Department of Obstetrics and Gynaecology, Osaka University Medical School, Fukushimaku Osaka 553, Japan
RESTORATION OF OESTROGEN POSITIVE FEEDBACK EFFECT ON LH RELEASE BY BROMOCRIPTINE IN HYPERPROLACTINAEMIC PATIENTS WITH GALACTORRHOEA-AMENORRHOEA
By Toshihiro
Aono, Akira Miyake, Takenori Shioji Motoi Yasuda, Koji Koike and Keiichi Kurachi ABSTRACT
Five mg of bromocriptine was administered for 3 weeks to 8 hyperprolactinaemic women with galactorrhoea-amernorrhoea, in whom the response of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to 100 \g=m\g of iv LH-releasing hormone (LH-RH) had been evaluated. Twenty mg of conjugated oestrogen (Premarin\s=r\) was injected iv any day between the 10th and 12th day from the initiation of the treatment, and serum LH levels were serially determined for 120 h. Hyperresponse of LH with normal FSH response to LH-RH was observed in most patients. Bromocriptine treatment for 10 to 12 days significantly suppressed mean (\m=+-\se) serum prolactin (PRL) levels from 65.1 \m=+-\23.0 to 10.4 \m=+-\2.0 ng/ml, while LH (12.6 \m=+-\2.1 to 24.8 \m=+-\5.9 mIU/ml) and oestradiol (40.1 \m=+-\7.6 to 111.4 \m=+-\20.8 pg/ml) levels increased significantly. Patients on bromocriptine treatment showed LH release with a peak at 48 h after the injection of Premarin. The mean per cent increases in LH were significantly higher than those in untreated patients with galactorrhoea-amenorrhoea between 32 and 96 h after the injection. The present results seem to suggest that the restoration of LH-releasing response to oestrogen following suppression of PRL by bromocriptine may play an important role in induction of ovulation in hyperprolactinaemic patients with galactorrhoea-amenorrhoea.
It has been reported that basal and LH-RH-stimulated LH and FSH secretions well maintained in hyperprolactinaemic anovulatory conditions (Del Pozo et al. 1974; Aono et al. 1976; Healy et al. 1977; Boyd et al. 1977). But cyclic
are
discharge of LH in response to oestrogen stimulation is impaired in most patients (Glass et al. 1975; Aono et al. 1976). The inhibitory action of hyper¬ prolactinaemia on the follicular maturation is suggested by some investigators (McNatty et al. 1974; Mroueh 8c Siler-Khodr 1976). The suppression of PRL level by bromocriptine in these patients can stop abnormal lactation and can induce ovulation (Thorner et al. 1974; Del Pozo et al. 1974; Selli et al. 1975; Dickey 8c Stone 1976; Mroueh 8c Siler-Khodr 1977). For the mechanism of bromocriptine-induced ovulation, the following three possibilities can be considered. Firstly bromocriptine may increase FSH secre¬ tion; secondly, bromocriptine may stimulate follicular maturation directly with¬ out an increase in gonadotrophin secretion; thirdly, bromocriptine itself or the suppression of PRL may restore LH discharge in response to oestrogen stimula¬ tion. In the present
study the response of LH to iv oestrogen galactorrhoea-amenorrhoea is assessed during the suppression by bromocriptine treatment.
in patients with of PRL secretion
MATERIALS AND METHODS
Patients
Eight hyperprolactinaemic women aged 25 to 35 years with galactorrhoea and amenorrhoea of more than 6 months' duration volunteered for the study. Their clinical data and laboratory data are shown in Table I. Onset of galactorrhoeaamenorrhoea was post-partum in 5, post-abortive in 2 and idiopathic in one patient. Duration of amenorrhoea varied from 7 months to 8 years and galactorrhoea of various degree was noted in all cases. Thyroid functions were normal, polytomography of sella turcica with the use of hypocyloidal movement and ophthalmologic examination revealed no pituitary tumour in any of the patients. Methods 1. LH-RH test. The test was carried out before bromocriptine treatment. One hundred ug of synthetic LH-RH (Daiichi Pharmaceutical Co.) was administered iv in the morning after overnight fasting. Blood samples were collected 0, 15, 30, 60 and 120 min after the injection, and serum levels of LH and FSH were determined by double antibody radioimmunoassay (RIA) as described previously (Aono et al. 1972). Ten normal cyclic women aged from 21 to 31 years with average cycle lengths of 28 to 35 days were also tested during the follicular phase (D3.9) and served as the control. -
2. Oestrogen provocation test. Bromocriptine (Sandoz Ltd.) 2.5 mg b.i.d. was admin¬ istered to 8 patients for 3 weeks. Any day between 10 to 12 days from the initiation of the treatment, 20 mg of conjugated oestrogens, Premarin® (Ayerst Laboratories) was administered iv around 9 a. m. in order to evaluate LH-releasing capacity. Serum levels oí LH were assayed 0, 8, 24, 32, 48, 56, 72, 96 and 120 h after the injection. Ten normal cyclic women aged 21 to 38 years with average cycle lengths of 27 to 35 days during the mid-follicular phase (D7_()) and 10 hyperprolactinaemic patients aged 25 to -
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36 years with galactorrhoea-amenorrhoea were also tested without treatment. Patients with pituitary adenoma were not included in this group of patients. Serum levels of PRL, FSH, LH and oestradiol were determined by specific RIA (^4orco et al. 1976, 1978) before and 10 to 12 days after the initiation of bromocriptine treatment (just prior to Premarin injection). Statistical analysis of data was performed by Student's ¿-test.
3. Clinical observation. Basal body temperature chart was recorded and genital was checked during bromocriptine and Premarin treatments in all patients.
bleeding
-
RESULTS 1. LH-RH test
Individual responses of LH and FSH levels to iv LH-RH injection are shown in Fig. 1. Basal LH and FSH levels were normal in 6, elevated in one and low in one patient. LH response was supranormal in 7 and normal in one patient, while FSH response was normal in 6 and excessive in 2 patients. 2. Hormonal
change during bromocriptine
treatment
Serum levels of PRL, FSH, LH and oestradiol before and during bromo¬ treatment are depicted in Fig. 2. The changes in the mean ( ± se)
criptine
250
E
120
200-
E
\
D E
100 80-
150 co
60
S 100
CO
4050
20
30
60 Minutes
120
30
60
120
Minutes
Fig.
1.
Responses of LH and FSH levels to single iv injection of 100 ßg of LH-RH in hyper¬ prolactinaemic patients with galactorrhoea-amenorrhoea. Shaded areas represent ranges of response of 10 normal cyclic women during the follicular phase (D^q).
PRL
ng/ml
FSH mlU/ml
mlU/m
Pg/m
50-
40
30
20
Before
During
Before
Serum levels of PRL, after the initiation of
FSH,
During
Before
Pig. 2. LH and oestradiol
(Eg)
Before
During
before and 10 to 12 days in patients with
bromocriptine treatment (2.5 mg b.i.d.) galactorrhoea-amenorrhoea.
Table 2. The mean serum levels of PRL, LH, FSH and oestra¬ diol before and 10 to 12 days after the initiation of bromocriptine treatment (2.5 mg b.i.d.) in 8 patients with galactorrhoea-amenorrhoea. Mean ± Hormones
Before treatment
PRL
se
During bromocriptine
65.1
± 23.0
10.4
11.1
±
1.4
12.6 ±
1.5
12.6 ±
2.1
24.8 ±
5.!
40.1 ±
7.6
± 2.0*
(ng/ml) FSH
(mlU/ml) LH
(mlU/ml) Oestradiol
During
111.4 ± 20.8"
(pg/ml) Difference from pre-treatment * < 0.05, (a ¿-test for paired observation was used).
**
< 0.01
are shown in Table 2. Elevated serum levels of PRL (range; 29.2 to 176.0 ng/ml) were suppressed by bromocriptine to the normal range in 7 and infranormal in one patient. The decrease in the mean PRL level was significant (P < 0.01). Basal FSH level of 4.6 to 16.5 mlU/ml showed no
hormone levels
Serum LH levels increased in 6 out of 8 patients and the mean increase was significant (P < 0.05). Basal oestradiol levels varied from 16.0 to 81.1 pg/ml and oestradiol levels increased during bromocriptine treatment in all but one patient (R. S.) with significant (P
RESTORATION OF OESTROGEN POSITIVE FEEDBACK EFFECT ON LH RELEASE BY BROMOCRIPTINE IN HYPERPROLACTINAEMIC PATIENTS WITH GALACTORRHOEA-AMENORRHOEA
By Toshihiro
Aono, Akira Miyake, Takenori Shioji Motoi Yasuda, Koji Koike and Keiichi Kurachi ABSTRACT
Five mg of bromocriptine was administered for 3 weeks to 8 hyperprolactinaemic women with galactorrhoea-amernorrhoea, in whom the response of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to 100 \g=m\g of iv LH-releasing hormone (LH-RH) had been evaluated. Twenty mg of conjugated oestrogen (Premarin\s=r\) was injected iv any day between the 10th and 12th day from the initiation of the treatment, and serum LH levels were serially determined for 120 h. Hyperresponse of LH with normal FSH response to LH-RH was observed in most patients. Bromocriptine treatment for 10 to 12 days significantly suppressed mean (\m=+-\se) serum prolactin (PRL) levels from 65.1 \m=+-\23.0 to 10.4 \m=+-\2.0 ng/ml, while LH (12.6 \m=+-\2.1 to 24.8 \m=+-\5.9 mIU/ml) and oestradiol (40.1 \m=+-\7.6 to 111.4 \m=+-\20.8 pg/ml) levels increased significantly. Patients on bromocriptine treatment showed LH release with a peak at 48 h after the injection of Premarin. The mean per cent increases in LH were significantly higher than those in untreated patients with galactorrhoea-amenorrhoea between 32 and 96 h after the injection. The present results seem to suggest that the restoration of LH-releasing response to oestrogen following suppression of PRL by bromocriptine may play an important role in induction of ovulation in hyperprolactinaemic patients with galactorrhoea-amenorrhoea.
It has been reported that basal and LH-RH-stimulated LH and FSH secretions well maintained in hyperprolactinaemic anovulatory conditions (Del Pozo et al. 1974; Aono et al. 1976; Healy et al. 1977; Boyd et al. 1977). But cyclic
are
discharge of LH in response to oestrogen stimulation is impaired in most patients (Glass et al. 1975; Aono et al. 1976). The inhibitory action of hyper¬ prolactinaemia on the follicular maturation is suggested by some investigators (McNatty et al. 1974; Mroueh 8c Siler-Khodr 1976). The suppression of PRL level by bromocriptine in these patients can stop abnormal lactation and can induce ovulation (Thorner et al. 1974; Del Pozo et al. 1974; Selli et al. 1975; Dickey 8c Stone 1976; Mroueh 8c Siler-Khodr 1977). For the mechanism of bromocriptine-induced ovulation, the following three possibilities can be considered. Firstly bromocriptine may increase FSH secre¬ tion; secondly, bromocriptine may stimulate follicular maturation directly with¬ out an increase in gonadotrophin secretion; thirdly, bromocriptine itself or the suppression of PRL may restore LH discharge in response to oestrogen stimula¬ tion. In the present
study the response of LH to iv oestrogen galactorrhoea-amenorrhoea is assessed during the suppression by bromocriptine treatment.
in patients with of PRL secretion
MATERIALS AND METHODS
Patients
Eight hyperprolactinaemic women aged 25 to 35 years with galactorrhoea and amenorrhoea of more than 6 months' duration volunteered for the study. Their clinical data and laboratory data are shown in Table I. Onset of galactorrhoeaamenorrhoea was post-partum in 5, post-abortive in 2 and idiopathic in one patient. Duration of amenorrhoea varied from 7 months to 8 years and galactorrhoea of various degree was noted in all cases. Thyroid functions were normal, polytomography of sella turcica with the use of hypocyloidal movement and ophthalmologic examination revealed no pituitary tumour in any of the patients. Methods 1. LH-RH test. The test was carried out before bromocriptine treatment. One hundred ug of synthetic LH-RH (Daiichi Pharmaceutical Co.) was administered iv in the morning after overnight fasting. Blood samples were collected 0, 15, 30, 60 and 120 min after the injection, and serum levels of LH and FSH were determined by double antibody radioimmunoassay (RIA) as described previously (Aono et al. 1972). Ten normal cyclic women aged from 21 to 31 years with average cycle lengths of 28 to 35 days were also tested during the follicular phase (D3.9) and served as the control. -
2. Oestrogen provocation test. Bromocriptine (Sandoz Ltd.) 2.5 mg b.i.d. was admin¬ istered to 8 patients for 3 weeks. Any day between 10 to 12 days from the initiation of the treatment, 20 mg of conjugated oestrogens, Premarin® (Ayerst Laboratories) was administered iv around 9 a. m. in order to evaluate LH-releasing capacity. Serum levels oí LH were assayed 0, 8, 24, 32, 48, 56, 72, 96 and 120 h after the injection. Ten normal cyclic women aged 21 to 38 years with average cycle lengths of 27 to 35 days during the mid-follicular phase (D7_()) and 10 hyperprolactinaemic patients aged 25 to -
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36 years with galactorrhoea-amenorrhoea were also tested without treatment. Patients with pituitary adenoma were not included in this group of patients. Serum levels of PRL, FSH, LH and oestradiol were determined by specific RIA (^4orco et al. 1976, 1978) before and 10 to 12 days after the initiation of bromocriptine treatment (just prior to Premarin injection). Statistical analysis of data was performed by Student's ¿-test.
3. Clinical observation. Basal body temperature chart was recorded and genital was checked during bromocriptine and Premarin treatments in all patients.
bleeding
-
RESULTS 1. LH-RH test
Individual responses of LH and FSH levels to iv LH-RH injection are shown in Fig. 1. Basal LH and FSH levels were normal in 6, elevated in one and low in one patient. LH response was supranormal in 7 and normal in one patient, while FSH response was normal in 6 and excessive in 2 patients. 2. Hormonal
change during bromocriptine
treatment
Serum levels of PRL, FSH, LH and oestradiol before and during bromo¬ treatment are depicted in Fig. 2. The changes in the mean ( ± se)
criptine
250
E
120
200-
E
\
D E
100 80-
150 co
60
S 100
CO
4050
20
30
60 Minutes
120
30
60
120
Minutes
Fig.
1.
Responses of LH and FSH levels to single iv injection of 100 ßg of LH-RH in hyper¬ prolactinaemic patients with galactorrhoea-amenorrhoea. Shaded areas represent ranges of response of 10 normal cyclic women during the follicular phase (D^q).
PRL
ng/ml
FSH mlU/ml
mlU/m
Pg/m
50-
40
30
20
Before
During
Before
Serum levels of PRL, after the initiation of
FSH,
During
Before
Pig. 2. LH and oestradiol
(Eg)
Before
During
before and 10 to 12 days in patients with
bromocriptine treatment (2.5 mg b.i.d.) galactorrhoea-amenorrhoea.
Table 2. The mean serum levels of PRL, LH, FSH and oestra¬ diol before and 10 to 12 days after the initiation of bromocriptine treatment (2.5 mg b.i.d.) in 8 patients with galactorrhoea-amenorrhoea. Mean ± Hormones
Before treatment
PRL
se
During bromocriptine
65.1
± 23.0
10.4
11.1
±
1.4
12.6 ±
1.5
12.6 ±
2.1
24.8 ±
5.!
40.1 ±
7.6
± 2.0*
(ng/ml) FSH
(mlU/ml) LH
(mlU/ml) Oestradiol
During
111.4 ± 20.8"
(pg/ml) Difference from pre-treatment * < 0.05, (a ¿-test for paired observation was used).
**
< 0.01
are shown in Table 2. Elevated serum levels of PRL (range; 29.2 to 176.0 ng/ml) were suppressed by bromocriptine to the normal range in 7 and infranormal in one patient. The decrease in the mean PRL level was significant (P < 0.01). Basal FSH level of 4.6 to 16.5 mlU/ml showed no
hormone levels
Serum LH levels increased in 6 out of 8 patients and the mean increase was significant (P < 0.05). Basal oestradiol levels varied from 16.0 to 81.1 pg/ml and oestradiol levels increased during bromocriptine treatment in all but one patient (R. S.) with significant (P
