Abstract: Pituitary prolactin adenoma is the most common type of functional pituitary adenoma, accounting for about 40-60% of all pituitary tumors encountered in clinical practice. Dopamine agonists represented by bromocriptine have achieved very good efficacy in the treatment of prolactinomas; surgery is still one of the main treatment methods, and a number of people currently advocate a combination of drug and surgery; radiotherapy is also an adjuvant treatment method.
Keywords: pituitary prolactinoma; bromocriptan; progress in surgical treatment.
The natural history of prolactinomas, especially their growth potential, is now better understood. From a clinical point of view, they can be divided into two main groups (although histopathologically indistinguishable): some prolactinomas seem to present only as microadenomas, they have clearer borders, have minimal growth potential and are very effective when surgically removed. Others show some aggressive growth potential and are often large adenomas by the time they are detected; they tend to recur in situ and are often difficult to completely remove surgically.
From some prospective clinical observations and incidental findings of lactogenic adenomas at autopsy we can assume that all macroadenomas develop from microadenomas, but not all microadenomas develop into macroadenomas. This is a very important clinical concept and has been repeatedly confirmed by a series of clinical observations. In an earlier report1 of 43 patients with untreated lactogenic microadenomas followed for 4 years by tomographic X-ray or CT, only 2 patients had tumor enlargement; similar results were obtained by Weiss2 and colleagues, who observed 27 patients with untreated lactogenic microadenomas for 6 years and found imaging-confirmed tumor enlargement in only 3 patients; and Sisam3 found that the tumor enlargement in 38 patients with untreated lactogenic microadenomas was confirmed by imaging. In another report4 , tumor enlargement was confirmed in 2 of 13 patients over 5 years of observation. From the above studies and some other similar clinical observation studies, we can conclude that the chances of lactogenic microadenoma developing into macroadenoma are small, about 3-7%; for macroadenoma, once found, most of them need treatment, so the natural history of the tumor is not clear.
1. Clinical manifestations.
Although the “amenorrhea-lactation” syndrome was noticed early, it was only in recent times that Forbes5 and his associates linked it to pituitary tumors.
The clinical manifestations of prolactinoma are divided into two main aspects: endocrine changes and tumor dominant effects. Since high PRL can affect the pulsatile release of GnRH, the initial endocrine function alteration is often hypogonadism. In women of reproductive age, it often manifests as various forms of menstrual disorders, typically secondary to amenorrhea, infertility, and 30% to 80% may have lactation. In the long-term course of the disease, hypogonadism due to estrogen deficiency is also seen. Nearly half of the patients have headaches, since the majority are microadenomas and headaches are not strongly related to tumor size. It is also difficult to explain that female patients with prolactinomas can exhibit a variety of psychiatric and vegetative symptoms, such as hostility, depression, anxiety, and weight gain.
In the absence of menstrual disorders as an early symptom, male and postmenopausal female patients often lack early manifestations and are often detected only after the onset of occupying effects. So the typical presentation is headache and visual dysfunction. Because the tumors are often large, they are often associated with varying degrees of hypopituitarism. In men, high PRL can also lead to hypogonadism, such as decreased sexual drive, impotence and relative infertility, but these symptoms are often overlooked by the patient or delayed by the physician because they are considered “functional”. About 1/3 of male patients exhibit lactation, but often require forceful breast compression.
Osteoporosis, a common complication of hyperprolactinemia, was previously thought to be a direct result of hyperprolactin, but is now more likely to be caused by hypogonadism.
2. Laboratory tests
Plasma PRL is usually less than 20 ng/L under normal circumstances, excluding pregnancy and lactation, and if PRL is greater than 200 ng/L, this alone is often sufficient to confirm the diagnosis of prolactin adenoma. However, for minor elevations, careful identification is needed. Some medications such as chlorpromazine, gastrodin, haloperidol, and isoptin can cause elevated prolactin; care should be taken to exclude hypothyroidism, chronic renal failure, and cirrhosis, especially hypothyroidism, which is often misdiagnosed as a tumor due to secondary pituitary enlargement.
After excluding medical diseases and drug effects, saddle area lesions should be considered. Generally, PRL greater than 200 ng/L is almost always caused by simple or mixed prolactin adenoma, if greater than 1000 ng/L suggests invasive prolactinoma; if PRL is less than 200 ng/L it may be a microadenoma, but other pituitary tumors or other lesions in the saddle area such as craniopharyngioma and lymphocytic pituitary inflammation can be caused by “pituitary stalk effect However, other pituitary tumors or other lesions in the saddle area, such as craniopharyngioma and lymphocytic pituitaryitis, can cause elevated PRL through the “pituitary stalk effect.
3.Treatment
The treatment of prolactin adenoma includes drug control, surgical resection and radiation therapy. Long-term clinical practice, especially the development of the last decade, various treatment options have been comprehensively studied. The existence of various treatment options is the best proof of their mutual advantages and limitations. Factors such as tumor size, PRL level, clinical presentation and patient’s requirements are all factors in choosing treatment options, especially in relation to medical or surgical treatment.
Internal treatment
Prolactinomas are the only pituitary adenomas for which drug therapy is effective and is the primary treatment option. Continuous administration of dopamine agonists can normalize PRL, restore fertility and reduce tumor size, making them the treatment of choice for most prolactinomas.
The mechanism of action of dopamine receptor agonists includes the classic bromodomain receptor model: first binding to D2 receptors on the cell surface, inhibition of adenylyl cyclase through a series of signaling mechanisms leading to a decrease in cAMP concentration and a decrease in intracellular Ca concentration, both of which act together to cause a decrease in prolactin synthesis and secretion. Histological examination of tumors from patients who had taken dopamine agonists preoperatively revealed a significant reduction in cytoplasm and atrophy of the rough endoplasmic reticulum and Golgi complex in sensitive patients. At the subcellular level, reduced PRL mRNA levels and diminished immunohistochemical response confirmed reduced PRL gene transcription and expression; PET also confirmed a significant reduction in tumor metabolism after drug administration; long-term dopamine agonist administration may lead to varying degrees of tumor tissue calcification, amyloidosis, and perivascular and interstitial fibrosis, the latter of which may adversely affect future surgical treatment.
There are two other points to note about drug therapy: first, although 90% to 95% of patients respond well to drug therapy, there are varying degrees of sensitivity, and significant decreases in PRL levels, tumor volume reduction and visual improvement can occur weeks, days or even hours after drug administration; there are still some patients who are completely resistant to the drug, with neither a decrease in PRL levels nor tumor reduction, and in these cases, it was found that In some cases, the dopamine receptor or post-receptor transmission mechanism of the tumor cells was found to be defective. Furthermore, with the exception of fibrosis, many of the drug’s effects are reversible, and maintenance of drug efficacy requires long-term administration. Almost without exception, plasma PRL and tumor size quickly return to pre-drug levels after drug discontinuation.
A large body of literature reports46 that bromocriptan and similar drugs such as Pergolide and Cabergolin49 are effective in the treatment of lactogenic adenomas. In an analysis of 13 literature reviews, 64% to 100% of female patients with prolactinoma who received bromocriptine as initial treatment had normalized PRL and 57% to 100% had restored menstruation and normal ovulation.9 Molitch9 reviewed a series of 19 published studies and approximately 77% of 236 patients had varying degrees of tumor reduction.
The reliable efficacy of drug therapy makes it the treatment of choice for most patients. For microadenomas, numerous reports have shown that 70% to 100% of patients had a reduction in PRL levels to normal, resumption of menstruation, cessation of lactation, restoration of fertility and tumor shrinkage. In the case of prolactinomatous macroadenomas, pharmacological treatment has significantly compromised the status of surgical treatment as the treatment of choice. In a retrospective analysis, 67% of 27 cases of lactational macroadenoma treated with bromocriptan alone returned to normal PRL and more than half of the patients had tumor shrinkage of 50% or more.
Surgical treatment.
Surgery was once the mainstay of treatment for prolactinomas, and the advent of dopamine agonists has led to a marked decline in its status. However, surgery remains one of the main treatments for prolactinoma and in some cases is still the most effective method. The main surgical modality is transsphenoidal surgery, and in recent years, with the development of endoscopy, endoscopic transsphenoidal pituitary adenoma resection has achieved better results; the current indications for surgical treatment are.
(1) Prolactin microadenoma: resistance or weak sensitivity to dopamine agonists; intolerance of drug side effects; patient refusal of long-term medication; prolactin macroadenoma; pituitary stroke; cystic prolactinoma; resistance or weak sensitivity to dopamine agonists; tumor decompensation in order to increase the effectiveness of drugs and radiotherapy; obvious invasion of the pterygoid sinus, drug therapy may lead to cerebrospinal fluid leakage; women who wish to become pregnant the risk of tumor enlargement during pregnancy can be reduced by surgical treatment; the presence of a predominant effect during pregnancy; an unclear diagnosis requiring exploration for pathological biopsy.
Pituitary stroke is one of the clearest indications for surgery; when MRI suggests that most of the tumor has a necrotic or hemorrhagic composition, drug therapy is often not good enough to shrink the tumor; cystic lesions of prolactinomas also do not shrink satisfactorily under the action of drugs, and surgery is the best option; a small percentage of patients cannot tolerate the side effects of bromocriptine, consider switching to carte blanche or other similar drugs; if still not tolerated, consider Another indication makes dopamine agonist resistance, which generally includes two cases. In this case, the tumor itself may not be a prolactin adenoma, but a pituitary stalk effect causing elevated prolactin. Both of these cases are indications for surgery; then there is the possibility that drug treatment may lead to cerebrospinal fluid leakage when the tumor severely invades the skull base, and surgery needs to be considered.
The greatest advantage of surgical treatment is that it can cure the tumor, but for macroadenomas, only a small number of patients can be cured. For all so-called “radical” resections, there is always a recurrence rate after a certain period of time.
(2) Microadenomas: Cure resection, i.e., postoperative reduction of prolactin to normal, is highest in microadenomas, especially in those with preoperative PRL less than 100 ng/L. In the Mayo series of 100 cases, the curettage rate for 32 microadenomas with preoperative PRL less than 100 ng/L was 88%. For large adenomas or those with high PRL, the surgical cure rate was significantly lower, and for cases with preoperative PRL greater than 100 ng/L, the surgical cure rate was only 50%. Similar findings have been reported in other studies.27 Molitch summarized 31 studies totaling 1224 cases of prolactin microadenomas, with an endocrinological cure rate of 71.2% without consideration of preoperative PRL levels. Also in a multicenter clinical study of 1518 cases, Zervas reported an overall surgical cure rate of approximately 74%.
(3) Macroadenomas: The results of surgical treatment of lactogenic macroadenomas are less than satisfactory; the Mayo Clinic reported that only 53% of patients with surgically treated macroadenomas ever achieved normal postoperative PRL levels; and for patients with localized invasion, the surgical cure rate was only 28%. Other clinical studies have reported similar results.9 Molitch9 summarized 31 studies totaling 1256 cases of lactogenic macroadenomas, with an overall surgical cure rate of only 31.8%. In a multicenter clinical study of 1,022 cases of lactogenic macroadenomas, Zervas reported an overall surgical cure rate of about 30 percent. In patients who fail pharmacologic therapy, most patients are surgically relieved of the tumor’s dominant effect, but endocrine cure is difficult to achieve.
Preoperative PRL levels predict the outcome of surgical treatment. The decreasing level of PRL in the immediate postoperative period is a useful indicator of surgical cure, and lower than normal levels, especially less than 10ng/L, often predict long-term cure; for those with postoperative PRL between 11 and 20ng/L, cure is also generally considered to be achieved, but these patients have the possibility of future recurrence29.
To improve the outcome of surgical treatment, some suggest preoperative dopamine agonist medication. In a retrospective controlled analysis, preoperative bromocriptine was applied in 20 cases,20 and the surgical cure rates were 87% and 50% for microadenomas and 33% and 17% for macroadenomas, respectively, in the control group alone; Weiss2 reported that in 19 patients with macroadenomas taking preoperative bromocriptine, 10 obtained a tumor shrinkage rate of 30% or more, and 70% of the affected patients returned to normal PRL after surgery, and the other 9 had a tumor In the other 9 cases, the tumor shrinkage was below 30%, and only 22% of PRL returned to normal after surgery. In China, Yu Chunjiang42 reported 30 cases of invasive giant adenoma in two groups, group A was treated with surgery first, and combined with drug therapy and radiotherapy after surgery, while group B was treated with drug therapy first, and some patients were considered for radiotherapy or surgery after tumor shrinkage. For preoperative drug treatment has theoretical feasibility, and combined with the hospital’s experience, this strategy can improve the surgical outcome to some extent.
4. Postoperative recurrence.
Postoperative recurrence must be taken into account when comprehensively evaluating the surgical effect. Generally speaking, tumor recurrence refers to elevated PRL, while recurrence is often not seen on imaging. The endocrinological recurrence rate varies widely among reports. Serri29 reported a 4-year recurrence rate of 50% for microadenomas and 80% for macroadenomas at 2.5 years, although this study was carefully designed and widely cited, and it has the highest recurrence rate reported to date. Post and Habas reported recurrence rates of 17% for microadenomas and 20% for macroadenomas, respectively, after more than 5 years of follow-up.
In most recurrence cases, especially in patients with microadenomas, there tends to be only elevated PRL with little evidence of imaging recurrence. For example, in a group of 58 patients with prolactin adenomas treated by butterfly surgery over a 10-year follow-up35, 43% had mild mild elevations of prolactin, but only 2 had imaging findings of tumor recurrence. This phenomenon is difficult to explain and is generally thought to be due to a pituitary stalk effect. In the vast majority of cases there is only a mild elevation of PRL, which is asymptomatic and self-resolving, and is rarely accompanied by evidence of imaging recurrence and generally does not require treatment.
5. Observation.
Microadenomas with no obvious symptoms and no requirement for fertility may be left untreated for the time being. Prolactin microadenomas develop slowly, and about 10% can disappear on their own without treatment. Regular monitoring of prolactin and MRI of the saddle area is necessary.
Radiation therapy.
Radiation therapy is rarely used for the treatment of prolactinomas because medication and surgery can cure and control them well. It is generally used for aggressive tumors that are not responsive to drugs and are difficult to remove surgically. Currently, the main types of radiotherapy are general radiotherapy, X-blade, and r-blade. From previous reports38-40, radiotherapy has a moderate effect on controlling tumor growth, but the proportion of normalized PRL varies from one report to another about 30-70%. The most common complication of radiotherapy is pituitary function, which is up to 100% 10 years after common radiotherapy. There are also radiation encephalopathy, tumor induction, and vision loss, etc. The long-term follow-up data for stereotactic radiotherapy is incomplete. From the current reports, the efficacy of tumor growth control is confirmed, but the endocrine cure rate is low, but the side effects are less than those of conventional radiotherapy.
Problems related to fertility and pregnancy: The three basic problems related to fertility and pregnancy are: infertility, tumor enlargement due to pregnancy, and the effect of treatment on the fetus.
The normal pituitary gland doubles in size during pregnancy, and tumors also increase in size, with symptomatic enlargement of about 1.6% for microadenomas and 4.5% for imaging. Macroadenomas are more likely to enlarge during pregnancy, with symptomatic and asymptomatic enlargement of 15.5% and 8.5%, respectively, while in patients who have undergone surgery or radiation therapy, the enlargement rate decreases significantly to approximately 4.3%.
In pregnant patients, the effect of treatment on the fetus must be considered. Previous clinical studies have shown that normalization of PRL, resumption of menstruation and ovulation and eventual pregnancy with bromocriptine discontinuation at 3-4 weeks of gestation does not increase the rate of malformation or miscarriage and does not affect fetal developmental indicators. There are also data showing that it is safe to take bromocriptan even during the whole pregnancy. The Department of Endocrinology of our hospital has conducted a systematic survey on the growth of the first batch of “bromocriptan” children in China, and found that their growth, intelligence and psychological development were not significantly different from those of normal births; however, some gender differences were found, with a predominance of males. Nevertheless, theoretically, the shorter the fetal exposure to the drug, the better. No complete information is available for other dopamine receptor agonists. Surgery of any kind during pregnancy increases the rate of fetal abortion, which is approximately 1.5-fold greater in the first trimester and 6-fold greater in the second trimester. From the available information, surgery has a greater effect on the fetus than drugs.
The pregnancy rate for patients with prolactin microadenoma is 85% for surgery and 80% for medication. For patients treated with bromocriptan, once pregnancy is detected, the medication should be stopped immediately and careful clinical observation should be made to detect symptoms caused by tumor enlargement as early as possible. Because PRL should be physiologically increased during pregnancy, it does not reflect tumor growth, but a significant increase often indicates tumor enlargement.
For patients with prolactin macroadenoma who wish to have children, several options are available, but all are designed to reduce the risk associated with tumor enlargement during pregnancy by 15-35%. One is the traditional conservative option of first surgical resection and if the PRL remains high after surgery, starting bromocriptine therapy until pregnancy, which greatly reduces the chance of tumor enlargement (4.7%); the other option is to take bromocriptine and discontinue it immediately after pregnancy.