Overview
Prolactin (PRL) is significantly different from growth hormone in that it has lactogenic activity. In humans, prolactin is a 23 kDa, 199 amino acid peptide synthesized and secreted primarily by the prolactin cells of the anterior pituitary gland. Pituitary PRL production is inhibited by dopamine in the hypothalamus and can lead to hyperprolactinemia if the pituitary stalk is blocked. Neuropeptide thyrotropin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP) do not stimulate pituitary PRL release significantly. Prolactin is the basis for postpartum milk production and secretion. During pregnancy, elevated estrogen levels stimulate pituitary lactogen cells and lead to increased PRL secretion. However, high estrogen levels inhibit the stimulation of the breasts by PRL, so that lactation does not occur until estrogen declines after delivery.
Prolactin adenoma is the most common hormone-secreting pituitary adenoma. It is predominantly seen in female patients and relatively uncommon in males. Some studies have shown that the detection rate of prolactin microadenoma at autopsy is about 5%, which shows that most patients with prolactin adenoma are undiagnosed during their lifetime. From a clinical point of view, prolactin adenomas can be roughly divided into prolactin microadenomas (<10 mm in diameter) and prolactin macroadenomas (>10 mm in diameter). In general, prolactin microadenomas are benign, some of them may spontaneously regress and in most cases remain intact for many years, with very few extensions causing local pressure symptoms. In a study of patients with untreated prolactin microadenomas, only 9 out of 139 patients (7%) were found to have enlarged tumors. However, prolactin macroadenomas may present with pressure symptoms, often increase in size if left untreated, and rarely disappear.
Pituitary prolactin adenomas are usually disseminated. Molecular genetics show that the majority of prolactin adenomas are monoclonal in origin, suggesting that an intrinsic pituitary defect may play an important role in pituitary tumorigenesis. Prolactin adenomas may incidentally be part of multiple endocrine neoplasia syndrome (MEN-1), but screening for MEN-1 in every patient with a prolactin adenoma is of little significance. Growth hormone (GH)-PRL-secreting mixed adenomas have become widely recognized, making the association of acromegaly with hyperprolactinemia more frequent. Malignant prolactin adenomas are rare, and treatment is occasionally effective with chemotherapy if it is not effective with surgery, radiation therapy, or dopamine agonist therapy; extracranial metastases to the liver, lungs, bone, and lymph nodes occur in a relatively small number of patients with malignant prolactin adenomas.
Clinical features of prolactin adenoma
The clinical features of prolactin adenoma are due to three factors: hyperprolactinemia, tumor-occupying effects, and varying degrees of pituitary hypoplasia. The clinical presentation of each patient is determined by the patient’s gender, age, and the size of the tumor. Briefly, hyperprolactinemia stimulates lactogenesis and suppresses the release of hypothalamic gonadotropin-releasing hormone (GnRH), resulting in hypothalamic gonadal hypofunction.
Most women with prolactin microadenoma usually have premenopausal sporadic menstruation and amenorrhea (90%) combined with or with overflow of breast milk (80%); non-ovarian infertility is also a common symptom. In addition to pregnancy, hyperprolactinemia causes secondary amenorrhea in 10-20% of cases. It is important to note that most women with overflowing breasts do not have menstrual disorders, hyperprolactinemia or pituitary tumors.
Because postmenopausal women already have decreased gonadal function and low estrogen levels, hyperprolactinemia is not typical in this age group until it progresses to pituitary macroadenomas causing headaches and/or visual disturbances.
In men with prolactinoma, the main symptoms are low libido, impotence and infertility due to reduced sperm count. These symptoms are often hidden or overlooked, especially in older men, so male prolactinomas are often detected only after the tumor has grown and developed symptoms of pressure. Male overflow is uncommon but does occur occasionally; weight gain is common in men with prolactin adenoma. In both sexes, prolactin adenoma is an uncommon cause of delayed puberty, and some scholars advocate that routine measurement of serum PRL should be performed in such patients.
The long-term effect of untreated hyperprolactinemia is the well-known reduction in bone mineral density. Studies of women with hyperprolactinemia and secondary amenorrhea have shown a decrease in bone trabecular BMD of approximately 20% (10%-26%) and cortical BMD of 6% (2.5-11%). In addition to the direct effect of hyperprolactinemia, decreased estrogen also leads to decreased bone mass. Longitudinal follow-up studies of untreated women with secondary amenorrhea suggest that BMD reduction is progressive in some cases, but not in all, such as those of overweight and hyperandrogenic patients. Treated hyperprolactinemia results in a return to menstruation and an increase in BMD, although not necessarily to normal. Male patients with hypogonadism secondary to hyperprolactinemia also have a significant reduction in BMD. Compared to adult patients, adolescent patients with prolactin adenoma already have lower BMD at diagnosis and less improvement after 2 years of treatment with dopamine agonists.
Diagnostic studies
Etiology of hyperprolactinemia
The etiology of hyperprolactinemia can be simply classified as physiological, pharmacological and pathological. Normal values of PRL are less than 500 mU/L (20 μg/L) in non-pregnant women and less than 300 mU/L (12 μg/L) in men. Pregnancy is the most common cause of hyperprolactinemic menopause, and plasma PRL concentrations can rise to 8,000 mU/L (320 μg/L) in late pregnancy. Normal breastfeeding is also associated with markedly elevated serum PRL. Dopamine can inhibit physiological PRL secretion, so application of dopamine receptor antagonists can often cause hyperprolactinemia, where plasma PRL levels can rise to 5,000 mU/L (200 μg/L). Pharmacologic hyperprolactinemia is a particular problem encountered in the clinical use of sedatives (chlorpromazine) and antiemetics (methotrexate). If a patient says it is not clear whether he or she is taking such drugs, such as painkillers and antiemetics for migraine, it can make the diagnosis difficult. Similarly, some over-the-counter herbal remedies or alternative therapies contain ingredients that cause elevated PRL. Therefore, a detailed medication history is essential. As for the pathologic cause of hyperprolactinemia, it is important to exclude primary hypothyroidism. Although 10% of patients have prolactin levels greater than 600 mU/L (24 μg/L), 40% of patients have only mild hyperprolactinemia. However, some young women with hypothyroidism rarely present with typical hypothyroid symptoms, but only with menstrual disorders and overflow of milk. After venipuncture, pregnancy, interfering medications and primary hypothyroidism have been excluded, significant hyperprolactinemia is usually associated with pituitary adenoma.
Interpretation of prolactin immunoassay results
Macromolecular prolactin
It is present in human plasma as a polymorphic macromolecule, and there are three main types analyzed by gel permeation chromatography: oligomeric PRL (23 kDa), macromolecular PRL (50-60 kDa), and giant PRL (150-170 kDa). Macroprolactin is a mixture of these PRLs. IgG antibodies to PRL are detected in most, but not all, PRL fluorometric analyses. The clinical significance and biological activity of macroprolactin remains controversial. Recent studies have suggested that this PRL is evident in the plasma of up to 20% of patients with hyperprolactin. However, many hyperprolactinemic patients do not have the typical symptoms of hyperprolactinemia and preliminary data suggest that this variation in prolactin levels is not associated with macroprolactin. Macromolecular prolactin can be detected by a simple polyethylene glycan deposition method. Nowadays, a detailed pituitary examination is rarely necessary after the detection of macromolecular prolactin in largely asymptomatic patients.
Prolactin HOOK effect
If plasma PRL concentrations are very high (as in some men with large prolactin adenomas), the amount of PRL antibodies may cause a state of antibody saturation during PRL immunoradiometric analyses (IRMAs), resulting in false low PRL results. This is known as the high-dose HOOK effect and has been found in other immunoassays (e.g., beta-human chorionic gonadotropin [hCG]). This artifact can lead to misdiagnosis and receipt of inappropriate surgery in patients with prolactinomatous macroadenomas. If IRMA is applied, plasma PRL should be analyzed after being diluted in any patient with a possible prolactinomatous macroadenoma.
Dynamic Prolactin Function Tests
A number of dynamic tests have been used to evaluate hyperprolactinemia. However, a recent survey found that only 15% of UK clinical endocrinologists routinely perform dynamic PRL testing, more often with thyrotropin-releasing hormone (TRH) than with dopamine antagonists. In our experience, intravenous (iv) dopamine antagonists (e.g., 10 mg of methotrexate) are an easy and feasible procedure and provide valid clinical information, especially in patients with mildly elevated PRL. In normal individuals, dopamine antagonist administration results in significantly elevated serum PRL levels (at least 3 times basal values) with mild or no elevation of serum thyrotropin-releasing hormone (elevation of TRH < 2 mU/L). In comparison, patients with minimal pituitary lesions can exhibit extremely high TSH responses (via short tab hypothalamic feedback) because of increased dopamine tensor action on anterior pituitary thyrotropic cells.
and colleagues reviewed 84 patients with hyperprolactinemia, and screening tests included domperidone tests and high-resolution magnetic resonance imaging (MRI). They found that 18 of the 20 patients with normal PRL response to domperidone had normal MRIs, and the other two had only microadenomas. In contrast, 18 of the 64 patients with an abnormal response had lesions larger than 10 mm in diameter, and the remaining 63% were microadenomas. Thus, the dopamine antagonism test can further classify patients with hyperprolactinemia, for whom detailed pituitary imaging is necessary. In contrast, a normal PRL response to domperidone does not require this test and reduces the use of such limited resources.
Webster and colleagues described 82 patients with hyperprolactinemia who underwent surgery for suspected prolactinomas, of whom 3 had no visible tumor and only 2 of all 82 patients had normal PRL and TSH responses to domperidone. Overall, 79% of the patients had normal plasma PRL in the early postoperative period, but 3 recurred during long-term follow-up. Two of these cases had persistent abnormal responses of PRL and TSH to domperidone, even when basal PRL levels were normal.
Thus, although few patients with prolactin microadenoma now require surgical treatment, these data are important because they show that dopamine antagonism tests can reasonably identify or exclude prolactin microadenoma. Clinicians may consider biochemical evidence helpful in the management of such patients when the histologic evidence for diagnosis is unclear.
The TRH test is less useful in identifying hyperprolactinemia, and is even said to be of little help in the diagnosis of hyperprolactinemia. However, this test is useful in the evaluation of GH-secreting pituitary adenomas or gonadotropin pituitary adenomas, where some patients show a bizarre stimulation of hormone release, so the TRH test is useful in the diagnosis of such patients.
Diagnostic value of basal serum prolactin values
Basal serum prolactin values in patients with pituitary lesions are of considerable diagnostic significance. Most patients with prolactin microadenoma have a basal serum prolactin concentration of less than 5000 mU/L (200ug/L); if the serum PRL exceeds 5000 mU/L, the diagnosis of prolactin macroadenoma is usually made, and if it exceeds 10,000 mU/L, the diagnosis of prolactin macroadenoma is confirmed. Although intraparietal craniopharyngiomas and many other neoplastic or inflammatory pathologies can resemble pituitary adenomas, a patient with a pituitary lesion with a serum PRL less than 2000 mU/L (80ug/L) is usually indicative of dyslinked hyperprolactinemia rather than neoplastic hormone production, which is most commonly seen in non-functioning pituitary macroadenomas.
Some patients with pituitary macroadenomas have intermediate levels of serum PRL (2000-5000 mU/L or 80-200ug/L) making dynamic PRL function measurements inconclusive; approximately 50% of these patients have a prolactin adenoma, while the rest have unlinked hyperprolactinemia.
Pituitary imaging and ophthalmic evaluation
Similar to other pituitary and parapituitary lesions.
Pituitary function
Large pituitary adenomas can lead to hypopituitarism by directly compressing normal pituitary tissue or by disrupting hypothalamic control mechanisms. Although patients with prolactin microadenomas tend to have normal levels of GH, adrenocorticotropic hormone (ACTH), and TSH, the degree of hypopituitarism in patients with prolactin macroadenomas appears to be proportional to the size of the tumor. Often, patients with pituitary PRL macroadenomas have approximately 20% decreased ACTH and TSH levels at the time of diagnosis, and are almost simultaneously associated with GH deficiency. All patients with prolactinomas should undergo a complete pituitary function test using the methods described in Chapter 12.
Treatment of pituitary prolactin adenoma
Treatment indications
Most patients with prolactin adenoma require aggressive treatment. Infertility, menstrual disorders combined with chronic hypogonadism (secondary to osteoporosis), refractory breast discharge, and the compressive effects of pituitary macroadenomas (especially visual disturbances) are all indications for treatment. As we have seen, patients with predominantly pharmacological treatment are being treated with dopamine agonists regardless of tumor size. However, it is worth noting that pituitary macroadenomas with mild PRL elevation are most likely nonfunctional pituitary adenomas, which require surgical treatment to relieve tumor compression and histological diagnosis. Some patients with prolactin microadenomas, especially those with normal cyclic hormone levels and BMD, can be followed up.
Dopamine agonists
The use of dopamine agonists has revolutionized the treatment of patients with prolactin adenomas. A representative of this class is bromocriptine, a semi-synthetic derivative of ergometrine, which has been in use since 1971. Globally, it is probably still the most widely used dopamine agonist, but since the application of other longer-acting and better-tolerated drugs such as Cabergoline (ergometrine) and Quinagolede (quinagolide), it has led to a change in the type of medication used, at least in the West. Following the publication of results from a large controlled study with bromocriptine, many endocrinologists in the United Kingdom now use Cabergoline as the preferred dopamine agonist; studies have demonstrated that Cabergoline is superior to bromocriptine in terms of tolerability, patient compliance, and efficacy. All dopamine agonists may have uncomfortable side effects, including (in descending order of importance): upper gastrointestinal discomfort (especially nausea), postural hypotension, and Raynaud’s sign; these side effects can be gradually minimized with planned tapered dosing and mealtime dosing.
and Quinagolede are newer dopamine agonists, which were approved for use in the United Kingdom a decade ago. Recent controlled studies of these drugs, both with each other and with bromocriptine, are summarized in Table 3. Bromocriptan normalized PRL levels in 57% of patients, whereas Cabergoline normalized PRL levels in 85% of patients and Quinagolede normalized PRL levels in 78% of patients. Cabergoline was better tolerated by patients, with only 37% of patients experiencing mild adverse effects and less than 3% of patients abandoning the drug as a result. Mild adverse reactions due to bromocriptan were observed in 67% of patients and discontinued in 13% of patients. Table 4 provides a summary of the recent literature on the efficacy and tolerability of Cabergoline.
Summarizing the data from 1484 patients treated with Cabergoline (972 with microadenomas and 513 with macroadenomas), PRL levels returned to normal in 87% of patients; adverse reactions occurred in 26% of patients, but only 1.7% of patients were unable to continue treatment with this drug. Cabergoline was effective (about 80%) and well tolerated (>90%) in the majority of patients (164) who were resistant to bromelain, and Calao and colleagues reported that 17 of 20 patients who were resistant to Quinagolide achieved normal serum prolactin levels after treatment with Cabergoline, although the difference in efficacy may be related to the patients’ resistance to Quinagolide. difference may be related to poor patient compliance with Quinagolide.
Bromocriptan is administered at a dose of 2.5 mg three times a day. Cabergoline is usually effective at doses of 0.5-1.0 mg once or twice a week, while Quinagoline is effective at 75-150ug daily. To reduce side effects, patients should be advised to take both of these new drugs with a nighttime snack before bedtime. It is worth noting that reports of acute psychiatric reactions to Quinagolide are rare but noteworthy, and it is unclear whether this serious side effect is drug-specific, as acute psychiatric symptoms have occasionally occurred in patients previously treated with high-dose bromocriptan.
Prolactin microadenoma
Dopamine agonists
The efficacy of dopamine agonists in the treatment of prolactin microadenomas is remarkable. In early studies of bromocriptan-treated patients, 80-90% of patients had normalized prolactin levels or menstrual cycles, and after 2 months, 70% of women were able to become pregnant. Within a few days or weeks the majority of patients experienced a disappearance or substantial reduction in breast milk production. In a recent controlled study of Cabergoline and Bromocriptine, the rate of return of menstrual cycle and pregnancy (1.0 mg twice a week) was 72% in patients on Cabergoline, compared to 52% on Bromocriptine (5.0 mg once every 2 days). The number of women who reached stable normal prolactin blood levels was higher in the Cbergoline group (83% vs. 58%).
With long-term treatment, microadenomas can shrink, although not as dramatically as in patients with lactogenic macroadenomas. Importantly, a small percentage of patients can be cured after a period of dopamine agonist treatment, but the mechanism is not clear. It is uncertain whether prolactin microadenomas are completely cured by dopamine agonists, but the recurrence of symptoms after drug treatment ranges from approximately 10-20%. It is thought that the presence of pregnancy after dopamine agonist therapy can increase the chance of tumor recurrence. Therefore, many endocrinologists recommend discontinuing dopamine agonist therapy every 2-3 years for further clinical evaluation and screening of PRL levels. When discontinuing Cabergoline long course therapy, it should be remembered that these women will still have 3-6 menstrual cycles.
Transsphenoidal sinus surgical treatment
In some centers, transsphenoidal sinus surgical treatment may be an alternative to pharmacological therapy. Indeed, surgery is the most radical treatment for patients who are intolerant or dopamine agonist resistant. The success of surgery depends critically on the experience of the surgeon and the size of the tumor. In most large pituitary treatment centers, 60-90% of patients achieve normal postoperative prolactin levels, with more dramatic surgical results in larger prolactin microadenomas (4-9 mm). Early application of dopamine agonists may impede surgery, but they are not affected as much as in the case of prolactin microadenomas as in the case of prolactin macroadenomas. We found that recurrence of hyperprolactinemia after surgery for tumors without imaging evidence is common; earlier reports showed this in up to 50% of patients with prolactin microadenomas, but a recent statistical analysis of 1224 patients with surgically treated prolactin microadenomas showed a recurrence rate of 17%. However, it should be emphasized that this follow-up period is not long enough. Using the return to normal prolactin levels as the primary indicator of cure, the long-term cure rate for surgery was found to be between 50% and 70%, so it may be reasonable for patients to consider surgery as an option. Of course, it is also important to note that transsphenoidal sinus access surgery has a low mortality rate in some centers (see Chapter 8) and that the risk of abnormal pituitary function as a result of the procedure is minimal, the latter being critical in patients who want to have children.
Observations (including oral contraceptives)
Longitudinal studies have shown that only 7% of prolactin microadenomas are able to develop into larger tumors. Therefore, it may not be necessary to start treatment for prolactin adenoma immediately in patients with prolactin microadenoma who have normal menstrual cycles and libido and have mild overflow and are not planning to become pregnant. Most endocrinologists recommend the following circulating steroid hormone levels before observing a patient with a prolactin microadenoma: mean estradiol >200 pmol/L (55 pg/mL in women and testosterone >7 nmol/L (2 ng/mL) in men, and BMD within a standard age-related variation. It is reasonable to monitor the patient’s PRL and E2 or T levels every 6-12 months and to measure BMD every 3-5 years in this setting. The safety of oral contraceptives is always an issue that needs to be studied in depth; there are many data confirming the safety of oral contraceptives in women with prolactin microadenoma treated with dopamine agonists, but no satisfactory studies have been reported on the use of oral contraceptives alone in the treatment of prolactin microadenoma. If the latter is applied, serum PRL should be checked every 3-6 months and treatment with a dopamine agonist should be added if serum PRL levels are above the desired value (e.g., when twice the basal value).
Pituitary PRL macroadenoma
Dopamine agonists
These drugs directly agonize pituitary D2 dopamine receptors, mimicking the effects of endogenous hypothalamic dopamine. In addition to reducing PRL secretion, D2 receptor agonism leads to a rapid decline in cellular protein synthesis mechanisms and therefore significantly suppresses the volume of prolactin adenoma cells. The effect on cellular protein synthesis, as well as the antimitotic effect, leads to a rapid and sustained tumor regression, so that this class of drugs can be used as the preferred approach for the treatment of patients with prolactinomatous adenomas, even for patients with occupancy effects.
The typical presentation after dopamine agonist treatment is an immediate (within hours) decrease in plasma PRL levels and rapid (within days or weeks) tumor regression; after a period of tumor shrinkage, the patient’s vision gradually improves to an extent comparable to surgical removal of the tumor; thus, the patient’s visual impairment is no longer an indication for emergency surgery. However, it is very important to check the prolactin level urgently in all patients with visual cross-compression due to pituitary macroadenoma. (and dilute the test – see “Interpretation of the results of lactin fluoroscopy”). See Figure 2 for clinical cases.
Degree of tumor retraction. In a meta-analysis of 271 typical lactogenic macroadenomas treated with dopamine agonists, 79% of the tumors shrank by more than a quarter and 89% shrank to varying degrees. Since 83% of patients in the PRL >100,000 mU/L (4000 μg/L) and 5000-10,000 mU/L (200-400 μg/L) groups showed significant tumor regression after dopamine agonist treatment, it was concluded that pretreatment PRL levels did not reliably predict the extent of tumor regression; and For those PRL macroadenomas causing optic cross compression, 85% of the tumors showed significant regression after treatment with dopamine agonists.
Time to retraction. Tumor regression can occur within 1 to 2 weeks of dopamine agonist application, and most regression occurs within the first 3 months of treatment (37, 38). However, in many patients, tumor regression is slower and can persist for several months. Repeated MRI examinations within 2 to 3 months of treatment with dopamine agonists have been recommended. If tumor regression is good, the interval between examinations is extended.
Degree of regression and recovery of vision. In a recent retrospective study, Colao and colleagues found that 110 patients with previously untreated (de novo) prolactinomatous macroadenomas had greater tumor regression after dopamine agonist therapy. Tumor regression was greater. After treatment with standard doses of Cabergoline, tumor regression was observed in 92% of untreated tumors, 42% of dopamine agonist-resistant patients, and 30% of dopamine agonist-resistant patients (>80% regression from pretreatment). In contrast, only 38% of patients with poor compliance or access to prior dopamine agonists who were switched to Cabergoline therapy had tumor regression.
Visual field deficits improved with drug treatment in % of patients. It is important to emphasize that although visual improvement often occurs early, the best results are achieved after several months; therefore, persistence of visual field defects is not an absolute indication for surgery.
Plasma PRL response. Decreased plasma PRL levels are usually accompanied by tumor regression. Analysis of all patients who showed tumor shrinkage showed at least 50% regression of plasma PRL, and in 58% of patients, plasma PRL was completely normal.
Improvement in pituitary function. Restoration of impaired anterior pituitary function has been shown to be associated with tumor shrinkage, and restoration of GH reserve is important, which may allow some patients to avoid expensive GH replacement therapy. Although the decrease in PRL and tumor shrinkage in male patients with prolactinomatous adenoma are more satisfactory with the above treatments, at least two-thirds of patients require androgen replacement therapy because their testosterone levels remain below normal. Details of female sexual function in medically treated prolactin macroadenomas are difficult to describe in words. In premenopausal women patients, regular menstrual cycles resume in more than 90% of patients. The effects on pregnancy are discussed in the following sections.
Dopamine agonist resistance: In general, acquired dopamine agonist resistance during treatment is rare, even in those with treatment cycles of 10 years or more. Only a dozen cases of drug resistance have been reported to date.
Withdrawal effects of dopamine agonists: Although usually prolactinomas are sensitive to dopamine agonists, drug treatment of prolactin macroadenomas does not seem to lead to a definite cure and therefore most patients have to undergo long-term treatment. Rapid re-increase in tumor size may occur after discontinuation of intermediate course therapy (up to 1 year), but is uncommon in long course therapy (several years). The recurrence of hyperprolactinemia in most patients suggests that tumor recurrence will occur after a period of time. Therefore, it is often clinically appropriate to reduce dopamine agonist dosage once tumor shrinkage occurs and persists.
Prolactinomas that do not retract
Approximately 10% of prolactin macroadenomas do not show tumor volume reduction with dopamine agonists. Despite the lack of tumor volume reduction, serum PRL levels are significantly decreased in most of these patients; the mechanism of this primary resistance is poorly understood, with some resistant tumors being found to have a more cystic component, some showing atypical histology, and others with defects in membrane-linked D2 dopamine receptors.
Treatment strategies
The diagnosis of prolactin macroadenoma is fairly certain in those with pituitary lesions and serum PRL greater than 5000 mU/L (200ug/L). Initial treatment with dopamine agonists is very effective in reducing tumor size. As mentioned in the section “Diagnostic value of basal serum PRL concentration”, the diagnosis is uncertain at PRL levels of 2000-5000 mU/L. The choice between dopamine agonists and surgery depends on a number of factors such as local pituitary surgery technique, the degree of visual impairment, the patient’s preference, and clinical judgment. Experimental treatment with dopamine agonists under close monitoring is absolutely reasonable, and surgery can be performed as long as visual loss or lesion reduction is still present after (at most 3 months of) treatment. In patients with nonprolactinomas, the application of dopamine agonists may enable up to 50% of patients to avoid surgery, but the visual loss will last longer in such patients. Notably, dopamine agonists decrease PRL secretion caused by normal and tumorigenic prolactin-secreting cells; therefore, plasma PRL decreases regardless of the presence of hyperprolactinemia. pituitary lesions with PRL levels less than 2000 mU/L are rarely prolactin adenomas, and therefore tumor excision for decompression and histologic diagnosis should be performed.
The role of radiotherapy and surgery
Most patients with prolactin macroadenomas can be treated with medication alone, especially those with fertility requirements; it should be noted that sometimes medication followed by shrinking tumors that invade toward the saddle base can cause cerebrospinal fluid (CSF) nasal leakage and make surgical treatment more difficult.
Some endocrinologists consider the use of baramine agonists alone to be inappropriate for the long-term treatment of prolactinomatous macroadenomas and recommend external radiation therapy. Although PRL levels are reduced for several years after radiation and dopamine agonists can be discontinued, this treatment may be associated with varying degrees of pituitary hypofunction.
An analysis of data from a meta-analysis of 1256 surgically treated prolactinomatous adenomas showed that only 32% of patients regained normal PRL levels; given the good results of drug therapy, only a small percentage of patients with prolactinomatous adenomas require surgical treatment. There are three conditions in which clinicians will consider surgery and in which the operator should be alert to dopamine agonist-induced fibrosis of the prolactin adenoma. They are.
First, because some patients with prolactin macroadenomas have considerable tumor volume on the saddle after their long-term dopamine agonist application; physicians may prefer surgical treatment over radiation therapy; however, tumor fibrosis, which is directly related to the duration of pharmacotherapy, may make surgery more difficult. Surgery is riskier if dopamine agonist therapy is administered for more than 3 months. External radiation therapy can now be safely applied to patients with persistent suprasellar occupancy, and in addition there have been reports of possible unexpected benefits of radiation therapy for tumor enlargement and vision loss; second, up to 10% of urothelial macroadenomas may require surgery; most patients should undergo surgery within a few months when they fail to shrink with dopamine agonists, especially if vision is impaired; third, a short course of dopamine agonist treatment can lead to shrinkage of the intersaddle tumor (uncommon in macroadenomas), and on top of this, some patients can be cured with the addition of surgery. However, this result has not been universally accepted. In general, if surgery is to be performed, pre-surgical drug therapy should be limited to a maximum of 3 months. Some treatment centers also perform gamma knife radiation therapy, especially for those patients who have failed dopamine agonist or minimally invasive surgical treatment.
Treatment recommendations
Estrogen has a significant effect on PRL synthesis and secretion.