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Is coasting valuable in all patients with any cause of infertility?

Despite major advances in assisted reproductive techniques (ART), there remains a considerable risk of developing life-threatening ovarian hyperstimulation syndrome (OHSS) as a result of supraphysiological stimulation of the ovaries. (1) OHSS has a reported incidence of 1 to 10% of all ART cycles. (2) Several preventive strategies have been introduced to avoid OHSS occurrence or to diminish its severity. Coasting is one of the most popular choices among physicians for the prevention of OHSS. (3-5) On the other hand, using a gonadotrophin-releasing hormone (GnRH) antagonist as an alternative method has been suggested as one of the preferred strategies to prevent OHSS in a long protocol. (1,6) However, there are some restrictions on the use of antagonist, for example in whose have had an inadequate response to the use of antagonists in the past, and the lack of accessibility to the antagonist in some countries. Accordingly, coasting has been advocated as an effective approach to avoid OHSS in polycystic ovary syndrome (PCOS) patients by several investigators. (1,7-9) The principle behind coasting is based on the phenomenon of apoptosis/necrosis. By withholding exogenous gonadotropins, mature follicles will survive for a few days, while the number of smaller follicles will reduce through atresia of granulosa cells during apoptosis. (9-11) Interestingly, there is insufficient evidence using identical criteria for the application of coasting, and many unknowns also remain regarding management of this treatment. (12) The debate on whether coasting has an effect on ART cycle outcomes, such as the number and quality of oocytes, is still ongoing. (13) However, the literature suggests that coasting does not exert a negative impact on in vitro fertilization (IVF) cycle outcome provided that its duration is not extended. (14-16)

The majority of studies have evaluated the impact of coasting on IVF outcome, (3) but the effect of coasting in patients with different infertility causes has not been previously explored. Therefore, our study was designed to determine the impact of coasting in women at risk of developing OHSS with male factor infertility (normal women) and women with PCOS.

METHODS

In this prospective observational follow-up study, we included 114 patients who showed a predisposition to developing OHSS during controlled ovarian stimulation before IVF/intracytoplasmic sperm injection (ICSI) and had undergone coasting at the Royan Institute Research Center, Iran, between June 2010 and December 2012.

Approval to conduct this study was obtained from the Institutional review Board of the Royan Institute research Center and the Royan Ethics Committee. All patients signed an informed consent authorizing the use of their information.

The patients were further subdivided into those with male factor infertility (n = 53) and PCOS (n = 61). The criteria for inclusion in the male infertility group were women with partners who had asthenospermia or who were candidates for percutaneous epididymal sperm aspiration (PESA) and those with 3-4 failed intrauterine insemination (IUI) cycles. Patients using sperm retrieved from testicular sperm aspiration (TESA) procedures and those using frozen sperm were excluded from the study. Women with PCOS who failed to have an adequate response to the antagonist in their previous induction ovulation were included in the study. PCOS was defined by the 2003 Rotterdam consensus criteria. (17)

All patients underwent conventional IVF/ICSI treatment with the standard long protocol using a GnRH agonist (Suprefact, Hoechst, Frankfurt, Germany) for pituitary suppression. In addition, a starting dose of 112.5 IU of recombinant human follicle-stimulating hormone (follitropin alfa pen; Gonal-F, Merck Serono S.A., Geneva) was used with or without Menopur (Ferring, Germany) to induce ovulation. Monitoring of cycles was performed by sonography and measurement of estradiol (E2) levels. Coasting started when serum E2 was more than 3000 pg/mL or there were at least 15 follicles with a size of 14-16 mm. During coasting, which was not more than four days, gonadotropin administration was withheld, whereas GnRH agonist was maintained. Furthermore, daily monitoring by sonography and serum E2 measurements was continued until E2 concentrations decreased by 50% of maximum rising. Ovarian puncture was performed 34-36 hours after human chorionic gonadotropin (hCG) administration.

The coasting duration was determined as the number of days from the last injection of gonadotropin to the hCG-day administration. The fertilization rate was calculated as the number of oocytes with two pronuclei divided by the number of injected oocytes when ICSI was performed and by all intact oocytes retrieved when IVF was performed. The results were analyzed according to the coasting periods for 1-4 days, separately in each group of infertile women with male factor and PCOS.

The statistical comparisons were performed using one-way analysis of variance (ANOVA), Kruskal-Wallis nonparametric analysis of variance and chi-square when appropriate. The results were reported as median (IQR; interquartile range). A p-value < 0.050 was considered statistically significant. Data analysis was performed using SPSS Statistics (SPSS Statistics Inc., Chicago, US) version 18.0.

RESULTS

In this study, the data of 114 women undergoing coasting were analyzed. Coasting was performed in 53 normal patients and 61 patients with PCOS. The demographic and hormonal levels compared with the duration of coasting by days (1-4) are presented separately in male factor infertile women and women with PCOS [Table 1]. There were no statistically significant differences between different days of coasting with regard to age, body mass index (BMI), and basal hormone levels. When comparing the E2 level at the start of coasting between coasting days, a statistically significant difference was observed in each group of normal women and women with PCOS (p = 0.036 and p = 0.005, respectively).

In normal females, the number of oocytes retrieved was significantly reduced after the second day of coasting (p = 0.004). Additionally, a statistically significant drop was observed in the number of metaphase II (MII) oocytes and fertilization rate after the third day (p = 0.006 and p = 0.006, respectively). On the other hand, in PCOS patients, no statistically significant differences were revealed between different days of coasting regarding the number and quality of oocytes retrieved and fertilization rate [Table 2].

DISCUSSION

OHSS is a serious complication related to ovulation induction which is sometimes seen in low-risk patients, but it is more likely to occur in high-risk patients. (3) PCOS is a well-known risk factor for OHSS. (12,13,18) Despite the widespread use of coasting treatment by physicians, (3,4) our findings do not provide explicit evidence that coasting is useful in the prevention of OHSS in all patients undergoing controlled ovarian hyperstimulation with any cause of infertility.

Many studies have addressed the effect of coasting on controlled ovarian hyperstimulation (COH) cycles. (9,12,15,19,20) A large body of evidence has advocated coasting as an effective method for preventing OHSS in high-risk groups without compromising pregnancy outcome. (7-9) In contrast, others have shown a decline in the number of oocytes obtained and oocyte quality in coasted cycles. (19,21,22) A recent Cochrane review demonstrated that randomized controlled trials performed for the prevention of OHSS by coasting were not powerful enough to confirm the efficiency of this method. (3,20)

Based on clinician experience, E2 levels for initiation of coasting is varied. (3,5) A retrospective analysis of 608 patients demonstrated that the initial level of E2 to start coasting might have an impact on oocyte quality. (3) Furthermore, a recent review study emphasized that coasting should be initiated with a serum E2 level greater than 3000 pg/mL. (23)

Our study revealed that coasting treatment and success varies with cause of infertility. Accordingly, in normal females, coasting with duration of more than two days is likely to exert an adverse effect on the number of oocytes, and coasting for more than three days negatively affects oocyte quality and fertilization rate. However, in contrast, coasting can be safely applied to infertile PCOS women in light of OHSS potential risks without compromising the outcome. Many investigators have used different criteria to specify the time of starting and ending of coasting and they have reported different results for the effect of coasting period on the prevention of OHSS and reproductive outcomes. (1,8,16,19,24) Some authors believe that too short a period of coasting may not be effective in preventing OHSS, whereas too long a period may have a less satisfactory outcome in terms of oocyte quality and endometrial receptivity. (5,15,23) Despite the debate over the coasting effect, there has almost been an agreement among studies that oocyte quality and pregnancy outcome are adversely affected after four days of coasting. (11,16,19)

The observed differences between our study and previous studies could be due to our patient selection according to the cause of infertility. In general, physiological mechanisms are probably involved in the adverse effects of coasting on outcome of treatment cycle in normal women compared to women with PCOS. This, in turn, may indicate that PCOS patients show less sensitivity to the manipulation occurring during coasting. This may be explained by the critical role of luteinizing hormone (LH) in the final stages of follicular maturation. The LH receptors of the follicles decrease following the coasting process, and this reduction is expected to be severe with longer coasting periods. Consequently, these follicles with a low number of functional LH receptors have a poor response to exogenous hCG, and so, final maturation will not be obtained. (9,13) On the other hand, granulosa cells from polycystic ovaries contain higher number of LH receptors compared with normal granulosa cells. (25) Accordingly, despite the loss of receptors following coasting, in women with PCOS there are relatively adequate receptors for supporting final maturation, whereas in normal women these endocrine changes are not tolerable by follicles. As our study showed, in women with male factor infertility, there was a decreasing trend in the number of oocytes obtained, and oocyte quality and fertilization rate with regard to the coasting days (even with periods less than four days).

CONCLUSION

Our results indicate that before making important treatment decisions in infertile patients at risk of developing OHSS, the impact of an infertility diagnosis should be considered. Accordingly, coasting for more than three days should be performed with caution in normal women who are at risk of developing OHSS. In this respect, an attempt to determine a recommended protocol for normal women, coasting for one or two days combined with another preventive method appears to be the most desirable option for avoiding OHSS. Obviously, the lack of research in this area and the potentially sensitive nature of OHSS makes it difficult to draw definite conclusions and further studies with a larger population is suggested.

Disclosure

The authors declared no conflicts of interest. No funding was received for this study.

ARTICLE INFO

Article history:

Received: 23 January 2016

Accepted: 1 August 2016

Online:

DOI 10.5001/omj.2016.82

Acknowledgements

The authors wish to express their gratitude to the Royan Institute and its staff.

REFERENCES

(1.) Moon HS, Joo BS, Moon SE, Lee SK, Kim KS, Koo JS. Short coasting of 1 or 2 days by withholding both gonadotropins and gonadotropin-releasing hormone agonist prevents ovarian hyperstimulation syndrome without compromising the outcome. Fertil Steril 2008 Dec;90(6):2172-2178.

(2.) Brinsden PR, Wida I, Tan SL, Balen A, Jacobs HS. Diagnosis, prevention and management of ovarian hyperstimulation syndrome. Br J Obstet Gynaecol 1995 Oct;102(10):767772.

(3.) Ulug U, Ben-Shlomo I, Bahceci M. Predictors of success during the coasting period in high-responder patients undergoing controlled ovarian stimulation for assisted conception. Fertil Steril 2004 Aug;82(2):338-342.

(4.) Delvigne A, Rozenberg S. Preventive attitude of physicians to avoid OHSS in IVF patients. Hum Reprod 2001 Dec;16(12):2491-2495.

(5.) Nardo LG, Cheema P, Gelbaya TA, Horne G, Fitzgerald CT, Pease EH, et al. The optimal length of 'coasting protocol' in women at risk of ovarian hyperstimulation syndrome undergoing in vitro fertilization. Hum Fertil (Camb) 2006 Sep;9(3):175-180.

(6.) Gustofson RL, Segars JH, Larsen FW. Ganirelix acetate causes a rapid reduction in estradiol levels without adversely affecting oocyte maturation in women pretreated with leuprolide acetate who are at risk of ovarian hyperstimulation syndrome. Hum Reprod 2006 Nov;21(11):2830-2837.

(7.) Garcia-Velasco JA, Isaza V, Quea G, Pellicer A. Coasting for the prevention of ovarian hyperstimulation syndrome: much ado about nothing? Fertil Steril 2006 Mar;85(3):547554.

(8.) Kovacs P, Matyas S, Kaali SG. Effect of coasting on cycle outcome during in vitro fertilization/intracytoplasmic sperm injection cycles in hyper-responders. Fertil Steril 2006 Apr;85(4):913-917.

(9.) Waldenstrom U, Kahn J, Marsk L, Nilsson S. High pregnancy rates and successful prevention of severe ovarian hyperstimulation syndrome by 'prolonged coasting' of very hyperstimulated patients: a multicentre study. Hum Reprod 1999 Feb;14(2):294-297.

(10.) Agrawal R, Tan SL, Wild S, Sladkevicius P, Engmann L, Payne N, et al. Serum vascular endothelial growth factor concentrations in in vitro fertilization cycles predict the risk of ovarian hyperstimulation syndrome. Fertil Steril 1999 Feb;71(2):287-293.

(11.) Moreno L, Diaz I, Pacheco A, Zuniga A, Requena A, Garcia-Velasco JA. Extended coasting duration exerts a negative impact on IVF cycle outcome due to premature luteinization. Reprod Biomed Online 2004 Nov;9(5):500504.

(12.) Delvigne A, Rozenberg S. A qualitative systematic review of coasting, a procedure to avoid ovarian hyperstimulation syndrome in IVF patients. Hum Repro ate 2002 May Jun;8(3):291-296.

(13.) Owj M, Tehrani Nejad ESh, Amirchaghmaghi E, Ezabadi Z, Baghestani AR. The effect of withholding gonadotropin (a coasting period) on the outcome of in vitro fertilization cycles. Eur J Obstet Gynecol Reprod Biol 2007 Jul;133(1):81-85.

(14.) Al-Shawaf T, Zosmer A, Hussain S, Tozer A, Panay N, Wilson C, et al. Prevention of severe ovarian hyperstimulation syndrome in IVF with or without ICSI and embryo transfer: a modified 'coasting' strategy based on ultrasound for identification of high-risk patients. Hum Reprod 2001 Jan;16(1):24-30.

(15.) Isaza V, Garcia-Velasco JA, Aragones M, Remohi J, Simon C, Pellicer A. Oocyte and embryo quality after coasting: the experience from oocyte donation. Hum Reprod 2002 Jul;17(7):1777-1782.

(16.) Ulug U, Bahceci M, Erden HF, Shalev E, Ben-Shlomo I. The significance of coasting duration during ovarian stimulation for conception in assisted fertilization cycles. Hum Reprod 2002 Feb;17(2):310-313.

(17.) Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81(1):19-25.

(18.) Delvigne A, Rozenberg S. Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update 2002 Nov-Dec;8(6):559-577.

(19.) Tortoriello DV, McGovern PG, Colon JM, Skurnick JH, Lipetz K, Santoro N. "Coasting" does not adversely affect cycle outcome in a subset of highly responsive in vitro fertilization patients. Fertil Steril 1998 Mar;69(3):454-460.

(20.) D'Angelo A, Brown J, Amso NN. Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2011 June 15;(6) CD002811.

(21.) Dhont M, Van der Straeten F, De Sutter P. Prevention of severe ovarian hyperstimulation by coasting. Fertil Steril 1998 Nov;70(5):847-850.

(22.) Fluker MR, Hooper WM, Yuzpe AA. Withholding Gonadotropins ("coasting") to minimize the risk of ovarian hyperstimulation during superovulation and in vitro fertilization-embryo transfer cycles. Fertil Steril 1999 Feb;71(2):294-301.

(23.) Levinsohn-Tavor O, Friedler S, Schachter M, Raziel A, Strassburger D, Ron-El R. Coasting-what is the best formula? Hum Reprod 2003 May;18(5>937-940.

(24.) Benadiva CA, Davis O, Kligman I, Moomjy M, Liu HC, Rosenwaks Z. Withholding gonadotropin administration is an effective alternative for the prevention of ovarian hyperstimulation syndrome. Fertil Steril 1997 Apr;67(4):724-727.

(25.) Krishna BM, Laloraya M. Insulin paradox and polycystic ovarian syndrome: implications on mechanism and pathogenesis. Health Sciences 2013;2(1):JS004D.

Tahereh Madani [1] *, Nadia Jahangiri [1], Poopak Eftekhari-Yazdi [2], Mahnaz Ashrafi [1,3] and Mohammadreza Akhoond [4]

[1] Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan institute for Reproductive Biomedicine, ACECR, Tehran, Iran

[2] Department of Embryology, Reproductive Biomedicine Research Center, Royan institute for Reproductive Biomedicine, ACECR, Tehran, Iran

[3] Department of Obstetrics and Gynecology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran

[4] Department of Statistics, Mathematical Sciences and Computer Faculty, Shahid Chamran University of Ahvaz, Ahvaz, Iran

* Corresponding author: [mail]tmadani@royaninstitute.org
Table 1: Comparison of age, BMI, basal hormone levels, and
stimulation days of women with male infertility and PCOS
according to the number of days coasting.

                               Coasting, days

                            1                  2

Male infertility

Patients, n                10                  16

Age, years          28.5 (25.2-32.7)    26.0 (24.0-27.0)

BMI, kg/[m.sup.2]   26.1 (23.6-28.8)    25.3 (21.7-27.0)

FSH, MIU/mL           4.3 (2.9-6.6)      6.0 (4.6-7.0)

LH, MIU/mL            2.9 (1.6-8.1)      6.1 (3.9-8.7)

TSH, MIU/mL           1.3 (0.7-1.8)      1.7 (1.1-2.4)

Pn, ng/mL           18.9 (14.6-566.2)   14.9 (9.5-28.0)

E2 at start of           2639.0              4332.0
coasting, pg/ml      (1036.0-4068.0)    (4006.0-5164.0)

E2 at hCG day,           2087.0              2925.0
pg/mL                (1793.0-4434.0)    (1663.0-4411.0)

PCOS

Patients, n                23                  20

Age, years          31.0 (25.7-35.2)    31.0 (28.0-33.0)

BMI, kg/[m.sup.2]   24.8 (23.8-29.2)    24.4 (22.7-27.6)

FSH, MIU/mL           7.3 (4.5-8.0)      4.2 (3.7-6.7)

lh, MIU/mL            5.5 (4.0-9.8)      7.6 (2.1-10.6)

TSH, MIU/mL           1.8 (0.6-2.2)       2 (1.0-2.8)

PRL, ng/mL            22.9 (14-168)     15 (10.1-133.5)

E2 at start of           3462.0              3353.0
coasting, pg/mL      (3163.0-4336.0)    (2059.0-4382.0)

E2 at hCG day,           2501.0              3419.0
pg/mL                (1774.0-4514.0)    (2390.0-5551.0)

                               Coasting, days               p-value

                            3                   4

Male infertility

Patients, n                19                   8

Age, years          30.0 (25.0-33.0)    28.0 (23.7-32.7)     0.260

BMI, kg/[m.sup.2]   22.6 (19.3-25.4)    22.9 (19.2-25.2)     0.090

FSH, MIU/mL           6.6 (5.2-7.4)       5.6 (3.8-7.1)      0.311

LH, MIU/mL            5.0 (2.7-8.6)       5.1 (4.1-7.9)      0.396

TSH, MIU/mL           1.8 (1.3-3.8)       1.8 (0.5-3.6)      0.376

Pn, ng/mL           38.5 (15.2-247.0)   35.1 (11.0-320.2)    0.400

E2 at start of           4856.0              5390.0          0.036
coasting, pg/ml      (3919.0-6517.0)     (4728.0-7809.0)

E2 at hCG day,           3265.0              4204.0          0.573
pg/mL                (2482.0-6581.0)     (627.0-5682.0)

PCOS

Patients, n                11                   7

Age, years          36.0 (29.0-38.0)     30 (29.0-32.0)      0.425

BMI, kg/[m.sup.2]   25.3 (21.2-26.4)    25.5 (24.3-28.4)     0.583

FSH, MIU/mL           5.0 (2.6-6.6)       4.0 (2.9-4.4)      0.261

lh, MIU/mL           6.8 (3.0-18.0)       6.3 (3.3-9.0)      0.881

TSH, MIU/mL           1.8 (0.8-2.6)       1.5 (0.8-3.0)      0.756

PRL, ng/mL          20.1 (4.6-162.5)    19.9 (9.7-286.0)     0.774

E2 at start of           5182.0              5358.0          0.005
coasting, pg/mL      (4360.0-7632.0)     (5263.0-6772.0)

E2 at hCG day,           5061.0              2203.0
pg/mL                (2549.0-6710.0)     (1110.0-4324.0)     0.109

Values given as median (IQR). The statistical comparisons were
performed by Kruskal-Wallis test. PCOS: polycystic ovarian syndrome;
BMI: body mass index; FSH: follicle stimulating hormone; LH:
luteinizing hormone; TSH: thyroid stimulating hormone; PRL:
prolactin; E2: estradiol; hCG: human chorionic gonadotropin.

Table 2: IVF outcome according to the duration of coasting in
women with male infertility and PCOS.

                                  Coasting, days

                             1                       2

Male infertility

Patients, n                 10                       16

Oocyte, mean       18.6 [+ or -] 2.4 (a)   15.3 [+ or -] 1.9 (ab)
[+ or -] SD

MII, mean          16.1 [+ or -] 2.2 (a)   13.2 [+ or -] 1.6 (a)
[+ or -] SD

Fertilization        60.2 (97/161) (a)       63.0 (136/216) (a)
rate, % (n)

PCOS

Patients, n                 23                       20

Oocyte               14.0 (10.0-20.0)         14.5 (8.2-18.5)

MII                   11.0 (8.0-16.0)         11.5 (4.5-15.0)

Fertilization         63.7 (235/369)           56.5 (169/299)
rate, % (n)

                               Coasting, days               p-value

                             3                   4

Male infertility

Patients, n                 19                   8

Oocyte, mean       13.1 [+ or -] 1.0 (b)   7.1 [+ or -]      0.002
[+ or -] SD                                   1.3 (c)

MII, mean          11.8 [+ or -] 0.9 (a)   6.7 [+ or -]      0.006
[+ or -] SD                                   1.3 (b)

Fertilization       57.3 (129/225) (a)     37.0 (20/54)      0.006
rate, % (n)                                     (b)

PCOS

Patients, n                 10                   7

Oocyte                10.5 (8.7-20.0)      9.0 (6.0-17.0)    0.433

MII                   9.5 (6.0-19.2)       7.0 (6.0-16.0)    0.698

Fertilization          65.2 (75/115)        63.2 (43/68)     0.202
rate, % (n)

Values given as median (IQR) unless otherwise stated; (a, (b), (c):
The same letter in each row indicates no significant difference
between days at 0.050 level. IVF: in vitro fertilization; PCOS:
polycystic ovarian syndrome; MII: metaphase II.
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Title Annotation:ORIGINAL ARTICLE
Author:Madani, Tahereh; Jahangiri, Nadia; Eftekhari-Yazdi, Poopak; Ashrafi, Mahnaz; Akhoond, Mohammadreza
Publication:Oman Medical Journal
Article Type:Report
Geographic Code:7IRAN
Date:Nov 1, 2016
Words:3529
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