Off-label drug use in the treatment

of polycystic ovary syndrome

Wendy Vitek, M.D.,a,b Snigdha Alur, M.D.,b and Kathleen M. Hoeger, M.D., M.P.H.a,b
a
Division of Reproductive Endocrinology and b Department of Obstetrics and Gynecology, University of Rochester Medical
Center, Rochester, New York

Polycystic ovary syndrome (PCOS) is a complex lifelong disorder with an etiology and pathophysiology that is not yet entirely under-
stood. Women with PCOS have clinical presentations that may vary from adolescence to menopause, including menstrual irregularity/
anovulation and symptoms of hyperandrogenism, such as acne and hirsutism. Over a lifetime, treatment needs and requirements can
change. Unfortunately, there are no Food and Drug Administrationapproved medications that are approved solely for the purpose of
PCOS, but the symptoms and presentation of PCOS are often amenable to several approved agents, such as oral contraceptives for the
indication of acne and clomiphene citrate for the indication of induction of ovulation. However, to meet the needs of women with PCOS,
off-label use of medications has ourished. This review explores the data for those agents that
do not carry an indication for PCOS but have been used for treating the signs and symptoms of Use your smartphone
PCOS. (Fertil Steril 2015;103:60511. 2015 by American Society for Reproductive Medicine.) to scan this QR code
Key Words: PCOS, drug therapy, hirsutism, insulin resistance and connect to the
discussion forum for
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P
olycystic ovary syndrome (PCOS) controlled trials on the use of these for the treatment of symptoms that
is dened by three criteria: medications for signs and symptoms are common in PCOS, such as irregular
hyperandrogenism, menstrual ir- of PCOS. Given the paucity of available menses, acne, and hirsutism. Eorni-
regularity/anovulation, and polycystic- options, however, these medications thine HCl 1% is indicated for hirsutism
appearing ovaries. The diagnostic are commonly used when approved and reduction in facial hair and inhibits
criteria, known as the Rotterdam 2004 treatments are ineffective or no the enzyme ornithine decarboxylase. In
criteria requires two of these criteria approved medication exists for the clinical trials, eornithine decreases
for diagnosis of the condition (1). The indication. This review discusses the unwanted facial hair and improves
main symptoms of PCOS include irreg- most common nonFood and Drug overall patient satisfaction regarding
ular bleeding, acne, hirsutism, and Administration (FDA)approved medi- the reduction in unwanted hair (3). Ev-
ovulatory dysfunction. In addition, cations in PCOS. The review is orga- idence supports its use in combination
though not specically part of the diag- nized by common medications used in with laser hair removal (4). Oral contra-
nosis, women with PCOS suffer from treatment, recognizing that several ceptives containing norethindrone ace-
metabolic disorders that are related to off-label medications are used for mul- tate, norgestimate, and drosperinone
insulin resistance. It is estimated that tiple purposes in PCOS. are approved for acne vulgaris, and me-
>75% of women with PCOS are insulin droxyprogesterone acetate is indicated
resistant when measured rigorously (2). for the control of menstrual irregularity
There are few medications that are FDA-APPROVED and amenorrhea which are common in
approved for the most common symp- MEDICATIONS FOR PCOS PCOS. Although oral contraceptives in
toms of PCOS, leading to the off-label There is no drug specically approved general appear to be effective for men-
use of medications that were approved by the FDA for the indication of strual control and acne, oral contracep-
for other indications. Overall, there PCOS. In addition, there are few medi- tives containing drosperinone are
are very few randomized or placebo- cations that are indicated or approved associated with an increased risk of
blood clots (5). Additionally in obese
Received November 3, 2014; revised January 11, 2015; accepted January 13, 2015.
W.V. has nothing to disclose. S.A. has nothing to disclose. K.M.H. has nothing to disclose.
patients with PCOS, oral contraceptives
Reprint requests: Kathleen M. Hoeger, M.D., M.P.H., Professor of Obstetrics and Gynecology, Division may be associated with worsening in-
of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Roches- sulin resistance (6). The details of these
ter Medical Center, Box 668, Rochester, New York 14642 (E-mail: kathy_hoeger@urmc.rochester.
edu). medications, including indications,
side effects, and mechanism of action
Fertility and Sterility Vol. 103, No. 3, March 2015 0015-0282/$36.00
Copyright 2015 American Society for Reproductive Medicine, Published by Elsevier Inc.
are summarized in Table 1. Both
http://dx.doi.org/10.1016/j.fertnstert.2015.01.019 approved and drugs used off label for

VOL. 103 NO. 3 / MARCH 2015 605

VIEWS AND REVIEWS

ovulation induction in infertility associated with PCOS are

abnormal undiagnosed
insufciency, increased
Renal impairment, adrenal
Sensitivity to components

disease, liver disease,

covered in a separate review in this series, so they are not

thromboembolism,

disease, pregnancy
Contraindications

breast cancer, liver

pregnancy, breast
included in this review.

Undiagnosed vaginal
uterine bleeding,

bleeding, heart
risk for venous
OFF-LABEL USES OF DRUGS FOR COMMON

cancer
MANIFESTATIONS IN PCOS
The most common symptoms of PCOS include irregular men-
strual cycles and hirsutism. However PCOS is also associated
category C
(includes FDA

category X

category X
with other metabolic abnormalities that warrant treatment.
Anomaly risk

pregnancy
category)

One of the most challenging aspects of PCOS is the high prev-

Pregnancy

Pregnancy

Pregnancy
alence of metabolic abnormalities, specically the high inci-
dence of insulin resistance, which is linked to the
pathophysiology of PCOS (2). Women with PCOS have high
rates of impaired glucose tolerance and diabetes (7). Although
reduces effectiveness

enzyme may reduce

Any drug that induces

there are approved medications for the treatment of diabetes,

Induction of CYP3A4
Pertinent drug

enzyme CYP3A4
interactions

effectiveness
regardless of its association with PCOS, there are no approved
medications that are approved for the treatment of insulin
None known

resistance. Women with PCOS are also noted to have high

rates of obesity, which complicates the metabolic picture
and is one of the most distressing aspects of the condition
for many women (8, 9). Women with PCOS often report
difculty with food cravings and appetite, which may be
blood pressure, nausea
menstrual irregularity,

thrombosis, increased
nausea and vomiting,

related to insulin resistance, and so they seek out

thromboembolism,
mood disturbance,
Main side effects

breast tenderness,
Headache, migraine,

management of insulin resistance as a way to control these

and vomiting

symptoms (10). Table 2 summarizes the major drugs used

hypertension
Spotting, breast
tenderness,
Skin irritation

off label in PCOS in the United States.

venous

Metformin, D-chiro-inositol, and Myo-inositol

One of the most common medications being used off label for
abnormal bleeding due
to hormonal imbalance

PCOS is metformin. From its initial description for manage-

Metabolized in the Treatment of secondary
Antiandrogen effect Metabolized in the Moderate acne vulgaris
<1% absorption; Hirsutism reduction in

ment of ovulation induction in PCOS, metformin has rapidly

FDA indication

amenorrhea and

risen to be one of the most requested medications for manage-

ment of the condition (11). A survey of Pubmed reveals >30
facial hair

meta-analyses of randomized trials and >70 systematic re-

views covering the role of metformin therapy in management
of PCOS, including ovulation induction, weight loss, men-
strual control, preterm birth, miscarriage, and hirsutism.
Despite the large number of analyses completed, there are
FDA-approved drugs or typical symptoms associated with PCOS.

liver; 2630 h
Excretion and

liver; 12.1 h
half-life 8 h

few large scale or randomized placebo-controlled trials

half-life

(RCTs) using metformin for PCOS, and there remains signi-

cant controversy of opinion with little conclusive data on its
effectiveness in PCOS. Metformin works as an insulin sensi-
tizing agent. Because insulin resistance is integral to the path-
increase in SHBG,

ophysiology of PCOS, it is reasonable to anticipate that

decrease in free

proliferative to

improvement in insulin resistance will improve many of the

decarboxylase

Vitek. Off-label use of drugs for PCOS. Fertil Steril 2015.

endometrium
Mechanism

testosterone
Inhibits enzyme
of action

symptoms of PCOS. Review of the largest trials of metformin

ornithine

secretory
Medroxyprogesterone Transforms

therapy in PCOS suggests that metformin has a limited role in

the management of reproductive consequences of PCOS (12).
The single largest RCT of metformin in PCOS failed to improve
fertility compared with clomiphene citrate (13). For the indi-
Ethinyl estradiol

cation of menstrual cycle regulation, meta-analysis suggested

Eornithine HCL 1%

norethindrone or
norgestimate or
Oral contraceptive:

that metformin improved menstrual pattern compared with

drosperinone
Drug (generic)

placebo (12). It is notable, however, that the studies are rela-

tively small (n <30) with signicant heterogeneity, increasing
TABLE 1

acetate

concern about the reliability of these ndings. When

compared with oral contraceptive, metformin therapy was
not as effective in improving menstrual patterns in several

606 VOL. 103 NO. 3 / MARCH 2015

VOL. 103 NO. 3 / MARCH 2015

TABLE 2

Drugs used off label in PCOS without FDA indication for specied use.
Anomaly risk
(includes FDA
Excretion and Pertinent drug pregnancy
Drug (generic) Mechanism of action half-life Off-label reproductive use Main side effects interactions category) Contraindications
Metformin Decreased hepatic Renal clearance with Ovulation induction, Gastrointestinal upset, Any drugs that Pregnancy Renal disease, creatinine
glucose production, no metabolism; menstrual regulation, vitamin B12 deciency affect renal category B >1.4, acute or chronic
intestinal absorption half-life 6.2 h hirsutism, weight loss function, IV metabolic acidosis;
of glucose; improved contrast dye should be stopped
insulin sensitivity by before IV contrast use,
increased glucose before surgery
uptake and utilization
Thiazolidinediones: PPAR-g receptor agonist; Actively metabolized Ovulation, menstrual Weight gain, edema, CYP2C8 inhibitors Pregnancy Heart failure, liver failure
pioglitazone, decreased insulin by the liver; regulation gastrointestinal, category C ALT >2.5 times the
rosiglitazone resistance in periphery half-life 37 h hepatic effects, heart upper limit of normal
and liver, hepatic failure, bladder cancer
glucose output; with pioglitazone
increased insulin-
dependent glucose
disposal
Statins: simvastatin, Selective inhibitor of Metabolized rapidly Decrease in Myopathy, liver Grapefruit juice, Pregnancy Active liver disease,
atorvastatin HMG-CoA reductase by the liver; hyperandrogenism dysfunction, coadministration category X pregnancy, couse with
half-life 2 h rhabdomyolysis with strong certain drugs such as
CYP3A4 inhibitors verapamil, diltiazem,
amlodipine,
amiodarone, danazol
D-chiro-inositol Putative insulin mediator, Renal clearance;
Classied as a Nausea, headache, None known No data in Bipolar disorder,
possible improved half-life when supplement, not FDA- fatigue pregnancy pregnancy
insulin sensitivity injected 5 h approved for any
indication; used in
PCOS for ovulation
induction, possible
decreased
testosterone
Glucagon-like Enhances glucose- Renal clearance; Weight loss in Nausea, vomiting, Acetaminophen, Pregnancy History of pancreatitis,
peptide receptor dependent insulin half-life: exenitide combination with diarrhea, headache, digoxin, lovastatin category C renal impairment,
agonists: exenitide, secretion, suppresses 2.4 h, liraglutide metformin in PCOS risk of pancreatitis, thyroid cancer
liraglutide increased glucagon, 13 h possible increased risk
slows gastric emptying of thyroid tumors with
liraglutide
Spironolactone Antagonist of aldosterone, Renal clearance; Hirsutism and acne Numbness, muscle pain, Other potassium- Pregnancy Acute renal insufciency,

Fertility and Sterility

binds receptors in the half-life 1.4 h weakness, dizziness, sparing diuretics, category C hyperkalemia
distal renal tubule; nausea NSAIDs, ACE
antiandrogen effect via inhibitors
competition for
androgen receptor,
suppresses cytochrome
P450, decreases
steroidogenesis
607

Vitek. Off-label use of drugs for PCOS. Fertil Steril 2015.

VIEWS AND REVIEWS

randomized trials (14). Regarding hirsutism, when metformin

Note: ACE angiotensin-converting enzyme; ALT alanine transaminase; CYP2C8 cytochrome P450 2C8; DHT dihydrotestosterone; HMG CoA 2-hydroxy-3-methylglutaryl coenzyme A; IV intravenous; NSAID nonsteroidal antiinammatory drug; PPAR
is compared with placebo or oral contraceptive, no signicant

Contraindications
benet is observed, suggesting that it should not be used for
the reduction of hirsutism in PCOS. The data on the use of
metformin in infertility are reviewed elsewhere in detail, but
Liver disease

Liver disease
meta-analyses are divided on the usefulness of metformin
for infertility, with the largest randomized trial powered for
live birth revealing no benet to metformin therapy (13).
Endocrine Society guidelines recommends against it use for
category D
(includes FDA

category X
Anomaly risk

pregnancy

ovulation induction, although Australian Alliance guidelines

category)
Pregnancy

Pregnancy

suggest possible benet in women with body mass index

(BMI) %30 kg/m2 or in combination with clomiphene, but
recommends clomiphene instead of metformin alone in
women with BMI >30 kg/m2 (15, 16). There is no evidence
that metformin affects the rate of pregnancy loss in PCOS,
No clinically important
reactions reported
Pertinent drug

although there are early data to suggest that there may be

interactions

some benet of preventing of preterm delivery (17, 18).

Given the metabolic impact of insulin resistance and the
known cardiovascular risk factors seen in PCOS, it is reason-
Warfarin

able to consider metformin therapy for improvement in cardi-

ometabolic risk. In those in the general population at risk for
diabetes due to impaired glucose tolerance, metformin signif-
Hot ashes, nausea, skin
rash, hepatic toxicity

icantly reduced the risk of developing diabetes (19). Women

Main side effects

with PCOS are included in risk groups at increased risk for

Breast tenderness

diabetes, but this indication for metformin has not been rigor-
ously studied in PCOS. There is little evidence yet that metfor-
min adds to the benet obtained by lifestyle modication for
diabetes risk reduction in women with PCOS. Overall, the role
for metformin in the treatment of PCOS is uncertain at best,
Off-label reproductive use

with limited high-quality data available. Additional well de-

Antiandrogen used for

Metabolized by the Antiandrogen used for

signed rigorous trials are needed to evaluate any benet of

metformin in PCOS.
D-chiro-inositol is an inositol isomer present in inositol
hirsutism

hirsutism

phosphoglycans and is a proposed mediator of insulin action.

A related isomer is myo-inositol. Both of these proposed insu-
lin sensitizers have been tested in PCOS, although few studies
used placebo control. Meta-analysis could not be performed
on these agents owing to the lack of adequately sized random-
liver; half-life 6 h

ized trials (12). In review of two randomized trials including

Excretion and

half-life 9.6 h
Inhibits androgen uptake, Renal clearance,
half-life

d-chiro-inositol and inositol there was very modest evidence

for improvement in ovulation (20, 21). There was insufcient
evidence for improved metabolic parameters or reproductive
hormones. A small follow-up trial with the use of myo-
inositol isomer also suggested modest ovulation improvement
(22). Overall, there is limited evidence supporting utility of
binding of androgen

testosterone to DHT
Mechanism of action

Inhibitor of type II 5a-

inositol isomers in improving metabolic or reproductive per-

reductase; blocks
inhibits nuclear

formance in PCOS.
Vitek. Off-label use of drugs for PCOS. Fertil Steril 2015.
conversion of

Thiazolidinediones
peroxisome proliferator-activated receptor.

The group of drugs known as thiazolidinediones are approved

for treatment of type 2 diabetes. They are peroxisome prolif-
eratoractivated receptor g agonists associated with
decreased insulin resistance in periphery and liver, hepatic
Drug (generic)

glucose output, and increased insulin-dependent glucose

TABLE 2

Continued.

disposal. Because of the improvement in insulin resistance,

Finasteride
Flutamide

they have been used in the treatment of PCOS. Of the original

thiazolidinediones approved in the United States, troglitazone
was removed from the market because of hepatotoxicity and

608 VOL. 103 NO. 3 / MARCH 2015


only rosiglitazone and pioglitazone are available in the U.S.
Both are FDA category C for pregnancy owing to the potential
for fetal growth restriction. There is also evidence of weight
gain with the use of these agents. Data regarding troglitazone
are not included in this review, because it is no longer avail-
able in the U.S.
Limited RCTs are available regarding treatment of PCOS
with the use of these agents. Rosiglitazone was associated
in one study with improved menstrual patterns with minimal
impact on serum testosterone levels (23). In a small RCT, rosi-
glitazone improved the metabolic markers of adiponectin and
resistin, which correlated with a reduction in serum free fatty
acids associated with improved insulin resistance (24).
Adolescent women with PCOS were also studied with the
use of rosiglitazone. Compared with oral contraceptive, rosi-
glitazone improved the cardiovascular risk prole in obese
adolescents (25). Pioglitazone improved menstrual pattern
in small RCTs (with a total of 70 randomized patients). There
was minimal improvement in reproductive hormones, howev-
er (26). In a small RCT of young women with PCOS there were
signicant improvements in measures of insulin action with
pioglitazone, and a reduced ovarian hyperandrogenic
response to GnRH agonist stimulation (24). Overall, the data
are suggestive of modest menstrual improvements with rela-
tively little impact on reproductive hormones, but given the
concerns about side effects, including increased body weight
seen with these agents and the risk potential in pregnancy,
they have a limited role in the treatment of PCOS in
reproductive-age women without diabetes.
Glucagon-like Peptide 1 Receptor Agonists and
Analogues
Glucoagon-like peptide 1 (GLP1) is an incretin, or gut peptide
hormone, that augments insulin secretion in response to oral
glucose intake, inhibits glucagon secretion, delays gastric
emptying, and reduces food intake and appetite. Lower active
GLP1 levels have been observed in patients with insulin-
resistant states, such as type 2 diabetes mellitus, PCOS, and
lean PCOS (27, 28). GLP1 receptor agonists and analogues
improve glucose homeostasis and reduce body weight.
Exenatide is a short-acting GLP1 receptor agonist that has
been evaluated in a small randomized trial of exenatide alone,
metformin alone, or a combination of exenatide and metfor-
min in overweight women with PCOS and insulin resistance
(29). Sixty patients were randomized and 42 patients
completed the study. The combination of exenatide and met-
formin for 24 weeks resulted in improved menstrual cyclicity,
ovulation rate, free androgen index, insulin sensitivity, and
reduced weight and abdominal fat compared with either exe-
natide or metformin alone. Liraglutide is a long-acting GLP1
analogue that hass an amino acid sequence similar to GLP1.
The combination of liraglutide and metformin has been eval-
uated in a small randomized trial of obese nondiabetic women
with PCOS who failed to lose weight with metformin (30).
Forty patients were randomized and 36 patients completed
the study. Combination treatment for 12 weeks resulted in
an average weight loss of 6.5  2.8 kg, which was signi-
cantly greater than the weight loss observed with liraglutide
VOL. 103 NO. 3 / MARCH 2015
Fertility and Sterility
alone (3.8  3.7 kg) and metformin alone (1.2  1.4 kg). In
addition, there was a signicant decrease in waist circumfer-
ence with combination treatment. Signicant weight loss has
also been reported in a larger cohort of overweight and obese
women with PCOS with insulin resistance treated with lira-
glutide, metformin, and lifestyle modication (31). Common
side effects of liraglutide include transient nausea (11%
48%) and vomiting (4%15%). The combination of liraglutide
and metformin does not appear to increase the frequency of
nausea and vomiting compared with liraglutide alone (32).
Although nausea may contribute to the weight loss observed
with liraglutide, signicant weight loss was observed in indi-
viduals who did not experience nausea while taking liraglu-
tide (33). Liraglutide may lead to weight loss in women with
PCOS by altering eating behaviors. After 12 weeks of liraglu-
tide, uncontrolled eating and emotional eating were
decreased as measured by the Three-Factor Eating Question-
naire in obese women with PCOS (34). Although these agents
are promising for the treatment of insulin resistance and
obesity associated with PCOS, larger placebo-controlled
studies in women with PCOS are needed. Further studies
should assess long-term weight loss, reproductive outcomes,
and risk of pancreatitis in women with PCOS who are treated
with GLP1 agonists and analogues.
Statins
Statins inhibit the enzyme hydroxymethylglutaryl coenzyme
A reductase and decrease the production of cholesterol, the
precursor to sex steroids. Statins appear to improve hyperan-
drogenemia by decreasing androstenedione and testosterone
biosynthesis and inhibiting theca cell growth (35). Despite
these benecial effects, there is no evidence that statins
improve menstrual regularity, ovulation rates, hirsutism, or
acne in women with PCOS (36). In addition, an RCT of atorvas-
tatin versus placebo in women with PCOS found decreased in-
sulin sensitivity after 6 months of treatment (37). Given the
side effects of statins (myopathy, liver dysfunction, impair-
ment of glucose metabolism), teratogenicity, and availability
of effective alternatives, statins should not be prescribed for
the treatment of hyperandrogenemia in women with PCOS.
Statins alone and in combination with metformin have been
shown to decrease C-reactive protein, triglycerides, and total
and low-density lipoprotein cholesterol levels in women with
PCOS and can be considered for the treatment of dyslipidemias
in women with PCOS who are not trying to conceive (15, 38).
Antiandrogens Flutamide, Finasteride, and
Spironolactone
One of the hallmark characteristics of PCOS is hyperandro-
genism. Hirsutism is a challenging condition that contributes
separately to the distress experienced by women with PCOS.
Several antiandrogenic medications have therefore been pro-
posed to control such symptoms as acne and hirsutism in
PCOS. There are limited RCTs investigating the antiandrogens
utamide, nasteride, and spironolactone.
Flutamide is a nonsteroidal antiandrogen that inhibits
androgen uptake and binding of androgens to target tissues.
Although it is FDA approved as an oral regimen for the
609
VIEWS AND REVIEWS
treatment of prostate cancer, one of its other well studied ben-
ets is a reduction in hirsutism. A mean reduction of 910
points of the Ferriman-Gallwey score has been reported by
several RCTs studying the effects of utamide treatment on
hirsutism over 612 months (39). The common dosage is
125250 mg/d. Benets are not conned to hirsutism alone,
although data on its other uses are more conicting. A study
evaluating the effect of utamide on ovulation in women
with PCOS found that treatment signicantly increased the
percentage of ovulatory cycles and regular menstrual cycles
(40). In contrast, a noncontrolled trial assessing its effects
on adolescent girls with hyperandrogenism found that
although utamide caused a marked decrease in the hirsutism
score and testosterone levels, there was no substantial effect
on the pattern of menstrual cycles (41). The combination of
utamide with metformin has gained attention in the litera-
ture as a way to manage the PCOS spectrum by countering
both the hyperandrogenic and hyperinsulinemic features of
the syndrome. This regimen has been found to be superior
to oral contraceptives alone in nonplacebo-controlled trials
(42). One of the major concerns associated with utamide is
the risk of severe hepatotoxicity. Evidence on its association
has been conicting however. In a meta-analysis, several
studies found no evidence of hepatotoxicity in women treated
over a year with utamide (42). Case studies reporting such
instances show a relationship between liver damage and
length of treatment and were generally regarded as low-
quality evidence. Studies comparing the combination of
utamide with metformin found that low-dose polytherapy
provided greater clinical benet than high-dose monotherapy
while also preserving liver function (43). Still, the cost and
risk of hepatocellular toxicity often deter clinicians from us-
ing utamide as a rst-line treatment (44). In addition, its
teratogenicity requires contraception (45, 46).
Finasteride is a type II 5a-reductase inhibitor that inhibits
the production of dihydrotestosterone. It is available as either
a 5-mg or a 1-mg pill and is typically used to treat prostate
cancer and male alopecia. It has also been demonstrated to
improve female hirsutism compared with placebo (43).
When compared with nasteride, however, several studies
suggest that utamide has a superior effect on reducing the
Ferriman-Gallwey score (39, 46). Finasteride is better
tolerated than utamide, with minimal associated
hepatotoxicity (45). It is imperative to use this medication
with contraception as well, owing to its potential for
inhibiting virilization in male fetuses (43).
Spironolactone is a diuretic and aldosterone antagonist
that also acts as an antagonist for the androgen receptor. Its
other mechanisms of action include inhibiting ovarian and
adrenal steroidogenesis, acting as an androgen receptor
antagonist in hair follicles, and directly inhibiting 5a-reduc-
tase activity. The usual dosage ranges from a 25- to a 100-mg
pill twice a day (47). It has been demonstrated to reduce hir-
sutism over 6 months compared with placebo and has been
found to be as effective as nasteride (39). Similarly to nas-
teride, spironolactone has been shown to be less effective than
utamide (48). Combining nasteride with spironolactone
could be more benecial than using spironolactone alone
for reducing hirsutism (39). Potential side effects of spirono-
610
lactone include fatigue, postural hypotension, dizziness, and
hyperkalemia (44). Approximately 20% of women using this
medication have had increased menstrual frequency as well
(49). Owing to its potential for causing ambiguous genitalia
in the male fetus, it is recommended to use spironolactone
with oral contraceptive pills, given their synergistic effects
when treating PCOS patients (44).
Antiandrogenic medications remain a reasonable option
to treat hirsutism and acne in PCOS. Combinations of these
medications with each other or with metformin may offer
some benet over monotherapy, but contraception should
be used whenever treating sexually active patients with anti-
androgens owing to their demonstrated teratogenicity.
CONCLUSION
Given the limited number of agents that are approved for
treatment of the most common symptoms in PCOS, there is
a proliferation of off-label use of medications approved for
other indications. This speaks to a clear need for new drugs
to treat a prevalent condition with both reproductive and
metabolic consequences. Unfortunately, there are no deni-
tive studies published for these drugs, and the few placebo-
controlled trials show limited benets for key outcome
measures. Additionally the side effect proles are not fully
evaluated in these young women. This speaks to a real need
for adequately powered placebo-controlled trials with key
outcomes relevant to the treatment of women with PCOS.
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