Info

The Migraine And Headache Program

Latest Treatments for Migraine

Get Instant Access

164/267

^Includes idiopathic hyperprolactinemia and empty sella.

Criteria differ between studies and imaging was performed on only subgroups of patients. c74% after 6 mo, the remainder after higher doses (up to 3.5 mg/wk) for 18 to 24 mo. 92% in patients who had no previous exposure to dopamine agonists, with complete disappearance in 61%.

^Includes idiopathic hyperprolactinemia and empty sella.

Criteria differ between studies and imaging was performed on only subgroups of patients. c74% after 6 mo, the remainder after higher doses (up to 3.5 mg/wk) for 18 to 24 mo. 92% in patients who had no previous exposure to dopamine agonists, with complete disappearance in 61%.

drugs, together with a snack, just before retiring to bed. It is worth noting that acute psychotic reactions have been described with quinagolide, albeit rarely. It is unclear whether this important side effect is drug specific because acute psychosis was encountered occasionally in previous patients treated with large bromocriptine doses.

Microprolactinomas

Dopamine Agonists

Medical therapy is remarkably effective in the treatment of microprolactinoma. In the early studies of patients treated with bromocriptine, normoprolactinemia or ovulatory cycles were restored in 80%-90% of patients. Fertility returned within 2 mo in 70% of women. Galactorrhea disappeared or was greatly reduced in the majority of patients, usually within a few days or weeks. In the more recent comparative study of cabergoline and bromocriptine, resumption of ovulatory cycles or occurrence of pregnancy was documented in 72% of cabergoline patients (up to 1.0 mg twice weekly) compared with 52% in the bromocriptine group (up to 5.0 mg twice daily) (14). The number of women with stable normoprolactinemia was also higher in the cabergoline group (83% vs 58%).

Tumor shrinkage occurs during long-term treatment, although this is less critical than for patients with macroprolactinomas. Importantly, a minority of patients may be cured after a period of dopamine agonist treatment. The mechanism is unknown. The probability of cure remains unclear but perhaps between 10% and 20% of microprolactinomas remit with time. It has been suggested that a dopamine agonist-induced pregnancy increases the chances of remission (36). For these reasons, most endocrinologists interrupt dopamine agonist treatment every 2-3 yr, for further clinical assessment and PRL testing. In doing so, one should remember that women may continue to have ovulatory cycles for 3-6 mo after withdrawal of the long-acting drug cabergoline (23).

Transsphenoidal Surgery

In some centers, transsphenoidal surgery may be offered as an alternative to medical therapy. Indeed, surgery may be essential if the patient is intolerant of or resistant to dopamine receptor agonists. Surgical success is critically dependent on surgical experience and tumor size. In most large centers, normoprolactinemia is achieved postoperatively in 60% to 90% of patients, with results for larger microprolactinomas (4-9 mm diameter) being significantly better than for smaller ones (11). Previous dopamine agonist therapy may hamper surgery but this is less troublesome for microprolactinomas than it is for macro-prolactinomas. Recurrence of hyperprolactinemia, usually without radiologically evident tumor, is well recognized. Early reports suggested this might occur in up to 50% of microprolactinoma patients, but a recent meta-analysis of 1224 surgically treated microprolactinomas gave a recurrence figure of 17% (2). However, it should be stressed that long-term follow-up is still quite short. Using normo-prolactinemia as the main criterion of cure, it is probably reasonable to speak of a long-term surgical cure rate of between 50% and 70% when counseling patients with respect to choice of therapy. It is, of course, important also to mention the small but measurable morbidity of transsphenoidal surgery (see Chapter 8), together with the small risk of loss of normal pituitary function. The latter would be particularly important if the patient wished fertility.

Owing to the excellent therapeutic responses to either dopamine agonists or transsphenoidal surgery, radiotherapy is no longer considered acceptable primary therapy for microprolactinoma.

Observation (Including Oral Contraception)

Longitudinal studies suggest that only 7% of microprolactinomas progress to larger lesions. Hence, in a woman with a microprolactinoma who has normal menses and libido and nontroublesome galactorrhoea and who does not wish to become pregnant, there may be no clear indication for antiprolactinoma therapy. Before recommending simple observation of a microprolactinoma, most endo-crinologists would wish to confirm adequate circulating sex steroid concentrations (mean estradiol >200 pmol/L [55 pg/mL]) in a woman and testosterone >7 nmol/L (2 ng/mL) in a man), together with BMD within one standard deviation of age-related mean values. In this situation it would be reasonable to monitor the patient with 6-12 monthly serum PRL and estradiol/testosterone estimations, supplemented with bone densitometry every 3-5 yr, thus enabling individualized timing of any intervention. The question of oral contraceptive safety often arises. There are good data confirming the safety of oral contraceptive in combination with a dopamine agonist in women with microprolactinomas but no satisfactory prospective studies of treatment with an oral contraceptive alone. If the latter course of action is taken, serum PRL should be checked every 3-6 mo, with the addition of dopamine agonist therapy should the serum PRL level rise above an arbitrary target level (e.g., twice the basal level).

Macroprolactinomas

Dopamine Agonists

These drugs directly activate pituitary D2 dopamine receptors, mimicking the action of endogenous hypothalamic dopamine. In addition to reducing PRL secretion, D2 receptor stimulation results in rapid involution of the cellular protein synthetic machinery and thus marked reduction in lactotroph cell size. This effect, together with an antimitotic action, accounts for the rapid and sustained tumor shrinkage, which enables these drugs to be used as primary therapy for patients with larger prolactinomas, even those with pressure effects.

Dopamine agonist treatment is followed typically by a rapid fall in serum PRL (within hours) and tumor shrinkage (within days or weeks). Tumor regression is often followed by an improvement in visual function over a (short) time course that rivals that seen after surgical decompression of the chiasm. Thus, patients with macroprolactinomas with visual failure are no longer the neurosurgical emergency they were previously regarded to be. Nevertheless, it is important that all patients with a pituitary macrolesion producing chiasmal compression should have serum PRL measured urgently (and checked in dilution—see "Interpretation of Prolactin Immunoassay Result," earlier). An illustrative patient is shown in Fig. 2.

Shrinkage rates. A meta-analysis of 271 well-characterized macroprolactinomas treated with dopamine agonists showed that 79% of tumors shrank by more than a quarter and 89% shrank to some degree (37). The pretreatment PRL level is not a reliable predictor of tumor shrinkage, because 83% of tumors showed significant tumor shrinkage in both the >100,000 mU/L (4000 ^g/L) and 500010,000 mU/L (200-400 ^g/L) groups. Of the macroprolactinomas large enough to produce chiasmal compression, 85% showed significant tumor shrinkage.

Time course of shrinkage. Tumor shrinkage can be demonstrated with a week or two of starting dopamine agonist therapy, and most shrinkage takes place during the first 3 mo of treatment (37,38). However, in many patients, shrinkage continues at a slower rate during many months. It is recommended to repeat MRI 2-3 mo after commencing dopamine agonist therapy and, if there has been an acceptable response, at longer intervals thereafter.

Amount of shrinkage and visual recovery. Approx 40% of macroprolactinomas treated with dopamine agonists for between 1 and 3 mo show tumor-size reduction of at least one half. Of those treated for 1 yr or longer, almost 90% show such shrinkage (37). Colao and colleagues in a recent prospective study of110 patients with macroprolactinoma have suggested that tumor shrinkage is greater in previously untreated (de novo) patients (35). Tumor shrinkage (>80% of pretreatment volume) was noted, with standard doses of cabergoline in 92% of de novo patients, compared with 42% of dopamine-agonist-intolerant and 30% of dopam-ine-agonist-resistant patients. Tumor shrinkage was only 38% in patients with previously responsive tumors switched to cabergoline because of poor compliance with or nonavailability of a previous dopamine agonist.

Visual field defects improve in approx 90% with these abnormalities. It is important to stress that although early visual improvement occurs frequently, it may be several months before maximum benefit accrues. Thus, persistence of a visual field defect is not an absolute indication to proceed to surgery.

Serum PRL responses. Suppression of serum PRL usually accompanies successful tumor shrinkage. Indeed, all of the responsive patients in the meta-analy-sis showed a fall in serum PRL of at least 50%, and in 58% of patients serum PRL became entirely normal (37).

Effects on pituitary function. Several investigators have demonstrated recovery of impaired anterior pituitary function in association with tumor shrinkage. Importantly, these data have been extended recently to include recovery of GH

Fig. 2. This 26-yr-old-man presented via the ophthalmology clinic with a 6-mo history of headache and decreased color vision and a 1-mo history of bitemporal visual field loss. He also described episodes suggestive of temporal lobe epilepsy. Initial serum prolactin level was enormously raised at 821,000 mU/L (normal <300) and MRI showed a 7.4-cm invasive macroadenoma, extending into the right temporal lobe (left hand panel). Serum testosterone was reduced at 4 nmol/L and gonadotropin concentrations were low. Thyroid and adrenal functions were normal. He commenced cabergoline 0.5 mg twice weekly, and the dose was incremented to 1 mg twice weekly after 4 mo. His headaches subsided within 1 mo, visual fields were normal after 4 mo and the TLE episodes disappeared. Serum prolactin fell to 84,060 mU/L after 4 d and to 12,790 mU/L after 9 mo. MRI showed a considerable reduction in tumor size after 3 mo of medical therapy (right hand panel).

Fig. 2. This 26-yr-old-man presented via the ophthalmology clinic with a 6-mo history of headache and decreased color vision and a 1-mo history of bitemporal visual field loss. He also described episodes suggestive of temporal lobe epilepsy. Initial serum prolactin level was enormously raised at 821,000 mU/L (normal <300) and MRI showed a 7.4-cm invasive macroadenoma, extending into the right temporal lobe (left hand panel). Serum testosterone was reduced at 4 nmol/L and gonadotropin concentrations were low. Thyroid and adrenal functions were normal. He commenced cabergoline 0.5 mg twice weekly, and the dose was incremented to 1 mg twice weekly after 4 mo. His headaches subsided within 1 mo, visual fields were normal after 4 mo and the TLE episodes disappeared. Serum prolactin fell to 84,060 mU/L after 4 d and to 12,790 mU/L after 9 mo. MRI showed a considerable reduction in tumor size after 3 mo of medical therapy (right hand panel).

reserve, which may obviate the need for expensive GH replacement in a proportion of patients (39,40). In contrast, it is worth noting that at least two thirds of men with successfully treated prolactinomas have persistently subnormal testosterone levels and require androgen supplementation (37). Details of gonadal function in women with medically treated macroprolactinomas are difficult to glean from the literature. Cyclical menses return in more than 90% of premenopausal women. The effects on pregnancy are discussed in "Pregnancy and Prolactinomas," following.

Dopamine agonist resistance. Overall, the acquisition of dopamine agonist resistance during therapy is rare, even with treatment periods of10 or more years. A handful of cases have been described, however (37).

Dopamine agonist withdrawal. Although prolactinomas usually remain sensitive to dopamine agonists, the drugs do not appear to provide a definitive cure for macroprolactinoma and most patients have to remain on long-term therapy.

Immediate tumor re-expansion may occur after drug withdrawal following medium-term therapy (up to 1 yr). Such re-expansion is less common after long-term treatment (several years), but the return of hyperprolactinemia in most patients suggests that tumor regrowth would occur over time. In practice, the dose of dopamine agonist can often be reduced considerably once initial tumor regression has been achieved, with ongoing satisfactory control of tumor size.

Nonshrinking prolactinomas. Approx 10% of genuine macroprolactinomas fail to regress during dopamine agonist therapy. The mechanism of this primary resistance is obscure because most patients with nonshrinking tumors have marked suppression of serum PRL levels. Some resistant tumors have large cystic components, some have atypical histology, and some have a deficiency of membrane-bound D2 dopamine receptors (37).

Management strategies. Macroprolactinoma is virtually certain if serum PRL is greater than 5000 mU/L (200 ¡g/L) in a patient with a pituitary macrolesion, and primary treatment with a dopamine agonist has an excellent chance of tumor volume reduction. As noted in"Diagnostic Value of the Basal Serum Prolactin Concentration," earlier, a serum PRL level between 2000 and 5000 mU/L (80200 ¡¡g/L) presents some diagnostic uncertainty. The choice between dopamine agonists and surgery will depend on several factors, including local surgical expertise, the severity of any visual failure, patient preference, and clinical judgment. A closely supervised dopamine agonist therapy trial is perfectly reasonable, provided surgery is performed in the event of visual deterioration or failure of the lesion to shrink after, at most, 3 mo of therapy. Using dopamine agonists, visual failure will persist for longer if the lesion is not a prolactinoma, but up to 50% of patients will avoid surgery. It is important to note that dopamine agonists reduce PRL secretion from both normal and tumorous lactotrophs; therefore, serum PRL is likely to fall, irrespective of the cause of the hyperprolactinemia. Pituitary macrolesions associated with PRL levels less than 2000 mU/L (80 ¡g/L) are rarely prolactinoma, and surgery should be undertaken to decompress the lesion and provide a histologic diagnosis.

The Present Role of Radiotherapy and Surgery

Medical treatment alone is an acceptable option for most patients with macroprolactinoma, particularly those with fertility needs in whom adjunctive therapy might compromise gonadotropin function. Physicians should be aware of the infrequent complication of cerebrospinal fluid (CSF) rhinorrhea, which may occur after shrinkage of inferiorly invasive tumors and may be difficult to correct surgically.

Some endocrinologists consider that dopamine agonist therapy alone is unsuitable for long-term management of macroprolactinoma and recommend external beam radiotherapy. Although PRL levels fall during a several-year period after radiotherapy, enabling dopamine agonist withdrawal in a propor tion of patients, this treatment is likely to be followed by varying degrees of hypopituitarism.

A meta-analysis of 1256 macroprolactinomas treated with primary surgery showed PRL normalization in only 32% of patients (2). Consequently, in view of the effectiveness of medical treatment, only a minority of patients with large tumors should now require surgical intervention. There are three situations in which some clinicians might consider surgery, and a cautionary note on the effect of dopamine agonists on prolactinoma fibrosis is necessary.

First, some macroprolactinomas have considerable suprasellar tissue, even after prolonged dopamine agonist therapy, and some clinicians may be inclined to debulk these tumors before radiotherapy. However, there is a direct relationship between tumor fibrosis and duration of medical treatment such that surgery is made much more difficult and may even be hazardous if dopamine agonists have been given for more than 3 mo (38,41). Furthermore, it is now clear that external radiotherapy can be given safely to patients with persistent suprasellar disease, and anecdotal reports of tumor swelling and visual deterioration have assumed undeserved prominence. Second, up to 10% of macroprolactinomas may require surgery after failure of dopamine agonist shrinkage, most of which are likely to be treated surgically within a few months of presentation, particularly if vision is compromised. Third, it is possible that if short-term dopamine agonist therapy produces a compact intrasellar tumor, which will be uncommon with large adenomas, some may be curable by subsequent surgery. This remains unproven. Overall, it would seem prudent to limit pre-operative medical treatment to a maximum of 3 mo, if surgery is to be undertaken. Gamma Knife radiosurgery is offered in few specialized centers, especially in situations where PRL cannot be normalized with dopamine agonists or microsurgery (42).

Pregnancy and Prolactinomas

Management Recommendations

Estrogens have a marked effect on PRL synthesis and secretion, and the hormonal changes of normal pregnancy cause marked lactotroph hyperplasia. MRI studies have confirmed a gradual doubling in pituitary volume during gestation. In view of these effects of pregnancy on normal lactotrophs, it is not surprising that prolactinomas may also increase in size.

The potential risk to the patient depends on the prepregnancy size of the prolactinoma. For women with microprolactinomas, the risk of clinically relevant tumor expansion is small indeed—less than 2%. Dopamine agonists can be safely stopped in such patients as soon as pregnancy is confirmed. Nevertheless, they should be advised to report for urgent assessment in the event of severe headache or any visual disturbance. Routine endocrine review may be arranged on two or three occasions during the pregnancy, but formal charting of visual fields is unnecessary and measurement of serum PRL provides no useful infor mation, given the considerable PRL rise during normal gestation. Patients can safely breast-feed their infants.

There has been some controversy concerning the risk of pregnancy for women with larger prolactinomas. In early reviews, macroprolactinoma expansion was reported to occur in nearly 40%, but many of these women received ovulation induction with gonadotrophins and not dopamine agonists. More recent reviews suggest that symptomatic macroprolactinoma expansion occurs in well under 20% of women. The figure is probably 5% or lower in women, given a several-month course of dopamine agonist before conception (43).

Some clinicians continue to recommend conservative debulking surgery or even radiotherapy before pregnancy in women with macroprolactinomas to reduce the likelihood of major tumor expansion. However, dopamine agonists may be safely employed as sole therapy, using the following strategy. Medical treatment should be used for a minimum of 6 mo preferably 12 mo, together with follow-up MRI to assess residual suprasellar extension, before conception is attempted. If the tumor has shrunk to within the fossa, the dopamine agonist can be withdrawn once pregnancy is confirmed, with a less than 10% chance of re-expansion problems. If neurologic problems do occur, bromocriptine should be started during the pregnancy and this will restore tumor control in nearly all cases (38). If there is significant suprasellar tumor before conception, the choice is between debulking surgery or continuing bromocriptine throughout the pregnancy. The latter is effective but present experience is limited to slightly more than 100 women.

Dopamine Agonist Safety

There is no evidence of teratogenicity in the offspring of women treated with simple bromocriptine-induced ovulation or those treated throughout pregnancy with the drug. Nevertheless, the oldest bromocriptine child is still only 25 years old, and it is prudent not to use the drug during pregnancy unless absolutely necessary.

Safety data for the newer dopamine agonists, cabergoline and quinagolide, are limited to a few hundred pregnancies, compared with several thousand for bromocriptine. Nevertheless, no new problems have yet emerged. As of May 1999, the manufacturer of cabergoline had data on 334 pregnancies in 301 women treated with the drug. The spontaneous abortion rate in 294 pregnancies with known outcome was 9.5%, well within the expected range. The fetal malformation rate also falls within reported ranges for the general population, and no malformation has occurred more than once. Because clinical experience is limited in relation to pregnancy and because the drug has a long half-life, it is still recommended that cabergoline be stopped 1 mo before intended conception. However, this is clinically inconvenient and requires repeated monitoring of prolactin and ovarian status. Ultimately, it is hoped that sufficient safety data will be gathered to enable the drug to be used in the same way as bromocriptine. As of March 1999, the manufacturer of quinagolide had data on 178 pregnancies in 159 women treated with the drug, 14.6% of whom ended in spontaneous abortion. Nine fetal malformations were diagnosed, including two infants with Down syndrome. These figures also fall within the expected normal ranges. Quinagolide has an intermediate duration of action and, in acknowledgment of the limited pregnancy experience, the data sheet recommends that the drug be withdrawn as soon as pregnancy is confirmed.

Was this article helpful?

0 0
Naturally Cure Your Headaches

Naturally Cure Your Headaches

Are Headaches Taking Your Life Hostage and Preventing You From Living to Your Fullest Potential? Are you tired of being given the run around by doctors who tell you that your headaches or migraines are psychological or that they have no cause that can be treated? Are you sick of calling in sick because you woke up with a headache so bad that you can barely think or see straight?

Get My Free Ebook


Post a comment