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Fertilisation and implantation failure in an oral contraceptive user
European Journal of Obstetrics & Gynecology and Reproductive Biology 104 (2002) 73–75
Case report
Fertilisation and implantation failure in an oral contraceptive user I. Noci*, M. Marchionni, M. Fambrini, R. Cioni, G. Scarselli Department of Gynaecology, Perinatology and Human Reproduction University of Florence, V. le Morgagni 85, 50134 Firenze, Florence, Italy Received 11 April 2001; received in revised form 3 January 2002; accepted 22 January 2002
Abstract We report the case of a young woman taking a low-dose oral contraceptive (gestodene 0.075 mg and ethinylestradiol 0.02 mg) in whom we documented by both hormonal assays and sonographic evaluations the occurrence of ovulation, oocyte fertilization and embryo implantation. However, the implantation process did not complete and only a biochemical pregnancy was registered. On the basis of known actions of estroprogestin on endometrium that are not conducive to implantation, it is possible that the pregnancy loss was originated by oral contraceptive’s hormonal influence at endometrial level. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Contraception; Implantation failure; Pill; Post-conceptional effect
1. Introduction The basic mechanism by which estroprogestins exert their contraceptive effect relies on ovulation suppression that takes place as early as the first cycle of pill taking; this action is due to the suppression of the positive feedback of estradiol and, as a consequence, to the lack of LH surge that would lead, under physiological conditions, to ovulation. Besides ovulation suppression, which is generally held as the main contraceptive mechanism, other actions exerted by estroprogestins at different levels of the female reproductive tract are thought to minimize the risk of pregnancy even in case of ovulatory escape. At the level of the cervix, progestins cause an increase in the viscosity and cellularity of the mucus, thus obstructing the penetration of spermatozoa [1]. At the level of fallopian tubes, estroprogestins reduce blood flow as well as mucus secretion, and bring about modifications of ciliar motility and of the oviduct as a whole [2]. Estroprogestins can also influence the endometrium by producing a reduction in the proliferative activity; in particular, they would induce a precocious secretory activity and a pseudodecidualization of the stroma, thus making the endometrium unsuitable for implantation even in those cases when fertilization occurs [3]. However, the antinidation
* Corresponding author. Tel.: þ39-55-4277550; fax: þ39-55-434330. E-mail address: [email protected] (I. Noci).
activity of oral contraceptives is generally unknown and, so far, has been only supposed [4]. Unintended pregnancies have been reported in women using oral contraceptives, in consequence of both misuse and method failure [5]. However, clinical data available derive from women carrying a pregnancy to term as well as subjects terminating their pregnancies by abortion. In the present paper we report a case of unintended pregnancy, observed at a very early stage and spontaneously aborted, in which the clinically available data suggest that an action of the pill at the endometrial level could be responsible for the implantation failure.
2. Case report The patient C.P., aged 27, para 0, came very anxious to the outpatient service of our department for counselling, because of the lack of withdrawal bleeding following a 3-week-cycle of pill taking; serum human chorionic gonadotropin free b subunit (bhCG) determinations advised by her private gynaecologist had showed seemingly conflicting results. At the time of our visit, medical and gynaecologic histories were recorded. The patient had a congenital intolerance to yeast and allergy to some antibiotics. Her menstrual periods had previously been regular; she had been taking oral contraceptives containing gestodene 0.075 mg and
0301-2115/02/$ – see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 0 1 - 2 1 1 5 ( 0 2 ) 0 0 0 5 4 - 4
74
I. Noci et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 104 (2002) 73–75
Fig. 1. Transvaginal sonographic evaluation of the endometrium showing an intense decidual reaction.
ethinylestradiol 0.02 mg for the last two years before observation. On days 7 and 14 of the last cycle of oral contraceptives, the patient had two episodes of vomiting and diarrhoea following the intake of food containing yeast (frozen pizza); both these episodes were referred to occur 5–6 h after the intake of the pill. Before completing the cycle of oral contraceptives, the patient had a mild bleeding, whereas no withdrawal bleeding was observed at the time expected after three weeks of pill taking. No medications had been taken by the patient during this period. Eighteen days after the last pill, a determination of serum levels of bhCG showed a value of 134 IU/l. A week later, serum bhCG was not detectable (value <1 IU/l). Two days after, the patient came to our department. At the gynaecological examination, no pathological features were found. The patient underwent a transvaginal ultrasound scan that documented the presence of a haemorrhagic corpus luteum in the left ovary (31 mm 33 mm) and of a marked decidual reaction of the endometrium (thickness ¼ 12 mm) (Fig. 1), thereby confirming that ovulation had actually occurred and corroborating the results of the first bhCG determination. We proposed to monitor serum bhCG levels in the next days. Undetectable values of bhCG were found in subsequent determinations, until the patient experienced a heavy vaginal bleeding on day 37 after the last pill. One month later, a transvaginal ultrasound scan revealed the presence of a recently formed corpus luteum in the right ovary and a periovulatory endometrial pattern, thus documenting the resumption of ovarian cycle; the left ovary, where a corpus luteum was present in the previous cycle, showed a homogeneous sonographic pattern.
3. Discussion In our case report, there are two main aspects deserving a careful comment. First, the issue of ovulation. Undoubtedly, the presence of a sonographically documented corpus luteum in the left ovary and the positive bhCG values demonstrate the occurrence of ovulation and therefore the failure of what is considered the main contraceptive mechanism of estroprogestins. This was probably due to the episodes of vomiting occurred, in agreement with literature data on pregnancies in oral contraceptives’ users. Indeed, it has been reported that 22.8–46% of the patients on pill who became pregnant had had a vomiting/diarrhoea episode in the last month of pill taking, with consequent missed absorption of hormones, temporary fall in their circulating levels and loss of efficacy [6]. However, no data is available from literature as to the time period between pill assumption and the vomiting/ diarrhoea episodes. The manufacturers’ recommendations usually report that vomiting and/or diarrhoea occurring within 3–4 h from pill intake can result in a compromised contraceptive action. Therefore, one might infer that in cases when this time interval is longer, the hormonal substances are absorbed properly. In our patient, the time interval was 5–6 h, hence, if contraceptive failure is attributable to inadequate intestinal absorption, it would be required to revise the pharmacokinetic characteristics of low-dose preparations like that used by the patient. There is a second issue to consider, that is pregnancy and its clinical progression. The values of bhCG at first determination together with the sonographic appearance of a marked decidual reaction of the endometrium (Fig. 1) are indicative of oocyte fertilization and subsequent embryo
I. Noci et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 104 (2002) 73–75
implantation. In fact, bhCG is produced by the trophoblast in such a large quantity to enable bhCG serum determinations by specific and sensible assays only after the embedding of the blastocyst into the decidua [7]. Moreover, the endometrial thickness in oral contraceptive’s users is usually very reduced, [3] and for this reason a 12 mm endometrial thickness is most likely due to the presence of a pregnancy induced decidual reaction. Therefore, we had full evidence of the failure of accessory contraceptive mechanisms acting at tubal and cervical level, prior to fertilization. However, in this patient only a biochemical pregnancy occurred; in other words, the implantation process did not complete. Both stopped or delayed ovulation and prevention of implantation can explain the effect of emergency contraception with the Yuzpe regimen, depending on the phase of menstrual cycle [8]. It would therefore be tempting to suggest that in our case report the pregnancy loss was influenced by an adverse effect of estroprogestins on endometrial receptivity, similar to that postulated for the antinidation activity. It has been reported that about 62% of conceptuses are lost before 12 weeks, 92% of which in a subclinical way, [9] and it is likely that a significant proportion of very early losses are due to the intrinsic biological complexity of the implantation process in the humans [10]. Therefore, it is possible that the very early pregnancy loss observed in our patient is related to this latter paraphysiological phenomenon; however, on the basis of suggested actions of estroprogestins on endometrium that are not conducive to implantation, [3] it is
75
also possible that the pregnancy loss was originated by oral contraceptive’s hormonal influence at endometrial level and, in this respect, our case report would support the hypothesis of a post-conceptional ‘‘contraceptive’’ mode of action for the pill, an issue that can also provide matter of thought from the ethical point of view to last generation low-dose oral contraceptive users.
References [1] Franklin RD, Kutteh WH. Characterisation of immunoglobulins and cytokines in human cervical mucus: influence of exogenous and endogenous hormones. J Reprod Immunol 1999;42(2):93–106. [2] Buhi WC, Alvarez IM, Kouba AJ. Secreted proteins of the oviduct. Cells Tissues Organs 2000;166(2):165–79. [3] Coll Capdevila C. Dysfunctional uterine bleeding and dysmenorrhea. Eur J Contracept Reprod Health Care 1997;2(4):229–37. [4] Bayle B. Antinidation activity of oral contraceptives. Contracept Fertil Sex 1994;22(6):391–5. [5] Skjldestad FE. Oral contraceptive failures among women terminating their pregnancy. Acta Obstet Gynecol Scand 2000;79(7):580–5. [6] Hansen TH, Lundvall F. Factors influencing the reliability of oral contraceptives. Acta Obstet Gynecol Scand 1997;76(1):61–4. [7] Hay DL, Lopata A. Chorionic gonadotropin secretion by human embryos in vitro. J Clin Endocrinol Metab 1988;67(6):1322–4. [8] Wellbery C. Emergency contraception. Arch Fam Med 2000;9: 642–6. [9] Edmons DK, Linday KS, Miller JF, Williamson E, Wood PJ. Early embryonic mortality in women. Fertil Steril 1982;38(4):447–53. [10] Lessey BA. The role of endometrium during embryo implantation. Hum Reprod 2000;15:39–50.
Case report
Fertilisation and implantation failure in an oral contraceptive user I. Noci*, M. Marchionni, M. Fambrini, R. Cioni, G. Scarselli Department of Gynaecology, Perinatology and Human Reproduction University of Florence, V. le Morgagni 85, 50134 Firenze, Florence, Italy Received 11 April 2001; received in revised form 3 January 2002; accepted 22 January 2002
Abstract We report the case of a young woman taking a low-dose oral contraceptive (gestodene 0.075 mg and ethinylestradiol 0.02 mg) in whom we documented by both hormonal assays and sonographic evaluations the occurrence of ovulation, oocyte fertilization and embryo implantation. However, the implantation process did not complete and only a biochemical pregnancy was registered. On the basis of known actions of estroprogestin on endometrium that are not conducive to implantation, it is possible that the pregnancy loss was originated by oral contraceptive’s hormonal influence at endometrial level. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Contraception; Implantation failure; Pill; Post-conceptional effect
1. Introduction The basic mechanism by which estroprogestins exert their contraceptive effect relies on ovulation suppression that takes place as early as the first cycle of pill taking; this action is due to the suppression of the positive feedback of estradiol and, as a consequence, to the lack of LH surge that would lead, under physiological conditions, to ovulation. Besides ovulation suppression, which is generally held as the main contraceptive mechanism, other actions exerted by estroprogestins at different levels of the female reproductive tract are thought to minimize the risk of pregnancy even in case of ovulatory escape. At the level of the cervix, progestins cause an increase in the viscosity and cellularity of the mucus, thus obstructing the penetration of spermatozoa [1]. At the level of fallopian tubes, estroprogestins reduce blood flow as well as mucus secretion, and bring about modifications of ciliar motility and of the oviduct as a whole [2]. Estroprogestins can also influence the endometrium by producing a reduction in the proliferative activity; in particular, they would induce a precocious secretory activity and a pseudodecidualization of the stroma, thus making the endometrium unsuitable for implantation even in those cases when fertilization occurs [3]. However, the antinidation
* Corresponding author. Tel.: þ39-55-4277550; fax: þ39-55-434330. E-mail address: [email protected] (I. Noci).
activity of oral contraceptives is generally unknown and, so far, has been only supposed [4]. Unintended pregnancies have been reported in women using oral contraceptives, in consequence of both misuse and method failure [5]. However, clinical data available derive from women carrying a pregnancy to term as well as subjects terminating their pregnancies by abortion. In the present paper we report a case of unintended pregnancy, observed at a very early stage and spontaneously aborted, in which the clinically available data suggest that an action of the pill at the endometrial level could be responsible for the implantation failure.
2. Case report The patient C.P., aged 27, para 0, came very anxious to the outpatient service of our department for counselling, because of the lack of withdrawal bleeding following a 3-week-cycle of pill taking; serum human chorionic gonadotropin free b subunit (bhCG) determinations advised by her private gynaecologist had showed seemingly conflicting results. At the time of our visit, medical and gynaecologic histories were recorded. The patient had a congenital intolerance to yeast and allergy to some antibiotics. Her menstrual periods had previously been regular; she had been taking oral contraceptives containing gestodene 0.075 mg and
0301-2115/02/$ – see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 0 1 - 2 1 1 5 ( 0 2 ) 0 0 0 5 4 - 4
74
I. Noci et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 104 (2002) 73–75
Fig. 1. Transvaginal sonographic evaluation of the endometrium showing an intense decidual reaction.
ethinylestradiol 0.02 mg for the last two years before observation. On days 7 and 14 of the last cycle of oral contraceptives, the patient had two episodes of vomiting and diarrhoea following the intake of food containing yeast (frozen pizza); both these episodes were referred to occur 5–6 h after the intake of the pill. Before completing the cycle of oral contraceptives, the patient had a mild bleeding, whereas no withdrawal bleeding was observed at the time expected after three weeks of pill taking. No medications had been taken by the patient during this period. Eighteen days after the last pill, a determination of serum levels of bhCG showed a value of 134 IU/l. A week later, serum bhCG was not detectable (value <1 IU/l). Two days after, the patient came to our department. At the gynaecological examination, no pathological features were found. The patient underwent a transvaginal ultrasound scan that documented the presence of a haemorrhagic corpus luteum in the left ovary (31 mm 33 mm) and of a marked decidual reaction of the endometrium (thickness ¼ 12 mm) (Fig. 1), thereby confirming that ovulation had actually occurred and corroborating the results of the first bhCG determination. We proposed to monitor serum bhCG levels in the next days. Undetectable values of bhCG were found in subsequent determinations, until the patient experienced a heavy vaginal bleeding on day 37 after the last pill. One month later, a transvaginal ultrasound scan revealed the presence of a recently formed corpus luteum in the right ovary and a periovulatory endometrial pattern, thus documenting the resumption of ovarian cycle; the left ovary, where a corpus luteum was present in the previous cycle, showed a homogeneous sonographic pattern.
3. Discussion In our case report, there are two main aspects deserving a careful comment. First, the issue of ovulation. Undoubtedly, the presence of a sonographically documented corpus luteum in the left ovary and the positive bhCG values demonstrate the occurrence of ovulation and therefore the failure of what is considered the main contraceptive mechanism of estroprogestins. This was probably due to the episodes of vomiting occurred, in agreement with literature data on pregnancies in oral contraceptives’ users. Indeed, it has been reported that 22.8–46% of the patients on pill who became pregnant had had a vomiting/diarrhoea episode in the last month of pill taking, with consequent missed absorption of hormones, temporary fall in their circulating levels and loss of efficacy [6]. However, no data is available from literature as to the time period between pill assumption and the vomiting/ diarrhoea episodes. The manufacturers’ recommendations usually report that vomiting and/or diarrhoea occurring within 3–4 h from pill intake can result in a compromised contraceptive action. Therefore, one might infer that in cases when this time interval is longer, the hormonal substances are absorbed properly. In our patient, the time interval was 5–6 h, hence, if contraceptive failure is attributable to inadequate intestinal absorption, it would be required to revise the pharmacokinetic characteristics of low-dose preparations like that used by the patient. There is a second issue to consider, that is pregnancy and its clinical progression. The values of bhCG at first determination together with the sonographic appearance of a marked decidual reaction of the endometrium (Fig. 1) are indicative of oocyte fertilization and subsequent embryo
I. Noci et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 104 (2002) 73–75
implantation. In fact, bhCG is produced by the trophoblast in such a large quantity to enable bhCG serum determinations by specific and sensible assays only after the embedding of the blastocyst into the decidua [7]. Moreover, the endometrial thickness in oral contraceptive’s users is usually very reduced, [3] and for this reason a 12 mm endometrial thickness is most likely due to the presence of a pregnancy induced decidual reaction. Therefore, we had full evidence of the failure of accessory contraceptive mechanisms acting at tubal and cervical level, prior to fertilization. However, in this patient only a biochemical pregnancy occurred; in other words, the implantation process did not complete. Both stopped or delayed ovulation and prevention of implantation can explain the effect of emergency contraception with the Yuzpe regimen, depending on the phase of menstrual cycle [8]. It would therefore be tempting to suggest that in our case report the pregnancy loss was influenced by an adverse effect of estroprogestins on endometrial receptivity, similar to that postulated for the antinidation activity. It has been reported that about 62% of conceptuses are lost before 12 weeks, 92% of which in a subclinical way, [9] and it is likely that a significant proportion of very early losses are due to the intrinsic biological complexity of the implantation process in the humans [10]. Therefore, it is possible that the very early pregnancy loss observed in our patient is related to this latter paraphysiological phenomenon; however, on the basis of suggested actions of estroprogestins on endometrium that are not conducive to implantation, [3] it is
75
also possible that the pregnancy loss was originated by oral contraceptive’s hormonal influence at endometrial level and, in this respect, our case report would support the hypothesis of a post-conceptional ‘‘contraceptive’’ mode of action for the pill, an issue that can also provide matter of thought from the ethical point of view to last generation low-dose oral contraceptive users.
References [1] Franklin RD, Kutteh WH. Characterisation of immunoglobulins and cytokines in human cervical mucus: influence of exogenous and endogenous hormones. J Reprod Immunol 1999;42(2):93–106. [2] Buhi WC, Alvarez IM, Kouba AJ. Secreted proteins of the oviduct. Cells Tissues Organs 2000;166(2):165–79. [3] Coll Capdevila C. Dysfunctional uterine bleeding and dysmenorrhea. Eur J Contracept Reprod Health Care 1997;2(4):229–37. [4] Bayle B. Antinidation activity of oral contraceptives. Contracept Fertil Sex 1994;22(6):391–5. [5] Skjldestad FE. Oral contraceptive failures among women terminating their pregnancy. Acta Obstet Gynecol Scand 2000;79(7):580–5. [6] Hansen TH, Lundvall F. Factors influencing the reliability of oral contraceptives. Acta Obstet Gynecol Scand 1997;76(1):61–4. [7] Hay DL, Lopata A. Chorionic gonadotropin secretion by human embryos in vitro. J Clin Endocrinol Metab 1988;67(6):1322–4. [8] Wellbery C. Emergency contraception. Arch Fam Med 2000;9: 642–6. [9] Edmons DK, Linday KS, Miller JF, Williamson E, Wood PJ. Early embryonic mortality in women. Fertil Steril 1982;38(4):447–53. [10] Lessey BA. The role of endometrium during embryo implantation. Hum Reprod 2000;15:39–50.