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Induction of Ovulation in Women with Hyperprolactinemic Amenorrhea Using Clomiphene and Human Chorionic Gonadotropin or Bromocriptine*
FERTILITY AND STERILITY Copyright
©
Vol. 32, No.2, August 1979 Printed in U.8A.
1979 The American Fertility Society
INDUCTION OF OVULATION IN WOMEN WITH HYPERPROLACTINEMIC AMENORRHEA USING CLOMIPHENE AND HUMAN CHORIONIC GONADOTROPIN OR BROMOCRIPTINE*
EWA RADWANSKA, M.D., M.PHIL., DR.MED.SCI., M.R.C.O.G.t HUGH H. G. McGARRIGLE, B.S. VALERIE LITILE, M.B., B.S. DAPHNE LAWRENCE, B.S., PH.D. SPIROS SARRIS, M.B.:j: GERALD I. M. SWYER, M.A., D.PHIL., M.D., F.R.C.P., F.R.C.O.G.§
Endocrine Unit, Department of Obstetrics and Gynecology, University College Hospital, London, England
Clomiphene citrate (Clomid), when given alone, is generally considered ineffective in inducing ovulation in women with hyperprolactinemia. This study reports the treatment of 29 infertile women with hyperprolactinemic amenorrhea. Twenty-one patients (eighteen of whom had previously had no ovulation response to Clomid alone) were treated with a combined regimen ofClomid (l00 to 200 mg/day for 5 days) and two injections of 5000 IU of human chorionic gonadotropin (HCG), the first 8 to 10 days after Clomid withdrawal and a second injection 1 week later. Basal body temperature charts, conception, and/or plasma progesterone measurements showed that 19 patients ovulated (90%). There were 17 pregnancies in 12 of21 patients (57% pregnancy rate) with 15 single live births and two abortions. When bromocriptine (Parlode!) became available, a total of22 patients (including 14 patients previously treated with Clomid/HCG, six of them successfully) with amenorrhea associated with hyperprolactinemia were treated with this drug with dosages varying from 2.5 mg to 15 mg/day. Ovulation was confirmed in 20 patients (90%). There were 17 pregnancies in 15 patients (68% pregnancy rate) with 15 single live births and two first-trimester abortions. In all, 21 of 29 patients (73%) achieved one or more pregnancies resulting in live births with one or both of the above treatments. It is concluded that a combined Clomid/HCG regimen can often be used as an effective alternative to bromocriptine therapy in the treatment of infertility associated with hyperprolactinemic amenorrhea. Fertil Steril 32:187, 1979
Received February 6, 1979; revised April 13, 1979; accepted April 18, 1979. *Presented at the Thirty-Fifth Annual Meeting of The American Fertility Society, February 3 to 7, 1979, San Francisco, Calif. tPresent address and address for reprint requests: Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, West Markham Street, Little Rock, Ark. 72201. :j:Present address: Batlatzikosta, Athens 601, Greece. §Present address: 2 Prince Arthur Road, London, N.W.3., England.
Hyperprolactinemia may be a result of an idiopathic hypothalamic disorder or may be drugrelated, associated with primary hypothyroidism, chest wall injury, or a pituitary tumor or microadenoma. Significant hyperprolactinemia is often associated with anovulation and amenorrhea. Galactorrhea is a common occurrence in such women. It appears that hyperprolactinemia causes anovulation, but the mechanism is uncertain. It has been reported
187
188
August 1979
RADWANSKA ET AL.
that prolactin interferes with gonadotropin-releasing. hormone (GnRH) secretion by the hypothalamus! and that prolactin blocks the action of the gonadotropins on the ovary. 2 Hyperprolactinemia has been demonstrated to block the positive feedback effect of estrogens. 3 Women with hyperprolactinemic amenorrhea who are desir.ous of pregnancy require treatment directed at . restoration of ovulation function. Clomiphene citrate (Clomid) is usually ineffective in treating such patients. 4 • 5 Bromocriptine (Parlodel) has become, in many countries, an agent of choice in the treatment of infertility associated with hyperprolactinemia. A decrease in prolactin levels is usually accompanied by the restoration of ovulation and pregnancy.6-8 However, other investigators have reported successful induction of ovulation in spite of hyperprolactinemia, using direct stimulation of the ovaries by exogenous gonadotropins. 9 In this study we compare results of treatment of infertile amenorrheic women with hyperpro-
lactinemia using two methods of induction of ovulation: Clomid followed by HCG and· bromocriptine. MATERIALS AND METIIODS
Patients. Twenty-nine infertile women, ages 20 to 38 years (average 28), with amenorrhea of 1 to 10 years' duration (average 3.8 years), with or without galactorrhea, treated for induction of ovulation in the fertility clinic at University College Hospital in London between 1972 and 1976, had plasma prolactin levels greater than 60 ng/ml (Table 1) (during 1975-,.1976 measured prior to any induction of ovulation, in earlier patients confirmed retrospectively). Lateral skull x-rays were normal in all but two patients. Two patients with an enlarged sella turcica received radiotherapy for pituitary tumor. Fourteen of twenty-nine patients had been previously treated unsuccessfully with Clomid alone in doses up to 150 mg for 5 days. Other factors of infertility were excluded or corrected.
TABLE 1. Some Characteristics of Patients Treated with ClomidlHCG and with Bromocriptine Patient
Amenorrhea
Age Onset yr
Group 1 1 2 3 4 5 6 7 Group 2 8 9 10 11 12 13b 14 15 16 17 18 19 20 21 Group 3 22 23 24 25 26 27 28 29b
Galactorrhea
nglml
yr
32 25 32 26 28 27 27
Spontaneous Spontaneous Spontaneous Postpartum Postpartum Post-OCa Spontaneous
4 7 1 4 1 2 1
29 27 34 20 24 26 33 24 27 38 28 27 25 21
Spontaneous Primary Spontaneous Spontaneous Post-OC Postpartum Post-OC Post-OC Post-OC Postpartum Post-OC Spontaneous Post-OC Postpartum
6 1 4 6 6 6 2 9 1 2 2 5 5
23 29 29 30 38 27 30 29
Post-OC Post-OC Spontaneous Post-OC Spontaneous Postpartum Spontaneous Post-OC
5 3 7 2 10 2 1 3
aOC, oral contraceptive. bPituitary tumor, irradiated.
Prolactin
Duration
+
+
+ + + +
+ + + + + + +
155 574 84 268 145 134 93 >255 131 248 167 263 179 144 610 325 >125 122 275 1649 >200 135 176 649 127 161 65 138 >178
Vol. 32, No.2
INDUCTION OF OVULATION IN HYPERPROLACTINEMIA
Treatment and Clinical Procedures. The first treatment regimen consisted of the administration of Clomid orally in incremental dosages of 100 to 200 mg/day for 5 days followed by 5000 IV of human chorionic gonadotropin (HCG) injected intramuscularly 8 to 10 daysafterClomid withdrawal and again 1 week later, as described elsewhere. 5 • 1o Blood samples were obtained when possible just before the first HCG injection for measurement of plasma estradiol and 1 week ·later at the presumptive midluteal phase for plasma progesterone estimation. A second treatment regimen consisted of incremental continuous administration of bromocriptine (Parlodel) in dosages of 2.5 mg/day up to 15 mg/day (usually 5 mg to 7.5 mg) until adequate ovulatory function appeared to be restored, as judged by plasma progesterone estimation,biphasic basal body temperatures, and the occurrence of menses. Patients were advised to use mechanical contraception until apparently normal ovulatory cycles returned. The administration of bromocriptine was then continued at the dose level sufficient to maintain ovulatory function, and contraception was stopped. Bromocriptine was discontinued as soon as pregnancy was confirmed. Blood samples obtained at intervals, aimed at the presumptive ovulatory or luteal phase (such timing was more difficult than during the ClomidlHCG regimen, as responses varied to a greater extent) were used for estimation of prolactin, estradiol, and progesterone. Assays. Plasma estradiol was measured by radioimmunoassay following Sephadex LH-20 chromatography.lO Plasma progesterone was measured by a modified competitive proteinbinding method.l1 Plasma prolactin was estimated by specific double-antibody radioimmunoassay12 using the assay service provided by the Department of Chemical Pathology (Research) at St. Bartholomew's Hospital, London. RESULTS
The characteristics of patients under study and their plasma prolactin levels are presented in Table 1. The results of treatment of 29 infertile women with hyperprolactinemic amenorrhea using Clomid and HCG or bromocriptine are presented in Figure l. Patients were subdivided into three groups: group 1, seven patients treated with Clomid and HCG only; group 2, fourteen patients treated
Patient #
C10mid + HCG
189 Bromocriptine
••• ••
} '"00"'
X • • X •
o
8
9 10 11 12 13 * 14 15
16 17 18 19 20 21
••• ••• •
o o o 0** o 0** o o
•• ••• •• •
X •
••• ••
22 23 24 25 26
27
X •
28
0 0
29
*
GROUP 2.
0** 0 0** 0 0
f"oon
*
pituitary tumor. irradiated --- not used no pregnancy
o
• pregnancy-l i ve bi rth X pregnancy-abortion
**
no ovulation
FIG. 1. Results of treatment of infertile women with hyperprolactinemic amenorrhea using Clomid + HCG and bromocriptine.
with Clomid and HCG and subsequently with bromocriptine; and group 3, patients treated with bromocriptine only. Of 21 patients treated with Clomid and HCG (groups 1 and 2), 19 (90%) were judged to have ovulated as a result of treatment (pregnancy, biphasic basal body temperature, and/or plasma progesterone level greater than 10 ng/ml at midluteal phase). There were 17 pregnancies in 12 patients. Eight patients had one pregnancy (all delivered of single live infants at term). Two patients had two term pregnancies with single live infants. One patient had a full-term live birth, a first-trimester abortion, and then a term pregnancy again, with another live infant, all conceived after one course of treatment preceding each pregnancy. One patient aborted her first pregnancy at 10 weeks but conceived again during a second course of induction of ovulation with the same dose of Clomid (l00 mg) and HCG and delivered a live infant at term. The number of courses of Clomid and HCG preceding pregnancy varied from 1 to 8 (average of 2.6 courses/pregnancy). Six pregnancies were conceived during the first course of treatment. There were no complications during the pregnancies; in particular, no headaches, visual field defects, or other symptoms of possible pituitary tumor were encountered. Birth weights of in-
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RADWANSKA ET AL.
fants in this group of patients were recorded from 6 pounds to 8 pounds, 15 ounces. Seven infants were male and eight female. The over-all pregnancy rate during Clomid and HCG treatment was 57%. Nine patients failed to conceive on Clomid and HCG; two had no ovulatory response in spite of increasing the dose of Clomid to 200 mg/day for 5 days; the remaining seven patients had apparently normal ovulatory responses. Eight patients, unsuccessfully treated with Clomid and HCG, were subsequently treated with bromocriptine. Three conceived and delivered single live infants without complications. Five patients who were unsuccessfully treated with Clomid and HCG were also unsuccessful when treated with bromocriptine (treated for 3 to 10 months). In addition to patients unsuccessfully treated with Clomid and HCG, six patients who had one term pregnancy (in one case, two pregnancies) on Clomid and HCG were also treated with bromocriptine when they returned to the clinic desirous of another pregnancy. All of these patients conceived on treatment with bromocriptine and delivered live infants. One patient in this group had an enlarged sella turcica (a normal skull x-ray was reported 2 years previously) and received radiotherapy; this was followed by teratment with bromocriptine, conception with abortion at 11 weeks, further administration of bromocriptine, and an uncomplicated term pregnancy (Fig. 1, patient 13). Eight patients (group 3) were treated with bromocriptine without previous treatment with Clomid and HCG. However, four of these women had been unsuccessfully treated with Clomid only. Six patients conceived within one to seven cycles on bromocriptine. In this group, one patient had an abortion at 12 weeks followed by another pregnancy and the birth of a ninepound male infant, and one patient was delivered of a live female infant weighing 3 pounds, 11 ounces, at 34 weeks due to severe toxemia of pregnancy. The remaining four patients had uneventful pregnancies and full-term deliveries of live infants weighing 5 to 7 pounds. One patient has been treated unsuccessfully with bromocriptine for 19 cycles (all of which have been ovulatory) and artificial insemination to overcome hostile mucus. One patient who had radiologic evidence of a pituitary tumor (Fig. 1, patient 29) received radiotherapy but failed to ovulate during 5 months of bromocriptine therapy. The
over-all pregnancy rate on bromocriptine was
68%. The over-all pregnancy rate in the described group of 29 patients with hyperprolactinemic amenorrhea and infertility treated for induction of ovulation with Clomid and HCG and/or bromocriptine was 73%. Both ClomidlHCG and bromocriptine treatments yielded high success rates. Of 14 patients who were treated consecutively with both regimens, 6 responded to both and 5 were not successful on either regimen; in only three patients was bromocriptine effective, whereas Clomid and HCG were not. Therefore, 11 patients of 14 (78%) had the same success (or lack of success) with both treatments (group 2). As the Clomid and HCG regimen was always used first, it can be concluded that in almost 80% of patients with hyperprolactinemic amenorrhea, the response to Clomid and HCG was predictive of the response to bromocritpine. Pretreatment plasma estradiol levels in patients under study ranged from 21 to 56 pg/ml (mean ± SD = 36 ± 10). In patients who ovulated on Clomid and HCG, plasma estradiol values during the preovulatory phase ranged from 164 to 546 pg/ml (mean ± SD = 318 ± 117). Plasma progesterone values ranged from 11 to 48 ng/ml (mean ± SD = 24 ± 11) during the midluteal phase (Table 2). In patients who ovulated on bromocriptine, the timing of blood sampling was more difficult; however, in seven patients it was assessed retrospectively from the basal body temperature charts that blood samples corresponded with the preovulatory phase. In these patients estradiol values ranged from 130 to 950 pg/ml (mean ± SD = 329 ± 282). Blood samples were obtained from 12 patients at the midluteal phase while they were on bromocriptine; their progesterone values ranged from 12 to 38 ng/ml (mean ± SD = 21 ± 7; Table 2). Values of estradiol and progesterone in women under study during ovulatory cycles on treatment with Clomid and HCG and with bromocriptine were compared and the differences between the levels of these hormones durTABLE 2. Preovulatory Plasma Estradiol Levels and Midluteal Progesterone Levels in Women Who Had Ovulatory Responses to ClomidlHCG and Bromocriptine" ClomidlHCG
Bromocriptine ll
Estradiol
Progesterone
Estradiol
Progesterone
(pgim])
(ng/m])
(pg/ml)
(ng/m])
318 ± 117 n = 15
24± 11 n = 16
329 ± 282 n = 7
21 ± 7 n = 12
"Values are means ± standard deviation.
INDUCTION OF OVULATION IN HYPERPROLACTINEMIA
Vol. 32, No.2
TABLE 3. Plasma Prolactin Levels in Women
Treated with Bromocriptine a Before treatment
On bromocriptine
236 ± 179 ng/ml n = 14
14 ± 11 ng/ml n = 18
aValues are means ± standard deviation.
ing the two treatment regimens were not found to be statistically significant. Prolactin levels esimated in 18 patients during ovulatory cycles on bromocriptine ranged from 4 to 50 ng/ml (mean ± SD = 14 ± 11). In Table 3 they are compared with pretreatment levels of prolactin in the same patients, ranging from 65 to 610 (mean ± SD = 236 ± 179). DISCUSSION
Clomid has for the last 16 years been a primary treatment for induction of ovulation in amenorrhea and infertility. No significant side effects have been reported and no birth defects in the offspring born to mothers treated with Clomid have ben attributed to this treatment. It has, therefore, become a practice to use Clomid first in anovulatory patients desirous of pregnancy, leaving other potentially hazardous, newer, or less well-documented treatment regimens as a second choice. Since measurements of prolactin by radioimmunoassay became available, it has been recognized that some 20% to 30% of amenorrheic women (with or without galactorrhea) also have hyperprolactinemia. It has become evident that these women are often resistant to Clomid treatment. 4. 5 This has been thought to be a manifestation of a severe dysfunction of pituitary gonadotropin secretion in the presence of high prolactin levels, analogous to impaired GnRH response in puerperal women. 13, 14 It has also been postulated that prolactin blocks the action of gonadotropins on the ovary. 2 The in vitro inhibitory effect or prolactin on the production of progesterone by human granulosa cells has been demonstrated. 15 Since the introduction of bromocriptine, it has been noted by several investigators that suppression of prolactin levels is usually paralleled by the restoration of ovulation and the menstrual cycle,4, 6, 7 leading to an assumption that lowering of prolactin levels is necessary for resumption of gonadotropin production. Indeed, many successful pregnancies have resulted from this treatment, our present study being yet
191
another example of the effectiveness of bromocriptine in reversing gonadotropic dysfunction in women with hyperprolactinemia. However, it has been noted that the initiation of cyclic menses could occur despite continuing hyperprolactinemia. 7 It has also been clearly documented that induction of ovulation and pregnancy is possible in patients with hyperprolactinemia using direct stimulation of the ovaries by human gonadotropins. 9 Our understanding of the mechanism of Clomid-resistant anovulation in hyperprolactinemic women has improved since it was shown that, whereas the follicle-stimulating hormone (FSH) response to GnRH is usually normaP6-18 in the presence of hyperprolactinemia, the positive feedback mechanism of estrogen action is blocked. 3 This would explain why women with hyperprolactinemia have no ovulatory responses to Clomid alone, even if GnRH release is initiated as a result of Clomid treatment and FSH secretion and follicular development are adequate. The positive estrogen feedback usually fails, and no luteinizing hormone (LH) surge or ovulation is possible. In our previous study, LH was measured in 16 hyperprolactinemic women 8 to 10 days after Clomid administration and was low in 14 of them in spite of estradiol levels in the preovulatory range. 5 When appropriately timed HCG was given in addition to Clomid at the time of the expected maximal development of the follicle, to replace the necessary LH surge, as in the present study, a high ovulatory rate was achieved. It appears that the administration of bromocriptine results in restoration of ovulation in hyperprolactinemic amenorrhea by a mechanism different from that operative during treatment with Clomid and HCG. Prolactin levels during treatment with bromocriptine are temporarily suppressed, whereas Clomid has no suppressive effect on prolactin. 19, 20 The present study does not support a contention that the suppression of prolactin is a prerequisite for successful induction of ovulation. It also points out that direct stimulation of the ovaries with menopausal gonadotropins is not always necessary in such hypothalamic disturbances as hyperprolactinemic amenorrhea. Substituting HCG for LH appears in many women to be sufficient for correcting the underlying abnormality of positive estrogen feedback. Clomid (combined with HCG) could therefore be used for induction of ovulation in amenorrhea
192
RADW ANSKA ET AL.
with hyperprolactinemia. Its advantages are short duration of teatment courses which are discontinued before conception and a long clinical experience with its use. Patients resistant to and/or unsuccessful on Clomid and HCG may then be treated with bromocriptine, and some of them may respond to such a different regimen. This drug, however, is administered daily and is not discontinued until conception and embryogenesis have already taken place. This raises certain anxiety, although to date the reported outcomes of bromocriptine-induced pregnancies have not been associated with an increased incidence of fetal abnormalities. 21 In conclusion, in the present study, pregnancy rates of 57% with the use of Clomid and HCG and of 68% with the use of bromocriptine in infertile amenorrheic women with hyperprolactinemia showed that both these regimens can be successful. REFERENCES 1. Lachelin GCL, Abu-Fadil S, Yen SSC: Functional delineation of hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 44:1163, 1977 2. Besser GM: Amenorrhoea-its investigation and the assessment of the role of prolactin. In The Endocrine Function of the Human Ovary, Edited by VHT James, M Serio, G Giusti. London, Academic Press, 1976, p 261 3. Glass MR, Shaw RW, Butt WR, Edwards RL, London DR: An abnormality of oestrogen feedback in amenorrhoea-galactorrhea. Br Med J 3:274, 1975 4. Pepperell RJ, Evans JR, Brown JB, Smith MA, Healy D, Burger HG: Serum prolactin levels and the value of bromocriptine in the treatment of anovulatory infertility. Br J Obstet Gynaecol 84:58, 1977 5. McGarrigle HHG, Sarris S, Little V, Lawrence D, Radwanska E, Swyer GIM: Induction of ovulation with clomiphene and human chorionic gonadotrophin in women with hyperprolactinaemic amenorrhoea. Br J Obstet Gynaecol 85:692, 1978 6. Thorner MO, Besser GM, Jones A, Dacie J, Jones AE: Bromocriptine treatment of female infertility: report of 13 pregnancies. Br Med J 3:694, 1975 7~ Wiebe RH, Hammond CB, Handwerger S: Treatment of functional amenorrhea-galactorrhea with 2-bromoergocryptine. Fertil Steril 28:426, 1977
August 1979
8. Zarate A, Canales ES, Forsbach G, Fernandez-Lazala R: Bromocriptine. Clinical experience in the induction of pregnancy in amenorrhea-galactorrhea syndrome. Obstet Gynecol 52:442, 1978 9. Archer DF, Josimovich JB: Ovarian response to exogenous gonadotropins in women with elevated serum prolactin. Obstet Gynecol 48:155,1976 10. Swyer GIM, Radwanska E, McGarrigle HHG: Plasma oestradiol and progesterone estimation for the monitoring of induction of ovulation with clomiphene and chorionic gonadotrophin. Br J Obstet Gynaecol 82:794, 1975 11. Radwanska E, Swyer GIM: Plasma progesterone estimation in infertile women and in women under treatment with clomiphene and chorionic gonadotrophin. J Obstet Gynaecol Br Commonw 81:107,1974 12. McNeilly AS: Radioimmunoassay of human prolactin. Proc R Soc Med 66:863, 1973 13. Canales ES, Zarate A, Garido J, Leon C, Soria J, Schally AV: Study on the recovery of pituitary FSH function during puerperium using synthetic LRH. J Clin Endocrinol Metab 38:1140,1974 14. LeMaire WJ, Shapiro AG, Riggal F, Yang NST: Temporary pituitary insensitivity to stimulation by synthetic LRF during the postpartum period. J Clin Endocrinol Metab 38:916, 1974 15. McNatty KP, Sawers RS, NcNeilly AS: A possible role for prolactin in control of steroid secretion by the human graafian follicle. Nature 250:653, 1974 16. WentzAC, JonesGS, RoccoL, MatthewsRR: Gonadotropin response to luteinizing hormone-releasing hormone administration in secondary amenorrhea and galactorrhea syndromes. Obstet Gynecol 45:256, 1975 17. Archer DF, Sprong JW, Nankin HR, Josimovich JB: Pituitary gonadotropin response in women with idiopathic hyperprolactinemia. Fertil Steril 27:1158, 1976 18. Spellacy WN, Cantor B, Kalra PS, Buhi WC, Birk SA: The effect of varying prolactin levels on pituitary luteinizing hormone and follicle-stimulating hormone response to gonadotropin-releasing hormone. Am J Obstet Gynecol 132:157, 1978 19. Seki K, Seki M, Okumura T, Huang K: Effect of clomiphene citrate on serum prolactin in infertile women with ovarian dysfunction. Am J Obstet GynecoI124:125, 1976 20. Canales ES, Lasso P, Soria J, Zarate A: Effect of clomiphene on prolactin secretion and lactation in puerperal women. Br J Obstet Gynaecol 84:758, 1977 21. March CM: Update: bromocriptine, endocrine and fertility. AFS Newsletter Forum, Serono Symposia, Birmingham Ala, p 3, 1978
©
Vol. 32, No.2, August 1979 Printed in U.8A.
1979 The American Fertility Society
INDUCTION OF OVULATION IN WOMEN WITH HYPERPROLACTINEMIC AMENORRHEA USING CLOMIPHENE AND HUMAN CHORIONIC GONADOTROPIN OR BROMOCRIPTINE*
EWA RADWANSKA, M.D., M.PHIL., DR.MED.SCI., M.R.C.O.G.t HUGH H. G. McGARRIGLE, B.S. VALERIE LITILE, M.B., B.S. DAPHNE LAWRENCE, B.S., PH.D. SPIROS SARRIS, M.B.:j: GERALD I. M. SWYER, M.A., D.PHIL., M.D., F.R.C.P., F.R.C.O.G.§
Endocrine Unit, Department of Obstetrics and Gynecology, University College Hospital, London, England
Clomiphene citrate (Clomid), when given alone, is generally considered ineffective in inducing ovulation in women with hyperprolactinemia. This study reports the treatment of 29 infertile women with hyperprolactinemic amenorrhea. Twenty-one patients (eighteen of whom had previously had no ovulation response to Clomid alone) were treated with a combined regimen ofClomid (l00 to 200 mg/day for 5 days) and two injections of 5000 IU of human chorionic gonadotropin (HCG), the first 8 to 10 days after Clomid withdrawal and a second injection 1 week later. Basal body temperature charts, conception, and/or plasma progesterone measurements showed that 19 patients ovulated (90%). There were 17 pregnancies in 12 of21 patients (57% pregnancy rate) with 15 single live births and two abortions. When bromocriptine (Parlode!) became available, a total of22 patients (including 14 patients previously treated with Clomid/HCG, six of them successfully) with amenorrhea associated with hyperprolactinemia were treated with this drug with dosages varying from 2.5 mg to 15 mg/day. Ovulation was confirmed in 20 patients (90%). There were 17 pregnancies in 15 patients (68% pregnancy rate) with 15 single live births and two first-trimester abortions. In all, 21 of 29 patients (73%) achieved one or more pregnancies resulting in live births with one or both of the above treatments. It is concluded that a combined Clomid/HCG regimen can often be used as an effective alternative to bromocriptine therapy in the treatment of infertility associated with hyperprolactinemic amenorrhea. Fertil Steril 32:187, 1979
Received February 6, 1979; revised April 13, 1979; accepted April 18, 1979. *Presented at the Thirty-Fifth Annual Meeting of The American Fertility Society, February 3 to 7, 1979, San Francisco, Calif. tPresent address and address for reprint requests: Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, West Markham Street, Little Rock, Ark. 72201. :j:Present address: Batlatzikosta, Athens 601, Greece. §Present address: 2 Prince Arthur Road, London, N.W.3., England.
Hyperprolactinemia may be a result of an idiopathic hypothalamic disorder or may be drugrelated, associated with primary hypothyroidism, chest wall injury, or a pituitary tumor or microadenoma. Significant hyperprolactinemia is often associated with anovulation and amenorrhea. Galactorrhea is a common occurrence in such women. It appears that hyperprolactinemia causes anovulation, but the mechanism is uncertain. It has been reported
187
188
August 1979
RADWANSKA ET AL.
that prolactin interferes with gonadotropin-releasing. hormone (GnRH) secretion by the hypothalamus! and that prolactin blocks the action of the gonadotropins on the ovary. 2 Hyperprolactinemia has been demonstrated to block the positive feedback effect of estrogens. 3 Women with hyperprolactinemic amenorrhea who are desir.ous of pregnancy require treatment directed at . restoration of ovulation function. Clomiphene citrate (Clomid) is usually ineffective in treating such patients. 4 • 5 Bromocriptine (Parlodel) has become, in many countries, an agent of choice in the treatment of infertility associated with hyperprolactinemia. A decrease in prolactin levels is usually accompanied by the restoration of ovulation and pregnancy.6-8 However, other investigators have reported successful induction of ovulation in spite of hyperprolactinemia, using direct stimulation of the ovaries by exogenous gonadotropins. 9 In this study we compare results of treatment of infertile amenorrheic women with hyperpro-
lactinemia using two methods of induction of ovulation: Clomid followed by HCG and· bromocriptine. MATERIALS AND METIIODS
Patients. Twenty-nine infertile women, ages 20 to 38 years (average 28), with amenorrhea of 1 to 10 years' duration (average 3.8 years), with or without galactorrhea, treated for induction of ovulation in the fertility clinic at University College Hospital in London between 1972 and 1976, had plasma prolactin levels greater than 60 ng/ml (Table 1) (during 1975-,.1976 measured prior to any induction of ovulation, in earlier patients confirmed retrospectively). Lateral skull x-rays were normal in all but two patients. Two patients with an enlarged sella turcica received radiotherapy for pituitary tumor. Fourteen of twenty-nine patients had been previously treated unsuccessfully with Clomid alone in doses up to 150 mg for 5 days. Other factors of infertility were excluded or corrected.
TABLE 1. Some Characteristics of Patients Treated with ClomidlHCG and with Bromocriptine Patient
Amenorrhea
Age Onset yr
Group 1 1 2 3 4 5 6 7 Group 2 8 9 10 11 12 13b 14 15 16 17 18 19 20 21 Group 3 22 23 24 25 26 27 28 29b
Galactorrhea
nglml
yr
32 25 32 26 28 27 27
Spontaneous Spontaneous Spontaneous Postpartum Postpartum Post-OCa Spontaneous
4 7 1 4 1 2 1
29 27 34 20 24 26 33 24 27 38 28 27 25 21
Spontaneous Primary Spontaneous Spontaneous Post-OC Postpartum Post-OC Post-OC Post-OC Postpartum Post-OC Spontaneous Post-OC Postpartum
6 1 4 6 6 6 2 9 1 2 2 5 5
23 29 29 30 38 27 30 29
Post-OC Post-OC Spontaneous Post-OC Spontaneous Postpartum Spontaneous Post-OC
5 3 7 2 10 2 1 3
aOC, oral contraceptive. bPituitary tumor, irradiated.
Prolactin
Duration
+
+
+ + + +
+ + + + + + +
155 574 84 268 145 134 93 >255 131 248 167 263 179 144 610 325 >125 122 275 1649 >200 135 176 649 127 161 65 138 >178
Vol. 32, No.2
INDUCTION OF OVULATION IN HYPERPROLACTINEMIA
Treatment and Clinical Procedures. The first treatment regimen consisted of the administration of Clomid orally in incremental dosages of 100 to 200 mg/day for 5 days followed by 5000 IV of human chorionic gonadotropin (HCG) injected intramuscularly 8 to 10 daysafterClomid withdrawal and again 1 week later, as described elsewhere. 5 • 1o Blood samples were obtained when possible just before the first HCG injection for measurement of plasma estradiol and 1 week ·later at the presumptive midluteal phase for plasma progesterone estimation. A second treatment regimen consisted of incremental continuous administration of bromocriptine (Parlodel) in dosages of 2.5 mg/day up to 15 mg/day (usually 5 mg to 7.5 mg) until adequate ovulatory function appeared to be restored, as judged by plasma progesterone estimation,biphasic basal body temperatures, and the occurrence of menses. Patients were advised to use mechanical contraception until apparently normal ovulatory cycles returned. The administration of bromocriptine was then continued at the dose level sufficient to maintain ovulatory function, and contraception was stopped. Bromocriptine was discontinued as soon as pregnancy was confirmed. Blood samples obtained at intervals, aimed at the presumptive ovulatory or luteal phase (such timing was more difficult than during the ClomidlHCG regimen, as responses varied to a greater extent) were used for estimation of prolactin, estradiol, and progesterone. Assays. Plasma estradiol was measured by radioimmunoassay following Sephadex LH-20 chromatography.lO Plasma progesterone was measured by a modified competitive proteinbinding method.l1 Plasma prolactin was estimated by specific double-antibody radioimmunoassay12 using the assay service provided by the Department of Chemical Pathology (Research) at St. Bartholomew's Hospital, London. RESULTS
The characteristics of patients under study and their plasma prolactin levels are presented in Table 1. The results of treatment of 29 infertile women with hyperprolactinemic amenorrhea using Clomid and HCG or bromocriptine are presented in Figure l. Patients were subdivided into three groups: group 1, seven patients treated with Clomid and HCG only; group 2, fourteen patients treated
Patient #
C10mid + HCG
189 Bromocriptine
••• ••
} '"00"'
X • • X •
o
8
9 10 11 12 13 * 14 15
16 17 18 19 20 21
••• ••• •
o o o 0** o 0** o o
•• ••• •• •
X •
••• ••
22 23 24 25 26
27
X •
28
0 0
29
*
GROUP 2.
0** 0 0** 0 0
f"oon
*
pituitary tumor. irradiated --- not used no pregnancy
o
• pregnancy-l i ve bi rth X pregnancy-abortion
**
no ovulation
FIG. 1. Results of treatment of infertile women with hyperprolactinemic amenorrhea using Clomid + HCG and bromocriptine.
with Clomid and HCG and subsequently with bromocriptine; and group 3, patients treated with bromocriptine only. Of 21 patients treated with Clomid and HCG (groups 1 and 2), 19 (90%) were judged to have ovulated as a result of treatment (pregnancy, biphasic basal body temperature, and/or plasma progesterone level greater than 10 ng/ml at midluteal phase). There were 17 pregnancies in 12 patients. Eight patients had one pregnancy (all delivered of single live infants at term). Two patients had two term pregnancies with single live infants. One patient had a full-term live birth, a first-trimester abortion, and then a term pregnancy again, with another live infant, all conceived after one course of treatment preceding each pregnancy. One patient aborted her first pregnancy at 10 weeks but conceived again during a second course of induction of ovulation with the same dose of Clomid (l00 mg) and HCG and delivered a live infant at term. The number of courses of Clomid and HCG preceding pregnancy varied from 1 to 8 (average of 2.6 courses/pregnancy). Six pregnancies were conceived during the first course of treatment. There were no complications during the pregnancies; in particular, no headaches, visual field defects, or other symptoms of possible pituitary tumor were encountered. Birth weights of in-
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RADWANSKA ET AL.
fants in this group of patients were recorded from 6 pounds to 8 pounds, 15 ounces. Seven infants were male and eight female. The over-all pregnancy rate during Clomid and HCG treatment was 57%. Nine patients failed to conceive on Clomid and HCG; two had no ovulatory response in spite of increasing the dose of Clomid to 200 mg/day for 5 days; the remaining seven patients had apparently normal ovulatory responses. Eight patients, unsuccessfully treated with Clomid and HCG, were subsequently treated with bromocriptine. Three conceived and delivered single live infants without complications. Five patients who were unsuccessfully treated with Clomid and HCG were also unsuccessful when treated with bromocriptine (treated for 3 to 10 months). In addition to patients unsuccessfully treated with Clomid and HCG, six patients who had one term pregnancy (in one case, two pregnancies) on Clomid and HCG were also treated with bromocriptine when they returned to the clinic desirous of another pregnancy. All of these patients conceived on treatment with bromocriptine and delivered live infants. One patient in this group had an enlarged sella turcica (a normal skull x-ray was reported 2 years previously) and received radiotherapy; this was followed by teratment with bromocriptine, conception with abortion at 11 weeks, further administration of bromocriptine, and an uncomplicated term pregnancy (Fig. 1, patient 13). Eight patients (group 3) were treated with bromocriptine without previous treatment with Clomid and HCG. However, four of these women had been unsuccessfully treated with Clomid only. Six patients conceived within one to seven cycles on bromocriptine. In this group, one patient had an abortion at 12 weeks followed by another pregnancy and the birth of a ninepound male infant, and one patient was delivered of a live female infant weighing 3 pounds, 11 ounces, at 34 weeks due to severe toxemia of pregnancy. The remaining four patients had uneventful pregnancies and full-term deliveries of live infants weighing 5 to 7 pounds. One patient has been treated unsuccessfully with bromocriptine for 19 cycles (all of which have been ovulatory) and artificial insemination to overcome hostile mucus. One patient who had radiologic evidence of a pituitary tumor (Fig. 1, patient 29) received radiotherapy but failed to ovulate during 5 months of bromocriptine therapy. The
over-all pregnancy rate on bromocriptine was
68%. The over-all pregnancy rate in the described group of 29 patients with hyperprolactinemic amenorrhea and infertility treated for induction of ovulation with Clomid and HCG and/or bromocriptine was 73%. Both ClomidlHCG and bromocriptine treatments yielded high success rates. Of 14 patients who were treated consecutively with both regimens, 6 responded to both and 5 were not successful on either regimen; in only three patients was bromocriptine effective, whereas Clomid and HCG were not. Therefore, 11 patients of 14 (78%) had the same success (or lack of success) with both treatments (group 2). As the Clomid and HCG regimen was always used first, it can be concluded that in almost 80% of patients with hyperprolactinemic amenorrhea, the response to Clomid and HCG was predictive of the response to bromocritpine. Pretreatment plasma estradiol levels in patients under study ranged from 21 to 56 pg/ml (mean ± SD = 36 ± 10). In patients who ovulated on Clomid and HCG, plasma estradiol values during the preovulatory phase ranged from 164 to 546 pg/ml (mean ± SD = 318 ± 117). Plasma progesterone values ranged from 11 to 48 ng/ml (mean ± SD = 24 ± 11) during the midluteal phase (Table 2). In patients who ovulated on bromocriptine, the timing of blood sampling was more difficult; however, in seven patients it was assessed retrospectively from the basal body temperature charts that blood samples corresponded with the preovulatory phase. In these patients estradiol values ranged from 130 to 950 pg/ml (mean ± SD = 329 ± 282). Blood samples were obtained from 12 patients at the midluteal phase while they were on bromocriptine; their progesterone values ranged from 12 to 38 ng/ml (mean ± SD = 21 ± 7; Table 2). Values of estradiol and progesterone in women under study during ovulatory cycles on treatment with Clomid and HCG and with bromocriptine were compared and the differences between the levels of these hormones durTABLE 2. Preovulatory Plasma Estradiol Levels and Midluteal Progesterone Levels in Women Who Had Ovulatory Responses to ClomidlHCG and Bromocriptine" ClomidlHCG
Bromocriptine ll
Estradiol
Progesterone
Estradiol
Progesterone
(pgim])
(ng/m])
(pg/ml)
(ng/m])
318 ± 117 n = 15
24± 11 n = 16
329 ± 282 n = 7
21 ± 7 n = 12
"Values are means ± standard deviation.
INDUCTION OF OVULATION IN HYPERPROLACTINEMIA
Vol. 32, No.2
TABLE 3. Plasma Prolactin Levels in Women
Treated with Bromocriptine a Before treatment
On bromocriptine
236 ± 179 ng/ml n = 14
14 ± 11 ng/ml n = 18
aValues are means ± standard deviation.
ing the two treatment regimens were not found to be statistically significant. Prolactin levels esimated in 18 patients during ovulatory cycles on bromocriptine ranged from 4 to 50 ng/ml (mean ± SD = 14 ± 11). In Table 3 they are compared with pretreatment levels of prolactin in the same patients, ranging from 65 to 610 (mean ± SD = 236 ± 179). DISCUSSION
Clomid has for the last 16 years been a primary treatment for induction of ovulation in amenorrhea and infertility. No significant side effects have been reported and no birth defects in the offspring born to mothers treated with Clomid have ben attributed to this treatment. It has, therefore, become a practice to use Clomid first in anovulatory patients desirous of pregnancy, leaving other potentially hazardous, newer, or less well-documented treatment regimens as a second choice. Since measurements of prolactin by radioimmunoassay became available, it has been recognized that some 20% to 30% of amenorrheic women (with or without galactorrhea) also have hyperprolactinemia. It has become evident that these women are often resistant to Clomid treatment. 4. 5 This has been thought to be a manifestation of a severe dysfunction of pituitary gonadotropin secretion in the presence of high prolactin levels, analogous to impaired GnRH response in puerperal women. 13, 14 It has also been postulated that prolactin blocks the action of gonadotropins on the ovary. 2 The in vitro inhibitory effect or prolactin on the production of progesterone by human granulosa cells has been demonstrated. 15 Since the introduction of bromocriptine, it has been noted by several investigators that suppression of prolactin levels is usually paralleled by the restoration of ovulation and the menstrual cycle,4, 6, 7 leading to an assumption that lowering of prolactin levels is necessary for resumption of gonadotropin production. Indeed, many successful pregnancies have resulted from this treatment, our present study being yet
191
another example of the effectiveness of bromocriptine in reversing gonadotropic dysfunction in women with hyperprolactinemia. However, it has been noted that the initiation of cyclic menses could occur despite continuing hyperprolactinemia. 7 It has also been clearly documented that induction of ovulation and pregnancy is possible in patients with hyperprolactinemia using direct stimulation of the ovaries by human gonadotropins. 9 Our understanding of the mechanism of Clomid-resistant anovulation in hyperprolactinemic women has improved since it was shown that, whereas the follicle-stimulating hormone (FSH) response to GnRH is usually normaP6-18 in the presence of hyperprolactinemia, the positive feedback mechanism of estrogen action is blocked. 3 This would explain why women with hyperprolactinemia have no ovulatory responses to Clomid alone, even if GnRH release is initiated as a result of Clomid treatment and FSH secretion and follicular development are adequate. The positive estrogen feedback usually fails, and no luteinizing hormone (LH) surge or ovulation is possible. In our previous study, LH was measured in 16 hyperprolactinemic women 8 to 10 days after Clomid administration and was low in 14 of them in spite of estradiol levels in the preovulatory range. 5 When appropriately timed HCG was given in addition to Clomid at the time of the expected maximal development of the follicle, to replace the necessary LH surge, as in the present study, a high ovulatory rate was achieved. It appears that the administration of bromocriptine results in restoration of ovulation in hyperprolactinemic amenorrhea by a mechanism different from that operative during treatment with Clomid and HCG. Prolactin levels during treatment with bromocriptine are temporarily suppressed, whereas Clomid has no suppressive effect on prolactin. 19, 20 The present study does not support a contention that the suppression of prolactin is a prerequisite for successful induction of ovulation. It also points out that direct stimulation of the ovaries with menopausal gonadotropins is not always necessary in such hypothalamic disturbances as hyperprolactinemic amenorrhea. Substituting HCG for LH appears in many women to be sufficient for correcting the underlying abnormality of positive estrogen feedback. Clomid (combined with HCG) could therefore be used for induction of ovulation in amenorrhea
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RADW ANSKA ET AL.
with hyperprolactinemia. Its advantages are short duration of teatment courses which are discontinued before conception and a long clinical experience with its use. Patients resistant to and/or unsuccessful on Clomid and HCG may then be treated with bromocriptine, and some of them may respond to such a different regimen. This drug, however, is administered daily and is not discontinued until conception and embryogenesis have already taken place. This raises certain anxiety, although to date the reported outcomes of bromocriptine-induced pregnancies have not been associated with an increased incidence of fetal abnormalities. 21 In conclusion, in the present study, pregnancy rates of 57% with the use of Clomid and HCG and of 68% with the use of bromocriptine in infertile amenorrheic women with hyperprolactinemia showed that both these regimens can be successful. REFERENCES 1. Lachelin GCL, Abu-Fadil S, Yen SSC: Functional delineation of hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 44:1163, 1977 2. Besser GM: Amenorrhoea-its investigation and the assessment of the role of prolactin. In The Endocrine Function of the Human Ovary, Edited by VHT James, M Serio, G Giusti. London, Academic Press, 1976, p 261 3. Glass MR, Shaw RW, Butt WR, Edwards RL, London DR: An abnormality of oestrogen feedback in amenorrhoea-galactorrhea. Br Med J 3:274, 1975 4. Pepperell RJ, Evans JR, Brown JB, Smith MA, Healy D, Burger HG: Serum prolactin levels and the value of bromocriptine in the treatment of anovulatory infertility. Br J Obstet Gynaecol 84:58, 1977 5. McGarrigle HHG, Sarris S, Little V, Lawrence D, Radwanska E, Swyer GIM: Induction of ovulation with clomiphene and human chorionic gonadotrophin in women with hyperprolactinaemic amenorrhoea. Br J Obstet Gynaecol 85:692, 1978 6. Thorner MO, Besser GM, Jones A, Dacie J, Jones AE: Bromocriptine treatment of female infertility: report of 13 pregnancies. Br Med J 3:694, 1975 7~ Wiebe RH, Hammond CB, Handwerger S: Treatment of functional amenorrhea-galactorrhea with 2-bromoergocryptine. Fertil Steril 28:426, 1977
August 1979
8. Zarate A, Canales ES, Forsbach G, Fernandez-Lazala R: Bromocriptine. Clinical experience in the induction of pregnancy in amenorrhea-galactorrhea syndrome. Obstet Gynecol 52:442, 1978 9. Archer DF, Josimovich JB: Ovarian response to exogenous gonadotropins in women with elevated serum prolactin. Obstet Gynecol 48:155,1976 10. Swyer GIM, Radwanska E, McGarrigle HHG: Plasma oestradiol and progesterone estimation for the monitoring of induction of ovulation with clomiphene and chorionic gonadotrophin. Br J Obstet Gynaecol 82:794, 1975 11. Radwanska E, Swyer GIM: Plasma progesterone estimation in infertile women and in women under treatment with clomiphene and chorionic gonadotrophin. J Obstet Gynaecol Br Commonw 81:107,1974 12. McNeilly AS: Radioimmunoassay of human prolactin. Proc R Soc Med 66:863, 1973 13. Canales ES, Zarate A, Garido J, Leon C, Soria J, Schally AV: Study on the recovery of pituitary FSH function during puerperium using synthetic LRH. J Clin Endocrinol Metab 38:1140,1974 14. LeMaire WJ, Shapiro AG, Riggal F, Yang NST: Temporary pituitary insensitivity to stimulation by synthetic LRF during the postpartum period. J Clin Endocrinol Metab 38:916, 1974 15. McNatty KP, Sawers RS, NcNeilly AS: A possible role for prolactin in control of steroid secretion by the human graafian follicle. Nature 250:653, 1974 16. WentzAC, JonesGS, RoccoL, MatthewsRR: Gonadotropin response to luteinizing hormone-releasing hormone administration in secondary amenorrhea and galactorrhea syndromes. Obstet Gynecol 45:256, 1975 17. Archer DF, Sprong JW, Nankin HR, Josimovich JB: Pituitary gonadotropin response in women with idiopathic hyperprolactinemia. Fertil Steril 27:1158, 1976 18. Spellacy WN, Cantor B, Kalra PS, Buhi WC, Birk SA: The effect of varying prolactin levels on pituitary luteinizing hormone and follicle-stimulating hormone response to gonadotropin-releasing hormone. Am J Obstet Gynecol 132:157, 1978 19. Seki K, Seki M, Okumura T, Huang K: Effect of clomiphene citrate on serum prolactin in infertile women with ovarian dysfunction. Am J Obstet GynecoI124:125, 1976 20. Canales ES, Lasso P, Soria J, Zarate A: Effect of clomiphene on prolactin secretion and lactation in puerperal women. Br J Obstet Gynaecol 84:758, 1977 21. March CM: Update: bromocriptine, endocrine and fertility. AFS Newsletter Forum, Serono Symposia, Birmingham Ala, p 3, 1978