In short-term studies, pergolide has been shown to effectively lower PRL levels. Then stop and bring the slide back in until you line them back up again. None of the panhypopituitary patients improved after surgery These patients may develop visual disturbance, associated with severe headache, altered consciousness, and vascular collapse. He re-timed the motors in the front and back of the slide so that they would start operating at the same speeds again. There is a lot to consider when purchasing your RV.
They are a game-changer. Our first RV had zero slides. It made hosting guests or walking past each other, ever, pretty much impossible. We now have two slides: These two opposing slides are fantastic for opening up the room and giving us a lot of floor space. If you prefer a more open concept RV, finding a rig with opposing slides is key. They are known to be finicky, but the space is worth it.
After purchasing our rig, we heard a few negative comments and reviews of full-length slides. We have had our large slide worked on three times in the past 18 months. In each instance, the slide was not coming in correctly. The front would come in faster than the back, or vice versa. Once the difference was so bad, our slide was out 6 inches in the back and not at all in the front. It was a nightmare! He re-timed the motors in the front and back of the slide so that they would start operating at the same speeds again.
He said this happens often, especially with larger slides carrying a lot of weight. A friendly mechanic in Denver taught us a trick to re-time our slides ourselves, should we ever get into trouble again. Our dinette slide was giving us trouble and when took it out one day, there was almost a inch difference between the front and back of the slide. It was dangerously close to getting stuck and Heath was outside manually pushing one side of the slide in while I religiously held down the button inside.
Typically when bringing in your slides, you hold down the button and do not stop for any reason. I remember the dealer drilling this fact into us when we bought ours. Do not stop while bringing in or taking out the slides! However, when they start getting out of time, you can re-time them yourself by taking the slide out a few inches at a time, or until you notice the sides of the slide are going out at different speeds.
Then stop and bring the slide back in until you line them back up again. Repeat until you have the slide out all the way. It would sometimes take a full five minutes just to get out slide all the way out! After learning this trick, we would take the slide out three or four inches, using the lines of the faux tile linoleum to measure if each side of the slides were moving out at the same pace. It took about 20 sessions of bringing the slide all the way out and all the way back in, inching it back and forth the whole time, but our slide did re-time itself.
Since getting repairs at RV service shops is often expensive or impossible, it felt amazing to be able to fix this issue ourselves. That was almost a year ago now and we have had zero issues with our slide since! Side note before we move on: The less weight on a slide the better! You have the least amount of control over the height of your RV. I noted average heights for each type of rig in this post for reference. It is not a huge deal.
Low clearances are rare, especially in the west and in the south. It likely will never affect visiting a specific destination, though it may alter your route. I recommend using at least one of these to check your route for clearances. Craniotomy, which is rarely indicated, is reserved for tumors that are inaccessible via the transsphenoidal approach. Such cases might include patients with large tumors with suprasellar, parasellar, or unusual intracranial extensions, such as those extending toward the frontal or temporal lobes Favorable experience with variations of the standard transsphenoidal approach have recently been described and provide alternatives to transcranial approaches, even for previously unapproachable lesions involving the cavernous sinus and parasellar region Giant and invasive prolactinomas cannot be cured by surgery, regardless of the surgical technique employed or the experience of the neurosurgeon; therefore, if undertaken, the goal of surgery under these circumstances is to debulk with the prospect of improving symptoms related to mass effects Recent technological advances have catapulted minimally invasive endoscopic techniques to the forefront of transsphenoidal surgery The main advantage afforded by endoscopy is the superior panoramic view.
Some surgeons exploit endoscopy as an adjunctive visualizing tool, but increasingly, the endoscope is being used as a stand-alone operating instrument, used in one of several different ways. The most common method consists of an endoscopic endonasal unilateral approach, permitting removal of the entire tumor through the nostril. In addition to the wide surgical view, endoscopy provides three additional potential benefits, including: For the neurosurgeon, the major obstacle to adopting the endoscopic technique is that of the need to acquire novel surgical skills 45 , Although the number of reported cases and follow-up duration are limited, preliminary studies suggest that complication rates of the endonasal endoscopic approach may be comparable to, or perhaps slightly lower than, those observed using the traditional operating microscope 47 Two studies comparing outcomes of endonasal endoscopic microsurgery and sublabial microsurgery specifically for prolactinomas found no differences in initial surgical remission rates but fewer minor complications associated with endoscopic or endoscopic-assisted procedures 52 , Currently, intraoperative imaging is used by most neurosurgical centers, both for guidance to reach the sphenoid sinus and sella and to assess the extent of tumor resection.
C-arm videofluoroscopy is the most widely used guidance device. This technique is achieved by segmentation and three-dimensional reconstruction of the tumor and adjacent structures. Neuronavigation is most valuable in reoperations where the anatomy may be distorted, but it is also helpful in surgeries involving large, invasive or suprasellar tumors and in cases where the carotid arteries are closely approximated or kinked 40 , Because the morphology of the tumor and neurovascular structures shift during tumor resection, frameless stereotaxy cannot be used to estimate the extent of tumor removal.
Moreover, these systems have the disadvantage of requiring greater set-up time. Whether the use of neuronavigational systems improves surgical cure rates or reduces the frequency of complications is unknown. Intraoperative MRI has been used in some centers to delineate tumor borders and to accurately monitor the extent of tumor resection This imaging modality is in an evolving stage of development and improvement. A comprehensive evaluation of the different available MRI systems has been reported by Albayrak et al.
The predominant opinion is that intraoperative MRI will have limited use in resecting purely sellar microadenomas but may be beneficial for assessing the adequacy of resection of supra- and parasellar extensions Long-term results are not available to determine whether this application improves surgical outcomes. Use of ultrasonography is chiefly used in transcranial procedures performed in the resection of giant macroadenomas.
The advantage of ultrasound over MRI is the provision of real-time feedback to the surgeon during tumor removal. Because indications to resect giant invasive prolactinomas requiring craniotomy are extraordinarily rare, this imaging modality, in its current form, is suspected to have limited application for the surgical management of prolactinomas. Regardless of the innovative operative techniques and imaging modalities emerging, the specific surgical treatment plan of a patient with a prolactinoma ultimately depends upon the availability, familiarity, and expertise of these instruments for the neurosurgical center and neurosurgeon to which one refers their patients.
Definitive data on the impact of these advances on surgical outcomes are not yet available. Surgical outcomes are highly dependent upon the expertise and experience of the neurosurgeon, as well as the size of the tumor. Surgical results from 50 published series are summarized in Table 4. Criteria for inclusion in this analysis consists of the following: Combining data from all 50 series, of Within these series, the surgical success rates were highly variable.
Clearly, for the macroadenomas the success rate in large part was dependent on the size of tumors chosen for surgery. In many series, the objective was, appropriately, debulking of a very large tumor rather than cure, and in other series very large tumors were not operated upon. Although surgical series reported from the last decade have used some of the newer techniques described above, the results from these series cannot be strictly compared with those of early series because of differences in the patient populations.
In the past 1015 yr, most patients were treated with dopamine agonists first, and only those resistant to or intolerant of these drugs or whose tumors did not decrease in size were referred for surgery. In some series, it was reported that prior use of dopamine agonists made it more difficult to remove the tumor see Section III.
E for a more extensive discussion of this. Overall, it does not appear that surgical outcomes are substantially different now compared with 20 yr ago, but a formal analysis cannot be carried out for the above-stated reasons. In a number of series, it was the impression that PRL levels were more predictive of surgical success than actual size of the tumor. An obvious explanation for this finding is lacking, because one would expect higher PRL levels in more highly differentiated tumors, which might thereby impart a greater likelihood of complete tumor resection.
It is unknown whether the extent of dural invasion and the degree of histological differentiation of a tumor correlate with PRL levels in prolactinomas. Gonadal function is almost uniformly restored in both sexes upon achievement of normoprolactinemia after successful surgical resection 63 In young women, normal LH pulsatility is restored as early as the eighth postoperative day 66 , Often normal reproductive function is obtained even with PRL levels slightly above normal, but because such patients appear to have a much greater chance of recurrence of more significant hyperprolactinemia see Section III.
F , they cannot be deemed definitively cured. Patients with macroadenomas of all types may be hypopituitary before surgery and, because of the extent of surgery sometimes performed, may have significant changes in pituitary function postoperatively. In an analysis of 84 patients with macroadenomas 36 were prolactinomas , Nelson et al. One third with some pituitary deficits before surgery improved, and one third with such deficits had worsened pituitary function after surgery.
None of the panhypopituitary patients improved after surgery One of the most controversial areas regarding the surgical management of prolactinomas involves the likelihood of a recurrence of hyperprolactinemia in patients who have undergone an initial remission. In part, this reflects differences in the level of neurosurgical expertise. It is possible, and even likely, that surgical series with relatively short follow-up times will underestimate the true recurrence rate because the time to recurrence of hyperprolactinemia in some tumors may be lengthy As for surgical cure, most often, recurrence is defined as the discovery of an elevated PRL level at any point in the postoperative surveillance period after an initial surgical remission.
On the other hand, some authors use less stringent criteria, regarding patients with mild asymptomatic hyperprolactinemia as in remission Given all of these factors, a true assessment of recurrence rates is difficult to establish. Adding further confusion to the controversy are series reporting that recurrence of mild hyperprolactinemia in some women after adenomectomy for prolactinomas resolves with time, and therefore may not definitively reflect operative failure 73 , One important study described the course of eight patients who developed recurrent hyperprolactinemia 2 to 10 yr postoperatively and who were monitored thereafter without treatment One patient was found to have primary hypothyroidism and became normoprolactinemic with l -T 4 therapy, thus accounting for her PRL elevation.
Of the remaining seven patients, four underwent a spontaneous remission of hyperprolactinemia. This course of relapse, followed by a second remission, has not been widely reported. It is unknown whether these experiences are atypical or whether they reflect a more frequent outcome that has simply gone unrecognized thus far. From the series compiled in Table 4 , recurrence rates for microadenomas [ of It should be emphasized that under most circumstances, the recurrence is detected biochemically hyperprolactinemia , not necessarily with radiographic documentation of tumor regrowth.
In a series of patients with microadenomas operated upon by Dr. Jules Hardy, of 58 patients with a normal PRL postoperatively, 25 had a relapse of hyperprolactinemia after a mean of 3. Overall long-term surgical cure rates may be calculated based upon series that have reported both initial remission rates and recurrence rates, understanding that these numbers reflect somewhat of a reporting bias, because they are derived from neurosurgeons who are willing to publish their data.
Based on the initial remission rate of For patients with macroadenomas, with an initial remission rate of These general numbers may be given to patients when counseling them with respect to choices of therapy. Neurosurgeons who have compiled their own data on surgical cures and remission may provide patients with more meaningful personal estimates for cure, based upon their individual statistics.
For patients with giant prolactinomas and those with considerable cavernous sinus invasion, the chance for surgical cure is essentially zero 76 A number of studies have analyzed factors that might predict initial surgical remission and likelihood for long-term cure. As discussed above, several studies have identified an inverse relationship between preoperative PRL levels and chances for initial surgical remission 57 , 60 62 , 72 , 79 Initial surgical success is also correlated with adenoma stage 58 , A low immediate postoperative PRL level has been shown to be an excellent predictor of long-term surgical cure 82 , An extensive debate regarding the effects of pretreatment with dopamine agonists on surgical outcomes for prolactinomas has pervaded the surgical literature in the past.
In the hands of some neurosurgeons, it is the impression that dopamine agonist treatment induces tumor fibrosis, creating a tough tumor consistency that made surgical removal difficult. However, the majority of other series investigating this issue have not corroborated these results 72 , 85 Because surgery for prolactinomas in the present era most often follows a trial of dopamine agonist therapy, the decision of whether or not to use a dopamine agonist has already been made.
Complications from transsphenoidal surgery for microadenomas are quite infrequent, the mortality rate being at most 0. The mortality rate for transsphenoidal surgery for all types of secreting and nonsecreting macroadenomas is 0. With surgery, either further worsening or improvement may occur Surgery involving craniotomy is much more hazardous. Although most authorities recommend transsphenoidal surgery as a second line option for prolactinomas, some experts continue to advocate surgery as a potentially curative procedure in selected patients 72 , 92 , 95 , These experts propose that young patients with microadenomas who have a good chance of cure could avoid the need for extended medical therapy.
Enthusiasm for this perspective is tempered by recent evidence that withdrawal of cabergoline may lead to sustained remission in some cases 97 , Couldwell and Weiss 99 make an economic argument that surgical intervention is less expensive than lifelong medical therapy. On the other hand, a surgery complicated by hypopituitarism has the potential to incur significantly higher costs with replacement of pituitary hormones and lead to higher morbidity secondary adrenal insufficiency over many years.
Admittedly, hypopituitarism is an unlikely complication for the resection of a microprolactinoma in the hands of an experienced neurosurgeon. One should also bear in mind that with the expected upcoming availability of cabergoline in generic form, even an uncomplicated transsphenoidal surgery may prove to be more expensive than the cost of medical therapy. Given its efficacy and safety, as discussed in Section V , medical therapy remains the first line therapy for the treatment of prolactinomas.
The availability of highly effective medical and surgical therapies for the majority of prolactinomas has rendered the role of radiotherapy in the management of prolactinomas as one of adjunctive therapy. In most cases, radiotherapy is used after failed transsphenoidal surgery and medical therapy. Rarely, in a few centers, it has been administered postoperatively as a prophylactic measure to prevent growth of a remnant tumor.
Today, several methodologies for the delivery of radiotherapy are available. Conventional fractionated external beam radiotherapy involves the use of several ports to concentrate an x-ray beam on the pituitary fossa by a crossfire technique while the patient is immobilized in an individually shaped plastic mask.
Stereotactic conformal radiotherapy SCRT is also a fractionated form of radiotherapy, but uses stereotactic techniques to deliver radiation with higher precision. The underlying principle of SCRT is to shape the radiation beams to conform to the shape of the tumor, thereby reducing radiation exposure to surrounding normal brain Most recently, single dose radiotherapy has become widely available and is being increasingly used.
This form of radiotherapy delivers a necrotizing dose to the tumor, which has been stereotactically defined using three-dimensional image processing. The hallmark of this type of radiotherapy is the sharp dose gradient of radiation at the treatment field edges, which reduces the dose of radiation to the surrounding normal brain tissue. This results in multiple small radiation spheres that are combined in a multiple isocenter technique to conform to the shape of nonspherical pituitary tumors An alternative method of delivering single-dose radiation therapy is with the use of a LINAC-based system that has been modified to limit mechanical instability and inaccuracy , There is no clear advantage for either of these single-dose techniques gamma knife vs.
Treatment of pituitary adenomas with single-dose radiation therapy using heavy-charge particle proton beams is very limited, because few centers have the facilities to provide this form of radiotherapy, due to its high operational and maintenance costs As of yet, there are no adequate studies to conclude whether there is one mode of single dose radiotherapy that has superior efficacy or safety.
Regardless of the delivery system, the aim of all high precision techniques is to minimize radiation exposure to the surrounding normal tissue. The combination of better immobilization and high-definition three-dimensional imaging has been the most important determinant of improvements in modern radiotherapyless so the technique of delivery The two general therapeutic goals for performing radiotherapy in prolactinomas are: However, it is possible that persistent postradiotherapy elevations of PRL in patients with prolactinomas are due to a radiation effect and are not caused by hypersecretion from residual tumor There are several important caveats regarding the critical interpretation of data in clinical studies of the efficacy of radiotherapy for the treatment of prolactinomas.
The first relates to the definitions of tumor control endpoints. Tumor control may be defined with either endocrinological normalization of PRL levels or volumetric long-term radiographic assessment of tumor size parameters. Moreover, many of the series do not report the mean or median duration of follow-up. Under these circumstances, the data do not provide an appropriate measure of efficacy.
The second important observation is that the majority of the studies are retrospective, single-arm analyses. Few of them report the rate of decline of PRL. Finally, and most importantly, many of the studies are confounded by the inclusion of patients who were receiving concomitant medical therapy. A number of patients in whom cure was reported continued to require dopamine agonist therapy.
Therefore, in some cases, it is impossible to separate out any PRL-lowering effects of radiotherapy from the effects of dopamine agonists. In the present review, we have chosen to confine the analysis to the normalization of hyperprolactinemia. It should nevertheless be acknowledged that in many cases the goal of radiotherapy for treatment-resistant tumors was control of growth or alleviation of mass effects. To accurately assess the efficacy of radiotherapy for these situations, standard criteria for growth control would be necessary.
In all of these settings, normalization of hyperprolactinemia was infrequent, with an overall normalization rate for the entire series of When normal PRL levels were achieved, it was only with an extended latency in most cases. Conventional radiotherapy after noncurative surgery rarely normalizes PRL levels. Two series of patients who received LINAC-based fractionated radiotherapy after unsuccessful transsphenoidal surgery achieved PRL normalization rates similar to those receiving conventional fractionated radiotherapy The remainder of the studies in this group included patients treated with a dopamine agonist or with all three modalities surgery, dopamine agonists, and radiotherapy.
Thus, it is uncertain what specific effect radiotherapy had in PRL lowering, or normalization, in these patients. Because these prolactinomas often represent the most therapy-resistant tumors, normalization of hyperprolactinemia may not have been feasible. Therefore, the rates of normalization are expected to be poor. In many of these cases, the goal of radiotherapy may have been to control further growth or to relieve mass effects on cranial nerves.
One could argue that the short follow-up duration among these series may have underestimated the complete response rate for these tumors treated with single-dose radiotherapy. Only one study reported the outcomes of patients treated with single-dose stereotactic radiotherapy as primary therapy for prolactinomas Follow-up beyond 2 yr was available for 77 patients who were not receiving bromocriptine.
Normalization of PRL in the absence of concomitant medical therapy was attained in 16 Normoprolactinemia was achieved in five patients, all of whom were able to discontinue medical therapy. Treatment with radiosurgery failed entirely in four patients. The advantages and disadvantages of various modes of radiotherapy are important considerations when referring a patient with a prolactinoma to a radiotherapist.
Although it is true that a large single dose of radiation is more effective in cell death than the same dose delivered in several smaller fractions, large single doses of radiation are more toxic to normal tissue than similar doses given in a fractionated manner. In the early days of single-dose radiotherapy, high doses for large pituitary adenomas near the optic apparatus resulted in a high incidence of optic neuropathy To achieve an acceptable fall-off gradient with single-session therapy, current practice aims at limiting irradiation of the optic apparatus to single doses of less than 8 Gy , , , As a result, pituitary adenomas with significant suprasellar extension, or those with less than 5-mm clearance between the tumor margin and the optic apparatus are poor candidates for single-dose radiotherapy , , On the other hand, tumors with cavernous sinus invasion can be good candidates for single-dose radiotherapy, because the cranial nerves in the cavernous sinus are relatively radio-resistant , , Prospective evaluations of the rate of PRL normalization in head-to-head comparisons of fractionated vs.
Even if such series were to exist, one would need to critically analyze the comparability of the tumors in each group. For conventional radiotherapy, there is no restriction as to the size of the tumor or the proximity to the optic apparatus. As noted above, prolactinomas treated with single-dose radiotherapy will largely consist of intrasellar adenomas well away from the optic apparatus. In contrast, prolactinomas treated with fractionated radiotherapy consist of not only intrasellar adenomas, but also large adenomas with suprasellar extension that may lie in close proximity to the optic apparatus.
Complete hormonal and tumor growth responses are undoubtedly more difficult to achieve in this latter category of tumors. In addition to patient convenience, one of the proposed advantages of single-dose radiotherapy over fractionated radiotherapy is its shorter latency to hormonal and tumor size responses. It appears likely that single-dose radiotherapy lowers PRL levels more rapidly than conventional external beam radiotherapy, although prospective comparative studies are not available to verify this claim.
Six of the 21 series listed in Table 5 reported the latency to normalization of PRL levels for their patients with prolactinomas treated with single-dose radiotherapy; these responses ranged from 1 to 2 yr , , , The latency to normalization of hyperprolactinemia for conventional external beam radiotherapy is on the order of several years. Hypopituitarism is likely secondary to hypothalamic and pituitary damage, although the former is considered of primary importance Recently, it has been discovered that the consequences of hypopituitarism may be more significant than issues related to hormone replacement dosing and monitoring.
A recent large prospective study from the United Kingdom showed that the standardized mortality rate was higher in patients with hypopituitarism that had been treated with radiotherapy compared with those who had not received radiotherapy A large proportion of this excess was due to a significant increase in cerebrovascular disease-associated deaths in the radiotherapy group.
Additional complications that occur months to years after radiotherapy of pituitary adenomas include cerebrovascular accidents, optic nerve damage, neurological dysfunction, and soft tissue reactions , Conventional radiotherapy is associated with an increased risk of secondary radiation-induced intracranial malignancies, with a cumulative risk of 2.
The incidence of hypopituitarism after single-dose stereotactic radiotherapy is difficult to establish at present. These analyses are confounded by factors such as previous pituitary surgery in some individuals. Cranial neuropathies have been reported after single-dose radiotherapy. A high incidence of optic neuropathies was reported in the early use of single-dose therapy when higher doses were administered.
With dose changes and technical improvements, these adverse effects are less frequent. The severity of these cases ranges from nonspecific visual loss to blindness , , Radiation necrosis of surrounding brain tissue occurs in approximately 0. As of yet with limited follow-up, there have been no reported cases of secondary intracranial malignancies who have undergone single-dose radiotherapy.
Overall, radiotherapy has a very limited role in the treatment of patients with prolactinomas. The very high rate of efficacy of dopamine agonists see Section V along with the high complication rates of radiotherapy render treatment with this modality rarely necessary. The few patients who now require radiotherapy are those who do not respond to dopamine agonists and who cannot then be cured by surgery. When a large tumor remains after surgery, then conventional radiotherapy is the best modality.
However, a small residual tumor, especially when involving the cavernous sinus, may be better treated with stereotactic radiotherapy. The compounds used in clinical practice to treat prolactinomas are all dopamine receptor agonists. Among these, bromocriptine, cabergoline, pergolide, and quinagolide are the most commonly used. The dopamine agonists lisuride and terguride are less frequently used, as is metergoline, a serotonin antagonist.
Bromocriptine, pergolide, and cabergoline are all ergot derivatives. The only nonergot derivative that is used in clinical practice is quinagolide. The chemical structures of the most used compounds are shown in Fig. The ergot-derivative dopamine agonists comprise a group of indole alkaloids that are predominantly found in various species of the ascomycete Claviceps The ergot alkaloids can all be considered derivatives of the tetracyclic ergoline skeleton and can be divided into two main groups based on their structural characteristics The first group includes all lysergic acid derivatives of the acid amide types, such as amine alkaloids ergonovine and the structurally more complex ergopeptines ergotamine, ergocristine.
The ergot alkaloids and their derivatives have a wide spectrum of pharmacological actions that include central, neurohumoral, and peripheral effects, mediated by norepinephrine, serotonin, and dopamine receptors. The diversity of biological properties of ergot derivatives is likely due to diverse mechanisms of action at the cellular and molecular levels Because ergot derivatives interact with different receptor sites, it is not surprising that the drugs developed as well as the natural alkaloids display a number of side effects Biochemical structure of dopamine agonists.
Quinagolide is a nonergot derivative. The octahydrobenzyl g -quinolines are a group of nonergot oral medications that also function as dopamine agonists with specific D 2 receptor activity Quinagolide is the most active octahydrobenzyl g -quinoline and is about 35 times more potent than bromocriptine. The octahydrobenzo g -quinolines bind more specifically to dopamine receptors than the ergot derivatives bromocriptine, CQP , and pergolide , TSH-releasing hormone, serotonin, estrogens, endogenous opiates, and vasoactive intestinal polypeptide stimulate PRL secretion, but their role is clearly minor compared with that of dopamine Classically, dopamine receptors have been divided into D 1 receptors, which stimulate adenylyl cyclase activity, and D 2 receptors, which inhibit this enzyme ; three further discrete receptor subtypes have been described D 3 , D 4 , and D 5 with less activity on PRL secretion Dopamine inhibition of PRL secretion is mediated by the D 2 dopamine receptors expressed by normal and tumorous lactotrophs D 2 receptors belong to the family of G protein-coupled receptors, characterized by a single polypeptide chain containing seven hydrophobic transmembrane domains: Additionally, dopamine inhibits arachidonic acid release from pituitary cells independently from the other transduction mechanisms Two isoforms generated by alternative splicing of the D 2 dopamine receptor have been described These two isoforms differ by a amino acid additive sequence located within the third intracytoplasmic loop that interacts with G proteins: Stimulation of D 2 receptors by dopamine reduces adenylyl cyclase activity that consequently reduces intracellular cAMP levels in normal as well as in tumoral lactotrophs It is likely that all dopaminergic ergot derivatives share similar mechanisms of action Dopamine agonists reduce the size of prolactinomas by inducing a reduction in cell volume via an early inhibition of secretory mechanism, and a late inhibition of gene transcription and PRL synthesis , as well as causing perivascular fibrosis and partial cell necrosis There may also be a true antimitotic effect of these drugs.
Histologically there is a reduction in secretory activity and cell size, an increase in immunoreactive PRL cellular content and inhibition of exocytosis More than 25 yr ago, bromocriptine was introduced into clinical practice as the first medical treatment for prolactinomas Bromocriptine-mesylate is a semisynthetic ergot derivative that has D 2 receptor agonist and D 1 antagonist properties.
It has a relatively short elimination half-life, so that it is usually taken two or three times daily, although once daily may be effective in some patients. Generally, the therapeutic doses are in the range of 2. In most patients, headache and visual field defects improve dramatically within days after the first administration of bromocriptine, with gonadal and sexual function improving even before complete normalization of serum PRL levels.
Prolonged bromocriptine treatment has been associated with increased fibrosis of prolactinomas and with increasing tumor consistency. PRL normalization with bromocriptine is also associated with an increase in bone density both in women and in men and with improvement of semen quality in men Other formulations of bromocriptine, long-acting and the long-acting repeatable forms for im injections, an intranasal powder, and an intravaginal tablet, were developed to overcome side effects such as nausea, vomiting, postural hypotension, and headache see Section VI.
These reactions were considered to be due to the rapid absorption of bromocriptine, which is administered two or three times a day, thus causing high blood levels. However, despite promising data , none of these formulations were ever introduced in the pharmaceutical market for hyperprolactinemia. Bromocriptine as a first-generation dopamine receptor agonist has been largely superseded by more potent compounds with longer lasting effects and improved side effect profiles.
Nevertheless, bromocriptine is still widely used to treat prolactinomas, primarily in young women desiring pregnancy see Section IX. Cabergoline is a D 2 selective agonist widely used to treat prolactinomas. It strongly suppresses PRL secretion both in vivo and in vitro and preliminary studies showed a significant PRL inhibition within 12 h after treatment with cabergoline and bromocriptine in cultured pituitary cells from estradiol-induced rat pituitary tumors , Inhibition of de novo PRL synthesis was more pronounced with cabergoline than bromocriptine treatment The continued oral administration of cabergoline significantly reduced both PRL levels and the weight of the pituitary during 1560 d of treatment as compared with bromocriptine One single dose of cabergoline 0.
In healthy men, single doses of 0. In healthy women with regular menses, cabergoline at doses of 0. The beneficial effects of cabergoline in resolving hyperprolactinemia are widely known Table 6. A remarkable tumor-shrinking effect of cabergoline has been observed in patients with macroprolactinomas Moreover, Colao et al. Cabergoline treatment is also effective and safe in patients with prolactinomas with onset in childhood or adolescence see Section X.
The superiority of cabergoline over bromocriptine was supported by a comparative retrospective study by Di Sarno et al. Based on these data, cabergoline treatment is clearly indicated as the primary approach to macroprolactinomas. Lastly, cabergoline seems to induce fewer side effects than other dopamine agonists see Section VI. At present, cabergoline is certainly the most effective compound to treatment prolactinomas, with very good patient compliance with long-term treatment regimens.
Tumor shrinkage with cabergoline. Data are derived from Ref. B, Comparison of tumor reduction responses in micro- and macroprolactinoma with bromocriptine or cabergoline. Pergolide is a synthetic ergoline derivative with long-acting D 2 and D 1 agonist properties. This dopamine agonist is approximately times more potent than bromocriptine and suppresses PRL secretion for up to 24 h after a single dose , allowing effective control of hyperprolactinemia with once daily dosing.
Pergolide has advantages over bromocriptine in that it only requires once-a-day dosing and is approximately one fifth of the cost. In short-term studies, pergolide has been shown to effectively lower PRL levels. In an open-label, randomized, controlled, multicenter study, Lamberts and Quik reported that bromocriptine and pergolide were equally effective in lowering serum PRL levels and in inducing tumor shrinkage; a high incidence of adverse events, such as nausea, dizziness, vomiting, asthenia, headache, and decrease in blood pressure, was reported with both drugs.
Data concerning the reduction of macroprolactinoma size by pergolide are limited In the series of 22 patients with macroprolactinomas treated with pergolide reported by Freda et al. Prior studies of pergolide therapy of both micro- and macroprolactinomas have shown high rates of PRL normalization; PRL levels were normalized in 37 of 41 , 17 of 18 , and 16 of 25 subjects treated for periods from 624 months. The ability of pergolide and bromocriptine to lower PRL also seems to be similar , , , but some patients who have not responded well to bromocriptine have been reported to achieve better suppression of hyperprolactinemia with pergolide In a recent study enrolling 22 de novo patients with macroprolactinomas, Orrego et al.
Quinagolide is an octahydrobenzyl g -quinoline nonergot oral dopamine agonist with specific D 2 receptor activity. Several studies demonstrated that once-daily quinagolide treatment in women with hyperprolactinemia reduced PRL levels and tumor size and relieved gonadal dysfunction, thereby restoring fertility In analogy with the results of cabergoline, treatment with quinagolide effectively reduced PRL levels, with normalization of sperm parameters within 3 months in 13 of 14 men In a prospective, multicenter trial conducted in 26 patients with macroprolactinomas who received once-daily quinagolide for 24 wk, tumor size decreased in 21 patients, regular menses were restored in 11 of 15 premenopausal women, and sexual function improved in five of seven males From this study, it appears that quinagolide is at least as effective as bromocriptine.
However, there was no significant difference between the treatment groups with respect to the PRL levels at the end of the study. Both drugs were able to restore menses and fertility and reduce the incidence of galactorrhea in similar proportions of patients Side effects, however, limited the continuation of bromocriptine but not of quinagolide treatment in another comparative study In a randomized, cross-over study, 20 patients with hyperprolactinemia received once-daily quinagolide or twice-weekly cabergoline for 12 wk, with the two treatment phases separated by a washout period of 12 wk with placebo A higher percentage of patients achieved normal PRL levels with cabergoline compared with quinagolide 90 vs.
In another study, Di Sarno et al. Treatment with quinagolide for 12 months was followed by a month washout period, and then cabergoline treatment was given for a further month period. The month withdrawal of dopamine agonist therapy was introduced in this protocol to evaluate the recurrence of hyperprolactinemia. At the end of the washout period, PRL levels increased in all patients, but were significantly lower than the PRL levels measured at baseline before initiation of quinagolide therapy.
After 12 months of withdrawal from cabergoline treatment, recurrence of hyperprolactinemia was observed in all patients with macroprolactinomas and 19 of the 23 patients with microprolactinomas. Nine patients completed both treatment cycles; the clinical effects were similar with the two drugs and, interestingly, only one patient remained resistant to both dopamine agonists. Quinagolide is currently available in several European countries and in Canada but is not available in the United States.
Lisuride hydrogen maleate is another synthetic ergot derivative, with PRL-inhibitory activity in experimental models of hyperprolactinemia At a dose of 0. In another study enrolling patients with macroprolactinomas, Liuzzi et al. Terguride, an analog of lisuride, binds to D 2 receptors. In a cohort of 20 patients with hyperprolactinemia, Dallabonzana et al. Neither lisuride nor terguride is currently used in the treatment of prolactinomas. Metergoline is a nonselective antagonist for 5-hydroxytryptamine-1B and 5-hydroxytryptamine-1D receptors that has been used to treat hyperprolactinemia in the past.
In a group of lactating women, metergoline treatment induced significantly higher responses of PRL to metoclopramide as compared with those treated with either bromocriptine or lisuride Similar results were reported by Crosignani et al. In another study by the same group , 20 patients with hyperprolactinemic amenorrhea-galactorrhea were treated with one or more of the following serotonin antagonists: Among the 11 patients without evidence of pituitary tumor, resumption of menses was observed in five, two of whom had ovulatory cycles; one patient became pregnant; ovulation occurred only during treatment with metergoline.
In the group of nine patients with enlarged sellae, three experienced isolated episodes of bleeding, whereas two had three and four menses each, respectively; all cycles were anovulatory. Metergoline treatment restored menses in 37 patients; 28 patients ovulated, and eight of them became pregnant Although these studies reported an efficacy of metergoline in normalizing gonadal function and in restoring fertility in women, no data are available in patients with macroprolactinomas or in men with hyperprolactinemia.
Metergoline is seldom, if ever, used today in the treatment of prolactinomas. By far, the greatest experience in treating patients with prolactinomas has been with bromocriptine and cabergoline. In head-to-head randomized, prospective comparison studies , retrospective analyses , and general clinical experience, cabergoline has been shown to be more effective in lowering PRL levels to normal, reducing tumor size, and having less adverse effects.
As noted below, patients are less likely to be resistant to the therapeutic effects of cabergoline; furthermore, most patients found to be resistant to bromocriptine subsequently respond to cabergoline. Finally, treatment with cabergoline affords a greater chance of obtaining permanent remission and successful withdrawal of medication, compared with treatment with bromocriptine see Section VIII. Thus, in general, cabergoline is preferable to bromocriptine as an initial therapeutic agent.
There is much less experience with pergolide and quinagolide in the primary treatment of patients with prolactinomas. However, these drugs appear to have similar efficacy and adverse event profiles compared with bromocriptine see Section VI. When used in very high doses, pergolide appears to have an increased association with organ fibrosis, including cardiac valve fibrosis.
Therefore, pergolide should be avoided if high doses are needed. Depending upon pricing in some countries, pergolide may be less expensive than other dopamine agonists, and this may factor into its use. Pergolide has not been approved by the U. The single exception to a preference for cabergoline may be for treatment of women who wish to become pregnant.
As discussed in Section VI. C , the safety database for bromocriptine is far larger than that for cabergoline for fetal outcomes. Although there are no particular worrisome aspects of this smaller database for cabergoline, some clinicians and patients feel more comfortable using bromocriptine when fertility is the desired outcome. On the other hand, the small safety databases for pergolide and quinagolide are worrisome, and we specifically recommend avoiding their use when fertility is the desired outcome.
The adverse effects of bromocriptine may be grouped into three categories: Symptoms tend to occur after the initial dose and with dosage increases, but can be minimized by introducing the drug at a low dosage 0. Sometimes, tolerance develops to the adverse effects, but occasionally, therapy withdrawal or dose reduction followed by a more gradual reintroduction is required.
Nausea tends to be more persistent. Other reported gastrointestinal effects include dry mouth, dyspepsia, and symptoms suggestive of reflux esophagitis , The syncope is rare, although it may be observed even after a small initial dose 1. These symptoms can often be avoided by taking the drug at bedtime or while recumbent, but tolerance usually develops rapidly making this precaution unnecessary after the first few days. However, this reaction is rare at the low doses used to control PRL hypersecretion.
Other less frequent side effects include leg cramps, flushing, and nasal congestion 31 , The most frequent neurological adverse effects include headache and drowsiness. Psychiatric adverse effects are infrequent at the bromocriptine doses required to control PRL hypersecretion; however, low doses have been associated with mania in postpartum patients , , Signs and symptoms of psychosis or exacerbation of preexisting psychosis have been associated with the use of bromocriptine The symptoms, which included auditory hallucinations, delusional ideas, and mood alterations, entirely remitted when the drug was reduced in dosage or discontinued In a short-term trial in which bromocriptine was given to 16 individuals with psychiatric disorders who were previously stabilized on neuroleptic agents, exacerbation of psychoses was not observed Although these data are reassuring, this study included a small number of subjects with a limited exposure to bromocriptine 10 wk.
Thus, the safety of dopamine agonists in this population remains to be established. Other symptoms, usually associated with higher doses of bromocriptine, include anxiety, depression, confusion, auditory hallucinations, hyperactivity, disinhibition, insomnia, daytime somnolence, and paranoia , , Moreover, dyskinesias similar to those observed with levodopa are well-recognized effects of high-dosage treatment Other reported adverse effects include paraesthesia, nightmare, blurred vision, diplopia at high doses and reversible ototoxicity in patients with chronic hepatic disease , Individual case reports of postpartum women and other adults treated with bromocriptine have suggested a causal association between the use of bromocriptine and hypertension, thromboembolic events, severe leukopenia, hyponatremia, and edema However, conclusive evidence that these events were drug-induced is lacking.
In the United States, the FDA has determined that bromocriptine should not be used to treat postpartum lactation. Hyponatremia has been associated with the use of bromocriptine in patients with cirrhosis and hepatic encephalopathy Side effects associated with the use of cabergoline are similar to those reported for the other dopamine agonists, but are generally less frequent, less severe, and of shorter duration Some effects subside with dose reduction or continued use in many patients The long half-life of cabergoline, which results in a relatively flat plasma drug concentration, may be advantageous with respect to the induction of side effects Diarrhea, drowsiness, somnolence, paresthesias, and dyspnea are less commonly reported.
Generally, hypotension is asymptomatic, because only one of patients treated with cabergoline for the inhibition of lactation and three of patients treated with cabergoline for hyperprolactinemia developed symptomatic hypotension. Side effects such as thromboembolic events or psychosis have not been reported in patients with pituitary adenomas treated with cabergoline. Pleuropulmonary inflammatory-fibrotic syndrome has been described in a few patients Both multivalvular and single mitral valve heart disease have been described.
In one case of cabergoline-associated valvular disease, cardiac symptoms improved with discontinuation of the drug ; mitral valve replacement was required in the second Although causality has not been proven, the similarity of the echocardiographic findings, time course, and partial reversal of symptoms in these cases suggests that the use of the dopamine agonists in high doses may have been responsible for these adverse cardiac effects.
Therefore, extreme caution should be exercised in titrating patients to high doses of cabergoline or pergolide, and patients treated with higher doses should be monitored for this adverse effect when the drug is prescribed. In general, the nature and incidence of most side effects reported with pergolide are similar to those of bromocriptine , , Nausea, vomiting, dizziness, headache, and postural hypotension are the most commonly reported effects.
In one study, however, flushing, fever, and flu-like symptoms were reported more commonly in adults treated with pergolide than in those treated with bromocriptine As with the other dopamine agonists, daytime somnolence is commonly reported at very high doses Mild insomnia and mild rashes were the only side effects observed more commonly in pergolide-treated children compared with placebo. As discussed above, cases of pergolide-associated valvular heart disease have been reported in adults with Parkinson disease treated with doses much higher than those used for the treatment of hyperprolactinemia , An FDA survey of reported cases of pergolide-associated valvular heart disease did not establish causality, as a result of insufficient information and absence of histological data Nonetheless, the growing number of reported cases of valvular heart disease at higher doses warrants routine clinical cardiac assessment of patients who are treated with higher doses.
Most adverse effects reported in adults taking quinagolide are consistent with those reported for other dopamine agonists, although they occur perhaps less frequently than with bromocriptine , , As with bromocriptine, psychotic symptoms have been observed rarely, including personality or behavioral changes, hypomania, and delusions , In one double-blind, randomized 6-month study in 22 women with persistent hyperprolactinemia, quinagolide was significantly better tolerated compared with bromocriptine No changes in blood biochemistry, hematology, blood pressure or pulse rate were reported in trials performed with quinagolide, confirming the favorable safety profile , , , Although dopamine agonists have been proven to be successful in normalizing PRL levels, alleviating symptoms of hyperprolactinemia, and reducing tumor size, a subset of individuals with prolactinomas do not respond satisfactorily to these agents In general, prolactinomas exhibit varying degrees of responsiveness to the class of dopamine agonists, ranging from complete response at one end of the spectrum to total resistance at the other.
In addition, individual prolactinomas may respond variably to selected dopamine agonists, such that tumors that respond poorly or incompletely to one dopamine agonist may respond well to another. The concept of dopamine agonist resistance must be distinguished from that of dopamine agonist intolerance, in which adverse effects of the medication prevent the achievement of an effective response. Obviously, the percentage of patients deemed resistant to a particular drug will depend upon this dose threshold.
The desired biological response in the treatment of hyperprolactinemia in women is the achievement of ovulation regardless of the actual PRL level achieved. However, because this level varies on an individual basis, is difficult to define, and is not provided in most papers, for the purposes of the present analysis, dopamine agonist resistance with respect to hormone levels will be defined as the failure to achieve normoprolactinemia.
The molecular factors underlying the ability of some prolactinomas to escape dopaminergic control are not fully understood. It is worth noting that the overall number of human prolactinomas that have been characterized on a molecular level, directly comparing resistant and responsive prolactinomas, is limited. These studies are inherently challenging for the following reasons. First, human-derived prolactinoma cell lines are relatively unavailable Therefore, in vitro studies of these tumors are largely restricted to the use of primary short-term cultures.
The substantial genetic heterogeneity among these tumors complicates our ability to dissect out individual factors that are responsible for the development of drug resistance. The obvious candidate for a molecular alteration leading to dopamine agonist resistance is the lactotroph dopamine D 2 receptor itself Fig. Thus far, mutations in the D 2 receptor have not been identified in human prolactinomas, although it should be noted that a limited number of these tumors have been subject to such a molecular analysis Several studies have examined the expression and affinity of D 2 receptors in resistant prolactinomas, as well as proximal downstream signaling effectors of the D 2 receptor