Prolactin adenoma is the most common type of functional pituitary adenoma, accounting for 40%-45% of adult pituitary adenomas, and is most common in women aged 20-50 years, with a male to female ratio of approximately 1:10. Standardized diagnosis and treatment of pituitary prolactin adenoma is important for 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 tend to have altered menstrual cycles, with varying degrees of scanty menstruation 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, resulting in 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 a small number of patients may also experience lactation. (3) Weight gain: the specific cause is unclear and may be related to sodium and water retention, abnormal fat differentiation, hypogonadism and abnormal hypothalamic function.
2. Local pressure symptoms of tumor: Most commonly 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 fifth 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 compression of normal pituitary tissue by macroadenoma may also cause other signs of impaired anterior pituitary function, such as hypothyroidism or hypoadrenocorticism.
3. Multi-hormone adenoma or multiple endocrine adenomatosis symptoms: Prolactin mixed adenomas that combine growth hormone, thyroid stimulating hormone, and adrenocorticotropic hormone secretion may be accompanied by other anterior pituitary hormone overproduction, such as acromegaly, hyperthyroidism, and Cushing’s syndrome.
In addition, pituitary tumors can 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 adenoma, usually in macroadenoma. Acute pituitary stroke may 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 adenoma, the requirements for venous blood sampling for prolactin measurement are: eat a normal breakfast (carbohydrate type, avoid protein and fatty foods) and take blood by venipuncture after a 0.5 h break from 10:30-11:00 am. The diagnosis of prolactin adenoma is supported if serum prolactin is >100 – 200 ug/L and other specific causes of hyperprolactinemia are excluded. If the serum prolactin is <100 ug/L, the diagnosis must be made with caution in the context of the specific case.
2. Imaging of the saddle area: MRI-enhanced imaging of the saddle area can help to detect pituitary adenoma, and dynamic enhancement imaging can help to detect pituitary microadenoma.
Differential diagnosis
1. Pathological hyperprolactinemia: mostly seen in hypothalamus? Pituitary disorders, 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 caused by impaired hypothalamic dopamine production or blockage of pituitary portal blood flow, resulting in dopamine and other PIF not reaching the adenopituitary gland.
Hyper-PRLemia due to increased PRL-releasing factor (PRF) is seen in primary hypothyroidism and stressful stimuli. Hyperprolactinemia in patients with chronic renal failure is due to impaired glomerular filtration of prolactin. Patients with cirrhosis have elevated blood prolactin due to impaired inactivation of estrogen and prolactin in the liver.
2. Physiological hyperprolactinemia: It occurs mainly during pregnancy, nipple irritation or stress. During pregnancy, the prolactin level tends to increase gradually, reaching a peak at the time of delivery, but the magnitude of the increase varies from person to person, and the cause of the increase 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 antihypertensives, opiates and H2-blockers.
Dopamine receptor antagonists are drugs with tranquilizing, sedative or antiemetic effects, as well as antidepressants and antipsychotics, whose prolactin levels generally do not exceed 100 ug/L at commonly used doses; chlorpromazine and metoclopramide (gastroflucan) have the strongest effect, with 25 mg of chlorpromazine increasing serum prolactin levels by 5-7 times in normal subjects. Prolactin levels can be increased more than 15-fold with long-term treatment with gastropromazine.
Drug treatment of pituitary prolactin adenoma
1. Indications for pharmacological treatment: The purpose of treatment is different for different sizes of pituitary prolactin adenomas. 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.
Dopamine agonist therapy is preferred for pituitary prolactin adenomas, and the recommended treatment regimen is shown in Figure 1.
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.
Drug of choice: Dopamine agonists (DA), the first choice of treatment for patients with PRL adenomas, are 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 they are indicated for tumors of all sizes. Because pergolide and quinagolide are less commonly used, they are not recommended in this consensus.
(1) Bromocriptine: Dosing: The initial dose of bromocriptine (2.5 mg/tablet) therapy is 0.625-1. 25 mg/d, recommended to be taken orally at night with a snack before bedtime. A slow titration schedule and bedtime snack are used to reduce upper gastrointestinal discomfort and upright hypotension. 7.5 mg/d is the effective therapeutic dose and may be titrated up to 15 mg/d if tumor volume and PRL are not well controlled.
Continued dose increases do not further improve treatment outcomes. Therefore, high doses above 15 mg are not recommended, but rather a change to treatment with capsaicin. 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) Cabergoline: The initial therapeutic dose of 0.5 mg/tablet is 0.25-0.5 mg/week, and the dose is increased by 0.25-0.5 mg/month until the PRL is normal, and rarely requires more than 3 mg/week.
(3) Adverse drug reactions: Adverse drug reactions of bromocriptine include: headache, dizziness, nausea, vomiting, peptic ulcer and other gastrointestinal symptoms, nasal congestion, constipation, postural hypotension, and even shock in severe patients; fatigue, anxiety, depression, alcohol intolerance; drug-induced pituitary tumor stroke. The adverse reactions of cabergoline are the same as bromocriptine, the gastrointestinal adverse reactions are milder than bromocriptine, others include psychiatric disorders, potential heart valve disease.
Prolactin microadenoma treatment: 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 who have stopped menstruating 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 prolactinomatous and giant adenomas: In addition to controlling PRL levels and preserving pituitary function, treatment of patients with prolactinomatous or giant adenomas involves reducing the size of the tumor to improve clinical symptoms. DA remains the treatment of choice for the vast majority of patients with prolactinomatous or giant adenomas, except for acute tumor stroke-induced dramatic vision loss requiring emergency surgical decompression.
DA treatment is usually effective in restoring visual function and is 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 necessary, once every 3 months after the start of treatment, then once every 6 months, and at longer intervals thereafter.
The goal of treatment is to keep PRL levels as normal as possible, and it is best to reduce PRL levels to the lowest possible value in order to minimize the size of the tumor or even cause it to disappear. Even if PRL levels are reduced to normal, adequate doses of DA are still required to further reduce the size of the tumor.
When PRL levels remain normal for at least two years and tumor size decreases by more than 50%, then DA tapering is considered, as low doses maintain stable PRL levels and tumor size during this phase. However, discontinuation of treatment can lead to tumor enlargement and recurrence of hyperprolactinemia. For this reason, close follow-up is necessary after dose reduction or discontinuation in patients with large or giant adenomas.
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 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 are: (1) Rapid relief of endocrine abnormalities and reduction of blood prolactin to normal range. (2) To preserve normal pituitary function. (3) Minimize tumor recurrence. (4) Cerebrospinal fluid leak repair.
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 pharmacological treatment.
Indications for surgery: (1) Pituitary microadenomas that have failed to respond to drug therapy for 3-6 months or have poor results. (2) Patients who cannot tolerate a large response to drug therapy. (3) Giant pituitary adenoma with significant optic pathway compression, where pharmacological treatment cannot control prolactin and reduce the size of the tumor. If the blood prolactin level decreases to normal after 3-12 months of drug treatment, but the tumor volume remains unchanged, the possibility of pituitary non-functional adenoma should be considered.
(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) Those who have a stroke of pituitary tumor caused by medication or other reasons, and who show severe headache and acute visual 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 according to experienced surgeons, with full consideration of the patient’s willingness to operate.
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 of patients with macroadenomas achieve normality, about 50%, 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 ug/L. Dopamine agonists can cause partial tumor fibrosis, but it is controversial whether they increase the difficulty and risk of surgery. Some authors have recently suggested that preoperative pharmacotherapy may improve the rate of total tumor resection.
In patients with normal postoperative prolactin levels, recurrence is observed in 0%-40% of patients over time. 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 for the efficacy of surgery.
It has been suggested that those with prolactin levels below 10 ug/L immediately after surgery have not seen recurrence 5 years after surgery. The recurrence rate is significantly higher in pituitary macroadenomas than in 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 hypopituitarism, transient or persistent uremia, and inappropriate antidiuretic hormone (ADH) secretion, with the incidence of persistent postoperative anterior hypopituitarism negatively correlating with tumor size. Other complications include damage to the optic nerve, peripheral neurovascular injury, cerebrospinal fluid nasal leak, nasal septal perforation, sinusitis, skull base fracture, and rare complications such as 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 rate of surgical complications for pituitary microadenomas is no more than 5%, with a mortality rate of <1%< span="">, and the complications are mostly transient uropygias. Although the complication rate of open surgery is high, drug-resistant giant pituitary adenomas are, after all, a minority, and the goal of surgery is to reduce the size of the tumor as much as possible, not to excise it completely. Patients are recommended to complete the surgery in hospitals with rich experience in pituitary tumor surgery, which can reduce surgical complications, preserve the function of the residual pituitary gland and improve the surgical efficacy.
Radiotherapy for pituitary prolactinoma
External beam radiotherapy (EBRT) and stereotactic radiosurgery (SRS) treatment
Indications: Because dopamine agonist drug therapy has good efficacy in prolactin adenoma, and surgical resection of the tumor or decompression can rapidly relieve the occupying effect and clinical symptoms, EBRT and SRS are mostly used as options for patients with drug ineffectiveness, intolerance, post-surgical residuals, recurrence, or some aggressive, malignant prolactin adenoma.
2. Methodology and dosimetry: Currently, EBRT includes Intensity-modulated Radiotherapy (IMRT) and Image-guided Radiotherapy (IGRT), which can achieve image localization and target shaping of treatment. The typical total treatment dose is 45-54 Gy, 1.8-2 Gy/d, 5d 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 doses), is precisely focused on the target area under the guidance of a stereotactic head frame to kill tumor cells more effectively. The most common devices include gamma knives, modified linear gas pedals, and proton Cambodian 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, up to 20-35 Gy for small secretory adenomas with a certain latency of efficacy.
3. Efficacy evaluation: Whether EBRT or SRS, tumor growth control alone can reach 8g%-100%; normalization of hyperprolactin levels is only about 30%. The latency period for normalization of hyperprolactin levels is reported to be months to years, and SRS is shorter than that of EBRT.
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 with these drugs after 1 week of radiation therapy.
Adverse effects: The cumulative risk of pituitary hypoplasia after conventional radiotherapy can be more than 50% or even 100% in 10-20 years after treatment. The probability of damage to the optic nerve is 1-2%. Neurocognitive impairment should not be neglected in distant cerebrovascular disease after radiotherapy.
VII. 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.
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 luteal maintenance, the drug should be discontinued after 12 weeks of gestation; 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 for the entire duration of pregnancy.
In patients with pre-pregnancy pituitary prolactin adenoma, clinical manifestations such as visual field defects, headache, vision loss, especially visual field defects or cavernous sinus syndrome should be taken into account, and in case of tumor stroke, bromocriptine should be added immediately. (near term).
Lactation in patients with 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 of patients with pituitary prolactin adenoma
1. Infertility-related treatment for female patients with prolactin adenoma: (1) Medication for those who still do not ovulate even after normal prolactin levels. However, it should be noted that oral ovulatory drugs are only suitable for patients with certain function of hypothalamic-pituitary axis, i.e. those who can have withdrawal bleeding with progesterone alone, and those with large pituitary adenoma or severe surgical destruction of pituitary tissue are not effective.
(2) Gonadotropin ovulation promotion in patients with low gonadotropin: 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, which 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 urogenital gonadotropin (HMG) can be used to promote follicle maturation followed by HCG to induce ovulation.
2. Treatment of infertility in men with prolactin adenoma: After pituitary prolactin adenoma is treated with medication and blood PRL levels are reduced to normal, the abnormal function of the hypothalamic-pituitary-gonadal axis in men can generally be restored to normal, erectile dysfunction and low libido can be significantly improved, and the ability to produce sperm can be gradually restored.
In some patients with gonadotropin cell dysfunction due to pituitary tumor compression or surgical injury, testosterone levels cannot be normalized even after serum PRL levels are reduced.