You are on page 1of 9

doi: 10.1111/j.1472-8206.2010.00916.

REVIEW Pharmacotherapy of polycystic ovary

syndrome – an update
Fundamental & Clinical Pharmacology

Lekha Sahaa*, Sharonjeet Kaura, Pradip Kumar Sahab

Institute of Medical Education and Research (PGIMER), Department of Pharmacology, Postgraduate Institute of Medical
Education and Research (PGIMER), Chandigarh-160012, India
Department of OBG, Government Medical College and Hospital, Sector-32, Chandigarh-160030, India

melatonin, Polycystic ovary syndrome (PCOS) is a persisting challenge to clinical and basic
N-acetyl cysteine, research scientists as none of the presently available medications have been fully able
PCOS, to combat these consequences. The aim of the present review is to summarize the
pharmacotherapy, different lines of treatment available for the different symptomologies that women
statins with PCOS presents. In this comprehensive review, search was made for various
treatment options available for PCOS by using Cochrane library, Pubmed, Medline, in
Received 24 May 2010;
addition to the relevant printed medical journals and periodicals. The search results
revised 24 September 2010; revealed that oral contraceptives containing oestrogen and progesterone regularize
accepted 30 November 2010 the menstruation, antiandrogens like spironolactone and drosperinone have proven
to be effective in hirsutism and acne, clomiphene is the gold standard for ovulation
induction, but multiple pregnancies and clomiphene failure add to its limitation.
*Correspondence and reprints: Hence, aromatase inhibitors like letrozole, low-dose gondotropins, and ovarian
drilling procedure have shown to be beneficial effect in clomiphene-resistant cases.
Insulin sensitizers such as metformin, thiazolidinediones, and D-chiro-inositol
increase insulin sensitivity and improve ovulation rate. Recently, melatonin, N-
acetyl cysteine, acarbose, and statins have shown positive results in different
symptomologies of PCOS. The results show that PCOS treatment constitutes varied
line of treatment depending upon the clinical features with which a woman is
presenting. Still, unfortunately, none of the treatments are fully able to combat the

persisting challenge for clinical and basic research

Polycystic ovary syndrome (PCOS) is one of the most Three key diagnostic features of polycystic ovary
common endocrine disorders in women of reproductive syndrome are hyperandrogenism, chronic anovulation,
age and is the most frequent cause of hyperandrogenism and polycystic ovaries on ultrasonography [6,7]. Impor-
and oligoanovulation [1,2], both of which have sub- tantly, other conditions like congenital adrenal hyper-
stantial psychological, social, and economic conse- plasia, Cushing’s syndrome, and androgen-secreting
quences [3]. An increased awareness of this disorder in tumors which known to cause or to mimic the features
the general population and medical communities has of polycystic ovary syndrome must be excluded prior to
taken place in recent years with the knowledge diagnosis. Although obesity, insulin resistance, and
that women with polycystic ovary syndrome are sus- metabolic syndrome are frequently present in women
ceptible to metabolic syndrome [4,5] and its associated with polycystic ovary syndrome, they are not regarded
comorbidities. Therefore, polycystic ovary syndrome is a as intrinsic disturbances of the disorder. The prevalence

ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Société Française de Pharmacologie et de Thérapeutique
54 Fundamental & Clinical Pharmacology 26 (2012) 54–62
Pharmacotherapy in the treatment of PCOS 55

of polycystic ovary syndrome, as defined by the 1990 of assisted reproduction techniques (ART) [18]. Apart
National Institutes of Health (NIH) criteria, in unselected from this, weight loss, diet, and exercise have been
populations of women of reproductive age is between 6.5 shown to improve hyperinsulinemia, menstrual abnor-
and 8%. Mexican American women might have a higher malities, and ovulation rates [19].
prevalence of polycystic ovary syndrome than white or
black American women [8]. Immigrant populations from
the Indian subcontinent to the UK and Australian
women of aboriginal heritage also have a high preva- Menstrual irregularities
lence of polycystic ovary syndrome [9]. Adoption of the The abnormal hormonal concentrations characteristic
2003 Rotterdam criteria for the diagnosis of this disorder of polycystic ovary syndrome might predispose women
will presumably increase the prevalence of polycystic with this disorder to development of endometrial
ovary syndrome because the scope for inclusion is cancer, although the data that support this finding
broader than it is with the 1990 NIH criteria [10]. are not very convincing [20]. The number of men-
strual cycles is less important than the avoidance of
endometrial hyperplasia, and intermittent induction of
menstruation by any means, most commonly by
The potential health consequences of polycystic ovary progestagens or administration of oral contraceptives,
syndrome are a lifelong issue. There is little doubt that either cyclically or continuously, prevents abnormal
the prevalence of impaired glucose tolerance and uterine proliferation. Use of combined oral contracep-
diabetes mellitus is increased substantially in women tives is the most common treatment for the symptoms
with polycystic ovary syndrome [11,12]. Conversion of polycystic ovary syndrome because they interfere
rates of glucose tolerance from normal to abnormal are with androgen activity via several mechanisms, includ-
accelerated in polycystic ovary syndrome [13,14], and ing reduced androgen production, increased hepatic
up to 10% of women with this disorder develop diabetes SHBG synthesis, and competitive binding to androgen
during the third or fourth decade [15]. The evidence for receptors by some progestagens. However, the potential
increased cardiovascular disease in women with poly- long-term metabolic side effects of combined oral
cystic ovary syndrome is less clear, although cardio- contraceptives in women with polycystic ovary syn-
vascular risk factors are substantially increased, drome are being debated, especially as women with
including hyperlipidemia, hyperandrogenemia, hyper- this disorder have a propensity for the development of
tension, markers of a prothrombotic state, and markers obesity and metabolic abnormalities. Combined oral
of inflammation. Altered vascular and endothelial contraceptives have been shown to decrease insulin
function in young women with polycystic ovary syn- sensitivity, impair glucose tolerance, and alter lipid
drome is well documented, and increased death rates profiles in healthy populations of women, but seem-
from cardiovascular disease have been shown in ingly not to a degree that affects the risk of diabetes
women with menstrual irregularity (possibly with mellitus or cardiovascular disease [21]. Published work
polycystic ovary syndrome) [15]. There have been on the metabolic consequences of combined oral
several definitions of metabolic syndrome [16] and contraceptives in women with polycystic ovary syn-
several reports of an increased prevalence of metabolic drome is equivocal, and studies generally do not satisfy
syndrome in women with polycystic ovary syndrome the criteria for evidence-based medicine [21]. There-
[17]. fore, the assumption that the use of combined oral
contraceptives in women with the syndrome is safe is
premature, especially because women with this disor-
der often start taking oral contraceptives early in
Various interventions have been proposed for the treat- adolescence, continue taking them for long periods,
ment modalities of PCOS, but the optimal treatment for and are already susceptible to metabolic perturbations.
infertile women with PCOS has not yet been defined. Treatments that couple combined oral contraceptives
Pharmaceutical agents include clomiphene citrate (CC), with insulin sensitizers, antiandrogens, or both are
insulin-sensitizing agents, gonadotropins, and gonado- emerging with potential beneficial effects on metabolic
tropin-releasing hormone (GnRH) analogs; surgical abnormalities, especially in young women with the
include laparoscopic ovarian drilling and the application syndrome [22].

ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Société Française de Pharmacologie et de Thérapeutique
Fundamental & Clinical Pharmacology 26 (2012) 54–62
56 L. Saha et al.

Like NICE guidelines, the Society of Obstetrician and

Gynaecologist of Canada (SOGC) also provides guidelines
Women with polycystic ovary syndrome form the largest for ovulation induction [24]. The recommendations are
group of women with ovulatory dysfunction, which is as follows:
characterized by chronic anovulation in the presence of • Weight loss, exercise, and lifestyle modifications have
normal follicular stimulating hormone (FSH) and oestra- been proven effective in restoring ovulatory cycles and
diol concentrations. Induction of ovulation is the first-line achieving pregnancy in overweight women with PCOS
treatment for this class of anovulation and is aimed at and should be the first-line option for these women (level
introducing an endocrine milieu that promotes growth of evidence II-3A). Morbidly obese women should seek
and ovulation of a single dominant follicle with conse- expert advice about pregnancy risk (level of evidence
quent singleton pregnancy. According to the National III-A).
Institute of Clinical Excellence (NICE) guidelines [23], the • Clomiphene citrate has been proven effective in ovula-
recommendations for ovulation induction are as follows: tion induction for women with PCOS and should be
• Anti-oestrogens: Women with World Health Organiza- considered the first-line therapy. Patients should be
tion Group II ovulation disorders (hypothalamic pituitary informed that there is an increased risk of multiple
dysfunction) such as polycystic ovary syndrome should be pregnancies with ovulation induction using CC. (level of
offered treatment with clomifene citrate (or tamoxifen) as evidence I-A)
the first line of treatment for up to 12 months because it is • Metformin combined with CC may increase ovulation
likely to induce ovulation. Women should be informed of rates and pregnancy rates but does not significantly
the risk of multiple pregnancies associated with both improve the live birth rate over that of CC alone (level of
clomifene citrate and tamoxifen. evidence I-A). Metformin may be added to CC in women
• Metformin: Anovulatory women with polycystic ovary with clomiphene resistance who are older and who have
syndrome who have not responded to clomifene citrate visceral obesity (level of evidence I-A).
and who have a body mass index of more than 25 should • Gonadotropin should be considered second-line therapy
be offered metformin combined with clomifene citrate for fertility in anovulatory women with PCOS. The
because this increases ovulation and pregnancy rates. treatment requires ultrasound and laboratory monitor-
Women prescribed metformin should be informed of the ing. High costs and the risk of multiple pregnancy and
side effects associated with its use (such as nausea, ovarian hyperstimulation syndrome are drawbacks of
vomiting, and other gastrointestinal disturbances). the treatment (level of evidence II-2A).
• Ovarian drilling: Women with polycystic ovary syn- • Laparoscopic ovarian drilling may be considered in
drome who have not responded to clomifene citrate should women with clomiphene-resistant PCOS, particularly
be offered laparoscopic ovarian drilling because it is as when there are other indications for laparoscopy (level of
effective as gonadotropins treatment and is not associated evidence I-A). Surgical risks need to be considered in
with an increased risk of multiple pregnancies. these patients (level of evidence III-A).
• Gonadotropin: Women with World Health Organization • In vitro fertilization should be reserved for women with
Group II ovulation disorders such as polycystic ovary PCOS who fail gonadotropin therapy or who have other
syndrome who do not ovulate with clomifene citrate (or indications for IVF treatment (level of evidence II-2A).
tamoxifen) can be offered treatment with gonadotropins. Clomiphene citrate is a selective oestrogen-receptor
Human menopausal gonadotropin, urinary follicle-stim- modulator that antagonizes the negative feedback of
ulating hormone, and recombinant follicle-stimulating endogenous oestrogen on the hypothalamic–pituitary
hormone are equally effective in achieving pregnancy, axis. Treatment with CC should return luteinizing
and consideration should be given to minimizing cost hormone (LH) to normal and increase FSH secretion,
when prescribing. thereby stimulating follicle growth and ovulation. CC
• Gonadotropin-releasing hormone analogs: Women with has been the gold standard treatment for induction of
polycystic ovary syndrome who are being treated with ovulation in women with polycystic ovary syndrome for
gonadotropins should not be offered treatment with many decades [25,26], and a meta-analysis has shown
gonadotropin-releasing hormone agonist concomitantly that the use of CC is six times more likely to result in
because it does not improve pregnancy rates, and it is pregnancy than is placebo in such women (numbers
associated with an increased risk of ovarian hypersti- needed to treat = 5.9, 95% CI 3.6–16.7) [25]. It is given
mulation. in a dose of 50–250 mg per day for 5 days starting from

ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Société Française de Pharmacologie et de Thérapeutique
Fundamental & Clinical Pharmacology 26 (2012) 54–62
Pharmacotherapy in the treatment of PCOS 57

days 2–5 of spontaneous or induced bleeding starting about the possibility of fetal abnormalities as a result of
with the lowest dose and raising the dose in increments aromatase inhibition has led to avoidance of these drugs
of 50 mg/day each cycle until an ovulatory cycle is in some countries.
achieved. In practice, the commonly use regimen is a or women with PCOS who do not respond to clomifene
starting dose of 100 mg per day from day 4 or 5 and has citrate, gonadotropins have been used as ovulation
found no advantage in using a daily dose of more than induction agents. 513 Human menopausal gonadotropin
150 mg which seems to significantly increase neither is a purified extract from human postmenopausal urine; it
the ovulation rate nor follicular recruitment. This sort of contains both FSH and LH. FSH alone is available in a
regimen will cut down the number of ‘superfluous’ cycles variety of preparations, which are either derived from
of treatment until ovulation is achieved and until those human menopausal urine or as a recombinant peptide
resistant to clomiphene are identified. A course of 3–6 produced by cultured cells. A systematic review of 14
ovulatory cycles is usually sufficient to know whether randomized controlled trial (RCTs) found no significant
pregnancy will be achieved using CC before moving on to differences between hMG (both FSH and LH) and urinary
more complex treatment as approximately 75% of the FSH (uFSH) in terms of pregnancy rate per cycle (OR
pregnancies achieved with clomiphene occur within the 0.89; 95% CI 0.53–1.49), multiple pregnancy rate (OR
first three cycles of treatment. 0.62; 95% CI 0.11–3.58), miscarriage rate (OR 0.85;
A prospective follow-up of thin women with ovulatory 95% CI 0.24–2.95), ovulation rate per cycle (OR 0.75;
dysfunction has shown high conception rates in ovula- 95% CI 0.52–1.07), or overstimulation rate per cycle (OR
tory responders treated with clomiphene, approaching 0.85; 95% CI 0.40–1.81) [30] [Evidence level 1a].
50% after three cycles of treatment and 75% within nine A systematic review of four RCTs compared recombi-
cycles [25]. The examination of follicle development by nant FSH (rFSH) and uFSH in patients with PCOS who
ultrasonography and measurement of serum concentra- were resistant to clomifene citrate found no significant
tions of oestradiol might help to avoid multifollicular differences between pregnancy rate (OR 0.95; 95% CI
development. One of the side effects of CC is increased risk 0.64–1.41), miscarriage rate (OR 1.26; 95% CI 0.59–
of multiple pregnancies, which is possibly reduced by 2.70), multiple pregnancy rate (OR 0.44; 95% CI 0.16–
tailoring the treatment regimen to account for patients’ 1.21), or ovulation rate (OR 1.19; 95% CI 0.78–1.80)
characteristics that predict specific outcomes [25]. [31] [Evidence level 1a].
Despite a high degree of efficacy, some women with Induction of ovulation with gonadotropins has been
polycystic ovary syndrome are resistant to CC and do not shown to be very effective as a low-dose regimen with
ovulate, or fail to achieve pregnancy despite ovulation. gradual increase in dose as needed after close examina-
Failure to achieve pregnancy might be attributed to tion of hormone and ultrasound response, and some
adverse effects of CC on the endometrium [27]. Factors investigators suggest that this regimen is preferable to CC
that affect resistance to CC or failure to achieve preg- for first-line treatment in women with polycystic ovary
nancy are, in order of importance, hyperandrogenemia, syndrome [32]. Alternative methods of gonadotropins
obesity, ovarian volume, and menstrual dysfunction. induction, such as treatment onset with a high dose
Like CC, aromatase inhibitors also reduce oestrogen followed by a gradual reduction (step-down protocol),
stimulation of the hypothalamic–pituitary axis, but do so demand more skills and are not more effective than the
by reducing oestrogen biosynthesis. Patients who are low-dose regimen [33]. Overall, ovulation induction with
resistant to clomiphene are more sensitive to induction of gonadotropins has a reasonable success rate both in
ovulation with aromatase inhibitors such as letrozole terms of ovulation and in terms of cumulative pregnancy
along with the advantage of having lesser side effect on rates. As with CC, multiple pregnancies remain a major
endometrial thickness than has CC, and possibly a lower drawback of gonadotropins. In addition, polycystic
risk of multiple pregnancies [28]. In most of the clinical ovaries are very sensitive to gonadotropic stimulation
trials, aromatase inhibitors used in a range of 5–7.5 mg/ and ovarian hyperstimulation syndrome is a serious,
day for 5 days; no adverse effects were observed with this potentially life-threatening, outcome of induction of
higher dose because the drug is completely eliminated ovulation with gonadotropins in patients with polycystic
within a short time because of its very short half-life and ovaries [34].
have shown that there is less ovarian stimulation with Surgical methods of ovulation induction for women
letrozole than with CC [29] which might contribute to a with clomifene citrate–resistant PCOS include laparo-
lower risk of multiple pregnancies. However, concern scopic ovarian drilling with diathermy. This technique is

ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Société Française de Pharmacologie et de Thérapeutique
Fundamental & Clinical Pharmacology 26 (2012) 54–62
58 L. Saha et al.

designed to create several surface lesions of the ovary, and should be viewed in context with all available
which may help to correct endocrine abnormalities and therapies. These therapies can effectively manage the
trigger ovulation. A systematic review of four RCTs established metabolic derangements in the polycystic
found no significant differences between laparoscopic ovary syndrome, but whether they can prevent them is
ovarian drilling after 6- to 12-month follow-up and 3–6 not yet established.
cycles of ovulation induction with gonadotropins in Both metformin (a biguanide) and thiazolidinedione
cumulative pregnancy rate (OR 1.42; 95% CI 0.84– (pioglitazone and rosiglitazone) have been used to reduce
2.42) or miscarriage rate (OR 0.61; 95% CI 0.17–2.16) insulin resistance. Although metformin is a multiaction
in women with clomifene citrate–resistant PCOS [35] in nature by causing increase in sensitivity of peripheral
[Evidence level 1a]. Multiple pregnancy rates were tissues to insulin, it also appears to influence ovarian
considerably reduced in those women who conceived steroidogenesis directly [39,40]. This effect does not
following laparoscopic drilling (OR 0.16; 95% CI 0.03– appear to be primarily responsible for the attenuation of
0.98). There was insufficient evidence to support any ovarian androgen production in women with the poly-
one surgical technique over another relating to adhesion cystic ovary syndrome. Rather, metformin inhibits the
formation [35] [Evidence level 1a]. output of hepatic glucose, necessitating a lower insulin
Insulin sensitizers, including thiazolidinediones which concentration and thereby probably reducing the andro-
includes pioglitazone, rosiglitazone and troglitazone [36] gen production of theca cells.
and D-chiro-inositol [37], have also been shown to A meta-analysis (2003) of 13 studies in which
increase ovulation and reduce hyperandrogenism in metformin was administered to 543 participants [41]
women with polycystic ovary syndrome, but metformin reported that patients taking metformin had an odds
remains the most commonly used agent. D-chiro-inositol ratio for ovulation of 3.88 (95% confidence interval,
is an agent that can be found naturally in fruits and 2.25–6.69) when compared with placebo and an odds
vegetables and utilize the body’s insulin and promote ratio for ovulation of 4.41 (95% confidence interval,
ovulation and overall health. Deficiency of D-chiro- 2.37–8.22) for metformin plus CC when compared with
inositol has been postulated in some studies to cause CC alone. Metformin also improved fasting insulin levels,
insulin resistance seen in women with PCOS. blood pressure, and levels of low-density lipoprotein
Metformin is not approved by the US Food and Drug cholesterol. The dose of metformin advocated from
Administration (FDA) to induce ovulation. However, the different clinical studies ranges from 1000 mg/day to
studies have shown that metformin has a substantial 2000 mg/day in divided doses.
benefit in the induction of ovulation in women with But in a recent study (2010), comparing insulin-
polycystic ovary syndrome. In a meta-analysis, ovulation sensitizing drugs (metformin, rosiglitazone, pioglitazone,
was achieved in 46% of women who received metformin, D-chiro-inositol) in women with polycystic ovary syn-
compared with 24% in the placebo group (numbers drome presenting with oligoamenorrhoea and subfertil-
needed to treat = 4.4), which is similar to the benefit ity reported that metformin is still of benefit in improving
conferred by CC [38]. Patients on metformin often clinical pregnancy and ovulation rates but there is no
experience unpleasant side effects of nausea, bloating, evidence that metformin improves live birth rates when
cramps, and diarrhea, and they should be counseled to it is used alone or in combination with clomiphene, or
start with 250–500 mg PO daily and increase as when compared with CC. Therefore, the use of metfor-
tolerated to the optimal daily dose of 500–750 mg three min in improving reproductive outcomes in women with
times daily with food. Metformin can also be dosed PCOS appears to be limited [42].
850 mg PO twice daily, or a long-acting formulation
(Glumetza) can be used to improve compliance.
Skin and hair disorders can be substantial in women with
A reduction in insulin levels pharmacologically amelio- polycystic ovary syndrome and are physically and
rates sequelae of both hyperinsulinemia and hyper- psychologically very damaging. Although standard
androgenemia. The place of insulin reduction therapies commercial cosmetic approaches are used initially, ovar-
in treating the polycystic ovary syndrome is evolving ian suppression through oral contraceptives is widely

ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Société Française de Pharmacologie et de Thérapeutique
Fundamental & Clinical Pharmacology 26 (2012) 54–62
Pharmacotherapy in the treatment of PCOS 59

prescribed for hirsutism and acne, especially in the oxidative stress may be responsible for poor oocyte
adolescent population. This treatment option has the quality. Studies have demonstrated that there are
advantage of regulating the menstrual cycle and provid- increased lipid peroxidation products both in serum
ing contraception. Oral contraceptives act by inhibiting and in follicular fluids [47,48] and also the ratio of
LH that causes the reduction in androgen levels and also apoptotic granulosa cells is greater in women with
increases the concentration of sex hormone–binding PCOS[49]. Significantly increased oxidative stress may
globulin leading to decrease in the free testosterone cause granulosa cells and oocyte damage by lipid
concentration. Among the various antiandrogens like peroxidation, protein oxidation, and DNA damage in
spironolactone and cyproterone acetate, cyproterone the follicle. Levels of urinary 6-sulfatoxymelatonin, the
(2 mg/day) in combination with oestrogen is one of the major enzymatic metabolite of melatonin, is reportedly
most effective treatments of hirsutism. Spironolactone and higher in women with PCOS compared to women
oral contraceptives appear to be synergistic. Spirononlac- without this condition [50]. Elevated melatonin en-
tone acts by inhibiting the binding of testosterone and 5a hances LH secretion, LH pulse amplitude, and LH
testosterone to androgen receptors, which effectively treat response to GnRH [50]. Even if there are high concen-
hirsutism and acne. Spironolactone shows its antiminer- trations of melatonin in serum, women with PCOS have
alocorticoid and moderate antiandrogenic effect at dose of a deficiency of this indoleamine in their ovarian follicles.
100–200 mg/day. While choosing a progestin compo- Increased serum melatonin in PCOS may be a feedback
nent, progesterone with antiandrogenic properties should response to the deficient levels of melatonin in the ovary
be chosen like desogestrel and norgestimate. This has been [50]. The high levels of melatonin in the FF are essential
overcome by newer analog of spironolactone, drospire- for follicle growth, ovulation, and oocyte quality,
none, that possesses progestational and antiandrogenic whereas reduced follicular melatonin concentrations
activity and when given in combination with oestrogen may be responsible for anovulation and poor oocyte
causes less metabolic effect [43]. Flutamide, another quality in PCOS [50]. With the current understanding of
antiandrogen, is found to be useful except its adverse melatonin’s essential functions in the human ovary,
reaction on liver. melatonin could become an important medication for
Glucocorticoids are found to be effective only in case of improving ovarian function and oocyte quality and open
excess androgen levels inside the body, which was new opportunities for the management of several ovar-
reported by study conducted by Vanky et al. [44]. Finas- ian diseases.
teride, an antiandrogen, causes the inhibition of the 5a
type 2 reductase in contrast to presence of 5a type 1 in N-acetyl cysteine and PCOD
pilosebaceous unit, hence making it not much effective in N-acetyl cysteine (NAC) inhibits oxidative stress and
treatment of androgen-related cutaneous manifestations. prevents hyperglycemia-induced insulin resistance.
Eflornithine hydrochloride, an inhibitor of the enzyme Study by Fulghesu et al. [51] has demonstrated that in
ornithine decarboxylase in human skin, has been PCOS patients with hyperinsulinemia, treatment with
approved for topical use in treating facial hirsutism. NAC results in improvement of insulin sensitivity and a
In women with polycystic ovary syndrome, insulin significant decline in plasma testosterone and lipid levels.
sensitizers (metformin or thiazolidinediones) promote Kilic-Okman and Kucuk [52] have also described NAC as
ovulation and lower androgen levels by about 20%, but an effective medication for the reduction in serum
there is little evidence of a clinically significant improve- insulin and testosterone levels and improvement of
ment in hirsutism with the use of these agents [42,45]. homocysteine status as well as lipid profiles among
For androgenic alopecia in women, 2–5% topical minox- patients with PCOS. Study by Rizk et al. [53] has noted
idil is regarded as the most effective treatment [46]. that the combination of CC and NAC increases ovulation
and pregnancy rates in CC-resistant PCOS patients who
also suffer from infertility. In 2007, Badawy et al. [54]
also noted that NAC would be effective in the induction
of ovulation when compared to placebo and the addition
Melatonin and PCOD of NAC to a CC regimen in patients with PCOS would
Not only anovulation but also decreased oocyte and increase ovulation rates significantly. A recent study by
embryo quality may be a cause of infertility in wo- Saghar Salehpour et al. [55] has also concluded that
men with PCOS. The reactive oxygen species–induced NAC promotes improvement in lipid profile, hormonal

ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Société Française de Pharmacologie et de Thérapeutique
Fundamental & Clinical Pharmacology 26 (2012) 54–62
60 L. Saha et al.

levels, ovulation, and consequently the long-term health on thecal proliferation and steroidogenesis. Another
status of women with PCOS through inhibition of mechanism postulated is inhibition of oxidative stress–
oxidative stress and improvement of peripheral tissue mediated increases in cellular proliferation, steroidogen-
to insulin sensitivity. Taking its lack of adverse effects esis, and insulin resistance. Hence, a dual role of
into consideration, NAC can be regarded as an appro- blockage of oxidative stress along with statin-mediated
priate substitute for insulin-reducing medications in the improvement in lipid profile can have a beneficial effect
treatment of patients with PCOS. on the long-term cardiovascular morbidity and mortality
associated with PCOS [61].
Acarbose and PCOS
Acarbose is an oral tablet used in the management of type
2 diabetes [56,57]. Acarbose reduces the postprandial rise
in both serum glucose and insulin levels by inhibiting a- The potential health consequences of PCOS are lifelong
glucosidase, an enzyme responsible for the intestinal issue. PCOS is a persisting challenge for clinical and basic
absorption of carbohydrates, and hence decreases the research scientists as none of the presently available
serum androgen concentrations in hyperinsulinemic medications have been fully able to combat these conse-
premenopausal women. Dose-related adverse effects, quences. Clomiphene still remains the first-line treatment
including flatulence, diarrhea, and abdominal distention, for ovulation induction. Newer ovulation-inducing agents
may be minimized by titration. Unlike other antidiabetic have been developed with proven efficacy in clomiphene-
drugs, acarbose does not cause hypoglycemia because it resistant cases. Insulin sensitizers have been an additive
does not stimulate insulin release. Acarbose exhibits a low effect in controlling the metabolic abnormalities and
systemic absorption profile. Various studies have demon- improving ovulation rate along with clomiphene. Cos-
strated that acarbose therapy improves various clinical metic issues like hirsutism are effectively treated with
manifestations of PCOS, including insulin resistance, signs antiandrogen, and newer antiandrogens like drospire-
and symptoms of hyperandrogenism, menstrual irregu- none have been proven to be efficacious without any
larity, obesity (in women with BMI > 30 kg/m2), and adverse consequences.
The importance of maintaining good glycemic control
and normal insulin levels in women with PCOS makes
acarbose a drug worthy of further investigation in large- We declare that we have no conflict of interest.
scale, randomized, double-blind, placebo-controlled stud-
ies. Until such trials are conducted, it is too early to
determine whether acarbose should be a routinely
recommended treatment strategy for PCOS, either by 1 Carmina E., Rosato F., Janni A., Rizzo M., Longo R.A. Extensive
itself or in combination with other medications. clinical experience: relative prevalence of different androgen
excess disorders in 950 women referred because of clinical
hyperandrogenism. J. Clin. Endocrinol. Metab. (2006) 91 2–6.
Statins in PCOS
2 Ehrmann D.A. Polycystic ovary syndrome. N. Engl. J. Med.
Statins are selective inhibitors of 3-hydroxy-3-methyl- (2005) 352 1223–1236.
glutaryl-coenzyme A (HMG-CoA) reductase, the rate- 3 Azziz R., Marin C., Hoq L., Badamgarav E., Song P. Health care-
limiting enzyme in the cholesterol biosynthetic pathway, related economic burden of the polycystic ovary syndrome
decreasing total cholesterol and LDL levels. Statins during the reproductive life span. J. Clin. Endocrinol. Metab.
directly inhibit the production of cholesterol, the sub- (2005) 90 4650–4658.
strate for testosterone, and can improve hyperandrogen- 4 Ehrmann D.A., Liljenquist D.R., Kasza K., Azziz R., Legro R.S.,
Ghazzi M.N. Prevalence and predictors of the metabolic
emia apart from limiting the actions of insulin and IGF-I
syndrome in women with polycystic ovary syndrome. J. Clin.
on the ovary not only by decreasing N-linked glycosyl- Endocrinol. Metab. (2006) 91 48–53.
ation leading to maturation of insulin and Type I IGF-I 5 Essah P.A., Nestler J.E. The metabolic syndrome in polycystic
receptors, apart from decreasing isoprenylation of small ovary syndrome. J. Endocrinol. Invest. (2006) 29 270–280.
GTPases, such as Ras and Rac, which are the mediators 6 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Work-
of the insulin signaling pathway [61]. Hence, blockade of shop Group. Revised 2003 consensus on diagnostic criteria and
the mevalonate pathway by statins can lead to an long-term health risks related to polycystic ovary syndrome.
Fertil. Steril. (2004) 81 19–25.
abrogation of the stimulatory effects of hyperinsulinemia

ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Société Française de Pharmacologie et de Thérapeutique
Fundamental & Clinical Pharmacology 26 (2012) 54–62
Pharmacotherapy in the treatment of PCOS 61

7 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Work- 22 Ibanez L., de Zegher F. Low-dose flutamide-metformin therapy
shop Group. Revised 2003 consensus on diagnostic criteria and for hyperinsulinemic hyperandrogenism in non-obese adoles-
long-term health risks related to polycystic ovary syndrome cents and women. Hum. Reprod. Update (2006) 12 243–252.
(PCOS). Hum. Reprod. (2004) 19 41–47. 23 NICE guidelines published in February, 2004. http://www.
8 Goodarzi M.O., Quinones M.J., Azziz R., Rotter J.I., Hsueh W.A.,
Yang H. Polycystic ovary syndrome in Mexican-Americans: 24 Tannys D.R., Vause M.D., Ottawa O.N., Anthony P., Cheung
prevalence and association with the severity of insulin resis- M.D., Vancouver B.C. Ovulation Induction in Polycystic Ovary
tance. Fertil. Steril. (2005) 84 766–769. Syndrome. J. Obstet. Gynaecol. Can. (2010) 32 495–502.
9 Davis S.R., Knight S., White V., Claridge C., Davis B.J., Bell R. 25 Van Santbrink E.J., Fauser B.C. Ovulation induction in nor-
Preliminary indication of a high prevalence of polycystic ovary mogonadotropic anovulation (PCOS). Best. Pract. Res. Clin.
syndrome in indigenous Australian women. Gynecol. Endocri- Endocrinol. Metab. (2006) 20 261–270.
nol. (2002) 16 443–446. 26 Beck J.I., Boothroyd C., Proctor M., Farquhar C., Hughes E. Oral
10 Azziz R. Controversy in clinical endocrinology: diagnosis of anti-oestrogens and medical adjuncts for subfertility associated
polycystic ovarian syndrome: the Rotterdam criteria are with anovulation. Cochrane Database Syst. Rev. (2005) 1
premature. J. Clin. Endocrinol. Metab. (2006) 91 781–785. CD002249.
11 Legro R.S., Kunselman A.R., Dodson W.C., Dunaif A. Preva- 27 Palomba S., Russo T., Orio F. Jr et al. Uterine effects of
lence and predictors of risk for type 2 diabetes mellitus and clomiphene citrate in women with polycystic ovary syndrome:
impaired glucose tolerance in polycystic ovary syndrome: a a prospective controlled study. Hum. Reprod. (2006) 21 2823–
prospective, controlled study in 254 affected women. J. Clin. 2829.
Endocrinol. Metab. (1999) 84 165–169. 28 Fatemi H.M., Kolibianakis E., Tournaye H., Camus M., Van
12 Ehrmann D.A., Barnes R.B., Rosenfield R.L., Cavaghan M.K., Steirteghem A.C., Devroey P. Clomiphene citrate versus letroz-
Imperial J. Prevalence of impaired glucose tolerance and ole for ovarian stimulation: a pilot study. Reprod. Biomed.
diabetes in women with polycystic ovary syndrome. Diabetes Online (2003) 7 543–546.
Care (1999) 22 141–146. 29 Casper R.F., Mitwally M.F. Review: aromatase inhibitors for
13 Boudreaux M.Y., Talbott E.O., Kip K.E., Brooks M.M., Witchel ovulation induction. J. Clin. Endocrinol. Metab. (2006) 91 760–
S.F. Risk of T2DM and impaired fasting glucose among PCOS 771.
subjects: results of an 8-year follow-up. Curr. Diab. Rep. (2006) 30 Nugent D., Vandekerckhove P., Hughes E., Arnot M., Lilford R.
6 77–83. Gonadotrophin therapy for ovulation induction in subfertility
14 Legro R.S., Gnatuk C.L., Kunselman A.R., Dunaif A. Changes in associated with polycystic ovary syndrome. Cochrane Database
glucose tolerance over time in women with polycystic ovary Syst. Rev. (2000) 4 CD000410.
syndrome: a controlled study. J. Clin. Endocrinol. Metab. (2005) 31 Bayram N., van Wely M., van Der Veen F. Recombinant FSH
90 3236–3242. versus urinary gonadotrophins or recombinant FSH for
15 Solomon C.G., Frank B.H., Andrea D. Menstrual cycle irregu- ovulation induction in subfertility associated with polycystic
larity and risk for future cardiovascular disease. J. Clin. ovary syndrome. Cochrane Database Syst. Rev. (2001) 2
Endocrinol. Metab. (1999) 87 2013–2017. CD002121.
16 Alberti K.G., Zimmet P., Shaw J. The metabolic syndrome – 32 Lopez E., Gunby J., Daya S., Parrilla J.J., Abad L., Balasch J.
a new worldwide definition. Lancet (2005) 366 1059–1062. Ovulation induction in women with polycystic ovary syndrome:
17 Coviello A.D., Legro R.S., Dunaif A. Adolescent girls with randomized trial of clomiphene citrate versus low-dose recom-
polycystic ovary syndrome have an increased risk of the binant FSH as first line therapy. Reprod. Biomed. Online (2004)
metabolic syndrome associated with increasing androgen levels 9 382–390.
independent of obesity and insulin resistance. J. Clin. Endocri- 33 Christin-Maitre S., Hugues J.N. A comparative randomized
nol. Metab. (2006) 91 492–497. multicentric study comparing the step-up versus step-down
18 Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Work- protocol in polycystic ovary syndrome. Hum. Reprod. (2003)
shop Group. Consensus on infertility treatment related to 18 1626–1631.
polycystic ovary syndrome. Hum. Reprod. (2008) 23 462–477. 34 Mulders A.G., Eijkemans M.J., Imani B., Fauser B.C. Prediction
19 Norman R.J., Kidson W.J., Cuneo R.C., Zacharin M.R. Metfor- of chances for success or complications in gonadotrophin
min and intervention in polycystic ovary syndrome. Endocrine ovulation induction in normogonadotrophic anovulatory
Society of Australia, the Australian Diabetes Society and the infertility. Reprod. Biomed. Online (2003) 7 170–178.
Australian Paediatric Endocrine Group. Med. J. Aust. (2001) 35 Farquhar C., Vandekerckhove P., Arnot M., Lilford R. Laparo-
174 580–583. scopic ‘drilling’ by diathermy or laser for ovulation induction in
20 Hardiman P., Pillay O.C., Atiomo W. Polycystic ovary anovulatory polycystic ovary syndrome. Cochrane Database
syndrome and endometrial carcinoma. Lancet (2003) 361 Syst. Rev. (2000) 1. Ovulation Induction in Polycystic Ovary
1810–1812. Syndrome, CD001122. Update in: Cochrane Database Syst.
21 Vrbikova J., Cibula D. Combined oral contraceptives in the Rev. (2001) 4, CD001122.
treatment of polycystic ovary syndrome. Hum. Reprod. Update 36 Azziz R., Ehrmann D., Legro R.S. et al. Troglitazone improves
(2005) 11 277–291. ovulation andhirsutism in the polycystic ovary syndrome:

ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Société Française de Pharmacologie et de Thérapeutique
Fundamental & Clinical Pharmacology 26 (2012) 54–62
62 L. Saha et al.

a multicenter, double blind, placebo-controlled trial. J. Clin. 49 Sun C.L., Qiao J., Hu Z.X., Zhang T., Chen Y.Y. Expression of
Endocrinol. Metab. (2001) 86 1626–1632. novel apoptosis-related protein PDCD5 in granulosa cells of
37 Nestler J.E., Jakubowicz D.J., Reamer P., Gunn R.D., Allan G. polycystic ovary syndrome. Beijing Da. Xue. Xue. Bao. (2005)
Ovulatory and metabolic effects of D-chiro-inositol in the poly- 37 476–493.
cystic ovary syndrome. N. Engl. J. Med. (1999) 340 1314–1320. 50 Tamura H., Nakamura Y., Korkmaz A. et al. Melatonin and
38 Lord J.M., Flight I.H., Norman R.J. Metformin in polycystic the ovary: physiological and pathophysiological implications.
ovary syndrome: systematic review and meta-analysis. BMJ Fertil. Steril. (2009) 92 328–343.
(2003) 327 951–953. 51 Fulghesu A.M., Ciampelli M., Muzj G. et al. N-acetylcysteine
39 Mansfield R., Galea R., Brincat M., Hole D., Mason H. Metformin treatment improves insulin sensitivity in women with polycystic
has direct effects on human ovarian steroidogenesis. Fertil. ovary syndrome. Fertil. Steril. (2002) 77 1128–1135.
Steril. (2003) 79 956–962. 52 Kilic-Okman T., Kucuk M. N-acetyl-cysteine treatment for
40 Attia G.R., Rainey W.E., Carr B.R. Metformin directly inhibits polycystic ovary syndrome. Int. J. Gynaecol. Obstet. (2004) 85
androgen production in human thecal cells. Fertil. Steril. 296–297.
(2001) 76 517–524. 53 Rizk A.Y., Bedaiwy M.A., Al-Inany H.G. N-acetylcysteine is a
41 Lord J.M., Flight I.H.K., Norman R.J. Insulin-sensitising drugs novel adjuvant to clomiphene citrate in clomiphene citrate-
(metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro- resistant patients with polycystic ovary syndrome. Fertil. Steril.
inositol) for polycystic ovary syndrome. Cochrane Database (2005) 83 367–370.
Syst. Rev. (2003) 3 CD003053. 54 Badawy A., State O., Abdelgawad S. N-Acetyl cysteine and
42 Tang T., Lord J.M., Norman R.J., Yasmin E., Balen A H. clomiphene citrate for induction of ovulation in poly-cystic
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitaz- ovary syndrome: a cross-over trial. Acta Obstet. Gynecol. Scand.
one, D-chiro-inositol) for women with polycystic ovary (2007) 86 218–222.
syndrome, oligoamenorrhoea and subfertility. Cochrane 55 Salehpour S., Tohidi M., Akhound M.R., Amirzargar N. N acetyl
Database Syst. Rev. (2010) 1 CD003053. cysteine, a novel remedy for poly cystic ovarian syndrome. Int.
43 Mathur R., Levin O., Azziz R. Use of ethinylestradiol/drospire- J. Fertil. Steril. (2009) 3 66–73.
none combination in patients with the polycystic ovary 56 Acarbose. Lexi-Comp Online.
syndrome. Ther. Clin. Risk. Manag. (2008) 4 482–497. (accessed 2010 Feb 10).
44 Vanky E., Kjotrod S.B., Maesel A., Bjerve K.S., Carlsen S.M. 57 Davis S.N. Insulin, oral hypoglycemic agents, and the phar-
Dexamethasone reduces androgen levels in metformin-treated macology of the endocrine pancreas, in: Brunton L. (Ed.),
patients with polycystic ovary syndrome. Fertil. Steril. (2004) Goodman & Gilman’s the pharmacological basis of therapeu-
81 459–462. tics, 11th edn, McGraw-Hill, New York, 2006, pp. 1613–
45 Harborne L., Fleming R., Lyall H., Norman J., Sattar N. 1645.
Descriptive review of the evidence for the use of metformin in 58 Sönmez A.S., Yasar L., Savan K. et al. Comparison of the effects
polycystic ovary syndrome. Lancet (2003) 361 1894–1901. of acarbose and metformin use on ovulation rates in clomi-
46 Lucky A.W., Piacquadio D.J., Ditre C.M. et al. A randomized, phene citrate–resistant polycystic ovary syndrome. Hum.
placebo-controlled trial of 5% and 2% topical minoxidil Reprod. (2004) 20 175–179.
solutions in the treatment of female pattern hair loss. J. Am. 59 Penna I.A.A., Canella P.R.B., Reis R.M., Silva de Sá M.F.,
Acad. Dermatol. (2004) 50 541–553. Ferriani R.A. Acarbose in obese patients with polycystic ovarian
47 Gonzalez F., Rote N.S., Minium J., Kirwan J.P. Reactive syndrome: a double-blind, randomized, placebo controlled
oxygen species induced oxidative stress in the development study. Hum. Reprod. (2005) 20 2396–2401.
of insulin resistance and hyperandrogenism in polycystic 60 Penna I.A.A., Canella P.R., Vieira C.S., Silva de Sá M.F., dos Reis
ovary syndrome. J. Clin. Endocrinol. Metab. (2006) 91 336– R.M., Ferriani R.A. Cardiovascular risk factors are reduced with
340. a low dose of acarbose in obese patients with polycystic ovary
48 Yildirim B., Demir S., Temur I., Erdemir R., Kaleli B. Lipid syndrome. Fertil. Steril. (2007) 88 519–522.
peroxidation in follicular fluid of women with polycystic ovary 61 Kodaman P.H., Duleba A.J. Statins: do they have potential in
syndrome during assisted reproduction cycles. J. Reprod. Med. the treatment of polycystic ovary syndrome? Semin. Reprod.
(2007) 52 722–726. Med. (2008) 26 127–138.

ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Société Française de Pharmacologie et de Thérapeutique
Fundamental & Clinical Pharmacology 26 (2012) 54–62