Open Access Journal of Contraception Dovepress

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Open Access Full Text Article REVIEW

Hormonal contraception in women with

polycystic ovary syndrome: choices, challenges,
and noncontraceptive benefits
This article was published in the following Dove Press journal:
Open Access Journal of Contraception
2 February 2017
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Anderson Sanches de Melo Abstract: Polycystic ovary syndrome (PCOS) is an endocrine disorder among women of
Rosana Maria dos Reis reproductive age characterized by chronic anovulation and polycystic ovary morphology and/or
Rui Alberto Ferriani hyperandrogenism. Management of clinical manifestations of PCOS, such as menstrual irregu-
Carolina Sales Vieira larities and hyperandrogenism symptoms, includes lifestyle changes and combined hormonal
contraceptives (CHCs). CHCs contain estrogen that exerts antiandrogenic p­ roperties by trig-
Department of Gynecology and
Obstetrics, Ribeirão Preto School gering the hepatic synthesis of sex hormone-binding globulin that reduces the free testosterone
of Medicine, University of São Paulo, levels. Moreover, the progestogen present in CHCs and in progestogen-only ­contraceptives
Ribeirão Preto, São Paulo, Brazil suppresses luteinizing hormone secretion. In addition, some types of progestogens directly
antagonize the effects of androgens on their receptor and also reduce the activity of the 5α
reductase enzyme. However, PCOS is related to clinical and metabolic comorbidities that may
limit the prescription of CHCs. Clinicians should be aware of risk factors, such as age, smoking,
obesity, diabetes, systemic arterial hypertension, dyslipidemia, and a personal or family history,
of a venous thromboembolic event or thrombophilia. This article reports a narrative review of
the available evidence of the safety of hormonal contraceptives in women with PCOS. Consid-
erations are made for the possible impact of hormonal contraceptives on endocrine, metabolic,
and cardiovascular health.
Keywords: polycystic ovary syndrome, hormonal contraceptive, lipid metabolism, carbohydrate
metabolism, hyperandrogenism, thrombosis

Introduction
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder with
prevalence rates ranging from 5% to 13.9% in women of reproductive age.1,2 PCOS
is mainly characterized by chronic anovulation, polycystic ovary morphology, and
hyperandrogenism. However, there is considerable interindividual variation in the
presentation of diverse clinical and metabolic symptoms that vary across ethnic groups
and geographic regions.1,3
Together with lifestyle changes, combined hormonal contraceptives (CHCs) are
the first-line management options for clinical manifestations of PCOS, specifically
Correspondence: Carolina Sales Vieira
Department of Gynecology and menstrual irregularity, hirsutism, and acne.4–7 CHCs contain an estrogen component
Obstetrics, Ribeirão Preto School of (ethynylestradiol [EE], estradiol valerate, or estradiol) and a progestogen compo-
Medicine, University of São Paulo, Av.
dos Bandeirantes, 3900 - 14049-900 -
nent that vary in terms of composition and affinity to receptors of other steroid
Ribeirão Preto, São Paulo, Brazil hormones (mineralocorticoids, glucocorticoids, androgens, and estrogen). Both
Tel +55 16 3602 2818
Fax +55 16 3633 0946
estrogen and progestogen contribute to management of the clinical manifestations of
Email [email protected] hyperandrogenism.8,9

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PCOS are associated with clinical and metabolic comor- clinical guidelines, observational, and interventional stud-
bidities that may limit the prescription of CHCs in women ies evaluating the effects of the use of any hormonal con-
with PCOS. Common risk factors for cardiovascular diseases traception in women or with or without diagnosed PCOS.
(CVDs), such as systemic arterial hypertension (SAH), obe- Only published full-text articles in English were included.
sity, dyslipidemia, metabolic syndrome (MeTS), and type 2 We prioritized the results of meta-analyses and guidelines/
diabetes mellitus (DM2), can develop in women with PCOS consensus.
by the fourth decade of life.5,10–12 According to the Medical The following search strategy was used: ((polycystic
Eligibility Criteria for Contraceptive Use of the World Health ovary syndrome) AND (hormonal contraceptive) AND (lipid
Organization (WHO), some of these comorbidities (MeTS, metabolism)), ((polycystic ovary syndrome) AND (hormonal
SAH, DM2 with vasculopathy, and dyslipidemia plus another contraceptive) AND (carbohydrate metabolism OR insulin)),
risk factors) are considered to be category 3 (a condition where ((polycystic ovary syndrome) AND (hormonal contraceptive)
the theoretical or proven risks usually outweigh the advantages AND (systemic arterial hypertension)), ((polycystic ovary
of using the method) or 4 (a condition which represents an syndrome) AND (hormonal contraceptive) AND (obesity)),
unacceptable health risk if the contraceptive method is used) ((polycystic ovary syndrome) AND (hormonal contraceptive)
(Table 1). In both categories, progestogen-only contraceptives AND (thrombophilia)), ((polycystic ovary syndrome) AND
(POCs) are typically considered a safer option for women (hormonal contraceptive) AND (mellitus diabetes type 2)),
presenting with risk factors for CVD.13 In cases of present- ((polycystic ovary syndrome) AND (hormonal contraceptive)
ing with contraindications to CHC, POCs or nonhormonal AND (dyslipidemia)), and ((polycystic ovary syndrome)
contraceptives13 can be coadministered with antiandrogen AND (hormonal contraceptive) AND (metabolic syndrome)).
medication to control hyperandrogenism symptoms.14 The narrative synthesis of identified data was conducted.
Because of the paucity of data about the impact of CHCs First, the benefits of CHCs on hyperandrogenism symptoms
on cardiovascular and metabolic parameters in PCOS patients, and endometrial cancer in women with PCOS are considered.
most recommendations are based on studies involving ovula- Next, the six most important negative effects of hormonal
tory women. The objective of this narrative review is to present contraceptives are considered in the context of their use in
an evaluation of the evidence on available hormonal contra- women with PCOS.
ceptives, their noncontraceptive benefits, and adverse effects
in women with PCOS, according to the Medical Eligibility Noncontraceptive benefits of
Criteria for Contraceptive Use of the WHO.13 A specific focus
of this review is considerations for endocrine, metabolic, and
hormonal contraception in women
cardiovascular health of women with PCOS. with PCOS
Management of hyperandrogenism
Review criteria symptoms
The PubMed electronic bibliographic database was searched Hyperandrogenism is the most prominent diagnostic com-
from January 1960 to September 2015 to identify reviews, ponent of PCOS.3 Decrease in clinical manifestations of
hyperandrogenism is considered not only to have esthetical
Table 1 Eligibility criteria of the World Health Organization benefits but also to contribute to a reduction of risk factors
Category Eligibility Use of the for metabolic disorders.4
method Evidence suggests that CHCs decrease h­ yperandrogenism
1 A condition for which there is no restriction Yes symptoms by reducing production of androgens. More spe-
for the use of the contraceptive method cifically, the estrogen component of CHCs has been shown
2 A condition where the advantages of Yes
using the method generally outweigh the
to increase the hepatic synthesis of sex hormone-binding
theoretical or proven risks globulin (SHBG), subsequently reducing the free testosterone
3 A condition where the theoretical or proven No that can bind the androgen receptor.15 This antiandrogen effect
risks usually outweigh the advantages of
is more prominent with the use of EE than with the use of
using the method
4 A condition which represents an No natural estrogen.15 A systematic review of 42 experimental
unacceptable health risk if the contraceptive studies with meta-analysis demonstrated that independent of
method is used. the type of progestogens present in combined oral contracep-
Note: Reprinted from Medical eligibility criteria for contraceptive use, Fifth edition,
tives (COCs) containing 20–35 µg EE, the use of COCs was
World Health Organization, 1–267, Copyright 2015. Available from: http://www
.who.int/reproductivehealth/publications/family_planning/MEC-5/en/.13 associated with a 61% reduction of free testosterone levels.

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Dovepress Hormonal contraception and polycystic ovary syndrome

However, COCs containing low doses (20 µg) of EE or con- Antiandrogen drugs
sisting of second-generation progestogens (levonorgestrel) (spironolactone, cyproterone, or
Contraindication to finasteride)
had a smaller effect on the increase of SHBG compared to CHC +
COCs containing higher EE doses or other progestogens Effective contraception
(CU-IUD or POC)
(50% vs 150%–250% increase SHBG).16 PCOS
In addition to these antiandrogen properties, progesto-
No contraindication to CHC *Any CHC
gen promotes negative feedback on the surge of luteinizing
hormone, as a result reducing the ovarian androgen produc- Figure 1 Flowchart for contraceptive choice for PCOS women.
tion. Some progestogens can directly antagonize the effects Note: *Any CHC, although preference should be given to those containing
ethinylestradiol.
of androgens on the androgen receptor and also reduce the Abbreviations: CHC, combined hormonal contraceptive; CU-IUD, cupper
activity of the 5α reductase enzyme, which converts testos- intrauterine device; PCOS, polycystic ovary syndrome; POC, progestogen-only
contraceptive.
terone to dihydrotestosterone, the latter being a highly potent
androgen.9 COCs containing cyproterone acetate have been
shown to have a higher antiandrogen activity than desogestrel Endometrial cancer
and drospirenone in long-term users (12 months or more), but A systematic review with meta-analysis of eleven case–
not in short-/medium-term users (up to 6 months).17 control studies concluded that compared to women without
Based on this evidence, the Endocrine Society Clinical PCOS, women with PCOS are at three times higher risk for
Practice Guideline, the American Society of Reproductive endometrial cancer (odds ratio [OR] 2.79, 95% confidence
Medicine, and the European Society of Human Reproduction interval [95% CI] 1.31–5.95) at any age, but not for ovar-
and Embryology have recommended the use of COCs as the ian or breast cancer.20 While this estimate might have been
initial pharmacological treatment of choice for women with overstated as a result of inclusion of studies that used self-
PCOS, but the guidelines do not suggest any specific combi- reported diagnosis of PCOS and with possible selection
nation of compounds.5 The European Society of Endocrinol- biases related to failure to control for body mass index (BMI),
ogy specifically recommends COCs containing cyproterone overall PCOS presents a prominent risk factor for endome-
acetate for a more effective management of hyperandrogen- trial cancer.20 General population data show that hormonal
ism.18 However, in the presence of estrogen contraindication, contraceptive users have a lower incidence of endometrial
drugs with an antiandrogen effect should be used in combina- cancer than nonusers.21,22 A prospective observational study
tion with effective contraceptives (nonhormonal methods or is needed to confirm this effect of hormonal contraceptives
POCs).18 Similarly, the Androgen Excess and PCOS Society in women with PCOS.
has established a protocol for the treatment of hirsutism in
which the COCs of choice are those containing progestogens Choices and challenges
with a greater antiandrogen potential, such as cyproterone, Systemic arterial hypertension
chlormadinone, and drospirenone. SAH can be found in women with PCOS,10 especially as one
Nonoral methods containing EE have not been discussed of the diagnostic criteria for MeTS.23 However, comorbidi-
in these clinical guidelines, possibly due to scarcity of evi- ties detected in PCOS, such as obesity, dyslipidemia, and
dence. However, these contraceptive methods can be expected insulin resistance, can justify SAH independently of PCOS
to exert antiandrogen properties by reducing free testosterone itself.8 In an attempt to exclude these possible confounding
and increasing SHBG. Since some POCs have the ability to factors, Chen et al24 demonstrated a positive correlation of
inhibit luteinizing hormone secretion, POCs may also have total testosterone levels and free androgen index with blood
some effect on the improvement of hyperandrogenism. In pressure. High blood pressure levels were also identified in
ovulatory women, the etonogestrel implant was shown to be the parents of women with PCOS compared to the parents
associated with a reduction of testosterone and SHBG after of healthy women matched for age and BMI.25
12 weeks of use.19 The effect of POCs in women with PCOS, Endogenous estradiol can result in the vasodilation of
however, still requires investigation. Based on the existing blood vessels26 by increasing the production of nitric oxide
clinical guidelines, a possible flow diagram of eligibility of and appropriate collagen synthesis, thus reducing arterial
hormonal contraceptives for women with PCOS is presented pressure.27 In turn, endogenous progesterone supports this
in Figure 1. hypotensive action by having an antimineralocorticoid

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de Melo et al Dovepress

effect.28 However, EE that is present in most of CHCs, due to Lipid metabolism

its greater potency compared to estradiol, elevates the produc- Dyslipidemia is associated with PCOS independently of
tion of the hepatic angiotensinogen, which causes an elevation weight.38 Of the variables associated with lipid profile,
of blood pressure via the rennin–angiotensin–­aldosterone CHCs have a greater negative impact on triglyceride (TG)
system, regardless of the route of administration.26 Despite levels, causing more than 40% of an increase in TG levels
the development of new progestogens, only drospirenone has in women without PCOS39,40 and of up to 75% in women
the antimineralocorticoid activity of endogenous progester- with PCOS,37,41 regardless of the route of EE administration.
one, regardless of the EE dose present in COCs.29–31 In addition, women with PCOS who do not use CHCs may
As a result, systolic arterial hypertension is regarded an also show a reduction of high density lipoprotein (HDL)-
adverse effect of COCs.32 Several studies have shown an cholesterol, whereas increases in total cholesterol and low
association between hypertension and the use of COCs with density lipoprotein-cholesterol levels are less frequent.42
a high EE dose, although an increased blood pressure was In general, EE administered by any route increases very
observed even with the use of monophasic pills containing low density lipoprotein-cholesterol and TG levels.40 Proges-
30 µg EE.33 In a cohort study, an increased relative risk of togens play a significant modulatory role in the elevation of
1.8 (95% CI=1.5–2.3) to develop systolic arterial hyperten- TG and HDL-cholesterol levels promoted by estrogens.43 In
sion was observed in COC users compared to nonusers.34 In contrast, the administration of POCs does not seem to inter-
addition, higher diastolic arterial pressure levels and a poorer fere with the lipid profile.44 However, DMPA is associated
pressure control have been reported in hypertensive women with increased low density lipoprotein and reduced HDL
using COCs compared to hypertensive nonusers, regardless levels, although this negative effect is transitory and does
of age, body weight, or hypertensive drugs used.35 A reduc- not persist 2 years after the discontinuation of this method.45
tion in pressure levels of hypertensive women was detected A meta-analysis has demonstrated that the use of COCs
~6 months after the interruption of COC use.36 for at least 3 months was significantly associated with an
The negative effect of EE appears to be independent of increase in HDL and TG levels in women with PCOS,
the route of administration of CHCs since the hepatic activa- although these changes were not clinically significant.46 To
tion promoted by EE occurs independently of the route of the best of our knowledge, there is no information of the
CHC administration.37 Within this context, POCs have the effect of POCs on the lipid profile of women with PCOS.
advantage of having no negative effect on blood pressure, The 2009 Medical Eligibility Criteria of the WHO
thus representing a safe contraceptive method in women considered the use of combined contraceptive methods for
with PCOS.13 women with hypertriglyceridemia as category 3 due to the
In conclusion, according to the eligibility criteria of the increased risk of CVD and pancreatitis. However, a recent
WHO, the use of CHCs is not indicated for women with systematic review with meta-analysis, based on limited data
hypertension with or without PCOS, regardless of the route from poor-quality observational studies, has demonstrated
of administration or estrogen type. If a woman with PCOS that women with known dyslipidemia using CHCs may be
presents associated SAH, the eligible treatment methods are at increased risk for myocardial infarction (MI) and may
POCs or nonhormonal contraceptives. However, in women experience a minimal increase in risk for arterial or venous
with severe SAH (≥160×100 mmHg) or with associated vas- thrombosis but the use of CHC was not associated with a high
culopathy, the depot medroxyprogesterone acetate (DMPA) risk of pancreatitis.47 Based on this evidence, according to
is category 3 and the CHCs are category 4 (Table 2).13 the 2015 version of the WHO Medical Eligibility Criteria for

Table 2 Medical eligibility criteria for hormonal contraceptive use in women with SAH
COC/RING/PATCH CIC POP DMPA ENG/LNG IMPLANTS LNG-IUS
Controlled SAH 3 3 1 2 1 1
Uncontrolled SAH (mmHg)
 140–159×90–99 3 3 1 2 1 1
  ≥160×≥100 4 4 2 3 2 2
Vascular disease 4 4 2 3 2 2
Note: Reprinted from Medical eligibility criteria for contraceptive use, Fifth edition, World Health Organization, 1–267, Copyright 2015. Available from: http://www.who.int/
reproductivehealth/publications/family_planning/MEC-5/en/.13
Abbreviations: CIC, combined injectable contraceptive; COC, combined oral contraceptive; DMPA, depot medroxyprogesterone acetate; ENG, etonogestrel; LNG,
levonorgestrel; LNG-IUS, levonorgestrel-releasing intrauterine system; POP, progestogen-only pill; SAH, systemic arterial hypertension.

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Dovepress Hormonal contraception and polycystic ovary syndrome

Contraceptive Use, women in reproductive age with known the route of administration and estrogen type (EE or natural),
dyslipidemias without other known cardiovascular risk fac- CHCs have a limited effect on carbohydrate metabolism, and
tors can generally use any hormonal contraceptive method.13 therefore no adverse effects for endocrine health. The authors,
In the presence of one of these risk factors, all CHCs should however, were unable to draw strong recommendations based
be avoided. DMPA has been classified as the category 3 due on this evidence as the majority of studies compared different
its negative effect on HDL levels in women with dyslipidemia types of contraceptives, had small sample sizes, high lost-to-
and cardiovascular risk factors (Table 3).13 follow-up rates, poorly described methodologies, and failed
to control for BMI.52
Carbohydrate metabolism and insulin In a systematic review with meta-analysis of four ran-
sensitivity domized controlled trials comparing COCs with metformin
PCOS is a risk factor for DM2.48 Approximately 30% of in PCOS, metformin was found to be superior in terms of
women with PCOS have reduced glucose tolerance and reduction of fasting insulin, albeit the two treatments showed
~10% of them have DM2. For comparison, prevalence no significant difference in fasting glucose levels or the onset
rates of reduced glucose tolerance and undiagnosed DM2 of DM2. To establish the safest option in terms of metabolic
in healthy women aged 20–44 years are 7.8% and 1%, outcome of hormonal contraceptives, trials evaluating the
respectively.48 long-term effects of these medications are needed.53
Insulin resistance seems to play an important role in the In summary, evidence suggests that women with PCOS
physiopathology of PCOS.49 The first studies that evaluated should use CHCs containing low EE doses (<50 µg) as
the effect of COCs on glucose metabolism in healthy women these do not affect carbohydrate metabolism or pose a risk
showed a negative effect on glucose tolerance. However, of developing DM2. According to the Medical Eligibility
these studies were conducted in the 1960s; at this time, Criteria for Contraceptive Use of the WHO, CHCs can still
high-dose COCs were used (EE doses of 50 µg or higher).50,51 be used by patients with associated PCOS and diabetes,
A comprehensive systematic review with meta-analysis of regardless of insulin use. However, POCs or nonhormonal
observational studies has shown that the use of COCs for at contraceptives should be used in the presence of associated
least 3 months was not associated with negative effects on vasculopathy (or diabetes of >20 years’ duration), except
glucose metabolism as measured by the hyperinsulinemic DMPA since this compound is associated with the reduction
euglycemic clamp, fasting glucose to insulin ratios, and of HDL levels (Table 4).13
homeostatic model assessments.46
A systematic review and meta-analysis of 31 trials on Body weight
the participation of CHCs in carbohydrate metabolism in Many clinicians and users have observed weight gain during
women without DM2 has demonstrated that independent of the use of hormonal contraception, with a consequent early

Table 3 Medical eligibility criteria for hormonal contraceptive use in women with dyslipidemia
COC/RING/PATCH CIC POP DMPA ENG/LNG IMPLANTS LNG-IUS
Dyslipidemia with no other risk factors 2 2 2 2 2 2
Dyslipidemia with other risk factors 3/4 3/4 2 3 2 2
Note: Reprinted from Medical eligibility criteria for contraceptive use, Fifth edition, World Health Organization, 1–267, Copyright 2015. Available from: http://www.who
.int/reproductivehealth/publications/family_planning/MEC-5/en/.13
Abbreviations: CIC, combined injectable contraceptive; COC, combined oral contraceptive; DMPA, depot medroxyprogesterone acetate; ENG, etonogestrel; LNG,
levonorgestrel; LNG-IUS, levonorgestrel-releasing intrauterine system; POP, progestogen-only pill.

Table 4 Medical eligibility criteria for hormonal contraceptive use in women with diabetes mellitus (DM) associated or not with
vasculopathy
COC/RING/PATCH CIC POP DMPA ENG/LNG IMPLANTS LNG-IUS
DM (regardless of insulin use)
Nonvascular disease 2 2 2 2 2 2
Nephropathy, retinopathy, 3/4 3/4 2 3 2 2
neuropathy, or another vascular disease or
diabetes of >20 years duration
Note: Reprinted from Medical eligibility criteria for contraceptive use, Fifth edition, World Health Organization, 1–267, Copyright 2015. Available from: http://www.who
.int/reproductivehealth/publications/family_planning/MEC-5/en/.13
Abbreviations: CIC, combined injectable contraceptive; COC, combined oral contraceptive; DM, diabetes mellitus; DMPA, depot medroxyprogesterone acetate; ENG,
etonogestrel; LNG, levonorgestrel; LNG-IUS, levonorgestrel-releasing intrauterine system; POP, progestogen-only pill.

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de Melo et al Dovepress

discontinuation of the method despite its efficacy or delay in the authors concluded that there is limited evidence of weight
its prescription.54–56 Several mechanisms have been proposed gain when using POCs. Except for DPMA, mean gain was <2
to the mechanisms underlying this observed impact of hor- kg up to 12 months for most studies, but the weight change
monal contraceptives on weight gain, but none of them has of the POC group generally did not differ significantly from
been fully confirmed.57 groups using another contraceptives.59
Specific research evidence on the association between A group of Danish authors recently carried out two
CHCs and body weight in women with PCOS appears to be randomized controlled trials which demonstrated that the
lacking entirely, but many studies have investigated effects use of metformin alone or in combination with COCs was
of different hormonal contraceptives on body weight in associated with weight loss and improved body composition
healthy women. In a retrospective study on 2,138 women compared with the use of COCs alone.60,61 One of these stud-
uninterruptedly using DMPA, the levonorgestrel-releasing ies revealed a small but significant weight gain in the group
intrauterine system (LNG-IUS), or the copper intrauterine taking COCs alone, leading the authors to a conclusion that
device (Cu-IUD), 1 year follow-up all groups showed an metformin use with or without COCs should be considered
increase in body weight, compared to baseline, with a mean as an alternative for the treatment of PCOS to avoid weight
weight gain of 1.3, 0.7, and 0.2 kg in the DMPA, LNG- gain with COCs alone.61
IUS, and Cu-IUD groups, respectively (P<0.0001). After Overall, the authors of a systematic review with meta-
10 years of use, the mean weight had risen by 6.6, 4.0, and analysis of as many as 49 trials on the link between combina-
4.9 kg among the DMPA, LNG-IUS, and Cu-IUD users, tion contraceptives and weight change in healthy women were
respectively. DMPA users had gained more weight than the unable to confidently determine the effect of combination
LNG-IUS (P=0.0197) and Cu-IUD users (P=0.0294). The contraceptives on weight.54 They have suggested a need for
authors concluded that users of hormonal and nonhormonal trials with a placebo or nonhormonal group to control for
contraceptive methods gained a significant amount of weight other factors, including changes in weight over time.54
over the years, but DMPA users gained more weight over a The WHO, however, considers any hormonal contracep-
treatment period of up to 10 years than women using either tive method to be adequate for obese women who have no
the LNG-IUS or Cu-IUD.58 other associated risk factors for CVD.13 Due to the absence of
A Cochrane review evaluated the relationship between evidence in women with PCOS, data for the general popula-
various forms of POCs and their association with weight tion have been applied to draw recommendations to women
gain,59 albeit the presence of PCOS was not considered with PCOS62 (Table 5).
in the review. The authors have identified two studies that
investigated weight gain in DMPA users compared to Cu- Metabolic syndrome
IUD users: while one study showed no significant difference, PCOS is commonly associated with MeTS, which is diag-
the other showed a statistically significant weight gain in nosed by the presence of at least three of the following crite-
the DMPA group at 1 year (mean difference [MD] =2.28 ria: waist circumference ≥88 cm, fasting glycemia ≥100 mg/
kg; 95% CI 1.79–2.77), 2 years (MD =2.71 kg; 95% CI dL, TGs ≥150 mg/dL, HDL <50 mg/dL, and blood pressure
2.12–3.30), and 3 years (MD =3.17 kg; 95% CI 2.51–3.83), ≥130/85 mmHg.23 Prevalence rates of MeTS in women with
with this difference being significant only for patients with PCOS vary according to the region under study. For example,
normal weight or overweight. Regarding body composition, prevalence rates in the US range from 43% to 46%.63,64 To
the meta-analysis included two studies showing that DMPA
users had a greater increase in body fat (%) (MD 11.00; 95%
Table 5 Medical eligibility criteria for hormonal contraceptive
CI 2.64–19.36) and a greater decrease in lean body mass
use in obese women without any other cardiovascular risk factors
(%) (MD −4.00; 95% CI −6.93 to −1.07) compared to users
COC/RING/ CIC POP DMPA ENG/LNG LNG-IUS
of other hormonal methods. Another study, included in the PATCH IMPLANTS
meta-analysis, demonstrated that the LNG-IUS group showed Obesity 2 2 1 1/2 1 1
an increase in body fat mass (2.5% vs −1.3%, respectively; Note: Reprinted from Medical eligibility criteria for contraceptive use, Fifth edition,
P=0.029) and a reduction of percent change in lean body World Health Organization, 1–267, Copyright 2015. Available from: http://www
.who.int/reproductivehealth/publications/family_planning/MEC-5/en/.13
mass (−1.4% vs 1.0%, respectively; P=0.027) in relation to Abbreviations: CIC, combined injectable contraceptive; COC, combined oral
contraceptive; DMPA, depot medroxyprogesterone acetate; ENG, etonogestrel;
Cu-IUD users, although no significant change in body weight LNG, levonorgestrel; LNG-IUS, levonorgestrel-releasing intrauterine system; POP,
was observed between groups. Despite these considerations, progestogen-only pill.

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Dovepress Hormonal contraception and polycystic ovary syndrome

compare, three to six times lower prevalence rates were increased risk of VTE (characterized by deep vein throm-
reported in Italy (5%–17.3%)65 and even four to 20 times bosis and pulmonary embolism) and those not taking oral
lower prevalence rates were reported for women in People’s contraceptives had a 1.5-fold increased risk.70
Republic of China (2.3%–12.2%).66 In Brazil, prevalence A systematic review of observational studies demon-
rates of MeTS range from 33.3% to 45.4%, depending on strated that women with PCOS have a twofold increased
the PCOS phenotype.67 The observed differences are likely risk of CVD than the population without PCOS (relative risk
to be related to factors inherent to a specific population 2.02; 95% CI 1.47–2.76), a risk that remained ~1.5 times
under the study. Especially regarding PCOS phenotypes, higher after adjusting for BMI (relative risk 1.55; 95% CI
diagnostic criteria, diet, and lifestyle may interfere with 1.27–1.89).71 In a systematic review and a meta-analysis of
the prevalence of this syndrome. Overall, regardless of the five studies, the risk of nonfatal stroke was twofold higher
diagnostic criterion of PCOS, the prevalence of MeTS in among climacteric women with a history of PCOS com-
women with PCOS is at least twice as high as the prevalence pared to the population without PCOS (OR 1.94; 95% CI
population without PCOS.68 1.19–3.17). However, there was no significant difference for
MeTS is associated with an increased risk of arterial MI and/or mortality due to CVD.72
thrombosis events since it was linked to the development of A recent Cochrane systematic review with meta-analysis,
atherosclerosis. In addition, it has been reported that MeTS inclusive of nonrandomized trials, showed that the risk of MI
is associated with a twofold increase in the risk of venous or CVA was only increased in women using COCs contain-
thromboembolism (VTE).23 ing ≥50 µg of estrogen, with the prescription of COCs with
The presence of MeTS in the general population is <50 µg of estrogen showing to be safe regarding the risk
associated with a twofold increase in the risk of developing of MI (OR 0.9, 95% CI 0.8–1.0) or CVA (OR 1.0, 95% CI
CVD.23 Since women with PCOS are at an increased risk of 0.9–1.1).73
MetS and cardiovascular events,69 a hormonal contracep- A Danish historical cohort study included 1,626,158
tive method should be chosen with caution in women with women aged 15–49 years without a history of CVD or cancer.
PCOS associated with MeTS. According to the WHO, only The authors concluded that the absolute risks of CVA and
POCs (except for DMPA) and nonhormonal contraceptives MI associated with the use of COCs were low. This risk was
are suitable for women with MeTS that carries multiple increased by a factor of 0.9–1.7 with COCs that included
risk factors for CVD. The DMPA has unfavorable meta- EE at a dose of 20 μg and by a factor of 1.3–2.3 with those
bolic effects, such as a reduction of HDL levels, which that included EE at a dose of 30–40 μg, with no differences
limit its use in situations of an increased cardiovascular in risk according to progestin type.74
risk (Table 6).13 Regarding VTE, a Danish historical cohort study con-
ducted on 8,010,290 women aged 15–49 years without a
Arterial and venous thrombosis history of thrombotic disease demonstrated that, compared
CVDs include MI, angina, cerebrovascular accidents (CVA), to nonusers of CHCs, the relative risk of confirmed VTE in
and peripheral vascular disease (ie, peripheral arterial disease, users of COCs containing 30–40 µg EE varied according to
venous thrombosis, and deep vein thrombosis). In women the type of progestogen present. After adjusting for time of
with PCOS, those who were taking COCs had a twofold use, the rate of confirmed VTE was 2.2 (1.7–3.0) for users
of COCs with desogestrel, 2.1 (1.6–2.8) for users of COCs
Table 6 Medical eligibility criteria for hormonal contraceptive with gestodene, and 2.1 (1.6–2.8) for users of COCs with
use in women with MeTS
drospirenone compared to users of COCs with levonorg-
COC/ CIC POP DMPA ENG/LNG LNG-IUS estrel. The risk of confirmed VTE was not increased with
RING/ IMPLANTS
PATCH
the use of POCs. The authors concluded that users of COCs
MeTS 3/4 3/4 2 3 2 2
with desogestrel, gestodene, or drospirenone were at least
Note: Reprinted from Medical eligibility criteria for contraceptive use, Fifth edition, at twice the risk of VTE compared with users of COCs with
World Health Organization, 1–267, Copyright 2015. Available from: http://www levonorgestrel.75 However, this result was not confirmed in a
.who.int/reproductivehealth/publications/family_planning/MEC-5/en/.13
Abbreviations: CIC, combined injectable contraceptive; COC, combined oral prospective, controlled, noninterventional cohort study con-
contraceptive; DMPA, depot medroxyprogesterone acetate; ENG, etonogestrel;
LNG, levonorgestrel; LNG-IUS, levonorgestrel-releasing intrauterine system; MeTS,
ducted in the US and in six European countries. In this study,
metabolic syndrome; POP, progestogen-only pill. the use of COCs containing drospirenone was associated

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de Melo et al Dovepress

with similar risk of venous and arterial thromboembolism Although it is safe to prescribe any hormonal contracep-
compared to COCs without drospirenone or COCs contain- tive to obese women with no other associated risk factors,
ing levonorgestrel.76 obesity alone can involve approximately a 24-fold increase
Another Cochrane systematic review and meta-analysis in the risk of VTE among COC users compared to nonusers
concluded that all COCs were associated with an increased of COCs with a BMI <25 kg/m2.79 For this reason, although
risk of VTE, but the size of the effect depended both on the obesity is not a contraindication for CHC use, caution should
progestogen used and the dose of EE.77 The authors have be taken in the association of CHC use and obesity.
estimated that the relative risk of VTE for COCs with 30–35 It is important to point out that screening for thrombo-
μg ethinylestradiol and gestodene, desogestrel, cyproterone philia before prescribing a hormonal contraceptive is not
acetate, or drospirenone was similar and ~50%–80% higher recommended.80 Table 7 presents the WHO’s Medical Eligi-
than for COCs with levonorgestrel. On this basis, the COCs bility Criteria for Contraceptive Use in women with arterial
with lower dose of EE with levonorgestrel would be safer and venous thrombosis.13 The main clinical conditions related
in order to reduce the risk of VTE.77 However, this result to prescription of hormonal contraceptives in women with
should be considered with caution since the review was PCOS are summarized in Table 8.
inclusive of both chronic users (several years) of COCs
containing levonorgestrel and recent users of COCs con- Conclusion
taining other progestogens. This is an important limitation CHCs are the first-choice treatment options for PCOS. This
because the first year of CHC use involves a higher risk of review suggests one of the important reasons for their use
VTE.75–77 Despite the difference in thrombogenic potential is evident reduction of hyperandrogenism symptoms and
according to the antiandrogen effect of progestogens, the endometrial cancer risk. However, metabolic disorders
absolute risk for VTE is small among healthy women in may be aggravated or even triggered by the use of some
reproductive age. CHCs.
Another historical Danish cohort study assessed the Many clinical guideline recommendations for hormonal
risk of VTE in 1,626,158 users of nonoral products com- contraceptive use in women with PCOS are based on studies
pared to the standard reference COC with levonorgestrel in women without PCOS. Consequently, clinicians should
and 30–40  µg estrogen or nonusers aged 15–49 years. still evaluate each patient individually and consider the pres-
The authors concluded that users of transdermal patches ence of risk factors, such as age, smoking, obesity, diabetes,
or vaginal rings have a 7.9 and 6.5 times increased risk of SAH, dyslipidemia, and a personal or family history of a
VTE compared with nonusers of CHC of the same age.74 In venous thromboembolic events or thrombophilia. Table 8
a meta-analysis of randomized controlled trials and case– summarizes the recommendation of hormonal contraceptive
control, cohort, and cross-sectional studies, the relative risk use in the presence of comorbidities. When the use of estro-
of VTE was 0.90 (95% CI: 0.57–1.45) for POC users, 0.61 gen is contraindicated for the patient or when multiple risk
(95% CI: 0.24–1.53) for LNG-IUS users, and 2.67 (95% factors for CVD are present or intolerance of EE occurs, the
CI: 1.29–5.53) for DMPA users, compared to nonusers. The use of POCs or nonhormonal contraceptives is recommended.
authors concluded that the use of POC was not associated If these methods do not adequately control the symptoms of
with an increased risk of VTE compared with nonusers of hyperandrogenism, an alternative is to combine a POC or a
hormonal contraception and that the relationship between nonhormonal method with an antiandrogen medication, such
DMPA and VTE needs to be further investigated.78 as spironolactone, cyproterone, or finasteride.

Table 7 Medical eligibility criteria for hormonal contraceptive use in women with a history of arterial or venous thrombosis
COC/RING/PATCH CIC POP DMPA ENG/LNG IMPLANTS LNG-IUS
Personal history of DVT/PE or thrombophilia 4 4 2 2 2 2
History of stroke or ischemic heart disease 4 4 2/3* 3 2/3* 2/3*
Notes: Reprinted from Medical eligibility criteria for contraceptive use, Fifth edition, World Health Organization, 1–267, Copyright 2015. Available from: http://www.who
.int/reproductivehealth/publications/family_planning/MEC-5/en/.13 *If the ischemic episode occurred during the use of POC (POP, implant, and LNG-IUS), the method is
defined as category 3; if the patient has a personal history of ischemic heart disease and the event occurred before the use of POC, the method is defined as category 2 and
can be started.
Abbreviations: CIC, combined injectable contraceptive; COC, combined oral contraceptive; DMPA, depot medroxyprogesterone acetate; DVT/PE, deep venous
thrombosis/pulmonary embolism; ENG, etonogestrel; LNG, levonorgestrel; LNG-IUS, levonorgestrel-releasing intrauterine system; POC, progestogen-only contraceptive;
POP, progestogen-only pill.

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Dovepress Hormonal contraception and polycystic ovary syndrome

Table 8 Summary of medical eligibility criteria for hormonal contraceptive use in women with comorbidities related to polycystic
ovary syndrome
COC/RING/PATCH CIC POP DMPA ENG/LNG IMPLANTS LNG-IUS
Controlled SAH 3 3 1 2 1 1
Uncontrolled SAH (mmHg) or vascular disease
  140–159×90–99 3 3 1 2 1 1
  ≥160×≥100 4 4 2 3 2 2
MeTS 4 4 2 3 2 2
Dyslipidemia with no other risk factors 2 2 2 2 2 2
Dyslipidemia with other risk factors 3/4 3/4 2 3 2 2
DM (regardless of insulin use)
 Nonvascular disease 2 2 2 2 2 2
Nephropathy, retinopathy, neuropathy, or 3/4 3/4 2 3 2 2
another vascular disease or
diabetes of >20 years of duration
Obesity 2 2 1 1/2 1 1
Personal history of DVT/PE or thrombophilia 4 4 2 2 2 2
History of stroke or ischemic heart disease 4 4 2/3* 3 2/3* 2/3*
Notes: Reprinted from Medical eligibility criteria for contraceptive use, Fifth edition, World Health Organization, 1–267, Copyright 2015. Available from: http://www.who
.int/reproductivehealth/publications/family_planning/MEC-5/en/.13 *If the ischemic episode occurred during the use of POC (POP, implant, and LNG-IUS), the method is
defined as category 3; if the patient has a personal history of ischemic heart disease and the event occurred before the use of POC, the method is defined as category 2 and
can be started.
Abbreviations: CIC, combined injectable contraceptive; COC, combined oral contraceptive; DM, diabetes mellitus; DMPA, depot medroxyprogesterone acetate; DVT/PE,
deep venous thrombosis/pulmonary embolism; ENG, etonogestrel; LNG, levonorgestrel; LNG-IUS, levonorgestrel-releasing intrauterine system; MeTS, metabolic syndrome;
POC, progestogen-only contraceptive; POP, progestogen-only pill; SAH, systemic arterial hypertension; POC, progestogen-only contraceptive.

Disclosure 11. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO.
The prevalence and features of the polycystic ovary syndrome in
The authors report no conflicts of interest in this work. an unselected population. J Clin Endocrinol Metabol. 2004;89(6):
2745–2749.
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