POLYCYSTIC OVARY SYNDROME N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate-resistant patients with polycystic ovary syndrome Ahmed Y. Rizk, M.D.,a Mohamed A. Bedaiwy, M.D.,b and Hesham G. Al-Inany, M.D.c
a Department of Obstetrics and Gynecology, Benha University, Benha; b Department of Obstetrics and Gynecology AssiutSchool of Medicine, Assiut; and c Department of Obstetrics and Gynecology, Cairo University, Cairo, Egypt
Objective: To evaluate the effect of N-acetyl-cysteine (NAC), a mucolytic drug with insulin sensitizing properties, as an adjuvant therapy in subjects with polycystic ovary syndrome (PCOS) resistant to clomiphene citrate (CC). Design: Placebo-controlled, double-blind randomized trial. Setting: University-based hospital and private infertility practice. Patient(s): One hundred fifty women diagnosed with CC-resistant PCOS, aged 18 -39 years undergoing therapy for infertility were included. Intervention(s): The patients were assigned randomly to receive either NAC 1.2 g/d (group I) or placebo (group II) with CC 100 mg/d for 5 days starting at day 3 of the cycle. Main Outcome Measure(s): Ovulation rate and pregnancy rate (PR). Result(s): Combination of CC and NAC significantly increased both ovulation rate and PR in women with CC-resistant PCOS (49.3% vs. 1.3% and 21.3% vs. 0%, respectively). No cases of ovarian hyperstimulation syndrome (OHSS) were reported in the NAC group; two cases of miscarriage (12.5%) were reported. Conclusion(s): The NAC as an adjuvant to CC was more effective than placebo for CC-resistant patients with PCOS. It is safe and well tolerated. (Fertil Steril 2005;83:367-70. 2005 by American Society for Reproductive Medicine.) Key Words: N-acetyl-cysteine, polycystic ovary syndrome, clomiphene citrate resistance, pregnancy
Polycystic ovary syndrome (PCOS) affects up to 10% of
A promising agent is N-acetyl-cysteine (NAC). It is a safe
women of reproductive age, in which hyperandrogenism,
and well-tolerated mucolytic drug that softens tenacious
enlarged cystic ovaries, and chronic anovulation often coex-
mucous secretions. It is the acetylated precursor of both
ist with obesity, hyperinsulinemia, and insulin resistance
amino acid L-cysteine and reduced glutathione It has
Obesity in women with PCOS is rather high, ranging
been shown to have proven activity on insulin secretion in
from 30%- 60% whereas hyperinsulinemia is present in
pancreatic cells, as well as on the regulation of the insulin
more than 50% of patients with PCOS.
receptor in human erythrocytes In addition, it is a pow-erful antioxidant and a potential therapeutic agent in the
Clomiphene citrate (CC) therapy has variable success
treatment of cancer, and other diseases characterized by the
rates in anovulatory women; however, it is the lowest in
generation of free oxygen radicals The peak plasma level
women with PCOS, particularly those with insulin resis-
of NAC is attained 1 hour after an oral dose and it disappears
tance. Currently there is increasing evidence that insulin
from the plasma after 12 hours. The biological activity of
sensitizers are particularly effective in inducing ovulation
NAC is attributed to its sulfhydryl group, which enhances
in patients with PCOS However, not all cases respond
glutathione-S-transferase activity aiding in the protection of
to insulin sensitizers Exploring other mechanisms to
induce or augment ovulation in CC-resistant patients is adesirable goal in reproductive medicine.
To our knowledge, the potential reproductive effects of
NAC were never evaluated. The NAC may be a noveltreatment option for augmenting or inducing ovulation in
Received March 31, 2004; revised and accepted July 16, 2004.
patients with chronic anovulation including PCOS. Conse-
Presented at the 20th annual meeting of the European Society of Human
quently, the current study was performed to evaluate the
Reproduction and Embryology, Berlin, Germany, June 27-30, 2004.
effect of NAC administration as an adjuvant to CC on
Reprint requests: Ahmed Rizk, M.D., Benha University, P.O. 113, Benha,
ovulation and pregnancy rates (PR) as compared to placebo
Kaloubia, Egypt (FAX: 002-013-26-70-80; E-mail: ahmadrezk@yahoo. com).
Fertility and Sterilityா Vol. 83, No. 2, February 2005
Copyright 2005 American Society for Reproductive Medicine, Published by Elsevier Inc. MATERIALS AND METHODS
ipant had only one treatment cycle. Allocation was done by
The present study was conducted in a university-based hos-
a third party (nurse). The NAC and placebo were supplied in
pital and private infertility practice between March 2002 and
identical sachets. The patients and the physician monitoring
November 2003. We studied 150 women affected by PCOS,
the cycles were blinded to the identity of each medication.
aged 18 -39 years. As described elsewhere PCOS wasdiagnosed by a finding of bilaterally normal or enlarged
ovaries (ovarian volume Ͼ12 cm3) with the presence of at
The primary outcome was the ovulation rate in the treatment
least 7-10 peripheral cysts per ovary. No patient showed
cycle. Secondary outcomes included PR, number of follicles of
hyperprolactinemia, clinical evidence of hypercorticism, or
Ն18 mm, the serum E concentration, serum P, and endome-
thyroid dysfunction. All patients had to have at least one
trial thickness. The major safety end points were the incidence
patent fallopian tube observed at hysterosalpingography or
of ovarian hyperstimulation syndrome (OHSS) and multiple
laparoscopy. The patients' male partners underwent a semen
gestations. An ongoing pregnancy was defined as a viable
analysis and the results were determined to be adequate
pregnancy at least 12 weeks after hCG administration.
according to the latest WHO guidelines.
Eligible patients could not have been receiving any hor-
monal medications except P for withdrawal bleeding for 2
months before the study. No patient had taken any medica-
Estradiol was measured with an RIA using direct double-
tion known to affect carbohydrate metabolism for at least 3
antibody kits (Pantex, Santa Monica, CA). The assay sensi-
months before the study. The body mass index (BMI) was
tivity was 10 pg/mL. The interassay and intra-assay preci-
calculated according to the following formula: body weight
sion of low, middle, and high controls were 14.2% and 16%,
in kilograms/height in meters squared and obesity was de-
10.6% and 7.9%, and 11.4% and 4.2%, respectively. Folli-
fined as BMI Ͼ30 kg/m2. Informed consent was obtained
cle-stimulating hormone and LH were measured with the
from each patient before the entry into the study. The study
fluorimetric enzyme immunoassay kits (Baxter Diagnostics
was approved by Benha School of Medicine Institutional
Inc., Miami, FL). The assay sensitivity of both assays was
0.3 mIU/mL. The interassay and intra-assay precision oflow, middle, and high controls were 1.5% and 4.3%, 2.95%
Patients who met the inclusion criteria were found to have
and 2.1%, and 3.15% and 3%, respectively, for FSH. For
CC resistance, which was defined as lack of ovulation after
LH, the values were 6.35% and 8.1%, 2.9% and 1.9%, and
treatment with CC, 100 mg, for 5 days in three consecutive
2.8% and 2.5%, respectively. Progesterone was measured
with an RIA using the antibody coated-tube method (Coat-A-Count; Diagnostic Products Corporation, Los Angeles,
CA). The sensitivity of this assay was 0.02 ng/mL. The
Amenorrheic patients began treatment with induction of
interassay precision of low, middle, and high controls for the
menses using P-in-oil (100 mg). On day 3, each patient
assay was 8.8%, 3.6%, and 3.9%, respectively. Insulin was
underwent a baseline ultrasonographic examination. Clomi-
measured with Axsym insulin diagnostic division 100 (Ax-
phene citrate, 100 mg, was given from day 3 until day 7. In
sym; Abbot, IL). The sensitivity of the assay was 6 -24
addition to the CC, each patient was selected randomly to
mIU/mL. The interassay and intra-assay precision of low,
receive either NAC (Sedico, Cairo, ARE), in a dose of 1.2
middle, and high controls were 6 -10 u/mL, 32- 48 u/mL,
g/d orally, or a placebo (sugar) of the same volume twice
daily from day 3 until day 7. Monitoring of the cycle in-cluded transvaginal determination of the mean follicular
diameter and measurement of serum E levels. Monitoring
The proportion of pregnancies that occurred in each group
intervals were determined by patient response. Human cho-
was compared with Fisher's exact test. Comparisons of
rionic gonadotropin was administered when at least one
serum levels between the NAC and placebo groups were
follicle measured 18 mm and the E level had increased.
analyzed with Student's t test. A P level of Ͻ.05 was
Timed intercourse was advised 24 -36 hours after hCG
injection. A serum P level was checked on cycle days 21-22. A serum hCG level was determined 14 days after hCG
injection if menses had not yet occurred. Pregnancy wasdefined as an increase in the serum hCG level on serial
A total of 150 patients were randomized to (NAC: n ϭ 75;
determinations at least 2 days apart.
placebo: n ϭ 75) in a total of 150 CC cycles. As shown inthere was no difference in age, infertility duration,BMI, weight/height, and in FSH/LH during the cycles in
Randomization and Blinding
which NAC or placebo was given. All participants had BMI
In both groups, patients were randomized to receive CC and
Ͼ25 kg/m2 and the mean BMI in both groups was Ͼ30
either NAC or placebo using sealed envelopes. Each partic-
kg/m2 (obese). The mean E level and the number of follicles
Use of N-acetyl-cysteine in patients with PCOS Comparison of the baseline features and clinical outcomes of the two treatment groups. Variable P value
aOnly one follicle was shown to be more than 18 mm in one patient. Rizk. Use of N-acetyl cysteine in patients with PCOS. Fertil Steril 2005.
Ͼ18 mm at the time of hCG administration in the NAC
values The NAC is commonly used as a safe mucolytic
group were significantly higher than the placebo group.
drug, and at higher doses it increases the cellular levels of
Similarly, significantly higher ovulation rates as well as PRs
reduced glutathione, an antioxidant, which has been shown to
influence insulin receptor activity It has been shown thatNAC is able to improve insulin secretion in response to glucose.
There were five cases of multiple pregnancies in the NAC
Moreover, its administration was proposed for the prevention of
group. No cases of OHSS were reported. There were two
endothelial damage due to oxidant agents in non-insulin-depen-
cases of miscarriage (12.5%) (one singleton and one multiple
pregnancy). On performing subgroup analysis in the NACgroup, it was found that at insulin level Ͼ20 /mL there
More recently, it has also been shown to have other
were 8 pregnancies (one twin) of 35 (22.8%), whereas at
diverse biological effects, notably: antiapoptotic anti-
insulin Ͻ20 /mL, 8 pregnancies (three multiple pregnan-
oxidant protection against focal ischemia inhibi-
cies) of 40 (20%) were observed (odds ratio ϭ 1.14, 95%
tion of phospholipid metabolism, proinflammatory cytokine
confidence interval [CI] ϭ 0.38 -3.36).
release, and protease activity The NAC may exert thesame effects at the ovarian level and these activities may beas important as its insulin-enhancing effects in inducing
Clomiphene citrate failure is a frequent encounter in patientswith PCOS. Insulin resistance is a cause of CC failure in
In the current study, NAC was well tolerated by all the
patients with PCOS, not only in obese, but in lean patients as
patients and no adverse effects were observed. The results of
well In addition, hyperinsulinemia might influence
our study are encouraging. We obtained a significant in-
ovarian as well as adrenal steroidogenesis. Consequently,
crease of both ovulation and PRs in the NAC group. All
insulin-lowering drugs were proved effective in the treat-
participants in our study had only one cycle and this facili-
ment of patients with PCOS. The potential insulin-sensitiz-
tated completion of our study. In addition, the study partic-
ing properties of NAC in patients with PCOS were recently
ipants were on oral medications of well-known tolerability
explored To our knowledge, no previous study
and compliance. These two factors made this study achieve
focused on the reproductive functions as an end point as a
a high level of compliance and completion. Furthermore, no
result of NAC treatment in patients with PCOS.
manifestations of OHSS were reported.
Besides its insulin-sensitizing effect NAC treatment induced
Based on the previous hypothesis that NAC treatment is
a significant decrease in T levels and in free androgen index
effective only in those patients who were compromised from
a metabolic point of view the lack of any positive
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