Ropinirole for the Treatment of Hyperprolactinemia: A Dose-Escalation Study of Efficacy and Tolerability

Abstract

Context

Treatment of hyperprolactinemia with ergoline dopamine agonists (DAs) can be complicated by intolerance and resistance.

Objective

This study examines the efficacy and tolerability of the nonergot DA ropinirole for the long-term treatment of hyperprolactinemia.

Methods

Twelve hyperprolactinemic women were treated with ropinirole in a 6-month, open-label, dose-escalation trial; 7 of the 12 continued treatment in an extension study for up to 17 months. Ropinirole doses were uptitrated to achieve normal prolactin (PRL) levels, restore menses, and eliminate galactorrhea.

Results

Two of the 12 participants were DA naive; 6 of 12 were ergot DA intolerant; and 1 of 12 had known ergot DA resistance. Baseline PRL levels were 126.2 ± 41.4 ng/mL (SEM). Ropinirole was uptitrated from 0.125 to 0.25 mg/h to a median total daily dose (TDD) of 2 mg/d (1-4 mg/d [interquartile range]). PRL normalization was achieved in 50% of the participants (5 with microadenomas and 1 with idiopathic hyperprolactinemia) at a median effective TDD of 1 mg/d. Of the patients achieving PRL normalization, 83% were ergot DA intolerant. A persistent partial biochemical response (PRL reduction >50% from baseline) was achieved in 17% of the participants. During treatment, menses resumed in 67% of amenorrheic patients; galactorrhea resolved in 67%. Mild adverse effects were reported in 92% of participants; however, ropinirole was not discontinued because of intolerance even among the 50% of individuals with a prior history of ergot DA intolerance and resultant medication discontinuation.

Conclusion

These data demonstrate the efficacy and tolerability of ropinirole for the treatment of hyperprolactinemia in patients with microprolactinomas and idiopathic hyperprolactinemia and suggest ropinirole may represent a novel therapeutic alternative for treating hyperprolactinemic disorders in patients with ergot DA intolerance.

Pathologic hyperprolactinemia is frequently encountered in the practice of endocrinology. It is caused by benign lactotrophic adenomas most commonly but can result from other hypothalamic/pituitary disorders that interfere with dopamine secretion or delivery, and from idiopathic etiologies. Hyperprolactinemia may cause hypogonadism, infertility, low bone density, and galactorrhea, and when secondary to prolactinomas may give rise to headaches, hypopituitarism, and visual loss. Physiologically, prolactin (PRL) secretion is tonically inhibited by dopamine, allowing for its excess to be treated medically even when it results from tumoral secretion. Accordingly, dopamine agonists (DAs) are the mainstay of medical therapy.

Pharmacologically, DAs are categorized as either ergot-derived (bromocriptine, cabergoline) or nonergot-derived compounds (quinagolide, ropinirole). Bromocriptine and cabergoline are Food and Drug Administration approved for the treatment of hyperprolactinemia and prolactinomas in the United States; quinagolide is approved in Europe and Canada. Despite diverse chemical structures, all DAs suppress PRL secretion by binding to D2 receptors on pituitary lactotrophs or PRL-secreting tumoral cells. However, differences in the receptor selectivity of each DA affect the biochemical efficacy and side effect profile of each drug. Bromocriptine and cabergoline have been shown to decrease PRL concentrations, reduce tumor size, and restore gonadal function. However, cabergoline is preferred for the treatment of prolactinomas due to a superior efficacy and tolerability profile in head-to-head trials (1, 2). Despite the efficacy of ergot DAs, pharmacologic resistance and medication intolerance limit their use in some patients (3). In seminal studies examining the treatment of hyperprolactinemia, medication discontinuation rates of up to 3.9% and 12% have been reported with cabergoline and bromocriptine therapy, respectively (1, 4). Bromocriptine and cabergoline lack D2-receptor specificity and exhibit affinity for D1 and α-adrenoceptors, which can potentiate side effects (5). Although cabergoline is better tolerated, it has a high affinity for the serotonin 5-hydroxytryptamine receptor subtype 2B (5HT-2B) expressed on cardiac valves (6), raising concerns about its extended use and prompting some experts to recommend periodic echocardiographic monitoring in patients treated long term or with high doses (2, 7-10).

In contrast, the nonergot DA quinagolide demonstrates marked D2 receptor selectivity and negligible affinity for α receptors or for the 5HT-2B receptors expressed on cardiac valves (11, 12); however, it is not available in the United States. Ropinirole is a newer nonergot DA that is selective for the D2/D3 receptor and, like quinagolide, exhibits negligible in vitro activity at the 5HT-2B receptor and other receptor subtypes (1). Although currently Food and Drug Administration approved only for the treatment of Parkinson disease and restless leg syndrome, it has been shown to suppress PRL concentrations as effectively as bromocriptine in healthy volunteers (13, 14). Furthermore, in patients with hyperprolactinemia, the administration of single doses of ropinirole ranging from 0.5 to 2.0 mg results in a dose-response reduction in PRL concentrations (15). Given the efficacy of ropinirole for acute PRL suppression and the limitations of traditional ergoline DAs, we examined the long-term safety and efficacy of ropinirole as a treatment for hyperprolactinemia and prolactinomas in a 6-month, open-label, dose-escalation trial and extension study.

Materials and Methods

Participants

Patients with hyperprolactinemia and prolactinomas were recruited for this open-label, dose-escalation study from the Columbia University Irving Medical Center's Neuroendocrine Unit, general endocrine clinics affiliated with New York Presbyterian Hospital, and from clinicaltrials.gov. This study was approved by the Columbia University Irving Medical Center Institutional Review Board, and signed informed consent was obtained prior to participation. Sixteen patients were enrolled. One was deemed ineligible after completing the screening visit; 2 relocated out of state prior to receiving the first dose of medication; and 1 woman was withdrawn after week 1 of the study following a decision to pursue surgical resection of her pituitary macroprolactinoma.

Twelve women participated longitudinally. Participant characteristics are depicted in Table 1. Two of the 12 participants were DA naive. Ten individuals had previously been treated with the ergot DAs bromocriptine and cabergoline. Of the patients previously treated with DAs, 1 of 10 had a known history of resistance to the ergot DAs bromocriptine and cabergoline, defined by a failure to normalize PRL levels or reduce tumor size by 50% on maximally tolerated doses of bromocriptine and cabergoline (2), and 6 of 10 had a history of ergot DA intolerance characterized by undesirable side effects (nausea, vomiting, headaches, myalgias) that resulted in medication discontinuation. Among the patients with DA intolerance, 6 of 6 had a history of intolerance to cabergoline and 4 of 6 also had a history of intolerance to bromocriptine; 2 of 6 were never treated with bromocriptine. All participants were off DAs for a minimum of 4 weeks prior to enrollment. Continuation of oral contraceptives pills (ethinyl estradiol 20 mcg/norethindrone 1.0 mg) was permitted for the duration of the study in a single patient with a history of dysmenorrhea; however, patients treated with other medications known to interfere with PRL secretion and metabolism were excluded. Hyperprolactinemia (prolactin > 25 ng/mL) was confirmed at the time of screening and again at the baseline study visit. Patients with prolactinomas larger than 15 mm, visual field abnormalities, or pituitary tumors less than 5 mm from the optic chiasm were excluded, as were patients with a history of radiotherapy. All participants had a baseline magnetic resonance imaging (MRI) scan of the pituitary during the 3 months prior to participation or at study entry; 8 of 12 (67%) had a microadenoma, 2 of 12 (17%) had a macroadenoma, 1 of 12 (8%) had a partially empty sella (PES), and 1 of 12 (8%) had idiopathic hyperprolactinemia. All participants were female, with a mean age of 34.8 ± 2.6 (SEM) years. On a self-reported survey, 4 of 12 (33%) identified as Black/African American, 6 of 12 (50%) as White, and 2 of 12 (17%) as other. Furthermore, 9 of 12 (75%) patients identified as non-Hispanic and 3 of 12 (25%) identified as Hispanic. Participants had normal renal, hepatic, and thyroid function and no history of previous radiation, excessive alcohol use, or current pregnancy. A negative β-human chorionic gonadotropin test was confirmed prior to study entry, and patients agreed to use barrier contraception for the duration of the trial.

Table 1.

Patient demographics and baseline characteristics

Participant characteristics N = 12
Age mean ± SEM, y	34.8 ± 2.6
Race n (%)
Black/African American	4 (33)
White	6 (50)
Other	2 (17)
Ethnicity n (%)
Hispanic	3 (25)
Non-Hispanic	9 (75)
Female sex n (%)	12 (100)
Baseline prolactin mean ± SEM, ng/mL	126.2 ± 41.4
History of ergot DA intolerance n (%)a	6 (50)
Known resistance to ergot DA n (%)b	1 (8)

Averages reported as mean ± SEM.

Abbreviation: DA, dopamine agonist.

^a Of the 6 patients with DA intolerance, all 6 were intolerant to cabergoline, 4 of 6 were also intolerant to bromocriptine, and 2 of 6 were bromocriptine naive.

^b The single patient with known DA resistance was resistant both to cabergoline and bromocriptine.

Study Design

This was a single-center, outpatient, prospective 24-week dose-escalation trial of ropinirole for the treatment of hyperprolactinemia, with an option for open-label extension for up to 17 months. Patients were screened and enrolled between December 2016 and June 2019. All visits were conducted in the Irving Institute for Clinical and Translational Research, our outpatient clinical research center. Hyperprolactinemia (PRL > 25 ng/mL) was confirmed in all participants at the time of screening and again at the baseline study visit. Macroprolactinemia was ruled out using polyethylene glycol precipitation. Patients were assessed at baseline, 2 and 4 weeks after starting therapy, and then once monthly thereafter for 24 weeks. Patients completing the 24-week study who demonstrated a biochemical response to ropinirole were eligible for an open-label extension study with assessments every 2 months. Oral ropinirole was initiated at a dose of 0.25 mg/h for 7 days then increased to 0.25 mg twice daily for 7 days in all participants except 1 with severe DA intolerance who was initiated on 0.125 mg/h. Dose adjustments were made every 2 weeks for 4 weeks and then every 4 weeks thereafter until 24 weeks, based on PRL levels and drug tolerability to a maximum daily dose of 6 mg. If PRL levels remained greater than the upper limit of normal (PRL > 25 ng/mL), the dose was incrementally increased in the absence of adverse events (AEs) to a maximum dose of 6 mg/d. In those with persistent adverse symptoms, a dose reduction was recommended. At each visit, patients answered questions pertaining to galactorrhea, menstrual activity, and adverse side effects known to occur with ropinirole. Side effects were graded according to the National Cancer Institute Common Terminology Criteria, version 4.03. Treatment compliance was reviewed by pill count and history. A physical examination that included the measurement of blood pressure and weight was conducted at each visit. A pregnancy test was conducted in all premenopausal participants, and a blood sample was collected for PRL for each visit as well. Comprehensive metabolic panels were analyzed for safety at 2, 4, 12, and 24 weeks.

Efficacy Criteria

A complete biochemical response was defined as normalization of PRL levels to (<25 ng/mL). Partial clinical efficacy was defined as a serum PRL reduction of 50% or greater from baseline. Clinical efficacy was defined as the occurrence of menstruation in a patient with a baseline history of amenorrhea. Resolution of galactorrhea and reported normalization of libido were also considered indices of clinical improvement.

Assays

Serum PRL was measured in duplicate by 2-site chemiluminescent enzyme immunometric assay using the Immulite 1000 Analyzer (Siemens Healthcare Diagnostics). The reference range for serum PRL is 1.9 to 25 ng/mL for women. Intra-assay and interassay coefficients of variation are 6.8% and 9.6%, respectively.

Radiologic Evaluations

Radiologic assessment of the pituitary consisted of an MRI scan obtained before and after the administration of gadolinium chelate 0.1 mmol/kg intravenous bolus. The MRI studies were performed at baseline in all patients who had not undergone pituitary imaging during the 3 months prior to enrollment and were compared to subsequent MRIs completed at 24 weeks. All tumor diameters were measured by a blinded neuroradiologist (A.G.K.). The pituitary lesions were localized on a T1-weighted post-contrast coronal MRI obtained at 3-mm slice thickness. The lesions were defined by drawing 2 perpendicular lines representing the long and short lesions’ diameters in millimeters. Tumor shrinkage was assessed as a reduction of the maximal tumor diameter compared with the baseline by a semiquantitative 4-point scale as follows: less than 10% as absent, 10% to 20% as mild, 20% to 30% as moderate, and as more than 30% as remarkable (16-19).

Statistical Analysis

The statistical analysis was performed by t test for paired data. We summarized changes from baseline in clinical end point parameters descriptively and tabulated proportion of patients with AEs. Data are reported as mean ± SEM unless otherwise specified. The statistical analysis was performed using the PRISM GraphPad package. The results were considered statistically significant at P values less than .05.

Results

Eleven patients completed at least 24 weeks of ropinirole therapy; one was lost to follow-up after 16 weeks. Seven participants entered the extension study and continued treatment with ropinirole. Five of 7 individuals remained on ropinirole for 1 year; 2 of 7 remained on ropinirole for 17 months because of delays in conducting the final visit due to the ongoing COVID 19 pandemic in New York City at the time of the study. Mean baseline PRL levels were 126.2 ± 41.4 ng/mL (SEM). Ropinirole was initiated at a dose of 0.125 to 0.25 mg/h and at 24 weeks TDD ranged from 1 mg/d to 6 mg/d, with a median dose of 2 mg/d (1-4 mg/d [interquartile range]). At 24 weeks, 7 of 12 patients had a final treatment dose that was less than or equal to 2 mg/d given in divided twice-daily doses. Five of 12 had final treatment doses greater than or equal to 4 mg/d.

Biochemical efficacy

Fig. 1 shows the change in PRL concentrations in each of the 12 participants, beginning at baseline and following ropinirole therapy, demonstrating PRL normalization in 50% during the initial 24-week treatment period. Of the women achieving normal PRL, 5 had microadenomas and 1 had an idiopathic hyperprolactinemia (Table 2). Collectively, mean PRL levels fell from a baseline concentration of 126.2 ± 41.4 ng/mL to a nadir of 63.0 ± 26.3 ng/mL (SEM) on ropinirole therapy in all patients. However, when the single patient with known resistance to DA therapy was excluded from the analysis, mean nadir PRL levels were significantly lower than baseline values (39.6 ng/mL vs 87.7 ng/mL; P<.0001). Among those patients achieving PRL normalization, median ropinirole dose was 1.0 mg/d (interquartile range, 1-2 mg/d) with a dose range of 1.0 to 4.0 mg/d given in a divided dose (Table 3). Among the patients who did not achieve PRL normalization, a partial biochemical response was achieved in 2 of 6 patients at at least 1 time point during treatment. One of the 2 patients achieving a partial biochemical response had a final TDD of 1 mg, while the other required a TDD of 6 mg (see Table 3).

Figure 1.

Changes in serum prolactin (ng/mL) concentrations in each of the 12 participants, at baseline (•) and following ropinirole therapy, demonstrating prolactin normalization in 50% during the initial 24-week treatment period.

Table 2.

Prolactin concentrations at baseline and during long-term ropinirole treatment in 12 patients with hyperprolactinemia

Patient, age/sex	DA resistance	DA intolerance	Etiology	Baseline PRL, ng/mL	PRL nadir, ng/mL	PRL 24 wk, ng/mL	Terminal PRL >24 wk, ng/mL	% PRL suppression at 24 wk
1. 35 F	N	N	Micro	79	25	77.5	60.4	23.5
2. 21 F	Y	N	Macro	549	320	690	N/A	−25.7a
3. 41 F	N	N	PES	91	55.1	85.8	N/A	5.7
4. 41 F	N	N	Micro	115	49.3	50.1b	N/A	56.4
5. 25 F	N	N	Macro	232	162.3	162.3	N/A	30
6. 26 F	N	Y	Micro	117	48.4	56.9	59.8	48.9
7. 45 F	N	Y	Idiopathic	49.2	17.2	20.6	19	61.4
8. 37 F	N	Y	Micro	38.1	14.7	14.7	17.2	54.9
9. 32 F	N	Y	Micro	36.2	19	22.1	16.6	54.1
10. 26 F	N	N	Micro	49.8	4.81	4.81	10.2	79.5
11. 38 F	N	Y	Micro	75.1	21.6	21.6	12.8	83
12. 50 F	N	Y	Micro	82.4	18.1	18.1	12.4	85

Reference range for PRL concentrations less than 25 ng/mL in nonpregnant women.

Abbreviations: DA, dopamine agonist; F, female; idiopathic, idiopathic hyperprolactinemia; macro, macroadenoma; micro, microadenoma; N, no; PES, partially empty sella; PRL, prolactin; Y, yes.

^a PRL increased by 25.7% at final visit compared to baseline.

^b Data available for only 16 weeks of treatment.

Table 3.

Biochemical efficacy of ropinirole treatment as a function of total daily dose at final study visit

Response to treatment
Total daily dose, mg/24 h	PRL normalization n (%)	Partial PRL response (≥50% suppression) n (%)	No response (<50% suppression) n (%)
1.0	4 (33)	0 (0)	0 (0)
2.0	1 (8)	1 (8)	1 (8)
4.0	1 (8)	0 (0)	2 (17)
6.0	0 (0)	1 (8)	1 (17)
Total	6 (50)	2 (17)	4 (33)

Abbreviation: PRL, prolactin.

Of the patients not achieving normalization or a partial biochemical response, mean PRL levels decreased by 20 ± 13% at a median TDD of ropinirole of 4.0 mg/d (2.0-6.0 mg/d). Among the 7 patients who participated in the extension study, 6 of 7 had normal prolactin levels at the 24-week entry point, and 6 of 7 had normal PRL levels at study completion, evincing stable PRL normalization for up to 17 months (see Table 2). In the single patient who had persistently elevated PRL levels on entry into the extension study, after 12 months of treatment with ropinirole, her PRL concentration decreased by 49% from baseline and the tumor size remained stable. In the single participant with documented ergot DA resistance, PRL concentrations decreased from 529 to 320 ng/mL after 12 weeks of ropinirole treatment on the maximum dose studied (6 mg/d) but rose to 690 ng/mL at 24 weeks.

Clinical efficacy

Menses, galactorrhea, libido

At baseline, 1 of 12 women had undergone a prior hysterectomy and 1 of 12 women refused to discontinue oral contraceptive pills. Of the remaining 10 of 12 participants, 9 of 10 reported amenorrhea at the start of the study and 1 of 10 reported regular menses despite hyperprolactinemia. During ropinirole treatment, menses occurred in 6 of 9 (67%) women, 5 of 6 of whom achieved PRL normalization, and 1 of 6 of whom achieved a partial response. One woman had persistent amenorrhea even after PRL normalization and was subsequently diagnosed with premature ovarian insufficiency. Galactorrhea was present in 6 of 12 participants at baseline and resolved in 4 of 6 (67%), all of whom achieved PRL normalization following treatment with ropinirole.

Weight, heart rate, blood pressure

Weight, heart rate, and blood pressure were not affected by treatment with ropinirole (Table 4). The mean weight was 74.2 ± 4.3 kg at baseline vs 75.1 ± 4.9 kg at 24 weeks (P = .4). The mean heart rate 73.2 ± 3.1 bpm at baseline vs 73.2 ± 2.1 bpm at 24 weeks. Mean baseline systolic and diastolic blood pressure were unchanged from baseline at 24 weeks (P = .3).

Table 4.

Changes in clinical parameters during ropinirole treatment reported as mean± SEM

	Baseline	Wk 24	Absolute change	P
Weight, kg	74.2 ± 4.3	75.1 ± 4.9	0.9 ± 0.9	.4
BMI	26.9 ± 1.5	27.2 ± 1.7	0.3 ± 0.3	.3
Systolic blood pressure, mm Hg	111.1 ± 3.2	111.8 ± 2.9	0.75 ± 2.5	.8
Diastolic blood pressure, mm Hg	71.1 ± 1.5	68 ± 2.9	−3.1 ± 2.7	.3
Heart rate, bpm	73.2 ± 3.1	73.2 ± 2.1	0 ± 2.8	>.9

Abbreviations: BMI, body mass index; bpm, beats per minute.

Effects of long-term treatment with ropinirole on tumor volume

All of the tumors were solid. None exhibited hemorrhagic deterioration. Among the 7 participants with pituitary microadenomas identified on baseline MRI scan who completed 24 weeks of treatment with ropinirole, tumor resolution was observed in 1woman. A mild decrease in tumor size (10%-20%) was observed in 1 woman, and tumor size remained unchanged in 3 of 7. In 2 participants a mild increase in tumor size was observed at 24 weeks, with an increase of maximal tumor diameter from 3.0 to 3.5 mm and from 5.6 to 6.6 mm in the 2 women, respectively, despite normal PRL levels at 24 weeks. Of the 2 participants with macroadenomas, maximal tumors diameters at baseline were 10.9 mm and 12.9 mm. The former exhibited tumor stability and the latter exhibited a mild decrease in tumor size (17%) over the course of 6 months. In the patient with idiopathic hyperprolactinemia, the MRI scan was unchanged following 24 weeks of ropinirole treatment. In the patient with the PES, interpretation of the 24-week MRI scan was limited by motion artifact.

Tolerability

There were no changes in renal or kidney function. Grade 1 mild AEs were recorded in 92% of participants. Fatigue (58%), nausea (50%), and headache (33%) were most common (Table 5). Dizziness and confusion/brain fog were reported in 25% of the participants, respectively. Heartburn/indigestion was reported in 2 of 12 (16%) women at a single visit and 1 of 12 (8.3%) women reported body aches at a single visit. Reported AEs declined after month one of the study. Grade 2 and higher AEs related to taking ropinirole were not reported, and ropinirole was not discontinued due to intolerance. All 6 participants with a history of ergot DA intolerance remained on ropinirole for the duration of the 24-week study, and all 6 opted to continue treatment with ropinirole in the extension study, resulting in a duration of ropinirole treatment of up to 17 months in this ergot DA-intolerant subgroup.

Table 5.

Most common adverse events reported at any time during ropinirole treatment as assessed by National Cancer Institute Common Terminology Criteria, version 4.03

Clinical adverse event	Adverse events score
	Grade 1 n, %	Grade 2-4 n, %
Fatigue/Drowsiness	7 (58)	0
Nausea	6 (50)	0
Headache	4 (33)	0
Dizziness	3 (25)	0
Confusion/Brain fog	3 (25)	0

Discussion

This is the first study to examine the long-term efficacy and tolerability of the nonergot DA ropinirole for the treatment of hyperprolactinemic disorders. The results demonstrate that treatment of hyperprolactinemia with low-dose ropinirole for 24 weeks induces PRL normalization and improvement in clinical symptoms of hyperprolactinemia in a subset of patients. The study cohort included patients with microadenomas and macroadenomas, and idiopathic hyperprolactinemia, and 58% of the patients had known intolerance and/or resistance to ergot DAs. Yet, despite this inclusive patient sample, stable PRL normalization was achieved in 50% and a partial biochemical response was observed in 17% of patients treated with ropinirole for 24 weeks and sustained in the extension study for up to 17 months, demonstrating the long-term efficacy of ropinirole. Additionally, ropinirole showed good efficacy in improving hyperprolactinemic symptoms, resolving galactorrhea in 67% patients, and inducing resumption of menstruation in 67% of patients who were amenorrheic at the start of the study. Importantly, ropinirole treatment effectively normalized PRL levels in 83% of patients in whom treatment with ergot DAs was contraindicated due to medication intolerance and resulted in a partial biochemical response in 17%. Furthermore, no one withdrew because of ropinirole intolerance. These finding are highly relevant and suggest ropinirole represents a safe and effective alternative medical therapy for the treatment of hyperprolactinemia, particularly in patients with ergot DA intolerance.

When ropinirole's efficacy is examined by etiological subgroups, long-term treatment resulted in PRL normalization in the single participant with idiopathic hyperprolactinemia in this cohort, but not in the woman with a PES. Among microprolactinomas (n = 8), PRL normalization was achieved in 63% of patients treated with ropinirole in total, and in 71% of those considered fully evaluable based on 24 weeks of uninterrupted dose-escalation therapy. Among the patients with macroprolactinomas (n = 2), treatment with ropinirole did not normalize PRL levels despite a progressive dose increase to 6 mg daily. While DAs have repeatedly been shown to more effectively reduce PRL levels in microadenomas compared to macroadenomas (4), the observed efficacy of ropinirole for PRL suppression in macroadenomas was likely affected by the fact that 1 of the 2 patients had a known history of ergot DA resistance. While ropinirole was not effective in this patient, given approximately 50% of patients with bromocriptine resistance have been shown to exhibit a biochemical response to the nonergot DA quinagolide (20, 21), further study of ropinirole's effectiveness in this patient population is warranted.

In the present study, most patients who achieved PRL normalization (83%) did so at an effective ropinirole dose of 2 mg/day or less given in divided doses. In a single patient, the effective dose was 4 mg/day. It is possible greater efficacy may have been observed if higher doses of ropinirole had been used, given data from a pharmacokinetic-pharmacodynamic study examining the acute effects of ropinirole on PRL concentrations showed higher doses led to a greater degree of PRL suppression in individual patients (15). While the maximum dose of ropinirole approved for the treatment of restless leg syndrome is only 3 mg/day, doses of up to 18 mg/day are approved for the treatment of Parkinson disease, indicating a more aggressive dose-escalation protocol could be considered for the treatment of prolactinomas in future studies.

Currently cabergoline is the preferred DA for the treatment of hyperprolactinemia because of its superior efficacy and tolerability profile (2). In a retrospective study of 455 patients, cabergoline normalized PRL levels in 86% of evaluable patients with therapeutic efficacy ranging based on the etiology of hyperprolactinemia—92% of 244 patients with idiopathic hyperprolactinemia or microprolactinomas, and 77% of 181 patients with macroprolactinomas (4). In a prospective, 24-week, multicenter trial of 459 hyperprolactinemic women, PRL normalization was similarly achieved in 83% of participants treated with cabergoline compared to 59% treated with bromocriptine (1). Ovulatory cycles occurred in 72% of cabergoline-treated and 52% of bromocriptine-treated participants (1). By comparison, in a large-scale meta-analysis consisting of 33 studies and 827 hyperprolactinemic patients, quinagolide was shown to normalize PRL levels in 69% of cases. While larger studies and head-to-head comparisons are clearly needed, this study suggests that ropinirole may be as effective as bromocriptine and quinagolide.

When hyperprolactinemia is due to a prolactinoma, the therapeutic goal not only includes lowering PRL levels, but also inducing tumor shrinkage to attenuate mass effect when present and to achieve tumor regression and cure when possible. Due to the small size of the cohort, this study was not powered to definitively determine the effect of ropinirole treatment on tumor size. However, the data demonstrate beneficial but varying effects in our participant population. Among those with pituitary microadenomas completing 24 weeks of treatment, tumor resolution was observed in one woman, a mild decrease in tumor size (10%-20%) was observed in one woman, and tumor stability was seen in 3 of 7 women. Two patients exhibited an increase in maximal tumor diameter at 24 weeks despite achieving sustained PRL normalization beginning at 8 weeks and 20 weeks, respectively. Although the increase in tumor size was modest (0.5-1 mm), it is difficult to reconcile tumor growth in the face of PRL normalization. It is possible that the tumor growth observed after 24 weeks of ropinirole treatment occurred during the dose-escalation period, prior to PRL normalization or suppression. While less likely, measurement error is also a possibility. Among the macroadenomas studied, although PRL normalization was not achieved, one patient demonstrated tumor stability, and the other a mild decrease in tumor size (17%), following 24 weeks of treatment. Among patients with a diagnosis of idiopathic hyperprolactinemia or PES, there was no evidence of tumor growth.

In the present study, 92% of patients reported adverse symptoms when questioned directly about 16 specific side effects known to be associated with DAs and in an open-ended fashion. All documented AEs were scored as mild and were consistent with those observed with other DAs, including fatigue, nausea, headache, and dizziness/orthostasis. As with bromocriptine, cabergoline, and other DAs with D3 receptor affinity, it should be noted that ropinirole can be associated with impulse control disorders, although none were reported in this study (22). In a head-to-head trial by Webster et al (1) comparing cabergoline and bromocriptine for the treatment of women with microprolactinomas and other hyperprolactinemic disorders, AEs were reported in only 68% of patients treated with cabergoline in an open-label fashion, and in 78% of those taking bromocriptine. When Homburg et al (23) examined the nonergot DA quinagolide (available in the European market) vs bromocriptine in a double-blind study of 22 hyperprolactinemic women, only 69% of quinagolide-treated patients reported AEs compared to 82% of bromocriptine-treated patients, 3 of 11 of whom discontinued the study because of severe adverse reactions. While ropinirole's tolerability profile may appear less favorable, the trial by Webster et al excluded patients with DA intolerance entirely, and in the cohort studied by Homburg et al only 23% of patients had a history of DA intolerance associated with medication discontinuation (23). In contrast, half the cohort in the present study had a known history of ergot DA intolerance, which likely influenced the observed frequency of AEs. In the general population, DA intolerance affects 3% to 12% of patients and strategies for overcoming it are limited (24). Medical therapy is often precluded in these patients, and those requiring treatment commonly undergo transsphenoidal surgery despite data showing only 38% of them achieve remission and up to 46% require DA therapy postoperatively to control PRL levels (25). Ropinirole represents a worthwhile medical treatment alternative in these patients.

Although this study did not examine cardiac outcomes, it is worth noting that unlike cabergoline and bromocriptine, ropinirole has negligible affinity for the 5HT-2B receptor commonly found on heart valves (5). The effect of long-term treatment with ropinirole on cardiac valves in patients with hyperprolactinemia requires further study; however, to date ropinirole use has not been associated with valvulopathies in patients with Parkinson disease and restless leg syndrome, and therefore it may be a more favorable option for the treatment of hyperprolactinemia in patients for whom cardiac adverse effects are a concern. It should be noted that for females with hyperprolactinemia who are desirous of fertility, there are few safety data on transplacental transfer and the teratogenic risks of ropinirole in human pregnancy (26). While Dostal et al (26, 27) described 2 cases of patients treated with 2 mg daily of ropinirole alone who delivered healthy offspring, ropinirole is not currently recommended for use during gestation because of the dearth of safety data. Notably, ropinirole is also more affordable than other DAs. Even though cabergoline and bromocriptine are generic, the cost of these medications is an ongoing issue for many patients. At the doses used to treat hyperprolactinemia, the average monthly cost of bromocriptine and cabergoline are $168 and $343, respectively, depending on the dose. Given that the retail price for generic ropinirole at the doses shown to normalize serum PRL in our study is approximately $30/month, ropinirole may represent a more cost-effective option for treatment of hyperprolactinemia. Nonetheless, it is important to note the limitations of this study. While there were not exclusions based on biological sex, only female patients were successfully enrolled in this study. Additionally, despite clear hyperprolactinemia mean baseline PRL concentrations were relatively low and although prolactinomas often require long-term treatment, the majority of patients in this study were treated for only 24 weeks.

In conclusion, the results of the present study demonstrate that the nonergot DA ropinirole is a viable treatment option for hyperprolactinemia that is particularly effective in patients with microprolactinomas and idiopathic hyperprolactinemia. Ropinirole is remarkably well tolerated in patents who have previously discontinued ergot DAs because of substantial side effects and should be considered as a pharmacologic treatment alternative in these individuals.

Abbreviations

5HT-2B

5-hydroxytryptamine receptor subtype 2B

AE

adverse event

DA

dopamine agonist

MRI

magnetic resonance imaging

PES

partially empty sella

PRL

prolactin

TDD

total daily dose

Funding

This work was supported by the National Center for Advancing Translational Sciences (National Institutes of Health grant Nos. UL1-TR-000040 and UL1-RR-024156), Irving Institute for Clinical and Translational Research/Clinical Trials Office Pilot Award (to G.P.W.), and the National Institutes of Health grant No. DK112093 (to G.P.W.).

Disclosures

The authors have no disclosures.

Data Availability

Some or all data sets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Clinical Trial Information

Clinical trial registration No. NCT03038308 (registered January 31, 2017).