Effect of four oral contraceptives on thyroid hormones, adrenal and blood pressure parameters

doi:10.1016/S0010-7824(03)00006-4

Contraception

Volume 67, Issue 5, May 2003, Pages 361-366

https://doi.org/10.1016/S0010-7824(03)00006-4 Get rights and content

Abstract

In a double-blind, controlled, randomized, four-arm, bicentric clinical study, the effect of four oral contraceptives (OCs) on thyroid hormone parameters, cortisol, aldosterone, endothelin-1 and angiotensin II was investigated. Four groups composed of 25 volunteers each (ages between 18 and 35 years) were treated for six cycles with monophasic combinations containing 21 tablets with either 30 μg ethinylestradiol (EE) + 2 mg dienogest (DNG) (30EE/DNG), 20 μg EE + 2 mg DNG (20EE/DNG), 10 μg EE + 2 mg estradiol valerate (EV) + 2 mg DNG (EE/EV/DNG) or 20 μg EE + 100 μg levonorgestrel (LNG) (EE/LNG). The study was completed by 91 subjects. Blood samples were taken by venipuncture after at least 12 h fasting on Day 21–26 of the control cycle and on Day 18–21 of the first, third and sixth treatment cycle. There was a significant increase in triiodothyronine (T3) and thyroxine (T4) by 20–40% in all treatment cycles, while thyroid-stimulating hormone was significantly increased only with EE/EV/DNG. Treatment with the DNG-containing OCs caused no change in free T4 (FT4) and a transitory reduction in free T3 (FT3) levels during the first cycle. During intake of EE/LNG, FT4 rose slightly, while FT3 was not altered. The pronounced rise in the serum concentrations of cortisol appeared to be related to the EE dose. During the first three cycles of treatment, no effect on angiotensin II levels was observed, while in the sixth cycle a significant decrease was measured in all treatment groups. The four OCs did not influence the serum concentrations of endothelin-1 and no consistent effects were found concerning those of aldosterone. The results suggest that the three DNG-containing and the LNG-containing low-dose OCs may increase T3, T4 and cortisol due to an elevated binding to serum globulins, while the free proportion of the hormones is not or only slightly changed. Therefore, these OCs have only minor effects on thyroid function, adrenal and blood pressure serum parameters.

Introduction

Oral contraceptives (OCs) are well known to affect the serum concentrations of various endocrine parameters, which under normal conditions are not involved in the regulation of ovarian activity. Treatment with estrogens or OCs is associated, e.g., with an increase in thyroxine (T4) and triiodothyronine (T3), or cortisol [1], [2], [3], [4], [5]. These elevated values may lead to misinterpretations if treatment with OCs of the patients is not known to the physician. In women using OCs, the rise in the levels of total T3 and T4 as well as of cortisol is caused by an increase in the serum-binding capacity of thyroxine-binding globulin (TBG) and corticosteroid-binding globulin (CBG), which reduces the clearance of the respective hormones. On the other hand, an increased serum binding leads to a reduction of the free proportion of these hormones. Therefore, the resulting amount of free T3 (FT3), free T4 (FT4) and free cortisol in the circulation as well as thyroid and adrenal function may be unchanged during treatment with OCs.

The rise in TBG and CBG levels is due to the pronounced effect of ethinylestradiol (EE) on hepatic globulin synthesis, which is dose-dependent and, to a certain degree, can be modulated by the progestogen component [6]. Therefore, according to the composition of the preparations, changes in circulating hormonal parameters may differ. In addition, it cannot be excluded that OCs may directly affect synthesis and release of adrenal or thyroid hormones. It has previously been demonstrated that sex steroids containing an ethinyl group may reduce adrenal steroid biosynthesis by inhibiting certain cytochrome P-450 enzymes [7]. Oral contraceptives are also known to increase plasma renin substrate (angiotensinogen) due to the pronounced hepatic effect of EE [8]. This might be accompanied by a rise in plasma renin activity, angiotensin II and aldosterone levels [9].

In the present study we investigated the effect on the plasma concentrations of thyroid hormones, some adrenal hormones and hormones involved in the regulation of blood pressure, of monophasic combinations of 2 mg dienogest (DNG) with either 30 μg or 20 μg ethinyl estradiol (EE) or 10 μg EE plus 2 mg estradiol valerate (EV) as compared with an OC containing 20 μg EE and 100 μg levonorgestrel (LNG).

Section snippets

Design of the study

One hundred healthy volunteers between 18 and 35 years of age with regular menstrual cycles and without contraindications for the use of OCs were included in this randomized double-blind study. The women had not used any hormonal medication for at least 4 weeks prior to the study and did not use drugs that were known to influence the effects of OCs. A general and gynecological examination including a Papanicolaou smear and a pregnancy test, as well as the assessment of the general safety

Results

Screening was carried out with 110 subjects, of whom 100 women were randomized and received medication. Eight subjects discontinued the study prematurely, and from one subject no data were available from the treatment phase. Ninety-one subjects completed the study. The statistical analysis was carried out with the data of all 99 subjects who received any study medication and from whom data from the treatment phase were available (full-analysis set).

The four treatment groups were comparable in

Discussion

Most studies on the effects of OCs revealed an increase in the levels of T4, while T3 and TSH were increased or unchanged [1], [2], [10], [11], [12]. The present investigation revealed a rise in total T3 and T4 during treatment with all four preparations with a slightly more pronounced effect in the DNG-containing groups as compared to EE/LNG. The rise in T3 and T4 is suggested to be associated with the significant increase in the serum level of TBG which was also higher during treatment with

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Original research articleEffect of four oral contraceptives on thyroid hormones, adrenal and blood pressure parameters

Abstract

Introduction

Section snippets

Design of the study

Results

Discussion

Contraception

Contraception

Lancet

Steroids

Contraception

Eur J Obstet Gynecol Reprod Biol

Contraception

Am J Obstet Gynecol

Contraception

Fertil Steril

Serum TSH and serum T3 levels during normal menstrual cycles and during cycles on oral contraceptives

Acta Endocrinol

The increase in plasma and saliva cortisol levels in pregnancy is not due to the increase in corticosteroid binding globulin levels

J Clin Endocrinol Metab

Biologic effects of various doses of ethinyl estradiol in postmenopausal women

Obstet Gynecol

Effect of oral contraceptives on plasma androgenic steroids and their precursors

Obstet Gynecol

Original research article
Effect of four oral contraceptives on thyroid hormones, adrenal and blood pressure parameters