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Predicted ovulatory response to 2-brom-alpha-ergocryptine (CB-154) in amenorrhea-galactorrhea syndromes
Predicted ovulatory response to 2-brom-alpha-ergocryptine (CB- 154) in amenorrhea-galactorrhea syndromes A. B. SHEWCHUK.
M.D..
13. CORENBLUM, N.
PAIRAUDEAU,
C.
EZRIN.
M.D.,
F.R.C.S.(C.) F.R.C.P.(C.)
M.D.,
M.D.,
G. D.
ADAMSON,
Twonto,
Ontario.
F.R.C.S.(C.)
F.R.C.P.(C) M.D..
F.R.C.S.(C.)
Canada
Adenohypophyseal function was evaluated in 20 consecutive patients with hyperprolactinemic amenorrhea-galactorrhea in an attempt to predict ovulatory response with 2-brom-alpha-ergocryptine (CB-I 54) therapy. Pituitary fossa tomography and response to insulin, thyrotropin-releasing hormone, and luteinizing hormone-releasing hormone were correlated with the return of ovulatory cycles. Fourteen of 15 patients demonstrating normal pretreatment sellar volume ovulated, compared with 0 of 5 showing increased volume. Thirteen of 14 with adequate adenohypophyseal reserve of growth hormone and luteinizing hormone ovulated, compared with 0 of 6 and 1 of 6, respectively, with inadequate reserve. Serum prolactin suppression to normal occurred in 19 of 20 patients but could not predict response. Only 2 of 10 patients receiving clomiphene citrate ovulated and neither conceived, while 8 of the 10 ovuMed with CB-154 and 6 of 7 desiring pregnancy conceived. C8-154 is an effectii “fertility drug” and response to therapy can usually be predicted. (AM. J. OBSTET. GYNECOL. 136:652, 1980.)
THE LACTO'TR 0 PH s (mammotrophs or prolactin cells) of the anterior pituitary produce and secrete prolactin. Nonpregnant women demonstrate a circadian periodicity with peak values during the night and episodic minute-to-minute variations; increments during these peaks may reach values 50% above baseline.’ Tonic prolactin secretion is inhibited by hypothalamic prolactin-inhibiting factor (PIF) via the hypothalamic-pituitary portal system, and one may postulate a short-loop feedback inhibitory control mechanism.’ Thyrotropin-releasing hormone (TRH) will stimulate prolactin secretion and may function as a prolactinreleasing factor.” Hyperprolactinemia may occur as a result of deFrom the D~ppartmentof Obstetric& und Gynaucolofl, und thr DizGs,vn of Endocrinology, Department of Medicine. Toronto Gneral Hospital, and thP Ilniwrsit~ of‘ Toronto. Reren’ed
for publication
,4rwpttjd
April
F&w?
26. 1979.
12, 1979.
Refwint requests: Dr. Alan B. Shewhuk, Sprcial Di&wstic’Unit, 5 Norman Urguhurt W&g,, Toronto General Hospital, 101 College St., Toronto, Ontario, Can& M5G 11.7.
652
creased PIF, associated with primary hypothalamic disease (e.g., sarcoidosis) or the hypersecretion of primat-) pituitary disease. Physiologic and pathologic hyperprolactinemia is usually associated with anovulation, which could he explained by five possible mechanisms: ( I) The same hypothalamic functional disturbance or disease causing decreased PIF could affect cyclic luteinizing-releasing hormone (LRH) function. (2) Hyperprolactinemia itself may inhibit LRH release. (3) Isolation of‘ the pituitary from hypothalamic control by a stalk-section syndrome would result in uninhibited prolactin secretion and decreased LE-l secretion. (4) The destruction of’ pituitary gonadotrophs by a lactotrophic tumor (prolactinoma) would produce a similar result. (5) Hyperprolactinemia may antagonize the ovarian steroidogenic response to gonadotropin?, ’ and inhibit estrogenl, 5 and progesterone production.” The ergot alkaloid 2-Br-cr-ergocryptine (CB-1 .i?, Sandoz) is a potent antiprolactinrmic drug. Prolactin levels usually fall promptly in response to oral administration, remain low for 12 hours,” and are associated with cessation of galactorrhea and restoration of nor0002-9378/80/050652+07$00.70/0
0 1980 The C. V. Mosby
Co.
Volume Number
136 5
Table
Predicted
of
I. Summary
Response P
G
26 37 23 27 28 28
0 0 1 1 1 1
0 0 2 1 3 1
60 180 32 24 12 84
48 180 23 24 12 84
Spontaneous Post delivery Post delivery Post pill Post delivery
43 158 151 35 125 200
32
0
0
60
60
Spontaneous
80
8
28
0
1
18
18
Post pill
63
9
43
0
0
240
240
10
40
8
8
3
2
11
29
0
0
72
72
Spontaneous
724
12
35
1
1
84
84
Post delivery
161
13
29
0
0
24
24
Spontaneous
174
14
26
0
0
24
24
Post pill
15
27
0
0
72
72
Spontaneous
26
0
0
108
6
Post pill
3160
17*
30
2
2
72
24
Post pill
34
18
30
0
0
156
144
19*
35
0
0
48
4
20
42
0
0
280
Group 16
Month.5of
Basal hPRL. (nglml)
Age
Group 1 1 2 3 4 5 6 Group 2 7
response
to CB-154
653
patients Month of amenorrhea
Case No.
ovulatory
galactowhea
Galactorrhea
clom$hene
Spontaneous
151
Post pill
35
91 200
Pituitary
fossa
tomogramc N N N N N N Microadenoma Microadenoma Microadenoma Microadenoma Microadenoma Microadenoma Microadenoma Microadenoma Microadenoma
V&al
fiea
Desired
Pregnancy
N N N N N N
No Yes Yes Yes Yes No
N
Yes
? defect
No
N
No
N
No
N
No
N
Yes
N
Yes
N
No
N
No
3
N: Normal. *Previous surgery
-
Spontaneous Post pill Spontaneous
0
716 115 >6500
Macroadenoma Macroadenoma Macroadenoma Macroadenoma Macroadenoma
Abnormal
No
N
No
N
No
N
No
N
No
and irradiation.
ma1 menses.‘0-12 This antiprolactin effect is manifest on the isolated pituitary gland, and in pituitary cell cultures, implying a direct action on pituitary lactotrophs.s If hyperprolactinemia causes anovulation by inhibition of cyclic hypothalamic releasing hormones or antagonism of ovarian steroidogenesis, its suppression should result in the restoration of normal cyclic ovarian activity if there is adequate hypothalamic pituitary gonadotropic reserve. No such response, however, would occur if there is significant and irreversible destruction of hypothalamic or pituitary tissue by the underlying disease. The purpose of this report is to demonstrate that suppression of hyperprolactinemia by CB-154 will restore normal cyclic ovulation and fertility in some patients with amenorrhea-galactorrhea. This response may be predicted by the pretreatment assessment of
hypothalamic and pituitary reserve and function, and will occur in patients who do not respond to ovulation stimulation by clomiphene citrate. Methods and material Twenty consecutive patients presenting with amenorrhea-galactorrhea and hyperprolactinemia underwent a complete endocrine evaluation and assessment of thyroid, adrenal, and ovarian function. It was possible to divide these patients into three groups on the basis of pituitary fossa tomography (Table I). Group 1 had no abnormality, Group 2 had abnormal sellar configuration but normal sellar volume (microadenoma), and Group 3 had enlarged sellar volume (macroadenoma). Two patients in Group 3 had previous pituitary surgery or irradiation. Basal serum prolactin was measured before and dur-
654
Shewchuk et al Am
March 1, 1980 1. Obsret. Gynrcol.
5erwn
pmlactin w/ml
:
I
positive response to group1
‘1
negative response to CB 154
CB154
n --.... m _.-.-
Fig. 1. Effect of C:B-I 54 on serum fxolactin at one month. Table
II. Ovulatcuy
response
to CB-154
.----JJ 0 0 + i-
f + 0 + 0 + 0 0 + 0 0 0 0 0
Legend: 0 = iInovulatory pregnancy; A := aborted.
0 t t
P i + + + + + 0 P + t + 0 0 0 0 0
0 P + P P + + + + + 0 P + + + 0 0 0 0 0
0
P P P P i + + t + 0 P P t + 0 0 0 0 0
0 P .A I’ P 4 + + t + 0 1’ 1’ t 0 0 0 0 0
0 P P P +
t + P I’ 0 0 0 0 0
cycle; + = ovulatory cycle; P =
ing theraIn \\ith CR-154. Return of. cyclic ovarian function v+as doc.umented with basal body temperature graphs during therapy. Seven patients in this series wished to or were encouraged to conceive: mechanical conrraception was otherwise provided. Ten of 20 patients had also been treated with clomiphene citrate to induce ovulation. Pituitary reserve and function were evaluated with a simultaneous intravenous bolus injection of thyrotro-
pin-releasing hormone (T‘RH), 200 pg (Calbiochem). luteinizing hormone-releasing hormone (LHRH), 100 pg (Ayerst), and insulin, 0. 15 units/kg, as prev,iously described.“’ Blood was drawn at 15, 30, 4.5, 60. and 90 minutes and peak response documented for assay of prolactin (hPRL), hTSH, hLH, hCH, and corr’isol. Homologous radioimmunoassays of hCH and hTSH were performed by means of charcoal separation and hLH and hPRL by means of the doubly-arltibodv technique. lodination of all hormones was performed by modification of the method of Greenwood and associates.rJ Sensitivity of the prolactin assay is 1.5 ngiml, and the normal range for serum prolactin is 5 to ?5 rig/ml. Materials for the prolactin assay were provided by Drs. H. Friesen and A. Burton. Plasma cortisol was measured by competitive protein-binding radioassav.‘” Normal pituitary reserve was defined as: 1. Prolactin (hPRL)-increment greater than 20 ngiml and double the baseline 2. TSH-increment greater than 6 mu/ml 3. LH--increment greater than 4 mIUim1 1. hCH-increment greater than 8 rig/ml 5. Cortisol-increment greater than 6.0 pgidl After evaluation of pituitary function and reserve, all patients were treated with CB-154, 2.5 mg twice daily, with monthly gynecologic and endocrine follow-up (Table II). A positive therapeutic response was defined as a return of cyclic menses with a biphasic basal body temperature (BBT) graph and/or pregnancy and a negative response as no menses and/or a monophasic BBT graph. Minimal side effects were noted; a few patients noted
Volume Number
136 5
Predicted
ovulatory
response
to CB-154
655
ATSH p/
“’
25.
pOSitiVe response
to CB I54
negative
response
to C8154
group I 0 ----_--_ pJ -.-.-
Fig. 4. TSH
response
to TRH,
200 pg.
A prolactin rig/ml
>300 300-
_. 7d
--: _.
_._._._._.--.-
--.---
i positive group I n -_------_ m-.---
response
to CB 154
Fig. 3. Prolactin
response
nausea and faintness related to postural hypotension but these symptoms regressed with continuation of therapy and no patients dropped out of the study. Therapy was stopped if a sustained thermogenic BBT response of more than 18 days was noted and pregnancy suspected. Treatment was otherwise continued for six months.
Results Suppression of hyperprolactinemia by CB-154 (Fig. 1). Serum prolactin decreased in all patients after one month of CB- 154. Five of six patients in Group 1, seven of nine patients in Group 2, and four of five patients in
negative response to
to TRH,
CB 154
200 pg.
Group 3 experienced suppression to normal levels. Case 20 suppressed from more than 6,500 rig/ml to 430 rig/ml. After three months of therapy, normal levels were noted in all patients except Case 20. A follow-up serum prolactin level was not recorded in Case 5, who conceived on her first month of therapy. Correlation of pituitary reserve with response to CB-154. TSH response to TRH, 200% (Fig. 2). TRH stimulated a normal TSH response in 9 of 10 patients who had a positive response to CB- 154 and in 6 of 6 patients who had a negative response to CB-154. This factor could not be used to predict response to CB-154.
656
Shewchuk et al.
March 1, 1980 Am. j. Obstet. Gynecol.
A cortirol P 9401
40
1
I
positive response to Cs 154
negative
response
to
CB 154
Fig. 4. Cortisol response to hypoglycemia. Table
III.
Comparative
response
to CR-154
versus previous
response
to clomiphene
Response to clomiphme treatment with rlomiphene citrate
citrate
citrate Response to CB-154
PwviouJ CTOUp
I 2 3
Total
Table
IV. Summary
Dewed pregnancy
5/6 419 l/5
415 314 011
10120
T/l0
of predictive
factors
Ovulatory Predictizw
factor
Pituitary fossa: Normal Microadenoma Macroadenoma Suppression of hyperprolactinemia by CB- 154 Normal reserve of pituitar): hCH LH
TSH ACTH Prolactin response to TRH
Ovulation
Positive
response to CB-154 Negative
516
l/6
919 O/5
019 515
14114
516
13114
016 116 616 516
1304
9110 12/14 2114
Ii6
Proluctin respww to TRH (Fig. 3). TRH stimulated a normal prolactin response in only 3 of 6 patients in Group 1. 0 of 9 patients in Group 2, and 0 of 5 patients in Group 3. This factor could not he used to predict response to CB- 154. Co&sol response to hypoglycemia (Fig. 4). Although we could not demonstrate a correlation between normal cortisol response and ovulation, it is interesting that
Pregnancy
Ovulation
Pregnancy
215 o/4
o/4 o/3
415 414
314 213
Oil 2/10
o/o 017
Oil 8110
O/O 617
both patients with an inadequate cortisol response also did not respond to CB-154. LH WS~OFLJP to hLRH (Fig. 5). Four of six Group I patients demonstrated a normal LH reserve, but 5 of 6 responded with normal ovulatory cycles. Case 6 had very recently discontinued estrogen replacement therapy, which may have altered her LH response. Normal L.H reserve was seen in 9 of 9 patients in Group 2; all had a positive ovulatory response. Only 1 of 5 patients in Group 3 had a normal LH reserve. but none responded as defined. Thus, a normal LH reserve was noted in 13 of 14 patients who ovulated; 5 of 6 who did not ovulate had a blunted LH response. It is apparent that the demonstration of adequate LH reserve will usually predict a positive response to CB-154. lnadequate LH reserve makes a response to CB-154 unlikely. hGH respow to hypoglycemia (Fig. 6). Normal hGH reserve was demonstrated in 5 of 6 Group 1 patients, 8 of 9 Group 2 patients, and 0 of 5 Group 3 patients. The poor response in Case 10 was probably related to inadequate hypoglycemia. Normal hGH reserve was present in 13 of 14 patients who ovulated on CB-154 and 0 of 6 who did not. hGH reserve will thus predict
Volume Number
Predicted
136 5
ovulatory
response
to CB-154
657
A U-l mu/ml
40
positive
response
to
CB 154
negative
response to CB 154
group1 n ------_---. m -._.-
Fig. 5. LH response to LRH,
posltlve gmup I ___ p _____-__--. me.--
response
lo Cal54
negative
100 pg.
response
to CB 154
Fig. 6. hGH response to hypoglycemia. the response sense.
to CB-154
in both a positive and negative
Ovubtory response to CB-154 Five of 6 patients in Group 1 showed a normal ovulatory response by the second month of therapy (Table II). Four of 6 wished to conceive and all did. One of 4 aborted but again conceived after resumption of therapy. Nine of 9 patients in Group 2 ovulated, although 5 months of therapy were required to produce a response in Case Il. This correlated with a delayed fall in serum prolactin levels. Three of 9 wished to conceive and two did. Case 8 had a questionable visual field defect and used contraception until this could be accu-
rately defined and reassessed while she was on therapy. None of the 5 patients in Group 3 responded despite significant suppression of hyperprolactinemia. Two episodes of anovulatory bleeding occurred in Case 18. Thus, 14 of 20 patients responded with normal ovulatory cycles as defined and 6 of 20 did not. Pretreatment pituitary reserve and function were compared in these two groups of patients in an attempt to demonstrate that normal pituitary reserve and sellar tomography will predict a positive response and abnormal reserve, a negative response. Ten of 20 patients in this series had also been treated with clomiphene citrate to stimulate ovulatory cycles; 7 of 10 wished to conceive (Table 111). An ovulatory response was recorded in only 2 of 10 and 0 of 7 con-
658
Shewchuk
et al
March 1. 1980 Am. J. Obstct. Gynecol.
ceived. Eight of 10, however. did ovulate after suppression of hyperprolactinemia with CB- 154 and 6 of 7 conceived (Table II I). Sunmuuy of pndictive Eactors (Table IV). Fifteen of 20 patients had either normal pituitary fossae (6 of 20) or minor changes in configuration suggestive of a microadenoma (9 of 20). Fourteen of 15 responded to CB-154. Five of 20 had previous surgery and/or irradiation and/or major seilar changes; 0 of 5 responded. pituitary fossa tomography is a useful factor in predicting the response to CB-154 (Table IV). Prolactin suppression to normal levels occurred in I9 of 20 patients but could not be used to predict response. Normal hcH and LH reserve predicted a positive response in 13 of 14 patients and a negative response in
6 of 6 and 5 of 6. respectively. could not predict a negative response to TRH was normal lated after CB- 154 and in 1 of no predictive value.
TSH and response. in only 2 6 who did
ACTS reserve The prolactin of 14 who ovunot and was of
Amenorrhea-galactorrhea recurred in all patients after cessation of therapy with CB-154 or completion of pregnancy. All patients who conceived were followed up with visual field examinations, pituitary fossa tomography, and urine specific gravity during and after pregnancy. Bromocryptine was supplied for this study by the Medical Services Department of Sandoz Pharmaceuticals
1. Sassin, J. F., Fran&. G., Weitzman, E. D., and Kepen, S.: Human prolactin: 24-hour pattern with increased release during sleep, Science 177:1205, 19i2. 2. Gould, B. K., Randall, R., Kempers. R. D., and Ryan, R. J.: Galactorrhea, Springfield, Illinois, 1974, Charles C Thomas, Publisher. 3. Jacobs, L. S., Snyder, P. J., Wilbur, J. F., Utiger, R. D.. and Daughaday, W. H.: Increased serum prolactin after synthetic TRH in man, J. Clin. Endocrinol. Metah. 33396, 1971. 1. Tyson, J. E., Friesen, H. G., and Anderson, M. S.: Human lactational and ovarian response to endogenous prolactin release, Science 177~897, 1972. 5. Reyes, F. I.. Winter, J. S. D., and Faiman, C.: Pituitary ovarian inter-relationships during the puerperium, AM. J. OBSTET. GYNECOL. 589:59, 1972. 6. McNatty, K. P., Sawers, R. S., and McNeilly, A. S.: A possible role for prolactin in control of steroid secretion by the human Graafian follicle, Nature 250:653, 1974. 7. Turkington, R. W.: Secretion of prolactin by patients with pituitary and hypothalamic tumors, J Clin. Endocrinol. Metab. 34:159, 1972. 8. de1 Pozo, E,.. and Fluckiger, E.: Prolactin inhibition: Ex-
perimental and clinical studies, Proceedings of the International Symposium on Human Prolactin, Brussels, June 12-14, 1973. de1 Pozo, E., Brun de1 Re, R., Varga, L., and Friesen. H.: J. Clin Endocrinol. Metab. 35:768, 1972. Besser, G. M., Parke, L., and Edwards, C. R. N., et al: Galactorrhea: Successful treatment with reduction of plasma prolactin levels by Brom-Ergocryptine. Br. Med. J. 39:669, 1972. Thorner, M. O., McNeilly, A. S., Hagan, C., and Besser, G. M.: Long-term treatment of galactorrhea and hypogonadism with Bromocryptine, Br. Med. J. 2:419, 1974. de1 Pozo, E., Varga, L., Wyss, H., Toms, G.. Friesen, H., Wenner, R., Vetter, L., and Nettwiler, A.: Clinical and normal response to bromocryptine (CB-154) in the galactorrhea syndromes, J. Clin Endocrinol. Metab. 39:18, 1974. Sterja, D. A., Van Loon, G. R.. Corenblum, B., et al,: Ann. R. Coil. Physicians Surgeons Can. 8:19, 1975. (Abstract.) Greenwood, F. C., Hunter, W. M., and Glover. J. S.: Biothem. J. 89:114, 1963. Murphy, B. E. P.: J. Clin. Endocrinol. Metab. 27:973, 1967.
Comment
9. 10.
11. 12.
13. 14. 15.
M.D..
13. CORENBLUM, N.
PAIRAUDEAU,
C.
EZRIN.
M.D.,
F.R.C.S.(C.) F.R.C.P.(C.)
M.D.,
M.D.,
G. D.
ADAMSON,
Twonto,
Ontario.
F.R.C.S.(C.)
F.R.C.P.(C) M.D..
F.R.C.S.(C.)
Canada
Adenohypophyseal function was evaluated in 20 consecutive patients with hyperprolactinemic amenorrhea-galactorrhea in an attempt to predict ovulatory response with 2-brom-alpha-ergocryptine (CB-I 54) therapy. Pituitary fossa tomography and response to insulin, thyrotropin-releasing hormone, and luteinizing hormone-releasing hormone were correlated with the return of ovulatory cycles. Fourteen of 15 patients demonstrating normal pretreatment sellar volume ovulated, compared with 0 of 5 showing increased volume. Thirteen of 14 with adequate adenohypophyseal reserve of growth hormone and luteinizing hormone ovulated, compared with 0 of 6 and 1 of 6, respectively, with inadequate reserve. Serum prolactin suppression to normal occurred in 19 of 20 patients but could not predict response. Only 2 of 10 patients receiving clomiphene citrate ovulated and neither conceived, while 8 of the 10 ovuMed with CB-154 and 6 of 7 desiring pregnancy conceived. C8-154 is an effectii “fertility drug” and response to therapy can usually be predicted. (AM. J. OBSTET. GYNECOL. 136:652, 1980.)
THE LACTO'TR 0 PH s (mammotrophs or prolactin cells) of the anterior pituitary produce and secrete prolactin. Nonpregnant women demonstrate a circadian periodicity with peak values during the night and episodic minute-to-minute variations; increments during these peaks may reach values 50% above baseline.’ Tonic prolactin secretion is inhibited by hypothalamic prolactin-inhibiting factor (PIF) via the hypothalamic-pituitary portal system, and one may postulate a short-loop feedback inhibitory control mechanism.’ Thyrotropin-releasing hormone (TRH) will stimulate prolactin secretion and may function as a prolactinreleasing factor.” Hyperprolactinemia may occur as a result of deFrom the D~ppartmentof Obstetric& und Gynaucolofl, und thr DizGs,vn of Endocrinology, Department of Medicine. Toronto Gneral Hospital, and thP Ilniwrsit~ of‘ Toronto. Reren’ed
for publication
,4rwpttjd
April
F&w?
26. 1979.
12, 1979.
Refwint requests: Dr. Alan B. Shewhuk, Sprcial Di&wstic’Unit, 5 Norman Urguhurt W&g,, Toronto General Hospital, 101 College St., Toronto, Ontario, Can& M5G 11.7.
652
creased PIF, associated with primary hypothalamic disease (e.g., sarcoidosis) or the hypersecretion of primat-) pituitary disease. Physiologic and pathologic hyperprolactinemia is usually associated with anovulation, which could he explained by five possible mechanisms: ( I) The same hypothalamic functional disturbance or disease causing decreased PIF could affect cyclic luteinizing-releasing hormone (LRH) function. (2) Hyperprolactinemia itself may inhibit LRH release. (3) Isolation of‘ the pituitary from hypothalamic control by a stalk-section syndrome would result in uninhibited prolactin secretion and decreased LE-l secretion. (4) The destruction of’ pituitary gonadotrophs by a lactotrophic tumor (prolactinoma) would produce a similar result. (5) Hyperprolactinemia may antagonize the ovarian steroidogenic response to gonadotropin?, ’ and inhibit estrogenl, 5 and progesterone production.” The ergot alkaloid 2-Br-cr-ergocryptine (CB-1 .i?, Sandoz) is a potent antiprolactinrmic drug. Prolactin levels usually fall promptly in response to oral administration, remain low for 12 hours,” and are associated with cessation of galactorrhea and restoration of nor0002-9378/80/050652+07$00.70/0
0 1980 The C. V. Mosby
Co.
Volume Number
136 5
Table
Predicted
of
I. Summary
Response P
G
26 37 23 27 28 28
0 0 1 1 1 1
0 0 2 1 3 1
60 180 32 24 12 84
48 180 23 24 12 84
Spontaneous Post delivery Post delivery Post pill Post delivery
43 158 151 35 125 200
32
0
0
60
60
Spontaneous
80
8
28
0
1
18
18
Post pill
63
9
43
0
0
240
240
10
40
8
8
3
2
11
29
0
0
72
72
Spontaneous
724
12
35
1
1
84
84
Post delivery
161
13
29
0
0
24
24
Spontaneous
174
14
26
0
0
24
24
Post pill
15
27
0
0
72
72
Spontaneous
26
0
0
108
6
Post pill
3160
17*
30
2
2
72
24
Post pill
34
18
30
0
0
156
144
19*
35
0
0
48
4
20
42
0
0
280
Group 16
Month.5of
Basal hPRL. (nglml)
Age
Group 1 1 2 3 4 5 6 Group 2 7
response
to CB-154
653
patients Month of amenorrhea
Case No.
ovulatory
galactowhea
Galactorrhea
clom$hene
Spontaneous
151
Post pill
35
91 200
Pituitary
fossa
tomogramc N N N N N N Microadenoma Microadenoma Microadenoma Microadenoma Microadenoma Microadenoma Microadenoma Microadenoma Microadenoma
V&al
fiea
Desired
Pregnancy
N N N N N N
No Yes Yes Yes Yes No
N
Yes
? defect
No
N
No
N
No
N
No
N
Yes
N
Yes
N
No
N
No
3
N: Normal. *Previous surgery
-
Spontaneous Post pill Spontaneous
0
716 115 >6500
Macroadenoma Macroadenoma Macroadenoma Macroadenoma Macroadenoma
Abnormal
No
N
No
N
No
N
No
N
No
and irradiation.
ma1 menses.‘0-12 This antiprolactin effect is manifest on the isolated pituitary gland, and in pituitary cell cultures, implying a direct action on pituitary lactotrophs.s If hyperprolactinemia causes anovulation by inhibition of cyclic hypothalamic releasing hormones or antagonism of ovarian steroidogenesis, its suppression should result in the restoration of normal cyclic ovarian activity if there is adequate hypothalamic pituitary gonadotropic reserve. No such response, however, would occur if there is significant and irreversible destruction of hypothalamic or pituitary tissue by the underlying disease. The purpose of this report is to demonstrate that suppression of hyperprolactinemia by CB-154 will restore normal cyclic ovulation and fertility in some patients with amenorrhea-galactorrhea. This response may be predicted by the pretreatment assessment of
hypothalamic and pituitary reserve and function, and will occur in patients who do not respond to ovulation stimulation by clomiphene citrate. Methods and material Twenty consecutive patients presenting with amenorrhea-galactorrhea and hyperprolactinemia underwent a complete endocrine evaluation and assessment of thyroid, adrenal, and ovarian function. It was possible to divide these patients into three groups on the basis of pituitary fossa tomography (Table I). Group 1 had no abnormality, Group 2 had abnormal sellar configuration but normal sellar volume (microadenoma), and Group 3 had enlarged sellar volume (macroadenoma). Two patients in Group 3 had previous pituitary surgery or irradiation. Basal serum prolactin was measured before and dur-
654
Shewchuk et al Am
March 1, 1980 1. Obsret. Gynrcol.
5erwn
pmlactin w/ml
:
I
positive response to group1
‘1
negative response to CB 154
CB154
n --.... m _.-.-
Fig. 1. Effect of C:B-I 54 on serum fxolactin at one month. Table
II. Ovulatcuy
response
to CB-154
.----JJ 0 0 + i-
f + 0 + 0 + 0 0 + 0 0 0 0 0
Legend: 0 = iInovulatory pregnancy; A := aborted.
0 t t
P i + + + + + 0 P + t + 0 0 0 0 0
0 P + P P + + + + + 0 P + + + 0 0 0 0 0
0
P P P P i + + t + 0 P P t + 0 0 0 0 0
0 P .A I’ P 4 + + t + 0 1’ 1’ t 0 0 0 0 0
0 P P P +
t + P I’ 0 0 0 0 0
cycle; + = ovulatory cycle; P =
ing theraIn \\ith CR-154. Return of. cyclic ovarian function v+as doc.umented with basal body temperature graphs during therapy. Seven patients in this series wished to or were encouraged to conceive: mechanical conrraception was otherwise provided. Ten of 20 patients had also been treated with clomiphene citrate to induce ovulation. Pituitary reserve and function were evaluated with a simultaneous intravenous bolus injection of thyrotro-
pin-releasing hormone (T‘RH), 200 pg (Calbiochem). luteinizing hormone-releasing hormone (LHRH), 100 pg (Ayerst), and insulin, 0. 15 units/kg, as prev,iously described.“’ Blood was drawn at 15, 30, 4.5, 60. and 90 minutes and peak response documented for assay of prolactin (hPRL), hTSH, hLH, hCH, and corr’isol. Homologous radioimmunoassays of hCH and hTSH were performed by means of charcoal separation and hLH and hPRL by means of the doubly-arltibodv technique. lodination of all hormones was performed by modification of the method of Greenwood and associates.rJ Sensitivity of the prolactin assay is 1.5 ngiml, and the normal range for serum prolactin is 5 to ?5 rig/ml. Materials for the prolactin assay were provided by Drs. H. Friesen and A. Burton. Plasma cortisol was measured by competitive protein-binding radioassav.‘” Normal pituitary reserve was defined as: 1. Prolactin (hPRL)-increment greater than 20 ngiml and double the baseline 2. TSH-increment greater than 6 mu/ml 3. LH--increment greater than 4 mIUim1 1. hCH-increment greater than 8 rig/ml 5. Cortisol-increment greater than 6.0 pgidl After evaluation of pituitary function and reserve, all patients were treated with CB-154, 2.5 mg twice daily, with monthly gynecologic and endocrine follow-up (Table II). A positive therapeutic response was defined as a return of cyclic menses with a biphasic basal body temperature (BBT) graph and/or pregnancy and a negative response as no menses and/or a monophasic BBT graph. Minimal side effects were noted; a few patients noted
Volume Number
136 5
Predicted
ovulatory
response
to CB-154
655
ATSH p/
“’
25.
pOSitiVe response
to CB I54
negative
response
to C8154
group I 0 ----_--_ pJ -.-.-
Fig. 4. TSH
response
to TRH,
200 pg.
A prolactin rig/ml
>300 300-
_. 7d
--: _.
_._._._._.--.-
--.---
i positive group I n -_------_ m-.---
response
to CB 154
Fig. 3. Prolactin
response
nausea and faintness related to postural hypotension but these symptoms regressed with continuation of therapy and no patients dropped out of the study. Therapy was stopped if a sustained thermogenic BBT response of more than 18 days was noted and pregnancy suspected. Treatment was otherwise continued for six months.
Results Suppression of hyperprolactinemia by CB-154 (Fig. 1). Serum prolactin decreased in all patients after one month of CB- 154. Five of six patients in Group 1, seven of nine patients in Group 2, and four of five patients in
negative response to
to TRH,
CB 154
200 pg.
Group 3 experienced suppression to normal levels. Case 20 suppressed from more than 6,500 rig/ml to 430 rig/ml. After three months of therapy, normal levels were noted in all patients except Case 20. A follow-up serum prolactin level was not recorded in Case 5, who conceived on her first month of therapy. Correlation of pituitary reserve with response to CB-154. TSH response to TRH, 200% (Fig. 2). TRH stimulated a normal TSH response in 9 of 10 patients who had a positive response to CB- 154 and in 6 of 6 patients who had a negative response to CB-154. This factor could not be used to predict response to CB-154.
656
Shewchuk et al.
March 1, 1980 Am. j. Obstet. Gynecol.
A cortirol P 9401
40
1
I
positive response to Cs 154
negative
response
to
CB 154
Fig. 4. Cortisol response to hypoglycemia. Table
III.
Comparative
response
to CR-154
versus previous
response
to clomiphene
Response to clomiphme treatment with rlomiphene citrate
citrate
citrate Response to CB-154
PwviouJ CTOUp
I 2 3
Total
Table
IV. Summary
Dewed pregnancy
5/6 419 l/5
415 314 011
10120
T/l0
of predictive
factors
Ovulatory Predictizw
factor
Pituitary fossa: Normal Microadenoma Macroadenoma Suppression of hyperprolactinemia by CB- 154 Normal reserve of pituitar): hCH LH
TSH ACTH Prolactin response to TRH
Ovulation
Positive
response to CB-154 Negative
516
l/6
919 O/5
019 515
14114
516
13114
016 116 616 516
1304
9110 12/14 2114
Ii6
Proluctin respww to TRH (Fig. 3). TRH stimulated a normal prolactin response in only 3 of 6 patients in Group 1. 0 of 9 patients in Group 2, and 0 of 5 patients in Group 3. This factor could not he used to predict response to CB- 154. Co&sol response to hypoglycemia (Fig. 4). Although we could not demonstrate a correlation between normal cortisol response and ovulation, it is interesting that
Pregnancy
Ovulation
Pregnancy
215 o/4
o/4 o/3
415 414
314 213
Oil 2/10
o/o 017
Oil 8110
O/O 617
both patients with an inadequate cortisol response also did not respond to CB-154. LH WS~OFLJP to hLRH (Fig. 5). Four of six Group I patients demonstrated a normal LH reserve, but 5 of 6 responded with normal ovulatory cycles. Case 6 had very recently discontinued estrogen replacement therapy, which may have altered her LH response. Normal L.H reserve was seen in 9 of 9 patients in Group 2; all had a positive ovulatory response. Only 1 of 5 patients in Group 3 had a normal LH reserve. but none responded as defined. Thus, a normal LH reserve was noted in 13 of 14 patients who ovulated; 5 of 6 who did not ovulate had a blunted LH response. It is apparent that the demonstration of adequate LH reserve will usually predict a positive response to CB-154. lnadequate LH reserve makes a response to CB-154 unlikely. hGH respow to hypoglycemia (Fig. 6). Normal hGH reserve was demonstrated in 5 of 6 Group 1 patients, 8 of 9 Group 2 patients, and 0 of 5 Group 3 patients. The poor response in Case 10 was probably related to inadequate hypoglycemia. Normal hGH reserve was present in 13 of 14 patients who ovulated on CB-154 and 0 of 6 who did not. hGH reserve will thus predict
Volume Number
Predicted
136 5
ovulatory
response
to CB-154
657
A U-l mu/ml
40
positive
response
to
CB 154
negative
response to CB 154
group1 n ------_---. m -._.-
Fig. 5. LH response to LRH,
posltlve gmup I ___ p _____-__--. me.--
response
lo Cal54
negative
100 pg.
response
to CB 154
Fig. 6. hGH response to hypoglycemia. the response sense.
to CB-154
in both a positive and negative
Ovubtory response to CB-154 Five of 6 patients in Group 1 showed a normal ovulatory response by the second month of therapy (Table II). Four of 6 wished to conceive and all did. One of 4 aborted but again conceived after resumption of therapy. Nine of 9 patients in Group 2 ovulated, although 5 months of therapy were required to produce a response in Case Il. This correlated with a delayed fall in serum prolactin levels. Three of 9 wished to conceive and two did. Case 8 had a questionable visual field defect and used contraception until this could be accu-
rately defined and reassessed while she was on therapy. None of the 5 patients in Group 3 responded despite significant suppression of hyperprolactinemia. Two episodes of anovulatory bleeding occurred in Case 18. Thus, 14 of 20 patients responded with normal ovulatory cycles as defined and 6 of 20 did not. Pretreatment pituitary reserve and function were compared in these two groups of patients in an attempt to demonstrate that normal pituitary reserve and sellar tomography will predict a positive response and abnormal reserve, a negative response. Ten of 20 patients in this series had also been treated with clomiphene citrate to stimulate ovulatory cycles; 7 of 10 wished to conceive (Table 111). An ovulatory response was recorded in only 2 of 10 and 0 of 7 con-
658
Shewchuk
et al
March 1. 1980 Am. J. Obstct. Gynecol.
ceived. Eight of 10, however. did ovulate after suppression of hyperprolactinemia with CB- 154 and 6 of 7 conceived (Table II I). Sunmuuy of pndictive Eactors (Table IV). Fifteen of 20 patients had either normal pituitary fossae (6 of 20) or minor changes in configuration suggestive of a microadenoma (9 of 20). Fourteen of 15 responded to CB-154. Five of 20 had previous surgery and/or irradiation and/or major seilar changes; 0 of 5 responded. pituitary fossa tomography is a useful factor in predicting the response to CB-154 (Table IV). Prolactin suppression to normal levels occurred in I9 of 20 patients but could not be used to predict response. Normal hcH and LH reserve predicted a positive response in 13 of 14 patients and a negative response in
6 of 6 and 5 of 6. respectively. could not predict a negative response to TRH was normal lated after CB- 154 and in 1 of no predictive value.
TSH and response. in only 2 6 who did
ACTS reserve The prolactin of 14 who ovunot and was of
Amenorrhea-galactorrhea recurred in all patients after cessation of therapy with CB-154 or completion of pregnancy. All patients who conceived were followed up with visual field examinations, pituitary fossa tomography, and urine specific gravity during and after pregnancy. Bromocryptine was supplied for this study by the Medical Services Department of Sandoz Pharmaceuticals
1. Sassin, J. F., Fran&. G., Weitzman, E. D., and Kepen, S.: Human prolactin: 24-hour pattern with increased release during sleep, Science 177:1205, 19i2. 2. Gould, B. K., Randall, R., Kempers. R. D., and Ryan, R. J.: Galactorrhea, Springfield, Illinois, 1974, Charles C Thomas, Publisher. 3. Jacobs, L. S., Snyder, P. J., Wilbur, J. F., Utiger, R. D.. and Daughaday, W. H.: Increased serum prolactin after synthetic TRH in man, J. Clin. Endocrinol. Metah. 33396, 1971. 1. Tyson, J. E., Friesen, H. G., and Anderson, M. S.: Human lactational and ovarian response to endogenous prolactin release, Science 177~897, 1972. 5. Reyes, F. I.. Winter, J. S. D., and Faiman, C.: Pituitary ovarian inter-relationships during the puerperium, AM. J. OBSTET. GYNECOL. 589:59, 1972. 6. McNatty, K. P., Sawers, R. S., and McNeilly, A. S.: A possible role for prolactin in control of steroid secretion by the human Graafian follicle, Nature 250:653, 1974. 7. Turkington, R. W.: Secretion of prolactin by patients with pituitary and hypothalamic tumors, J Clin. Endocrinol. Metab. 34:159, 1972. 8. de1 Pozo, E,.. and Fluckiger, E.: Prolactin inhibition: Ex-
perimental and clinical studies, Proceedings of the International Symposium on Human Prolactin, Brussels, June 12-14, 1973. de1 Pozo, E., Brun de1 Re, R., Varga, L., and Friesen. H.: J. Clin Endocrinol. Metab. 35:768, 1972. Besser, G. M., Parke, L., and Edwards, C. R. N., et al: Galactorrhea: Successful treatment with reduction of plasma prolactin levels by Brom-Ergocryptine. Br. Med. J. 39:669, 1972. Thorner, M. O., McNeilly, A. S., Hagan, C., and Besser, G. M.: Long-term treatment of galactorrhea and hypogonadism with Bromocryptine, Br. Med. J. 2:419, 1974. de1 Pozo, E., Varga, L., Wyss, H., Toms, G.. Friesen, H., Wenner, R., Vetter, L., and Nettwiler, A.: Clinical and normal response to bromocryptine (CB-154) in the galactorrhea syndromes, J. Clin Endocrinol. Metab. 39:18, 1974. Sterja, D. A., Van Loon, G. R.. Corenblum, B., et al,: Ann. R. Coil. Physicians Surgeons Can. 8:19, 1975. (Abstract.) Greenwood, F. C., Hunter, W. M., and Glover. J. S.: Biothem. J. 89:114, 1963. Murphy, B. E. P.: J. Clin. Endocrinol. Metab. 27:973, 1967.
Comment
9. 10.
11. 12.
13. 14. 15.