Pantarhei Bioscience, PO Box 464, 3700 AL Zeist, The Netherlands.
Hum Reprod Update. 2014 Jan-Feb;20(1):76-105. doi: 10.1093/humupd/dmt038. Epub 2013 Sep 29.
BACKGROUND; Combined oral contraceptives (COCs) reduce levels of androgen, especially testosterone (T), by inhibiting ovarian and adrenal androgen synthesis and by increasing levels of sex hormone-binding globulin (SHBG). Although this suppressive effect has been investigated by numerous studies over many years, to our knowledge no systematic review concerning this issue had been performed. This systematic review and meta-analysis was performed to evaluate the effect of COCs on concentrations of total T, free T and SHBG in healthy women and to evaluate differences between the various types of COCs (e.g. estrogen dose, type of progestin) and the assays used to assess total T and free T.
A review of the literature was performed using database searches (MEDLINE, EMBASE and the Cochrane Central Register of Clinical Trials) and all publications (from inception date until July 2012) investigating the effect of COCs on androgen levels in healthy women were considered eligible for selection. Three reviewers were involved in study selection, data extraction and critical appraisal. For the meta-analysis, data on total T, free T and SHBG were extracted and combined using random effects analysis. Additional subgroup analyses were performed to evaluate differences between the various types of COCs (e.g. estrogen dose, type of progestin) and the assays used to assess total T or free T.
A total of 151 records were identified by systematic review and 42 studies with a total of 1495 healthy young women (age range: 18-40 years) were included in the meta-analysis. All included studies were experimental studies and 21 were non-comparative. Pooling of the results derived from all the included papers showed that total T levels significantly decreased during COC use [mean difference (MD) (95% confidence interval, CI) -0.49 nmol/l (-0.55, -0.42); P < 0.001]. Significantly lower levels of free T were also found [relative change (95% CI) 0.39 (0.35, 0.43); P < 0.001], with a mean decrease of 61%. On the contrary, SHBG concentrations significantly increased during all types of COC use [MD (95% CI) 99.08 nmol/l (86.43, 111.73); P < 0.001]. Subgroup analyses revealed that COCs containing 20-25 µg EE had similar effects on total and free T compared with COCs with 30-35 µg EE. In addition, suppressive effects on T levels were not different when comparing different types of progestins. However, subgroup analyses for the estrogen dose and the progestin type in relation to changes in SHBG levels did show significant differences: COCs containing second generation progestins and/or the lower estrogen doses (20-25 µg EE) were found to have less impact on SHBG concentrations.
The current literature review and meta-analysis demonstrates that COCs decrease circulating levels of total T and free T and increase SBHG concentrations. Due to the SHBG increase, free T levels decrease twice as much as total T. The estrogen dose and progestin type of the COC do not influence the decline of total and free T, but both affect SHBG. The clinical implications of suppressed androgen levels during COC use remain to be elucidated.
复方口服避孕药（COC）通过抑制卵巢和肾上腺雄激素合成以及增加性激素结合球蛋白（SHBG）水平来降低雄激素，尤其是睾酮（T）的水平。尽管多年来已有许多研究探讨了这种抑制作用，但据我们所知，尚未对此问题进行系统评价。本系统评价和荟萃分析旨在评估 COC 对健康女性总 T、游离 T 和 SHBG 浓度的影响，并评估各种 COC（如雌激素剂量、孕激素类型）和评估总 T 和游离 T 时使用的检测方法之间的差异。
使用数据库搜索（MEDLINE、EMBASE 和 Cochrane 临床试验中央注册库）进行文献综述，并考虑了所有研究（从开始日期到 2012 年 7 月），这些研究都调查了 COC 对健康女性雄激素水平的影响。三名审查员参与了研究选择、数据提取和批判性评估。对于荟萃分析，提取了总 T、游离 T 和 SHBG 的数据，并使用随机效应分析进行了组合。还进行了额外的亚组分析，以评估各种 COC（如雌激素剂量、孕激素类型）和评估总 T 或游离 T 时使用的检测方法之间的差异。
通过系统评价共确定了 151 条记录，纳入了 42 项研究，共纳入了 1495 名健康年轻女性（年龄范围：18-40 岁）进行荟萃分析。所有纳入的研究均为实验研究，其中 21 项为非对照研究。汇总所有纳入论文的结果表明，COC 使用期间总 T 水平显著下降[平均差异（MD）（95%置信区间，CI）-0.49 nmol/L（-0.55，-0.42）；P < 0.001]。游离 T 水平也明显降低[相对变化（95%CI）0.39（0.35，0.43）；P < 0.001]，平均下降 61%。相反，所有类型的 COC 均能使 SHBG 浓度显著升高[MD（95%CI）99.08 nmol/L（86.43，111.73）；P < 0.001]。亚组分析显示，与含有 30-35 µg EE 的 COC 相比，含有 20-25 µg EE 的 COC 对总 T 和游离 T 具有相似的作用。此外，比较不同类型的孕激素时，T 水平的抑制作用没有差异。然而，关于雌二醇剂量和孕激素类型与 SHBG 水平变化的亚组分析确实显示出显著差异：含有第二代孕激素和/或较低雌激素剂量（20-25 µg EE）的 COC 对 SHBG 浓度的影响较小。
目前的文献综述和荟萃分析表明，COC 降低循环总 T 和游离 T 水平，并增加 SHBG 浓度。由于 SHBG 增加，游离 T 水平下降的幅度是总 T 的两倍。COC 的雌激素剂量和孕激素类型并不影响总 T 和游离 T 的下降，但都影响 SHBG。COC 使用期间雄激素水平抑制的临床意义仍有待阐明。
