Observational Study Medicine ®

OPEN

Letrozole for patients with polycystic ovary

syndrome
A retrospective study
∗
Hui-juan Guang, MBa, Feng Li, MBb, Jun Shi, MBc,

Abstract
This retrospective study investigated the efficacy and safety of letrozole for patients with polycystic ovary syndrome (PCOS).
Totally, 136 cases of infertility women with PCOS were analyzed. Of those, 68 patients received letrozole, and were assigned to
Letrozole group. The other 68 cases received clomiphene, and were assigned to clomiphene group. Patients in both groups were
treated up to 5 treatment cycles. The primary endpoint included infant outcomes. The secondary endpoints consisted of the number
of women in conception, pregnancy, pregnancy loss, and ovulation. In addition, any kinds of adverse events were also recorded.
Cases in the Letrozole group did not show better outcomes neither in primary endpoint (live birth, P = .11; birth weight, P = .95;
infant gender, P = .85), nor in secondary endpoints (the number of women in conception, P = .07; pregnancy, P = .12; pregnancy
loss, P = .47; pregnancy loss in first trimester, P = .70; and ovulation, P = .09), compared with cases in the clomiphene group.
Moreover, no adverse events differ significantly between 2 groups.
This study demonstrated that the efficacy of letrozole is not superior to the clomiphene in patients with PCOS.
Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKbH4TTImqenVFccdJZs1d9VqiRzevcfO38v9spmA7X6mEg/QnltcwRE on 11/22/2018

Abbreviation: PCOS = polycystic ovary syndrome.

Keywords: clomiphene, efficacy, letrozole, polycystic ovary syndrome

1. Introduction Letrozole is an aromatase inhibitor that was used as an

ovulation inductor in anovulatory infertility women with more
Polycystic ovary syndrome (PCOS) is one of the most causes that
than 56 mm endometrial thickness.[23,24] It inhibits estrogen
affect the women of childbearing age,[1–4] and often leads to
production by repressing the enzyme aromatase.[25] It has been
infertility.[5–7] It is diagnosed based on the hyperandrogenism,
reported that letrozole can inhibit estrogen levels by at least 97%
oligomenorrhea, and polycystic ovaries on ultrasonography.[8–
10] to 99%.[26] The other studies also reported that letrozole is
Its prevalence has been reported to vary from 6.8% to 18%
effective in clomiphene-resistant patients, and also resulted in
according to the different diagnostic criteria.[11,12] Its symptoms
ovulation of 62% cases, and pregnancy of 14.7%.[27,28]
often bring psychologic disorders for patients with PCOS.[13,14]
Additionally, no adverse events have been reported on fetus.[28]
These conditions often consist of depression, anxiety, irregular
However, current data are still insufficient to support the idea
menstrual periods, and even the infertility.[14–17]
that letrozole can be utilized effectively to treat such condition.
Various managements were proposed for infertile women with
Therefore, in this retrospective study, we investigated the efficacy
PCOS.[18–20] However, the optimal management option has not
and safety of letrozole for infertility women with PCOS.
been addressed satisfied. Although multiple treatments including
weight reduction, clomiphene citrate, metformin, gonadotropins,
and ovary cauterization have been reported to treat such condition, 2. Materials and methods
the efficacy still has insufficient evidence to support.[21,22]
2.1. Ethics
This retrospective study was approved by the Ethical Committee
Editor: Qinhong Zhang. of Hanzhong People’s Hospital, and The Ninth Hospital of
The authors have no funding and conflicts of interest to disclose. Xi’an. It was conducted based on the Declaration of Helsinki. All
a
Department of Gynecology, b Department of Ultrosound, Hanzhong People’s patients provided the written informed consent form.
Hospital, Hanzhong, c Department of Gynecology, The Nineth Hospital of Xi’an,
Shaanxi, China.
∗
Correspondence: Jun Shi, Department of Gynecology, The Nineth Hospital of
2.2. Design
Xi’an, East section No 151 of S. 2nd Huan Road, Xi’an, Shaanxi 710054, China A total of 136 cases of infertility women with PCOS were analyzed
(e-mail: [email protected]).
in this retrospective study. All cases were completed from January
Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.
2016 to December 2017 at Hanzhong People’s Hospital, and The
This is an open access article distributed under the terms of the Creative
Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is Ninth Hospital of Xi’an. Sixty-eight cases underwent letrozole, and
permissible to download, share, remix, transform, and buildup the work provided were assigned as a Letrozole group. The other 68 cases received
it is properly cited. The work cannot be used commercially without permission clomiphene, and were assigned as a clomiphene group. No
from the journal. randomization and blinding were applied, except the data analyst
Medicine (2018) 97:44(e13038) was blinded in this study. All the cases were allocated to the
Received: 14 September 2018 / Accepted: 8 October 2018 different groups according to the different treatments they received.
http://dx.doi.org/10.1097/MD.0000000000013038 All cases in both groups received the treatment up to 5 cycles.

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Guang et al. Medicine (2018) 97:44 Medicine

2.3. Patients Table 1

All cases of infertile women with PCOS from 18 to 45 years old Comparison of patient characteristics between 2 groups.
were analyzed in this study. The PCOS was diagnosed by Letrozole group Clomiphene group
modified Rotterdam criteria.[29] All included cases had no major Variable (n = 68) (n = 68) P
medical disorders, and their male partners were also required to Age, y 28.3 (6.7) 27.5 (7.1) .50
participate in this study. Moreover, all subjects had ovulatory Race (Asian China) 68 (100.0) 68 (100.0) –
dysfunction, polycystic ovaries, or increased ovarian vol- Occupation
ume.[30,31] Furthermore, all patient cases had normal uterine Employed 63 (92.6) 60 (88.2) .39
cavity, and at least 1 patent fallopian tube. The sperm Unemployed 5 (7.4) 8 (11.8) –
concentration of a male partner should have at least 14 Body mass index 28.4 (3.3) 27.8 (3.7) .32
million/mL, and both couples are committed to have regular Duration of infertility, y 4.3 (3.2) 4.6 (3.4) .60
intercourse during the study period. However, patients were Oligomenorrhea 51 (75.0) 55 (80.9) .41
excluded if they had taken confounding medications, such as Menometrorrhagia 2 (2.9) 3 (4.4) .65
Regular menstruation 15 (22.1) 10 (14.7) .27
primarily sex steroids, and mimic PCOS. In addition, cases were
Hirsutism 20 (29.4) 18 (26.5) .70
also excluded if they previously received the study medication History of previous miscarriage 16 (23.5) 15 (22.1) .84
within past 3 months. Mean luteinizing hormone on 10.1 (4.0) 10.0 (4.2) .89
day 3 of menstruation, mlU/mL
2.4. Treatment schedule Mean follicle-stimulating hormone on 5.3 (1.9) 5.2 (2.1) .77
day 3 of menstruation, mlU/mL
The 68 patients in the Letrozole group received letrozole, 2.5 mg Mean thyroid-stimulating hormone, 1.8 (0.8) 1.9 (0.7) .44
per pill daily, and the other 68 subjects in the clomiphene group mlU/mL
taken clomiphene, 50 mg per pill daily. All patients in both Mean estradiol on day 3 of 91.1 (22.4) 90.7 (21.8) .92
groups underwent letrozole or clomiphene starting on cycle day 3 menstruation, pg/mL
for consecutive 5 days for up to 5 menstrual cycles. If there was a Data are present as mean ± standard deviation or number.
nonresponse or a poor ovulatory response occurred, the dose was
increased in subsequent cycles in the either group. The maximum
daily dose of letrozole was 7.5 mg, and clomiphene was 150 mg.
ovulation (P = .09, Table 3), compared with patients who
received clomiphene.
2.5. Outcome measurements The adverse events in both groups are listed in Table 4. There
The primary endpoint was infant outcome. The secondary were not significant differences in all adverse events between 2
endpoints comprised of the number of women in conception, groups. No treatment related death in women occurred in either
pregnancy, pregnancy loss, and ovulation. Additionally, adverse group, except 1 fetal death in the clomiphene group (Table 4).
events were also recorded during the treatment period.
4. Discussion
2.6. Statistical analysis Letrozole plays very important role in the treatment of infertility
The sample size was calculated based on the previous published women with PCOS. However, its efficacy is still inconsistent,
study with an ovulation rate of 53.3%.[32] Thus, the desired especially when compared with clomiphene.
sample size for each group was estimated to be 68 patients with Previous systematic review and meta-analysis reported that
25% difference between 2 groups, and a power of 80% in letrozole could significantly enhance the live birth and pregnancy
this study. rates in patients with PCOS.[33,34] However, the other meta-
All outcome and characteristic values were analyzed by using analysis did not find positive efficacy of letrozole when compared
SPSS software (SPSS V.17.0, IBM Corp, Armonk, NY). Contin- with clomiphene.[35,36] The results of the present study are
uous non-normally value was analyzed by Mann–Whitney U test, consistent with the previous studies.[35,36]
while normally variables were performed by t test. Categorical The results of this retrospective study showed that no
value was conducted by Chi-squared test. P <.05 was defined as significant differences of adverse events were detected between
having a statistical significance. 2 groups. In addition, patients in the Letrozole group did not
exert better outcomes in primary endpoint of live birth, birth
weight, and infant gender; and also in secondary endpoints of the
3. Results
A total of 136 cases of infertility women with PCOS were
Table 2
analyzed in this retrospective study. All the characteristic values
Comparison of primary endpoints between 2 groups.
of included cases are showed in Table 1. No significant
differences regarding all values were detected between 2 groups Primary endpoints Letrozole group (n = 68) Clomiphene group (n = 68) P
in this study. Live birth 20 (29.4) 12 (17.6) .11
The results showed that patients who received letrozole did not Singleton 18/20 (90.0) 12/12 (100.0) .44
exert better outcomes in neither primary endpoint, including live Twin 2/20 (10.0) 0/12 (0) –
birth (P = .11, Table 2), birth weight (P = .95, Table 2), infant Birth weight, g 3251.7 (533.6) 3246.0 (601.4) .95
gender (P = .85, Table 2); nor the secondary endpoints, Infant gender
comprising of the number of women in conception (P = .07, Male 11/20 (55.0) 7/12 (58.3) .85
Female 9/20 (45.0) 5/12 (41.7) –
Table 3), pregnancy (P = .12, Table 3), pregnancy loss (P = .47,
Table 3), pregnancy loss in first trimester (P = .70, Table 3), and Data are present as mean ± standard deviation or number (%).

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Guang et al. Medicine (2018) 97:44 www.md-journal.com

Table 3 Software: Hui-juan Guang.

Comparison of secondary endpoints between 2 groups. Supervision: Jun Shi, Feng Li.
Validation: Jun Shi, Hui-juan Guang.
Letrozole group Clomiphene group
Visualization: Jun Shi.
Secondary endpoints (n = 68) (n = 68) P
Writing – original draft: Jun Shi, Hui-juan Guang, Feng Li.
No. of women with conception 27 (39.7) 17 (25.0) .07 Writing – review & editing: Jun Shi, Hui-juan Guang, Feng Li.
No. of women with pregnancy 22 (32.4) 14 (20.6) .12
No. of women with pregnancy loss 5 (7.4) 3 (4.4) .47
No. of women with pregnancy 4 (5.9) 3 (4.4) .70 References
loss in first trimester
[1] Meier RK. Polycystic ovary syndrome. Nurs Clin North Am
No. of women with ovulation 59 (86.8) 51 (75.0) .09 2018;53:407–20.
Data are present as number (%).
[2] Marciniak A, Lejman-Larysz K, Nawrocka-Rutkowska J, et al.
Polycystic ovary syndrome - current state of knowledge. Pol Merkur
Lekarski 2018;44:296–301.
[3] Smyka M, Grzechocinska B, Wielgos M. The role of lifestyle changes in
the treatment of polycystic ovary syndrome. Neuro Endocrinol Lett
Table 4 2018;38:521–7.
Comparison of adverse events between 2 groups. [4] Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology,
diagnosis and treatment. Nat Rev Endocrinol 2018;14:270–84.
Letrozole group Clomiphene group
[5] Tanbo T, Mellembakken J, Bjercke S, et al. Ovulation induction in
Adverse events (n = 68) (n = 68) P polycystic ovary syndrome. Acta Obstet Gynecol Scand 2018;97:
Hot flushes 15 (22.1) 23 (33.8) .13 1162–7.
Fatigue 15 (22.1) 9 (13.2) .18 [6] Legro RS. Ovulation induction in polycystic ovary syndrome: current
options. Best Pract Res Clin Obstet Gynaecol 2016;37:152–9.
Dizziness 8 (11.8) 5 (7.4) .39
[7] Joham AE, Palomba S, Hart R. Polycystic ovary syndrome, obesity, and
Ectopic pregnancy 1 (1.5) 0 (0) .50
pregnancy. Semin Reprod Med 2016;34:93–101.
Heterotopic pregnancy 0 (0) 1 (1.5) .50 [8] Kamboj MK, Bonny AE. Polycystic ovary syndrome in adolescence:
Hospitalization 1 (1.5) 2 (2.9) .57 diagnostic and therapeutic strategies. Transl Pediatr 2017;6:248–55.
Congenital anomaly 1 (1.5) 0 (0) .50 [9] The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop
Fetal death 0 (0) 1 (1.5) .50 GroupRevised 2003 consensus on diagnostic criteria and long-term
health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:
Data are present as mean (range). 19–25.
HADS = hospital anxiety and depression scale. [10] The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop
GroupRevised 2003 consensus on diagnostic criteria and long-term
health risks related to polycystic ovary syndrome (PCOS). Hum Reprod
2004;19:41–7.
number of women with conception, pregnancy, pregnancy loss, [11] Teede H, Deeks A, Moran L. Polycystic ovary syndrome: a complex
condition with psychological, reproductive and metabolic manifes-
pregnancy loss in first trimester, and ovulation, compared with
tations that impacts on health across the lifespan. BMC Med
subjects in the clomiphene group. Additionally, no significant 2010;8:41.
differences in adverse events were found between 2 groups. It [12] Saad AK. Polycystic ovary syndrome: diagnosis and management of
indicated that letrozole and clomiphene have similar efficacy and related infertility. Obstet Gynaecol Reprod Med 2009;19:263–70.
safety in treating infertility women with PCOS. [13] Cipkala-Gaffin J, Talbott EO, Song MK, et al. Associations between
psychologic symptoms and life satisfaction in women with polycystic
This retrospective study had several following limitations. First ovary syndrome. J Womens Health (Larchmt) 2012;21:179–87.
of all, the sample size was still relative small, which may affect the [14] Cooney LG, Dokras A. Depression and anxiety in polycystic ovary
results of this study. Then, this retrospective study had its own syndrome: etiology and treatment. Curr Psychiatry Rep 2017;19:83.
intrinsic limitation, which may impact its results. Thirdly, this [15] Butterworth J, Deguara J, Borg CM. Bariatric surgery, polycystic ovary
syndrome, and infertility. J Obes 2016;2016: 1871594.
study did not include comprehensive endpoints, such as quality of
[16] Bergh CM, Moore M, Gundell C. Evidence-based management of
life in infertility women with PCOS, because it just analyzed the infertility in women with polycystic ovary syndrome. J Obstet Gynecol
outcome data based on the completed cases only. Fourth, this Neonatal Nurs 2016;45:111–22.
study did not utilize randomization and blinding, which may [17] Aubuchon M, Legro RS. Polycystic ovary syndrome: current infertility
increase the risk of case selection. Therefore, the future studies management. Clin Obstet Gynecol 2011;54:675–84.
[18] Zhou J, Yang L, Yu J, et al. Efficacy of acupuncture on menstrual
should avoid all these limitations. frequency in women with polycystic ovary syndrome: Protocol for a
randomized, controlled trial. Randomized controlled trial. Medicine
(Baltimore) 2017;96:e8828.
5. Conclusion [19] Zeng XL, Zhang YF, Tian Q, et al. Effects of metformin on pregnancy
The results of this retrospective study did not find that the efficacy outcomes in women with polycystic ovary syndrome: A meta-analysis.
Medicine (Baltimore) 2016;95:e4526.
of letrozole is superior to clomiphene for the treatment of [20] Wang J, Zhu L, Hu K, et al. Effects of metformin treatment on serum
infertility women with PCOS. levels of C-reactive protein and interleukin-6 in women with polycystic
ovary syndrome: a meta-analysis: a PRISMA-compliant article. Medicine
(Baltimore) 2017;96:e8183.
Author contributions [21] Jirege PR, Patill RS. Comparison of endocrine and ultrasound profiles
during ovulation induction with clomiphene citrate and letrozole in
Conceptualization: Jun Shi, Hui-juan Guang, Feng Li. ovulatory volunteer women. Fertil Steril 2010;93:174–83.
Data curation: Jun Shi, Hui-juan Guang, Feng Li. [22] Rouzi AA, Ardawi MS. A randomized controlled trial of the efficacy of
Formal analysis: Hui-juan Guang. rosiglitazone and clomiphene citrate versus metformin and clomiphene
Investigation: Jun Shi, Feng Li. citrate in women with clomiphene citrate-resistant polycystic ovary
syndrome. Fertil Steril 2006;85:428–35.
Methodology: Hui-juan Guang. [23] Franik S, Eltrop SM, Kremer JA, et al. Aromatase inhibitors (letrozole)
Project administration: Feng Li. for subfertile women with polycystic ovary syndrome. Cochrane
Resources: Jun Shi, Feng Li. Database Syst Rev 2018;5:CD010287.

3
Guang et al. Medicine (2018) 97:44 Medicine

[24] Hu S, Yu Q, Wang Y, et al. Letrozole versus clomiphene citrate in from a multicenter randomized clinical trial. Fertil Steril 2014;101:
polycystic ovary syndrome: a meta-analysis of randomized controlled 258–69.
trials. Arch Gynecol Obstet 2018;297:1081–8. [31] Legro RS, Schlaff WD, Diamond MP, et al. Total testosterone assays in
[25] Rajan RK, M SS, Balaji B. Soy isoflavones exert beneficial effects on women with polycystic ovary syndrome: precision and correlation with
letrozole-induced rat polycystic ovary syndrome (PCOS) model through hirsutism. J Clin Endocrinol Metab 2010;95:5305–13.
anti-androgenic mechanism. Pharm Biol 2017;55:242–51. [32] Palomba S, Orio FJr, Nardo LG, et al. Metformin administration versus
[26] Pavone ME, Bulun SE. Clinical review: the use of aromatase inhibitors laparoscopic ovarian diathermy in clomiphene citrateresistant women
for ovulation induction and superovulation. J Clin Endocrinol Metab with polycystic ovary syndrome: a prospective parallel randomized
2013;98:1838–44. double-blind placebo-controlled trial. J Clin Endocrin Metab 2004;89:
[27] Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of 4801–9.
ovulation in patients with an inadequate response to clomiphene citrate. [33] Ray PB, Ray A, Chakraborti PS. Comparison of efficacy of letrozole and
Fertil Steril 2001;75:305–9. clomiphene citrate in ovulation induction in Indian women with
[28] Abu Hashim H, Shokeir T, Badawy A. Letrozole versus combined polycystic ovarian syndrome. Arch Gynecol Obstet 2012;285:873–7.
metformin and clomiphene citrate for ovulation induction in clomiphene- [34] Roy KK, Baruah J, Singla S, et al. A prospective randomized trial
resistant women with polycystic ovary syndrome: a randomized comparing the efficacy of letrozole and clomiphene citrate in induction of
controlled trial. Fertil Steril 2009;94:1405–9. ovulation in polycystic ovarian syndrome. J Hum Reprod Sci 2012;5:20–5.
[29] Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop [35] He D, Jiang F. Meta-analysis of letrozole versus clomiphene citrate in
GroupRevised 2003 consensus on diagnostic criteria and long-term polycystic ovary syndrome. Reprod Biomed Online 2011;23:91–6.
health risks related to polycystic ovary syndrome. Fertil Steril 2004;81: [36] Requena A, Herrero J, Landeras J, et al. Reproductive Endocrinology
19–25. Interest Group of Spanish Society of Fertility. Use of letrozole in assisted
[30] Legro RS, Brzyski RG, Diamond MP, et al. The Pregnancy in Polycystic reproduction: a systematic review and metaanalysis. Hum Reprod
Ovary Syndrome II study: baseline characteristics and effects of obesity Update 2008;14:571–82.