V Pergialiotis and others SCH in PCOS 176:3 R159R166

Review

MANAGEMENT OF ENDOCRINE DISEASE

The impact of subclinical hypothyroidism on
anthropometric characteristics, lipid, glucose
and hormonal profile of PCOS patients:
a systematic review and meta-analysis
VasiliosPergialiotis1,2, PanagiotisKonstantopoulos1, AnastasiaProdromidou1,
VenetiaFlorou1, NikolaosPapantoniou2 and Despina NPerrea1
Correspondence
1
Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical should be addressed
School, Athens, Greece, and 2Third Department of Obstetrics/Gynaecology, Athens University Medical to V Pergialiotis
School, Attikon Hospital, Athens, Greece Email
pergialiotis@yahoo.com
European Journal of Endocrinology

Abstract
Objective: Subclinical hypothyroidism (SCH) is encountered in 1025% of women with PCOS. To date, it remains
unclear whether this coexistence influences the severity of metabolic and hormonal profile of these patients. The
purpose of our systematic review is to investigate this potential relation.
Methods: We systematically searched Medline, Scopus, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials
(CENTRAL) and Google Scholar databases together with reference lists from included studies. All prospective and
retrospective observational cohort studies that investigated the impact of subclinical hypothyroidism on hormonal
and metabolic parameters of PCOS patients were included. The methodological quality of studies was assessed with
the OttawaNewcastle criteria. Statistical meta-analysis was performed with the RevMan 5.3 software.
Results: Twelve studies were finally included in the present review, which enrolled 2341 PCOS patients. Among
them, 577 had subclinical hypothyroidism, whereas the remaining 2077 were PCOS women with normal thyroid
function. The presence of SCH significantly affected HDL (MD 3.92mg/dL 95% CI: 6.56, 1.29) and triglycerides levels
(26.91mg/dL 95% CI: 3.79, 50.02). HOMA-IR was also affected (MD 0.82 95% CI: 0.15, 1.50). On the other hand, LDL,
fasting glucose and 2-h OGTT were not influenced. Similarly, prolactin, FSH, LH, LH/FSH ratio and sex hormone-binding
globulin remained unaffected.
Conclusion: Subclinical hypothyroidism does not influence the hormonal profile of women with PCOS. On the other
hand, it results in mild metabolic abnormalities, which are not clinically important in a short-term setting.

European Journal of
Endocrinology
(2017) 176, R159R166

Introduction
Polycystic ovary syndrome (PCOS) is an endocrine disorder
that affects young women. Its prevalence ranges between
5% and 10% (1). It is frequently correlated with metabolic
abnormalities such as dyslipidemia, insulin resistance,
type 2 diabetes mellitus (DM) and the metabolic syndrome,
thus contributing to the pathogenesis of cardiovascular
disease (2, 3). Overt hypothyroidism has been linked to
altered lipid profile and insulin insensitivity (4, 5, 6).
Similarly, subclinical hypothyroidism (SCH) (which
is described by elevated levels of thyroid-stimulating

www.eje-online.org 2017 European Society of Endocrinology Published by Bioscientifica Ltd.

DOI: 10.1530/EJE-16-0611 Printed in Great Britain
 Review V Pergialiotis and others SCH in PCOS 176:3 R160

hormone (TSH) with normal free thyroxine levels)
has been associated with decreased glucose disposal,
increase of sex hormone-binding globulin (SHBG) levels,
hyperlipidemia, increases in serum total cholesterol
(TC), low-density lipoprotein cholesterol (LDL) and total
triglyceride levels weight gain and insulin resistance in
the general population (7, 8, 9, 10) .The treatment of SCH
in the general population remains controversial in our
era as there is lack of substantial evidence to reach firm
conclusions (11). Current recommendations, however,
suggest that infertile women who wish to conceive should
be treated if TSH values exceed 4IU/L (12).
Besides metabolic alterations, PCOS is associated with
distinctive alterations of reproductive hormones. Increases
in luteinizing hormone-to-follicle-stimulating hormone
ratio (LH/FSH) and circulating androgens contribute to
the occurrence of the traditional phenotype of PCOS
which includes acne, hirsutism and acanthosis nigricans.
Insulin resistance is also apparent in the majority of the
cases. Hypothyroidism, on the other hand, has not been
European Journal of Endocrinology
full-text articles were also screened to determine if they
were eligible for inclusion in the present meta-analysis.
Case reports and review articles were excluded from the
tabulation and analysis of results. Animal studies were
also excluded. Panagiotis Konstantopoulos and Venetia
Florou tabulated the selected indices in structured forms.
Any discrepancies in the methodology, retrieval of articles
and statistical analysis were resolved by consensus.
Literature search and data collection
The electronic search was based on Medline (19662016),
Scopus (20042016), Popline (19742016), ClinicalTrials.
gov (20082016) and CENTRAL (19992016) databases.
References of articles that were retrieved in full text were
also screened to reduce the potential article losses. We
also aimed to restrict the maximum number of keywords
to avoid the possibility of losing articles that could
contribute to our meta-analysis. Search strategies and

results are shown in Figure1.

linked to any of these disorders, apart from cases in which
it coexists with PCOS. Subclinical hypothyroidism is
frequently encountered among women with PCOS. It is
estimated that its prevalence in this specific population
ranges between 10% and 25% (13).
To date, it remains unclear whether SCH aggravates
the severity of metabolic and hormonal alterations of
women who suffer from PCOS. The aim of the present
study is to investigate this hypothesis by summarizing the
results of previous studies in the field. To accomplish this,
we evaluated the phenotypic, hormonal and metabolic
characteristics of PCOS women with and without SCH.
Our search strategy included the MeSH terms
(hypothyroidism [MeSH Terms] OR hypothyroidism [All
Fields]) AND (polycystic ovary syndrome [MeSH Terms]
OR (polycystic [All Fields] AND ovary [All Fields] AND
syndrome [All Fields]) OR polycystic ovary syndrome
[All Fields] OR (polycystic [All Fields] AND ovary [All
Fields]) OR polycystic ovary [All Fields]). The PRISMA
flow diagram schematically presents our strategy (Fig. 1).

Methods

Study design

The present study was conducted according to the

Preferred Reporting Items for Systematic Review and
Meta-analyses (PRISMA) guidelines (14). The criteria of
inclusion were determined in advance. We did not restrict
our search in specific date range or languages. The search
strategy was conducted in three stages. At the first stage
(electronic search), we screened the titles and/or abstracts
of all articles to determine whether they could be eligible
for tabulation. At the second stage (evaluation of articles
that were retrieved in full text from the previous stage), we
kept all prospective and retrospective observational studies
that reported the metabolic and hormonal profiles of PCOS Figure1
patients with subclinical hypothyroidism. References of Search flow diagram.

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 Review V Pergialiotis and others SCH in PCOS 176:3 R161

Table 1 Methodological characteristics of included studies that result in heterogeneity.

Reference Type of study OttawaNewcastle Exclusion criteria SCH definition

(30) Prospective 6 N/A TSH >4.2IU/mL

(29) Prospective 7 21-hydroxylase-deficient non-classical adrenal TSH 2.0IU/L
hyperplasia; hyperandrogenism, insulin resistance and
acanthosis nigricans syndrome; an androgen-secreting
neoplasm; elevated levels of prolactin; Cushing
syndrome; any history of manifest hypothyroidism or
hyperthyroidism or any history of thyroid surgery; or
use of thyroid hormone or iodine medication;
hormonal therapy, (oral contraceptive pills or steroid
medications)
(32) Prospective 6 21-hydroxylase-deficient non-classical adrenal SCH>2.5IU/L
hyperplasia; hyperandrogenism, insulin resistance and
acanthosis nigricans (HAIRAN) syndrome; an androgen-
secreting neoplasm; or any history of manifest thyroid
dysfunction, surgery or thyroid hormone medication;
thyroid autoimmunity; hormonal therapy, including
oral contraceptive pills or steroid medications, within
6months
(22) Prospective 7 Use of hormonal preparation, androgens or drugs TSH 5.09.0IU/L
affecting metabolic function+ glucose tolerance;
diabetes mellitus; thyroid, renal, hepatic, cardiac
dysfunction; non-classical adrenal hyperplasia;
Cushings syndrome; hyperprolactinemia
European Journal of Endocrinology

(23) Prospective 7 DM; hyperprolactinemia; congenital adrenal Hyperplasia; N/A

hypothyroidism or hyperthyroidism; Cushings disease;
hypertension; hypercholesterolemia; history of
neoplasm; any medication intake (e.g., insulin-
sensitizing drugs, oral contraceptives, antiandrogens,
statins, aspirin, corticosteroids and GnRH agonists and
antagonists)
(24) Prospective 7 Chronic diseases such as overt hypothyroidism and TSH 4.510IU/L
hyperthyroidism; kidney or liver failure;
hyperprolactinemia; late-onset adrenal hyperplasia;
diabetes
(31) Retrospective N/A N/A TSH 510IU/L
(27) Prospective 7 Clinical thyroid dysfunction; medication affecting TSH>5.0lU/L
carbohydrates, lipids, hormones
(26) Prospective 7 Hypertension; hypercholesterolemia; congenital adrenal TSH>4.0IU/L
hyperplasia; hypothyroidism or hyperthyroidism;
Cushings disease; hyperprolactinemia; specific
medications (e.g. oral contraceptives, corticosteroids,
GnRH agonists and antagonists, insulin-sensitizing
drugs, antiandrogens, aspirin)
(25) Prospective 7 History of diabetes mellitus; hyperprolactinemia; TSH>3.75IU/L
congenital adrenal hyperplasia; hypothyroidism or
hyperthyroidism; Cushings disease; renal; hepatic; or
cardiac dysfunction; a history of ovarian or adrenal
neoplasm+medication (e.g. oral contraceptives,
insulin-sensitizing drugs, statins, radioactive Iodine,
Levothyroxine, corticosteroids and GnRH agonists and
antagonists) within 6 months of the enrolment
(28) Prospective 7 Different disorders with similar symptoms; subclinical/ TSH 420U/mL
overt hyperthyroidism; thyreostatic treatment
(33) Prospective 7 Previously diagnosed thyroid disease; receiving hormonal TSH2.5 IU/L
therapy within 6 months of initial visit

N/A=data were not available.

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 Review V Pergialiotis and others
Quality assessment
The quality assessment of individual studies included in
the present systematic review was based on the Ottawa
Newcastle scale. This scale evaluates three separate
domains that refer to 1) selection of study groups,
2) comparability of groups and 3) ascertainment of outcomes
(15). The maximum score in the OttawaNewcastle Scale
is 9, and in the present meta-analysis, we predetermined
that studies with a score >7 had low risk of bias. On the
other hand, studies with a score that was lower than 5 were
highly suspicious of bias and studies with an intermediate
score (between 5 and 7) were considered as moderate risk.
Statistical analysis
The meta-analysis was performed with the Review
Manager (RevMan) 5.3 software (Copenhagen: The Nordic
Cochrane Centre, The Cochrane Collaboration, 2011). Pooled
mean differences (MD) and their 95% confidence intervals
European Journal of Endocrinology
(CI) were calculated with the DerSimonianLaird random
effect model (REM). We did not take into account the
evaluation of the I2 test during the interpretation of study
heterogeneity because the significant methodological
differences depicted in Table 1 rendered necessary the
calculation with the aforementioned model (REM) (16).
The small number of enrolled studies in the present meta-
analysis precluded assessment of publication bias (17).
Definitions
We investigated the alterations of metabolic parameters
in patients with PCOS and SCH including serum
total cholesterol (TC), triglycerides (TG), high-density
lipoprotein (HDL), LDL, fasting glucose and homeostatic
Figure2
Mean difference for HOMA-IR. The overall effect was statistically significant (P=0.005). (Vertical line=no difference point
between the two regimens. Squares=mean differences; Diamonds=pooled mean differences for all studies.
Horizontallines=95% CI).
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SCH in PCOS 176:3 R162
model assessment for insulin resistance (HOMA-IR).
The anthropometric and hormonal alterations were also
assessed including systolic and diastolic blood pressure,
body mass index (BMI), waist circumference, waist-to-hip
ratio, prolactin (PRL), FSH, LH, LH-to-FSH ratio andSHBG.
Results
Excluded studies
Four studies were excluded after reading the full text
(18, 19, 20, 21). Two of them investigated the impact of
subclinical hypothyroidism on the metabolic profile of
PCOS; however, they also have a control group of healthy
women without PCOS which does not meet the eligibility
criteria (18, 20). One more study assessed the influence
of different parameters on PCOS but did not investigate
the outcomes assessed in the present meta-analysis (21).
In addition, the last one was excluded as it presents
outcomes related to the correlation between PCOS and
autoimmune markers (19).
Included studies
Twelve studies were finally included in the present review,
which enrolled 2654 PCOS patients (22, 23, 24, 25, 26,
27, 28, 29, 30, 31, 32, 33). Among them, 577 women had
PCOS and SCH and the remaining 2077 had PCOS only.
The methodological characteristics of included studies are
presented in Table1.
Metabolic profile
The LDL values did not differ among the two groups (MD
5.75mg/dL 95% CI: 2.41, 13.91). On the other hand, HDL
 Review V Pergialiotis and others
Figure3
Mean difference for fasting glucose. The overall effect was not statistically significant (P=0.17). (Vertical line=no difference
point between the two regimens. Squares=mean differences; Diamonds=pooled mean differences for all studies.
Horizontallines=95% CI).
levels were significantly decreased in PCOS patients with
subclinical hypothyroidism (MD 3.92mg/dL 95% CI:
6.56, 1.29). Triglycerides levels were elevated in the
same group (26.91mg/dL 95% CI: 3.79, 50.02). HOMA-IR
was also affected by SCH (MD 0.82 95% CI: 0.15, 1.50
Fig.2), whereas in the case of fasting glucose, therewas
European Journal of Endocrinology
no difference (MD 1.62mg/dL 95% CI: 0.71, 3.94 Fig.3).
Four studies reported the outcomes of oral glucose
tolerance test. Three of them did not reveal significant
differences. Specifically, Celiketal. reported that the 120-
min oral glucose tolerance test (OGTT) was comparable
among SCH and controls (108.76 mg/dL 42.68 vs
98.32mg/dL33.28, P=0.630) (23). Pei et al. confirmed
these findings (6.54mmol/L2.57 vs 6.73mmol/L2.22
P=0.98) as well as Trummer et al. (99 (83111) vs 96
(81117), P=0.562) (26, 28). Luetal., on the other hand,
observed significant differences at 120min (7.042.59 vs
6.251.80mmol/L, P=0.015) (33).
Anthropometric characteristics and blood pressure
Neither systolic blood pressure nor diastolic blood
pressure differed among the two groups (MD 0.11mmHg
95% CI: 1.89, 2.11, P= 0.91) and (MD 0.36 mmHg
95% CI: 1.20, 1.91, P= 0.88) respectively. The same
was also observed in the case of waist circumference
(MD 1.39cm 95% CI: 1.02, 3.81, P=0.26), waist/hip
ratio (MD 0.01 95% CI: 0.01, 0.03, P=0.43) and BMI
(MD 0.95kg/m2 95% CI: 0.10, 2.00, P=0.08).
Hormonal profile
The hormonal profile of patients was underreported
among the two groups among studies included in
the present meta-analysis. An analysis of results was
possible in the case of total testosterone levels, which
SCH in PCOS 176:3 R163
did not significantly differ among PCOS women with
subclinical hypothyroidism (MD 0.29nmol/L, 95% CI:
0.09, 0.67, P=0.13). Three studies reported results for
PRL. Among them, Benetti-Pintoetal. showed higher PRL
levels in PCOS women with SCH when compared with
women with normal thyroid function (17.747.74 vs
14.0410.27ng/mL P=0.01) (24). However, this
observation was not confirmed by Dittrich et al. and
Ganieetal. (10.767.70 vs 8.534.40ng/mL, P=NS and
513.04295.65pmol/L vs 565.21386.95pmol/L, P=NS)
(22, 32). FSH and LH values were also similar among the
two groups. Specifically, neither Ganieetal. (6.52.4 vs
5.32.2IU/mL and 6.04.2 vs 5.74.4IU/mL P=NS)
(22) nor Enzevaei et al. (8.032.70 vs 8.222.24IU/mL
P=0.217 and 9.217.53 vs 10.118.46IU/mL, P=0.805)
(25), Dittrich et al. (6.43 1.97 vs 8.36 13.01IU/mL,
P=NS and 8.675.44 vs 8.345.72IU/mL, P=NS) (32) or
Luetal. (4.961.41 vs 5.111.27 P=0.431 and 9.534.32
vs 10.554.82, P=0.122) observed any differences (33).
The LH/FSH ratio was reported by four studies. None of
them reported significant differences (22, 25, 27, 33).
Finally, among the four studies that reported outcomes
related to SHBG levels, only Dittrich reported that they
were significantly reduced in the study group (33.6517.21
vs 43.5518.20nmol/L, P=0.01) (27, 28, 29, 32).
Sensitivity analysis
After performing a sensitivity analysis by consecutively
excluding studies included in the present meta-analysis,
we observed that the study of Enzevaeietal. significantly
influenced the level of statistical significance in the case
of the metabolic profile parameters (25). An e-mail has
been sent to the corresponding author of this single study
to confirm our findings; however, we did not receive
aresponse.
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 Review V Pergialiotis and others SCH in PCOS 176:3 R164

Discussion To date, there is no consensus regarding the impact of

PCOS on ASCVD. This is why it has not been introduced
According to the findings of our study, the coexistence among the potential risk factors in these guidelines. The
of SCH and PCOS results in mild alterations of serum coexistence of SCH and PCOS and its impact on ASCVD
lipids, which do not have clinical significance. is also not mentioned. It is our belief that future studies
Insulin resistance may also be slightly affected, as could elucidate this field.
indicated by the HOMA-IR levels. However, current data
in the field remain inconclusive because the remaining
indices (such as OGTT, insulin levels, Matsuda index Strengths and weaknesses of our study
and QUICKI index) were underreported. In the case
The findings of our study are based on a systematic
of the hormonal profile, PCOS women with SCH had
review of the literature. No language or date restriction
minor alterations in total testosterone levels. On the
was applied; therefore, the possibility of potential article
other hand, FSH, LH and their ratio were not affected by
losses is small. The majority of included studies were
the presence of SCH.
prospective, and given their methodological quality
Our study supports the findings of recent studies
assessment, biases were limited. Patients with chronic
concerning the additive effect of SCH on the metabolic
diseases such as diabetes mellitus, metabolic disorders
profile of patients with conditions such as obesity
(e.g. hypercholesterolemia) and hormonal dysfunction
(34, 35). The pathophysiological processes behind this
(hyperprolactinemia etc) were also excluded from the
observation have not been completely elucidated. To
majority of included studies, thereby reducing analytical
date, it is established that thyroid hormones promote
European Journal of Endocrinology

and exclusion bias.

the activity of 3-hydroxy-3methylglutaryl-coenzyme A
On the other hand, the definition of SCH differed
(HMG-CoA) reductase. They also upregulate the LDL
between studies; however, we managed to overcome this
receptor gene (36). The reduction of HMG-CoA reductase
barrier by introducing the DerSimonianLaird random
activity that accompanies hypothyroidism results in
effects model, which takes into account potential
altered total cholesterol and LDL levels. Substitution
differences between included studies. Publication bias
therapy with thyroxine improves these abnormalities,
has also been observed in the cases of several variables
and it is estimated that within 46 weeks the lipid profile
that were underreported, hence rendering impossible
is significantly improved (4, 37). An inverse correlation of
their meta-analysis and interpretation. Another
these two disorders has also been suggested by two study
potential of our study is the applicability of these
groups, which observed that the correction of insulin
results to women with PCOS in the general population.
resistance with metformin resulted in TSH suppression
Previously, Luque-Ramirez et al. suggested that
(in patients with overt or subclinical hypothyroidism)
patients with PCOS studied in the clinical setting may
(38, 39). Hence, a direct correlation of these two diseases
significantly differ from those in the general population
seems to be present, which underlines the necessity for
in terms of androgen excess, obese phenotype and so
future research in the field.
forth (41).
Despite the fact that the observed alterations in
serum levels are of minimal clinical significance, it
remains unknown whether these have the potential to Conclusion
increase cardiovascular morbidity in a long-term basis.
The current classification of hyperlipidemia is based To date, there is no direct evidence to support that SCH
on the adult treatment panel IV (ATP-IV) guidelines exerts a detrimental impact on the metabolic and hormonal
(40). According to these recommendations, lifetime profile of PCOS patients. Therefore, supplementation with
risk assessment should be offered in 2059-year-old thyroid hormones is not justified until further evidence
patients and repeated every 46 years. The atherosclerotic becomes available in the field. On the other hand, the
cardiovascular disease (ASCVD) prevention tool stratifies mild metabolic alterations that are evident in patients
patients in four separate stating groups. Among them, with SCH and PCOS compared to PCOS patients without
there is a group of individuals without clinical ASCVD or SCH might result in significant morbidity in a long-
diabetes aged 4075 years with an LDL of 70189mg/dL term setting. However, this hypothesis remains, to date,
and an estimated 10-year ASCVD risk of 7.5% or higher. arguable, as there are no data relevant to this field.

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 Review V Pergialiotis and others
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of this review.
Funding
This research did not receive any specific grant from any funding agency in
the public, commercial or not-for-profit sector.
Author contribution statement
V P conceived the idea, formed the tables and revised the MS. P K searched
the literature, tabulated data and wrote the MS. A P searched the
literature, tabulated data and wrote the MS. V F searched the literature,
tabulated data and wrote the MS. D N P searched the literature, provided
consultation and revised the MS. N P wrote the MS, reviewed the tables,
provided consultation and revised the MS.
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Received 20 July 2016
Revised version received 2 November 2016
Accepted 22 December 2016