Oral, transdermal and vaginal combined contraceptives induce an increase in markers of chronic inflammation and impair insulin sensitivity in young healthy normal-weight women: a randomized study.
OBJECTIVE
What is the effect of alternative administration routes of combined contraceptives (CCs) on androgen secretion, chronic inflammation, glucose tolerance and lipid profile?


CONCLUSIONS
The use of oral, transdermal and vaginal CCs impairs glucose tolerance and induces chronic inflammation.


BACKGROUND
Oral CCs worsen insulin sensitivity and are associated with increased levels of circulating inflammatory markers, whereas the metabolic effects of transdermal and vaginal CCs have been reported to be minimal. This is the first study comparing three different administration routes of CCs on metabolic variables.


METHODS
This randomized (computer-generated) open-label 9-week follow-up study was conducted at the Oulu University Hospital, Finland. Fasting blood samples were collected at baseline and thereafter at 5 and 9 weeks of treatment, and serum levels of 17-hydroxyprogesterone, androstenedione, testosterone, C-reactive protein (CRP), sex hormone-binding globulin (SHBG), glucose, insulin, C-peptide, total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were measured. Oral glucose tolerance tests were performed and plasma levels of pentraxin 3 (PTX-3) were measured at 0 and 9 weeks. The randomization list, with an allocation ratio of 1:1:1 and block size of six, was computer generated and constructed by a pharmacist at the Oulu University Hospital. The research nurse controlled the randomization list and assigned participants to their groups at the first visit.


METHODS
Forty-two of 54 healthy women who entered the study used oral contraceptive pills (n = 13), transdermal contraceptive patches (n = 15) or contraceptive vaginal rings (n = 14) continuously for 9 weeks. Inclusion criteria were regular menstrual cycles, at least a 2-month washout as regards hormonal contraceptives and no medication.


RESULTS
Serum levels of SHBG increased and consequently the free androgen index (FAI) decreased in all study groups from baseline to 9 weeks of treatment [FAI, oral: 1.3 (95% confidence interval, CI: 0.94; 1.62) to 0.40 (0.25; 0.54); transdermal: 1.2 (0.96; 1.4) to 0.36 (0.30; 0.43); vaginal: 1.6 (1.1; 2.1) to 0.43 (0.29; 0.58), P < 0.001 in all groups]. Insulin sensitivity was reduced at 9 weeks in all three groups according to the Matsuda index [oral: 7.3 (5.5; 9.0) to 5.6 (3.9; 7.3); transdermal: 9.1 (6.7; 11.4) to 6.6 (4.5; 8.8); vaginal: 7.7 (5.9; 9.5) to 5.4 (3.9; 7.0), P= 0.004-0.024]. Levels of HDL cholesterol, triglycerides and CRP rose in all three groups [CRP, oral: 0.70 (0.38; 1.0) to 5.4 (1.0; 9.9) mg/l; transdermal: 0.77 (0.45; 1.1) to 2.9 (1.4;4.4) mg/l; vaginal: 0.98 (0.52; 1.4) to 3.7 (-0.25; 7.7, a negative value due to skewed distribution to right) mg/l, P≤ 0.002 in all groups] and PTX-3 levels increased in the oral and transdermal study groups (P = 0.007 and P = 0.002).


CONCLUSIONS
Although the long-term consequences of the present results remain undetermined, these findings emphasize the importance of monitoring glucose metabolism during the use of CCs, especially in women with known risks of type 2 diabetes or cardiovascular diseases.    BIAS, LIMITATIONS, GENERALIZABILITY:   The number of subjects was relatively low. Moreover, the 9-week exposure to CCs is too short to draw conclusions about the long-term health consequences. However, as the subjects were healthy, normal-weight young women, the possible alterations in the glucose and inflammatory profiles among women with known metabolic risks might be even greater.


BACKGROUND
This work was supported by grants from the Academy of Finland, the Sigrid Jusélius Foundation, the Finnish Medical Foundation, the Research Foundation of Obstetrics and Gynecology, Oulu University Scholarship Foundation, the North Ostrobothnia Regional Fund of the Finnish Cultural Foundation, the Tyyni Tani Foundation of the University of Oulu and the Finnish-Norwegian Medical Foundation. No competing interests.


BACKGROUND
NCT01087879.
Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu FIN-90029, Finland.
T
T
Piltonen
J
J
Puurunen
P
P
Hedberg
A
A
Ruokonen
S J
SJ
Mutt
K H
KH
Herzig
A
A
Nissinen
L
L
Morin-Papunen
J S
JS
Tapanainen
D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D000279:Administration, Cutaneous; D000282:Administration, Intravaginal; D000328:Adult; D000728:Androgens / Q000097:blood / Q000378:metabolism; D000735:Androstenedione / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose; D002096:C-Peptide / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D003271:Contraceptive Agents, Female / Q000008:administration & dosage / Q000009:adverse effects*; D003277:Contraceptives, Oral, Combined / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008074:Lipoproteins / Q000097:blood; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D013739:Testosterone / Q000097:blood
D000728:Androgens; D015415:Biomarkers; D001786:Blood Glucose; D002096:C-Peptide; D003271:Contraceptive Agents, Female; D003277:Contraceptives, Oral, Combined; D007328:Insulin; D008074:Lipoproteins; D012738:Sex Hormone-Binding Globulin; D013739:Testosterone; D000735:Androstenedione; D019326:17-alpha-Hydroxyprogesterone; D002097:C-Reactive Protein; D005947:Glucose