Gynecol. Endom'nol. 6 (1992) 119-126
Vaginal bromocriptine - clinical and biochemical effects J. Ginsburg, P. Hardiman and M . Thomas*
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Departments of Endocrinology and *Chemical Pathology, Royal Free Hospital School of Medicine, London, UK Key words: VAGINALBROMOCRIPTINE, HYFJERPROLACTINEMIA, NORMOPROLACTINEMIA
ABSTRACT Adverse efects occur in over 50% ofwomen taking oral bromocnptine, causing at least 10% to discontinue treatment. Although the drug is absorbedjom the vagina and reportedly caused no side-efects in one patient intolerant o f oral bromocnptine, long-tm clinical efects of daily vaginal administration have not been assessed. W e have now given bromomptine vaginallyfor up to 2 years to 3 1 hypqrolactinemic andfive normoprolactinemic women, 17 o f whom were intolerant o f oral bromomptine. The drug was well absorbed j o m the vagina and a daily dosage o f 2.5 mg lowered semm prolactin levels in 28 ofthe hyperprolactinemuwomen (in 11 to within normal limits), restored menstrual cyclicity, and abolishedgalactowhea; one ofthefour infertilewomen conceived. Minor side-effects omwed in only three women. Vaginal administration is clinically efective, avoids the adverse efects oforal therapy and could be the first-line treatmentf o r patients requiring bromocriptine.
INTRODUCTION Bromocriptine was originally used to inhibit puerperal lactation' and to treat galactorrhea2, amenorrhea and infertility3.4associated with hyperprolactinemia. It has also been found to be effective in conditions where prolactin levels are not elevated, such as parkinsonism5, acromegalf, mastalgia7and the premenstrualsyndromes.Unfor-
tunately, however, bromocriptine induces sideeffects such as nausea, vomiting, vertigo, constipation, headache, postural hypotension and drowsiness in 5 0 4 8 % of subjects', which significantly limit its acceptability, particularly in conditions where the side-effects can be more disturbing than the original complaint. Alternative oral preparations" reported to have fewer side-effects have proved to be disappointing. O n the basis that the gastrointestinal effects result fiom a local effect of bromocriptine, it would be reasonable to try parented administration of the drug. Good absorption of bromocriptine after acute vaginal adrmnistration in healthy women", and diminished gastrointestinal effects in hyperprolactinemic ~ o m e n ' ~ .have ' ~ , been reported in short-term studies. There has, however, been no long-term clinical assessment of the effects of chronic, daily vaginal bromocriptine administration. We have now given M y vaginal bromocriptine to hyperprolactinemic women who were intolerant of oral therapy. In view of the good response observed in the initial patients, vaginal therapy was offered instead of oral bromocriptine to hyperprolactinemic women presenting de novo and also to normoprolactinemic women with galactorrhea, mastalgia and the premenstrual syndrome.
Correspondence: Dr J. Ginsburg, Department of Endocrinology, Royal Free Hospital School of Medicine, London W UK
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PATIENTS The patients were 38 women who were given vaginal bromocriptine treatment after fidl investigation (including a computed tomographic scan in the hyperprolactinemic women) and exclusion of hypothyroidism. Two nonnoprolactinemic women failed to attend for follow-up. The results fiom the remaining 36 women are reported here and are shown in Tables 1-3. A total of 31 women were hyperprolactinemic (prolactin > 400 mU/1); the remaining five were normoprolactinemic. Of these women, 17 had previously been treated with oral bromocriptine, but had discontinued medication because of adverse side-effects. Of the hyperprolactinemic women, 17 were amenorrheic and four oligomenorrheic (cycle length > 6 weeks); the remaining ten had regular cycles. There were 11 with galactorrhea,four with infertility, one with mastalgia, one with vertigo, one with headache, one with symptoms of the premenstrual syndrome and two had previously undergone pituitary surgery for a macroadenoma. One woman was receiving psychotropic therapy with sulpiride. Computed tomographic scanning demonstrated a pituitary microadenoma in seven women, a partially empty sella in four, and no tumor recurrence in the women with a macroadenoma and previous surgery. The five nonnoprolactinemic women had not previously received oral bromocriptine. Two women had galactorrheaand oligomenorrhea,two mastalgia and one premenstrual headache.
METHODS Women were instructed to insert one 2.5 m g bromocriptine tablet high into the vagina at night, before retiring. Serum prolactin was measured 1 week later and at regular intervals thereafier. In subjects in whom prolactin failed to fillto within the reference range ( < 400 mUA), the dose of bromocriptine was increased at monthly intervals by 2.5 mg to a maximum daily dose of 15 mg. In order to determine the optimum treatment regimen for individual patients, the acute effects of vaginal bromocriptine were initially assessed in 11 of the women who had not previously taken bromocriptine, and in one who had discontinued oral
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treatment 1 month previously. After initial control blood sampleshad been taken, the women inserted a 2.5 mg tablet of bromocriptine into the vagina. Further samples were taken at 15 and 30 min and 1, 2,4, 8 and 24 h thereafter, for measurement of prolactin and bromocriptine concentrations. Serum bromocriptine levels were also determined during chronic therapy. Serum prolactin was measured using a standard radioimmunoassaytechnique and bromocriptine by the radioimmunoassay described by Schran14. In view of our finding that vaginal bromocriptine was clinically effective,we also investigatedthe effects ofrectal administrationin three healthy male volunteer doctors. The protocol used was the same as that described above for vaginal administration, except that bromocriptine was inserted into the rectum.
RESULTS Clinical response
Hyperprolactinemu women Regular menstruation was restored within 4 months in ten of the 17 amenorrheic women and in three of the four with oligomenorrhea. Galactorrheawas alleviated in six of the 11women who initially reported this condition. To date, one of the four infertile women has conceived. The four women with vertigo, mastalgia, headache and the premenstrual syndrome all reported alleviation of their symptoms during vaginal bromocriptine therapy. Side-effects occurred in only one woman slight nausea which subsided after 2 weeks of treatment.
Normoprolactinemic women Bromocriptine alleviated symptoms in the woman with premenstrual headache and in one of the two women with mastalgia. The two women with galactorrhea and oligomenorrhea discontinued therapy afier only 2 weeks because of vaginal imtation.
GynecologicalEndocrinology
Vaginal bromocriptine
Ginsburg et al.
Table 1 Clinical details of hyperprolactinemic patients, previously treated with oral bromocriptine and now treated with vaginal bromocriptine
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Subject
Age (years)
Complaint and diagnosis
Side-effects with oral bromocriptine
Prolactin (mU/1)
1
24
amenorrhea galactorrhea microadenoma
nausea
> 5000
2
40
amenorrhea galactorrhea macroadenoma (surgery, 1985)
nausea vertigo
> 5000
19
amenorrhea microadenoma
nausea
2607
38
amenorrhea oligomenorrhea empty sella
hypertension
1146
44
galactorrhea normal C T
vomiting
2048
41
amenorrhea galactorrhea microadenoma
nausea
1078
10
21
amenorrhea normal CT
nausea
967
12
22
amenorrhea microadenoma
nausea
1619
13
36
premenstrual syndrome mastalgia normal C T
none
1101
17
38
amenorrhea galactorrhea
19
36
amenorrhea normal C T
nausea
1361
20
38
amenorrhea galactorrhea
nausea
1512
21
25
amenorrhea normal C T
nausea
2183
24
34
infertility macroadenoma (surgery, 1980)
nausea
2218
31
45
galactorrhea
nausea
607
36
43
oligomenorrhea empty sella
nausea
2387
38
40
mastalgia microadenoma
nausea
4257
postural hypotension
1622
C T = computed tomography
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Vaginal brornocriptine
women
Age Subject (years)
Age Subject (years)
3
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Table 3 Clinical details of normoprolactinemic
Table 2 Clinical details of hyperprolactinemic patients treated with vagmal bromocriptine de novo
20
4
38
6
37
11
45
14
24
16
29
18
26
22 23
43 31
25 28
25 35
Prolactin Complaint and diagnosis
(mull)
oligomenorrhea microadenoma oligomenorrhea normal CT infertility normal CT vertigo oligomenorrhea microadenoma oligomenorrhea normal CT amenorrhea normal CT amenorrhea normal CT galactorrhea amenorrhea normal CT
2221
amenorrhea
2559 1460
infertility empty sella galactorrhea 45 29 amenorrhea 49 33 galactorrhea empty sella infertility 40 34 microadenoma CT = computed tomography
1581 1470 2439
15 26 32 30 35 37
Prolactin Complaint and diagnosis
22 oligomenorrhea 31
33 28 32
galactorrhea premenstrual syndrome mastalgia galactorrhea mastalgia premenstrualsyndrome
(mull) 151 285 167 122 219 80
1161 5000
6642 3538 639 1566
2841 2267
4000
-
d
3000
969
Endocrine response and bromocriptine levels Hyperprolactinemic women Bromocriptine in a daily dosage of only 2.5 mg per vaginam, lowered prolactin levels within 2 weeks in 28 of the 31 hyperprolactinemic women and had no effect in three (one of whom was the subject receiving sulpiride) (Figure 1) (Table 4). The prolactin level fell to within the normal range in 11 women. Overall, serum prolactin fell sigdcantly (p < 0.0001) in the 31 normoprolactinemic women, fiom a mean value of 2122.1 f 217.6 to 1029.8 f 204.2 mU/l. The women in whom prolactin levels fell to normal had a significantly lower prolactin concentration (p < 0.005) before starting treatment, than those who remained hyper-
122
1000
0
Pre bro-riptine
Post bmmocnptine
Figure 1 Serum prolactin concentration(mull)in 31 hyperprolactinemic women before and after a daily dosage of 2.5 mg vaginal bromocriptine prolactinemic - 1293.3 f 183.2 and 2487.8 2 273.3 mU/l, respectively.
Gynecological Endocrinology
Vaginal bromocriptine
Ginsburg et al.
Table 4 Chronic response to vagnal bromocriptine in hyperprolactinemic women Prolactin (mU/1) Subject
Before
Intolerant
of oral therapy
1
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2
5
> 5000
After
1236 1047 1019 947
Interval Dose (months) (mg) Side-gects
1 4 5 10
2.5 5.0 7.5 7.5
none
1 3 4 5
2.5 5.0 7.5 10.0
none
3415 1904 1859 1135
1 3 4 5
2.5 5.0 7.5 10.0
none
none
> 5000 > 5000 > 5000 15000 > 5000 2607
7
1146
216 458
1 10
2.5 2.5
8
2048
1250 898 1227 1429
1 3 4 5 6
2.5 5.0 7.5 10.0 15.0
Table 4 continued Prolactin (mU/1) Subject
Before
Interval
Dose
(months) (mg) Side-efects
Patients treated with vaginal bromocriptine de novo 3 none 870 1622 2.5 1
4
1581
< 50 356
1 6
2.5
none
6
1470
865 448
1 2
2.5 5.0
none
11
2439
738 525 187 185
1 2 6 7
2.5 5.O 5.0 5.0
none
14
1161
898 96 1
1 2
2.5 5.0
none
16
6642
2430 2703 3119
1 3 5
2.5 5.0 7.5
none
18
3507
3684
1
2.5
none
22
639
262
1
2.5
none
23
1566
246
1
2.5
none
25
2559
807 528
1 2
2.5 5.0
none
28
1460
323
1
2.5
none
29
2841
137
1
2.5
none
33
2267
842
1
2.5
none
969
500
1
2.5
none
initial nausea
Afier
9
1078
< 45 228 46
1 3 7
2.5 2.5 2.5
none
10
967
337
1
2.5
none
12
1619
1324 1784
1 2
2.5 5.0
none
530
1 6
2.5 2.5
none
34
< 45
None of the women who remained hyperprolactinemic on a bromocriptine dosage of2.5 mg became normoprolactinemic when the dose was increased to 5 mg (13 women), 7.5 mg (six women), 10mg (three women) or 15mg (one woman). Doubling the dose of bromocriptine &om 2.5 to 5 mg &d not significantly affect the prolactin concentration - 1812.5 f 397.3 and 1744.5 f 387.4 mU/l, respectively. There was, however, some fall in those in whom the dose was increased fiom 5 to 7.5, fiom 7.5 to 10 and fiom 10 to 15 mg, the corresponding figures being 2641.8 k 709.8 to 1997.3 f 624.3, 3067.5 to 2454.0 and 1227 to 1429 mU/1 (Table 2).
13
1101
17
1622
1090
1
2.5
none
19
1361
225
1
2.5
none
20
1512
667
1
2.5
21
2183
1091
1 2
817
3
2.5 5.0 7.5
none
-
24
2218
2352
1
2.5
none
31
607
268
1
2.5
none
36
2267
1354
1
2.5
none
38
4257
1073
1
2.5
none
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Vaginal brornocriptine
2000
-
o Bromomiptine@g/ml) 0 0 0 -
prolactin(rnUil) 0
0
8 ’J 1000-
0
f
0 0
v1
0
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0 0
0 -
$9
I
I
I
1
I
Time (hours)
Figure 2 Mean serum prolactin (mU/1) and bromocriptine concentration (pg/ml) in 12 hyperprolactinemic women for up to 24 h &er 2.5 mg vaginal bromocriptine
The mean serum bromocriptine concentration during chronicadministration(2.5 mgper vaginam daily) was 525.6 f 100.0 pg/ml in ten women. The corresponding figures in those receiving 5 m g (six women), 7.5m g (two women) and 10 mg (two women) were 507.7 f 158.9, 624.0 and 1015.5 pg/ml, respectively. There was, moreover, no evidence of a ‘fill-off in bromocriptine absorption (asjudged by the serum bromocriptine concentration) during prolonged therapy.
Table 5 Chronic response to vaginal bromocriptine in normoprolactinemic women ~~
Prohi’ Subject
Before
(mu/1)
Interval
Dose
Aft.* (months) (mg) Side-effects
15
151
C45
1
2.5 vaginal initation
26
-
94 360
1 2
2.5 none 2.5
30
122
-
1
2.5 vaginal
initation
Normoprolactinemic women
32
-
The mean prolactin concentration in the four normoprolactinemic women who attended for follow-up fell firom 143.7 to 77.3 mU/1 during treatment with bromocriptine 2.5mg per vaginam (Table 5).
35
219
399
37
80
67
Acute response to vaginal bromocriptine
1
2.5 none 2.5 none
3
2.5 none
The mean bromocriptine concentration was significantly increased 2 h after vaginal administration and reached a peak (713 -+ 166 pg/ml) after 4 h. The level was s t i l l raised (148 f 11.3 pg/ml) h e r 24 h (Figure 2).
Vaginal administration
Rectal administration
The mean prolactin concentration fell &om 1813 f 456 to 978 f 245 mUA 8 h afier administration of a single 2.5 mg dose of bromocriptine in 12 women. The level was stiU sigdicantly reduced (at 1305 f 491 mU/l), 24 h after administration.
The mean prolactin concentration in the three men fell only slightly. Bromocriptine was not detected up to 24 h after rectal administrationin two ofthese men and reached only very low levels (peak 9 pg/ml) after 24 h in the third.
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Vaginal bromocnptine
Ginsburg et al.
DISCUSSION
influence on the serum prolactin concentration. It is of interest that the chronic response to bromocriptine, that is the fill in prolactin levels afier severalweeks oftherapy, did not correlate with the acute effects observed over 24 h. Severe side-effects with vagnal bromocriptine were conspicuous by their absence. This contrasts with oral administration where side-effects occur in more than 50% of patients and are sufficiently severe to cause 10% to dscontinue treatment. Nausea &er oral bromocriptine has been attributed to a local effect on the stomach16,which would explain why nausea does not occur when the drug is given vaginally. That headache and vertigo (which are thought to result 6-om a central effect on the brain) are also avoided by vagmal administration, may be explained in terms of metabolites of bromocriptine, produced by hepatic metabolism, rather than the drug itself, being responsible for these symptoms. Rectal bromocriptine for the treatment of hyperprolactinemia in men would not seem feasible. The drug was apparently not absorbed at all in two subjects and to a minimal degree in the third. Many drugs are well absorbed from the rectum but not, apparently, bromocriptine. Whether this failure of absorption relates to the higher pH of the rectum as compared to the vagina, or to some other fictor in our study, is not known. In the light of our experience, we now use vaginal bromocriptine as first-line treatment in women who are prepared and able to administer it by t h s route and we recommend that it is not reserved for those who experience side-effects with oral therapy. The absence of side-effects with vaginal administration should aid compliance, particularly in condtions such as the premenstrual syndrome or mastalgia, where the adverse effects of oral therapy may outweigh the therapeutic benefits. A sustained release preparation of bromocriptine, as devised for delivery of progestogens” or estriol18,would improve compliance considerably.
Bromocriptine given vaginally is clinically effective, alleviating symptoms associated with hyperprolactinemia. Thus, menstrual cyclicity was restored in 13 of the 21 women with amenorrhea or oligomenorrhea, one of the four infertile women conceived, and galactorrhea was alleviated in six of 11 women. Premenstrual problems, mastalgia, headache and vertigo were also alleviated. But, in contrast to oral bromocriptine, vaginal application is extremely well tolerated and does not give rise to significant side-effects. In a dosage of only 2.5 mg, vaginal bromocriptine reduced levels of prolactin in 28 (90.3%)of the 31 hyperprolactinemic women, and in 11 (35.5%)of these women, the level fell to within normal limits. we found In keeping with previous bromocriptine to be well absorbed from the vagina, peak levels being very similar to those seen with oral therapy. O n the basis that as much as 99%of the drug is absorbed from the vagma, but only 28% from the gut (of which 94%is metabolized during the first-pass through the liver, so that only 4% of an oral dose reaches the systemic circulation unchanged)14,it is perhaps surprising that bromocriptine levels are not higher with vaginal than with oral administration. We found absorption of bromocriptine to be delayed until 2 h afier vagnal adrmnistration,peak levels being reached only afier 4 h. In a previous study, however, Vermesh” reported peak bromocriptine levels after 12 h. By contrast, peak levels occur withm 2 h after an oral dose. The ‘fd-off in bromocriptine levels is much slower after vaginal administration compared with oral therapy. Ths could explain why a single daily dose is sufficient with vaginal therapy, whereas twice or thrice daily regmens are required when the drug is given by mouth. This, together with the absence of side-effects, should ensure considerably improved compliance with vaginal therapy. That bromocriptine levels remain elevated for 24 h after vaginal adrmnistration may account for the absence of a further f d in prolactin levels when the dose is increased. It has been suggested that a -~ bromocriptine concentration of 200pg/ml produces maximal suppression of prolactin secretion. This level is achieved and sustained with a dose of only 2.5 mg given vaginally. A larger dose would, therefore, be no more effective in terms of its
GynecologicalEndocrinology
ACKNOWLEDGEMENTS We would like to thank Dr Roland Finckh of Sandoz Pharma Ltd., Basel, for his assistance with the bromocriptine assay. P. Hardiman was supported by the Stanley Thomas Johnson Foundation.
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Vaginal bromomptine
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REFERENCES 1. Varga, L., Lutterbeck, P. M., Pryor,J. S., Wenner, R. and Erb, H. (1972). Suppression of puerperal lactation with an ergot alkaloid. A double blind study. Br. Med.]., 2 , 7 4 3 4 2. Besser, G. M., Parkes. L., Edwards. C. R. W., Forsyth, I. A. and McNeilly, A. S. (1972). Galactorrhoea: successfd treatment with reduction of plasma prolactin levels by bromoergocriptine. Br. Med. J., 3,669-72 3. Thorner, M. O., Besser, G. M., Hagen, C. and McNeilly, A. S. (1974). Long term treatment of galactorrhoea and hypogonadism with bromocriptine. Br. Med. J., 2,419-22 4. Thorner, M. andBesser, G. M. (1978).Bromocriptine treatment of hyperprolactinaemic hypogonadism. Acta Endocrinol., 88 (Suppl. 216), 131-46 5. Parkes, J. D. (1979). Bromocriptine in the treatment of Parkinsonism. Drugs, 17,365-82 6. Bateman, D. E. andTunbridge, W. M. G. (1979). Bromocriptine in the treatment of acromegaly. Drugs, 17,359-64 7. Mansel, R. E. and Doghotti, L. (1990). European multicentre trial of bromocriptine in cyclic mastalgia. Lancet, 335,191-3 8. Andersch, B., Hahn, L., Wendestam, C. and Abrahmsonn, L. (1978). Treatment ofthe premenstrual syndrome with bromocriptine. Acta Endocrinol., 88 (Suppl. 16), 165-74 9. Cuellar, F. G. (1980). Bromocriptine mesylate (Pardolel)in the management of amenorrhoedgalactorrhoea associated with hyperprolactinaemia. Obstet. Gynecol., 55, 278-84 10. LeWitt, P. A., Gopinathan, G., Ward, C.D., Sanes, J. N., Dambrosia, J. M., Durso, R. and Canle, D. B. (1982). Lisuride versus bromocriptine
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Ginsburg et al. treatment in Parkinson’s disease: a double-blind study. Neurology, 32, 69-72 11. Vermesh, M., Fossum, G. T. and Kletzky, 0. A. (1988). V a g d bromocriptine: pharmacology and effect on serum prolactin in normal women. Obstet. Gynecol., 72, 693-8 12. Katz, E., Schran, H. F. and Adashi, E. Y. (1989). Successful treatment of a prolactin-producing pituitary macroadenoma with intravagd bromocriptine mesylate: a novel approach to intolerance of oral therapy. Obstet. Gynecol., 73, 517-20 13. Kletzky, 0.A. and Vermesch, M. (1989). Effectiveness ofvaglnalbromocriptinein treating women with hyperprolactinaemia. Fertil. Steril., 51,269-72 14. Schran, H. F., Bhuta, H. J. and Thorner, M. 0. (1980). The pharmokinetics of bromocriptine. In Goldstein, M., Caine, D., Lieberrnan, A. and Thorner, M. (eds). Ergot Compounds and Brain Function - Neuroendocrine and Neuropsychiatric Aspects, p. 222. (New York Raven Press) 15. Katz,E., Schran,H. F., Weiss,B. E., Adashi, E. Y. and Hassell, A. (199 1). Increased circulating levels of bromocriptine after vaginal compared with oral administration. Fertil. Stm’l.,’55, 882-4 16. Wass, J. A., Thorner, M. O., Besser, G. M., Moms, D., Stuart Mason, A., Liuzzi, A. and Chiodini, P. G. (1976). Gastrointestinalbleedingin patients on bromocriptine. Lancet, 2,851 17. Dicdusy, E. and Landgren, B. M. (1981). New delivery systems: vaginal rings. In Chang, C. F., Griftin, D. and Woolman, A. (eds.) Recent Advances in Fem‘lity Regulation, pp. 43-69. (Geneva: Atar S A) 18. Ginsburg, J., O’Reilly, B., Fink, R. S., Collins, W. P. and Weiss, P. (1987). Hormonal effects of a new sustained release vaginal oestriol pessary. J. Gynecol. Endorrinol., 3, 1-7
Gynecological Endocrinology
Vaginal bromocriptine - clinical and biochemical effects J. Ginsburg, P. Hardiman and M . Thomas*
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Departments of Endocrinology and *Chemical Pathology, Royal Free Hospital School of Medicine, London, UK Key words: VAGINALBROMOCRIPTINE, HYFJERPROLACTINEMIA, NORMOPROLACTINEMIA
ABSTRACT Adverse efects occur in over 50% ofwomen taking oral bromocnptine, causing at least 10% to discontinue treatment. Although the drug is absorbedjom the vagina and reportedly caused no side-efects in one patient intolerant o f oral bromocnptine, long-tm clinical efects of daily vaginal administration have not been assessed. W e have now given bromomptine vaginallyfor up to 2 years to 3 1 hypqrolactinemic andfive normoprolactinemic women, 17 o f whom were intolerant o f oral bromomptine. The drug was well absorbed j o m the vagina and a daily dosage o f 2.5 mg lowered semm prolactin levels in 28 ofthe hyperprolactinemuwomen (in 11 to within normal limits), restored menstrual cyclicity, and abolishedgalactowhea; one ofthefour infertilewomen conceived. Minor side-effects omwed in only three women. Vaginal administration is clinically efective, avoids the adverse efects oforal therapy and could be the first-line treatmentf o r patients requiring bromocriptine.
INTRODUCTION Bromocriptine was originally used to inhibit puerperal lactation' and to treat galactorrhea2, amenorrhea and infertility3.4associated with hyperprolactinemia. It has also been found to be effective in conditions where prolactin levels are not elevated, such as parkinsonism5, acromegalf, mastalgia7and the premenstrualsyndromes.Unfor-
tunately, however, bromocriptine induces sideeffects such as nausea, vomiting, vertigo, constipation, headache, postural hypotension and drowsiness in 5 0 4 8 % of subjects', which significantly limit its acceptability, particularly in conditions where the side-effects can be more disturbing than the original complaint. Alternative oral preparations" reported to have fewer side-effects have proved to be disappointing. O n the basis that the gastrointestinal effects result fiom a local effect of bromocriptine, it would be reasonable to try parented administration of the drug. Good absorption of bromocriptine after acute vaginal adrmnistration in healthy women", and diminished gastrointestinal effects in hyperprolactinemic ~ o m e n ' ~ .have ' ~ , been reported in short-term studies. There has, however, been no long-term clinical assessment of the effects of chronic, daily vaginal bromocriptine administration. We have now given M y vaginal bromocriptine to hyperprolactinemic women who were intolerant of oral therapy. In view of the good response observed in the initial patients, vaginal therapy was offered instead of oral bromocriptine to hyperprolactinemic women presenting de novo and also to normoprolactinemic women with galactorrhea, mastalgia and the premenstrual syndrome.
Correspondence: Dr J. Ginsburg, Department of Endocrinology, Royal Free Hospital School of Medicine, London W UK
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Vhginal brommptiw
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PATIENTS The patients were 38 women who were given vaginal bromocriptine treatment after fidl investigation (including a computed tomographic scan in the hyperprolactinemic women) and exclusion of hypothyroidism. Two nonnoprolactinemic women failed to attend for follow-up. The results fiom the remaining 36 women are reported here and are shown in Tables 1-3. A total of 31 women were hyperprolactinemic (prolactin > 400 mU/1); the remaining five were normoprolactinemic. Of these women, 17 had previously been treated with oral bromocriptine, but had discontinued medication because of adverse side-effects. Of the hyperprolactinemic women, 17 were amenorrheic and four oligomenorrheic (cycle length > 6 weeks); the remaining ten had regular cycles. There were 11 with galactorrhea,four with infertility, one with mastalgia, one with vertigo, one with headache, one with symptoms of the premenstrual syndrome and two had previously undergone pituitary surgery for a macroadenoma. One woman was receiving psychotropic therapy with sulpiride. Computed tomographic scanning demonstrated a pituitary microadenoma in seven women, a partially empty sella in four, and no tumor recurrence in the women with a macroadenoma and previous surgery. The five nonnoprolactinemic women had not previously received oral bromocriptine. Two women had galactorrheaand oligomenorrhea,two mastalgia and one premenstrual headache.
METHODS Women were instructed to insert one 2.5 m g bromocriptine tablet high into the vagina at night, before retiring. Serum prolactin was measured 1 week later and at regular intervals thereafier. In subjects in whom prolactin failed to fillto within the reference range ( < 400 mUA), the dose of bromocriptine was increased at monthly intervals by 2.5 mg to a maximum daily dose of 15 mg. In order to determine the optimum treatment regimen for individual patients, the acute effects of vaginal bromocriptine were initially assessed in 11 of the women who had not previously taken bromocriptine, and in one who had discontinued oral
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treatment 1 month previously. After initial control blood sampleshad been taken, the women inserted a 2.5 mg tablet of bromocriptine into the vagina. Further samples were taken at 15 and 30 min and 1, 2,4, 8 and 24 h thereafter, for measurement of prolactin and bromocriptine concentrations. Serum bromocriptine levels were also determined during chronic therapy. Serum prolactin was measured using a standard radioimmunoassaytechnique and bromocriptine by the radioimmunoassay described by Schran14. In view of our finding that vaginal bromocriptine was clinically effective,we also investigatedthe effects ofrectal administrationin three healthy male volunteer doctors. The protocol used was the same as that described above for vaginal administration, except that bromocriptine was inserted into the rectum.
RESULTS Clinical response
Hyperprolactinemu women Regular menstruation was restored within 4 months in ten of the 17 amenorrheic women and in three of the four with oligomenorrhea. Galactorrheawas alleviated in six of the 11women who initially reported this condition. To date, one of the four infertile women has conceived. The four women with vertigo, mastalgia, headache and the premenstrual syndrome all reported alleviation of their symptoms during vaginal bromocriptine therapy. Side-effects occurred in only one woman slight nausea which subsided after 2 weeks of treatment.
Normoprolactinemic women Bromocriptine alleviated symptoms in the woman with premenstrual headache and in one of the two women with mastalgia. The two women with galactorrhea and oligomenorrhea discontinued therapy afier only 2 weeks because of vaginal imtation.
GynecologicalEndocrinology
Vaginal bromocriptine
Ginsburg et al.
Table 1 Clinical details of hyperprolactinemic patients, previously treated with oral bromocriptine and now treated with vaginal bromocriptine
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Subject
Age (years)
Complaint and diagnosis
Side-effects with oral bromocriptine
Prolactin (mU/1)
1
24
amenorrhea galactorrhea microadenoma
nausea
> 5000
2
40
amenorrhea galactorrhea macroadenoma (surgery, 1985)
nausea vertigo
> 5000
19
amenorrhea microadenoma
nausea
2607
38
amenorrhea oligomenorrhea empty sella
hypertension
1146
44
galactorrhea normal C T
vomiting
2048
41
amenorrhea galactorrhea microadenoma
nausea
1078
10
21
amenorrhea normal CT
nausea
967
12
22
amenorrhea microadenoma
nausea
1619
13
36
premenstrual syndrome mastalgia normal C T
none
1101
17
38
amenorrhea galactorrhea
19
36
amenorrhea normal C T
nausea
1361
20
38
amenorrhea galactorrhea
nausea
1512
21
25
amenorrhea normal C T
nausea
2183
24
34
infertility macroadenoma (surgery, 1980)
nausea
2218
31
45
galactorrhea
nausea
607
36
43
oligomenorrhea empty sella
nausea
2387
38
40
mastalgia microadenoma
nausea
4257
postural hypotension
1622
C T = computed tomography
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Vaginal brornocriptine
women
Age Subject (years)
Age Subject (years)
3
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Table 3 Clinical details of normoprolactinemic
Table 2 Clinical details of hyperprolactinemic patients treated with vagmal bromocriptine de novo
20
4
38
6
37
11
45
14
24
16
29
18
26
22 23
43 31
25 28
25 35
Prolactin Complaint and diagnosis
(mull)
oligomenorrhea microadenoma oligomenorrhea normal CT infertility normal CT vertigo oligomenorrhea microadenoma oligomenorrhea normal CT amenorrhea normal CT amenorrhea normal CT galactorrhea amenorrhea normal CT
2221
amenorrhea
2559 1460
infertility empty sella galactorrhea 45 29 amenorrhea 49 33 galactorrhea empty sella infertility 40 34 microadenoma CT = computed tomography
1581 1470 2439
15 26 32 30 35 37
Prolactin Complaint and diagnosis
22 oligomenorrhea 31
33 28 32
galactorrhea premenstrual syndrome mastalgia galactorrhea mastalgia premenstrualsyndrome
(mull) 151 285 167 122 219 80
1161 5000
6642 3538 639 1566
2841 2267
4000
-
d
3000
969
Endocrine response and bromocriptine levels Hyperprolactinemic women Bromocriptine in a daily dosage of only 2.5 mg per vaginam, lowered prolactin levels within 2 weeks in 28 of the 31 hyperprolactinemic women and had no effect in three (one of whom was the subject receiving sulpiride) (Figure 1) (Table 4). The prolactin level fell to within the normal range in 11 women. Overall, serum prolactin fell sigdcantly (p < 0.0001) in the 31 normoprolactinemic women, fiom a mean value of 2122.1 f 217.6 to 1029.8 f 204.2 mU/l. The women in whom prolactin levels fell to normal had a significantly lower prolactin concentration (p < 0.005) before starting treatment, than those who remained hyper-
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1000
0
Pre bro-riptine
Post bmmocnptine
Figure 1 Serum prolactin concentration(mull)in 31 hyperprolactinemic women before and after a daily dosage of 2.5 mg vaginal bromocriptine prolactinemic - 1293.3 f 183.2 and 2487.8 2 273.3 mU/l, respectively.
Gynecological Endocrinology
Vaginal bromocriptine
Ginsburg et al.
Table 4 Chronic response to vagnal bromocriptine in hyperprolactinemic women Prolactin (mU/1) Subject
Before
Intolerant
of oral therapy
1
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2
5
> 5000
After
1236 1047 1019 947
Interval Dose (months) (mg) Side-gects
1 4 5 10
2.5 5.0 7.5 7.5
none
1 3 4 5
2.5 5.0 7.5 10.0
none
3415 1904 1859 1135
1 3 4 5
2.5 5.0 7.5 10.0
none
none
> 5000 > 5000 > 5000 15000 > 5000 2607
7
1146
216 458
1 10
2.5 2.5
8
2048
1250 898 1227 1429
1 3 4 5 6
2.5 5.0 7.5 10.0 15.0
Table 4 continued Prolactin (mU/1) Subject
Before
Interval
Dose
(months) (mg) Side-efects
Patients treated with vaginal bromocriptine de novo 3 none 870 1622 2.5 1
4
1581
< 50 356
1 6
2.5
none
6
1470
865 448
1 2
2.5 5.0
none
11
2439
738 525 187 185
1 2 6 7
2.5 5.O 5.0 5.0
none
14
1161
898 96 1
1 2
2.5 5.0
none
16
6642
2430 2703 3119
1 3 5
2.5 5.0 7.5
none
18
3507
3684
1
2.5
none
22
639
262
1
2.5
none
23
1566
246
1
2.5
none
25
2559
807 528
1 2
2.5 5.0
none
28
1460
323
1
2.5
none
29
2841
137
1
2.5
none
33
2267
842
1
2.5
none
969
500
1
2.5
none
initial nausea
Afier
9
1078
< 45 228 46
1 3 7
2.5 2.5 2.5
none
10
967
337
1
2.5
none
12
1619
1324 1784
1 2
2.5 5.0
none
530
1 6
2.5 2.5
none
34
< 45
None of the women who remained hyperprolactinemic on a bromocriptine dosage of2.5 mg became normoprolactinemic when the dose was increased to 5 mg (13 women), 7.5 mg (six women), 10mg (three women) or 15mg (one woman). Doubling the dose of bromocriptine &om 2.5 to 5 mg &d not significantly affect the prolactin concentration - 1812.5 f 397.3 and 1744.5 f 387.4 mU/l, respectively. There was, however, some fall in those in whom the dose was increased fiom 5 to 7.5, fiom 7.5 to 10 and fiom 10 to 15 mg, the corresponding figures being 2641.8 k 709.8 to 1997.3 f 624.3, 3067.5 to 2454.0 and 1227 to 1429 mU/1 (Table 2).
13
1101
17
1622
1090
1
2.5
none
19
1361
225
1
2.5
none
20
1512
667
1
2.5
21
2183
1091
1 2
817
3
2.5 5.0 7.5
none
-
24
2218
2352
1
2.5
none
31
607
268
1
2.5
none
36
2267
1354
1
2.5
none
38
4257
1073
1
2.5
none
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Vaginal brornocriptine
2000
-
o Bromomiptine@g/ml) 0 0 0 -
prolactin(rnUil) 0
0
8 ’J 1000-
0
f
0 0
v1
0
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0 0
0 -
$9
I
I
I
1
I
Time (hours)
Figure 2 Mean serum prolactin (mU/1) and bromocriptine concentration (pg/ml) in 12 hyperprolactinemic women for up to 24 h &er 2.5 mg vaginal bromocriptine
The mean serum bromocriptine concentration during chronicadministration(2.5 mgper vaginam daily) was 525.6 f 100.0 pg/ml in ten women. The corresponding figures in those receiving 5 m g (six women), 7.5m g (two women) and 10 mg (two women) were 507.7 f 158.9, 624.0 and 1015.5 pg/ml, respectively. There was, moreover, no evidence of a ‘fill-off in bromocriptine absorption (asjudged by the serum bromocriptine concentration) during prolonged therapy.
Table 5 Chronic response to vaginal bromocriptine in normoprolactinemic women ~~
Prohi’ Subject
Before
(mu/1)
Interval
Dose
Aft.* (months) (mg) Side-effects
15
151
C45
1
2.5 vaginal initation
26
-
94 360
1 2
2.5 none 2.5
30
122
-
1
2.5 vaginal
initation
Normoprolactinemic women
32
-
The mean prolactin concentration in the four normoprolactinemic women who attended for follow-up fell firom 143.7 to 77.3 mU/1 during treatment with bromocriptine 2.5mg per vaginam (Table 5).
35
219
399
37
80
67
Acute response to vaginal bromocriptine
1
2.5 none 2.5 none
3
2.5 none
The mean bromocriptine concentration was significantly increased 2 h after vaginal administration and reached a peak (713 -+ 166 pg/ml) after 4 h. The level was s t i l l raised (148 f 11.3 pg/ml) h e r 24 h (Figure 2).
Vaginal administration
Rectal administration
The mean prolactin concentration fell &om 1813 f 456 to 978 f 245 mUA 8 h afier administration of a single 2.5 mg dose of bromocriptine in 12 women. The level was stiU sigdicantly reduced (at 1305 f 491 mU/l), 24 h after administration.
The mean prolactin concentration in the three men fell only slightly. Bromocriptine was not detected up to 24 h after rectal administrationin two ofthese men and reached only very low levels (peak 9 pg/ml) after 24 h in the third.
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Vaginal bromocnptine
Ginsburg et al.
DISCUSSION
influence on the serum prolactin concentration. It is of interest that the chronic response to bromocriptine, that is the fill in prolactin levels afier severalweeks oftherapy, did not correlate with the acute effects observed over 24 h. Severe side-effects with vagnal bromocriptine were conspicuous by their absence. This contrasts with oral administration where side-effects occur in more than 50% of patients and are sufficiently severe to cause 10% to dscontinue treatment. Nausea &er oral bromocriptine has been attributed to a local effect on the stomach16,which would explain why nausea does not occur when the drug is given vaginally. That headache and vertigo (which are thought to result 6-om a central effect on the brain) are also avoided by vagmal administration, may be explained in terms of metabolites of bromocriptine, produced by hepatic metabolism, rather than the drug itself, being responsible for these symptoms. Rectal bromocriptine for the treatment of hyperprolactinemia in men would not seem feasible. The drug was apparently not absorbed at all in two subjects and to a minimal degree in the third. Many drugs are well absorbed from the rectum but not, apparently, bromocriptine. Whether this failure of absorption relates to the higher pH of the rectum as compared to the vagina, or to some other fictor in our study, is not known. In the light of our experience, we now use vaginal bromocriptine as first-line treatment in women who are prepared and able to administer it by t h s route and we recommend that it is not reserved for those who experience side-effects with oral therapy. The absence of side-effects with vaginal administration should aid compliance, particularly in condtions such as the premenstrual syndrome or mastalgia, where the adverse effects of oral therapy may outweigh the therapeutic benefits. A sustained release preparation of bromocriptine, as devised for delivery of progestogens” or estriol18,would improve compliance considerably.
Bromocriptine given vaginally is clinically effective, alleviating symptoms associated with hyperprolactinemia. Thus, menstrual cyclicity was restored in 13 of the 21 women with amenorrhea or oligomenorrhea, one of the four infertile women conceived, and galactorrhea was alleviated in six of 11 women. Premenstrual problems, mastalgia, headache and vertigo were also alleviated. But, in contrast to oral bromocriptine, vaginal application is extremely well tolerated and does not give rise to significant side-effects. In a dosage of only 2.5 mg, vaginal bromocriptine reduced levels of prolactin in 28 (90.3%)of the 31 hyperprolactinemic women, and in 11 (35.5%)of these women, the level fell to within normal limits. we found In keeping with previous bromocriptine to be well absorbed from the vagina, peak levels being very similar to those seen with oral therapy. O n the basis that as much as 99%of the drug is absorbed from the vagma, but only 28% from the gut (of which 94%is metabolized during the first-pass through the liver, so that only 4% of an oral dose reaches the systemic circulation unchanged)14,it is perhaps surprising that bromocriptine levels are not higher with vaginal than with oral administration. We found absorption of bromocriptine to be delayed until 2 h afier vagnal adrmnistration,peak levels being reached only afier 4 h. In a previous study, however, Vermesh” reported peak bromocriptine levels after 12 h. By contrast, peak levels occur withm 2 h after an oral dose. The ‘fd-off in bromocriptine levels is much slower after vaginal administration compared with oral therapy. Ths could explain why a single daily dose is sufficient with vaginal therapy, whereas twice or thrice daily regmens are required when the drug is given by mouth. This, together with the absence of side-effects, should ensure considerably improved compliance with vaginal therapy. That bromocriptine levels remain elevated for 24 h after vaginal adrmnistration may account for the absence of a further f d in prolactin levels when the dose is increased. It has been suggested that a -~ bromocriptine concentration of 200pg/ml produces maximal suppression of prolactin secretion. This level is achieved and sustained with a dose of only 2.5 mg given vaginally. A larger dose would, therefore, be no more effective in terms of its
GynecologicalEndocrinology
ACKNOWLEDGEMENTS We would like to thank Dr Roland Finckh of Sandoz Pharma Ltd., Basel, for his assistance with the bromocriptine assay. P. Hardiman was supported by the Stanley Thomas Johnson Foundation.
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Vaginal bromomptine
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REFERENCES 1. Varga, L., Lutterbeck, P. M., Pryor,J. S., Wenner, R. and Erb, H. (1972). Suppression of puerperal lactation with an ergot alkaloid. A double blind study. Br. Med.]., 2 , 7 4 3 4 2. Besser, G. M., Parkes. L., Edwards. C. R. W., Forsyth, I. A. and McNeilly, A. S. (1972). Galactorrhoea: successfd treatment with reduction of plasma prolactin levels by bromoergocriptine. Br. Med. J., 3,669-72 3. Thorner, M. O., Besser, G. M., Hagen, C. and McNeilly, A. S. (1974). Long term treatment of galactorrhoea and hypogonadism with bromocriptine. Br. Med. J., 2,419-22 4. Thorner, M. andBesser, G. M. (1978).Bromocriptine treatment of hyperprolactinaemic hypogonadism. Acta Endocrinol., 88 (Suppl. 216), 131-46 5. Parkes, J. D. (1979). Bromocriptine in the treatment of Parkinsonism. Drugs, 17,365-82 6. Bateman, D. E. andTunbridge, W. M. G. (1979). Bromocriptine in the treatment of acromegaly. Drugs, 17,359-64 7. Mansel, R. E. and Doghotti, L. (1990). European multicentre trial of bromocriptine in cyclic mastalgia. Lancet, 335,191-3 8. Andersch, B., Hahn, L., Wendestam, C. and Abrahmsonn, L. (1978). Treatment ofthe premenstrual syndrome with bromocriptine. Acta Endocrinol., 88 (Suppl. 16), 165-74 9. Cuellar, F. G. (1980). Bromocriptine mesylate (Pardolel)in the management of amenorrhoedgalactorrhoea associated with hyperprolactinaemia. Obstet. Gynecol., 55, 278-84 10. LeWitt, P. A., Gopinathan, G., Ward, C.D., Sanes, J. N., Dambrosia, J. M., Durso, R. and Canle, D. B. (1982). Lisuride versus bromocriptine
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