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Human vaginal epithelial immunity and influences of hormonal contraceptive usage
Umeå University, Faculty of Medicine, Clinical Microbiology, Immunology/Immunchemistry. Umeå University, Faculty of Medicine, Clinical Sciences, Obstetrics and Gynaecology.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The vagina is the port of entry for sexually transmitted diseases in women. Its epithelium constitutes the luminal border, thus comprising an important defence barrier. The objective of this work was to investigate the mechanisms of importance in the immune defence of the vaginal epithelium of healthy, fertile women, and possible menstrual cycle changes. Effects of hormonal contraceptive usage on oestrogen receptor (ER) and progesterone receptor (PR) expression were studied. The contribution of epithelial cell to the immune defence was estimated by assaying their expression of antimicrobial defensins and the epithelial thickness.

Vaginal biopsies and serum samples were collected during the follicular and luteal phases in regularly menstruating women (controls) and in users of combined oral contraceptives (COCs), levonorgestrel implants (LNGs), or depot-medroxyprogesterone acetate injections (DMPAs). Fifteen healthy women (aged 20–34 years) were enrolled in each group. Morphometry was performed on vaginal tissue stained with haematoxylin/eosin and by immunohistochemistry using monoclonal antibodies against immune cell markers, PR, and ER. Expression of mRNA for human α-defensins HD-5 and HD-6, and human β-defensins (HBD) 1 to 4 were determined by real-time qRT-PCR and in situ hybridization.

In controls, the epithelium was 261 ± 16 μm thick and harboured 241 ± 35 leukocytes (CD45+) per mm2. T lymphocytes (CD3+) dominated. Both αβ T cells and γδ T cells were present with an approximate 4-fold dominance of αβ T cells. Cytotoxic T cells (CD8+) were more frequent than T helper cells (CD4:CD8 ratio: 0.7 ± 0.1). Macrophages (CD68+) constituted the second-largest population, followed by Langerhans cells (CD1a+). B cells, natural killer cells, monocytes and granulocytes were generally absent. No differences were found between the follicular and luteal phase. All four β-defensins analysed for were detected in vaginal epithelium and most samples expressed at least two. HBD-2 and HBD-3 were most frequent. HBD-3 and HBD-4 expressing cells were localized in the parabasal and intermediate cell layers. α-defensins were not detected.

The epithelium was significantly thicker (333 ± 9 μm) in COC, LNG, and DMPA users than in controls, and commonly showed hyperplasia. In DMPA and LNG users the frequency of intraepithelial leukocytes (CD45+) was increased, explained by increased frequencies of both αβ and γδ T cells. In DMPA users there was also a selective increase in CD8+ T cells. PR expression was significantly reduced in DMPA users compared with controls, COC and LNG users. COC and particularly DMPA users often had undetectable levels of serum E2.

In conclusion, both adaptive immunity, i.e. intraepithelial T cells, and innate defence mechanisms, i.e. intraepithelial macrophages and β-defensins, are believed to contribute to the immune defence in the human female lower genital tract. These parameters did not change during the menstrual cycle but hormonal contraceptive usage, especially DMPA, affected the quality of the epithelium. The use of DMPA and LNG was correlated with the accumulation of T cells within the epithelium. The effects of these changes on the risk of contracting infections are yet to be determined.

Place, publisher, year, edition, pages
Umeå: Klinisk mikrobiologi , 2005. , 92 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 977
Keyword [en]
human vaginal epithelium, hormonal contraceptives, epithelial thickness, intraepithelial immune cells, steroid receptors, steroid hormones, defensins
Research subject
Obstetrics and Gynaecology
Identifiers
URN: urn:nbn:se:umu:diva-595ISBN: 91-7305-923-4 (print)OAI: oai:DiVA.org:umu-595DiVA: diva2:143903
Public defence
2005-10-07, Föreläsningssal A 103 (Astrid Fagraeus salen), byggnad 6A, våning 1, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Available from: 2005-09-22 Created: 2005-09-22 Last updated: 2009-11-16Bibliographically approved
List of papers
1. Influence of Hormonal Contraceptives on the Immune Cells and Thickness of Human Vaginal Epithelium
Open this publication in new window or tab >>Influence of Hormonal Contraceptives on the Immune Cells and Thickness of Human Vaginal Epithelium
2003 (English)In: Obstetrics and Gynecology, ISSN 0029-7844, E-ISSN 1873-233X, Vol. 102, no 3, 571-582 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To determine whether use of steroid hormone contraceptives modifies immune defense parameters of the vaginal epithelium in humans. METHODS: Vaginal biopsies were collected during the follicular and luteal phases in regularly menstruating women (controls) and in women using combined oral contraceptives, depot-medroxyprogesterone acetate injections, or levonorgestrel implants. Fifteen healthy women (aged 20-34 years) were enrolled in each group. Biopsies were analyzed in a blinded manner. Epithelial thickness was estimated by morphometry. Immune cells were analyzed by immunomorphometry with cell-type-specific monoclonal antibodies. RESULTS: The epithelium of controls harbored 241+/-35 leukocytes (CD45+ cells) per mm2 (mean+/-1 standard error of the mean), and the thickness was 261+/-16 microm. T lymphocytes (CD3+) dominated, and cytotoxic or suppressor T cells (CD8+) were more frequent than T helper cells (CD4:CD8 ratio: 0.7+/- 0.1). Macrophages (CD68+) constituted the second-largest population, followed by Langerhans cells (CD1a+). B cells, natural killer cells, monocytes, and granulocytes were generally absent. There were no significant differences between the follicular and luteal phases. The epithelium was significantly thicker in all three groups that used hormonal contraceptive (333+/-9 microm) compared with controls, and it exhibited superficial hyperplasia. The frequency of intraepithelial leukocytes (CD45+) was increased in depot-medroxyprogesterone acetate (P<.001) and levonorgestrel implant users (P<.04). In depot-medroxyprogesterone acetate users, this was explained by an increased frequency of the CD8+ T lymphocyte subset. CONCLUSION: Hormonal contraceptives induce hyperplasia of the vaginal epithelium. The significant changes in the intraepithelial leukocyte population in depot-medroxyprogesterone acetate and levonorgestrel implant users most probably reflect altered local immune capacity.

National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-4689 (URN)10.1016/S0029-7844(03)00618-5 (DOI)12962945 (PubMedID)
Available from: 2005-09-22 Created: 2005-09-22 Last updated: 2013-04-11Bibliographically approved
2. Increased Frequency of both αβ and γδT Lymphocytes in Human Vaginal Epithelium of Progestin-Only Contraceptive Users
Open this publication in new window or tab >>Increased Frequency of both αβ and γδT Lymphocytes in Human Vaginal Epithelium of Progestin-Only Contraceptive Users
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4690 (URN)
Available from: 2005-09-22 Created: 2005-09-22 Last updated: 2010-01-13Bibliographically approved
3. Steroid receptor expression in vaginal epithelium of healthy fertile women and influences of hormonal contraceptive usage.
Open this publication in new window or tab >>Steroid receptor expression in vaginal epithelium of healthy fertile women and influences of hormonal contraceptive usage.
2005 (English)In: Contraception, ISSN 0010-7824, E-ISSN 1879-0518, Vol. 72, no 5, 383-392 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The objective of this study was to evaluate whether long-term usage of hormonal contraceptives modifies the steroid receptor expression in the human vaginal epithelium of healthy young women. METHODS: In a cross-sectional study, three groups of hormonal contraceptive users [combined oral contraceptives (COCs), levonorgestrel implants (LNG) and depot medroxyprogesterone acetate injections (DMPAs)] were compared to controls. Fifteen subjects (20-34 years) were enrolled to each group. Vaginal biopsies were collected at two occasions from each subject, and serum concentrations of E(2) and progesterone were measured. Monoclonal antibodies directed against progesterone receptors (PRs) and estrogen receptors (ERs) were used in immunohistochemistry on formalin-fixed tissue sections of vaginal mucosa. A program for immunohistomorphometric quantification was devised to estimate frequency of epithelial steroid receptor-expressing cells. RESULTS: Progesterone receptor expression was markedly down-regulated and significantly reduced in DMPA users compared to controls, COC and LNG users. In DMPA users, the ER expression was significantly elevated in the first compared to the second sample, and significantly elevated compared to LNG users. Estradiol concentration in serum was significantly reduced in hormonal contraceptive users compared to controls. CONCLUSIONS: Steroid receptor expression in human vaginal epithelium is altered by long-term use of DMPA compared to controls.

National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-21210 (URN)10.1016/j.contraception.2005.05.018 (DOI)16246667 (PubMedID)
Available from: 2009-04-07 Created: 2009-04-07 Last updated: 2013-04-17
4. Prominent Expression of β-defensins 2 and 3 in Vaginal Epithelial Cells of Healthy Fertile Women
Open this publication in new window or tab >>Prominent Expression of β-defensins 2 and 3 in Vaginal Epithelial Cells of Healthy Fertile Women
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:umu:diva-4692 (URN)
Available from: 2005-09-22 Created: 2005-09-22Bibliographically approved

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