Prolactin secretion in endometriotic patients

GYNEGOWGY

European Journal of Obstetrics & Gynecology and Reproductive Biology 72 (1997) 89 92

ELSEVIER

Prolactin secretion in endometriotic patients Toshifumi

Machida*,

Michiyoshi

Taga, Hiroshi

Minaguchi

Department ~/" Obstetrics and Gynecology, Yokohama City University School Of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236, Japan

Received 27 August 1996: revised 3 October 1996~ accepted 18 October 1996

Abstract Objective: To clarify a significance of prolactin (PRL) for infertility in endometriosis. Study designs: For seventy endometriotic patients with or without infertility, serum PRL concentrations measured by radioimmunoassay before and 30 rain after 500/~g of thyrotropin-releasing hormone (TRH) injection were analyzed in relation to the Revised American Fertility Society score in endometriosis as well as to the outcome of the treatment for endometriotic infertility. Results: While no significant relationship was found between the basal PRL levels and the stage of endometriosis or the outcome of the treatment for infertility, the PRL value after TRH injection was significantly greater in the patients who did not become pregnant than those who did (P < 0.05). Conclusions: Occult hyperprolactinemia may be involved in infertility in endometriotic patients. © 1997 Elsevier Science Ireland Ltd. Keyword~: Prolactin: Endometriosis; Infertility: Prolactin responses to thyrotropin-releasing hormone; Occult hyperprolactinemia

I. Introduction

Both endometriosis and abnormal prolactin (PRL) secretion are important infertility causing factors. While endometriosis has a strong association with infertility, the exact reason for impaired fertility in endometriotic women is still unknown. Several factors, such as altered prostaglandin secretion, cytokine secretion, luteal phase defect, autoimmune phenomena, and disorder of P R L secretion have been proposed as causes of infertility in patients with endometriosis [1-5]. Although there are several clinical and experimental reports suggesting a relationship between endometriosis and abnormal PRI_ secretion [6-9], it is still controversial as to whether abnormal P R L secretion is directly involved in infertility in patients with endometriosis. To clarify a significance of P R L for infertility in endometriosis, we compared the basal P R L level and the P R L response to thyrotropin-releasing hormone ( T R H ) with the severit?

*Corresponding author. Tel: +81 45 7872691; fax: +81 45 7013536.

of endometriosis as well as with the outcome of the treatment for infertility in endometriotic patients.

2. Materials and methods 2.1. Subjects

A total of seventy endometriotic patients between 18 and 44 years of age (average 32.6 years of age) who underwent laparoscopy or laparotomy and were found to have endometriosis, were studied. Forty women in these patients complained of infertility, in which male factor and anovulation were excluded. We classified the stage of endometriosis according to the Revised American Fertility Society (R-AFS) score [10]. 2.2. Blood sampling and measurement o f P R L

For the evaluation of the basal level of P R L as well as the P R L response to T R H , blood was collected prior to and 30 min after intramuscular injection of 500 #g T R H in all patients before laparoscopy or laparotomy. Blood sampling was performed in the early follicular

0301-2115,'97/$17.00 (G 1997 Elsevier Science Ireland Ltd. All rights reserved Pll S0301-211 5(96)02649-8

T. Machida e¢ a/. Em'opean Jomwal of ()h.stelric.s & Gy#leuo/oKvam/ Rdl~rOdtu'lit'e BiolokL" 72 (1997) 89 92

90

phase of the menstrual cycle. The serum was separated after blood sampling and kept at - 20°C until the P R L measurement. The concentrations of P R L were determined by double-antibody radioimmunoassay ( R I A ) using P R L Kit Daiichi II (Daiichi Isotope Institute, Tokyo). We considered the P R L secretion as normal if its basal level was below 25 ng/ml and the P R L value at 30 min after T R H injection was below 160 ng/ml. 2.3. Follow-up study q f endometriotic patients

160" mean±S.E, 120

80 rY ck

40

stage

I

stage II

stage III

Stage of Endometriosis (R AFS)

We followed-up for more than 6 months, 40 endometriotic infertile patients who desired pregnancy. During a follow-up period, drug treatment for endometriosis was done by danazol or gonadotropin-releasing h o r m o n e ( G n - R H ) agonist in 21 patients, whereas no drug treatment was carried out in another 19 patients.

2.4. Statistical anah'sis Statistical analysis was performed using Student's t-test, Kruskal-Wallis test and one-factor A N O V A . The analysis of variance was carried out using Bartlett test. A P value o f less than 0.05 was considered statistically significant.

3. Results

The numbers o f endometriotic patients in stage I, II, I11 and IV were 12, 7, 27 and 24, respectively. Figs. 1 and 2 illustrate the basal P R L level and the P R L response to T R H , respectively, in each R - A F S stage in endometriosis. The mean values o f the basal P R L level in the patients with stage 1, II, II1 and IV were 11.8, 5.8. 16.9, 24.9 ng/ml, respectively (Fig. 1), showing that they were greater in the moderate or severe stage of endometriosis than those in the minimal or mild stage. 40mean±S.E

30E

c 20" J no_

10-

stage

n

I11

stage I11 stage Stage of Endometriosis (R-AFS) 1

stage

[l

Fig. 1. The mean ( + S.E.) wllues of the basal PRL level in endometriotic palients with stage 1 (n= 12), 11 (n=7), Ill (n-27), and IV (n = 24) classified by the R-AFS score.

l

stage IV

Fig. 2. The mean ( + S.E.) PRL values at 30 min after 5//0 pg TRH injection in endometriotic patients with stage I (n = 12). II (n = 7), Ill (n = 27), and IV (n = 24) classitied by the R-AFS score. The mean P R L values at 30 min after T R H injection in the patients with stage I, II, Ill and IV were 66.2, 39.4, 79.2, 127.6 n g m l , respectively (Fig. 2). Similarly, the endometriotic patients with moderate or severe stage had a greater P R L response to T R H than those with minimal or mild stage. However, these differences were not statistically significant. The patients were grouped into four groups according to the outcome of the treatment and pregnancy during a follow-up period (Table 1). During the followup period for 22.0 + 5.2 (mean 4-S.E.) months, 15 out of 40 infertile endometriotic patients became pregnant with (group 1 : 8 patients) or without {group 2; 7 patients) treatment for endometriosis by danazol or G n - R H agonist. In addition to the treatment by these drugs, some patients were subsequently treated by several kinds o f therapy such as clomiphene citrate administration, h M G ; h C G injection, artificial insemination, or in vitro fertilization,'embryo transfer for their particular cause of infertility other than endometriosis. Another 25 patients did not become pregnant during the follow-up period for 25.3 __0.4 (mean 4-S.E.) months with (group 3 : 1 3 patients) or without (group 4; 12 patients) treatment by danazol or G n - R H agonist. The mean ages of the patients who became pregnant and those who did not were 29.6 4- 1.17 {mean_+ S.E.) and 30.9 4- 0.96 (mean _+ S.E.) years, respectively. The mean values of the R - A F S score in pregnancy cases and nonpregnancy cases were 27.3 4- 7.72 (mean _+ S.E.) and 33.0 4- 6.27 {mean + S.E.), respectively. There was no significant difference in follow-up period, mean age and mean value o f the R - A F S score between the two groups. The mean basal P R L values in pregnancy cases (16.1 + 4 . 7 4 ng,ml) did not differ from that in nonpregnancy cases {17.24- 1.66 ng/ml) (Fig. 3), whereas the mean P R L value in response to T R H in nonpregnancy cases {95.6 4- 7.65 ng,,ml) was signiticantly greater than that in pregnancy cases (69.3 4-9.12 ng:nfl) ( P < 0 . 0 5 ) (Fig. 4).

T Machida el al. ,' European Journal o/" Obstetrics & Gym'co/oXLvam/ R(Twoduclire Biolo,k,v 72 (1997) 89 92

91

Table I The outcome of the treatment for infertility in endometriotic patients

Group Group Group Group

I 2 3 4

Treatment

Pregnancy

No. of patients

Follo~-up periods months)~

Age (years)'~

R-AFS score ~'

(+) (-I (+) ( )

(+l (+) ( ) ( )

8 7 13 12

27.9_+7.9 15.3+5.4 30.2_+7.1 22.7+_4.5

30.0_+_1.8 29.1 + 1.4 30.7+ 1.6 31.1 ~ 1.0

30.3_+9.1 23.9_+12.7 52.4_+8.4 11.9_+4.2

The patients were grouped into four groups by the treatment and the result after operation. Treatment ( + ), drug treatment for endometriosis was done by danazol or gonadotropin-releasing hormone agonist. Treatment ( ), no drug treatment was carried out for endometriosis. ' Results are expressed as mean + S.E.

4. Discussion

Hirschowitz et al. [7] described a new syndrome consisting of galactorrhea and endometriosis by reporting that eight of nine endometriotic patients had galactorrhea. Hargrove and Abraham [8] also reported seven cases of galactorrhea in 14 endometriotic patients. In the experimental studies [9,11,12], ectopic pituitary grafting induced an early and high incidence of uterine adenomyosis associated with hyperprolactinemia in some strains of mice. These findings indicate a close relation between endometriosis and PRL secretion. With regard to the PRL secretion in endometriotic patient, there have been conflicting results among investigators. Acien et al. [5] reported that the PRL response to T R H was significantly greater in endometriotic patients than in normal women and that the PRL response to T R H before treatment was significantly higher in patients who after danazol treatment showed persistent endometriosis at the second laparoscopy, suggesting a possible prediction of therapeutic results in endometriosis by T R H testing. Muse et al. [4] also reported that the PRL response to T R H in patients with moderate endometriosis was significantly greater than that observed in patients with mild endometriosis,

suggesting that the PRL response to T R H was related with the severity of endometriosis. On the other hand, Panidis et al. [13] reported that basal PRL levels showed no statistically significant difference between non-endometriotic women and patients with endometriosis, and Arumugam observed no increase in the PRL levels with the severity of endometriosis [14]. While in our current study the differences in the basal PRL level and the PRL response to T R H were not statistically significant among four stages in the R-AFS score, they were greater in endometriotic patients with stage III and IV than those in stage 1 and II, suggesting that the magnitude of the PRL secretion is related to the severity of endometriosis. In order to analyze the involvement of PRL in infertility in an endometriotic patient, we compared the PRL secretion with the outcome of the fertility of infertile women with endometriosis during the followup period. The PRL response to T R H was the only factor that showed the difference between the infertile women who became pregnant and those who did not, because the mean PRL value in response to T R H in nonpregnancy cases was significantly greater than that m pregnanc3 cases. This finding is consistent with the report of Muse et al. [4], who suggested that relative

,°[

140 mean:SE.

mean±S.E.

i

i 201

E

! J Q.

Jn., 13_

lod

ol

120-

f - - p <0.05---,

100-

-}

8060-

40-

pregnancy

I

20pregnancy

nonpregnancy

nonpregnancy

Fig. 3. The comparison of the mean (+-S.E.) basal PRL values between pregnancy cases (groups 1 and 2) and nonpregnancy cases (groups 3 and 4). The mean basal PRL values in pregnancy cases did not differ from that in nonpregnancy cases.

Fig. 4. The comparison of the mean ( + S.E.) PRL values in response to 500 /~g TRH between pregnancy cases {groups I and 2) and nonpregnancy cases (groups 3 and 41. The mean PRL value in response to TRH m nonpregnancy cases ~vas significantly greater than that in pregnancy cases (P < 0.05).

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T. Machida et al. /European Journal 0/' Obstetrics & Gynecology and Reproductive Biology 72 (1997) 89- 92

h y p e r p r o l a c t i n e m i a may be responsible for the infertility associated with endometriosis since they observed that some infertile w o m e n with endometriosis exhibited a greater capacity for P R L secretion t h a n n o r m a l women. Therefore, occult hyperprolactinemia, in which the P R L response to T R H b u t n o t the basal level of P R L is high, is t h o u g h t to be one of the infertility factors in endometriotic infertile patients. While it is well k n o w n that h y p e r p r o l a c t i n e m i a is an i m p o r t a n t cause of infertility a n d that b r o m o c r i p t i n e therapy is effective for it, b r o m o c r i p t i n e also has a beneficial effect on n o r m o p r o l a c t i n e m i c infertile w o m e n as well if they have an exaggerated P R L response to T R H [15]. O u r current study indicates that latent disorder of P R L secretion might be involved in infertility in e n d o m e t r i otic patients. However, the m e c h a n i s m by which endometriosis induces such a subtle change in P R L secretion remains to be clarified, Chew et al. [16] reported that peritoneal fluid P R L c o n c e n t r a t i o n was elevated in infertile w o m e n with endometriosis and that it was higher in the luteal phase t h a n in the follicular phase, indicating that the P R L level in the luteal phase might be associated with e n d o m e t r i o t i c infertility. In conclusion, the present study suggests that P R L is related to endometriosis a n d that occult hyperprolactinemia is an i m p o r t a n t factor for infertility in endometriosis.

References [1] Drake TS, O'Brien WF, Ramwell PW, Metz SA. Peritoneal fluid thromboxane B2 and 6 keto-prostaglandin F~ alpha in endometriosis. Am J Obstet Gynecol 1981; 140:401 404.

[2] Kistner RW. Management of endometriosis in the infertile patient. Fertil Steril 1975; 26: 1151-1166. [3] Weed JC, Arquembourg PC. Endometriosis--can it produce an autoimmune response resulting in infertility? Clin Obstet Gynecol 1980; 23:885 893. [4] Muse K, Wilson EA, Jaward MJ. Prolactin hyperstimulation in response to thyrotropin-releasing hormone in patients with endometriosis. Fertil Steril 1982: 38:419 422. [5] Acien P, Loret M, Graells M. Prolactin and its response to the lutenizing hormone-releasing hormone tyrotropine-releasing hormone test in patients with endometriosis before, during, and after treatment with danazol. Fertil Steril 1989; 51: 774-.780. [6] Surrey ES, Halme J. Endometriosis as a cause of infertility. Obstet Gynecol Clin Nth Am 1989; 16: 79--91. [7] Hirschowitz JS, Soler NG, Wortsman J. The galactorrhea endometriosis syndrome. Lancet 1978; 1:896 898. [8] Hargrove JT, Abraham GK. Abnormal luteal function in patient with endometriosis. Fertil Steril 1980; 34: 302. [9] Mori T, Nagasawa H. Mechanism of development of prolactininduced adenomyosis in mice. Acta Anat 1983; 116:46 54. [10] The American Fertility Society. Revised American Fertility Society Classification of Endometriosis. Fertil Steril 1985; 43:351 352. [11] Mori T, Nagasawa H, Takahashi S. The induction of adenomyosis in mice by intrauterine pituitary isografts. Life Sci 1981; 29:1277 1282. [12] Mori T, Nagasawa H, Nakajima Y. Strain-difference in the induction of adenomyosis by intrauterine pituitary grafting in mice. Lab Anim Sci 1982; 32: 40-41. [13] Panidis D. Vavilis D. Rousso D. Panidou E. Kalogeropoulos A, Provocative test of prolactin before, during and after long-term danazol treatment in patients with endometriosis. Gynecol Endocrinol 1992: 6:19 24. [14] Arumugam K. Serum prolactin levels in infertile patients with endometriosis. Malays J Pathol 1991; 13:43 45. [15] Asukai K, Uemura T, Minaguchi H. The effect of Bromocriptine on Luteal Index in Normoprolactinemic women with Luteal Insufficiency.Abstracts Vlth World Congr Human Reprod 1987; 97. [16] Chew PCT, Peh KL, Loganath A, Gunasegaram R, Ratnam SS. Elevated peritoneal fluid lutenizing hormone and prolactin concentrations in infertile women with endometriosis, lnt J Gynecol Obstet 1990: 33:35 39.