Prolactin (PRL) adenoma is the most common functional pituitary adenoma, accounting for about 40-45% of functional pituitary adenomas in adults, with female patients aged 20-50 years old and a male to female ratio of about 1:10 in adults.
Standardized diagnosis and treatment of pituitary prolactin adenoma is of great significance for restoring and maintaining normal pituitary function and preventing tumor recurrence.
1. Clinical manifestations (omitted)
2. 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.
2.1 Hyperprolactinemia: For patients with suspected pituitary prolactin adenoma, the requirements for venous blood sampling for prolactin measurement are: eat a normal breakfast (type of carbohydrate, avoid protein and fatty foods), and take blood by venipuncture after a half-hour rest at 10:30-11:00 am. If serum prolactin >100-200ng/dl and other specific causes of hyperprolactinemia are excluded, the diagnosis of prolactin adenoma is supported. If serum prolactin is <100ng/dl, the diagnosis must be made with caution in the context of the specific situation.
2.2 Imaging of the saddle area: MRI-enhanced imaging of the saddle area helps to detect pituitary adenoma, and dynamic enhancement imaging helps to detect pituitary microadenoma.
3. Differential diagnosis (omitted)
4. Pharmacological treatment of pituitary prolactin adenoma
4.1 Indications for pharmacological treatment
The purpose of treatment is different for different sizes of pituitary prolactin adenoma. For patients with microprolactin adenomas, the aim of treatment is to control PRL levels and preserve gonadal and sexual function; for patients with large or giant prolactin adenomas, in addition to controlling PRL levels and preserving pituitary function, it is necessary to control and reduce tumor size, 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.
4.2 Drug selection
Dopaminergic agonist (DA), the treatment of choice for patients with PRL adenoma, is currently available as bromocriptine (BRC) and cabergoline (CAB), and others as pergolide and quinagolide. The drugs normalize PRL levels and reduce tumor size significantly in the majority of patients, and the treatment is indicated for tumors of all sizes. Because pergolide and quinagolide are less commonly used, they are not recommended in this consensus.
4.2.1 Bromocriptine
Dosing: The initial dose for BRC (2, 5 mg per tablet) treatment is 0, 625-1, 25 mg per day, recommended to be taken orally at night with snack before bedtime. Increase 1, 25mg at weekly intervals until reaching two or three tablets per day. The side effects of upper gastrointestinal discomfort and upright hypotension are reduced by a slow dosing schedule and by taking the tablets with a snack at bedtime. A dose of 7 or 5 mg per day is the effective therapeutic dose and can be gradually increased to 15 mg per day if tumor volume and PRL are not well controlled. continued dosing does not further improve the therapeutic outcome and therefore high doses above 15 mg are not recommended, but rather a change to CAB therapy is recommended. Since BRC 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.
4.2.2 Cabergoline
The initial therapeutic dose of CAB (0,5mg per tablet) is 0,25-0,5mg per week, and the dose is increased by 0,25-0,5mg per month until the PRL is normal, and the dose rarely needs to be more than 3mg per week. compared with BRC, CAB is more convenient to take and better tolerated by patients, and patients who are resistant to bromocriptine can choose CAB treatment.
4.2.3 Drug side effects
BRC side effects include: headache, dizziness, nausea, vomiting, peptic ulcer and other gastrointestinal symptoms, nasal congestion, constipation, postural hypotension, and even shock manifestations in severe patients; fatigue, anxiety, depression, alcohol intolerance; drug-induced pituitary tumor stroke. cAB side effects are the same as bromocriptine, gastrointestinal side effects are milder than bromocriptine, other include psychiatric disorders, potential heart valve disease.
4.3 Treatment of prolactin microadenoma
The primary goal of clinical treatment of PRL microadenomas is to preserve gonadal and reproductive function, and this goal is achieved significantly with drug therapy, i.e., the drugs are effective in controlling PRL levels, and with long-term effective DA therapy, 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 with menopause can receive estrogen therapy, but PRL levels should be evaluated periodically, including review of dynamic-enhanced MRI to observe changes in tumor size.
4.4 Treatment of prolactinomatous adenomas and giant adenomas
Treatment of patients with prolactinomatous or giant adenomas involves reducing tumor size to improve clinical symptoms in addition to controlling PRL levels and preserving pituitary function. 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 at longer intervals thereafter.
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 drops 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. For this reason, patients with large or giant adenomas need to be closely followed up after dose reduction or discontinuation.
5.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 levels, systemic condition, response to medication, the patient’s wishes, and fertility requirements. Since microadenomas account for the majority of pituitary prolactin adenomas and the majority do not grow, surgical intervention is not usually the first choice.
The goals of surgical treatment: (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 using a 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 sinus approach surgery is also an alternative to pharmacological treatment for patients with pituitary prolactin adenoma [11].
Indications for surgery: (1) Pituitary microadenomas that have been ineffective or poorly treated with medication for 3 to 6 months [5]. (2) Those who cannot tolerate a large response to drug therapy. (3) Giant pituitary adenoma with significant optic pathway compression, where drug therapy cannot control blood prolactin and reduce tumor size. Or after 3 to 12 months of drug treatment, blood prolactin level decreases to normal, but the tumor volume remains unchanged, the possibility of pituitary non-functional adenoma needs to be considered [6]. (4) Invasive pituitary adenoma with cerebrospinal fluid nasal leakage, or those who develop cerebrospinal fluid nasal leakage after drug treatment. (5) Those who have insufficient psychological tolerance to survive with tumor or refuse to take long-term drug therapy. (6) Those who have a stroke of pituitary tumor caused by medication or other reasons, showing severe headache and acute vision loss. (7) Pituitary macroadenoma with cystic degeneration, where drug therapy usually fails to reduce the size of the tumor. (8) High expectation of total surgical resection as perceived by experienced operators and with full consideration of the patient’s wishes for surgery [6].
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 to 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 giant invasive 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 the prognosis of surgery in patients with preoperative blood prolactin <200ng >200ng/mL [8]. Dopamine agonists can cause partial tumor fibrosis, but it is controversial whether they increase the difficulty and risk of surgery. Recently, some authors have suggested that preoperative pharmacotherapy can improve the rate of total tumor resection [7]. Recurrence is observed in 0% to 40% of patients with normal postoperative prolactin levels 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 the first postoperative day 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 ng/ml in the immediate postoperative period have not seen recurrence 5 years after surgery [9]. The recurrence rate of pituitary macroadenomas is significantly higher than that of microadenomas [10]. Those with 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 do not necessarily indicate residual tumor or recurrence.
Endocrine complications of transsphenoidal sinus surgery include anterior pituitary hypoplasia, transient or persistent uremia, and inappropriate antidiuretic hormone (ADH) secretion. The incidence of persistent postoperative anterior pituitary hypoplasia is negatively correlated with tumor volume size. Other complications include injury to the optic nerve, injury to the peripheral neurovascular, cerebrospinal fluid nasal leakage, nasal septal perforation, sinusitis, and skull base fracture, among which rare complications include injury to the cavernous sinus segment of the carotid artery, which 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 pituitary microadenoma surgery does not exceed 5%, and the mortality rate is <1%, and the complication is mostly transient uropygias. 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 remove it completely. It is recommended that patients complete the surgery at a hospital with extensive experience in pituitary tumor surgery, which can reduce surgical complications, preserve residual pituitary function, and improve surgical outcomes. < span="">
6. Radiotherapy for pituitary prolactin adenoma (omitted)
7. Pregnancy-related management of patients with pituitary prolactin adenoma
The basic principle is to limit fetal exposure to the drug to as little time as possible. The incidence of spontaneous abortion, intrauterine fetal death, and fetal malformation after pregnancy in women with pituitary prolactin adenoma treated with bromocriptine is similar to the incidence of obstetric abnormalities in normal women with pregnancy; patients with prolactin microadenoma have less tumor growth after pregnancy, whereas patients with macroadenoma have a 25% or greater likelihood of tumor growth after pregnancy.
In patients with microadenomas before 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 with fertility requirements, pregnancy should be allowed only after bromocriptine treatment to reduce the size of the adenoma, and the drug is recommended for the entire duration of pregnancy.
In normal individuals, PRL levels gradually increase after pregnancy, but not more than 300-400 ng/ml. In patients with pre-pregnancy pituitary prolactin adenoma, the main 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. if there is no improvement within 1 week, surgical treatment should be considered and pregnancy should be terminated as soon as possible ( when the pregnancy is close to full term).
8. Lactation in patients with pituitary prolactin adenoma
There is no evidence to support that breastfeeding stimulates tumor growth. In 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.