The Impact of Combined Hormonal Birth Control on Insulin Sensitivity and Inflammation - FACTS (2023)

By: Jessica Kerpez

Editor’s Note: This week, we feature a research review summarized by Jessica Kerpez, a medical student and former FACTS elective participant. While previous studies have identified decreased insulin sensitivity in women taking oral contraceptives, this was the first paper to evaluate how all three forms of contraceptives might impact inflammatory markers, lipid markers, and insulin levels

Introduction

With approximately 65% of women aged 15 to 49 currently using contraception[1] it is important to be aware of the broad effects that hormonal birth control can have on a woman’s health. This study by Piltonen et al was designed to evaluate three different administration routes of contraception, including transdermal, oral, and vaginal ring, and how these routes might influence markers of inflammation and insulin sensitivity.[2] Increased inflammation and reduced insulin sensitivity are risk factors that can lead to the development of different diseases, including Type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). [3]

The results of previous trials suggest oral combined contraceptives worsen glucose metabolism, whereas transdermal and vaginal contraceptives have little to no effect. Furthermore, the effect of combined contraceptives on lipid metabolism has been unclear, although the majority of studies indicate an increase in triglyceride and high-density lipoprotein cholesterol (HDL-C) levels following use of oral and transdermal contraceptives. [4] Prior research also identified an association between oral contraceptives (OCPs) and CVD, although the risk may be diminished upon discontinuation of OCPs. [5] The development of CVD can also be influenced by C-reactive protein (CRP,) a liver inflammatory marker, which is considered to be an independent risk factor for CVD. Few studies exist evaluating the effect of combined contraceptives on CRP levels.[6] Piltonen et al therefore designed the study to further investigate the mechanism by which all three forms of hormonal birth control could influence inflammatory markers, lipid markers, and insulin levels. [1]

“The results of previous trials suggest oral combined contraceptives worsen glucose metabolism, whereas transdermal and vaginal contraceptives have little to no effect.”

Methodology

The study evaluated a total of 54 healthy Caucasian women (aged 20-33) at Oulu University Hospital, Finland between September 2008 and December 2010. Participants had a BMI between 17.9-26.4 kg/m² with no medication use and regular menstrual cycles. The women were randomly assigned in equal numbers to one of three preparations: a combined oral contraceptive pill, a transdermal contraceptive patch, or a contraceptive vaginal ring. Blood pressures and glucose tolerance levels were measured at baseline. Normal ovarian function was verified via ultrasound. Exclusion criteria included impaired fasting glucose (IFG) or IGT, T2DM, type 1 diabetes, alcohol abuse, cigarette smoking, and any contraindications regarding use of combined contraceptives and lactation.

Fasting blood samples and levels of serum 17-hydroxyprogesterone, androstenedione, testosterone, sex hormone binding globulin (SHBG), total cholesterol, LDL/HDL, triglycerides, and high sensitivity CRP were collected at baseline, five weeks, and nine weeks. The oral glucose tolerance test was performed via a 75 g load of glucose, with IFG diagnosed at a glucose range of 6.1-6.9 mmol/L and IGT diagnosed when glucose levels at two hours were between 7.8-11.0 mmol/L. The study then plotted insulin and glucose levels using the area under the curve (AUC).

Results

Mean age, BMI, waist-to-hip ratio, and blood pressure were comparable at the end of the study compared to the beginning, except a very slight BMI increase from 21.6 kg/m2 to 22.0 kg/m² in the transdermal patch group. Serum levels of 17-OHP and androstenedione decreased significantly across all study groups. Testosterone levels were unchanged in the oral and vaginal ring groups but increased in the transdermal patch group. Serum levels of SHBG increased significantly over time. Fasting serum levels of insulin increased significantly from baseline for all three groups. The AUC of insulin also rose significantly for the oral (P ≤ 0.030) and transdermal (P ≤ 0.041) combined contraceptives, and a slight rise was observed in the vaginal ring group (P ≤ 0.013). In the transdermal patch group, serum levels of C-peptide rose from baseline to nine weeks, but this was not observed in the other formulations studied. The fasting insulin sensitivity index decreased in all three study groups.

“Fasting serum levels of insulin increased significantly from baseline for all three groups (and) … the fasting insulin sensitivity index decreased in all three study groups.”

Serum total cholesterol remained unchanged in all three groups, although triglyceride levels and HDL increased significantly. LDL cholesterol concentration rose significantly only in the oral contraceptive group. The total concentration of CRP was found to rise in all three study groups at 9 weeks, excluding five women from the analysis. The increase in SHBG levels was smaller in the vaginal ring group compared to the other two groups. The change in fasting glucose was highest in the vaginal ring group.

Discussion

This research was the first to evaluate how all three routes of hormonal birth control, oral, transdermal, and vaginal, can influence both insulin levels and inflammatory markers. Some of the key observations to note are that serum levels of SHBG increased across all three study groups, leading to a decrease in the free androgen index. Another key observation was that even though the fasting serum glucose levels were consistent at nine weeks, the insulin sensitivity decreased in all three study groups. Consistent with these findings, previous studies have also demonstrated decreased insulin sensitivity in the oral contraception group. However, this study was important as it was the first study to show this effect also applies to both transdermal and vaginal contraception. Furthermore, it also shed light on the effects of different types of hormonal birth control on cholesterol and triglyceride levels, largely unclear prior to the study; increased serum levels of HDL and triglycerides were observed in all three groups, whereas serum cholesterol was somewhat stable over time.

Combined contraceptives have these effects due to estrogen decreasing insulin sensitivity whereas progestin increases insulin response in conjunction with estrogen use. Estrogen also increases levels of HDL and decreases LDL, while progestin has the opposite effect.[6] It is important to look at an increase in HDL, as this is considered an independent inverse risk factor for diseases including CVD even when LDL levels are low. Elevated levels of the inflammatory marker CRP were found to increase in all study groups, a prognostic marker for the development of CVD [7].

The results found that all three formulations of combined hormonal birth control generally have an adverse effect on glucose metabolism and have the potential to cause chronic inflammation. This is noteworthy as it is the first study to demonstrate that not only oral, but also transdermal and vaginal routes of administration have these effects. Worsening insulin resistance and increased insulin levels have been implicated in the subsequent increase in CVD and type 2 diabetes mellitus. Therefore, the use of combined contraceptives needs to be used with caution, particularly in those patients with pre-existing conditions, including but not limited to obesity, type 2 diabetes, CVD, or an androgen deficiency disorder. Women should be aware of these effects and discuss with their doctor the full spectrum of options to meet their individual family planning or health care needs, including fertility awareness-based methods (FABMs).

“Fasting serum levels of insulin increased significantly from baseline for all three groups (and) … the fasting insulin sensitivity index decreased in all three study groups.”

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Disadvantages of the study include the 20% drop-out rate and the fact that the study was not blinded, which could impact the significance of the data collected. In future studies, it would be imperative to conduct a double-blind study with a larger sample size and higher retention rate. Furthermore, it would be beneficial to expand the cultural diversity of the subject population beyond Caucasian women, especially considering that women of different ethnicities have varying responses in their insulin and inflammatory marker levels. [8] Future studies should identify safe ranges for insulin or inflammatory marker levels to determine the point at which it may no longer be safe for women to continue using contraceptives and evaluate and suggest alternatives. FABMs are a safe alternative for family planning, with a number of different methods available for women and couples to use. For couples with limited time and resources to learn a method, or those that desire to learn a method online, the Billings Ovulation Method or the Standard Days Method may be valuable options. For women with irregular cycles, the Creighton Model, the Sympto-Thermal Method, or the Marquette Model may be a good fit; several of these methods offer a way to cross-check observations and have established protocols to address medical issues.

Sources

[1] Daniels K, Mosher WD, Jones J. Contraceptive methods women have ever used: United States, 1982–2010. National Health Statistics Reports; no 62. Hyattsville, MD: National Center for Health Statistics. 2013.
[2] Piltonen T, Puurunen J, Hedberg P, et al. 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. Hum Reprod. 2012;27(10):3046-3056. doi:10.1093/humrep/des225
[3] Haffner SM. Pre-diabetes, insulin resistance, inflammation and CVD risk. Diabetes Res Clin Pract. 2003 Jul;61 Suppl 1:S9-S18. doi: 10.1016/s0168-8227(03)00122-0. PMID: 12880690.
[4] Cagnacci A, Ferrari S, Tirelli A, Zanin R, Volpe A. Route of administration of contraceptives containing desogestrel/etonorgestrel and insulin sensitivity: a prospective randomized study. Contraception. 2009;80(1):34-39. doi:10.1016/j.contraception.2009.01.012
[5] Baillargeon JP, McClish DK, Essah PA, Nestler JE. Association between the current use of low-dose oral contraceptives and cardiovascular arterial disease: a meta-analysis. J Clin Endocrinol Metab. 2005;90:3863-3870.
[6] Mantovani A, Garlanda C, Doni A, Bottazzi B. Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3. J Clin Immunol. 2008;28:1 – 13.
[7] Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24(4):683-689. doi:10.2337/diacare.24.4.683
[8] White T, Jain JK, Stanczyk FZ. Effect of oral versus transdermal steroidal contraceptives on androgenic markers. Am J Obstet Gynecol. 2005;192(6):2055-2059. doi:10.1016/j.ajog.2005.02.067