Oral Contraceptive Effects on Testosterone Levels in Healthy Women: A Review of Research

By: Jordyn Prince, DO

Director’s Note: Associated risks and side effects of combined oral contraceptive (COC) are still not completely understood despite the high prevalence use in the general population. Below is a summary of the systematic review and meta-analysis titled, “The effect of combined oral contraception on testosterone levels in healthy women.” [19] Former FACTS elective student Jordyn Prince summarized the study published by Zimmerman et al on the relationship between COC use and androgen levels, including potential impact on sexual function. The study also sought to evaluate the various assessment methods for testosterone. Prince notes the need for further research on COC use in women with polycystic ovary syndrome (PCOS) and endometriosis, conditions discussed in depth during the two-week women’s health block of the FACTS online elective.

Introduction

Combined oral contraceptives (COCs) are frequently prescribed to healthy women as a means to avoid pregnancy, but they come with potential side effects and risks. COCs are hypothesized to reduce androgen levels, particularly testosterone (T), by three mechanisms: inhibiting ovarian synthesis, inhibiting adrenal synthesis, and increasing levels of sex hormone binding globulin (SHBG). [1-10] This relationship has been investigated, but its important clinical implications received little attention until recently.

“Combined oral contraceptives are hypothesized to reduce androgen levels, particularly testosterone (T), by three mechanisms: inhibiting ovarian synthesis, inhibiting adrenal synthesis, and increasing levels of sex hormone binding globulin.”

As normal total T (0.42-2.94 nmol/L) and free T levels (35-700 pmol/L) are already low in females, it is important to use accurate methods of assessment. [11-13] The most accurate method to determine total T is liquid chromatography-tandem mass spectrometry (LC-MS/MS), and to calculate free T concentration, equilibrium dialysis is best. Instead, calculation methods using total T, albumin, and SHBG concentration are often used in studies. [14-18]

In the first known systematic review and meta-analysis to examine this effect, Zimmerman et al sought to analyze the effect of COCs on levels of total T, free T, and SHBG in healthy women aged 18-40 years. [19] They performed additional subgroup analysis to examine the difference in effect between varying estrogen doses and progestin types, and to study different assessment methods to determine T levels.

Methodology

This study was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. [20-22] Three online databases were searched using keywords in titles and abstracts in addition to using ‘pearl growing’ to search reference lists for related articles. Two of the three main outcome parameters had to be reported. Exclusion criteria were as follows: studies in men or animals; women suffering from different reproductive pathologies; postmenopausal women; other types of contraception; other outcome parameters (e.g. cervical mucus); treatment duration less than a cycle; and bioequivalence/bioavailable studies.

Two of the three reviewers performed critical appraisal for bias, including selection, detection, performance, attrition, and reporting bias. Due to a lack of control groups in most of the studies, those comparing pre-treatment and end-of-treatment levels were used in the meta-analysis; study participants had not used hormonal contraceptives prior to the study treatment.

The mean difference (MD) and associated 95% confidence intervals (CI) were calculated based on the means of pre- and post-treatment levels. For standardization, the end of treatment point was calculated after 6 treatment cycles. Logarithms were used to reduce wide value ranges in the data, and heterogeneity in the results of different studies was examined using I².

For subgroup analysis, they compared 20-25 µg versus 30-35 µg ethinyl estradiol (EE) as well as progestin type (first through fourth generation) for all outcome parameters. Subgroup analysis also evaluated the methods used to determine total and free T.

Results

The initial search of databases yielded 2,371 records, and a review based on titles narrowed the search to 193 records. After removing duplicates, screening abstracts, and reviewing full texts with data processing, 42 studies were included in the meta-analysis. Due to examined outcome parameters, 39 studies were included in the meta-analysis to examine COC effect on total T and SHBG, and 29 studies were included for COC effect on free T.

Regarding methods to assess total T, 30 studies used direct immunoassay, 9 studies used an extraction/chromatography step before RIA, and no studies used the gold standard method, LC-MS/MS. For free T calculation, 18 studies used direct immunoassay, 8 studies used calculation, and 3 studies used the best method, equilibrium dialysis.

The total T concentration pooled from the studies showed a significantly lower level than pre-treatment levels (MD: -0.49 nmol/L; 95% CI: -0.5, -0.42). There was also a statistically significant decrease in free T levels (relative change: 0.39; 95% CI: 0.35, 0.43) with a mean decrease of 61%. There was a statistically significant increase in SHBG levels (MD: 99.08 nmol/L; 95% CI: 86.43, 111.73).

Subgroup analysis found similar decreases in total and free T levels for both dosages of EE and all generations of progestin. However, although SHBG concentrations significantly increased with all COC types, COCs with 20-25 µg EE and second generation progestins were associated with a lesser rise in SHBG levels. This was a statistically significant finding.

For determination of total T levels, there were lower differences in concentration when extraction or chromatography was used. However, the different methods to determine free T showed similar results.

“Subgroup analysis found similar decreases in total and free testosterone levels for both dosages of ethinyl estradiol and all generations of progestin.”

 Discussion

This study found that COC use in healthy women significantly lowered both total and free T levels and significantly increased SHBG levels. The average decrease in total T level was 31% compared to 61% for free T. These results are relevant, as T is responsible for various functions in healthy women, and its deficiency is thought to be associated with mood changes, decreased energy, cognitive disturbances, declines in muscle mass, and changes in sexual function. [16][23] Studies have also found decreased levels of androstenedione (AD), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone-sulfate (DHEA-S) following COC use; as these are precursors to reproductive hormones, this may have long term effects. [10][24-28] These are all important effects to consider when prescribing COCs, especially when fertility awareness-based methods (FABMs) are an evidence-based, safe alternative for family planning with similar effectiveness rates as COCs. [29]

“This study found that COC use in healthy women significantly lowered both total and free testosterone levels … and its deficiency is thought to be associated with mood changes, decreased energy, cognitive disturbances, declines in muscle mass, and changes in sexual function.”

Significant heterogeneity was found among studies for the main analyses of SHBG and free T levels. This might be explained by varying periods without hormonal contraception prior to study start, different types of COC used, and different timing of blood sample draws.

Limitations of this meta-analysis include using studies not well designed to prevent selection bias and having few studies with blinding in their design. Attrition bias due to incomplete outcomes data was the largest bias found among the studies. Also, the methodology used to find studies may have caused some related studies to be missed.

Further research is needed to examine the clinical implications of decreased T in women taking COCs. Future research could also evaluate the effect of COCs on these various testosterone levels in women with conditions such as endometriosis and PCOS.

References

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ABOUT THE AUTHOR

Jordyn Prince, DO

Jordyn Prince, DO graduated from the inaugural class at Oklahoma State University College of Osteopathic Medicine at the Cherokee Nation in Tahlequah, Oklahoma. She is starting residency in obstetrics and gynecology at St. Anthony Hospital. Dr. Prince completed her undergraduate education at the University of Oklahoma in Norman, Oklahoma, with majors in chemistry and biochemistry and a minor in Spanish. She is passionate about reproductive health equity and education. She enrolled in the FACTS elective to learn more about natural family planning methods, and plans to share them with her patients so they can feel more empowered in their decisions.