starting with HMG 75IU, 1 time/d, and continuous use of ultrasound to monitor follicle development for 5-7 d. If there is no obvious follicle development, increase the dose every 5-7 d.
It is important not to increase the Gn dosage too quickly to prevent severe ovarian hyperstimulation syndrome (OHSS) from occurring. HCG is injected when the maximum follicle diameter reaches 18toni.
VI. Treatment related to male HPRL infertility
After the blood prolactin level of HPRL is reduced to normal by drug treatment, the abnormal function of hypothalamus-pituitary-gonadal axis in men can generally be restored to normal, erectile dysfunction and low libido can be improved significantly, and the spermatogenic ability can be restored gradually. In some patients with gonadotropin cell dysfunction due to pituitary tumor compression, testosterone levels cannot be restored to normal even after serum prolactin levels drop, androgen supplementation therapy should be administered simultaneously to restore and maintain male secondary sexual characteristics or restore fertility with gonadotropin therapy. Dopamine receptor antagonists: phenothiazines, butylphenols and other neuropsychiatric drugs, gastrofacial, morpholine, sulpiride, etc.