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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 12  |  Issue : 1  |  Page : 17-20

The study of ovulatory pattern following use of clomiphene citrate and anastrozole in infertile women with ovulatory dysfunction: A comparative study


Department of Obstetrics and Gynecology, Jawaharlal Nehru Medical College, DMIMSDU, Wardha, Maharashtra, India

Date of Web Publication25-Jul-2017

Correspondence Address:
Deepti Shrivastava
Department of Obstetrics and Gynecology, Jawaharlal Nehru Medical College, DMIMSDU, Sawangi (M), Wardha, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jdmimsu.jdmimsu_14_17

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  Abstract 

Objective: To determine an efficacy of Anastrozole compared with clomiphene citrate to induce follicular growth and ovulation in infertile women with ovulatory dysfunction. Study Design: Comparative prospective study setting: The study was carried out in the department of Obstetrics and Gynaecology at AVBRH, Sawangi, Wardha. Patient(s): The study comprised a total of 100 infertile women (cycles) with ovulatory dysfunction. Intervention(s): Patient received anastrozole (1 mg /d;50 patient , 87 cycles) and CC (50 mg /d ;50 patient, 74 cycles) for 5 days , starting on day3 of mense. Result(s): In 1st treatment cycle the ovulation rates for anastrozole at 1 mg was 32% (n=50) ,compared with 54% (n=50) for Clomiphene citrate at 50 mg/d. in up to 3 cycles of treatment, cumulative ovulation rate was 59.4% with CC and 43.6% with anastrozole. Conclusion(s): CC 50 mg exerts a stronger stimulatory effect on follicular growth compared with 1 mg of anastrozole . Anastrozole was associated with significantly fewer mature and growing follicle and thicker endometrium.

Keywords: Anastrozole, infertile women, ovulatory dysfunction


How to cite this article:
Gupta M, Samal S, Shrivastava D, Bagde N, Mishra N, Gupta S. The study of ovulatory pattern following use of clomiphene citrate and anastrozole in infertile women with ovulatory dysfunction: A comparative study. J Datta Meghe Inst Med Sci Univ 2017;12:17-20

How to cite this URL:
Gupta M, Samal S, Shrivastava D, Bagde N, Mishra N, Gupta S. The study of ovulatory pattern following use of clomiphene citrate and anastrozole in infertile women with ovulatory dysfunction: A comparative study. J Datta Meghe Inst Med Sci Univ [serial online] 2017 [cited 2019 Jun 16];12:17-20. Available from: http://www.journaldmims.com/text.asp?2017/12/1/17/211574


  Introduction Top


For the past four decades, clomiphene citrate (CC) has been the primary treatment for infertility in the World Health Organization Group II anovulatory patients. Although ovulation is restored in approximately 70% of treated women, fewer than half achieve pregnancy.[1] Between 20% and 25% of women do not ovulate with CC.[2] Since CC has a long half-life, it may accumulate in the body and may lead to long-lasting depletion of estrogen receptors,[3] aromatase inhibitors have been proposed as a replacement for CC.[2],[4],[5],[6],[7],[8]

Aromatase inhibitors, such as anastrozole and letrozole, have been suggested as alternatives to CC. Aromatase inhibitors block the aromatase enzyme, which suppresses estrogen production.[6] Since aromatase inhibitors do not disrupt estrogen binding, the deleterious effect associated with CC may be avoided.[7] Other potential benefits of anastrozole include no significant accumulation in the blood [8] and a shorter half-life than CC.[9]

The objective of this study was to compare 1 mg anastrozole with 50 mg CC in terms of follicular development and ovulation in infertile women with ovulatory dysfunction.


  Methodology Top


This is a prospective study of ovulatory pattern following use of CC and Anastrozole in female infertility in a rural population attending the OBGY outpatient department (OPD) in AVBRH Sawangi (Meghe) Wardha. This study has been conducted for 2 years from September 2013 to August 2015.

Infertile women with ovulatory dysfunction were recruited, aged 18–35 years, inclusive, with a body mass index <35.0 kg/m 2, two patent fallopian tubes, and two functional ovaries. The patients' usual cycle length had to be either <21 or >35 days with six or more menses per year or >35 days with fewer than six menses per year. All patients provided written informed consent. A total of 100 women with infertility attending Obstetrics and Gynecology OPD were included in the study.

In Group A (50 cases), ovulation inducing drug 50 mg of CC was used orally from 2nd to 6th day. In Group B (50 cases), daily oral dose of 1 mg/day was administered for 5 consecutive days starting at menstrual days 2nd–6th, for 3 cycles.

All these cases were subjected to ultrasonography (USG) for follicular study from 9th to 15th day of menstruation/till the day of ovulation.

In these cases, transvaginal ultrasonography (TVS) study was performed for follicular growth and endometrial thickness.

TVS was done on every alternate day from the 9th day of the cycle until follicular diameter was >18 mm and then on a daily basis until ovulation was observed. Criteria for treatment discontinuation included an excessive response (four or more follicles >17 mm in diameter, with or without ovulation).


  Observation and Results Top


This is a prospective study of ovulatory pattern following the use of CC and Anastrozole in female infertility in a rural population attending the Obstetrics and Gynecology OPD in AVBRH, Sawangi (Meghe) Wardha.

A total of 100 patients attended the first cycle of Group A (50 cases) and Group B (50 cases).

In Group A, 27 patients ovulated and 23 patients anovulated which underwent the second cycle, of 23, four patients lost follow up, 13 ovulated and 6 remained anovulated. Six patients underwent 3rd cycle, in which one patient lost follow up and four patients ovulated.

In Group B, 16 patients ovulated and 34 patients anovulated which underwent second cycle, of 34, six patients lost follow up, 17 ovulated and 11 remained anovulated. Eleven patients underwent 3rd cycle, in which two patients lost follow up and five patients ovulated [Table 1].
Table 1: Number of cycles attended by patients

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Treatment group was well matched in term of baseline demographic characteristics and gynecology history [Table 2].
Table 2: Baseline demographics and clinical characteristics

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In first treatment cycle, the mean rate of growth of follicle was 2.14 ± 0.53 mm in Group A and 1.68 ± 0.37 mm in Group B. The mean of the preovulatory size of the follicle in Group A was 20.92 ± 1.52 mm and in Group B was 19.87 ± 0.80 mm.

The mean day of ovulation was 14.81 ± 1.54 in Group A and in Group B was 15.43 ± 1.15.

Ovulation rate was 54% in Group A 1st treatment cycle. Ovulation rate was 32% in Group B 1st treatment cycle. The mean endometrial thickness was more in Group B than Group A (10.14 ± 1.07 vs. 8.23 ± 0.92) [Table 3].
Table 3: Outcomes in first treatment cycle

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In cumulative cycles, the mean rate of growth of follicle was 2.34 mm in Group A and 1.75 mm in Group B. The mean of the preovulatory size of the follicle in Group A was 21.23 ± 1.61 mm and in Group B was 20.18 ± 0.98 mm.

Ovulation rate was 59.4% in Group A cumulative cycles. Ovulation rate was 43.6% in Group B cumulative cycle. Mean endometrial thickness was more in Group B than Group A (8.78 ± 0.86 vs. 10.66 ± 44) [Table 4].
Table 4: Outcomes for cumulative cycles

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  Discussion Top


In this study, analysis of age revealed that the maximum of 51% of cases was in the age group of 26–30 years. This higher incidence in the age group of 26–30 years is probably because the age of marriage in our area is approximately 22 years.[10] Hence, most of the women came, after 3–4 years of waiting for spontaneous conception, after the age of 26 years.

The decline of fecundability begins in the early 30s and accelerates during the late 30s and early 40 s.[11] The age-related decline infertility appears to be attributable to oocyte depletion.[12]

Analysis of duration of infertility had shown that through 66% of cases sought medical advice in 1–4 years of infertility, 34% came 4 years of infertility. The delay in seeking medical advice is probably due to the fact that our hospital is a rural based hospital and it drains maximum patient from rural population, who are mostly illiterate and ignorant and go to the local persons due to superstitions and seek medical advice as a last resort in present study analysis of follicular growth in 1st treatment cycle revealed that the mean follicular growth rate in Group A, was 2.14 ± 0.53 mm and in Group B was 1.68 ± 0.37 mm.

In Group A, the mean of cumulative rate of growth of follicle was 2.34/day and in Group B mean rate of growth of follicle was 1.75/day.

In this study, in Group A, the mean follicular size was 20.92 ± 1.52 mm and in Group B, it was 19.87 ± 0.80 mm, at the time of ovulation [Table 3] in the first cycle, it was found that the mean follicular diameter was higher in Group A at the time of ovulation, which was highly significant.

In cumulative cycles, Group A, mean follicular size was 21.23 ± 1.61 mm and In Group B, it was 20.18 ± 0.98 mm at the time of ovulation [Table 4].

USG showed free fluid in POD in 39.53% of cases, collaped or disappearance of the follicle in 23.25%, irregular margins in 18.6% of cases. Two signs (i.e. free fluid + collapsed, free fluid + irregular margins) of ovulation in 18.6% of cases.

In the present study, 58.13% of cases (majority) ovulated on 13th–15th day. In which 62.96% cases of Group A and 50% of cases of Group B ovulated on 13th–15th day with mean day of ovulation 14.81 ± 1.54 and 15.43 ± 1.15 in Group A and in Group B, respectively.

USG showed of the total 100 cases, 43 cases were ovulatory and 57 were anovulatory in 1st treatment cycle. In Group A, 54% cycles were ovulatory and 46%were anovulatory. In Group B 32% cycles were ovulatory and 68% were anovulatory [Table 3].

Overall ovulation in cumulative cycles was 59.4% in Group A and 43.6% in Group B. Other similar studies by Tredway et al.,[13] reported 65% in Group A and 36.7% in Group B [Table 4].

It was found that in Group B mean endometrial thickness, at the time of ovulation, was.[14] 14 + 1.07 mm which was more in Group B than in Group A (8.23 + 0.92 mm) [Table 3].

Comparing the mean endometrial thickness in the cumulative cycle following the use of the drug it was found that endometrial thickness is less in CC group [Table 4].

Anastrozole is a drug which can be used to increase the endometrial thickness in women who has thin endometrium [Table 4].

The possible explanation for this observation could be either histologic or ultrastructural abnormalities of endometrium due to the antiestrogenic effect of CC or endometrial estrogen receptor depletion by clomiphene citrate or both (Gonen and Casper, 1990).[15] This study is in full agreement with this concept.

Mitwally and Casper showed that aromatase inhibitors have minimal effects on the endometrium, compared with CC.

Cortínez et al.[16] found normal morphology of endometrium and full expression of pinopodes during the implantation window when aromatase inhibitors were used.

Correlating the age of women and the size of preovulatory follicle did not reveal any definite conclusion.

In this study, the analysis of the day of ovulation in relation to menstrual pattern revealed that In Group A, maximum of 59.26% of women with menstrual cycle of more than 35 days ovulated between 13th to 15th day of cycle, In Group B, 50% of cases with menstrual cycle of more than 35 days ovulated between 16th and 18th day of the cycle and 43.75% ovulated between 13th and 15th day. Hence, those with oligomenorrhea ovulated later than those with normal menstrual cycles During the study, cumulative pregnancy rate, in Group A was 13.63% and in Group B was 10.52% [Table 4].

From the present study, following conclusion is drawn:

Anovulation, infertility and oligomenorrhea are interrelated.

Follicles in CC cycles grow faster and are larger in size as compared to anastrozole cycles.

USG collapse or disappearance of the follicle, irregular margins of the follicle and free fluid in POD are reliable signs of ovulation. One or more than one sign should be looked for detecting ovulation. Transvaginal sonography remains the method of choice for follicular and endometrial thickness monitoring and detection of ovulation. Transvaginal sonography can be used for detection of ovulation and timed intercourse for achieving pregnancy in infertile women before subjecting them for cumbersome and expensive hormonal assay.

The present work indicates that CC has a stronger stimulatory effect on follicular growth and development and it is more effective in inducing ovulation in the patient as compared with Anastrozole. Hence, CC can be recommended as the first line drug for ovulation induction in cases with anovulatory infertility.

However, the result of this study showed that Anastrozole was associated with significantly fewer mature and growing follicle and thicker endometrium. Anastrozole may be helpful in situ ation in which multiple pregnancy is not desirable or in which the risk of ovarian hyperstimulation syndrome is high.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Homburg R. Clomiphene citrate – End of an era? A mini-review. Hum Reprod 2005;20:2043-51.  Back to cited text no. 1
    
2.
Mitwally MF, Casper RF. Aromatase inhibition: A novel method of ovulation induction in women with polycystic ovary syndrome. Reprod Technol 2001;10:244-7.  Back to cited text no. 2
    
3.
Mikkelson TJ, Kroboth PD, Cameron WJ, Dittert LW, Chungi V, Manberg PJ. Single-dose pharmacokinetics of clomiphene citrate in normal volunteers. Fertil Steril 1986;46:392-6.  Back to cited text no. 3
    
4.
Mitwally MF, Casper RF. Aromatase inhibitors for the treatment of infertility. Expert Opin Investig Drugs 2003;12:353-71.  Back to cited text no. 4
    
5.
Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001;75:305-9.  Back to cited text no. 5
    
6.
Fisher SA, Reid RL, Van Vugt DA, Casper RF. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril 2002;78:280-5.  Back to cited text no. 6
    
7.
Mitwally MF, Casper RF. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders. Fertil Steril 2002;77:776-80.  Back to cited text no. 7
    
8.
Mitwally MF, Casper RF. Aromatase inhibition reduces gonadotrophin dose required for controlled ovarian stimulation in women with unexplained infertility. Hum Reprod 2003;18:1588-97.  Back to cited text no. 8
    
9.
Kafy S, Tulandi T. New advances in ovulation induction. Curr Opin Obstet Gynecol 2007;19:248-52.  Back to cited text no. 9
    
10.
11.
Aubuchon M, Burney RO, Schust DJ, Yao MW. Infertility and assisted reproductive technology. In: Novak's Gynecology. 15th ed., Ch. 32. USA: Williams and Wilkins; 2013. p. 1133.  Back to cited text no. 11
    
12.
Gosden RG, Faddy MJ. Ovarian aging, follicular depletion, and steroidogenesis. Exp Gerontol 1994;29:265-74.  Back to cited text no. 12
    
13.
Tredway D, Schertz JC, Bock D, Hemsey G, Diamond MP. Anastrozole vs. clomiphene citrate in infertile women with ovulatory dysfunction: A phase II, randomized, dose-finding study. Fertil Steril 2011;95:1720-4.e1-8.  Back to cited text no. 13
    
14.
Holzer H, Casper R, Tulandi T. A new era in ovulation induction. Fertil Steril 2006;85:277-84.  Back to cited text no. 14
    
15.
Gonen Y, Casper RF. Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation for in vitro fertilization (IVF) J In Vitro Fert Embryo Transf 1990;7:146-52.  Back to cited text no. 15
    
16.
Cortínez A, De Carvalho I, Vantman D, Gabler F, Iñiguez G, Vega M. Hormonal profile and endometrial morphology in letrozole-controlled ovarian hyperstimulation in ovulatory infertile patients. Fertil Steril 2005;83:110-5.  Back to cited text no. 16
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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