European Journal of Obstetrics & Gynecology and Reproductive Biology 175 (2014) 191–193

Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb

Ultra-short term clomiphene citrate in high responder women with polycystic ovary syndrome: a case series Sefa Kelekci a,b,*, Serenat Eris b,1, Emine Demirel b,2 a b

Eagen Maternity and Gynaecology Education and Research Hospital, Izmir, Turkey Izmir Katip Celebi University, School of Medicine, Department of Obstetrics and Gynaecology, Izmir, Turkey

A R T I C L E I N F O

A B S T R A C T

Article history: Received 21 August 2013 Received in revised form 10 December 2013 Accepted 11 December 2013

Objective: To evaluate a new trial of short-term clomiphene citrate (CC) in high responder women with polycystic ovary syndrome (PCOS). Study design: This case series was conducted in the infertility outpatient clinics of two centres. Ovulation induction was performed with CC 50–100 mg a day in six high-responder women with PCOS who had a history of cancellation of treatment because of 3 mature follicles between March 2010 and June 2013. Induction was initiated on the third day of their cycles and the duration of induction was only two days. Demographic data of the patients, number of mature follicles on hCG day, ovulation rate, luteal phase length, pregnancy rate, and type of pregnancy were recorded. All data were analysed by SPSS packet programme (SPSS, 17.0, SPSS Inc., Chicago, IL, USA). Result(s): The median number of mature follicles and duration of the follicular phase were 1.3 (1–2) and 11.9 (11–14) days, respectively. The ovulation rate was 80% (12/15) and pregnancy rate per cycle was 26.6%. Conclusion(s): If this hypothesis is supported by large prospective randomised controlled studies, ultrashort term ovulation induction with CC may provide an alternative approach for high-responder women with PCOS who have a history of treatment cycle cancellations. ß 2014 Published by Elsevier Ireland Ltd.

Keywords: Clomiphene citrate Ovulation induction Ovulation rate PCOS Pregnancy rate

1. Introduction Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of fertile age, affecting 5–10% of the female population. The syndrome is characterised by chronic anovulation, hyperandrogenism, polycystic ovaries and decreased fertility [1]. Various interventions have been proposed ranging from lifestyle modifications, administration of pharmaceutical agents (such as clomiphene citrate (CC), insulin sensitising agents, gonadotrophins and gonadotrophin-releasing hormone (GnRH) analogues), the use of laparoscopic ovarian drilling and the application of assisted reproduction techniques (ART).

* Corresponding author at: I˙zmir Katip C¸elebi University School of Medicine, Department of Gynaecology and Obstetrics, Basin Sitesi, Yesilyurt, 35360 Izmir, Turkey. Tel.: +90 2322444444; fax: +90 2322431530; mobile: +90 5322085175. E-mail addresses: [email protected], [email protected] (S. Kelekci), [email protected] (S. Eris), [email protected] (E. Demirel). 1 Tel.: +90 2322444444/2322442433; fax: +90 2322431530; mobile: +90 5343252157. 2 Tel.: +90 2322444444/2322442433; fax: +90 2322431530; mobile: +90 5055846596. 0301-2115/$ – see front matter ß 2014 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.ejogrb.2013.12.023

CC remains the treatment of first choice for induction of ovulation in anovulatory women with PCOS. CC has some advantages. The cost of the medication is low, the oral route of administration is patient-friendly, there are relatively few adverse effects, and abundant clinical data are available regarding the safety of the drug. The multiple pregnancy rate is 10%, while hyperstimulation syndrome is rare [2]. Patients should be informed, however, that there is an increased risk of multiple pregnancy with ovulation induction using clomiphene citrate [3]. Furthermore, a few women with PCOS have a high response to CC even at the lowest dosage: it was concluded that a significant number of women (14%) developed three or more follicles, despite receiving low doses of clomiphene citrate [4]. Ovulation induction is a challenge for both physicians and patients in this high-responder group of PCOS. In order to prevent cycle cancellation and to save cost and time, we performed a new trial of ovulation induction with CC in women with PCOS who were previously known high-responders to traditional usage of CC. 2. Materials and methods This case series was conducted in infertility outpatient clinics of two centres affiliated to Katip C¸elebi University, between March

S. Kelekci et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 175 (2014) 191–193

192 Table 1 Historical data of six patients. Patients

Age (yr)

BMI (kg/m2)

CC dose (mg/d)

Follicle size (mm)

Follicle number

Cycle numbers

Results

1 2 3 4 5 6

22 25 26 20 30 23

21.4 23.1 23.8 19.7 20.1 21.3

50 50 100 50 50 100

16,18,19 18,19,19,20 16,17,19,20 17,18,20 16,17,17,18,21 17,18,18

3 4 4 3 5 3

1 1 2 1 1 2

Cancellation Cancellation Cancellation Cancellation Cancellation Cancellation

2010 and June 2013. All participants gave informed consent before inclusion in the study. Cases were composed of anovulatory PCOS women with a history of high response to CC. All women had had more than three follicles in prior ovulation induction cycles with the use of CC, and cycle cancellations as a result. PCOS was defined as the presence of hyperandrogenism (clinical and/or biochemical), ovarian dysfunction (oligo-anovulation and/or polycystic ovaries), and the exclusion of related disorders [5]. In our cases, PCOS was diagnosed according to the Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome [5]. The study protocol was approved by the Scientific Research Committee, and informed consent was obtained from all participants. The starting dose of CC was generally determined to be 50 or 100 mg/day according to previous ovulation induction cycles with CC. The duration of induction was only two days, starting on Day 3–4 after a spontaneous or progestin-induced withdrawal bleed. The addition of an ovulatory dose of hCG, 5000 IU, was performed when an ultrasonically demonstrated leading follicle attained a diameter of 18–21 mm, for the timing of intercourse. All patients also underwent venepuncture 7 or 8 days after ovulation for measurement of midluteal serum progesterone (MLP) levels. Luteal phase length (LPL) was measured with respect to day of ovulation and the next uterine bleeding if pregnancy had not occurred. If no menses occurred by the 16th day after ovulation, a pregnancy test measuring b-hCG levels by RIA (Diagnostic Products, Los Angeles, CA) was performed. If serum b-hCG levels were higher than 20 mIU/mL, the presence of a clinical pregnancy was confirmed later by transvaginal ultrasonography. Clinical pregnancy was defined as pregnancy detected with b-hCG by RIA and a positive fetal heartbeat at 7 weeks on ultrasound. Demographic data of the patients, number of mature follicles on hCG day, ovulation rate, luteal phase length, pregnancy rate, and type of pregnancy were recorded. All data were analysed by SPSS packet programme (SPSS, 17.0, SPSS Inc., Chicago, IL, USA).

3. Results A total of six women met the criteria for treatment as high responders. The historical data of these patients are summarised in Table 1. All women had more than three follicles in prior CC ovulation induction cycles with subsequent cancellations. Demographic data and fertility outcome of all six cases after the new trial are summarised in Table 2. The mean age was 24.3 yr (range, 22–30 yr). Mean body mass index (BMI) was 21.27 kg/m2. The median number of preovulatory follicles on day hCG was 1.3. Monofollicular development was observed in eight cycles out of twelve ovulatory cycles (66.6%). Mean follicular phase length was 11.9 days (range 11–14 days). Mean luteal phase length was also 13.3 days (range 12–14 days). Mean endometrial thickness on hCG day was 10.5 (range 8.5–12.2). The ovulation rate per cycle was 80%. The overall pregnancy rate per cycle was 26.6%. In other words, four of the six women (66.6%) became pregnant and all the pregnancies were singletons. The clinical pregnancy rate per cycle was also 26.6%. Perinatal outcomes were as follows: three out of four pregnancies resulted in live and healthy births. In one of our cases, induction of labour was performed at the 22nd week due to severe preeclampsia. 4. Comments In a large study of individualised CC treatment, ovulation was restored in approximately 80% of the patients, with a pregnancy rate of 35–40%, of which 75% of the pregnancies were achieved within the first three treatment cycles [6]. Due to the gap between ovulation and pregnancy rates, however, CC as a first choice in the treatment of PCOS has been questioned [7,8]. Another study reported a 13.19% (88/667 cycles) pregnancy rate with different doses of CC, with 84.09% (74/88) of the pregnancies being achieved

Table 2 Demographic data and fertility outcomes of fifteen cycles of six cases. Follicular phase (day)

Ovulation

Midluteal progesterone (ng/mL)

Pregnancy

Luteal phase (day)

8.5 9.3

12 11

Positive Positive

11.7 14.6

Negative Positive

14 –

2

10.4

12

Positive

13.6

Positive

0 1 2

7.9 11.4 10.8

– 12 14

Negative Positive Positive

1.4 15.0 13.6

Negative Negative Negative

– 12 14

50 100 100 100

0 1 2 2

8.3 12.2 10.5 9.6

– 11 11 12

Negative Positive Positive Positive

0.95 12.9 14.2 16.3

Negative Negative Negative Negative

– 14 12 14

1 2 3

50 100 100

0 1 1

8.4 10.9 12.1

– 12 12

Negative Positive Positive

2.1 24.8 28.3

Negative Negative Positive

– 13 –

1 2

100 100

1 1

10.7 9.7

13 11

Positive Positive

18.6 20.1

Positive Negative

– 14

Patient (number)

Cycle (number)

CC dose (mg/d)

1

1 2

50 50

1 1

2

1

100

3

1 2 3

50 100 100

4

1 2 3 4

5

6

Mature follicle (n)

Endometrial thickness (mm)

–

S. Kelekci et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 175 (2014) 191–193

within the first three treatment cycles: 10.9% (73/667) of the cases had CC resistance [9]. In our study, 80% of cycles were ovulatory, 66% of these displaying monofollicular development, and the pregnancy rate per cycle was 26.6%. This result is comparable with other studies mentioned above. Although the results of large trials suggest that monitoring by ultrasound is not mandatory to ensure a good outcome [10], the practice in many centres is to monitor the first cycle to allow adjustment of the dose in subsequent cycles based on the observed response. The RCOG and NICE guidelines recommend ultrasound monitoring during treatment with CC for ovulation induction. NICE recommend that ultrasound monitoring during at least the first cycle of treatment be offered to ensure that the woman is taking a dose that minimises the risk of multiple pregnancy [11]. Furthermore, monitoring of responses to ovulation induction is more and more important especially in high-responder women with PCOS. The majority of triplet and higher order multiple pregnancies now result from ovulation induction/superovulation rather than in vitro fertilisation. However, CC is still widely prescribed by gynaecologists and general practitioners who do not have access to ultrasound monitoring. It was concluded that a significant number of women (14%) developed three or more follicles, despite receiving low doses of CC [4]. CC remains the first line treatment for anovulatory PCOS, and the most important strategy for this approach should be monofollicular ovulation induction to prevent complications such as multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) [12]. In most previous studies, cycle cancellation has been advised when more than three follicles of 16 mm or larger were observed [13–15] in order to prevent OHSS and multiple pregnancies. In some studies, the limit was four or more follicles 14 mm [16,17]. In our country this limitation was regulated as three or more follicles in 2010. Cycle cancellation due to multiple follicular development remains a difficult situation for both physicians and patients. The introduction of even small amounts of follicle stimulating hormone (FSH) into the circulation, either directly with FSH injections or indirectly with pulsatile GnRH or CC, is capable of inducing ovulation and pregnancy in a large number of anovulatory women with PCOS. CC has been proven effective in ovulation induction for women with PCOS and should be considered the firstline therapy [12,18]. The most crucial event for development of a follicle is the activation of the aromatase system by FSH. Each month, the initial rise in FSH determines follicle selection. The FSH threshold concept is crucial to controlled ovarian stimulation, and states that all follicles potentially capable of undergoing preovulatory development have individual threshold requirements in individual FSH windows for stimulation by FSH [19]. Only a modest rise in FSH level is required to initiate recruitment of these follicles. It may be speculated that, in accordance with the FSH windows and threshold hypothesis, ‘the lowest rise in FSH for a short duration may result in monofollicular development’. Consequently, monofollicular development may ensue in highly controlled ovarian stimulation. In addition to the desirable central actions responsible for its efficacy as an ovulation-inducing agent, CC exerts undesirable and unavoidable adverse antiestrogenic effects in the periphery (endocervix, endometrium, ovary, ovum, and embryo) that explain the incoherence between the ovulation and conception rates observed in CC-treated patients. Numerous studies in women have described adverse effects on the quality or quantity of cervical mucus, endometrial growth and maturation, follicular or corpus luteum steroidogenesis, fertilisation, and embryo development. Conventional wisdom holds that these effects have distinct clinical consequences that are most apparent at higher doses or after longer durations of treatment, and that treatment with exogenous

193

supplemental oestrogen may help to minimise or negate them [20,21]. There is, however, little or no compelling evidence to support these notions. The success of overall pregnancy rates in our study may be provided by elimination of these adverse antioestrogenic effects by the application of short-term and low doses of CC. In conclusion, ovulation induction is a challenge for both physicians and patients in PCOS groups that are highly responsive to CC. If this hypothesis is supported by large prospective randomised controlled studies, ultra-short term ovulation induction with CC may provide an alternative approach for highresponder women with PCOS who have a history of treatment cycle cancellations. Conflicts of interest We have no financial or commercial conflicts of interest. References [1] The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod 2008;23:462–77. [2] Eijkemans MJ, Imani B, Mulders AG, Habbema JD, Fauser BC. High singleton live birth rate following classical ovulation induction in normogonadotrophic anovulatory infertility (WHO 2). Hum Reprod 2003;18:2357–62. [3] Vause TD, Cheung AP, Sierra S, et al. Ovulation induction in polycystic ovary syndrome. J Obstet Gynecol Can 2010;32:495–502. [4] Coughlan C, Fitzgerald J, Milne P, Wingfield M. Is it safe to prescribe clomiphene citrate without ultrasound monitoring facilities? J Obstet Gynecol 2010; 30:393–6. [5] Azziz R, Carmina E, Dewailly D, et al. Task force on the phenotype of the polycystic ovary syndrome of the androgen excess and PCOS society. The androgen excess and PCOS society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009;91:456–88. [6] Gysler M, March CM, Mishell Jr DR, Bailey EJ. A decade’s experience with an individualized clomifene treatment regimen including its effects on the postcoital test. Fertil Steril 1982;37:161–7. [7] Kamath MS, George K. Letrozole or clomiphene citrate as first line for anovulatory infertility: a debate. Reprod Biol Endocrinol 2011;9:86. [8] Homburg R. Clomiphene citrate – end of an era? A mini review. Hum Reprod 2005;20:2043–51. [9] Rajashekar L, Krishna D, Patil M. Polycystic ovaries and infertility: our experience. J Hum Reprod Sci 2008;1:65–72. [10] Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551–66. [11] National Institute for Health and Clinical Excellence. Fertility: assessment and treatment for people with fertility problems (update). CG11. London: National Institute for Health and Clinical Excellence; 2012. [12] Balen AH. Ovulation induction in the management of anovulatory polycystic ovary syndrome. Mol Cell Endocrinol 2013;373:77–82. [13] White DM, Polson DW, Kiddy D, et al. Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab 1996;81:3821–4. [14] Homburg R, Howles CM. Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements. Hum Reprod Update 1999;5:493–9. [15] Calaf AJ, Balda Ruiz JA, Romeu SA, et al. Ovulation induction with a starting dose of 50 IU of recombinant follicle stimulating hormone in WHO group II anovulatory women: the IO-50 study, a prospective, observational, multicentre, open trial. Br J Obstet Gynaecol 2003;110:1072–7. [16] Kamrava MM, Seibel MM, Berger MJ, Thompson I, Taymor ML. Reversal of persistent anovulation in polycystic ovarian disease by administration of chronic low-dose follicle-stimulating hormone. Fertil Steril 1982;37:520–3. [17] Hugues JN, Cedrin-Durnerin I, Howles CM, et al. The use of a decremental dose regimen in patients treated with a chronic low-dose step-up protocol for WHO Group II anovulation: a prospective randomized multicentre study. Hum Reprod 2006;21:2817–22. [18] Homburg R. The management of infertility associated with polycystic ovary syndrome. Reprod Biol Endocrinol 2003;1:109–17. [19] Brown JB. Pituitary control of ovarian function: concepts derived from gonadotrophin therapy. Aust NZ J Obstet Gynaecol 1978;18:47–54. [20] Bateman BG, Nunley WC, Kolp LA. Exogenous estrogen therapy for treatment of clomiphene citrate-induced cervical mucus abnormalities: is it effective? Fertil Steril 1990;54:577–9. [21] Ben-Ami M, Geslevich Y, Matilsky M, Battino S, Weiner E, Shalev E. Exogenous estrogen therapy concurrent with clomiphene citrate – lack of effect on serum sex hormones and endometrial thickness. Gynecol Obstet Invest 1994;37: 180–2.