Scholarly article on topic 'Letrozole versus laparoscopic ovarian drilling in infertile women with PCOS resistant to clomiphene citrate'

Letrozole versus laparoscopic ovarian drilling in infertile women with PCOS resistant to clomiphene citrate Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Mahmoud H. Ibrahim, M. Tawfic, Moamen M. Hassan, O.H. Sedky

Abstract Objective To compare the efficacy of letrozole and laparoscopic ovarian drilling (LOD) in the induction of ovulation in women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). Subjects and methods A total of 80 women with CC-resistant PCOS were enrolled and randomly allocated into groups A and B. Group A (n=40) underwent LOD, and group B (n=40) received 2.5mg letrozole from days 3 to 7 of menses for up to six cycles. A 6-month follow-up was performed. Results No statistically significant differences were found in the baseline clinical characteristics and the major serum hormone profiles, women receiving letrozole had a higher rate of ovulation (70 vs. 57.5%) and however, the differences were not statistically significant also there is significant decrease in MAH in group A. The pregnancy rate was 27.5% in group A versus 35% in group B and abortion rate was 18% in group A versus 7% in the other group. Conclusion Letrozole had superior reproductive outcomes compared with LOD in women with CC-resistant PCOS and seems to be a suitable first-line ovulation induction instead of LOD in those patients.

Academic research paper on topic "Letrozole versus laparoscopic ovarian drilling in infertile women with PCOS resistant to clomiphene citrate"

Middle East Fertility Society Journal xxx (2017) xxx-xxx

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Middle East Fertility Society Journal

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Original Article

Letrozole versus laparoscopic ovarian drilling in infertile women with PCOS resistant to clomiphene citrate

Mahmoud H. Ibrahim *, M. Tawfic, Moamen M. Hassan, O.H. Sedky

Department of Obstetrics and Gynecology, Minia University Hospital, El-Minia 61111, Egypt

ARTICLE INFO

Article history: Received 4 November 2016 Revised 14 January 2017 Accepted 9 February 2017 Available online xxxx

Keywords: Letrozole

Polycystic ovary syndrome Laparoscopic ovarian drilling

ABSTRACT

Objective: To compare the efficacy of letrozole and laparoscopic ovarian drilling (LOD) in the induction of ovulation in women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS).

Subjects and methods: A total of 80 women with CC-resistant PCOS were enrolled and randomly allocated into groups A and B. Group A (n = 40) underwent LOD, and group B (n = 40) received 2.5 mg letrozole from days 3 to 7 of menses for up to six cycles. A 6-month follow-up was performed. Results: No statistically significant differences were found in the baseline clinical characteristics and the major serum hormone profiles, women receiving letrozole had a higher rate of ovulation (70 vs. 57.5%) and however, the differences were not statistically significant also there is significant decrease in MAH in group A. The pregnancy rate was 27.5% in group A versus 35% in group B and abortion rate was 18% in group A versus 7% in the other group.

Conclusion: Letrozole had superior reproductive outcomes compared with LOD in women with CC-resistant PCOS and seems to be a suitable first-line ovulation induction instead of LOD in those patients.

© 2017 Middle East Fertility Society. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

The development of effective, simple, and safe treatments for PCOS as a cause of infertility is an important public health goal

[1]. Polycystic ovary syndrome (PCOS) is a common cause of reproductive endocrinopathy in women and is characterized by hyper-androgenism, chronic oligo-anovulation, and insulin-resistance

[2]. For an infertile woman with PCOS, clomiphene citrate (CC) remains the first-line treatment; however, 15-40% of women do not resume ovulation following CC treatment, which is defined as CC-resistance [3].

The most common treatments for CC-resistant PCOS are laparo-scopic ovarian drilling (LOD) and gonadotropin treatment. Successful pregnancy outcomes for both treatments have been reported [4]. However, the main disadvantages of LOD are the need for hos-pitalization, general anesthesia and may lead to pelvic adhesion and ovarian function decrease, which would hinder any subsequent pregnancies. Due to the high sensitivity of the ovaries to

Peer review under responsibility of Middle East Fertility Society.

* Corresponding author. E-mail address: hosnimahmoud60@yahoo.com (M.H. Ibrahim).

gonadotropin stimulation, treatment with human menopausal gonadotropin or pure follicle-stimulating hormone (FSH) is challenging to control and is individually administered to induce several ovulatory follicles, which incurs a substantially increased risk of multiple pregnancies and ovarian hyperstimulation syndrome (OHSS) [5]. In addition, the cost of gonadotropin treatment could add a financial burden to the infertile patient; therefore, a convenient, economic and safe treatment method for CC-resistant PCOS is required [6].

Letrozole (LE) is a potent and selective third-generation aro-matase inhibitor (AI), which can effectively and highly selectively block the production of estrogen without disturbing other steroidogenic pathways. LE was first used to treat breast cancer and was found to be superior to the previous gold standard tamoxifen, and more effective than others. Also, Mitwally and Casper [7], introduced LE to the ovulation induction field; since then, numerous investigations in LE-induced ovulation have been performed [8,9]. According to the reports, the ovulation rate in women with CC-resistant PCOS is between 54.6 and 84.4%. The aim of the present study was to compare LE with LOD, in order to determine a safer, more efficacious and economical method of treating CC-resistant PCOS.

http://dx.doi.org/10.1016/j.mefs.2017.02.003

1110-5690/® 2017 Middle East Fertility Society. Production and hosting by Elsevier B.V.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

M.H. Ibrahim et al./Middle East Fertility Society Journal xxx (2017) xxx-xxx

2. Subjects and methods

2.1. Patient selection

The present study followed 80 women attending the Endoscopy unit and outpatient clinic of Minia Infertility Research Unit (MIRU), EL-Minia, Egypt. The study was conducted during the period from 1st August 2015 to 30th March 2016. The women were diagnosed with PCOS based on the Revised 2003 Consensus Diagnostic Criteria for PCOS [10]. This study was approved by Minia University Ethical Committee, and an informed consent obtained from all participating women after the nature and purpose of the study had been explained to them and were fully understood.

2.2. Randomization

Randomization was achieved via the use of a randomization number allocated prior to dosing, once eligibility had been determined, and a randomization schedule was produced by an interactive voice response system vendor.

2.3. Inclusion criteria

Age >20 and <35 years old, Patients were diagnosed to have PCOS Criteria of diagnosis of PCO [10]. The definition requires two of the following three criteria for the diagnosis of PCOS Polycystic ovaries: by Ultrasonographic diagnosis, the modified 2003Rotterdam Consensus Workshop defines ultrasonographic criteria for PCO as the: presence of 12 or more follicles in an ovary, with each follicle measuring 2-9 mm in diameter and/ or ovarian volume >10 ml. Neither stromal density nor distribution of the follicles is included in this revised definition. One polycystic ovary is sufficient for diagnosis. Oligo or anovulation: clinically diagnosed as oligo-/amenorrhea, i.e., menstrual cycles longer than 35 days or amenorrhea (absence of menstrual cycle for 3 cycles or more). Hyperandrogenism: clinical and biochemical. The most common clinical manifestation of hyperandro-genism in women is hirsutism, followed by ovulatory and menstrual irregularity, acne and male pattern alopecia. The biochemical evidence of hyperandrogenism includes elevated serum LH (>10 l.U/l), elevated LH/FSH ratio >2 and/or raised concentrations of androgens (testosterone > 2.6 nmol/ml or free androgen index (FAl > 5). Normal HSG and their partners had normal semen analysis according to WHO criteria (WHO, 2010) and CC-resistant. If patients fail to respond to 150mg/day for 5 days for 3 consecutive cycles, they are considered as CC-resistant [11].

2.4. Exclusion criteria

Age less than 20 yr or more than 35 yr, non-PCOS, and those Patients with poor ovarian reserve i.e. hyperprolactinemia, hypo and hyperthyroidism, diabetic patients and Cushing's syndrome were excluded, non-classical congenital adrenal hyperplasia, current or previous (within the last 6 months) use of oral contraceptives, glucocorticoids, antiandrogens, antidiabetic or antiobesity drugs, or other hormonal drugs, any subject was affected by either neoplastic, metabolic, hepatic, or cardiovascular disorder or other concurrent medical illness (i.e. diabetes, renal disease, or malabsorptive disorders) were excluded, pelvic diseases, previous pelvic surgery, suspected peritoneal factor infertility, tubal infertility and male factor infertility were excluded with a hysterosalpingogram and with semen analysis, respectively.

2.5. Hormone assays and transvaginal ultrasound

The patients underwent baseline hormones assays for Follicular stimulating hormone (FSH), luteinizing hormone (LH), Prolactin (PRL), anti-mullerian hormone (AMH), Progesterone (P), Sex hormone binding globulin (SHBG) and free testosterone on the third day of menses, and the LH/FSH ratio was calculated. At the same time, the ovary volume and antral follicle counts were measured by transvaginal ultrasound. For patients with amenorrhea or with irregular cycles, the baseline hormone assays were taken randomly.

2.6. Intervention and follow-up

The women were randomly by the previously described method into either the LOD or group LE (groups A and B, respectively). No medical leading was made during the decision-making process. Once the patients had been allocated to one of the two groups, the treatment was revealed to the investigator; however, the doctor responsible for performing the transvaginal ultrasound follow-up assessment was blinded to the treatment groups.

ln group A, laparoscopy was performed under intravenous general anesthesia with the patient in a supine position. A 5mm incision was made in the navel, through which a long sheath punctured into the abdominal cavity, and the inflatable pneu-moperitoneum was placed. Another two 5-mm incisions were made on the right and left lower abdomen and the surgical instruments were inserted into the abdominal cavity. The patient was adjusted into a position with the head high up, the pelvic organs were exposed and a comprehensive exploration of the pelvic organs was made, focusing on the structure and position of the adjacent organs of the bilateral ovaries. Once immobilized, each ovary was cauterized at 4-6 points, using a monopolar elec-trosurgical needle, according to the size of each ovary. Following cauterization, a bilateral tubal hydrotubation with methylene blue was performed. During the procedure. The pelvis was irrigated using physiological saline. Ringer's solution plus dexam-ethasone was added into the abdominal cavity to avoid adhesion. The total duration of the procedure, as well as any intra-operative or post-operative complications, was noted. ln group B, 2.5 mg twice daily LE oral tablets were administered on the 3rd day of menses and then every day for 5 days [12]. Treatment was repeated for up to six cycles if the patient failed to ovulate, the patients were followed-up for 6 months after the treatment in both groups.

ln both groups, hormone levels were monitored every third day of menstruation in each cycle the following treatment up to 6 months, and comparisons were made with the baseline data after LE treatment or LOD surgery. Ovarian volume, follicle size were monitored on days 10, 12 and 14 of menses and the subsequent surveillance time-point was adjusted according to the individual situation until ovulation. Ovulation frequency and mean follicular diameters were recorded in both groups during the six cycles. Progesterone level was measured at day 21st of the cycle to document ovulation. Comparisons of menstrual pattern, hormonal profile and reproductive outcome between the two groups were made.

2.7. Statistical analysis

Data were collected and analyzed using the Statistical Package for Social Sciences software version 21. The measurement data are presented as the mean ± standard deviation. Proportions were compared using the v2 test. A P-value of <0.01 was considered to indicate a statistically significant difference.

M.H. Ibrahim et al./Middle East Fertility Society Journal xxx (2017) xxx-xxx

3. Results

3.1. Patient data

80 eligible patients were randomly assigned to group A (LOD, n = 40) or group B (LE treatment, n = 40). No statistically significant differences were found between the two groups in terms of age, BMI, duration of infertility, hirsutism, amenorrhea, ovarian volume (Table 1). There were insignificant differences as regarding baseline hormonal levels, including LH, FSH, LH/FSH, AMH, Progesterone, SHBG and free testosterone. The baseline hormones levels were taken at the third day of menstruation (Table 2).

3.2. Hormonal characteristics

In the second cycle after treatment, the hormones levels were again measured in the two groups up to 6 months (Table 3). Compared with the group B patients, the group A patients had a significantly lower LH level (8.21 ±0.76 vs. 10.91 ±1.15, P<0.01), LH/ FSH ratio (1.21 ±0.0.24 vs. 2.0±0.22, P<0.01), AMH level (5.37 ±1.57 vs. 8.28 ±2.54, P<0.01) and FAI level (8.2 ±0.69 vs. 10.43 ± 1.21, P<0.01), also there was significant increase in post-treatment FSH level in group A compared to group B (6.95 ± 0.98 vs. 5.66 ± 0.38, P < 0.01). There was a significant increase in Progesterone in comparing pre and post treatment level in both groups while the two groups had a similar level of Progesterone in post-treatment level and no significant change in the level of SHBG when comparing the pre- and post-treatment hormone levels. Also, there was a marked decrease in the ovarian volume and AFC in the group A compared to group B which was statistically significant.

3.3. Reproductive outcomes

The clinical and reproductive outcomes are presented in Table 4. The women were studied for up to 6 cycles in both groups. As regards to regularity of the cycles there was statistically significant increase in number of regular cycles in group B as compared to group A (35 (87.5%) vs. 25(62.5%), p < 0.05), Ovulation occurred in 23 out of 40 cases (57.5%) in group A (the LOD group) and 28 out of 40 cases (70%) in group B (the LE group) which was statistically insignificant (P > 0.05), and in comparing group A to group B after treatment there were statistically significant reduction in summed ovarian volume (8.1 ± 1.93 vs. 10.96 ±0.57) respectively

Table 1

Baseline clinical data of the studied groups.

Group A Mean ± S.D (Range) Group B Mean ± S.D (Range) P Value

Age/years 28.8 ±3.13 29.7 ±3.65 0.24

(24-34) (23-34)

BMI/kg/m2 29.11 ±1.62 29.21 ±1.72 0.773

(26.6-32.87) (26.67-33)

Type of infertility

Primary 32(80) 35(87.5) 0.363

Secondary 8(20) 5(12.5)

Hirsutism 20(50) 22(55) 0.654

Menstrual pattern

Regular 8(20) 9(22.5) 0.785

Oligomenorrhea 32(80) 31(77.5)

Duration of infertility

<3 years 6(15) 6(15) 0.624

3-6 years 18(45) 14(35)

>6 years 16(40) 20(50)

Data are mean ± standard deviation, or mean.

and AFC (12.5 ±2.39 vs. 16.87 ±2.52) respectively p< 0.001. The pregnancy rate was 35% higher in the group B (LE) than group A (LOD) 27.5%. The rate of abortions was lower in group B (7% versus 18%).

Table 2

Comparison between both groups as regards baseline hormonal profiles.

Group (A) Group (B) P-value

Ovarian volume (mm) 10.85 ± 1.72 10.75 ±1.62 0.787

(8-14.5) (7.35-14.15)

AFC 16.82 ±3.07 16.9 ±2.45 0.898

(12.5-20.9) (12.9-20.9)

LH, mIU/ml 11.8 ±1.27 11.35 ±1.58 0.159

(9.3-14.8) (8.3-14.5)

FSH mIU/ml 5.36 ± 0.57 5.45 ± 0.7 0.555

(4.4-6.9) (4.15-7.35)

LH/FSH Ratio 2.22 ± 0.33 2.11 ±0.35 0.137

(1.59-2.96) (1.13-2.87)

AMH, ng/ml 8.43 ± 2.08 8.05 ± 2.81 0.492

(4.5-11.9) (4-13.2)

Progesterone level, pg/ml 2.1 ± 0.22 2.08 ± 0.26 0.466

(1.6-2.5) (1.5-2.4)

FAI 10.36 + 1.22 10.43 + 1.21 0.806

(7.5-13.3) (7-13.1)

SHBG 31.67 + 1.38 31.56 + 1.27 0.732

(28.4-34.4) (28.4-34.7)

Data are mean ± standard deviation, or mean.

Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone; AFC, antral follicle count; AMH, antimullerian hormone; FAI, free androgen index; SHBG, sex hormone-binding globulin.

Table 3

Hormonal characteristics of patients following treatment in both groups.

Group A Mean ± S.D (Range) Group B Mean ± S.D (Range) P Value

LH, mIU/ml 8.21 ± 0.76 10.91 ±1.15 <0.001

(7-9.5) (8-13)

FSH, mIU/ml 6.95 ± 0.98 5.66 ± 0.38 <0.001

(5.2-8.7) (5.2-6.4)

LH/FSH ratio 1.21 ±0.24 2 ± 0.22 <0.001

(0.8-1.83) (1.51-2.46)

AMH, ng/ml 5.37 ±1.57 8.28 ± 2.54 <0.001

(3.1-8.2) (4-13.5)

Progesterone level, pg/ml 11.78 ±1.99 12.2 ±1.72 0.318

(8.78-14.78) (9.2-15.2)

FAI 8.2 + 0.69 10.43 + 1.21 <0.001

(7-10.5) (7-13.1)

SHBG 32.11+0.86 31.93 + 0.77 0.322

(31-35.6) (31-35.2)

Data are mean ± standard deviation, or mean.

Table 4

Comparison between both groups as regards reproductive outcomes following treatment.

Group A N(%) Group B N (%) P value

Ovulation, n/total n (%) 23 28 0.245

(57.5%) (70%)

Regular cycles, n/total n (%) 25 35 0.01

(62.5%) (87.5%)

Ovarian volume, ml 8.1 ±1.93 10.96 ±0.57 <0.001

(4.5-11.7) (10-12)

AFC 12.5 ±2.39 16.87 ±2.52 <0.001

(8.8-16.2) (12.8-20.9)

Pregnancy rate 11/40(27.5%) 14/40(35%) <0.235

Abortion rate 2/11(18%) 1/14(7%) <0.231

Data are mean ± standard deviation, or mean. AFC, antral follicle count.

M.H. Ibrahim et al./Middle East Fertility Society Journal xxx (2017) xxx-xxx

4. Discussion

CC-resistant PCOS is a challenging in treatment. Classically gonadotropins and LOD were the traditional treatment [4]. Although they are effective yet they are expensive and may carry risks. Recently letrozole was investigated to be an appropriate alternative [13].

We found that letrozole was more effective as a fertility treatment than LOD in women with the polycystic ovary syndrome. Ovulation, conception, and pregnancy were more likely after treatment with letrozole. The rate of pregnancy loss is less with letrozole.

There were marked a reduction in total ovarian volume (TOV) and antral follicle count (AFC), Antimullerian hormone (AMH) with a slight increase in the basal FSH level in group A while no change in these parameters in group B. These results were in agreement with Abdellah [14], Elnashar et al. [15] and Badawy et al. [16].

Our study showed that a higher baseline level of sex hormone-binding globulin, as compared with a lower level, and a lower free androgen index at baseline, as compared with a higher index, were associated with LOD.

The mean of BMI in our study was higher than the mean of BMI in other localities this could be explained by the nature of PCOS patients in Minia locality but with the same diagnostic criteria for the polycystic ovary syndrome. Lifestyle modification is not prerequisited from the patients before recruitment in the study. Although this modification is advised by professionals as there is no clear evidence that it increase reproductive outcome in obese patients [17,18].

The rate of ovulation in the group B (LE) was 70%, which was higher than that in the group A. Similarly Abdellah [14] who found the ovulation rate in letrozole group was 59%. Comparable results by Badawy et al. [16], who found ovulation rates of 55.3% in letrozole group. In contrast, Abu Hashim et al. [19] found that the ovulation rate was 65.4% in women who received letrozole and 69.3% in women who underwent LOD. The higher rate of ovulation in the group B (LE) was not statistically significant possibly related to small sample size.

In the present study, the pregnancy rate was higher in group B (LE) than in group A (LOD), although these differences were not statistically significant. The pregnancy rate of 35% in group B (LE), while in group A (LOD) was 27.5%.

The abortion rate was higher in group A (LOD) than in group B (LE) but without statistical significance (18% versus 7%). Ganesh et al. [13] reported similar results as regarding abortion rate. The number of abortions was small so the analysis is not powered enough to detect a statistical difference. The above-mentioned results (pregnancy rate and abortion rate) might be explained by the positive effect of letrozole on the endome-trium. During the study, there are no reported complications of laparoscopic ovarian drilling also, Letrozole was generally well tolerated.

In conclusion, compared with LOD treatment, LE treatment is more easily administered and more affordable. In addition, it was shown to improve the ovulation rate of patients with refractory PCOS, no hazards of general anesthesia as in LOD. So, LE may be considered a first-line treatment for clomiphene citrate-resistant PCOS.

Conflict of interest

We declare no conflict of interest.

Contributors

Mahmoud H. Ibrahim: Study design, data collection, analysis and manuscript writing. M. Tawfic: Study design and data collection. Moamen M. Hassan: Data collection and interpretation. Sedky OH: statistical analysis and interpretation.

Acknowledgement

We have not received any funding from any corporate body or pharmaceutical company.

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