Steroid receptor expression in the vulvar vestibular mucosa — effects of oral contraceptives and menstrual cycle

doi:10.1016/j.contraception.2007.06.014

Contraception

Volume 76, Issue 4, October 2007, Pages 319-325

https://doi.org/10.1016/j.contraception.2007.06.014 Get rights and content

Abstract

Background

The objective was to evaluate the influence of combined oral contraceptives (COC) and of the menstrual cycle on the steroid receptor expression in the vulvar vestibular mucosa of healthy women.

Study Design

Forty-five healthy women (20 with COC and 25 without) were included. Vestibular biopsies were obtained during the menstrual cycle. Estrogen receptors (ER) α and β, progesterone receptors (PR) A and B, glucocorticoid receptor and androgen receptor as well as the proliferation marker Ki67 were analyzed using immunohistochemistry followed by computerized image analysis.

Results

The vestibular stromal tissue of women using COC expressed more ERβ (p=.024) than that of women without COC. In the follicular phase, PRB was more abundant in the stromal tissue than in the luteal phase (p=.01).

Conclusions

ERβ is more abundant in the vulvar vestibular mucosa of women using COC than in that of women without COC. There is a cyclic variation in PRB in the vestibular mucosa in healthy women without COC.

Introduction

Combined oral contraceptives (COC) were first introduced in 1960 and are composed of 17α-ethinyl estradiol and various progestins [1], [2]. The steroid hormones exert their effects through the nuclear receptors of, e.g., estrogen (ER), progesterone (PR), androgen (AR) and glucocorticoid (GR) [3], [4]. The more recently described ER beta (ERβ) [5] is partially homologous to the first discovered ER, now denoted alpha (ERα) [6]. Although ERβ shares many functional characteristics with ERα, the molecular mechanisms regulating the transcriptional activity and the tissue location of ERβ differ from those of ERα [5], [7].

PRA is identical to PRB apart from lacking 164 amino acids from the N-terminal [8]. In the genital tract, from the vagina to the vulva, there is a gradual decrease in the concentration of ERα and PR [9], whereas the amount of AR is highest in the vulvar skin. The receptor expression is, however, a dynamic process, with up- and down-regulation of receptors depending on hormonal serum levels as well as sex hormone-binding globulin (SHBG) levels.

Studies evaluating the effect on genital tissues by COC have mainly focused on the morphology while the steroid receptor expression have been scantily investigated [10]. The endometrium, including vascular cells, shows a variation in the more abundant ERα and the less frequent ERβ [11] as well as in PRA and PRB [12] during the menstrual cycle. In another study on vaginal epithelium, higher ER concentrations were found in the follicular phase compared with the luteal phase as measured by enzyme immunoassay [13]. However, in a more recent study using immunohistochemistry, no differences were observed in the distribution of ER and PR during the menstrual cycle [14]. In a few studies, ERα has been identified in normal as well as in malignant vaginal and vulvar tissue [15]. Premenopausal women show a high level of ERβ in vaginal biopsies, whereas a manifest decline occurs after menopause regardless of estrogen replacement therapy [16]. The expression of ERβ in normal vulvar tissue has not been studied [15]. It is still unclear whether the vulvar steroid receptor expression is influenced by oral contraceptives and/or if there is a variation during the menstrual cycle in healthy young women [17], [18].

According to our experience, about 15% of young women seeking help for superficial dyspareunia did improve by omitting the hormonal contraception for 4–6 months. The nonkeratinized mucosa around the vaginal introitus is of endodermal origin. The immunoprotective barrier of this area is more vulnerable compared with the surrounding skin. The vestibule in contrast to the vagina is often affected by pain disorders [19].

Recently, we found morphological characteristics of the vestibular mucosa during COC use. Low and sparse dermal papillae were present in COC users as well as during the luteal phase in nonusers indicating a plausible gestagenic effect (Johannesson et al., in press).

The objective of the present study was to analyze the presence of sex steroid receptors in the vulvar vestibular mucosa during usage of COC and during the menstrual cycle in healthy young women.

Section snippets

Subjects

Forty-five women were included in the study, of which 20 (mean age, 23.7 years; range, 18–29 years) were on COC and 25 (mean age, 25.6; range, 19–34) used condoms. Inclusion criteria were to be healthy and sexually active, aged 18–35 years, either using COC or condoms as the only contraceptive method. Subjects were mainly recruited among university students. Inclusion criteria for the women on COC were usage of the pill for at least one year. Table 1 displays the COC contents. Inclusion

Results

The COC users had a mean COC duration of use of 6.1 years (range, 2–15 years). The mean age for starting COC was 17 years (range, 15–25 years). The mean body mass index was 22 (19–29) for the COC users, as compared to 22 (range, 19–28) for the nonusers. Five samples were excluded from the paired analysis between the follicular and the luteal phase because the progesterone concentrations in the luteal phase indicated that ovulation did not occur (<13 nmol/l). Serum concentrations of

Discussion

In this study we have shown that the vulvar vestibular expression of certain steroid hormone receptors varies during the menstrual cycle and seems to be influenced by hormonal contraception. The vestibular stroma of healthy women on COC express more ERβ than that of control women during the follicular phase. The fact that the staining intensity of ERβ in the epithelial cells was less prominent in COC users may indicate less receptors per cell. One interpretation of these findings may be that

Acknowledgment

We thank Joanna Onoszko and Nina Pettersson for valuable technical assistance.

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^☆: This study received financial support from The Swedish Research Council (project 73X-20137), and the Swedish Society of Medicine and Karolinska Institutet Research Foundation.

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Original research articleSteroid receptor expression in the vulvar vestibular mucosa — effects of oral contraceptives and menstrual cycle☆

Abstract

Background

Study Design

Results

Conclusions

Introduction

Section snippets

Subjects

Results

Discussion

Acknowledgment

Am J Obstet Gynecol

J Steroid Biochem Mol Biol

Contraception

Fertil Steril

J Steroid Biochem Mol Biol

Contraception

Biochem Pharmacol

Fertil Steril

Gynecol Oncol

Maturitas

J Sex Med

Science, medicine, and the future

BMJ

Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta

Endocrinology

Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern

J Clin Endocrinol Metab

Cloning of a novel receptor expressed in rat prostate and ovary

Proc Natl Acad Sci U S A

Colocalization of progesterone receptors A and B by dual immunofluorescent histochemistry in human endometrium during the menstrual cycle

J Clin Endocrinol Metab

An immunohistochemical study of androgen, oestrogen and progesterone receptors in the vulva and vagina

Br J Obstet Gynaecol

Presence of estrogen receptor beta in the human endometrium through the cycle: expression in glandular, stromal, and vascular cells

J Clin Endocrinol Metab

Menstrual variation of estrogen receptor content in vaginal tissue

Gynecol Obstet Invest

Original research article
Steroid receptor expression in the vulvar vestibular mucosa — effects of oral contraceptives and menstrual cycle☆