Effects of Female Sex Hormone Therapy on Nasal Mucosa

Abstract

Women worldwide commonly use combined oral contraceptives (COCs) and hormone replacement therapy(HRT). Nevertheless, there is still ambiguity regarding the possible influence of these hormone therapy on the nasal mucosa. A systematic review was performed according to PRISMA guidelines. We included publications analyzing how hormonal imbalance affects the nasal mucosa in women taking oral contraceptives or sex hormone replacement therapy. An electronic database search was conducted using PubMed (MEDLINE), The Cochrane Library, ClinicalTrials.gov for the identification of articles. The search used a combination of the following keywords: «rhinitis», «drug-reduced rhinitis», «oral contraceptive», «menopausal hormone replacement therapy». Our search of electronic date databases yielded 1016 articles; 7 studies were included in this systematic review. In the studies we analyzed, 5 studies assessed the effect of COCs on the occurrence of rhinitis and 2 assessing the impact of HRT. Histological results of the studies confirmed the changes in the nasal mucosa of patients taking oral contraceptives or sex hormone replacement therapy. Our systematic review reviewed the evidence on the effects of sex hormone therapy on the nasal mucosa. Estrogens exert a variety of effects on various organs, including the nasal mucosa via specific receptors, but the presence of ERs does not necessarily mean that they play a key role in all processes in the nasal mucosa. It may be that ERs only fulfil an auxiliary function or are involved in certain conditions - therefore, this systematic review provides a wide field for further research.

Introduction

Estrogens, as the main female sex hormones, play a key role in the regulation of various physiological processes in the body, including reproduction, metabolism, cardiovascular health and bone health. One aspect of the effects of estrogens is their effect on the nasal mucosa, which can lead to changes in its physiology and possibly to the development of nasal obstruction. Nasal obstruction has a significant impact on quality of life and can even lead to reduced performance and negatively affect social interactions.

During different periods of a woman’s life, such as menstrual cycle, pregnancy, menopause, and others, estrogen levels fluctuate significantly, which can affect the condition of the nasal mucosa. Hormone therapy (HT), including hormone replacement therapy (HRT) and combined oral contraceptives (COCs), is widely used to manage these hormonal fluctuations and associated symptoms.

Studies show that estrogen exerts its effects through specific receptors called estrogen receptors (ER), which are represented by two isoforms: alpha (ERα) and beta (ERβ). These receptors, located in various cellular localizations, including the nasal cavity provide selective action of hormones on tissues.

Several studies [1, 2] have investigated the effects of HT and СOCs on nasal physiology. The results of these studies point to the complex interactions between estrogens and receptors in the nasal mucosa and the possible consequences of these interactions, such as vasodilation and altered mucociliary clearance.

The relevance of this work is justified by the fact that at present there is no systematic review on the evaluation of the correlation between the hormonal status of women and the manifestation of rhinitis, with emphasis on the influence of female sex hormones, namely the level of estrogen, and its receptors on the nasal mucosa. During menstruation or pregnancy, the nasal mucosa is more swollen and more frequent and severe nosebleeds are possible during these periods [3].

This topic has been the subject of much discussion again only since the end of the 19th century, when scientists drew attention to the symptoms of nasal congestion, which were associated with hormonal changes during pregnancy and the menstrual cycle [3, 4]. Since then, the study of this issue has not stopped to this day.

The aim of this review is to assess the potential effects of estrogens on the nasal mucosa, adhering to strict inclusion and exclusion criteria. The review will synthesize the results of different studies and the potential clinical implications of hormonal therapy.

Materials and Methods

Our review was reported according to the PRISMA statement. This systematic review has been registered in the PROSPERO international prospective register by the National Institute for Health Research (NIHR) by number CRD42023481785.

An electronic database search was conducted using PubMed (MEDLINE), The Cochrane Library, ClinicalTrials.gov (last searched 15 February 2024) for the identification of randomized and non-randomized controlled trials. The search used a combination of the following keywords: «rhinitis», «drug-reduced rhinitis», «oral contraceptive», «menopausal hormone replacement therapy ». MeSH terms were used in PubMed: (“Rhinitis“(Mesh)) AND “Contraceptives, oral“(Mesh) OR “Estrogen Replacement Therapy“(Mesh). In the Cochrane Library the following additional terms were used: (Rhinitis, therapy-TH) between 2000 and 2024 in English in Trials. In the ClinicalTrials.gov the term «rhinitis» was used. The study was conducted in accordance with the PRISMA 2020 guidelines [5].

Inclusion criteria include studies that were conducted in adult women using oral contraceptives or undergoing sex hormone replacement therapy, with molecular and morphological methods of nasal mucosal assessment being mandatory.

Exclusion criteria are adolescents (under 18 years of age) and the elderly (over 70 years of age), individuals with existing rhinitis prior to the start of the study, and articles in languages other than English. In addition, participants with respiratory tract infections, individuals using hormone therapy other than for contraception, individuals with hormonal disorders, those using nasal sprays during the study, and those with a history of nasal or reproductive cancers will be excluded.

During the study selection process, the full texts of potentially relevant articles will be independently assessed by the authors for inclusion. In case of discrepancies, a third researcher intervenes to resolve the problem. Duplicate studies will be systematically removed to ensure the integrity of the dataset.

Data extraction will encompass key elements such as study design, sample size, patients age, intervention, comparison, assessment methods and study results. An Excel spreadsheet will be employed for meticulous recording of extracted data.

The quality of the selected studies will be evaluated by two independent investigators, and any disagreements will be resolved through discussion or consultation with a third investigator.

Each included study was assessed for risk of bias by two authors independently using the ROBINS-I tools for assessing non-randomized studies and RoB 2.0 [6, 7] for randomized trials according to the rules of the Cochrane guideline for systematic reviews. A visual traffic light graph for ROBINS-I was created using the Robvis tool [6, 8]. Any disagreement was resolved by a third author.

The analysis will include a synthesis of the findings to draw comprehensive conclusions about the effects of oral contraceptives and hormone replacement therapy on rhinitis in adult women. The purpose of this systematic review is to thoroughly examine the available literature, following strict inclusion and exclusion criteria.

Results

Our search of electronic date databases yielded 1016 articles (Fig. 1). The citation references of included studies were also checked. Seven articles that met the selection criteria were included in the final analyses.

Fig. 1.

Prisma 2020 flow diagram

The main morphological and molecular diagnostic methods used in the studies include histological, immunohistochemical analysis and ultramicroscopic (electron microscopy).

Risk of bias was assessed for a randomized study [9], for 6 non-randomized articles. The results of the work are presented in table form. We extracted data such as year of publication, study design, sample size, age of patients, intervention, comparison, assessment methods, and outcome measures (Table 1).

Table 1.

Description of selected studies included in the review

Year and author	Study design	Sample size	Patients age	Intervention	Comparison	Assessment methods	Main outcomes
Millas et al. 2011	Prospective comparative study	64	-	One group (А) of 32 women- nonusers of hormonal contraceptive pills.	Another group (В) of 32 women taking COCP, containing 15–25 mcg ethinyl estradiol.	Immunohistochemical examination of samples of the inferior nasal concha with an assessment of alpha and beta ER.	Beta receptor prevalence significantly lower in lamina propria cells in Group B vs. Group A (p = 019). Expression of beta receptors significantly higher than alpha receptors in respiratory epithelium cells and lamina propria glandular epithelium cells (p < 001). Beta receptors significantly more prevalent than alpha receptors in lamina propria cells, but only in Group B (p < 001). Semiquantitative values for alpha and beta areas, and between Groups A and B, show high similarity. Average relative optical density (ROD) of alpha receptors in respiratory epithelium cells: 276; beta receptors: 275. Average number of alpha receptors in glandular cells: 300; beta receptors: 308.
Millas et al. 2021	Prospective study	110	-	55 women without recent use of oral contraceptives (Group 1)	55 women using oral contraceptives regularly (Group 2) for at least 3 months.	Assessment of estrogen receptors, RNA extraction and reverse transcription reaction to cDNA were carried out.YWHAZ and CY were the chosen genes based on an analysis conducted using a geNorms spreadsheet to determine the control genes.	The findings revealed a prevailing expression of the ERa isoform that was 10–15 times higher compared to that of the ERß isoform, irrespective of the utilization of oral contraception.However, only the ERß isoform showed a positive correlation with the presence of rhinitis and its severity, with a correlation coefficient of 0.27 and a p-value of 0.09.However, only the ERß isoform showed a positive correlation with the occurrence of rhinitis and an evaluation of its severity (r = 0.27; p = 0.09).
Toppozada et al. 1984	Prospective study	25	Between 20 and 35 years of age	25 females were selected to receive the COCP (4 mg of norethisterone and 0.05 mg of ethinyl oestradiol).	-	Histochemical examination and examination under an electron microscope	Estrogen-induced squamous cell metaplasia, interepithelial edema, glandular hyperplasia, histiocyte proliferation, and fibrous tissue deposition were the diagnoses made for ten women who took the pills and experienced nasal symptoms. The histological alterations resembled those observed in chronic hypertrophic non-allergic rhinitis.
Caruso et al. 2008	Prospective study	35	From 51 to 56 years (mean age, 52.4 y)	Women received continuous-combined HT (1 mg 17 A-estradiol and 2 mg drospirenone).	-	Cytological changes of nasal middle and inferior turbinate respiratory epithelium were evaluated by using the maturation index	Women’s epithelial nasal cells showed improved trophic features following 17 A-estradiol/drospirenone intake as compared to baseline (P < 0.001), according to hematoxylin-eosin staining for the maturation index. With a ratioindex larger than 2, the smears obtained by HT highlighted the superficial and intermediate types of cells. Less than 20% of the cells were parabasal, and degenerative alterations in the superficial and intermediate cells were indicated by the karyopyknotic index. The research verified that ovarian steroids target the nasal airway epithelium. Like other progestogens, drippenone operates on nasal cells in a similar manner.
Caruso et al. 2007	Prospective study	47	56 postmenopausal women aged 50 to 56 years (average age 52.1 years)	30 mcg ethinylestradiol (EE) and 3 mg drospirenone (DRSP).	-	Rhinomanometry and olfactometry before the study and during the third and sixth cycles of the HT.	17 A estradiol/drospirenone hormone therapy improved rhinomanometric parameters compared to baseline (P < 0.001). Olfactometric threshold results showed increased sensitivity in third (P < 0.05) and sixth (P < 0.001) cycles of 17 A-estradiol/drospirenone therapy compared to baseline. Therapy may influence nasal breathing resistance and olfactory odor perception thresholds. Estrogens could impact plasticity and neuronal conduction time of olfactory system neurons. Drospirenone’s antimineralocorticoid action may reduce nose edema, improving interaction of odorous compounds with receptors.
Caruso et al. 2003	Prospective comparative study	103	55 treated with HT 45 to 60 years (average age 52.3 years) and 48 untreated women aged 43 to 62 years (average age 52.5 years)	HT group: − 12 women: oral conjugated estrogens (0.625 mg) + medroxyprogesterone acetate (5 mg) for 1–4 years − 9 women: transdermal estradiol patch + nomegestrole acetate (5 mg) for 1–5 years − 6 women: twice-weekly patch + dydrogesterone (10 mg) for 1–6 years − 7 women: sequential estradiol gel + oral nomegestrole acetate (5 mg) for 8 months to 2 years ET group: − 8 women: daily estradiol gel for 1 year to 16 months − 9 women: weekly transdermal estradiol patch for 2–6 years − 4 women: twice-weekly transdermal estradiol patch for 2–7 years	Сomparison of data with women who did not receive HRT	Cytological changes in the cells of the nose, middle and lower nasal concha are compared with the results of cytological examination of the vagina using the maturation index.	Similar trophic cytological features observed in nasal and vaginal samples of women receiving hormone therapy (HT) compared to controls. Women receiving sequential HT or ET showed superior trophic features in nasal cytological samples compared to those on continuous combined HT. Carapycnotic nuclei in women receiving ET or sequential HT displayed an eosinophilic surface-intermediate appearance with a maturation index > 50%, unlike controls and those on continuous combined HT. Comparable frequency of dystrophic symptoms observed between sequential HT and ET groups (13% vs. 9%); 83% of women on continuous combined HT experienced dystrophic manifestations. Maturation index of sequential HT recipients (38-43%) similar to controls, suggesting potential benefits in nasal respiratory epithelium. Estrogen targets not only vaginal cells but also nasal respiratory epithelium, with the type of hormonal regimen influencing HT activity in the nasal airway epithelium. HT may prevent and treat nasal respiratory epithelium dystrophy in postmenopausal women.
Caruso et al. 2006	Prospective randomized open clinical trial	73	From 19 to 38 years (mean age 26.9 + 5.7)	38 women on pill containing 30 mg ethinylestradiol (EE) plus 75 mg gestodene	35 women on pill containing 15 mg ethinylestradiol plus 60 mg gestodene.	Cytological changes on the nasal respiratory epithelium evaluated with the maturation index performed during the follicular, periovular, and luteal phases of the menstrual cycle, and on the sixth cycle of pill intake.	Comparable trophic cytological features were observed in the nasal and vaginal epithelium during the menstrual cycle and pill use, according to hematoxylin-eosin staining for the maturation index. In comparison to the luteal phase, the nasal and vaginal cytological samples displayed higher maturation indexes during the follicular and periovular phases. In comparison to women taking a pill containing 30 mg of EE, those taking a pill containing 15 mg of EE displayed lower trophic features in the nasal cytological samples.

Abbreviations: COCP- combined oral contraceptive pill, RQLQ- Rhinitis quality-of-life questionnaire, HT- hormone therapy, HRT- Hormone replacement therapy, OC- oral contraceptive, EE- ethinylestradiol, DRSP-drospirenone, ET-estrogen therapy.

The 2011 Ieda study [3] determined the concentration and distribution of ERs in the nasal mucosa by comparing 2 groups: group A of 32 women who didn’t use oral contraceptives (OC), and group B, which consisted of 32 women who took OC containing 15–25 mcg of ethinyl estradiol (EE). Samples obtained from the mucosa of the inferior turbinate were analyzed using immunohistochemical staining for alpha and beta ER. According to the results, the use of OC caused a decrease in the level of beta receptors only in the cells of the lamina propria. In both groups, a predominance of beta receptors was observed (p < 001). These results suggest that OC may affect cells such as fibroblasts, mast cells, plasma cells, and other inflammatory cells, since estrogen receptors play an important role in the immune response by modulating inflammatory processes.

Another Ieda 2021 work [10] was devoted to the quantitative determination of the concentration of ERα and ERβ mRNA receptors using PCR in a smear of the nasal mucosa of women receiving OC therapy by comparing 2 groups: 55 women with a regular menstrual cycle without using contraceptives and 55 women with a regular menstrual cycle who have used OC for more than 3 months. The results showed a predominant expression of the ERα isoform, 10–15 times higher than the ERβ isoform, regardless of OC use. But only the ERβ isoform was positively correlated with the presence of rhinitis and the assessment of its severity (r = 0.27; p = 0.09).

Toppozada et al. 1984 [11] studied ultrastructural and histochemical changes in the nasal mucosa with regular use of OC. 25 selected women were given 4 mg of norethisterone and 0.05 mg of EE. The results indicate that ten women who took the pill and experienced nasal symptoms exhibited squamous metaplasia, interepithelial edema, glandular hyperplasia, histiocyte proliferation, and fibrous tissue deposition. These effects were related to the action of estrogen. Histochemical changes were similar to those that develop in chronic hypertrophic nonallergic rhinitis.

Caruso 2006 and 2007 analyzed cytological changes in the nasal cavity epithelium in premenopausal women taking OC.

The 2006 Caruso study [9] determined the effect of monophasic OC on the nasal epithelium in premenopausal women. Cytological changes in the nasal epithelium were assessed using a maturation index carried out during the follicular, periovular, and luteal phases of the menstrual cycle, as well as during the sixth pill cycle. In the study, two groups of women take different doses of EE plus gestodene. The nasal respiratory epithelium, like the vaginal epithelium, was found to show trophic effects dependent on ovarian steroid levels. Both nasal and vaginal cytological samples showed higher maturation indices in both follicular and periovulatory phases than in the luteal phase.

Therefore, it was concluded that, along with vaginal cells, the nasal respiratory epithelium appears to be affected by changes in ovarian steroid levels during the menstrual cycle and by the iatrogenic effects of OC.

The 2007 Caruso study [12] determined the effects of an OC containing 30 mcg EE and 3 mg drospirenone on the nasal respiratory epithelium of premenopausal women. Cytological changes were also assessed using the maturation index during the different phases of the menstrual cycle and on the sixth cycle of the pill. The maturation index (MI) is the percentage of all cell types in the vaginal smear.

Both studies found that the maturation index of the nasal respiratory epithelium was dependent on changes in ovarian steroid levels during the menstrual cycle and on the iatrogenic effects of OC. In both cases, higher rates of epithelial maturation were observed in the follicular and periovulatory phases compared to the luteal phase. A 2006 study found that higher doses of EE caused more trophic changes compared to lower doses. A 2007 study confirmed that OC with 30 mcg EE and 3 mg drospirenone also have a significant effect on the nasal epithelium, similar to the effect of ovarian steroids during the follicular phase.

Caruso’s 2008 randomized study [13] examined the effect of drospirenone on the nasal airway epithelium in postmenopausal women receiving HRT. Cytological changes in the epithelium of the middle and inferior turbinates were assessed by comparing a smear taken at the beginning and on days 10–14 of the sixth cycle of HRT containing 1 mg of 17a-estradiol and 2 mg of drospirenone. According to the results, hematoxylin-eosin staining of nasal epithelial cells in women showed an improvement in trophic indicators when taking 17 A-estradiol/drospirenone compared to baseline indicators. The study confirmed that the nasal airway epithelium is a target for ovarian steroids. Drospirenone acts on nasal cells similarly to other progestogens.

The 2003 Caruso study [14] examined the effects of HRT on the nasal respiratory epithelium in postmenopausal women. Cytological changes of the cells of the nose, middle, and inferior turbinates were compared with the results of vaginal cytological examination using the maturation index. The doses of studied drugs are described in the table below (Table 1).

According to the results, women receiving sequential HT or estrogen therapy showed better trophic characteristics in nasal cytological samples compared to women receiving continuous combined HT. The effect of HT in the nasal airway epithelium may vary depending on the specific hormonal regimen employed. Existing research indicates that HT has the potential to prevent and potentially treat nasal respiratory epithelial dystrophy in postmenopausal women.

The risk of bias was assessed for one randomized trial (Fig. 2) [9] and for nine non-randomized studies (Fig. 3) by two reviewers independently (Y.X and Z.R), according to the Cochrane Handbook using RoB 2 for randomized trials and ROBINS-I for non-randomized trials. Visualization tools were created by the ROBVIS app [15]. The tool generates “traffic light” diagrams illustrating the domain-level assessments for each result, as well as weighted bar diagrams displaying the distribution of risk-of-bias assessments within each bias domain. The overall risk of bias for randomized trial was low. Non-randomized trials had equal possibilities of risks.

Fig. 2.

RoB 2.0 for randomized controlled trials

Fig. 3.

ROBINS-I for nonrandomized studies of interventions

However, the time of follow-up, investigated doses of drugs differ in the papers. Due to these limitations, it was not possible to perform a meta-analysis of the data.

Discussion

The study of the effects of female sex hormones on the nasal mucosa has been studied for a long time, but there is still no consensus on the pathogenesis of this condition. In clinical guidelines for non-allergic rhinitis, OC are one of the causes of drug-induced rhinitis, but the instructions for these drugs do not indicate their side effects on the nasal mucosa [16].

Estrogen is an important hormone for maintaining the health of both men and women. Main functions include maintaining glucose homeostasis, enhancing immunity, and maintaining cardiovascular and nervous system health. The amount, tissue-specific distribution and receptor affinity vary according to the phase of life. Estrogen levels begin to rise before a girl is born. During the reproductive years, estrogen levels increase during ovulation so that the female body can prepare for pregnancy. During menstruation, the concentration of the hormone in the blood decreases. The same happens when a woman enters menopause. Estrogen fulfils its various functions by binding to specific protein receptors [17, 18].

There are two isoforms of ERs: alpha and beta, which are highly specific to humans, provide selective hormonal action on tissues, on the nasal mucosa, and according to some authors the number of these receptors depends on age [19, 20].

In a study on postmenopausal women with symptoms of pathological nasal obstruction, authors [2] determined the presence of ER in glandular epithelial cells of the lamina propria, around venules, and in mastocytes and the cytoplasm of some epithelial cells, and the concentrations were more pronounced in the group receiving HRT compared to the control group [17, 21]. And in 2008, Philpott et al. searched for ERα and ERβ isoforms and progesterone receptor expression in lower nasal specimens from rhinitis patients [1, 21, 22]. Beta receptors were mainly found in the nuclei of glandular cells, around venules, and in other nasal mucosal cells in 24 of the 25 samples. However, none of the samples tested positive for ERα or progesterone receptors and, interestingly, no significant differences were found between men and women, atopic and non-atopic, smokers and non-smokers [17, 22].

And a study conducted in 2011 using an immunohistochemical method investigated the expression of ERα and ERβ in the nasal mucosa of women taking OC. It was found that the use of OC caused a decrease in ERβ levels only in the cells of the intrinsic lamina, and both the main and control groups showed a predominance of ERβ compared to ERα [3].

In a cross-sectional study, the number of ERβ in the nasal epithelium was found to correlate with the severity of rhinitis symptoms, and HRT may increase the risk of non-allergic rhinitis. However, it should be borne in mind that correlation does not imply causation and the influence of factors such as age or obesity, which may also influence the development of rhinitis, should be considered [23]. Another study [24] with opposite results evaluated the effect of HRT in postmenopausal women on nasal physiology by clinical diagnostic methods. According to the results: no statistically significant differences were found for any of the variables. Hormone therapy had no effect on nasal mucosa. The authors attribute the possible results to low estrogen levels.

Also, some authors who have investigated the relationship between hormone levels and nasal phenotypic changes have observed similar cytological changes between the nasal mucosa and the vaginal epithelium depending on the menstrual cycle [2, 4, 9, 11, 12]. In addition, some features of the nasal mucosa associated with high estrogen levels, such as vasodilation, increased vascularization and increased gland secretion, were observed. Although estrogen receptors have been found in the human nasal mucosa, its physiological and pathological effects on the nasal mucosa have not been fully established. It seems that cyclical fluctuations in hormone levels during the menstrual cycle and in cases of oral hormone pills, HRT are factors that influence the physiology of the nasal mucosa, but this issue is still controversial [25].

When identifying and interpreting conditions associated with inadequate or excessive estrogen levels, it should be remembered that the same estrogen may have different effects when interacting with different ER species [26].

Estrogens play an important role in the regulation of physiological processes in the nasal mucosa, affecting the activity of acetylcholinesterase and the level of acetylcholine in the blood. By inhibiting acetylcholinesterase, estrogens contribute to the increase in acetylcholine levels, which leads to vasodilation, increased blood filling of the nasal cavernous tissue, oedema and increased secretion of the mucous membrane [27].

Studies show that estrogen levels have a significant effect on the structure and function of the nasal mucosa. For example, Caruso, Nappi, Toppozada and Philpott found similarities in changes in the nasal and vaginal epithelium depending on the phases of the menstrual cycle. High estrogen levels are associated with vasodilation, increased vascularization and increased activity of nasal mucosal glands, which underlines the importance of hormonal changes in the regulation of the nasal mucosa.

The study by Nappi et al. showed that estrogens modulate the functions of the nasal mucosa by influencing the activity of cholinergic, adrenergic and sensory neuropeptides. For example, substance P levels were lower in postmenopausal women than in women of reproductive age, but significantly increased after hormone therapy. In the case of vasoactive intestinal peptide, no significant differences were observed without therapy, but hormone therapy caused its significant increase, indicating the role of estrogen in enhancing secretory and vascular responses of the nasal mucosa.

There was also a decrease in neuropeptide Y, a vasoconstrictor released with norepinephrine, in women receiving HT, confirming the inhibitory effect of estrogen on vasoconstrictor responses and promoting vasodilation. Taken together, this suggests that estrogens promote inflammation through regulation of neuropeptides and vascular tone in the nasal mucosa.

Another theory of estrogen’s mechanism of function is DNA mediated. Estrogen exerts its diverse functions in the following ways: by specific interaction with DNA and activation or inactivation of specific genes; or by ER action in the absence of ligand, repressing or activating response elements in DNA. Cells that are considered as targets for estrogenic action must have: either a large physiological effect following estrogenic stimulation or must contain a significant amount of ER that selectively concentrates and retains estrogens [17, 18].

Clearly, the mechanism by which female hormones affect nasal physiology remains to be understood, and the long-term effects of OC and HRT on ER expression and activity in the nasal cavity are yet to be assessed, as many questions still arise and remain regarding ER [26].

The effect of female sex hormones on nasal mucociliary clearance is also interesting. The results of few studies suggest a stimulatory effect of estrogen on the rate of nasal cavity mucociliary clearance, especially during the ovulatory phase of the menstrual cycle, when its content reaches a maximum level [28]. It is believed that this may be associated with vasodilation, improved microcirculation and good moisturization of the nasal mucosa against the background of increased levels of estrogenic hormones [4, 27].

Study [2] concluded that postmenopausal hypoestrogenemia can affect nasal function by causing nasal congestion of varying degrees and increased mucociliary clearance time despite normal rhinomanometry values.

In studies by [1] and [24] to measure mucociliary clearance time using the saccharin test, no statistical difference was found (either before or after contraceptives administration).

Thus, the study of the effect of sex hormones on mucociliary clearance, in our opinion, seems to be a promising direction.

However, our analysis showed no correlation between nasal obstruction and HT. Administration of HRT may improve nasal mucosal trophic through proliferative processes, but the long-term effects and impact on the mucosa at high estrogen levels remain poorly understood. But there remains no doubt that there are hormone-sensitive receptors in the nose that are in close contact with immuno-inflammatory cells. It is possible that taking HT and the presence of an underlying inflammatory factor such as allergies, viruses, etc. will increase the processes of proliferation, vasodilatation, which will subsequently lead to increased oedema and nasal obstruction.

Conclusion

Our systematic review reviewed the evidence on the effects of sex HT on the nasal mucosa. Estrogens exert a variety of effects on various organs, including the nasal mucosa via specific receptors, but the presence of ERs does not necessarily mean that they play a key role in all processes in the nasal mucosa. It may be that ERs only fulfil an auxiliary function or are involved in certain conditions - therefore, this systematic review provides a wide field for further research.

The relevance of our study lies in the lack of previous systematic reviews on this topic. However, on the downside, we note the paucity of scientific articles on this topic, including clinical randomized trials, and the impossibility of conducting a meta-analysis, so further clinical studies on a larger sample of patients are needed to definitively uncover the mechanisms underlying this relationship and to develop effective methods for the treatment and prevention of nasal diseases.

Author Contributions

Yang X.- protocol development, data collection, manuscript writing; Zhane R.- data collection, manuscript writing; Svistushkin V.- data collection, manuscript writing; Smolyarchuk E.- data collection, manuscript writing; Eremeeva K.- data collection, manuscript writing.

Funding

None.

Declarations

Disclosure Statement

None.

Conflict of Interest

None.