Department of Obstetrics and Gynaecology, Christchurch School of Medicine and Health Sciences and New Zealand Centre for Reproductive Medicine, Christchurch, New Zealand
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Christchurch Womens Hospital, Private Bag 4711, Christchurch, New Zealand. e-mail: john.evans{at}chmeds.ac.nz
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Abstract |
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Key words: atosiban/LH/ovulatory cycle/oxytocin
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Introduction |
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Materials and methods |
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In each cycle, follicular growth was monitored by serial vaginal scans and estradiol estimations between 12:00 and 13:00 from day 8 of the menstrual cycle. When a follicle was >15 mm diameter (measured in three dimensions), each subject was allocated at random to either a control or treatment group. In a control cycle, volunteers received a bolus of normal saline followed by 500 ml normal saline over a 2 h period. In a treatment cycle, volunteers received a bolus of 6.5 mg oxytocin antagonist (atosiban, Tractocile; Ferring AB, Malmo, Sweden), followed by an infusion at 300 µg/min in 500 ml normal saline over a 2 h period. The atosiban dose chosen has been shown to be safe and effective in studies in women with preterm labour (Goodwin et al., 1994; Moutquin et al., 2000
). All infusions took place between 14:00 and 16:00 at Christchurch Womens Hospital.
During all cycles, a blood sample was taken immediately before infusion (at the time of insertion of the i.v. access). Blood levels of LH were monitored at this time, after which the serum was removed and frozen for subsequent measurement of estradiol level. Blood LH measurements were carried out at 12 h intervals (20:00 and 08:00) in all women until a LH surge had been shown to occur. Transvaginal scans were undertaken to obtain evidence of ovulation.
The time from infusion to onset of the LH surge was quantified in two ways. First, a method based on a procedure widely used and validated in IVF clinics was employed. The standard logarithmic rate of LH increase (Hoff et al., 1983) was plotted and aligned through the first measured concentration of LH that was 50% above baseline. The intersect with the extended baseline was the time at which the surge was deemed to have started. Second, points along the rising phase of the surge were noted, and the rates of increase in LH concentrations calculated; the first point after a rate of increase in LH concentration over the previous 12 h of >1 IU/l per hour was deemed to be the first observed point of the LH surge. The actual rate of increase to this point over the 12 h period was noted, and called the initial observed rate of increase. The peak of the LH surge was confirmed by observation of descending concentrations of hormone. All hormone measurements were performed using immunoassays, with coefficients of variation <12%. The results of the control and treatment cycles were compared using a paired t-test or a one-way ANOVA as appropriate.
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Results |
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Discussion |
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Among the present women there was a reduction in maximum LH levels following antagonist infusion, and this was consistent with results from animal studies in which oxytocin receptor antagonists inhibited production of the LH surge (Johnston and Negro-Vilar, 1988; Robinson and Evans, 1990
). By contrast, the administration of oxytocin to rats at pro-estrus led to an advancement in the LH surge (Robinson and Evans, 1990
). Similarly, when oxytocin was delivered to women during the late follicular phase, the onset of the LH surge was advanced (Hull et al., 1995
). The present study provides evidence, for the first time, that the suppression of endogenous oxytocin activity in women can affect the ovulatory cycle. Thus, it is becoming increasingly apparent that oxytocin is a physiological component of the endocrinological system that regulates LH (Robinson and Evans, 1991
; Evans, 1999
; 2002).
Oxytocin is believed to have effects on LH release at both the hypothalamic (Johnston et al., 1990) and pituitary (Evans et al., 1995
) levels. However, the protocols used in such studies would require the peptide antagonist to cross the bloodbrain barrier in order to act hypothalamically. Although peptides may reach cells in circumventricular areas (Ermisch et al., 1985
), observations suggest that oxytocin and vasopressinand presumably also related peptidesare likely to cross the bloodbrain barrier only to a very limited extent (Ermisch et al., 1985
; Carter and Altemus, 1997
; Kang and Park, 2000
). Therefore, it seems most likely that the effect occurs directly at the pituitary.
A smaller effect of atosiban was seen on FSH, which might be less sensitive to oxytocin activity (Evans et al., 1989). The role of oxytocin in reproductive pathology is unclear, but it is possible that abnormalities in oxytocin regulation could be related to anovulation following follicular growth, as is occasionally seen in patients with polycystic ovary syndrome.
The place of oxytocin in LH regulation has been the subject of discussion for almost five decades (Shibusawa et al., 1955). Although most recent studies on this topic have been conducted in animal models, women demonstrate measurably higher levels of oxytocin in the peripheral blood at midcycle (Amico et al., 1981
; Mitchell et al., 1981
; Kumaresan et al., 1983
; Shukovski et al., 1989
). In the present investigation, an approach was used which had been shown previously to be successful in animal studies (Johnston and Negro-Vilar, 1988
; Robinson and Evans, 1990
), whereby endogenous oxytocin was inhibited by use of a receptor antagonist. Herein, for the first time, evidence is reported that endogenous oxytocin might be involved in LH regulation in women.
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Acknowledgements |
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References |
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Amico, J.A., Seif, S.M. and Robinson, A.G. (1981) Elevation of oxytocin and the oxytocin-associated neurophysin in the plasma of normal women during midcycle. J. Clin. Endocrinol. Metab., 53, 12291232.[Abstract]
Carter, C.S. and Altemus, M. (1997) Integrative functions of lactational hormones in social behavior and stress management. Ann. N. Y. Acad. Sci., 807, 164174.[Abstract]
Ermisch, A., Ruhle, H.J., Landgraf, R. and Hess, J.J. (1985) Blood-brain barrier and peptides. J. Cereb. Blood Flow Metab., 5, 350357.[ISI][Medline]
Evans, J.J. (1999) Modulation of gonadotropin levels by peptides acting at the anterior pituitary gland. Endocr. Rev., 20, 4667.
Evans, J.J. (2002) Peptides interact in gonadotrophin regulation. Arch. Physiol. Biochem., 110, 154161.[CrossRef][Medline]
Evans, J.J. and Catt, K.J. (1989) Gonadotrophin-releasing activity of neurohypophysial hormones: II. The pituitary oxytocin receptor mediating gonadotrophin release differs from that on corticotrophs. J. Endocrinol., 122, 107116.[Abstract]
Evans, J.J. and Tulloch, S. (1995) Effects of administration of oxytocin in association with gonadotrophin-releasing hormone on luteinizing hormone levels in rats in vivo. Peptides, 16, 145150.[CrossRef][ISI][Medline]
Evans, J.J., Robinson, G. and Catt, K.J. (1989) Gonadotrophin-releasing activity of neurohypophysial hormones: I. Potential for modulation of pituitary hormone secretion in rats. J. Endocrinol., 122, 99106.[Abstract]
Evans, J.J., Robinson, G. and Catt, K.J. (1992) The luteinizing hormone response to oxytocin is steroid-dependent. Neuroendocrinology, 55, 538543.[ISI][Medline]
Evans, J.J., Hurd, S.J. and Mason, D.R. (1995) Oxytocin modulates the luteinizing hormone response of the rat anterior pituitary to gonadotrophin-releasing hormone. J. Endocrinol., 145, 113119.[Abstract]
Goodwin, T.M., Paul, R., Silver, H., Spellacy, W., Parsons, M., Chez, R., Hayashi, R., Valenzuela, G., Creasy, G.W. and Merriman, R. (1994) The effect of the oxytocin antagonist atosiban on preterm uterine activity in the human. Am. J. Obstet. Gynecol., 170, 474478.[ISI][Medline]
Goodwin, T.M., Millar, L., North, L., Abrams, L.S., Weglein, R.C. and Holland, M.L. (1995) The pharmokinetics of the oxytocin antagonist atosiban in pregnant women with preterm uterine contractions. Am. J. Obstet. Gynecol., 173, 913917.[CrossRef][ISI][Medline]
Hoff, J.D., Quigley, M.E. and Yen, S.S. (1983) Hormonal dynamics at midcycle: a reevaluation. J. Clin. Endocrinol. Metab., 57, 792796.[Abstract]
Hull, M.L., Reid, R.A., Evans, J.J., Benny, P.S. and Aickin, D.R. (1995) Pre-ovulatory oxytocin administration promotes the onset of the luteinizing hormone surge in human females. Hum. Reprod., 10, 22662269.[Abstract]
Johnston, C.A. and Negro-Vilar, A. (1988) Role of oxytocin on prolactin secretion during proestrus and in different physiological or pharmacological paradigms. Endocrinology, 122, 341350.[Abstract]
Johnston, C.A., Lopez, F., Samson, W.K. and Negro-Vilar, A. (1990) Physiologically important role for central oxytocin in the preovulatory release of luteinizing hormone. Neurosci. Lett., 120, 256258.[CrossRef][ISI][Medline]
Johnston, C.A., Gelineau-Van Waes, J. and Templin, M.V. (1992) Physiological significance and interaction between oxytocin and central neuropeptide and monoamine neurotransmitters in the regulation of the preovulatory secretion of luteinizing hormone. Ann. N. Y. Acad. Sci., 652, 440442.[ISI][Medline]
Kang, Y.S. and Park, J.H. (2000) Brain uptake and the analgesic effect of oxytocin its usefulness as an analgesic agent. Arch. Pharm. Res., 23, 391395.[ISI][Medline]
Kerrigan, J.R., Yasin, M., Haisenleder, D.J., Dalkin, A.C. and Marshall, J.C. (1995) Regulation of gonadotropin subunit messenger ribonucleic acid expression in gonadotropin-releasing hormone (GnRH)-deficient female rats: effects of GnRH, galanin, GnRH-associated peptide, neuropeptide-Y and thyrotropin-releasing hormone. Biol. Reprod., 53, 17.[Abstract]
Kumaresan, P., Kumaresan, M., Hossini, M., Arellano, C. and Vasicka, A. (1983) Human ovulation and plasma oxytocin. Int. J. Gynaecol. Obstet., 21, 413418.[ISI][Medline]
Lundin, S., Broeders, A. and Melin, P. (1993) Pharmacokinetic properties of the tocolytic agent [Mpa1, D-Tyr(Et)2, Thr4, Orn8]-oxytocin (antocin) in healthy volunteers. Clin. Endocrinol., 39, 369374.[ISI][Medline]
Manning, M., Stoev, S., Cheng, L.L., Wo, N.C. and Chan, W.Y. (2001) Design of oxytocin antagonists, which are more selective than atosiban. J. Pept. Sci., 7, 449465.[CrossRef][ISI][Medline]
Mitchell, M.D., Haynes, P.J., Anderson, A.B.M. and Turnbull, A.C. (1981) Plasma oxytocin concentrations during the menstrual cycle. Eur. J. Obstet. Gynecol. Reprod. Biol., 12, 195200.[ISI][Medline]
Moutquin, J.M., Sherman, D., Cohen, H., Mohide, P.T., Hochner-Celnikier, D., Fejgin, M., Liston, R.M., Dansereau, J., Mazor, M., Shalev, E. et al. (2000) Double-blind, randomized, controlled trial of atosiban and ritodrine in the treatment of preterm labor: a multicenter effectiveness and safety study. Am. J. Obstet. Gynecol., 182, 11911199.[CrossRef][ISI][Medline]
OByrne, K.T., Lunn, S.F. and Coen, C.W. (1990) Central oxytocin stimulates luteinizing hormone release in the marmoset, a primate which fails to show lactationally-induced infertility. J. Neuroendocrinol., 2, 419421.[ISI]
Phaneuf, S., Asboth, G., MacKenzie, I.Z., Melin, P. and Lopez Bernal, A. (1994) Effect of oxytocin antagonists on the activation of human myometrium in vitro: atosiban prevents oxytocin-induced desensitization. Am. J. Obstet. Gynecol., 171, 16271634.[ISI][Medline]
Robinson, G. and Evans, J.J. (1990) Oxytocin has a role in gonadotrophin regulation in rats. J. Endocrinol., 125, 425432.[Abstract]
Robinson, G. and Evans, J.J. (1991) Oxytocin influences preovulatory follicular development and advances ovulation in rats. Acta Endocrinol., 125, 109112.[ISI][Medline]
Robinson, G., Evans, J.J. and Catt, K.J. (1992) Oxytocin stimulates LH production by the anterior pituitary gland of the rat. J. Endocrinol., 132, 277283.[Abstract]
Shibusawa, K., Saito, S., Fukuda, M., Kawai, T., Yamada, H. and Tomiza, K. (1955) Neurosecretion of oxytocin stimulates the release of the pituitary gonadotrophin. Endocrinol. Jpn., 2, 180187.
Shukovski, L., Healy, D.L. and Findlay, J.K. (1989) Circulating immunoreactive oxytocin during the human menstrual cycle comes from the pituitary and is estradiol dependent. J. Clin. Endocrinol. Metab., 68, 455460.[Abstract]
Thornton, S., Gillespie, J.I., Anson, L.C., Greenwell, J.R., Melin, P. and Dunlop, W. (1993) The effect of the oxytocin antagonists, CAP 476 and F327, on calcium mobilisation in single cultured human myometrial cells. Br. J. Obstet. Gynaecol., 100, 581586.[ISI][Medline]
Submitted on July 12, 2002; resubmitted on March 4, 2003; accepted on April 2, 2003.