Pituitary prolactin (PRL) adenomas are the most common functional pituitary adenomas, causing amenorrhea, lactation and infertility in women and hypoactive sexual desire and impotence in men. Prolactin macroadenomas can cause visual field disturbances, hypopituitarism and cavernous sinus invasion due to their dominant effect, and hyperprolactinemia can also cause osteoporosis due to its sex hormone suppressing effects. The goals of treatment for pituitary PRL adenoma are to normalize PRL, restore reproductive function, reduce tumor size, and relieve symptoms of hypogonadism. The treatment mainly includes medication with dopamine agonists and surgery, and radiation therapy is required for a very small number of cases where medication and surgery are ineffective.
1.Drug treatment The first choice for pituitary PRL adenoma is drug treatment. The mechanism of action is to block the transcription of PRL gene at the mRNA level after binding to D2 receptors in the cell membrane, and to make the cytoplasmic structure of lactinoma cells, especially the rough endoplasmic reticulum, which is the site of hormone synthesis and Golgi bodies, shrink significantly after lactinoma cells The atrophy of the cells can cause different degrees of calcification, amyloid precipitation, perivascular and tissue interstitial fibrosis due to the expansion of extracellular space, so the above mentioned drugs can not only reduce the blood PRL level, but also reduce the volume of PRL adenoma. Bromocriptine can normalize PRL and reduce tumor size in 80-90% of patients with pituitary PRL microadenomas and about 70% of patients with pituitary PRL macroadenomas. 90% of women with normalized PRL regained menstruation and fertility. It is a long-acting dopamine agonist with a longer duration of action compared to bromocriptine, requiring only 1-2 doses per week, with better efficacy and fewer side effects, and is more easily tolerated by patients and may be effective in patients resistant to other dopamine agonists.
Serum PRL levels need to be monitored regularly during long-term treatment with dopamine agonists, and the dose of medication should be adjusted according to PRL levels, while the frequency of MRI review can be determined on a case-by-case basis. In general, serum PRL levels correlate closely with tumor size, and it is rare to see a significant increase in tumor size prior to a significant increase in PRL. Statistical analysis of a large number of cases indicates that approximately 95% of untreated pituitary PRL microadenomas do not increase in size further. In pituitary PRL microadenomas, only regular monitoring of serum PRL is required, and MRI should be repeated only if serum PRL levels are elevated. when pituitary PRL adenomas are large, aggressive adenomas that are actively growing, MRI may be repeated more frequently, for example, once every 2-3 years. The histological markers Ki-67 and cell proliferation nuclear antigen (PCNA) in aggressive adenomas only respond to the proliferative activity of the tumor cells, and their prognostic value is limited.
All dopamine agonists have side effects, the incidence of which is about 4.5-12%. The most common side effects include nausea, vomiting, dry mouth, dyspepsia, dizziness, postural hypotension, headache, nasal insufflation and constipation. The above side effects mostly occur at the beginning of treatment and may be gradually tolerated by patients later, or may occur during treatment in some patients and be reversible after discontinuation of the drug. Patients with pituitary PRL adenoma rarely experience permanent side effects when taking 2.5-10 mg of bromocriptine daily or 0.25-2 mg of capsaicin weekly. However, there have been reports of pleural thickening, interstitial lung disease, plasma membrane fibrosis and cardiac regurgitation in patients with pituitary PRL adenomas in combination with Parkinson’s disease receiving high doses of bromocriptine, capsaicin or pergolide for prolonged periods of time. Therefore, cardiac ultrasound should be checked periodically in patients who are resistant to the drug and require high dose dopamine agonists.
Pregnancy may cause an increase in the size of pituitary PRL adenomas because estrogen stimulates the synthesis of prolactin and induces proliferation of prolactin cells. Approximately 3% of pituitary PRL microadenomas and 30% of pituitary PRL macroadenomas during pregnancy will show a significant increase in tumor size causing clinical symptoms. If pregnancy is one of the goals of treatment, bromocriptine should be preferred because its safety has been more and more extensively documented, with statistics of large cases showing that its use in early pregnancy does not increase the incidence of spontaneous abortion and congenital malformations in the infant, while once pregnancy is confirmed, bromocriptine should be discontinued and the patient should be monitored closely for changes in clinical signs at regular intervals and at least every three months A review of serum PRL is not necessary because PRL levels are not necessarily elevated in pregnancy and there is no correlation between PRL levels and increased tumor size.
The main disadvantage of dopamine agonist drug therapy is the possibility of recurrence of hyperprolactinemia and re-increase in tumor size after discontinuation of the drug. However, long-term application of dopamine agonists to pituitary PRL adenomas can cause perivascular fibrosis and cellular suicide in pituitary tissue, suggesting that dopamine agonists may permanently normalize PRL levels. In the comprehensive literature, pituitary PRL adenomas are treated with dopamine agonists for an average of 12-84 months and withdrawn after normalization of blood PRL, with an average follow-up of 6-60 months, of which 7-69% of patients continue to maintain blood PRL in the normal range. It is generally accepted that after treatment with dopamine agonists, pituitary PRL adenomas can be discontinued on a trial basis when the following criteria are met: normal PRL levels; MRI indicates the disappearance of the tumor or a 50% or more reduction in tumor volume; the tumor is more than 5 mm from the visual cross; and the cavernous sinus is not invaded. Microadenomas can be discontinued directly, while macroadenomas should be discontinued gradually, and blood PRL levels should be monitored closely after discontinuation.
Estrogen may play a role in the formation of pituitary prolactin adenomas, and oral contraceptives have an anti-estrogen effect. Oral contraceptives can also be used to treat hypogonadism in women with pituitary PRL microadenoma who do not have a childbearing requirement. Oral contraceptives are less expensive and have fewer side effects than dopamine agonists, but a mild increase in PRL may occur with oral contraceptives, and blood PRL levels need to be reviewed annually.
Although the basic and clinical research on the drug treatment of pituitary PRL adenoma has achieved great success in the past 30 years, with the development of transsphenoidal microsurgery, neuroendoscopic technology, neuronavigation technology and intraoperative MRI technology, transsphenoidal surgery for pituitary adenoma has become increasingly mature and safe, with a disability rate of less than 4% and a mortality rate of less than 0.6%. Transsphenoidal surgery has become the surgical procedure of choice for most pituitary adenomas, and it remains one of the main treatment modalities for pituitary PRL adenomas. According to the guidelines for the management of PRL adenomas developed at the 9th International Pituitary Conference held in San Diego in 2005, the classical indications for surgery for pituitary PRL adenomas include those who cannot tolerate the side effects of dopamine agonists, those who fail dopamine agonist therapy, those who develop cerebrospinal fluid leakage after treatment with dopamine agonists, and those with severe neurological deficits such as rapid vision loss or cranial nerve palsy due to tumor stroke. The dopamine agonists have been used to treat patients with severe neurological deficits such as rapid loss of vision or cranial nerve paralysis due to tumor stroke.
In recent years, it has been widely reported in the literature that pituitary PRL adenomas, especially PRL microadenomas, can be treated with butterfly surgery with very good results, at least comparable to those of dopamine agonist medication. In experienced neurosurgeons, the long-term cure rate for pituitary PRL adenomas after butterfly surgery can be 70-80%, and for pituitary PRL microadenomas, cystic PRL adenomas, and PRL adenomas confined to the saddle, the long-term cure rate can be as high as 80-92%, and for non-invasive pituitary PRL adenomas, the cure rate can be as high as 85.5% after butterfly surgery. For women with infertility due to pituitary PRL adenoma, as long as the blood PRL is normalized after surgery, their chances of pregnancy and childbirth can reach 90%, thus truly achieving the goal of eradication. In women with pituitary PRL macroadenoma who undergo surgery before conception, the chance of clinically significant increase in tumor size during pregnancy is reduced from 30% to 5%. Therefore, modern indications for surgical treatment of pituitary PRL adenomas may also include pituitary PRL microadenomas, cystic PRL adenomas, and non-invasive PRL adenomas, for which surgery may also be preferred. However, the long-term cure and remission rate of male pituitary PRL adenoma is only 23-35% after butterfly surgery alone, and it is difficult to achieve endocrinological cure for invasive pituitary PRL adenoma by surgery alone.
3.Radiotherapy Since most pituitary PRL adenomas can be treated very well with drugs and/or surgery, radiotherapy can only be used as an adjuvant treatment. Radiotherapy modalities for pituitary adenomas include conventional fractionated external radiation radiotherapy, stereotactic conformal fractionated radiotherapy and stereotactic single-dose radiotherapy, the latter of which is subdivided into gamma knife radiotherapy and linear accelerator-based stereotactic single-dose radiotherapy. Radiation therapy is generally considered only for pituitary PRL adenomas that have failed to respond to dopamine agonist medication and have tumor remnants after surgical treatment. Stereotactic single-dose radiotherapy is indicated for pituitary PRL adenomas that are confined to the saddle, are more than 5 mm away from the visual pathway, or develop mainly in the paracavernous sinus of the saddle. Fractionated radiotherapy is not only suitable for the aforementioned cases, but also for PRL adenomas that develop suprasellarly and are closer to the visual pathway. The effects of radiation therapy are slow to take effect, often taking one to several years to appear. Radiation therapy can better control the growth of pituitary PRL adenomas, but it is difficult to normalize serum PRL levels. The endocrinological remission rate of pituitary PRL adenomas after radiation therapy alone is only 0%-36.3%, with an average of 34.1% with conventional external radiation and 31.4% with single-dose stereotactic radiotherapy. The long-term complications of radiation therapy for pituitary adenoma are mainly hypopituitarism, with an average incidence of about 50% and a maximum of 78% over 10-20 years of follow-up; other complications include cerebrovascular accidents, optic nerve damage, neurological abnormalities and soft tissue reactions; hypopituitarism due to radiation therapy is even more dangerous than not receiving radiation therapy.