Occult hyperprolactinemia in infertile women

FRTILITY AND STRILITY Copyright e 1993 The American Fertility Society Printed on acidfree paper in U. S. A. Occult hyperprolactinemia in infertile women Kunio Asukai MD Tsuguo Uemura M.D Hiroshi Minaguchi MD. Department of Obstetrics and Gynecology Yokohama City University School of Medicine Yokohama Japan Objective: To define the hypersensitive status ofprl secretion in normoprolactinemic infertile women and determine the incidence of occult hyperprolactinemia among them Design: The potential for PRL secretion was examined in 463 women Setting: Outpatient clinic in a university hospital Patients: Three hundred sixty-seven infertile women and 96 healthy volunteers. Interventions: Patients were treated with bromocriptine 2.5 or 5 mg/d for 3 months. Main Outcome Measures: Prolactin response to thyrotropin-releasing hormone (TRH) circadian rhythm and serum PRL changes during the menstrual cycle. Results: Approximately 15% of infertile women showed an exaggerated response to TRH and 95% among them had clinical disorders such as galactorrhea luteal insufficiency and menstrual disturbances. Bromocriptine proved effective in 90% of these women. Transient hyperprolactinemia was observed at night in 80% of normal PRL responders who had galactorrhea. Bromocriptine was effective in 75% of these women. Transient hyperprolactinemia during the menstrual cycle was observed in 43% of normal PRL responders with luteal insufficiency 85% of whom responded to treatment with bromocriptine. Conclusion: In infertile women the TRH test helps in the selection of patients who may respond to bromocriptine. Among normal PRL responders 60% of patients with galactorrhea and 47% of those with luteal insufficiency recovered after bromocriptine treatment. From these results patients who exhibit clinical abnormalities such as galactorrhea and luteal insufficiency should undergo extensive PRL testing. Fertil Steril 1993;60:423-7 Key Words: Prolactin bromocriptine TRH test infertile women galactorrhea luteal insufficiency Received November 5 1992; revised and accepted June 1 1993. Reprint requests: Kunio Asukai M.D. Department of Obstetrics and Gynecology Yokohama Minami-Kyosai Hospital Mutsuura-cho 500 Kanazawa-ku Yokohama 236 Japan. It is well known that hyperprolactinemia induces galactorrhea and amenorrhea conditions that improve after treatment with the dopamine agonist bromocriptine. Recently it has been reported that some normoprolactinemic women with amenorrhea show an increased secretion of PRL in response to thyrotropin-releasing hormone (TRH) and menstrual cycles resume after treatment with bromocriptine (1 2). These findings indicate that these patients have masked hyperprolactinemia. However masked or occult hyperprolactinemia as a clinical entity has not been defined as yet. The present study was undertaken as an attempt to define masked/occult hyperprolactinemia and to determine its incidence among infertile normoprolactinemic women. MATRIALS AND MTHODS Serum PRL levels were measured every 2 to 3 days during the follicular and luteal phases in 90 normally menstruating women between 18 and 36 years of age. During the follicular phase PRL levels 30 minutes after the administration of 500 Jig TRH 1M were also examined. The normal menstrual cycle was determined by a biphasic BBT curve that Asukai et al. Occult hyperprolactinemia 423

included a luteal phase of at least 12 days. From these data the normal range of serum PRL and the normal range of the PRL response to TRH were established. According to these criteria 48 women who showed an exaggerated response of PRL to TRH (the exaggerated PRL group) were selected from among 305 infertile women 19 to 43 years of age. Thirty-two women in the exaggerated PRL group were treated with bromocriptine for 3 months. In the 19 normoprolactinemic women (24 to 36 years of age) with galactorrhea the PRL response to TRH was examined and bromocriptine was administered. In 9 of them blood samples were drawn during the follicular phase every 2 hours around the clock from an indwelling antecubital venous catheter without disturbing their sleep at night. The 24- hour patterns of PRL were compared with those of 6 normal women (19 to 41 years of age). In 24 of the normoprolactinemic patients (25 to 38 years of age) with luteal insufficiency the response to TRH was examined and bromocriptine was administered. The diagnosis criteria for luteal insufficiency were [1] hyperthermic phase of <11 days or [2] low sum P values «25 ngjml [80 mmoljl]) of three blood samples obtained every 2 days during the midluteal phase. In the other 19 normoprolactinemic patients (28 to 39 years of age) with luteal insufficiency blood samples were taken every day during the periovulatory phase and every 2 days during the luteal phase before and during bromocriptine treatment. All these patients were normal PRL responders. Prolactin P and other hormones were measured and the luteal index (the average P concentration during the luteal phase X days of the luteal phase) was calculated as described by Del Pozo (3). Patients received 5 mgjd of bromocriptine but patients complaining of nausea or vomiting because ofbromocriptine received 2.5 mgjd. In patients who received 5 mgjd bromocriptine the mean ± SD serum level of PRL was 2.3 ± 1.2 ngjml (75 ± 39 JlIUjmL) and maximum PRL level after TRH administration was <6 ngjml (195 JlIUjmL). Serum levels of PRL were determined by an immunoradiometric assay using monoclonal antibodies (Spac PRL Daiichi Isotope Co. Ltd. Tokyo Japan; World Health Organization First International Preparation 75j504). The intra-assay and interas say coefficients of variation were <10%. To confirm the day of LH surge and ovulation serum LH FSH 2 and P were also measured by RIA using commercial kits (Daiichi Isotope Co. Ltd.). RSULTS In normal women the mean ± SD PRL serum concentration was 4.2 ± 2.5 ngjml (137 ± 81 JlIU j ml) during the follicular phase and 4.0 ± 2.5 ngj ml (130 ± 81 JlIUjmL) during the luteal phase. The average PRL concentration except during the periovulatory phase was 4.1 ± 2.5 ngjml (133 ± 81 JlIUjmL) and the normal basal level of PRL was considered to be <10 ngjml (325 JlIUjmL) that is the mean ± 2SD. During the follicular phase the serum concentration of PRL in normal women (n = 90) was 47.3 ± 19.4 ngjml (1537 ± 630 JlIUjmL) 30 minutes after TRH and the upper limit of the normal range 30 minutes after TRH was set at 86 ngjml (2795 JlIUjmL). According to these criteria infertile women were divided into three groups: the normoprolactinemic group in which the basal level was <10 ngjml (325 JlIUjmL) and the PRL level after TRH was <86 ngjml (2795 JlIUjmL) (n = 208); the exaggerated responder group in which the basal level was <10 ngjml (325 JlIU jml) and the PRL level after TRH was >86 ngjml (2795 JlIUjmL) (n = 48); and the hyperprolactinemic group in which the basal PRL was> 10 ngjml (325 JlIU jml) (n = 49). Forty-eight (15.7%) of the 305 infertile women showed an exaggerated response of PRL to TRH and 46 (95.8%) among these 48 patients presented abnormal clinical findings: 9 had galactorrhea (18.8%) 22 luteal insufficiency (45.8%) 7 oligomenorrhea (14.6%) 5 anovulatory cycle (10.4 %) and 3 presented amenorrhea (6.3%). Bromocriptine was administered to most of these patients (n = 32); galactorrhea improved in 7 (87.5%) of 8 patients luteal insufficiency in 14 (93.3%) of 15 patients oligomenorrhea in 5 (83.3%) of 6 patients and anovulatory cycle became ovulatory in the 3 (100%) patients treated with bromocriptine. In patients with galactorrhea the average level of basal PRL was 5.9 ± 2.2 ngjml (192 ± 72 JlIU jml) and after TRH it was 68.2 ± 33.2 ngjml (2217 ± 1079 JlIUjmL) both of which were significantly higher (P < 0.05) than in normal women (4.2 ± 2.5 ngjml [137 ± 81 JlIUjmL] 47.3 ± 19.4 ngjml [1537 ± 630 JlIUjmL]) (Fig. 1). In eight of these nine patients (88.8%) galactorrhea improved after treatment with bromocriptine. According to the 24-hour pattern of PRL in normal women the PRL serum level was 4 to 6 ngjml (130 to 195 JlIUjmL) and it remained stable from 8:00 A.M. to 10:00 P.M. but a transient increase of PRL (8 to 14 ngjml [260 to 455 JlIUjmL]) was 424 Asukai et al. Occult hyperprolactinemia Fertility and Sterility

15 before after TRH ::J 10 " 00 ; c...j '\ 0::: :. ::l Q; ;. Figure 1 Serum PRL levels 5 (f) before and 30 minutes after t TRH (500 Jlg 1M) in controls (n = 90) and jn infertile. women with galactorrhea (n = 19) or with luteal insuffi- \ ciency (n = 24). The horizon- tal lines represent the mean values (conversion factor to SI 0 units 32.5). P < 0.05 significant differences versus con- controls galactorrhea trois. + 150 01. 100 _.-. " 1 50 0.A -+- Ji i1 luteal controls galactorrhea luteal insufficiency insufficiency \ observed from midnight to 6:00 A.M. In patients with galactorrhea PRL serum levels were the same as in the normal women from 8:00 A.M. to 2:00 P.M. but they increased from 4:00 to 6:00 P.M. and markedly high concentrations (14 to 26 ng/ml [455 to 845 JLIU/mL]) were detected from 10:00 P.M. to 6:00 A.M. (Fig. 2). Serum PRL levels of>20 ng/ml (650 JLIU /ml) were observed at night in eight of nine patients with galactorrhea. One patient with galactorrhea showed the same PRL pattern seen in normal women but this patient probably had sensitive mammary glands because of a previous delivery. In patients with galactorrhea there was a positive correlation between the PRL levels after TRH and the maximum values at night (P < 0_01 r = 0.7665 n = 15) (Fig. 3). In 24 patients with luteal insufficiency the average PRL serum level (6.5 ± 1.7 ng/ml [211 ± 55 JLIU/mL]; P < 0.05) and the PRL level after TRH (62.7 ± 30.7 ng/ml [2038 ± 998 JLIU/mL]; P < 0.05) were significantly higher than in the nor- :;.i 20 II: 0 en 10 3D 118:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:00 02:00 04:00 06:00 Cloek hour Figure 2 Circadian rhythm of serum PRL levels (mean ± S) in six normal women (O) and nine women with galactorrhea (e). P < 0.05 significant differences between the two groups. co 5 60 Y=0.2SX+7.D2 to R=0.77 "ii > P<O.OI.!! J a: Do '0 to >< 40 20. "- iii.a u 0 z 00 20 40 60 80 100 120 140 TRH-stimulated PRL levels (ng/ml) Figure 3 Correlation between serum nocturnal peak levels of serum PRL and the PRL levels 30 minutes after TRH administration in normal women (O) and patients with galactorrhea (e). Asukai et al. Occult hyperproiactinemia 425

moprolactinemic group (Fig. 1). ighteen of these patients were treated with bromocriptine and judging from the increases of serum P or the establishment of conception treatment proved effective in 13. Five of these 24 patients belonged to the group that showed exaggerated response to TRH and they responded very well to treatment with bromocriptine. In 7 of 19 normal PRL responders who had luteal insufficiency transient hyperprolactinemia (60% increase from the average levels) was observed in the periovulatory phase of the menstrual cycle in the late luteal phase or both. In these 7 patients the average serum level of P during the midluteal phase increased from 8.0 ± 1.0 ng/ml (25.4 ± 3.2 nmol/l) to 11.3 ± 2.9 ng/ml (35.9 ± 9.2 nmol/l) and the luteal index increased significantly (P < 0.05) from 116 ± 16 to 151 ± 26 after the treatment. Luteal insufficiency improved in 6 (85.7%) of these 7 patients judging from the establishment of conception or an increase of the luteal index (> 10 ng X days). But the luteal function improved in only 3 (25%) of 12 patients who did not experience transient hyperprolactinemia after treatment with bromocriptine. DISCUSSION According to the assay system employed in the present study the normal basal level of serum PRL was <10 ng/ml (325 IU /ml) and the normal upper limit 30 minutes after TRH injection was <86 ng/ml (2795 IU/mL). Based on these criteria we found that approximately 15% of the infertile patients examined showed an exaggerated response of PRL to TRH and that 95% of these patients exhibit at least one abnormal clinical sign such as galactorrhea luteal insufficiency oligomenorrhea anovulatory cycles or amenorrhea. When present these abnormalities improved in 83% to 100% of the patients after treatment with bromocriptine. Yamaguchi et al. (4) suggested that transient hyperprolactinemia at night induces luteal insufficiency and galactorrhea. Ben-David and Schenker (5) reported that transient hyperprolactinemia at midcycle might disturb fertilization and embryo implantation. In the present study only 44.4% (4/9) of the patients with galactorrhea belonged to the group that showed an exaggerated response of PRL to TRH but 88.9% (8/9) showed transient and marked hyperprolactinemia at night and responded to bromocriptine treatment. Only 20.8% (5/24) of the patients with luteal insufficiency exhibited an exaggerated response of PRL but 43.7% (7/16) showed transient hyperprolactinemia in the ovulatory phase the late luteal phase or both. High basal levels of PRL exaggerated responses to TRH transient hyperprolactinemia at night and transient hyperprolactinemia during the menstrual cycle seem to indicate a high potential of PRL secretion that is occult hyperprolactinemia because in patients with occult hyperprolactinemia PRL increased remarkably in response to TRH stimulation sex steroid hormone stimulation and during night time-sleep. In this study an increased potential to secrete PRL shortened the length of the luteal phase and suppression of PRL improved the luteal function. It is well known that hyperprolactinemia affects the hypothalamus-pituitary-ovarian system. Kauppila et al. (6) reported that the ovarian follicles are very sensitive to excess PRL during the recruitment period. On the other hand we have demonstrated (7) that metoclopramide a dopamine receptor antagonist induces hyperprolactinemia during the luteal phase but it does not shorten the length of the luteal phase or decrease serum P. These results suggested that the follicle was more sensitive to excess PRL than the corpus luteum. Occasional or transient hyperprolactinemia apparently affects the ovarian function less than hyperprolactinemia does although its mechanism of action may be the same as in hyperprolactinemia. Therefore it seems that an increased potencial to secrete PRL and transient hyperprolactinemia would affect follicle development and result in luteal insufficiency. In conclusion the TRH test was useful to select patients who would respond to treatment with bromocriptine. But among the normal responders 75% of infertile women with galactorrhea and 61 % of those with luteal insufficiency recovered after bromocriptine treatment. From these results it can be said that patients who exhibit clinical abnormalities such as galactorrhea and luteal insufficiency should undergo extensive PRL testing. RFRNCS 1. Corenblum B Taylor PJ. A rationale for the use of bromocriptine in patients with amenorrhea and normoprolactinemia. Fertil Steril 1980;34:239-41. 426 Asukai et al. Occult hyperproiactinemia Fertility and Sterility

2. Peillon F Vincens M Cesselin F Doumith R Mowszowicz I. xaggerated prolactin response of thyrotropin-releasing hormone in women with anovulatory cycles: possible role of endogenous estrogens and effect of bromocriptine. Fertil Steril 1982;37:530-5. 3. Del Pozo Wyss H Tolis G Alcaniz J Campana A Naftolin F. Prolactin and deficient luteal function. Obstet Gynecol 1979;53:282-6. 4. Yamaguchi M Aono T Koike K Nishikawa Y Ikegami H Miyake A et al. ffects of nocturnal hyperprolactinemia on ovarian luteal function and galactorrhea. ur J Obstet Gynecol Reprod Bioi 1991;39:187-91. 5. Ben-David M Schenker JG. Transient hyperprolactinemia: a correctable cause of idiopathic female infertility. J Clin ndocrinol Metab 1983;57:442-4. 6. Kauppila A Kirkinen P Orava M Vihko R. ffects of metoclopramide-induced hyperprolactinemia during early follicular development on human ovarian function. J Clin ndocrinol Metab 1984;59:875-81. 7. Demura T Asukai K Okamiya Y Matsuyama A Shirasu K Minaguchi H. Functional relationship of gonadotropin and prolactin in the ovary. In: Mizuno M Mori H Taketani Y editors. Role of PRL in human reproduction. Basel: Karger 1988:136-47. Asukai et al. Occult hyperprolactinemia 427