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Endocrine profiles in tamoxifen-induced conception cycles
FERTILITY AND STERILITY Copyright" 1984 The American Fertility Society
Vol. 42, No.4, October 1984 Printed in U.S A.
Endocrine profiles in tamoxifen-induced conception cycles
Choshin Tajima, M.D. Department of Obstetrics and Gynecology, Kumamoto University Medical School, Kumamoto, Japan
Twenty-five infertile women conceived while taking tamoxifen (TMX). Daily serum profiles of 5 of the 25 TMX -induced conception cycles were elucidated and compared with those found in 5 normal cycles. In spite of lower levels of follicle-stimulating hormone and luteinizing hormone during the follicular phases, estradiol concentrations were higher in the TMX-induced conception cycles. It is suggested that this may be due to a direct ovarian effect of TMX as one of its major mechanisms in the course of folliculogenesis. On the other hand, progesterone concentrations on days 6 and 7 during the luteal phases were also higher in the TMX -induced conception cycles. It is suggested that this may be due to a luteotropic influence at the blastocyst stage. Fertil Steril 42:548, 1984
Some information on hormone profiles in spontaneous pregnancy cycles is available, 1, 2 but detailed data have not been provided. Lenton et al. 3 elucidated the hormone profiles in spontaneous conception cycles in normal women, spontaneous conception cycles in subfertile women, conception cycles following clomiphene treatment, and conception cycles during bromocriptine treatment, and compared them with those of cyclic nonpregnant women. Mean concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E 2 ) were generally very similar to those of normal control cycles, which suggests that a conception cycle even in previously infertile women is likely to conform closely to normal conception cycles. Although there were nO significant differences in progesterone (P) secretion among the conception cycles, there were highly significant differences between the conception cycles and the nonpregnant cycles. Mean P concentrations in the conception group were highReceived March 19, 1984; revised and accepted June 6, 1984. Reprint requests: Chosin Tajima, M.D., Assistant Professor, Department of Obstetrics and Gynecology, Kumamoto University Medical School, Kumamoto 860, Japan. 548
Tajima Tamoxifen-induced conception cycles
er than those in the control women from days 3 to 8 following the LH peak. We have been studying the hormonal profiles of infertile patients treated with tamoxifen (TMX). In a previous article,4 we elucidated the endocrine profiles in TMX-induced ovulatory cycles. We fortunately obtained daily blood samples in five TMX treatment cycles during which conception occurred. In an attempt to elucidate the hormonal profiles in the TMX-induced conception cycles, daily FSH, LH, E 2 , and P concentrations were examined. The hormone levels obtained were compared with those of normal cycles. MATERIALS AND METHODS
Twenty-five infertile patients conceived in our clinic after taking 10 to 40 mg ofTMX daily for 5 consecutive days from the fifth day of menses. These patients consisted of 1 with secondary amenorrhea in which withdrawal bleeding by P had occurred, 3 with oligomenorrhea, 4 with anovulatory cycles, and 17 with luteal phase deficiency (LPD). Endometriosis, hyperprolactinemia, and androgen excess could not be found in these patients. Five of the 25 patients who conFertility and Sterility
Table 1. Clinical Information of Test Group Test group
Age (yr) Menarche (yr) Parity Height (em) Weight (kg) Duration of infertility (yr) Previous clinical diagnosis
Mean ± SEMa
1
2
3
4
5
30 13 GO,PO 160 47 2.0 LPD b
27 14 GO,PO 157 45 3.0 LPD
26 13 GO,PO 155 46 2.5 LPD
24 13 GO,PO 149 47 2.0 Anovc
26 12 GO, PO 159 48 3.0 Anov
26.6 ± 0.98 13.0 ± 0.32 156.0 ± 1.95 46.6 ± 0.51 2.5 ± 0.22
aStandard error of the mean. bLPD, luteal phase deficiency. cAnov, anovulatory cycle.
ceived while taking TMX were subjects for this study. Previously, two of the patients were amenorrheic, and three with LPD had been ovulatory regularly. Clinical information about the test group is shown in Table 1. Clinical assessment of anovulatory cycles was made on the basis of (1) a low monophase with regular cyclic menses, according to basal body temperature (BBT), and (2) anovulation confirmed by endometrial biopsy performed prior to the onset of menses. An LPD was assumed when the BBT pattern was typical of that of a shortened luteal phase « 12 days as the mean length of three consecutive cycles) and, in addition, when the histologic pattern of the endometrium was at least 2 days out-of-phase. The control group consisted of five cycles from normal menstruating volunteers with biphasic BBT and luteal phases lasting for 14 days or more. Previously they conceived at least more than one time, but they did not conceive in present control cycles. Their age, menarche, height, and weight ranged from 24 to 29 years of age, 12 to 14 years, 150 to 160 cm, and 45 to 53 kg, respectively. There were no significant differences between the groups with respect to age, menarche, height, and weight. In the test group, venous blood samples were obtained between 8:00 A.M. and 10:00 A.M. daily from the first day of TMX administration; and in the control group, they were taken daily throughout the cycle. The serum was separated and stored at - 20°C until the assays could be performed. Serum concentrations of LH, FSH, E 2 , and P were determined with radioimmunoassay kits obtained from Daiichi Radioisotope Laboratories, Ltd., Tokyo, Japan. The intraassay variations of LH, FSH, E 2 , and P were 3.8%, 5.1%, 9.9%, and 8.0%, respectively. The interassay variations were 4.2%, 7.9%, 10.9%, and 9.1%, respectively. All samples were assayed in duplicate. Vol. 42, No.4, October 1984
RESULTS Data on daily serum concentrations were obtained from 5 of the 25 TMX-induced conception cycles. The data were synchronized on the midcycle day of the LH surge, and therefore LH midcycle peaks have been designated as day o. Figures 1 through 4, respectively, show the patterns of serum concentrations of LH, FSH, E 2 , and P in FSH mlU ml
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Figure 1 The patterns of serum concentrations of FSH during TMX therapy. The normal range is shown in the background (mean ± standard deviation). Tajima Tamoxifen-induced conception cycles
549
LUTEINIZING HORMONE
LH mlU mI
300
Co...
The serum concentration patterns of LH were similar in the five cases and similar to those in the control group, excluding those on days 14 and 15, which showed apparent differences from those in the control group (Fig. 2). Mean concentrations ofLH during the follicular phases in the five individual cases were lower than those of the control group (Table 2).
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As shown in Figure 3, elevated E2 concentrations were observed during the follicular phases after TMX treatment. The mean E2 concentrations during the follicular phases in the five individual cases were higher in the TMX-induced conception cycles than in the normal cycles (Table 2). A secondary rise in E2 was observed between days 9 and 12 (Fig. 3).
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There were no apparent differences in the follicular phase P between the TMX-induced conception cycles and normal cycles, but the differences
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Figure 2 The patterns of serum concentrations of LH during TMX therapy. The normal range is shown in the background (mean ± standard deviation).
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As shown in Figure 1, the serum concentration patterns of FSH in each case following TMX administration were similar to those of the control group, shown in the background, although the late luteal rise in FSH seen in the control group was absent. 550
Tajima Tamoxifen-induced conception cycles
-'5
-'0
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.0
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Figure 3 The patterns of serum concentrations of E2 during TMX therapy. The normal range is shown in the background (mean ± standard deviation).
Fertility and Sterility
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tions at midcycle in the three TMX-induced conception cycles (cases 1, 2, and 3). The mean FSH and LH concentrations during the follicular phases were 10.9 ± 0.21 mIUlml and 17.9 ± 0.81 mIU/ml, respectively, which were significantly lower than those of the normal cycles. The mean and integrated follicular phase E2 concentrations were 170 ± 7.8 pg/ml and 2482 ± 121.8 pg/ml, respectively, which were significantly higher than those of the normal cycles. The mean E2 peak concentration at midcycle was 578 ± 74.1 pg/ml, which was significantly higher than that of the normal cycles of 318 ± 10.8 pg/ml; whereas the mean LH peak concentration was 103 ± 15.0 mIUlml, which was not significantly different from normal concentrations. The mean FSH and LH concentrations during the luteal phases were 8.6 ± 0.22 mIUlml and 26.5 ± 2.59 mIU/ml, respectively, which were not significantly different from normal concentrations. The mean and integrated luteal phase E2 concentrations during both cycles were 330 ± 36.3 pg/ml and 4949 ± 543.7 pg/ml and 156 ± 19.7 pg/ml and 2293 ± 323.4 pg/ml, respectively; and there were significant differences between the groups. The mean luteal phase P and integrated luteal phase P concentrations were 18.8 ± 1.47 ng/ml and 282 ± 22.1 ng/ml, respectively, which were significantly higher than those of the normal cycles of 9.7 ± 0.76 ng/ml and 140 ± 13.0 ng/ml, respectively. The mean daily concentrations on days 6 and 7 were significantly higher in the TMX-induced conception cycles than in normal cycles.
days from LH pMk
Figure 4 The patterns of serum concentrations of P during TMX therapy. The normal range is shown in the background (mean ± standard deviation).
in P profiles were pronounced in the luteal phase (Fig. 4). P concentrations during the luteal phases after day 2 were higher than normal in cases 4 and 5, but in cases 1, 2, and 3, those after day 5 or 6 were higher. The mean and integrated P concentrations during the luteal phases in each case were higher in the TMX-induced conception cycles than in normal cycles (Table 2). MEAN HORMONE CONCENTRATIONS
Table 3 shows the mean and integrated hormone concentrations during the follicular and luteal phases and the LH and E2 peak concentraVol. 42, No.4, October 1984
DISCUSSION
Although some information on the hormone consequences of TMX therapy in anovulatory or ovulatory infertile women is available,4-9 the endocrine profiles in TMX-induced conception cycles were not clear because of the difficulty in obtaining daily blood samples in TMX treatment cycles during which conception occurred. In the present study, the mean E2 concentration during the follicular phase after TMX treatment was significantly higher than those of normal cycles. By contrast, the concentrations of serum FSH and LH were not higher. These findings support the results reported by other investigators 9-11 that TMX may act directly on the ovary to stimulate E2 release without intermediate gonadotropin stimulation. Tajima Tamoxifen-induced conception cycles
551
Table 2. Serum Hormone Concentrations During the Follicular Phase, at Midcycle, and During the Luteal Phase Case 1
Mean of follicular phase FSH (mlUlml) LH (mlUlml) E2 (pg/ml) Integrated follicular phase E2 (pg/ml) Midcycle peak LH (mlU/ml) E2 (pg/ml) Mean of luteal phase (days 1 to 15) FSH (mlUlml) LH (mlU/ml) E2 (pg/ml) P (ng/ml) Integrated luteal phase (days 1 to 15) E2 (pg/ml) P (ng/ml)
2
10.4 16.3 188
11.1 19.7 168
Normal womena 4
3
11.2 17.7 155
5
16.1 18.7 231
7.5 15.2 195
13.1 ± 0.54 25.4 ± 1.55 107 ± 3.33
2184
2626
2637
3698
3318
1568 ± 84.8
82 544
88 749
140 440
79 669
132 649
202 ± 46.4 318 ± 10.8
8.8 23.3 310 18.4
9.0 23.3 415 15.9
8.1 32.8 265 22.1
11.6 23.6 146 25.6
3.8 11.4 158 50.1
8.1 22.7 156 9.7
4653 276
6222 239
3973 332
2191 384
2366 752
± ± ± ±
0.40 3.16 19.7 0.76
2293 ± 323.4 140 ± 13.0
aMean ± standard error of the mean.
Lenton et al. 3 reported that the clomiphene-induced elevations of follicular phase gonadotropin concentrations in the conception cycles following clomiphene treatment were associated with large and variable increases in preovulatory and luteal phase E2 secretion. In the present study, elevated E2 production during the follicular phase exerted its negative feedback on LH secretion. The reason that this' effect is not seen with clomiphene citrate, as mentioned in the articles of Lenton et al. 3 and WU,12 seems to be that clomiphene citrate enhances the gonadotropin-releasing hormonestimulated release of gonadotropin, whereas TMX does not. 13 In spite of the decreased LH production during the follicular phase based on the negative feedback of elevated E2 production, an early follicular rise in LH was observed in the TMX-induced ovulatory cycles, as reported in our previous article, in which we described the mech-
anism of TMX action on the hypothalamic-pituitary axis as well as on the human ovary. However, this was not seen in the present study. This difference may not be attributable to whether the cycles are TMX-induced ovulatory cycles or TMXinduced conception cycles, but may rather be attributable to previous menstrual history or the dosage of TMX or both. The data presented strongly support a direct ovarian effect ofTMX as one of its major mechanisms in the course of ovulation induction. In the present study, the serum P concentrations on days 6 and 7 were significantly higher in the TMX-induced conception cycles than in the normal cycles. The apparent differences in serum P concentrations between days 12 and 15 may be due to recovery of the corpus luteum after implantation, but the observation of higher levels of serum P on days 6 and 7 was the most interesting
Table 3. Serum Hormone Concentrations During the Follicular Phase, at Midcycle, and During the Luteal Phase Mean of follicular phase FSH
LH
mIUlml
LPD group (cases 1. 2, and Mean 10.9 SEM 0.21 Normal women 13.1 Mean 0.54 SEM Significant difference P value < 0.05
Intepated follicular phase
Midcycle peak
Ez
Ez
LH
Ez
pglml
pglml
mlUlml
pglml
Integrated luteal phase
Mean of luteal phase FSH
LH
mlUlml
Ez
P
Ez
P
pglml
nglml
pglml
nglml
Luteal phase P Day 6
Day 7
nglml
3) 17.9 0.81
170 7.8
2482 121.8
103 15.0
578 74.1
8.6 0.22
26.5 2.59
330 36.3
18.8 1.47
4949 543.7
282 22.1
22.6 1.97
24.4 1.51
25.4 1.55
107 3.3
1568 84.8
202 46.4
318 10.8
8.1 0.40
22.7 3.16
156 19.7
9.7 0.76
2293 323.4
140 13.0
13.4 1.33
13.0 1.47
NS
NS
0.02
0.01
0.05
0.001
0.01
NSa
0.05
0.01
0.01
0.01
0.01
aNS, not significant.
552
Tajima Tamoxifen-induced conception cycles
Fertility and Sterility
feature of the present study. These increased P concentrations on days 6 and 7 may be due to the TMX effect on the luteal function, as mentioned in our previous article. 7 Another possible explanation is that luteotropic influences from the products of the preimplantation embryo contribute to stimulation of P secretion. Fuchs and Beling14 reported that serum P concentrations, as well as the rate of rise in P levels, are greater in pregnant than in pseudopregnant does on days 5 to 8 after mating. They suggest that in the rabbit the maternal ovary recognizes the presence of blastocysts prior to implantation, and that the fertilized ova already exert a luteotropic influence at the blastocyst stage. Lenton et al. 3 studied hormonal profiles obtained throughout 26 conception cycles and 27 nonconception control cycles and observed mean P concentrations in the conception group to be higher than those in the control women from days 3 to 8 after the LH peak. They suggest that the higher conception cycle P concentrations during the early part of the luteal phase may be due to a preimplantation component of the maternal recognition pregnancy in women. Haour and Saxena 15 and Fujimoto et al. 16 demonstrated a substance immunologically and biologically similar to chorionic gonadotropin in rabbit preimplantation blastocysts. However, further investigations are needed to confirm these observations. Acknowledgments. I am grateful to leI, Osaka, Japan, for providing tamoxifen, and to Daiichi Radioisotope Laboratories, Ltd., Tokyo, Japan, for providing radioimmunoassay kits. I am indebted to Professor Masao Maeyama for his support and to Miss Sono Nanaki for her technical assistance. REFERENCES 1. Mishell DR, Thorneycroft IH, Nagata Y, Murata T, Nakamura RM: Serum gonadotropin and steroid patterns.in early human gestation. Am J Obstet Gynecol 117:631, 1973
Vol. 42, No.4, October 1984
2. Thomas K, De Hertogh R, Pizarro M, Van Exter C, Ferrin J: Plasma LH-HCG, 17f3-oestradiol, oestrone and progesterone monitoring around ovulation and subsequent nidation.Int J Fertil 18:65, 1973 3. Lenton EA, Sulaiman R, Sobowale 0, Cooke ID: The human menstrual cycle: plasma concentrations of prolactin, LH, FSH, oestradiol and progesterone in conceiving and non-conceiving women. J Reprod Fertil 65:131, 1982 4. T~ima C, Fukushima T: Endocrine profiles in tamoxifeninduced ovulatory cycles. Fertil Steril 40:23, 1983 5. Gerhard I, Runnebaum B: Comparison between tamoxifen and clomiphene therapy in women with anovulation. Arch Gynecol 227:279, 1979 6. Senior BE, Cawood ML, Oakey RE, McKiddie JM, Siddle DR: A comparison of the effects of clomiphene and tamoxifen treatment on the concentrations of oestradiol and progesterone in the peripheral plasma of infertile women. Clin Endocrinol (OxO 8:381, 1979 7. Fukushima T, Tajima C, Fukuma K, Maeyama M: Tamoxifen in the treatment of infertility associated with luteal phase deficiency. Fertil Steril 37:755, 1982 8. Tajima C: Tamoxifen in the treatment of infertile patients associated with inadequate luteal phase. Fertil Steril 41:470, 1984 9. Fukushima T, Maeyama M: Action oftamoxifen on folliculogenesis in the menstrual cycle of infertile patients. Fertil Steril 40:210, 1983 10. Sherman BM, Chapler FK, Crickard K, Wycoff D: Endocrine consequences of continuous antiestrogen therapy with tamoxifen in premenopausal women. J Clin Invest 64:398, 1979 11. Groom GV, Griffiths K: Effect of the anti-oestrogen tamoxifen on plasma levels of luteinizing hormone, folliclestimulating hormone, prolactin, oestradiol and progesterone in normal premenopausal women. J Endocrinol 70: 421, 1976 12. Wu CH: Plasma hormones in clomiphene citrate therapy. Obstet Gynecol 49:443, 1977 13. Adashi EY, Hsueh AJW, Bambino TH, Yen SSC: Disparate effect of clomiphene and tamoxifen on pituitary gonadotropin release in vitro. Am J PhysioI240:E125, 1981 14. Fuchs AR, Beling C: Evidence for early ovarian recognition of blastocysts in rabbits. Endocrinology 95:1054, 1974 15. Haour F, Saxena BB: Detection of a gonadotropin in the rabbit blastocyst before implantation. Science 185:444, 1974 16. Fujimoto S, Euker JS, Riegel GD, Dukelow WR: On a substance cross-reacting with luteinizing hormone in preimplantation blastocyst fluid of the rabbit. Proc Jpn Acad Sci 51;123, 1980
Tajima
Tamoxifen-induced conception cycles
553
Vol. 42, No.4, October 1984 Printed in U.S A.
Endocrine profiles in tamoxifen-induced conception cycles
Choshin Tajima, M.D. Department of Obstetrics and Gynecology, Kumamoto University Medical School, Kumamoto, Japan
Twenty-five infertile women conceived while taking tamoxifen (TMX). Daily serum profiles of 5 of the 25 TMX -induced conception cycles were elucidated and compared with those found in 5 normal cycles. In spite of lower levels of follicle-stimulating hormone and luteinizing hormone during the follicular phases, estradiol concentrations were higher in the TMX-induced conception cycles. It is suggested that this may be due to a direct ovarian effect of TMX as one of its major mechanisms in the course of folliculogenesis. On the other hand, progesterone concentrations on days 6 and 7 during the luteal phases were also higher in the TMX -induced conception cycles. It is suggested that this may be due to a luteotropic influence at the blastocyst stage. Fertil Steril 42:548, 1984
Some information on hormone profiles in spontaneous pregnancy cycles is available, 1, 2 but detailed data have not been provided. Lenton et al. 3 elucidated the hormone profiles in spontaneous conception cycles in normal women, spontaneous conception cycles in subfertile women, conception cycles following clomiphene treatment, and conception cycles during bromocriptine treatment, and compared them with those of cyclic nonpregnant women. Mean concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E 2 ) were generally very similar to those of normal control cycles, which suggests that a conception cycle even in previously infertile women is likely to conform closely to normal conception cycles. Although there were nO significant differences in progesterone (P) secretion among the conception cycles, there were highly significant differences between the conception cycles and the nonpregnant cycles. Mean P concentrations in the conception group were highReceived March 19, 1984; revised and accepted June 6, 1984. Reprint requests: Chosin Tajima, M.D., Assistant Professor, Department of Obstetrics and Gynecology, Kumamoto University Medical School, Kumamoto 860, Japan. 548
Tajima Tamoxifen-induced conception cycles
er than those in the control women from days 3 to 8 following the LH peak. We have been studying the hormonal profiles of infertile patients treated with tamoxifen (TMX). In a previous article,4 we elucidated the endocrine profiles in TMX-induced ovulatory cycles. We fortunately obtained daily blood samples in five TMX treatment cycles during which conception occurred. In an attempt to elucidate the hormonal profiles in the TMX-induced conception cycles, daily FSH, LH, E 2 , and P concentrations were examined. The hormone levels obtained were compared with those of normal cycles. MATERIALS AND METHODS
Twenty-five infertile patients conceived in our clinic after taking 10 to 40 mg ofTMX daily for 5 consecutive days from the fifth day of menses. These patients consisted of 1 with secondary amenorrhea in which withdrawal bleeding by P had occurred, 3 with oligomenorrhea, 4 with anovulatory cycles, and 17 with luteal phase deficiency (LPD). Endometriosis, hyperprolactinemia, and androgen excess could not be found in these patients. Five of the 25 patients who conFertility and Sterility
Table 1. Clinical Information of Test Group Test group
Age (yr) Menarche (yr) Parity Height (em) Weight (kg) Duration of infertility (yr) Previous clinical diagnosis
Mean ± SEMa
1
2
3
4
5
30 13 GO,PO 160 47 2.0 LPD b
27 14 GO,PO 157 45 3.0 LPD
26 13 GO,PO 155 46 2.5 LPD
24 13 GO,PO 149 47 2.0 Anovc
26 12 GO, PO 159 48 3.0 Anov
26.6 ± 0.98 13.0 ± 0.32 156.0 ± 1.95 46.6 ± 0.51 2.5 ± 0.22
aStandard error of the mean. bLPD, luteal phase deficiency. cAnov, anovulatory cycle.
ceived while taking TMX were subjects for this study. Previously, two of the patients were amenorrheic, and three with LPD had been ovulatory regularly. Clinical information about the test group is shown in Table 1. Clinical assessment of anovulatory cycles was made on the basis of (1) a low monophase with regular cyclic menses, according to basal body temperature (BBT), and (2) anovulation confirmed by endometrial biopsy performed prior to the onset of menses. An LPD was assumed when the BBT pattern was typical of that of a shortened luteal phase « 12 days as the mean length of three consecutive cycles) and, in addition, when the histologic pattern of the endometrium was at least 2 days out-of-phase. The control group consisted of five cycles from normal menstruating volunteers with biphasic BBT and luteal phases lasting for 14 days or more. Previously they conceived at least more than one time, but they did not conceive in present control cycles. Their age, menarche, height, and weight ranged from 24 to 29 years of age, 12 to 14 years, 150 to 160 cm, and 45 to 53 kg, respectively. There were no significant differences between the groups with respect to age, menarche, height, and weight. In the test group, venous blood samples were obtained between 8:00 A.M. and 10:00 A.M. daily from the first day of TMX administration; and in the control group, they were taken daily throughout the cycle. The serum was separated and stored at - 20°C until the assays could be performed. Serum concentrations of LH, FSH, E 2 , and P were determined with radioimmunoassay kits obtained from Daiichi Radioisotope Laboratories, Ltd., Tokyo, Japan. The intraassay variations of LH, FSH, E 2 , and P were 3.8%, 5.1%, 9.9%, and 8.0%, respectively. The interassay variations were 4.2%, 7.9%, 10.9%, and 9.1%, respectively. All samples were assayed in duplicate. Vol. 42, No.4, October 1984
RESULTS Data on daily serum concentrations were obtained from 5 of the 25 TMX-induced conception cycles. The data were synchronized on the midcycle day of the LH surge, and therefore LH midcycle peaks have been designated as day o. Figures 1 through 4, respectively, show the patterns of serum concentrations of LH, FSH, E 2 , and P in FSH mlU ml
Case I
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Case 5
40 30 20 10
-15
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Figure 1 The patterns of serum concentrations of FSH during TMX therapy. The normal range is shown in the background (mean ± standard deviation). Tajima Tamoxifen-induced conception cycles
549
LUTEINIZING HORMONE
LH mlU mI
300
Co...
The serum concentration patterns of LH were similar in the five cases and similar to those in the control group, excluding those on days 14 and 15, which showed apparent differences from those in the control group (Fig. 2). Mean concentrations ofLH during the follicular phases in the five individual cases were lower than those of the control group (Table 2).
200 '00 lamo .. fen
80
1'" day
80
40 20 0
300 .
Co.. ,
200 '00 80
ESTRADIOL
eo 40
As shown in Figure 3, elevated E2 concentrations were observed during the follicular phases after TMX treatment. The mean E2 concentrations during the follicular phases in the five individual cases were higher in the TMX-induced conception cycles than in the normal cycles (Table 2). A secondary rise in E2 was observed between days 9 and 12 (Fig. 3).
20 0
300 200 '00 80
tamolufen IO",&ct.y
80
HW
40 20 0 300
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PROGESTERONE
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There were no apparent differences in the follicular phase P between the TMX-induced conception cycles and normal cycles, but the differences
80 80 40 20 0 300
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200
800
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600
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200
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600
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15
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Figure 2 The patterns of serum concentrations of LH during TMX therapy. The normal range is shown in the background (mean ± standard deviation).
~Hj,
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800 600 400
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tamoll.fen 10mg d.ly
400
800
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-- .-
--
0
20·
400
Case 5 t.amo~,ten
40mg day
~W~
200
As shown in Figure 1, the serum concentration patterns of FSH in each case following TMX administration were similar to those of the control group, shown in the background, although the late luteal rise in FSH seen in the control group was absent. 550
Tajima Tamoxifen-induced conception cycles
-'5
-'0
-5
0
.0
.5
20
days trom LH peak
Figure 3 The patterns of serum concentrations of E2 during TMX therapy. The normal range is shown in the background (mean ± standard deviation).
Fertility and Sterility
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tions at midcycle in the three TMX-induced conception cycles (cases 1, 2, and 3). The mean FSH and LH concentrations during the follicular phases were 10.9 ± 0.21 mIUlml and 17.9 ± 0.81 mIU/ml, respectively, which were significantly lower than those of the normal cycles. The mean and integrated follicular phase E2 concentrations were 170 ± 7.8 pg/ml and 2482 ± 121.8 pg/ml, respectively, which were significantly higher than those of the normal cycles. The mean E2 peak concentration at midcycle was 578 ± 74.1 pg/ml, which was significantly higher than that of the normal cycles of 318 ± 10.8 pg/ml; whereas the mean LH peak concentration was 103 ± 15.0 mIUlml, which was not significantly different from normal concentrations. The mean FSH and LH concentrations during the luteal phases were 8.6 ± 0.22 mIUlml and 26.5 ± 2.59 mIU/ml, respectively, which were not significantly different from normal concentrations. The mean and integrated luteal phase E2 concentrations during both cycles were 330 ± 36.3 pg/ml and 4949 ± 543.7 pg/ml and 156 ± 19.7 pg/ml and 2293 ± 323.4 pg/ml, respectively; and there were significant differences between the groups. The mean luteal phase P and integrated luteal phase P concentrations were 18.8 ± 1.47 ng/ml and 282 ± 22.1 ng/ml, respectively, which were significantly higher than those of the normal cycles of 9.7 ± 0.76 ng/ml and 140 ± 13.0 ng/ml, respectively. The mean daily concentrations on days 6 and 7 were significantly higher in the TMX-induced conception cycles than in normal cycles.
days from LH pMk
Figure 4 The patterns of serum concentrations of P during TMX therapy. The normal range is shown in the background (mean ± standard deviation).
in P profiles were pronounced in the luteal phase (Fig. 4). P concentrations during the luteal phases after day 2 were higher than normal in cases 4 and 5, but in cases 1, 2, and 3, those after day 5 or 6 were higher. The mean and integrated P concentrations during the luteal phases in each case were higher in the TMX-induced conception cycles than in normal cycles (Table 2). MEAN HORMONE CONCENTRATIONS
Table 3 shows the mean and integrated hormone concentrations during the follicular and luteal phases and the LH and E2 peak concentraVol. 42, No.4, October 1984
DISCUSSION
Although some information on the hormone consequences of TMX therapy in anovulatory or ovulatory infertile women is available,4-9 the endocrine profiles in TMX-induced conception cycles were not clear because of the difficulty in obtaining daily blood samples in TMX treatment cycles during which conception occurred. In the present study, the mean E2 concentration during the follicular phase after TMX treatment was significantly higher than those of normal cycles. By contrast, the concentrations of serum FSH and LH were not higher. These findings support the results reported by other investigators 9-11 that TMX may act directly on the ovary to stimulate E2 release without intermediate gonadotropin stimulation. Tajima Tamoxifen-induced conception cycles
551
Table 2. Serum Hormone Concentrations During the Follicular Phase, at Midcycle, and During the Luteal Phase Case 1
Mean of follicular phase FSH (mlUlml) LH (mlUlml) E2 (pg/ml) Integrated follicular phase E2 (pg/ml) Midcycle peak LH (mlU/ml) E2 (pg/ml) Mean of luteal phase (days 1 to 15) FSH (mlUlml) LH (mlU/ml) E2 (pg/ml) P (ng/ml) Integrated luteal phase (days 1 to 15) E2 (pg/ml) P (ng/ml)
2
10.4 16.3 188
11.1 19.7 168
Normal womena 4
3
11.2 17.7 155
5
16.1 18.7 231
7.5 15.2 195
13.1 ± 0.54 25.4 ± 1.55 107 ± 3.33
2184
2626
2637
3698
3318
1568 ± 84.8
82 544
88 749
140 440
79 669
132 649
202 ± 46.4 318 ± 10.8
8.8 23.3 310 18.4
9.0 23.3 415 15.9
8.1 32.8 265 22.1
11.6 23.6 146 25.6
3.8 11.4 158 50.1
8.1 22.7 156 9.7
4653 276
6222 239
3973 332
2191 384
2366 752
± ± ± ±
0.40 3.16 19.7 0.76
2293 ± 323.4 140 ± 13.0
aMean ± standard error of the mean.
Lenton et al. 3 reported that the clomiphene-induced elevations of follicular phase gonadotropin concentrations in the conception cycles following clomiphene treatment were associated with large and variable increases in preovulatory and luteal phase E2 secretion. In the present study, elevated E2 production during the follicular phase exerted its negative feedback on LH secretion. The reason that this' effect is not seen with clomiphene citrate, as mentioned in the articles of Lenton et al. 3 and WU,12 seems to be that clomiphene citrate enhances the gonadotropin-releasing hormonestimulated release of gonadotropin, whereas TMX does not. 13 In spite of the decreased LH production during the follicular phase based on the negative feedback of elevated E2 production, an early follicular rise in LH was observed in the TMX-induced ovulatory cycles, as reported in our previous article, in which we described the mech-
anism of TMX action on the hypothalamic-pituitary axis as well as on the human ovary. However, this was not seen in the present study. This difference may not be attributable to whether the cycles are TMX-induced ovulatory cycles or TMXinduced conception cycles, but may rather be attributable to previous menstrual history or the dosage of TMX or both. The data presented strongly support a direct ovarian effect ofTMX as one of its major mechanisms in the course of ovulation induction. In the present study, the serum P concentrations on days 6 and 7 were significantly higher in the TMX-induced conception cycles than in the normal cycles. The apparent differences in serum P concentrations between days 12 and 15 may be due to recovery of the corpus luteum after implantation, but the observation of higher levels of serum P on days 6 and 7 was the most interesting
Table 3. Serum Hormone Concentrations During the Follicular Phase, at Midcycle, and During the Luteal Phase Mean of follicular phase FSH
LH
mIUlml
LPD group (cases 1. 2, and Mean 10.9 SEM 0.21 Normal women 13.1 Mean 0.54 SEM Significant difference P value < 0.05
Intepated follicular phase
Midcycle peak
Ez
Ez
LH
Ez
pglml
pglml
mlUlml
pglml
Integrated luteal phase
Mean of luteal phase FSH
LH
mlUlml
Ez
P
Ez
P
pglml
nglml
pglml
nglml
Luteal phase P Day 6
Day 7
nglml
3) 17.9 0.81
170 7.8
2482 121.8
103 15.0
578 74.1
8.6 0.22
26.5 2.59
330 36.3
18.8 1.47
4949 543.7
282 22.1
22.6 1.97
24.4 1.51
25.4 1.55
107 3.3
1568 84.8
202 46.4
318 10.8
8.1 0.40
22.7 3.16
156 19.7
9.7 0.76
2293 323.4
140 13.0
13.4 1.33
13.0 1.47
NS
NS
0.02
0.01
0.05
0.001
0.01
NSa
0.05
0.01
0.01
0.01
0.01
aNS, not significant.
552
Tajima Tamoxifen-induced conception cycles
Fertility and Sterility
feature of the present study. These increased P concentrations on days 6 and 7 may be due to the TMX effect on the luteal function, as mentioned in our previous article. 7 Another possible explanation is that luteotropic influences from the products of the preimplantation embryo contribute to stimulation of P secretion. Fuchs and Beling14 reported that serum P concentrations, as well as the rate of rise in P levels, are greater in pregnant than in pseudopregnant does on days 5 to 8 after mating. They suggest that in the rabbit the maternal ovary recognizes the presence of blastocysts prior to implantation, and that the fertilized ova already exert a luteotropic influence at the blastocyst stage. Lenton et al. 3 studied hormonal profiles obtained throughout 26 conception cycles and 27 nonconception control cycles and observed mean P concentrations in the conception group to be higher than those in the control women from days 3 to 8 after the LH peak. They suggest that the higher conception cycle P concentrations during the early part of the luteal phase may be due to a preimplantation component of the maternal recognition pregnancy in women. Haour and Saxena 15 and Fujimoto et al. 16 demonstrated a substance immunologically and biologically similar to chorionic gonadotropin in rabbit preimplantation blastocysts. However, further investigations are needed to confirm these observations. Acknowledgments. I am grateful to leI, Osaka, Japan, for providing tamoxifen, and to Daiichi Radioisotope Laboratories, Ltd., Tokyo, Japan, for providing radioimmunoassay kits. I am indebted to Professor Masao Maeyama for his support and to Miss Sono Nanaki for her technical assistance. REFERENCES 1. Mishell DR, Thorneycroft IH, Nagata Y, Murata T, Nakamura RM: Serum gonadotropin and steroid patterns.in early human gestation. Am J Obstet Gynecol 117:631, 1973
Vol. 42, No.4, October 1984
2. Thomas K, De Hertogh R, Pizarro M, Van Exter C, Ferrin J: Plasma LH-HCG, 17f3-oestradiol, oestrone and progesterone monitoring around ovulation and subsequent nidation.Int J Fertil 18:65, 1973 3. Lenton EA, Sulaiman R, Sobowale 0, Cooke ID: The human menstrual cycle: plasma concentrations of prolactin, LH, FSH, oestradiol and progesterone in conceiving and non-conceiving women. J Reprod Fertil 65:131, 1982 4. T~ima C, Fukushima T: Endocrine profiles in tamoxifeninduced ovulatory cycles. Fertil Steril 40:23, 1983 5. Gerhard I, Runnebaum B: Comparison between tamoxifen and clomiphene therapy in women with anovulation. Arch Gynecol 227:279, 1979 6. Senior BE, Cawood ML, Oakey RE, McKiddie JM, Siddle DR: A comparison of the effects of clomiphene and tamoxifen treatment on the concentrations of oestradiol and progesterone in the peripheral plasma of infertile women. Clin Endocrinol (OxO 8:381, 1979 7. Fukushima T, Tajima C, Fukuma K, Maeyama M: Tamoxifen in the treatment of infertility associated with luteal phase deficiency. Fertil Steril 37:755, 1982 8. Tajima C: Tamoxifen in the treatment of infertile patients associated with inadequate luteal phase. Fertil Steril 41:470, 1984 9. Fukushima T, Maeyama M: Action oftamoxifen on folliculogenesis in the menstrual cycle of infertile patients. Fertil Steril 40:210, 1983 10. Sherman BM, Chapler FK, Crickard K, Wycoff D: Endocrine consequences of continuous antiestrogen therapy with tamoxifen in premenopausal women. J Clin Invest 64:398, 1979 11. Groom GV, Griffiths K: Effect of the anti-oestrogen tamoxifen on plasma levels of luteinizing hormone, folliclestimulating hormone, prolactin, oestradiol and progesterone in normal premenopausal women. J Endocrinol 70: 421, 1976 12. Wu CH: Plasma hormones in clomiphene citrate therapy. Obstet Gynecol 49:443, 1977 13. Adashi EY, Hsueh AJW, Bambino TH, Yen SSC: Disparate effect of clomiphene and tamoxifen on pituitary gonadotropin release in vitro. Am J PhysioI240:E125, 1981 14. Fuchs AR, Beling C: Evidence for early ovarian recognition of blastocysts in rabbits. Endocrinology 95:1054, 1974 15. Haour F, Saxena BB: Detection of a gonadotropin in the rabbit blastocyst before implantation. Science 185:444, 1974 16. Fujimoto S, Euker JS, Riegel GD, Dukelow WR: On a substance cross-reacting with luteinizing hormone in preimplantation blastocyst fluid of the rabbit. Proc Jpn Acad Sci 51;123, 1980
Tajima
Tamoxifen-induced conception cycles
553