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The efficacy of bromocriptine in patients with ovulatory dysfunction and normoprolactinemic galactorrhea
FERTILITY AND STERILITY Copyright © 1985 The American Fertility Society
Vol. 44, No.5, November 1985 Printed in U.SA.
The efficacy of bromocriptine in patients with ovulatory dysfunction and normoprolactinemic galactorrhea
Santiago L. Padilla, M.D. *t Gary K. Person, M.D.:j: Paul G. McDonough, M.D. * Richard H. Reindollar, M.D. * Medical College of Georgia, Augusta, Georgia
Disorders of prolactin (PRL) production have been associated with menstrual dysfunction. Both overt and covert hyperprolactinemic states have been implicated by various clinical presentations. Classically, women with significant hyperprolactinemia demonstrate concomitant galactorrhea and amenorrhea. Infertile patients who did not have amenorrhea or galactorrhea have been described with nocturnal elevation of PRL only.1 Other women may have an ovulation disturbance, galactorrhea, and normal PRL values at blood sampling. Bromocriptine is effective in restoring ovulation in patients with hyperprolactinemia irrespective of concomitant galactorrhea. 2 Its use in anovulatory patients who have neither galactorrhea nor hyperprolactinemia is theoretically justified. 3 Clinically, this later use has demonstrated limited success. 4 - 6 The importance of galactorrhea as a diagnostic sign of relative hyperprolactinemia for patients with normal blood PRL determinations and ovulatory dysfunction has not yet been established. The purpose of this study was to determine whether the use of bromocrip-
Received March 12, 1985; revised and a~cepted July 17, 1985. *Reproductive Endocrinology Section, Department of Obstetrics and Gynecology. tReprint requests: Santiago L. Padilla, M.D., Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia 30912. :j:Department of Obstetrics and Gynecology. Vol. 44, No.5, November 1985
tine would correct galactorrhea and disorders of ovulation for biochemically euprolactinemic patients. MATERIALS AND METHODS
All patients undergoing infertility evaluation at the Medical College of Georgia from September 1979 to September 1984 were considered for inclusion in this study. Many of the patients had been studied previously by their referring physician and were considered to have unexplained infertility or were unresponsive to classical ovulation-induction therapy. Routine infertility investigations were initiated in all patients with male, tubal, and ovulation factors studied. Patients were asked to discontinue all ovulation-induction agents. Basal body temperature (BBT) charts were used for initial assessment of ovulation. Postcoital tests and diagnostic laparoscopies were performed at variable intervals during the investigation. All patients evaluated and found to have normoprolactinemic galactorrhea associated with an ovulation disturbance were entered in this study. Patients were categorized according to the severity of their ovulation disorder. Group I patients had chronic anovulation as evidenced by amenorrhea, monophasic BBT charts, and a positive medroxyprogesterone acetate withdrawal bleed. Group II patients were oligoovulatory as evidenced by biphasic BBT charts, with cycle lengths greater than 44 days. Group III patients demonPadilla et al. Communications-in-brief
695
1 Table 1. Clinical Data and Baseline Serum PRL Levels in Euprolactinemic Galactorrheic Patients with an Ovulation Disturbance D.W.
Age (yrs) Parity Mean serum PRL level {ng/mll
Group I (anovulatory) V.M. D.L. A.S.
30 0020 18
30 0000 9
29 0000 7
27 0000 12
S. G.
Group II (oligoovulatory) E.R. M.G. T. S.
21 0010 7
26 0030 4.6
strated consistently delayed ovulation defined as a thermogenic rise after cycle day 20. Further criteria for inclusion into this study consisted of (1) the presence of expressible unilateral or bilateral galactorrhea with fat globules demonstrable on microscopic evaluation, (2) a normal serum PRL value (i.e., 0 to 20 ng/ml) on one to three samples, (3) normal thyroid function studies, (4) a follicle-stimulating hormone concentration < 40 mIUlml, and (5) an otherwise negative medical history and physical examination. Serum PRL was measured by radioimmunoassay commercial kits (Serono Laboratories, Inc., Randolph, MA). The assay has a sensitivity of 1 to 2 ng/ml, with an interassay coefficient of variation of6.5% and an intraassay coefficient of variation of 4.6%. Bromocriptine therapy was initiated in all subjects, with 1.25 mg given nightly for 1 week, then increased to 2.5 mg twice daily. Ovulation was considered physiologic, with a thermogenic temperature rise occurring before cycle day 20 and an in-phase endometrium as dated by standard criteria. Once the ovulatory defect had been corrected for 3 months without achievement ofpregnancy, further evaluation of cervical, tubal, and peritoneal factors was undertaken.
RESULTS Twelve women between 21 and 34 years of age were studied. All patients had had infertility for a minimum of 18 months. Four patients had pri-
34 0010 15
24 1011 15
Group III (late ovulators) J. S.
L.L.
N.F.
K.D.
31 1031 10
26 0020 10.5
25 ·0000 7
29 1001 11
mary infertility and eight patients had secondary infertility. The study groups and the individual mean serum PRL values are described in Table 1. Table 2 summarizes the prior attempts at ovulation induction for each patient and subsequent outcome. Semen analysis was normal for all couples. Tubal patency was documented by hysterosalpingogram or by previous laparoscopy. Cervical factor had been evaluated by the referring physician for patients D. W., A. S., N. F., K. D., and M. G. before initiation of bromocriptine therapy and was considered normal. The cervical factor evaluation for the remaining patients was postponed until physiologic ovulation could be established. Physiologic ovulation occurred in all patients at least once after initiation of bromocriptine therapy alone and in 92%ofthe total cycles treated (Table 2). Four patients conceived during the first cycle and three patients conceived during the second cycle for a total pregnancy rate of 58%. Group I patients and one of the group II patients (E. R.) did not achieve pregnancy after initial bromocriptine therapy. Patient D. W. did not conceive after 8 months, and laparoscopy revealed stage II endometriosis. After treatment with Danocrine (danazol) and subsequent resolution of endometriosis as documented by laparoscopy, pregnancy was still not achieved with the use of bromocriptine with clomiphene citrate or with human menopausal gonadotropins. Patient V. M. adopted a child after four cycles and stopped the medication. Patient A. S. decided against preg-
Table 2. Previous Clomiphene Therapy and Response to Bromocriptinea Group I (anovulatory) D.L. V.M. A.S.
D.W.
Previous clomiphene therapy (mos) Bromocriptine therapy Cycles treated Ovulatory cycles Pregnancy outcome ~F,
696
Group II (oligoovulatory) E.R. M.G. T. S.
s. G.
Group III (late ovulators) J. S.
L.L.
N.F.
K. D.
12
6
6
24
6
0
7
3
5
0
18
12
8 8
4 4
4 1
12 12
1 1
3 3
1 1
2 2
1 1
2 2
1 1
2 2
Tu
PM
TF
TM
TF
TF
TF
term female infant; Tu, tubal pregnancy; PM, premature male infant; TM, term male infant. Padilla et al.
Communications-in-brief
Fertility and Sterility
nancy after 4 months of therapy. Patient D. L. had unexplained infertility after a thorough evaluation but:persisted with cyclic ovulation by BBT chart and endometrial biopsy. Patient E. R. discontinued the medication after 3 months of therapy because of side effects and conceived the .next month. She delivered a 1250-gm male infant after 32 weeks. Pregnancy outcome is included in Table 2. Spontaneous abortion did not occur. In one case (M. G.), a tubal pregnancy occurred. Patient T. S. developed premature labor at 34 weeks' gestation and delivered a 1950~gmmale infant. All other pregnancies were delivered at term. No congenital anomalies' were detected. DISCUSSION
Hyperprolactinemia is known to be associated with ovulatory dysfunction. Galactorrhea is an obvious clue for the detection of elevated PRL levels in anovulatory patients. The presence of galactorrhea in .patients with evidence .of ovulatory dysfunction and normal. serum PRL levels found in minimal blood samplings suggest an undetected disorder of PRL physiologic factors. The fact that the. galactorrhea disappeared in all of our patients on bromocriptine therapy lends support to this inference. Further, the ease with which bromocriptine corrected these ovulation disturbances is documented by our series and presents more supporting evidence for this hypothesis. The mechanisms responsible for ovulatory dysfunction in patients with normal PRL levels and galactorrhea are still speculative. PRL secretion has a normal circadian rhythm, with physiologic nocturnal elevation. 7 A pathologic exaggeration of this nighttime elevation was suggested by a study of infertile patients. 1 Other possible mechanisms might include either the secretion ofvariable molecular moieties of PRL with biologic activity but low immunoreactivity or an increased receptor sensitivity of the breast, hypothalamus, pituitary gland, or ovary to PRL stimulation. Multiple serum sampling of our patients might uncover covert elevations of PRL concentration. The inferences that variable degrees of pathologic PRL interference exist or that more than one .mechanism is responsible for ovulatory dysfunction in euprolactinemic-galactorrhea is suggested by the variable outcome in our three groups of patients. None of the anovulatory patients (group Vol. -«,No.5, November 1985
:I),all of the late ovulators (group III), and half of the oligoovulators (group II) achieved a viable pregnancy during at least 4 months ofbromocriptine therapy. The data from this preliminary study warrants a double-blind controlled investigation with more extensive serum PRLmeasurements to elucidate the mechanisms involved -in euprolactinemic ovulatory dysfunction associated with galactorrhea. SUMMARY
The response to bromocriptine therapy of 12 infertile women with ovulatory dysfunction and euprolactinemic galactorrhea was studied. Four of the subjects had anovulation, four had oligoovulation, and four .had delayed ovulation. Serum PRL levels in all 12 subjects were < 20 Ilg/ml. Normal ovulation occurred at least-once in all of the patients on bromocriptine therapy and in 38 -of 41 (92%) of the cycles. Seven :patients (58%) conceived-promptly with bromocriptinetherapy, and .-all subjects had cessation of galactorrhea within 1 month of the onset of therapy. The seven pregnancies included five normal term vaginal deliveries, one premature vaginal delivery, and one tubal pregnancy. The' results of this -study should be considered preliminary but suggest that the presence of euprolactinemic galactorrhea in patients with ovulatory dysfunction may still represent a covert disorder of' PRL physiologic factors. The prompt correction of these ovulation disturbances gives supporting evidence for this hypothesis and suggests that a short trial of bromocriptine therapy maybe warranted after minimal blood sampling. The differential outcome between our group of patients produces further evidence that variable ,mechanisms may be operative.
REFERENCES L Board JA, Storlazzi E, Schneider V: Nocturnal prolactin levels in- infertility. Fertil Steril 36:720, 1981 2, Barbieri-RL, Ryan KJ: Bromocriptine: endocrine pharmacology and therapeutic applications. Fertil Steril 39:727, 1983 3, -Seibel MM: Toward understanding the pathophysiology and treatment of polycystic ovary disease. Semin Reprod Endocrinol 2:297,1984 4. Corenblum B, Taylor PJ: A rationale for the use of bromocriptine in patients with amenorrhea and normoprolactinemia. Fertil Steril 34:239, 1980 Padillaet al. Communications-in-brief
. 697
5. Crosignani PG, Reschini E, Lombroso GC, Arosio M, Peracchi M: Comparison of placebo and bromocriptine in the treatment of patients with normoprolactinemic amenorrhea. Br J Obstet Gynaecol 85:773, 1978 6. Seibel MM, Oskowitz S, Kamrava M, Taymor ML: Preliminary observations on the response of low-dose bromo-
698
Padilla et al. Communications-in-brief
. criptine in normoprolactinemic patients with polycystic ovarian disease. Obstet Gynecol 64:213, 1984 7. Desir D, Van Eauter E, L'Hermite M: Effects of jet lag on hormonal patterns. Demonstration of an intrinsic circadian rhythmicity in plasma prolactin. J Clin Endocrinol Metab 55:849,1982
Fertility and Sterility
Vol. 44, No.5, November 1985 Printed in U.SA.
The efficacy of bromocriptine in patients with ovulatory dysfunction and normoprolactinemic galactorrhea
Santiago L. Padilla, M.D. *t Gary K. Person, M.D.:j: Paul G. McDonough, M.D. * Richard H. Reindollar, M.D. * Medical College of Georgia, Augusta, Georgia
Disorders of prolactin (PRL) production have been associated with menstrual dysfunction. Both overt and covert hyperprolactinemic states have been implicated by various clinical presentations. Classically, women with significant hyperprolactinemia demonstrate concomitant galactorrhea and amenorrhea. Infertile patients who did not have amenorrhea or galactorrhea have been described with nocturnal elevation of PRL only.1 Other women may have an ovulation disturbance, galactorrhea, and normal PRL values at blood sampling. Bromocriptine is effective in restoring ovulation in patients with hyperprolactinemia irrespective of concomitant galactorrhea. 2 Its use in anovulatory patients who have neither galactorrhea nor hyperprolactinemia is theoretically justified. 3 Clinically, this later use has demonstrated limited success. 4 - 6 The importance of galactorrhea as a diagnostic sign of relative hyperprolactinemia for patients with normal blood PRL determinations and ovulatory dysfunction has not yet been established. The purpose of this study was to determine whether the use of bromocrip-
Received March 12, 1985; revised and a~cepted July 17, 1985. *Reproductive Endocrinology Section, Department of Obstetrics and Gynecology. tReprint requests: Santiago L. Padilla, M.D., Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia 30912. :j:Department of Obstetrics and Gynecology. Vol. 44, No.5, November 1985
tine would correct galactorrhea and disorders of ovulation for biochemically euprolactinemic patients. MATERIALS AND METHODS
All patients undergoing infertility evaluation at the Medical College of Georgia from September 1979 to September 1984 were considered for inclusion in this study. Many of the patients had been studied previously by their referring physician and were considered to have unexplained infertility or were unresponsive to classical ovulation-induction therapy. Routine infertility investigations were initiated in all patients with male, tubal, and ovulation factors studied. Patients were asked to discontinue all ovulation-induction agents. Basal body temperature (BBT) charts were used for initial assessment of ovulation. Postcoital tests and diagnostic laparoscopies were performed at variable intervals during the investigation. All patients evaluated and found to have normoprolactinemic galactorrhea associated with an ovulation disturbance were entered in this study. Patients were categorized according to the severity of their ovulation disorder. Group I patients had chronic anovulation as evidenced by amenorrhea, monophasic BBT charts, and a positive medroxyprogesterone acetate withdrawal bleed. Group II patients were oligoovulatory as evidenced by biphasic BBT charts, with cycle lengths greater than 44 days. Group III patients demonPadilla et al. Communications-in-brief
695
1 Table 1. Clinical Data and Baseline Serum PRL Levels in Euprolactinemic Galactorrheic Patients with an Ovulation Disturbance D.W.
Age (yrs) Parity Mean serum PRL level {ng/mll
Group I (anovulatory) V.M. D.L. A.S.
30 0020 18
30 0000 9
29 0000 7
27 0000 12
S. G.
Group II (oligoovulatory) E.R. M.G. T. S.
21 0010 7
26 0030 4.6
strated consistently delayed ovulation defined as a thermogenic rise after cycle day 20. Further criteria for inclusion into this study consisted of (1) the presence of expressible unilateral or bilateral galactorrhea with fat globules demonstrable on microscopic evaluation, (2) a normal serum PRL value (i.e., 0 to 20 ng/ml) on one to three samples, (3) normal thyroid function studies, (4) a follicle-stimulating hormone concentration < 40 mIUlml, and (5) an otherwise negative medical history and physical examination. Serum PRL was measured by radioimmunoassay commercial kits (Serono Laboratories, Inc., Randolph, MA). The assay has a sensitivity of 1 to 2 ng/ml, with an interassay coefficient of variation of6.5% and an intraassay coefficient of variation of 4.6%. Bromocriptine therapy was initiated in all subjects, with 1.25 mg given nightly for 1 week, then increased to 2.5 mg twice daily. Ovulation was considered physiologic, with a thermogenic temperature rise occurring before cycle day 20 and an in-phase endometrium as dated by standard criteria. Once the ovulatory defect had been corrected for 3 months without achievement ofpregnancy, further evaluation of cervical, tubal, and peritoneal factors was undertaken.
RESULTS Twelve women between 21 and 34 years of age were studied. All patients had had infertility for a minimum of 18 months. Four patients had pri-
34 0010 15
24 1011 15
Group III (late ovulators) J. S.
L.L.
N.F.
K.D.
31 1031 10
26 0020 10.5
25 ·0000 7
29 1001 11
mary infertility and eight patients had secondary infertility. The study groups and the individual mean serum PRL values are described in Table 1. Table 2 summarizes the prior attempts at ovulation induction for each patient and subsequent outcome. Semen analysis was normal for all couples. Tubal patency was documented by hysterosalpingogram or by previous laparoscopy. Cervical factor had been evaluated by the referring physician for patients D. W., A. S., N. F., K. D., and M. G. before initiation of bromocriptine therapy and was considered normal. The cervical factor evaluation for the remaining patients was postponed until physiologic ovulation could be established. Physiologic ovulation occurred in all patients at least once after initiation of bromocriptine therapy alone and in 92%ofthe total cycles treated (Table 2). Four patients conceived during the first cycle and three patients conceived during the second cycle for a total pregnancy rate of 58%. Group I patients and one of the group II patients (E. R.) did not achieve pregnancy after initial bromocriptine therapy. Patient D. W. did not conceive after 8 months, and laparoscopy revealed stage II endometriosis. After treatment with Danocrine (danazol) and subsequent resolution of endometriosis as documented by laparoscopy, pregnancy was still not achieved with the use of bromocriptine with clomiphene citrate or with human menopausal gonadotropins. Patient V. M. adopted a child after four cycles and stopped the medication. Patient A. S. decided against preg-
Table 2. Previous Clomiphene Therapy and Response to Bromocriptinea Group I (anovulatory) D.L. V.M. A.S.
D.W.
Previous clomiphene therapy (mos) Bromocriptine therapy Cycles treated Ovulatory cycles Pregnancy outcome ~F,
696
Group II (oligoovulatory) E.R. M.G. T. S.
s. G.
Group III (late ovulators) J. S.
L.L.
N.F.
K. D.
12
6
6
24
6
0
7
3
5
0
18
12
8 8
4 4
4 1
12 12
1 1
3 3
1 1
2 2
1 1
2 2
1 1
2 2
Tu
PM
TF
TM
TF
TF
TF
term female infant; Tu, tubal pregnancy; PM, premature male infant; TM, term male infant. Padilla et al.
Communications-in-brief
Fertility and Sterility
nancy after 4 months of therapy. Patient D. L. had unexplained infertility after a thorough evaluation but:persisted with cyclic ovulation by BBT chart and endometrial biopsy. Patient E. R. discontinued the medication after 3 months of therapy because of side effects and conceived the .next month. She delivered a 1250-gm male infant after 32 weeks. Pregnancy outcome is included in Table 2. Spontaneous abortion did not occur. In one case (M. G.), a tubal pregnancy occurred. Patient T. S. developed premature labor at 34 weeks' gestation and delivered a 1950~gmmale infant. All other pregnancies were delivered at term. No congenital anomalies' were detected. DISCUSSION
Hyperprolactinemia is known to be associated with ovulatory dysfunction. Galactorrhea is an obvious clue for the detection of elevated PRL levels in anovulatory patients. The presence of galactorrhea in .patients with evidence .of ovulatory dysfunction and normal. serum PRL levels found in minimal blood samplings suggest an undetected disorder of PRL physiologic factors. The fact that the. galactorrhea disappeared in all of our patients on bromocriptine therapy lends support to this inference. Further, the ease with which bromocriptine corrected these ovulation disturbances is documented by our series and presents more supporting evidence for this hypothesis. The mechanisms responsible for ovulatory dysfunction in patients with normal PRL levels and galactorrhea are still speculative. PRL secretion has a normal circadian rhythm, with physiologic nocturnal elevation. 7 A pathologic exaggeration of this nighttime elevation was suggested by a study of infertile patients. 1 Other possible mechanisms might include either the secretion ofvariable molecular moieties of PRL with biologic activity but low immunoreactivity or an increased receptor sensitivity of the breast, hypothalamus, pituitary gland, or ovary to PRL stimulation. Multiple serum sampling of our patients might uncover covert elevations of PRL concentration. The inferences that variable degrees of pathologic PRL interference exist or that more than one .mechanism is responsible for ovulatory dysfunction in euprolactinemic-galactorrhea is suggested by the variable outcome in our three groups of patients. None of the anovulatory patients (group Vol. -«,No.5, November 1985
:I),all of the late ovulators (group III), and half of the oligoovulators (group II) achieved a viable pregnancy during at least 4 months ofbromocriptine therapy. The data from this preliminary study warrants a double-blind controlled investigation with more extensive serum PRLmeasurements to elucidate the mechanisms involved -in euprolactinemic ovulatory dysfunction associated with galactorrhea. SUMMARY
The response to bromocriptine therapy of 12 infertile women with ovulatory dysfunction and euprolactinemic galactorrhea was studied. Four of the subjects had anovulation, four had oligoovulation, and four .had delayed ovulation. Serum PRL levels in all 12 subjects were < 20 Ilg/ml. Normal ovulation occurred at least-once in all of the patients on bromocriptine therapy and in 38 -of 41 (92%) of the cycles. Seven :patients (58%) conceived-promptly with bromocriptinetherapy, and .-all subjects had cessation of galactorrhea within 1 month of the onset of therapy. The seven pregnancies included five normal term vaginal deliveries, one premature vaginal delivery, and one tubal pregnancy. The' results of this -study should be considered preliminary but suggest that the presence of euprolactinemic galactorrhea in patients with ovulatory dysfunction may still represent a covert disorder of' PRL physiologic factors. The prompt correction of these ovulation disturbances gives supporting evidence for this hypothesis and suggests that a short trial of bromocriptine therapy maybe warranted after minimal blood sampling. The differential outcome between our group of patients produces further evidence that variable ,mechanisms may be operative.
REFERENCES L Board JA, Storlazzi E, Schneider V: Nocturnal prolactin levels in- infertility. Fertil Steril 36:720, 1981 2, Barbieri-RL, Ryan KJ: Bromocriptine: endocrine pharmacology and therapeutic applications. Fertil Steril 39:727, 1983 3, -Seibel MM: Toward understanding the pathophysiology and treatment of polycystic ovary disease. Semin Reprod Endocrinol 2:297,1984 4. Corenblum B, Taylor PJ: A rationale for the use of bromocriptine in patients with amenorrhea and normoprolactinemia. Fertil Steril 34:239, 1980 Padillaet al. Communications-in-brief
. 697
5. Crosignani PG, Reschini E, Lombroso GC, Arosio M, Peracchi M: Comparison of placebo and bromocriptine in the treatment of patients with normoprolactinemic amenorrhea. Br J Obstet Gynaecol 85:773, 1978 6. Seibel MM, Oskowitz S, Kamrava M, Taymor ML: Preliminary observations on the response of low-dose bromo-
698
Padilla et al. Communications-in-brief
. criptine in normoprolactinemic patients with polycystic ovarian disease. Obstet Gynecol 64:213, 1984 7. Desir D, Van Eauter E, L'Hermite M: Effects of jet lag on hormonal patterns. Demonstration of an intrinsic circadian rhythmicity in plasma prolactin. J Clin Endocrinol Metab 55:849,1982
Fertility and Sterility