Prolactin (PRL) adenoma is the most common functional pituitary adenoma, accounting for about 40%-45% of functional pituitary adenomas in adults, and is most common in women aged 20-50 years old, with a male to female ratio of about 1:10. Standardized diagnosis and treatment of pituitary prolactin adenoma is of great significance in restoring and maintaining normal pituitary function and preventing tumor recurrence.
I. Clinical manifestations
The main clinical manifestations of pituitary prolactin adenoma are hypogonadism and its secondary symptoms, which may vary according to the age of onset, gender, duration and degree of prolactin increase; there may also be local pressure symptoms arising from pituitary occupancy; patients with mixed pituitary adenoma or multiple endocrine adenomatosis may also have other clinical manifestations corresponding to the increase of hormone level.
1. Clinical manifestations of hyperprolactinemia
(1), hypogonadism: Patients with prepubertal onset may show primary hypogonadism, i.e. primary amenorrhea in girls, no pubertal development in boys, and small testicular volume. Women of reproductive age mostly have changes in their menstrual cycle, with varying degrees of menstrual scarcity or even amenorrhea, which usually affects ovulation and causes infertility. Low serum estrogen levels can cause breast atrophy, loss of pubic hair, vulvar atrophy, reduced vaginal discharge, and osteoporosis. Decreased androgen levels in male patients can lead to decreased libido, impotence, decreased ejaculation and sperm count, infertility and osteoporosis. Because male patients have insidious symptoms and low specificity, they are often overlooked, leading to late consultation.
(2) Lactation: Spontaneous or triggered lactation occurs in 30% -80% of female patients with hyperprolactinemia, and the incidence of lactation is reduced after the development of hypogonadism due to low estrogen levels. Male patients may have mild mammary gland development and lactation may occur in a few patients.
(3), weight gain: the specific etiology is unclear, it may be related to sodium and water retention, abnormal fat differentiation, hypogonadism and abnormal hypothalamic function.
2.Tumor local compression symptoms
Mostly seen in pituitary prolactin macroadenoma. The most common local compression symptoms are headache and visual field defects (most commonly bilateral temporal hemianopia). If the tumor grows to both sides, it may encircle the cavernous sinus and affect the function of the third, fourth and sixth pairs of cerebral nerves and the ophthalmic branch of the V pair of cerebral nerves, causing eyelid ptosis, loss of pupillary reflex to light, diplopia, eye movement disorder and facial pain. If the tumor destroys the bone of the pterygoid or septal sinus, cerebrospinal fluid leakage may also occur. The macroadenoma may also cause other impaired anterior pituitary function, such as hypothyroidism or hypoadrenocorticism.
3.Multihormonal mixed adenoma or multiple endocrine adenomatosis symptoms
Prolactin mixed adenomas that combine growth hormone, thyroid stimulating hormone and adrenocorticotropic hormone secretion may be accompanied by excessive secretion of other anterior pituitary hormones, such as acromegaly, hyperthyroidism and Cushing’s syndrome. In addition, pituitary tumors can also be a manifestation of multiple endocrine adenomatosis (MEN), especially MEN-I. Therefore, attention should be paid to the presence of other endocrine gland abnormalities such as pancreatic neuroendocrine tumors and hyperparathyroidism.
4.Pituitary stroke
Pituitary stroke may occur in pituitary prolactin adenomas, usually in large adenomas. Acute pituitary stroke can be characterized by severe headache, often accompanied by nausea and vomiting, and in severe cases, acute optic nerve disorder, ptosis and other cranial nerve symptoms, or even coma. However, there are many asymptomatic pituitary strokes.
II. Diagnosis
The diagnosis of prolactin adenoma can be made by combining typical clinical manifestations with laboratory tests of hyperprolactinemia and imaging of the saddle area.
1, hyperprolactinemia: For patients with suspected pituitary prolactin adenoma, the requirements for venous blood sampling to measure prolactin are: eat a normal breakfast (type of carbohydrate, avoid protein and fatty foods), and take blood by venipuncture after 0.5 h of rest at 10:30-11:00 am. If serum prolactin > 100-200 μg/L and other specific causes of hyperprolactinemia were excluded, the diagnosis of prolactin adenoma was supported. If serum prolactin < 100 μg/L, the diagnosis must be made with caution in the context of the specific situation.
2. Imaging of the saddle area: MRI-enhanced imaging of the saddle area is helpful for the detection of pituitary adenoma, and dynamic enhancement imaging is helpful for the detection of pituitary microadenoma.
Differential diagnosis
1.Pathological hyperprolactinemia: It is mostly seen in hypothalamic-pituitary diseases, with pituitary prolactin adenoma being the most common. In addition, other hypothalamic-pituitary tumors, infiltrative or inflammatory diseases, nodal disease, sarcoidosis, as well as trauma and radiation injury are all due to impaired hypothalamic dopamine production or blockage of pituitary portal blood flow resulting in PIF such as dopamine not reaching the adenohypophysis. Hyper-PRLemia due to increased PRL-releasing factor (PRF) is seen in primary hypothyroidism and stressful stimuli. Hyperprolactinemia in patients with chronic renal failure due to impaired glomerular filtration clearance of prolactin. Patients with cirrhosis have elevated blood prolactin due to impaired inactivation of estrogen and prolactin in the liver.
2. Physiological hyperprolactinemia: It mainly occurs during pregnancy, nipple irritation or stress. During pregnancy, the level of prolactin tends to rise gradually, reaching a peak at the time of delivery, but the magnitude of the rise varies from person to person, and the cause of the rise is related to the high estrogen level during pregnancy.
3, pharmacological hyperprolactinemia: many common drugs can cause elevated prolactin levels, such as dopamine receptor antagonists, oral contraceptives containing estrogen, certain anti-hypertensive drugs, opiates and H2-blockers. Among them, dopamine receptor antagonists are some drugs with tranquilizing, sedative or antiemetic effects, as well as antidepressant and antipsychotic drugs. Prolactin levels can be increased more than 15-fold with long-term treatment with gastropromazine.
Drug treatment of pituitary prolactin adenoma
1. Indications for drug treatment: The purpose of treatment is different for different sizes of pituitary prolactin adenoma. For patients with prolactin microadenoma, the purpose of treatment is to control PRL level and preserve gonadal function and sexual function; for patients with large or huge prolactin adenoma, in addition to controlling PRL level and preserving pituitary function, it is necessary to control and reduce tumor volume, improve clinical symptoms and prevent recurrence.
Indications for drug therapy include: infertility, tumor-induced neurological symptoms (especially visual deficits), annoying lactation, chronic hypogonadism, altered pubertal development, and prevention of osteoporosis in women due to hypogonadism. Mild hyperprolactinemia, regular menstruation, women who want to get pregnant need to be treated.
2.Drug selection: Dopamine agonists (DA), the preferred treatment for patients with PRL adenoma, are now mainly bromocriptine (BRC) and cabergoline (CAB), and others are pergolide and quinagolide. The drugs normalize PRL levels and significantly reduce tumor size in the majority of patients, and they are indicated for tumors of all sizes. Because pergolide and quinagolide are less commonly used, they are not recommended by this consensus.
(1), Bromocriptine: Dosage: The initial dose of bromocriptine (2.5mg/tablet) treatment is 0.625-1.25mg/d, which is recommended to be taken orally at night with snack before bedtime. A slow dosing schedule and bedtime dosing with a snack is used to reduce upper gastrointestinal discomfort and upright hypotension. 7.5 mg/d is the effective therapeutic dose and may be increased gradually to 15 mg/d if tumor volume and PRL control are not satisfactory. continued dosing does not further improve the therapeutic effect. Therefore, a high dose of 15 mg or more is not recommended, but rather a change to cabergoline therapy. Since bromocriptine has been proven to be safe and effective, and is relatively inexpensive and available in most medical departments in China, bromocriptine is the drug of choice recommended for the treatment of prolactin adenoma in China.
(2).Carboglutinin: The initial therapeutic dose of 0.5mg/tablet is 0.25-0.5mg/week, and the dose is increased by 0.25-0.5mg/month until PRL is normal, and it is rarely needed to exceed 3mg/week. compared with bromocriptine, carboglutinin is more convenient to take and better tolerated by patients.
(3), adverse drug reactions: adverse reactions of bromocriptine include: headache, dizziness, nausea, vomiting, peptic ulcer and other gastrointestinal symptoms, nasal congestion, constipation, postural hypotension, severe patients may even show shock; fatigue, anxiety, depression, alcohol intolerance; drug-induced pituitary tumor stroke. The adverse reactions of cabergoline as bromocriptine, digestive tract adverse reactions than bromocriptine light, others include psychiatric disorders, potential heart valve disease.
Prolactin microadenoma treatment: The primary purpose of clinical treatment of PRL microadenoma is to preserve gonadal function and reproductive function, and drug therapy can significantly and effectively achieve this purpose, that is, drugs can effectively control PRL levels, and after long-term effective DA treatment, microadenomas often shrink and sometimes disappear. Since only 5-10% of microadenomas progress to macroadenomas, control of tumor size is not the primary goal of drug therapy and women who do not want to have children can be treated without DA. Women who have stopped menstruation can receive estrogen therapy, but PRL levels should be evaluated periodically, including review of dynamic enhancement MRI to observe changes in tumor size.
4. Treatment of prolactinoma macroadenoma and giant adenoma: To treat patients with prolactinoma macroadenoma or giant adenoma, in addition to controlling PRL levels and preserving pituitary function, tumor size should be reduced to improve clinical symptoms. DA remains the treatment of choice for the vast majority of patients with prolactinomatous or giant adenomas, with the exception of acute tumor stroke-induced dramatic vision loss requiring emergency surgical decompression. DA treatment is usually effective in restoring visual function with results comparable to surgical cross-visual decompression. Therefore, patients with macroadenoma with visual field loss are no longer considered neurosurgical emergencies. However, in some drug-resistant cases, tumor size does not decrease significantly for several months of drug treatment. Sustained reduction or even disappearance of the tumor takes months or even years. Regular MRI review after drug treatment is required, once every 3 months after starting treatment, then once every 6 months after that, and later at longer intervals.
The goal of treatment is to keep PRL levels as normal as possible, and it is best to lower PRL levels to the lowest possible value in order to minimize the size of the tumor or even to contribute to its disappearance. Even if the PRL level is reduced to normal, it is still necessary to take sufficient DA to further reduce the size of the tumor. When PRL levels remain normal for at least two years and tumor size is reduced by more than 50%, then DA tapering should be considered, because at this stage, low doses can maintain stable PRL levels and tumor size. However, discontinuation of treatment can lead to tumor enlargement and recurrence of hyperprolactinemia. Because of this, patients with large or giant adenomas need to be closely followed up after dose reduction or discontinuation.
V. Surgical treatment of pituitary prolactin adenoma
The choice of surgical treatment for pituitary prolactin adenoma should be based on a combination of the following: tumor size, blood prolactin level, systemic condition, response to medication, the patient’s wishes and fertility requirements. Microadenomas account for the majority of pituitary prolactin adenomas and the vast majority do not grow, so surgical intervention is not usually the first choice.
Surgical treatment aims to.
(1), Rapid relief of endocrine abnormalities and reduction of blood prolactin to normal range.
(2) Preserve normal pituitary function.
(3).Minimize tumor recurrence.
(4).Cerebrospinal fluid leak repair.
The vast majority of surgeries can be performed by transnasal pterygoid sinus approach, and only a few drug-resistant invasive giant pituitary adenomas require craniotomy. In recent years, with the development of instruments and equipment such as neuronavigation and endoscopy and the improvement of minimally invasive surgical techniques, experienced surgical teams can make the transsphenoidal sinus approach more precise, safer, with less damage and fewer complications. Therefore, transsphenoidal approach is another option for patients with pituitary prolactin adenoma in addition to drug treatment.
Indications for surgery.
(1).Pituitary microadenoma with ineffective or poor results after 3-6 months of drug treatment.
(2) Patients who cannot tolerate the large response to drug treatment.
(3) Giant pituitary adenoma with obvious visual pathway compression, and drug therapy cannot control blood prolactin and reduce tumor volume. Or after 3-12 months of drug treatment, the blood prolactin level decreases to normal, but the tumor volume remains unchanged, it is necessary to consider the possibility of pituitary non-functional adenoma.
(4).Invasive pituitary adenoma with cerebrospinal fluid nasal leakage, or cerebrospinal fluid nasal leakage after drug treatment.
(5), Those who have insufficient psychological ability to survive with tumor or refuse to take long-term medication.
(6).Pituitary tumor stroke caused by medication or other reasons, showing severe headache and acute vision loss.
(7), pituitary macroadenoma with cystic changes, drug therapy usually cannot reduce the size of the tumor.
(8), Experienced operators believe that there is a high expectation of total surgical resection and that the patient’s willingness to operate is fully considered.
There are almost no absolute contraindications to surgery, and the vast majority of relative contraindications are associated with poor general status and organ dysfunction. In these patients, treatment to improve the general condition should be performed prior to surgical treatment.
The surgical outcome is related to the experience of the surgeon, the size of the tumor, the degree of invasiveness and the duration of the disease. Surgical results for microadenomas are better than for larger adenomas. In most large pituitary treatment centers, 60-90% of patients with microadenomas achieve normal postoperative prolactin levels, while a lower percentage, about 50%, of patients with macroadenomas achieve normal, and the rate of postoperative biochemical remission for large, aggressive pituitary tumors is almost zero. Preoperative blood prolactin levels are negatively correlated with postoperative remission rates and can be used as a reference indicator to determine surgical prognosis in patients with preoperative blood prolactin <200>200 μg/L.7 Dopamine agonists can cause partial tumor fibrosis, but whether this increases the difficulty and risk of surgery. It is controversial. Recently, some authors have suggested that preoperative pharmacotherapy can improve the rate of total tumor resection cited. In patients with normal postoperative prolactin levels, recurrence is observed in 0%-40% of patients in the long term. Factors affecting the determination of recurrence are the criteria for postoperative remission, the duration of follow-up and the proportion of pituitary microadenomas. The recurrence rate at 5 years after surgery is approximately 20%. The blood PRL level on postoperative day 1 can reflect the prognosis more accurately and can be used as one of the evaluation indicators of the efficacy of surgery. Some operators believe that those whose prolactin levels fall below 10 μg/L immediately after surgery have not seen recurrence 5 years after surgery. The recurrence rate of pituitary macroadenomas is significantly higher than that of microadenomas. Mild postoperative prolactin elevation may also be associated with pituitary stalk effects due to pituitary stalk deviation or surgical damage to the pituitary stalk and does not necessarily indicate residual tumor or recurrence.
Endocrine complications of transsphenoidal surgery include anterior pituitary hypoplasia, transient or persistent uremia, and inappropriate secretion of antidiuretic hormone (ADH). Other complications include injury to the optic nerve, injury to the peripheral neurovascular, cerebrospinal fluid nasal leak, nasal septal perforation, sinusitis, and skull base fracture, among which rare complications include injury to the cavernous sinus segment of the carotid artery that can be life-threatening. However, in recent years, the complication rate of pituitary tumor surgery in experienced operators has been decreasing year by year. The overall complication rate of surgery for pituitary microadenomas does not exceed 5%. Mortality Although the complication rate of open surgery is high, drug-resistant giant pituitary adenomas are after all a minority, and the aim of surgery is to reduce the size of the tumor as much as possible, not to cut the tumor completely. It is recommended that patients go to hospitals with rich experience in pituitary tumor surgery to complete the surgery, which can reduce surgical complications, preserve residual pituitary function and improve surgical efficacy.
Radiotherapy for pituitary prolactin adenoma
External beam radiotherapy (EBRT) and stereotactic radiosurgery (SRS) treatment
1. Indications: Since dopamine agonist drug therapy has good efficacy in prolactin adenoma, and surgical resection of tumor or decompression can rapidly relieve the occupying effect and clinical symptoms, in most cases, EBRT and SRS are only used as options for patients with drug ineffectiveness, intolerance, residual or recurrence after surgery, or some aggressive or malignant prolactin adenoma.
2. Methodology and dosimetry: Currently, EBRT includes Intensity-modulated Radiotherapy (IMRT) and Image-guided Radiotherapy (IGRT) techniques, which can achieve image localization and target area shaping of treatment. The typical total treatment dose is 45 -54 Gy at 1.8-2 Gy/d, with 5d of treatment per week for 5 -6 weeks. It is used for larger, or aggressively growing tumors.
SRS is a special form of radiation therapy in which a single high dose of radiation, or a large fraction (≤5 times) of precisely focused irradiation on the target area, guided by a stereotactic head frame, kills tumor cells more effectively. The most common devices include gamma knives, modified linear gas pedals, and proton beam devices. A single dose of SRS, typically 12 -16 Gy around the target area for smaller tumors, is sufficient to control tumor growth. Higher doses are required to achieve normalization of hyperprolactin, and the dose can be as high as 20 – 35 Gy around the periphery for small secretory adenomas with a certain efficacy latency.
3. Efficacy evaluation: Whether EBRT or SRS, simple control of tumor growth can reach 89%-100%; normalization of hyperprolactin levels is only about 30%. The latency period for normalization of hyperprolactin levels has been reported to be months to years, and SRS is shorter than EBRT.
4. The problem of combined drug therapy: theoretically, drug therapy has a protective effect on tumor cells, which may affect the effect of radiation. It is better to stop the use of hormone suppressing drugs 1 – 2 months before radiation therapy, and then continue the treatment of these drugs after 1 week of radiation therapy.
5. Adverse effects: The cumulative risk of pituitary hypoplasia in 10-20 years after conventional radiotherapy can exceed 50%, and even 100% has been reported. the incidence of new pituitary hypoplasia after GKRS is about 0-33%, with a peak of 4-5 years. The probability of damage to the optic nerve is 1%-2%. Cerebrovascular disease in the distant post-radiotherapy period, neurocognitive impairment cannot be ignored.
VII. Pregnancy-related management of patients with pituitary prolactin adenoma
The basic principle is to limit fetal exposure to the drug for as little time as possible.24 Bromocriptine is safe for the fetus. The likelihood of tumor growth in patients with macroadenoma is more than 25%.
In patients with microadenomas prior to pregnancy, prolactin levels drop to normal and pregnancy is possible after regular menstruation resumes. However, due to the need for maintenance of luteal function, the drug should be discontinued after 12 weeks of pregnancy; for women with macroadenomas who have fertility requirements, pregnancy should be allowed only after bromocriptine treatment has reduced the size of the adenoma, and the drug is recommended throughout pregnancy.
In patients with pre-pregnancy pituitary prolactin adenoma, attention should be paid to clinical manifestations such as visual field defects, headache, vision loss, especially visual field defects or cavernous sinus syndrome, and in case of tumor stroke, bromocriptine should be added immediately, and if improvement is not seen within 1 week, surgical treatment and early termination of pregnancy should be considered ( when the pregnancy is close to full term).
VIII. Lactation medication in pituitary prolactin adenoma
There is no evidence to support that breastfeeding stimulates tumor growth. For women who wish to breastfeed, dopamine agonists should generally be used until the patient wishes to end breastfeeding, unless pregnancy-induced tumor growth requires treatment.
IX. Infertility-related treatment for patients with pituitary prolactin adenoma
1. Infertility-related treatment for female patients with prolactin adenoma: (l) medication for those who still do not ovulate even after normal prolactin levels. Oral ovulatory drugs such as clomiphene or letrozole can be used to promote ovulation, but it should be noted that oral ovulatory drugs are only suitable for patients with certain functions of hypothalamic-pituitary axis, i.e. those who can have withdrawal bleeding with progestin alone, and those with pituitary macroadenoma or more serious surgical destruction of pituitary tissue are not effective. (2) Gonadotropin ovulation promotion in low gonadotropin patients: Patients with low gonadotropin amenorrhea due to pituitary adenoma compression or postoperative destruction of pituitary tissue and impaired function can use exogenous human gonadotropin (Gn) to promote ovulation. gn is divided into human pituitary gonadotropin and human chorionic gonadotropin (hCG). Human pituitary gonadotropins are divided into follicle stimulating hormone (FSH) and luteinizing hormone (LH). For infertility treatment, human postmenopausal urinary gonadotropin (HMG) can be used to promote follicle maturation followed by HCG to induce ovulation.
2, male prolactin adenoma patients infertility related treatment: pituitary prolactin adenoma after drug treatment, blood PRL levels to normal, male hypothalamus – pituitary – gonadal axis functional abnormalities can generally be restored to normal, erectile dysfunction and low libido significantly improved, spermatogenic ability also gradually restored. Some patients with gonadotropin cell dysfunction due to pituitary tumor compression or surgical injury, whose testosterone level cannot be restored to normal even after the serum PRL level is reduced, should be treated with androgen supplementation at the same time to restore and maintain male secondary sexual characteristics or treated with gonadotropin to restore fertility.