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Context: Women with polycystic ovary syndrome (PCOS) have increased risk of preterm delivery.
Shortening of the cervix is a sign of preterm delivery.
Objective: This study aimed to investigate potential effect of metformin on cervical length and
whether androgen levels correlate with cervical length in PCOS pregnancies.
Design and Setting: This was a sub-study of a randomized, placebo-controlled, multicenter study
(The PregMet study) performed at 11 secondary or tertiary centers from 2005 to 2009.
Participants: Two-hundred sixty-one pregnancies of 245 women with PCOS, age 18 – 42 years
participated.
Interventions: Participants were randomly assigned to metformin or placebo from first trimester
to delivery.
Outcome Measurements: We compared cervical length and androgen levels in metformin and
placebo groups at gestational weeks 19 and 32. We also explored whether cervical length corre-
lated with androgen levels.
Results: We found no difference in cervical length between the metformin and the placebo groups
at gestational week 19 and 32. Dehydroepiandrosterone (DHEAS) tended to be higher in the
metformin group. There were no correlations between androgens and cervical length at week 19.
At gestational week 32, androstenedione (P ! .02) and DHEAS (P ! .03) showed a trend toward
negative correlation to cervical length. High androstenedione level correlated with shortening of
cervical length from week 19 to 32 when adjusted for confounders (P ! .003). T (P ! .03), DHEAS
(P ! .02), and free testosterone index (P ! .03) showed a similar trend.
Conclusion: Metformin in pregnancy did not affect cervical length in women with PCOS. High
maternal androgen levels correlated with cervical shortening from the second to the third trimester
of pregnancy, as a sign of cervical ripening. (J Clin Endocrinol Metab 101: 2325–2331, 2016)
ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: BMI, body mass index; BP, blood pressure; CI, confidence interval; DHEAS,
Printed in USA dehydroepiandrosterone; FTI, free T index; IVF, in vitro fertilization; PCOS, polycystic ovary
Copyright © 2016 by the Endocrine Society syndrome; PregMet, Metformin Treatment in Pregnant PCOS Women Study.
Received September 17, 2015. Accepted January 28, 2016.
First Published Online February 2, 2016
doi: 10.1210/jc.2015-3498 J Clin Endocrinol Metab, June 2016, 101(6):2325–2331 press.endocrine.org/journal/jcem 2325
2326 Shetelig Løvvik et al Cervical Length and Androgens in PCOS Pregnancy J Clin Endocrinol Metab, June 2016, 101(6):2325–2331
term deliveries compared with other developed countries. inal ultrasound examinations or 2) on androgens, and 3)
An increase from 9% in 1982 to 12% in 2003 was re- to explore whether there was any correlation between an-
ported (1). In 2012 the rate of preterm birth in the United drogen levels and cervical length in PCOS pregnancies.
States decreased to 9.7% (2, 3). In Norway, approxi-
mately 6% of all deliveries occur before gestational week
37 (4). The prevalence seems to be slowly increasing in Materials and Methods
most Western countries.
Polycystic ovary syndrome (PCOS) is a common con- The PregMet study
The present study is a substudy of the Metformin Treatment
dition, and recent studies suggest a prevalence of 15% in
in Pregnant PCOS Women (PregMet) study, which was a pro-
a general population (5, 6) and up to 30% among women spective, randomized, double-blind, multicenter trial, compar-
week 19 and week 32 of pregnancy. The specimens were cen- index (BMI), age, randomization to metformin/placebo, previ-
trifuged within 1 hour and stored at 5°C. Within 24 hours, the ous vaginal delivery, and cervix conisation. To adjust for mul-
specimens were frozen at "80°C. All blood samples were ana- tiple testing we chose a pragmatic approach and considered a P "
lyzed in 2009, after the last study participant had delivered. De- .01 as significant. P & .05 and ' .01 were considered as trends
hydroepiandrosterone (DHEAS) and SHBG were analyzed by toward significance. Results are given as #-coefficients with 95%
the ELISA technique with the reagents and calibrators supplied confidence intervals (CI), where CI not including zero suggests
by the manufacturer (DRG Instruments, GmbH). We used or- significance or a trend toward significance.
ganic solvent extraction (dichloromethane for T and ethyl ether
for androstenedione) prior to quantification to analyze serum T
and androstenedione. For quantification we used the ELISA
technique for T (DRG Instruments, GmbH) and Coat-A-Count Results
RIA kits (Diagnostic Products Corporation) for androstenedi-
Table 1. Differences in Cervical Length, Gestational Age at Delivery, Androgen and Insulin Levels in Pregnant PCOS
Women According to Metformin and Placebo Treatment
Metformin, Placebo, Crude Adjusted
Mean (SD) Mean (SD) P-Value ! (95% CI)b P-Valueb
Intention to treat analysis
n ! 129 n ! 125
Cervix wk 19, mm 42 (6) 43 (8) .73 0.002 ("0.01; 0.01) .67
n ! 126 n ! 117
Cervix wk 32, mm 37 (8) 36 (8) .70 "0.01 ("0.01; 0.01) .81
n ! 131 n ! 130
Gestational length, d 278 (10) 276 (15) .23 "0.003 ("0.01; 0.02) .27
did not affect cervical length or androgen levels at gesta- gestational week 32. If metformin has a protective effect
tional week 19 or 32. on preterm deliveries it might be exerted through path-
This study comprised women from The PregMet study. ways other than androgen synthesis or shortening of the
An epianalysis of the Pilot Study and the PregMet study cervix. Metformin could modulate inflammation, by re-
showed a possible protective effect of metformin on the ducing inflammatory cell numbers or inflammatory mark-
combined end-point; preterm delivery and second trimes- ers. Metformin has been shown to regulate the endome-
ter miscarriages (16). Our study only evaluates cervical trial cell function directly (26). Another theoretical
length in week 19 and 32 of pregnancy. Most of the pre- mechanism could be lowering of contractility threshold of
term deliveries in the PregMet study were “late preterm” the myometrium: one study reports that metformin does
(ie, after gestational week 34), which may explain why we not exert effect on the spontaneous or oxytocin-induced
did not find any difference in absolute cervical length at myometrial contractions in an in vitro model (27).
doi: 10.1210/jc.2015-3498 press.endocrine.org/journal/jcem 2329
Table 2. Correlations Between Cervical Length or Change in Cervical Length, Androgen, and Insulin Levels in
Pregnant PCOS Women in Gestational Week 19 and 32
Crude Adjusted
Crude " (CI) P-Value Adjusted " (CI)a P-Valuea
Gestational wk 19, n # 245
T, nmol/L 0.05 ("0.42; 0.53) .82 0.29 ("0.18; 0.75) .23
Androstenedione, nmol/L "0.15 ("0.32; 0.02) .08 "0.05 ("0.22; 0.12) .57
DHEAS, !mol/L "0.31 ("0.82; 0.21) .24 "0.08 ("0.58; 0.42) .76
SHBG, nmol/L 0.002 ("0.01; 0.01) .68 0.002 ("0.01; 0.01) .73
FTI 0.20 ("1.04; 1.43) .76 0.77 ("0.44; 1.98) .21
Insulin, pmol/L 0.01 ("0.004; 0.02) .16 0.01 (&0.001; 0.03) .04
In the third trimester of pregnancy, at week 32, high extracellular matrix composition and affect the mechan-
maternal androstenedione and DHEAS levels showed a ical strength of the cervix (12, 29).
tendency toward correlation to a short cervix. The cervix The idea of androgens affecting cervical ripening and
consists of fibroblasts, smooth muscle, epithelial, and im- by that causing preterm labor is supported by animal stud-
mune cells that secrete extracellular matrix (28). Andro- ies in which administration of supra-physiological doses
gens, estradiol, relaxin, and prostaglandin can alter the of androstenedione was injected in pregnant rhesus mon-
Table 3. Baseline Data of 261 Women With PCOS at Inclusion in First Trimester of Pregnancy
P
Alla Metformina Placeboa Valueb
n 261 131 130
Age, y 29.5 (4.4) 29.7 (4.3) 29.3 (4.4) .39
BMI, kg/m2 28.9 (6.8) 29.5 (7.1) 28.3 (6.4) .15
Systolic BP, mm Hg 118 (11.6) 119 (12.0) 117 (11.2) .39
Diastolic BP, mm Hg 73 (9.3) 73 (8.9) 72 (9.6) .52
Spontaneous pregnancy 151 [58] 75 [57] 76 [59] .84
Ovulation stimulation 68 [26] 39 [30] 29 [22] .17
IVF/ICSI 38 [15] 17 [13] 21 [16] .47
Smoking 20 [8] 14 [11] 6 [5] .07
Working/student 229 [88] 118 [90] 111 [85] .18
Unemployed 5 [2] 2 [2] 3 [2] .65
Cervical conisation 14 [5] 6 [5] 8 [6] .57
Parity
0 145 [56] 73 [56] 72 [55] .63
1( 116 [44] 58 [44] 58 [45] .96
Abbreviation: ICSI, .
a
Values given as mean (SD) or n [%] as appropriate.
b
t test independent samples, equality of means.
2330 Shetelig Løvvik et al Cervical Length and Androgens in PCOS Pregnancy J Clin Endocrinol Metab, June 2016, 101(6):2325–2331
keys causing preterm labor (30). This is in line with the may influence remodeling of the cervix, especially ripening
present observation that androstenedione correlated neg- of the cervix at term, and maybe also in preterm deliveries
atively with cervical length and change, whereas the other (31–34).
androgens investigated showed a tendency toward
correlation. Strengths and limitations
In other animal studies, administration of dihydrotes- Our study was performed in a setting with relatively
tosterone resulted in decreased cervical resistance, low prevalence of preterm labor (3, 4). If performed in a
whereas administration of the androgen receptor antag- setting with higher prevalence, such as in the United States
onist flutamide increased the resistance. Cervical resis- (2), it might have altered the results. This study is a sub-
tance was determined by the “cervical creep method,” an study of an randomized controlled trial, which might be a
and worldwide estimates of preterm birth rates in the year 2010 with 21. Timmons B, Akins M, Mahendroo M. Cervical remodeling during
time trends since 1990 for selected countries: A systematic analysis pregnancy and parturition. Trends Endocrinol Metab. 2010;21:
and implications. Lancet. 2012;379:2162–2172. 353–361.
4. Morken NH, Vogel I, Kallen K, et al. Reference population for 22. Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone
international comparisons and time trend surveillance of preterm reduces the rate of preterm birth in women with a sonographic short
delivery proportions in three countries. BMC Womens Health. cervix: A multicenter, randomized, double-blind, placebo-con-
2008;8:16. trolled trial. Ultrasound Obstet Gynecol. 2011;38:18 –31.
5. March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies 23. Romero R, Yeo L, Chaemsaithong P, Chaiworapongsa T, Hassan
MJ. The prevalence of polycystic ovary syndrome in a community SS. Progesterone to prevent spontaneous preterm birth. Semin Fetal
sample assessed under contrasting diagnostic criteria. Hum Reprod. Neonatal Med. 2014;19:15–26.
2010;25:544 –551. 24. Ji H, Dailey TL, Long V, Chien EK. Androgen-regulated cervical
6. Tehrani FR, Simbar M, Tohidi M, Hosseinpanah F, Azizi F. The ripening: A structural, biomechanical, and molecular analysis. Am J
prevalence of polycystic ovary syndrome in a community sample of Obstet Gynecol 2008;198:543 e541– e549.