Long-term treatment with a new repeatable injectable form of bromocriptine, Parlodel LAR, in patients with tumorous hyperprolactinemia

Vol. 52, No.6, December 1989

FERTILITY AND STERILITY

Printed on acid-free paper in U.S.A.

Copyright" 1989 The American Fertility Society

Long-term treatment with a new repeatable injectable form of bromocriptine, Parlodel LAR*, in patients with tumorous hyperprolactinemiat Enrica Ciccarelli, M.D.:!: Cataldo Miola, M.D.:!: Teresa Avataneo, M.D.§

Franco Camanni, M.D.:!: Gordon M. Besser, M.D., D.Sc.11 Ashley Grossman, M.D.II1f

University of Turin, Turin, Italy, and St Bartholomew's Hospitat London, United Kingdom

A new long-acting repeatable injectable form ofbromocriptine, (Parlodel LAR, Sandoz, Basle, Switzerland) has recently been developed. We studied the clinical, hormonal and radiological changes in six female patients with microprolactinomas and eight (3 female and 5 male) with macroprolactinomas receiving monthly injections of Parlodel LAR 50 to 100 mg for 6 months. Five patients with microadenomas and 4 with macroadenomas had normal prolactin (PRL) levels with Parlodel LAR 50 mg after one (5 patients), two (2 patients), or five (2 patients) injections; two patients with macroadenomas had normal or near normal PRL levels only after 4 monthly injections of 100 mg. Clinical improvement paralleled the changes in serum PRL. A complete normalization of a visual field defect occurred in one patient after 5 months of therapy. Marked shrinkage of the adenoma was shown by magnetic resonance and/or computed tomographical imaging in three patients with macroadenomas after 1 week. Side-effects were mild and usually transient. Parlodel LAR represents a novel treatment of hyperprolactinemic states which is both effective and well tolerated, and appears to be a useful alternative to oral therapy for long-term treatment. Fertil Steril52:930, 1989

Bromocriptine is a potent orally-active dopamine agonist drug acting on dopaminergic D2 receptors; it has a well recognised inhibitory action on prolactin (PRL) release,l,2 and also causes a decrease in PRL synthesis and of messenger ribonucleic acid (mRNA) transcription of the PRL gene in PRL-secreting cells.3 Moreover, oral bromocriptine has been shown to be effective in restoring gonadal function and to induce tumor shrinkReceived February 27,1989; revised and accepted August 3, 1989. * Parlodel LAR, Sandoz, Basle, Switzerland. t Supported in part by Sandoz, Basle, Switzerland. Department of Biomedicine, Division of Endocrinology, University of Turin, Italy. § Institute of Radiology, University of Turin. II Department of Endocrinology, St. Bartholomew's Hospital, London, Gt. Britain. Reprint requests: Ashley Grossman, M.D., Department of Endocrinology, St Bartholomew's Hospital, London, EC1A 7BE, United Kingdom.

*

930

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Repeatable bromocriptine injections

age in the majority of patients with PRL-secreting pituitary tumors. 4- 7 A long-acting injectable form of bromocriptine (Parlodel LA, Sandoz, Basle, Switzerland) has been shown to be highly effective in the control of hyperprolactinemia;s-12 it has a rapid onset of action and long-lasting activity. However, due to the long half-life of the carrier material, polylactic acid, Parlodel LA is unsuitable for long-term use and has therefore been used principally to initiate medical treatment in patients with prolactinomas. Recently, a new long-acting injectable form of bromocriptine, Parlodel LAR (Sandoz, Basle, Switzerland), has been developed; this form employs D,L-polylactid-co-glycolid-glucose as a carrier material, having an in vivo total mass degradation of less than 3 months. 13 This allows for the possibility of repeated injections of this depot formulation. Preliminary data in normal volunteers have shown that this drug had a very good local Fertility and Sterility

Table 1 Clinical, Hormonal, Visual Field, and Radiological Data Observed in 14 Hyperprolactinemic Patients Before Treatment with Parlodel LAR Case

Sex

Age

1 2 3 4 5 6 7 8 9

F F F F F F F M M M F F M M

32 31 24 40 40 32 14 32 31 47 45 41 59 39

Clinical symptoms

10

Scan (CT and/or MRI)

Normal Normal Normal Normal Normal Normal Normal Normal Normal Bilateral hemianopia Normal Normal Normal Normal

Microadenoma Microadenoma Microadenoma Microadenoma Microadenoma Microadenoma Macroadenoma Macroadenoma Macroadenoma Macroadenoma Macroadenoma Macroadenoma Macroadenoma Macroadenoma

"gIL

y

11 12 13 14

Visual field

PRLo

Ib SAc, G d G,I SA,G SA,G SA,G PAe,G G RL' RL SA,G SA,G RL RL

o Mean of values at 8,12,16, and 20 hours. b I, infertility. C SA, secondary amenorrhea; P A, primary amenorrhea.

and systemic tolerance, inducing a rapid and longlasting (up to 28 days) suppression ofPRL levels. 14 We have therefore studied the efficacy and the general and local tolerability of long-term treatment with Parlodel LAR in patients with tumorous hyperprolactinemia.

108 89 129 85 113 64 599 300 430 1,760 140 72 209 85

G, galactorrhea. epA, primary amenorrhea. I RL, reduced libido and potency. d

Six patients with PRL-secreting microadenomas (patients 1 to 6) and 8 with macroadenomas (patients 7 to 14) were studied. Clinical, hormonal, visual field, and radiological data are reported in Table 1. Patients 9 and 14 had previously undergone surgery with persistence of a large tumor. Patient 10 was panhypopituitary, whereas patient 9 was cortisol deficient; all other patients had normal endocrine function other than hyperprolactinemia as tested by basal and dynamic function tests. Five patients (patients 6, 7, 9, 11, and 14) had never been treated with bromocriptine, whereas the remaining nine patients had been off therapy for at least 3 months. All patients gave their informed consent to participate in the study, which was approved by the Ethical Committees of both hospitals. Parlodel LAR was administered by the deep intramuscular (1M) route at 8:00 AM once monthly. In all patients the initial dose of the drug was 50 mg. In certain patients with macroadenomas (patients 7 to 10) the dose was increased to 100 mg if the PRL levels were not suppressed to normal.

Plasma PRL levels were measured at 8, 12, 16, and 20 hours after the first injection, and then on days 1, 14, and 28 after each injection, up to a maximum period of 6 months. The patients were hospitalized for 48 hours after the first injection, and were gently mobilized after 6 to 8 hours. Subsequent injections were given on an ambulant out-patient basis. At each visit the patient was specifically questioned with respect to side-effects, and these were graded as mild, moderate, or severe. A full hormonal screen, including serum gonadotropins, thyroid stimulating hormone (TSH), triiodothyronine (T 3 ), thyroxine (T4 ), cortisol, progesterone (P), and estradiol (E 2 ) was obtained before and at the end of the observation period in every patient, as well as a routine toxicological screen of hemoglobin, white count, plasma urea, creatinine and electrolytes, liver enzymes, bilirubin, calcium, and phosphate. In addition, the five male patients had serum testosterone (T) estimations (normal range 3 to 11 ng/mL) at monthly intervals. All patients received nuclear magnetic resonance scans (Ansaldo RM Esatom Esaote 0.5 tesla [Ansaldo, Turin, Italy]; patients 9 to 11) and/or high resolution computed tomography after contrast enhancement (General Electric GE 8800 or 9800 [GEC, Slough, Great Britain]) before treatment, and at the end of 6 months treatment (except for the 2 patients who were pregnant). Patients with macroadenomas were scanned additionally at 1 week and 1 month after initiation of treatment. Plasma PRL levels were measured by standard

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MATERIALS AND METHODS

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Figure 1 Levels of circulating PRL in six patients with microprolactinomas given monthly injections of Parlodel LAR.

radioimmunoassay (RIA), using an unextracted technique; the tracer was 1251_ PRL, and standards calibrated against Medical Research Council (MRC) standard 75/504, Antiserum was raised in rabbits, and separation was achieved by means of a second (donkey anti-rabbit) antiserum. The within and between -assay coefficients of variations were 3.2% and 6.9%, respectively. All serum samples were separated at room temperature, and the serum rapidly frozen and stored at 20·C. As each patient study lasted 6 months, only the first 24 hours samples were batched: all other samples were assayed within 1 week of collection. Normal PRL levels are <20 p.g/L in females and <12 p.g/L in males.

RESULTS The plasma PRL-Iowering effect of Parlodel LAR 50 mg given once monthly for 6 months to patients with microprolactinomas is shown in Figure 1. A progressive reduction of PRL levels was observed in all patients. Persistently normal PRL levels were observed in three patients after the first (patient 1) or second (patients 3 and 5) injection, whereas patients 2 and 6 only demonstrated persistent normoprolactinemia after the fifth injection. Patient 4 showed a progressive fall in prolactin which, however, never became normal. 932

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Repeatable bromocriptine injections

Similar results were observed in patients with macroadenomas, as shown in Figures 2 and 3. Persistently normal PRL levels were recorded in patients 11 to 14 after the first injection (50 mg) (Fig. 2). The increase in the dose ofParlodel LAR to 100 mg induced normal or near normal PRL levels in patients 7 and 10 after 4 months of treatment (Fig. 3). In patient 8, plasma PRL was reduced to 19% of basal levels and remained stable after the second injection of 100 mg, but was never within the normal range. Patient 9 showed a highly variable response in which serum PRL was lowered but never became normal (Fig. 3). Regular menses were resumed during treatment in 5 out of 6 (patients 2, 4, 5, 6, and 11) of the previously amenorrheic patients. Moreover, two patients (patients 1 and 2) became pregnant after 2 and 5 months of treatment. Galactorrhea disappeared in all female patients. All male patients had a return of normal libido and potency in 1 to 5 months; in three of these patients serum T remained unchanged during treatment at the lower limit of the normal range (2.9,2.6, and 2.6 ng/mL), whereas in one (patient 13) the level ofT rose from 3.0 ng/mL to a peak of 9.3 ng/mL at 3 months. In patient 8, galactorrhea was still present in association with the persistent hyperprolactinemia. A complete normalization of the previously imFertility and Sterility

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Figure 2 Levels of circulating PRL in four patients with macroprolactinomas given monthly injections of Parlodel LAR 50 mg, in whom PRL was normalized after the first injection.

paired visual field was observed in patient 10 after 5 months of therapy. A marked and progressive reduction in the size of the adenoma was documented by nuclear magnetic resonance and/or computed tomographic scans in patients 9, 10, and 12. In patients 9 and 10 a reduction in size was observed after only 1 week of therapy. A central area of necro5Omo 600

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sis was shown by computed tomography in patient 7 after 6 months. Slight shrinkage was also seen in one patient with a microprolactinoma (Table 2). Mild nausea was reported for a few hours after the first injection in patient 1, while patient 12 vomited several times in the first 24 hours. Within the same time frame, four patients (6, 9, 11 and 14) developed symptomatic postural hypotension when initially mobilized; this was noted as 'severe' only in patient 9. No side-effects were noted in the remaining 8 patients. The only side-effects reported after subsequent injections were in patient 12, who developed transient vomiting within 24 hours after the second and third injection, and in patient 4 after the third injection. However, in this latter patient vomiting coincided with the onset of antibiotic therapy, and was not noted during previ0us or subsequent injections of Parlodel LAR. The injection was associated with slight transient stinging at the site of injection in a minority of patients. No changes were observed in serum gonadotropins, TSH, T 3, T 4, or cortisol during treatment; no changes were shown in the toxicological screen. DISCUSSION

Figure 3 Levels of circulating PRL in four patients with macroprolactinomas in whom the first injection of Parlodel LAR 50 mg was followed by monthly injections of 100 mg.

Our results indicate that Parlodel LAR is highly effective in lowering PRL levels in the majority of patients with hyperprolactinemia associated with pituitary tumors. This is in agreement with prelim-

Vol. 52, No.6, December 1989

Ciccarelli et al.

Time (monthl)

Tirne lmonths)

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Table 2 Change in Pituitary Tumor Size in 14 Patients with Hyperprolactinemia After Treatment with Parlodel LAR Case

Initial maximum diameter

Diameter at 6mos

em

1 2 3 4 5 6 7 8 9 10

0.2 to 0.3 0.3 0.3 0.5 0.2 to 0.3 0.5 1.8 3.0 2.5 5.0 1.2 2.1 1.6 2.0

11

12 13 14

Pregnant Pregnant NC· NC NC 0.3 Necrosis NC 0 1.9 NC 1.8 NC NC

• NC, no change.

inary observations in five macroadenomas. 15 As has been previously shown with Parlodel LA,8-11 a rapid reduction in PRL levels is usually obtained after the first injection, occasionally to within the normal range. However, a gradual return of PRL was observed by the 28th day in some cases. N evertheless, a progressive reduction to persistently normal PRL levels was shown after repetitive administration of the drug, even without any increase of the dose. Thus a partial response observed after the first administration does not exclude the possibility of a later normalization of plasma PRL. Improvement in clinical state was generally consistent with the change in PRL levels, and side-effects of treatment were usually mild and transient. The treatment was well tolerated, with few local or system side-effects, especially after the second injection. Parlodel LAR was also able to rapidly induce shrinkage of the macroadenoma in certain patients' as previously shown for both oral4-7 and injectable8-11 bromocriptine. However, in contrast to Van't Verlaat et a1.,15 50% of macroadenomas did not show any significant change in tumor size, despite the achievement of normoprolactinemia, although this does not preclude later onset of tumor shrinkage. It is also possible that in some of the patients with macroadenomas the hyperprolactinemia was secondary to stalk disconnection rather than true tumor secretion. This is certainly possible when the serum PRI;· is
Ciccarelli et aI.

Repeatable bromocriptine injections

prolactin). Such 'pseudoprolactinomas' show little or no shrinkage with dopamine agonists. 18 Thus, Parlodel LAR represents a novel advance in the treatment of hyperprolactinemic states which is both effective and well-tolerated. In patients who do not show normalization of PRL levels after a single injection, a progressive fall in PRL may occur after repeat injections of the same or a higher dose. Although not specifically investigated here, the rebound in PRL levels after each injection may respond to increasing the frequency of administration (eg, every 2 weeks) rather than the dose, and this may be the treatment of choice in those patients with particularly high or resistant levels of PRL. We have previously suggested that a depot formulation of bromocriptine may be especially useful in initiating therapy in patients who have previously been shown to be sensitive to the sideeffects of dopamine agonists, or who need rapid control of their serum prolactin.8,12 It now appears that Parlodel LAR is also suitable for the longterm control of such patients. It should be considered as alternative treatment for hyperprolactinemic patients unable or unwilling to take oral dopamine agonists, and as first-line therapy in the medical shrinkage of large prolactinomas. Tumors demonstrating clear diminution in size may then be treated definitively with radiotherapy. However, failure of shrinkage, particularly in the presence of a field defect, may require early surgical decompression. Acknowledgments. We are grateful to Miss Annabel Froud, Miss Catherine Richards, and Mrs. Anna Barberis for assistance in carrying out these studies, and to Miss Elzbieta Stawowska for secretarial assistance.

REFERENCES 1. Dannies PS: Prolactin: multiple intracellular processing routes plus several potential mechanisms for regulation. Biochem Pharmacol 31:2845, 1982 2. Yeo T, Thorner MO, Jones A, Lowry PJ, Besser GM: The effect of dopamine, bromocriptine, lergotrile and metoclopramide on prolactin release from continuously perifused columns of isolated rat pituitary cells. Clin Endocrinoll0: 123,1979 3. Maurer RA: Dopaminergic inhibition of PRL synthesis and PRL mRNA accumulation in cultured pituitary cells. J BioI Chem 255:8092, 1980 4. Wass JAH, Williams J, Charlesworth M, Kingsley DPE, Halliday AM, Doniach I, Rees LH, McDonald WI, Besser GM: Bromocriptine in the management of large pituitary tumours. Br Med J 284:1908, 1982 5. Nissim M, Ambrosi B, Bernasconi V, Giannattasio G, Gio-

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vannelli M A, Bassetti M, Vaccari N, Moriondo P, Spada A, Travaglini P, Faglia P: Bromocriptine treatment of macroprolactinomas: studies on the time course of tumour shrinkage and morphology. J Endocrinol Invest 5:409, 1982 Corenblum B, Taylor PJ: Long-term follow-up ofhyperprolactinemic women treated with bromocriptine. Fertil Steril 40:596, 1983 Molitch ME, Elton RL, Blackwell RE, Caldwell B, Chang RJ, Jaffe R, Joplin G, Robbins RJ, Tyson J, Thorner MO: Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicenter study. J Clin Endocrinol Metab 60:698, 1985 Grossman A, Ross R, Wass JAH, Besser GM: Depot-bromocriptine treatment of prolactinomas and acromegaly. Clin EndocrinoI24:231, 1986 Benker G, Gieshoff B, Treundlieb 0, Windeck R, Schulte HM Lancranjan I, Reinwein D: Parenteral bromocriptine in the treatment of hormonally active pituitary tumours. Clin EndocrinoI24:505, 1986 Montini M, Pagani G, Gianola D, Salmoiraghi M, Ferrari L, Lancranjan I: Long-lasting suppression and rapid shrinkage of prolactinomas after a long-acting injectable form of bromocriptine. J Clin Endocrinol Metab 63:266, 1986 Ciccarelli E, Ghigo E, Mazza E, Andreis M, Massara F, Lancranjan I, Camanni F: Effects of a new long-acting form

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ofbromocriptine on tumourous hyperprolactinemia. J Endocrinol Invest 10:179, 1987 Grossman A, Wass JAH, Besser GM: The rapid diagnosis of sensitivity or resistance to dopamine agonists with depot bromocriptine. Acta Endocrinol (Copenh) 116:275, 1987 Lancranjan I: Unpublished data Lancranjan I, Munger R, Temler E: Long-lasting PRL secretion inhibition produced by a new injectable form ofbromocriptine, Parlodel LAR, in normal volunteers. (Abstr.) Presented at the 3rd. Congress of the European Neuroendocrine Association, London, England, Sept. 11-14, 1987 Van't Verlaat J, Lancranjan I, Hendriks MJ, Croughs RJM: Primary treatment of macroprolactinomas with Parlodel LAR. Acta Endocrinol (Copenh) 119:51,1988. Ross RJM, Grossman A, Bouloux P, Rees LH, Doniach I, Besser GM: The relationship between serum prolactin and immunocytochemical staining for prolactin in patients with pituitary macroadenomas. Clin Endocrinol 22:227, 1985 Bevan JS, Burke CW, Esiri MM, Adams CBT: Misinterpretation of prolactin levels leading to management errors in patients with sellar enlargement. Am J Med 82:29, 1987 Grossman A, Ross R, Charlesworth M, Adams CBT, Wass JAH, Doniach I, Besser GM: The effect of dopamine agonist therapy on large functionless pituitary tumours. Clin Endocrinol 22:679, 1985

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