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Review
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 thus contributing to the pathogenesis of cardiovascular
that affects young women. Its prevalence ranges between disease (2, 3). Overt hypothyroidism has been linked to
5% and 10% (1). It is frequently correlated with metabolic altered lipid profile and insulin insensitivity (4, 5, 6).
abnormalities such as dyslipidemia, insulin resistance, Similarly, subclinical hypothyroidism (SCH) (which
type 2 diabetes mellitus (DM) and the metabolic syndrome, is described by elevated levels of thyroid-stimulating
hormone (TSH) with normal free thyroxine levels) full-text articles were also screened to determine if they
has been associated with decreased glucose disposal, were eligible for inclusion in the present meta-analysis.
increase of sex hormone-binding globulin (SHBG) levels, Case reports and review articles were excluded from the
hyperlipidemia, increases in serum total cholesterol tabulation and analysis of results. Animal studies were
(TC), low-density lipoprotein cholesterol (LDL) and total also excluded. Panagiotis Konstantopoulos and Venetia
triglyceride levels weight gain and insulin resistance in Florou tabulated the selected indices in structured forms.
the general population (7, 8, 9, 10) .The treatment of SCH Any discrepancies in the methodology, retrieval of articles
in the general population remains controversial in our and statistical analysis were resolved by consensus.
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 Literature search and data collection
be treated if TSH values exceed 4IU/L (12). The electronic search was based on Medline (19662016),
Besides metabolic alterations, PCOS is associated with Scopus (20042016), Popline (19742016), ClinicalTrials.
distinctive alterations of reproductive hormones. Increases gov (20082016) and CENTRAL (19992016) databases.
in luteinizing hormone-to-follicle-stimulating hormone References of articles that were retrieved in full text were
ratio (LH/FSH) and circulating androgens contribute to also screened to reduce the potential article losses. We
the occurrence of the traditional phenotype of PCOS also aimed to restrict the maximum number of keywords
which includes acne, hirsutism and acanthosis nigricans. to avoid the possibility of losing articles that could
Insulin resistance is also apparent in the majority of the contribute to our meta-analysis. Search strategies and
cases. Hypothyroidism, on the other hand, has not been
European Journal of Endocrinology
Methods
Study design
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Review V Pergialiotis and others SCH in PCOS 176:3 R161
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Review V Pergialiotis and others SCH in PCOS 176:3 R162
(CI) were calculated with the DerSimonianLaird random autoimmune markers (19).
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 Included studies
differences depicted in Table 1 rendered necessary the Twelve studies were finally included in the present review,
calculation with the aforementioned model (REM) (16). which enrolled 2654 PCOS patients (22, 23, 24, 25, 26,
The small number of enrolled studies in the present meta- 27, 28, 29, 30, 31, 32, 33). Among them, 577 women had
analysis precluded assessment of publication bias (17). PCOS and SCH and the remaining 2077 had PCOS only.
The methodological characteristics of included studies are
presented in Table1.
Definitions
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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Review V Pergialiotis and others SCH in PCOS 176:3 R163
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 did not significantly differ among PCOS women with
subclinical hypothyroidism (MD 3.92mg/dL 95% CI: subclinical hypothyroidism (MD 0.29nmol/L, 95% CI:
6.56, 1.29). Triglycerides levels were elevated in the 0.09, 0.67, P=0.13). Three studies reported results for
same group (26.91mg/dL 95% CI: 3.79, 50.02). HOMA-IR PRL. Among them, Benetti-Pintoetal. showed higher PRL
was also affected by SCH (MD 0.82 95% CI: 0.15, 1.50 levels in PCOS women with SCH when compared with
Fig.2), whereas in the case of fasting glucose, therewas women with normal thyroid function (17.747.74 vs
European Journal of Endocrinology
no difference (MD 1.62mg/dL 95% CI: 0.71, 3.94 Fig.3). 14.0410.27ng/mL P=0.01) (24). However, this
Four studies reported the outcomes of oral glucose observation was not confirmed by Dittrich et al. and
tolerance test. Three of them did not reveal significant Ganieetal. (10.767.70 vs 8.534.40ng/mL, P=NS and
differences. Specifically, Celiketal. reported that the 120- 513.04295.65pmol/L vs 565.21386.95pmol/L, P=NS)
min oral glucose tolerance test (OGTT) was comparable (22, 32). FSH and LH values were also similar among the
among SCH and controls (108.76 mg/dL 42.68 vs two groups. Specifically, neither Ganieetal. (6.52.4 vs
98.32mg/dL33.28, P=0.630) (23). Pei et al. confirmed 5.32.2IU/mL and 6.04.2 vs 5.74.4IU/mL P=NS)
these findings (6.54mmol/L2.57 vs 6.73mmol/L2.22 (22) nor Enzevaei et al. (8.032.70 vs 8.222.24IU/mL
P=0.98) as well as Trummer et al. (99 (83111) vs 96 P=0.217 and 9.217.53 vs 10.118.46IU/mL, P=0.805)
(81117), P=0.562) (26, 28). Luetal., on the other hand, (25), Dittrich et al. (6.43 1.97 vs 8.36 13.01IU/mL,
observed significant differences at 120min (7.042.59 vs P=NS and 8.675.44 vs 8.345.72IU/mL, P=NS) (32) or
6.251.80mmol/L, P=0.015) (33). 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
Anthropometric characteristics and blood pressure
them reported significant differences (22, 25, 27, 33).
Neither systolic blood pressure nor diastolic blood Finally, among the four studies that reported outcomes
pressure differed among the two groups (MD 0.11mmHg related to SHBG levels, only Dittrich reported that they
95% CI: 1.89, 2.11, P= 0.91) and (MD 0.36 mmHg were significantly reduced in the study group (33.6517.21
95% CI: 1.20, 1.91, P= 0.88) respectively. The same vs 43.5518.20nmol/L, P=0.01) (27, 28, 29, 32).
was also observed in the case of waist circumference
(MD 1.39cm 95% CI: 1.02, 3.81, P=0.26), waist/hip Sensitivity analysis
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). After performing a sensitivity analysis by consecutively
excluding studies included in the present meta-analysis,
we observed that the study of Enzevaeietal. significantly
Hormonal profile
influenced the level of statistical significance in the case
The hormonal profile of patients was underreported of the metabolic profile parameters (25). An e-mail has
among the two groups among studies included in been sent to the corresponding author of this single study
the present meta-analysis. An analysis of results was to confirm our findings; however, we did not receive
possible in the case of total testosterone levels, which aresponse.
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Review V Pergialiotis and others SCH in PCOS 176:3 R164
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Review V Pergialiotis and others SCH in PCOS 176:3 R165
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