Dudley et al.
December 1992
Am
8. Mizel SB, Dayner JM, Krane SM, Mergenhagen SE. Stimulation of rheumatoid synovial cell collagenase and prostaglandin production by partially purified Iymphocyteactivating factor (interleukin-I). Proc Natl Acad Sci USA 1981;78:2474-7. 9. Dayer JM, Beutler B, Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med 1985;162:2163-8. 10. Wilson T, Liggins GC, Aimer GP, Watkins EJ. The effect of progesterone on the release of arachidonic acid from human endometrial cells stimulated by histamine. Prostaglandins 1986;31 :343-60. 11. Schatz F, Markiewicz L, Barg P, Gurpide E. In vitro effects of ovarian steroids on prostaglandin F2o< output by human endometrium and endometrial epithelial cells. J Clin Endocrinol Metab 1985;61 :361-7. 12. Elderling .lA, Nay MG, Hoberg LM, Longcope C. McCracken JA. Hormonal regulation of prostaglandin production by rhesus monkey endometrium. J Clin Endocrinol Metab 1990;71 :596-604. 13. Csermely T, Demers LM, Hughes EC. Organ culture of human endometrium: effects of progesterone. Obstet Gynecol 1969;34:252-9.
J Obstet Gynecol
14. Mitchell MD, Edwin S, Romero RJ. Prostaglandin biosynthesis by human decidual cells: effects of inflammatory mediators. Prostaglandins Leokot Essent Fatty Acids 1990; 41:35-8. 15. Dudley DJ, Trautman MS, Edwin SS, Mitchell MD. Decidual cell biosynthesis of interleukin-6 and its regulation by cytokines. J Clin Endocrinol Metab 1992;74:884-9. 16. Abel MH, Baird DT. The effect of 17j3-estradiol and progesterone on prostaglandin production by human endometrium maintained in organ culture. Endocrinology 1980; 106: 1599-606. 17. NeulenJ, Zahradnik HP, Flecken U, Breckwoldt M. Effects of estradiol-17j3 and progesterone on the synthesis of prostaglandin F2o 5.0 ng/ml. Subjects were also screened for anemia and occult liver disease (by serum liver enzyme measurements) at this time. There were two treatment cycles during which each volunteer ingested either naltrexone (50 mg
Opiate antagonism and the menstrual cycle
1781
orally) or placebo on cycle days 1 through 13. Medications were administered 1 hour before anticipated bedtime. The order of administration was randomized by the pharmacist supplying the medications and blinded to the volunteers and investigators. There was one recovery cycle between the treatment cycles. Daily blood samples (5 ml) were drawn during both treatment cycles. Vaginal ultrasonography was performed daily beginning cycle day 10 until follicular collapse was observed. The mean diameter of the lead follicle was measured daily, as was endometrial thickness and appearance. 1O Endometrial biopsies were obtained approximately 10 to 12 days after follicular collapse and dated in a blinded fashion by one of the investigators and an experienced pathologist according to standard criteria. II Serum estradiol and progesterone levels were analyzed by radioimmunoassay (Pantex, Santa Monica, Calif.). All samples from an individual were analyzed in the same assay. Nonparametric paired analysis was carried out on variables of interest, namely, cycle length (total, follicular, and luteal), maximal follicular size, integrated progesterone levels through the luteal phase (calculated by means of the trapezoidal rule), and peak progesterone levels. The proportion of out-of-phase biopsy specimens was compared by means of Fisher's exact test. p values < 0.05 was considered significant. Data are expressed as mean ± SEM. Results
All subjects completed the entire study protocol. Six of the subjects complained of symptoms of anxiety, malaise, restlessness, difficulty concentrating, or insomnia during one of the treatment cycles. All such complaints were subsequently found to be associated with naltrexone treatment. No complaints were elicited during placebo cycles. Paired analysis indicated that neither total cycle length nor follicular or luteal phase length were affected by naltrexone treatment. Group data are summarized in Table I. One subject had a 5-day follicular phase during the naltrexone cycle, and one subject had a 5-day luteal phase on placebo, on the basis of temperature charting and ultrasonographic evidence of follicular collapse. Peak progesterone level in that cycle was 2.8 ng/ml. Because of the brevity of the luteal phase, no endometrial biopsy specimen was obtained in that subject. Endometrial specimens were obtained in all other naltrexone and placebo cycles. Results are presented in Table II. Blinded review of the endometrial biopsy specimens by one of the investigators and by an experienced pathologist revealed no effect of naltrexone on endometrial development. Only two specimens were read as 3 days out of phase, both in placebo cycles. As shown in Table I, two other measures of luteal function, namely, integrated serum progesterone and
1782
Brzyski, Viniegra, and Archer
400 350
December 1992 Am J Obstet Cynecol
•.........•
1 ..
Naltrexone
Placebo 0----0
Naltrexone A- ......... t,Placebo 6.
14
~
E ..... 01 .,e;
250
-
150
12
'0 200 'ti ca ( /)
18 16
300
'-
20
."
a
(Q
CD
..... CD
{b
-.
0 10 ::J
8
w
6
100
4
50
CD
S' (Q
......
~
2
0 -15
-10
-5
0
5
Cycle Day (0 • Ovulation)
10
Fig. l. Serum estradiol and progesterone levels in nine normal women taking naltrexone or placebo on menstrual cycle days 1 through 13.
Table I. Effects of naltrexone on menstrual cycle length and serum progesterone
Total cycle length (days) Follicular phase length (days) Luteal phase length (days) Peak progesterone (ng/ml) Integrated progesterone (ng/ml/day) Data expressed as mean
Placebo
Naltrexone
25.7 ± 0.5 13.6 ± 0.8
25.4 ± 0.9 12.4 ± 1.1
12.1 ± 0.9 15.2 ± 2.2 101.2 ± 14.6
13.0 ± 0.5 15.8 ± 2.8 10S.1 ± 12.S
± SEM.
peak progesterone levels, were unaffected by naltrexone. The peak serum progesterone levels were 15.2 ± 2.2 and 15.8 ± 2.8 ng/ml in placebo and naltrexone cycles, respectively. Fig. 1 illustrates that mean daily serum progesterone levels through the luteal phase in naltrexone and placebo cycles were also equivalent. Follicular phase events were also unaffected by naltrexone. There was no difference in the peak serum estradiol levels or the rate of increase in estradiol in placebo and naltrexone cycles (Fig. 1). The maximal follicular size observed before ovulation in naltrexone cycles was not significantly different from that in placebo cycles (21.5 ± 1.0 vs 20.8 ± 1.1 mm). Follicular growth rates for the 5 days before follicular collapse were also identical in placebo and treatment cycles, and endometrial thickness and pattern were similar in both study cycles (data not shown). There was no discernible effect of prior naltrexone treatment on the subsequent cycle on the basis of timing of ovulation and menstrual cycle length in the subjects' basal temperature charts.
Comment Opioid pep tides are thought to playa vital role in the central regulation of gonadotropin secretion, particularly in the luteal phase of the menstrual cycle.' Opioids have also been implicated in the regulation of the timing of the midcycle luteinizing hormone surge. 12 In the early follicular phase of the cycle, when estradiol and progesterone levels are low, endogenous opioids are still active at least in effecting the sleep-specific suppression of gonadotropin secretion. 6 This suppression phenomenon is interesting: It is not circadian but is specifically sleep related,13 it occurs in spite of absence of high levels of gonadal steroids, which seems to be a prerequisite for other opioid effects on gonadotropins, and it is absent in certain pathologic states."' 14 We speculated that disrupting this rhythmic suppression might adversely affect menstrual cycle events. However, the results of this study indicate that events in the normal follicular phase are not influenced significantly by opioid actions. Peak plasma levels of naltrexone are seen 1 hour after ingestion, and the dosage of naltrexone used in this study has been shown to completely block the analgesic effects of morphine for 24 hours. 15 We anticipated that administration of the agent near bedtime would produce maximal opioid blockade during sleep. In spite of this design, no significant opioid effects could be detected. These results complement those of Gindoff et al. 16 and Remorgida et aI., I7 who detected no effect of long-term naltrexone administration during the luteal phase on ovarian function in normal women. It is possible that naltrexone therapy might have affected the subsequent menstrual cycle, although no effect on ovulation or cycle length was seen
Opiate antagonism and the menstrual cycle
Volume 167 Number 6
1783
Table II. Effect of naltrexone on endometrial development Subject No. 1 2 3 4 5 6 7 8 9
Placebo Histologic day
I
Naltrexone
Cycle day
I
25 26 27 23
25 26 27 24
0 0 0 1
25 27 25 26
26 27 26 27
1 0 1 1
28 27 27
0 1 3
23 26 25 27 25
26 28 26 27 25
3 2 1 0 0
Cycle day
I
Histologic day
28 26 24
in the recovery cycles of those subjects who received naltrexone in the first treatment cycle. The difference in results observed between shortterm and longer term studies of naltrexone might be caused by differences in receptor specificity or affinity between the agents. However, naltrexone has been shown to be more potent than naloxone at antagonizing I.L receptors in vitro 'S and at precipitating opiate withdrawal in vivo. '9 It is possible that different routes of administration and different dosages might explain the differences, although the dosage of naltrexone used orally in this study has been shown to block the effects of large doses of morphine (up to 240 mg/day in humans).2o Inability to generate effective levels of naltrexone chronically or development of tolerance might also explain differences between naloxone and naltrexone, although dosages of naltrexone similar to those used in this study have been found to effectively block opiate effects after weeks 20 or months 21 of use. The side effects reported by 6 of the 9 subjects in naltrexone cycles suggest that pharmacologic effects occurred. We reasoned that long-term opioid antagonism would produce chronic disinhibition of gonadotropin secretion, which might disrupt events in the ovarian cycle. The long-term induction of an abnormal pattern of pulsatile gonadotropin secretion in normal women, produced by the pulsatile intravenous administration of gonadotropin-releasing hormone, has been shown to induce corpus luteum insufficiency in normal women. 22 In that study central opioid inhibition was bypassed by direct administration of gonadotropin-releasing hormone. In the current study pulsatile gonadotropin secretion was not investigated. Thus it is possible that not all the subjects had nocturnal slowing of pulsatile activity or that naltrexone may not have been effective at reversing the nocturnal slowing. These possibilities require additional investigation. However, the dosage of naltrexone used in our study has been shown to cause a short-term increase in luteinizing hormone in the early follicular phase."" The lack of effect of naltrexone on multiple menstrual cycle parameters suggests either
I
Lag
Lag
that gonadotropin secretion was not materially affected by the opiate antagonist or that antagonist-induced modifications in secretion were not relevant to the cycle parameters measured. In summary long-term administration of naltrexone to normal women through the follicular phase had no effect on (l) follicle growth and ovulation, (2) luteal phase progesterone production, or (3) endometrial development. REFERENCES 1. Ferin M, Van Vugt 0, Wardlaw S. The hypothalamic control of the menstrual cycle and the role of endogenous opioid peptides. Recent Prog Horm Res 1984;40:441-85. 2. Yen SSC, Quigley ME, Reid RL, Ropert JF, Cetel NS. Neuroendocrinology of opioid pep tides and their role in the control of gonadotropin and prolactin secretion. AM J OBSTET GYNECOL 1985; 152:485-93. 3. Ropert JF, Quigley ME, Yen SSC. Endogenous opiates modulate pulsatile luteinizing hormone release in humans. J Clin Endocrinol Metab 1981;52:583-5. 4. Quigley ME, Yen SSC. The role of endogenous opiates on LH secretion during the menstrual cycle. J Clin Endocrinol Metab 1980;51: 179-81. 5. Blankstein J, Reyes FI, Winter SO, Faiman C. Endorphins and the regulation of the human menstrual cycle. Clin Endocrinol 1981;14:287-94. 6. Rosamanith WG, Yen SSC. Sleep-associated decrease in luteinizing hormone pulse frequency during the early follicular phase of the menstrual cycle: evidence for an opioidergic mechanism. J Clin Endocrinol Metab 1987;65: 715-8. 7. Waldstreicher J, Santoro NF, Hall JE, Filicori M, Crowley WF. Hyperfunction of the hypothalamic-pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J Clin Endocrinol Metab 1988;66:165-72. 8. Cumming DC, Reid RL, Quigley ME, Rebar RW, Yen SSe. Evidence for decreased endogenous dopamine and opioid inhibitory influences on LH secretion in polycystic ovary syndrome. Clin Endocrinol 1984;20:643-8. 9. Wildt L, Leyendecker G. Induction of ovulation by the chronic administration of naltrexone in hypothalamic amenorrhea. J Clin Endocrinol Metab 1987;64:1334-5. 10. Veno J, Oehninger S, Brzyski RG, Acosta AA, Philput CB, Muasher SJ. Vltrasonographic appearance of the endometrium in natural and stimulated in vitro fertilization cycles and its correlation with outcome. Hum Reprod 1991;6: 901-4. 11. Noyes RT, Hertig AT, Rock J. Dating the endometrial biopsy. Ferti! Steril 1950; 1:3-25.
1784 Brzyski, Viniegra, and Archer
12. Rossmanith WG, Mortola JF, Yen SSC. Role of endogenous opioid pep tides in the initiation of the midcycle luteinizing hormone surge in normal cycling women. J Clin Endocrinol Metab 1988;67:695-700. 13. Kapen S, Boyar R, Hellman L, Weitzman ED. The relationship of luteinizing hormone secretion to sleep in women during the early follicular phase: effects of sleep reversal and a prolonged three hour sleep-wake schedule. J Clin Endocrinol MetabI976;42:1031-40. 14. Khoury SA, Reame NE, Kelch RP, Marshall JC. Diurnal patterns of pulsatile luteinizing hormone secretion in hypothalamic amenorrhea: reproducibility and responses to opiate blockade and an Ct2-adrenergic agonist. J Clin Endocrinol Metab 1987;64:755-62. 15. Physician's desk reference. 46th ed. Montvale, New Jersey: Medical Economics, 1992:937. 16. Gindoff PR, JeWele\liicz R, Hembree W. Wardlaw S, Ferin M. Sustained effects of opioid antagonism during the normal human· luteal phase. J Clin Endocrinol Metab 1988;66: 1000-4. 17. Remorgida V, Venturini PL, Anserini P, Salerno E, De Cecco L. Naltrexone in functional hypothalamic amenorrhea and in the normal luteal phase. Obstet Gynecol 1990;76: 1115-20.
December 1992 Am J Obstet Gynecol
18. Takemori AE, Portoghese PS. Comparative antagonism by naltrexone and naloxone of ]J., K, and 0' agonists. Eur J PharmacoI1984;104:101-4. 19. Cowan A. Use of the mouse jumping test for estimating antagonistic potencies of morphine antagonists. J Pharm Pharmacol 1976;28:177-82. 20. Martin WR, Jasinski DR, Mansky PA. Naltrexone, an antagonist for the treatment of heroin dependence. Arch Gen Psychiatry 1973;28:784-91. 21. Kleber HD, Kosten TR, Gaspari J, Topazian M. Nontolerance to the opioid antagonism of naltrexone. Bioi Psychiatry 1985;20:66-72. 22. Soules MR, Clifton DK, Bremner WJ, Steiner RA. Corpus luteum insufficiency induced by a rapid gonadotropinreleasing hormone-induced gonadotropin secretion pattern in the follicular phase. J Clin Endocrinol Metab 1987;65:457-64. 23. Teoh SK, Mendelson JH, Mello NK, Skupny A. Alcohol effects on naltrexone-induced stimulation of pituitary, adrenal, and gonadal hormones during the early follicular phase of the menstrual cycle. J Clin Endocrinol Metab 1988;66:1181-6.
December 1992
Am
8. Mizel SB, Dayner JM, Krane SM, Mergenhagen SE. Stimulation of rheumatoid synovial cell collagenase and prostaglandin production by partially purified Iymphocyteactivating factor (interleukin-I). Proc Natl Acad Sci USA 1981;78:2474-7. 9. Dayer JM, Beutler B, Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med 1985;162:2163-8. 10. Wilson T, Liggins GC, Aimer GP, Watkins EJ. The effect of progesterone on the release of arachidonic acid from human endometrial cells stimulated by histamine. Prostaglandins 1986;31 :343-60. 11. Schatz F, Markiewicz L, Barg P, Gurpide E. In vitro effects of ovarian steroids on prostaglandin F2o< output by human endometrium and endometrial epithelial cells. J Clin Endocrinol Metab 1985;61 :361-7. 12. Elderling .lA, Nay MG, Hoberg LM, Longcope C. McCracken JA. Hormonal regulation of prostaglandin production by rhesus monkey endometrium. J Clin Endocrinol Metab 1990;71 :596-604. 13. Csermely T, Demers LM, Hughes EC. Organ culture of human endometrium: effects of progesterone. Obstet Gynecol 1969;34:252-9.
J Obstet Gynecol
14. Mitchell MD, Edwin S, Romero RJ. Prostaglandin biosynthesis by human decidual cells: effects of inflammatory mediators. Prostaglandins Leokot Essent Fatty Acids 1990; 41:35-8. 15. Dudley DJ, Trautman MS, Edwin SS, Mitchell MD. Decidual cell biosynthesis of interleukin-6 and its regulation by cytokines. J Clin Endocrinol Metab 1992;74:884-9. 16. Abel MH, Baird DT. The effect of 17j3-estradiol and progesterone on prostaglandin production by human endometrium maintained in organ culture. Endocrinology 1980; 106: 1599-606. 17. NeulenJ, Zahradnik HP, Flecken U, Breckwoldt M. Effects of estradiol-17j3 and progesterone on the synthesis of prostaglandin F2o 5.0 ng/ml. Subjects were also screened for anemia and occult liver disease (by serum liver enzyme measurements) at this time. There were two treatment cycles during which each volunteer ingested either naltrexone (50 mg
Opiate antagonism and the menstrual cycle
1781
orally) or placebo on cycle days 1 through 13. Medications were administered 1 hour before anticipated bedtime. The order of administration was randomized by the pharmacist supplying the medications and blinded to the volunteers and investigators. There was one recovery cycle between the treatment cycles. Daily blood samples (5 ml) were drawn during both treatment cycles. Vaginal ultrasonography was performed daily beginning cycle day 10 until follicular collapse was observed. The mean diameter of the lead follicle was measured daily, as was endometrial thickness and appearance. 1O Endometrial biopsies were obtained approximately 10 to 12 days after follicular collapse and dated in a blinded fashion by one of the investigators and an experienced pathologist according to standard criteria. II Serum estradiol and progesterone levels were analyzed by radioimmunoassay (Pantex, Santa Monica, Calif.). All samples from an individual were analyzed in the same assay. Nonparametric paired analysis was carried out on variables of interest, namely, cycle length (total, follicular, and luteal), maximal follicular size, integrated progesterone levels through the luteal phase (calculated by means of the trapezoidal rule), and peak progesterone levels. The proportion of out-of-phase biopsy specimens was compared by means of Fisher's exact test. p values < 0.05 was considered significant. Data are expressed as mean ± SEM. Results
All subjects completed the entire study protocol. Six of the subjects complained of symptoms of anxiety, malaise, restlessness, difficulty concentrating, or insomnia during one of the treatment cycles. All such complaints were subsequently found to be associated with naltrexone treatment. No complaints were elicited during placebo cycles. Paired analysis indicated that neither total cycle length nor follicular or luteal phase length were affected by naltrexone treatment. Group data are summarized in Table I. One subject had a 5-day follicular phase during the naltrexone cycle, and one subject had a 5-day luteal phase on placebo, on the basis of temperature charting and ultrasonographic evidence of follicular collapse. Peak progesterone level in that cycle was 2.8 ng/ml. Because of the brevity of the luteal phase, no endometrial biopsy specimen was obtained in that subject. Endometrial specimens were obtained in all other naltrexone and placebo cycles. Results are presented in Table II. Blinded review of the endometrial biopsy specimens by one of the investigators and by an experienced pathologist revealed no effect of naltrexone on endometrial development. Only two specimens were read as 3 days out of phase, both in placebo cycles. As shown in Table I, two other measures of luteal function, namely, integrated serum progesterone and
1782
Brzyski, Viniegra, and Archer
400 350
December 1992 Am J Obstet Cynecol
•.........•
1 ..
Naltrexone
Placebo 0----0
Naltrexone A- ......... t,Placebo 6.
14
~
E ..... 01 .,e;
250
-
150
12
'0 200 'ti ca ( /)
18 16
300
'-
20
."
a
(Q
CD
..... CD
{b
-.
0 10 ::J
8
w
6
100
4
50
CD
S' (Q
......
~
2
0 -15
-10
-5
0
5
Cycle Day (0 • Ovulation)
10
Fig. l. Serum estradiol and progesterone levels in nine normal women taking naltrexone or placebo on menstrual cycle days 1 through 13.
Table I. Effects of naltrexone on menstrual cycle length and serum progesterone
Total cycle length (days) Follicular phase length (days) Luteal phase length (days) Peak progesterone (ng/ml) Integrated progesterone (ng/ml/day) Data expressed as mean
Placebo
Naltrexone
25.7 ± 0.5 13.6 ± 0.8
25.4 ± 0.9 12.4 ± 1.1
12.1 ± 0.9 15.2 ± 2.2 101.2 ± 14.6
13.0 ± 0.5 15.8 ± 2.8 10S.1 ± 12.S
± SEM.
peak progesterone levels, were unaffected by naltrexone. The peak serum progesterone levels were 15.2 ± 2.2 and 15.8 ± 2.8 ng/ml in placebo and naltrexone cycles, respectively. Fig. 1 illustrates that mean daily serum progesterone levels through the luteal phase in naltrexone and placebo cycles were also equivalent. Follicular phase events were also unaffected by naltrexone. There was no difference in the peak serum estradiol levels or the rate of increase in estradiol in placebo and naltrexone cycles (Fig. 1). The maximal follicular size observed before ovulation in naltrexone cycles was not significantly different from that in placebo cycles (21.5 ± 1.0 vs 20.8 ± 1.1 mm). Follicular growth rates for the 5 days before follicular collapse were also identical in placebo and treatment cycles, and endometrial thickness and pattern were similar in both study cycles (data not shown). There was no discernible effect of prior naltrexone treatment on the subsequent cycle on the basis of timing of ovulation and menstrual cycle length in the subjects' basal temperature charts.
Comment Opioid pep tides are thought to playa vital role in the central regulation of gonadotropin secretion, particularly in the luteal phase of the menstrual cycle.' Opioids have also been implicated in the regulation of the timing of the midcycle luteinizing hormone surge. 12 In the early follicular phase of the cycle, when estradiol and progesterone levels are low, endogenous opioids are still active at least in effecting the sleep-specific suppression of gonadotropin secretion. 6 This suppression phenomenon is interesting: It is not circadian but is specifically sleep related,13 it occurs in spite of absence of high levels of gonadal steroids, which seems to be a prerequisite for other opioid effects on gonadotropins, and it is absent in certain pathologic states."' 14 We speculated that disrupting this rhythmic suppression might adversely affect menstrual cycle events. However, the results of this study indicate that events in the normal follicular phase are not influenced significantly by opioid actions. Peak plasma levels of naltrexone are seen 1 hour after ingestion, and the dosage of naltrexone used in this study has been shown to completely block the analgesic effects of morphine for 24 hours. 15 We anticipated that administration of the agent near bedtime would produce maximal opioid blockade during sleep. In spite of this design, no significant opioid effects could be detected. These results complement those of Gindoff et al. 16 and Remorgida et aI., I7 who detected no effect of long-term naltrexone administration during the luteal phase on ovarian function in normal women. It is possible that naltrexone therapy might have affected the subsequent menstrual cycle, although no effect on ovulation or cycle length was seen
Opiate antagonism and the menstrual cycle
Volume 167 Number 6
1783
Table II. Effect of naltrexone on endometrial development Subject No. 1 2 3 4 5 6 7 8 9
Placebo Histologic day
I
Naltrexone
Cycle day
I
25 26 27 23
25 26 27 24
0 0 0 1
25 27 25 26
26 27 26 27
1 0 1 1
28 27 27
0 1 3
23 26 25 27 25
26 28 26 27 25
3 2 1 0 0
Cycle day
I
Histologic day
28 26 24
in the recovery cycles of those subjects who received naltrexone in the first treatment cycle. The difference in results observed between shortterm and longer term studies of naltrexone might be caused by differences in receptor specificity or affinity between the agents. However, naltrexone has been shown to be more potent than naloxone at antagonizing I.L receptors in vitro 'S and at precipitating opiate withdrawal in vivo. '9 It is possible that different routes of administration and different dosages might explain the differences, although the dosage of naltrexone used orally in this study has been shown to block the effects of large doses of morphine (up to 240 mg/day in humans).2o Inability to generate effective levels of naltrexone chronically or development of tolerance might also explain differences between naloxone and naltrexone, although dosages of naltrexone similar to those used in this study have been found to effectively block opiate effects after weeks 20 or months 21 of use. The side effects reported by 6 of the 9 subjects in naltrexone cycles suggest that pharmacologic effects occurred. We reasoned that long-term opioid antagonism would produce chronic disinhibition of gonadotropin secretion, which might disrupt events in the ovarian cycle. The long-term induction of an abnormal pattern of pulsatile gonadotropin secretion in normal women, produced by the pulsatile intravenous administration of gonadotropin-releasing hormone, has been shown to induce corpus luteum insufficiency in normal women. 22 In that study central opioid inhibition was bypassed by direct administration of gonadotropin-releasing hormone. In the current study pulsatile gonadotropin secretion was not investigated. Thus it is possible that not all the subjects had nocturnal slowing of pulsatile activity or that naltrexone may not have been effective at reversing the nocturnal slowing. These possibilities require additional investigation. However, the dosage of naltrexone used in our study has been shown to cause a short-term increase in luteinizing hormone in the early follicular phase."" The lack of effect of naltrexone on multiple menstrual cycle parameters suggests either
I
Lag
Lag
that gonadotropin secretion was not materially affected by the opiate antagonist or that antagonist-induced modifications in secretion were not relevant to the cycle parameters measured. In summary long-term administration of naltrexone to normal women through the follicular phase had no effect on (l) follicle growth and ovulation, (2) luteal phase progesterone production, or (3) endometrial development. REFERENCES 1. Ferin M, Van Vugt 0, Wardlaw S. The hypothalamic control of the menstrual cycle and the role of endogenous opioid peptides. Recent Prog Horm Res 1984;40:441-85. 2. Yen SSC, Quigley ME, Reid RL, Ropert JF, Cetel NS. Neuroendocrinology of opioid pep tides and their role in the control of gonadotropin and prolactin secretion. AM J OBSTET GYNECOL 1985; 152:485-93. 3. Ropert JF, Quigley ME, Yen SSC. Endogenous opiates modulate pulsatile luteinizing hormone release in humans. J Clin Endocrinol Metab 1981;52:583-5. 4. Quigley ME, Yen SSC. The role of endogenous opiates on LH secretion during the menstrual cycle. J Clin Endocrinol Metab 1980;51: 179-81. 5. Blankstein J, Reyes FI, Winter SO, Faiman C. Endorphins and the regulation of the human menstrual cycle. Clin Endocrinol 1981;14:287-94. 6. Rosamanith WG, Yen SSC. Sleep-associated decrease in luteinizing hormone pulse frequency during the early follicular phase of the menstrual cycle: evidence for an opioidergic mechanism. J Clin Endocrinol Metab 1987;65: 715-8. 7. Waldstreicher J, Santoro NF, Hall JE, Filicori M, Crowley WF. Hyperfunction of the hypothalamic-pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J Clin Endocrinol Metab 1988;66:165-72. 8. Cumming DC, Reid RL, Quigley ME, Rebar RW, Yen SSe. Evidence for decreased endogenous dopamine and opioid inhibitory influences on LH secretion in polycystic ovary syndrome. Clin Endocrinol 1984;20:643-8. 9. Wildt L, Leyendecker G. Induction of ovulation by the chronic administration of naltrexone in hypothalamic amenorrhea. J Clin Endocrinol Metab 1987;64:1334-5. 10. Veno J, Oehninger S, Brzyski RG, Acosta AA, Philput CB, Muasher SJ. Vltrasonographic appearance of the endometrium in natural and stimulated in vitro fertilization cycles and its correlation with outcome. Hum Reprod 1991;6: 901-4. 11. Noyes RT, Hertig AT, Rock J. Dating the endometrial biopsy. Ferti! Steril 1950; 1:3-25.
1784 Brzyski, Viniegra, and Archer
12. Rossmanith WG, Mortola JF, Yen SSC. Role of endogenous opioid pep tides in the initiation of the midcycle luteinizing hormone surge in normal cycling women. J Clin Endocrinol Metab 1988;67:695-700. 13. Kapen S, Boyar R, Hellman L, Weitzman ED. The relationship of luteinizing hormone secretion to sleep in women during the early follicular phase: effects of sleep reversal and a prolonged three hour sleep-wake schedule. J Clin Endocrinol MetabI976;42:1031-40. 14. Khoury SA, Reame NE, Kelch RP, Marshall JC. Diurnal patterns of pulsatile luteinizing hormone secretion in hypothalamic amenorrhea: reproducibility and responses to opiate blockade and an Ct2-adrenergic agonist. J Clin Endocrinol Metab 1987;64:755-62. 15. Physician's desk reference. 46th ed. Montvale, New Jersey: Medical Economics, 1992:937. 16. Gindoff PR, JeWele\liicz R, Hembree W. Wardlaw S, Ferin M. Sustained effects of opioid antagonism during the normal human· luteal phase. J Clin Endocrinol Metab 1988;66: 1000-4. 17. Remorgida V, Venturini PL, Anserini P, Salerno E, De Cecco L. Naltrexone in functional hypothalamic amenorrhea and in the normal luteal phase. Obstet Gynecol 1990;76: 1115-20.
December 1992 Am J Obstet Gynecol
18. Takemori AE, Portoghese PS. Comparative antagonism by naltrexone and naloxone of ]J., K, and 0' agonists. Eur J PharmacoI1984;104:101-4. 19. Cowan A. Use of the mouse jumping test for estimating antagonistic potencies of morphine antagonists. J Pharm Pharmacol 1976;28:177-82. 20. Martin WR, Jasinski DR, Mansky PA. Naltrexone, an antagonist for the treatment of heroin dependence. Arch Gen Psychiatry 1973;28:784-91. 21. Kleber HD, Kosten TR, Gaspari J, Topazian M. Nontolerance to the opioid antagonism of naltrexone. Bioi Psychiatry 1985;20:66-72. 22. Soules MR, Clifton DK, Bremner WJ, Steiner RA. Corpus luteum insufficiency induced by a rapid gonadotropinreleasing hormone-induced gonadotropin secretion pattern in the follicular phase. J Clin Endocrinol Metab 1987;65:457-64. 23. Teoh SK, Mendelson JH, Mello NK, Skupny A. Alcohol effects on naltrexone-induced stimulation of pituitary, adrenal, and gonadal hormones during the early follicular phase of the menstrual cycle. J Clin Endocrinol Metab 1988;66:1181-6.
