Effect of Foeniculum vulgare (fennel) on vaginal atrophy in postmenopausal women: A double-blind,randomized,placebo-controlled trial

Abstract

Objectives

This study was conducted to evaluate the effects of orally administered fennel on vaginal atrophy.

Materials and methods

In this double-blind, randomized, placebo-controlled trial, 60 postmenopausal women living in Mashhad, Iran, were randomly divided into an oral fennel group (n = 30) and a placebo group (n = 30). The Maturation Vaginal Index and maturation values were measured once at baseline and again upon a three-month follow-up.

Results

The paired t-test showed statistically significant changes in the Maturation Vaginal Index (i.e. a decline in the parabasal cells and an increase in the intermediate and superficial cells) and maturation values in both the fennel and placebo groups at the end of the trial compared to at baseline. Nonetheless, no significant differences were observed in the percentages of the parabasal (P = 0.191), intermediate (P = 0.219) and superficial (P = 0.82) cells, which was also the case for the maturation values (P = 0.64).

Conclusion

Fennel had no significant positive effects on vaginal atrophy in postmenopausal women. Nonetheless, more studies are recommended to be conducted using higher doses of fennel and larger sample sizes so as to verify the results of this study.

Keywords

Foeniculum maturation value postmenopausal women vaginal atrophy

Postmenopausal women often experience some symptoms of vaginal atrophy that are caused by reduced ovarian function, including distress, dryness, itching, burning and dyspareunia.¹ The real prevalence of vaginal atrophy remains unknown, especially due to under-reporting and since many women are under the impression that these symptoms are an expected part of aging.² Most menopausal symptoms (such as hot flashes) are mitigated or disappear over time, but vaginal symptoms continue to persist and often require therapeutic intervention.³ Postmenopausal women prescribed to use Hormone Replacement Therapy (HRT) often abandon their therapy because of the risk of HRT-related side-effects, including breast swelling or tenderness, bloating, bleeding or spotting.⁴ As a result, many postmenopausal women prefer compounds with non-hormonal materials (such as phytoestrogens) that offer a safer alternative.⁵ Phytoestrogens are plant substances with structure and functions identical to that of estradiol that can produce estrogenic effects.⁶ The use of phytoestrogens as a treatment for menopause symptoms has yielded varying results. Recently, a number of meta-analyses have been conducted on the effect of phytoestrogen on vaginal atrophy. Soy has been shown to have a borderline positive effect (P = 0.07) on vaginal atrophy.⁷ A significant improvement in symptoms of menopause was also observed with the administration of an 80-mg dose of red clover,⁸ while flaxseed did not significantly improve vaginal atrophy.⁹ Topical isoflavones have been shown to have a positive effect on vaginal atrophy.¹⁰

Foeniculum vulgare is a phytoestrogen with a wide distribution in most tropical and subtropical countries that also includes phenolic compounds, flavonoids (flavonoid glycosides and flavonoid aglycones), phenolic acids, hydroxycinnamic acids, coumarins and tannins.¹¹ The present study offers at least two rationales for using the oral route when the vaginal route has already been shown to be effective in improving vaginal atrophy.¹² First, the oral route has long been used in traditional medicine to treat obstructions in the liver, spleen and gallbladder and to also alleviate digestive complaints such as indigestion, colic, nausea and flatulence,^11,13,14 and if this study can confirm the positive effects of orally administered fennel on vaginal atrophy, other systems of the body can also benefit from the oral administration of fennel. Second, most of the patients are not comfortable with drug administration through the vaginal route. This study was therefore conducted to evaluate the effect of Foeniculum vulgare (fennel) on vaginal atrophy in postmenopausal women in Mashhad, Iran.

Materials and methods

This randomized, double-blind, placebo-controlled, clinical trial was designed to assess the effect of fennel on vaginal atrophy. The research project was approved by the Ethics Committee of Mashhad University of Medical Sciences and was implemented from January 2014 to June 2016 in accordance with the principles of the Declaration of Helsinki. All the subjects were recruited from the Medical Clinic of Imam Reza Hospital of Mashhad, Iran.

The study inclusion criteria were: (1) Postmenopausal status, defined as age 45 to 65 and the absence of vaginal bleeding for one year and (2) a normal mammogram obtained in the last year. The exclusion criteria were: (1) vaginal infection, (2) smoking, (3) the use of estrogen (systemic or vaginal) over the past 12 months or vaginal moisturizers or lubricants over the past six weeks, (4) history of endometrial or breast cancer, (5) allergy to fennel and (6) regular ingestion of phytoestrogen or soy-based products. All the participants signed informed consent forms and were ensured of the voluntary nature of participation in the study and their right to withdraw from it at any time.

Randomization

A total of 60 postmenopausal women living in Mashhad, Iran, were randomly assigned to a fennel group (n = 30) and a placebo group (n = 30). To determine the allocation sequence, the researchers first pointed at the random table with their eyes closed so as to choose the starting point; then, they moved their finger toward the right on the table to choose a number. Any number between 1 and 60 was acceptable, but numbers above 60 were ruled out. Repeated numbers were precluded and this process continued until 60 numbers were selected. To ensure allocation concealment, the random numbers were printed on plastic bottles. The first 30 bottles were filled by fennel and the rest with placebo and provided enough treatment for 90 days. The sequencing and packing were carried out by an employee of Barij Essence Pharmaceutical Neither Participants nor did clinical personnel not know that the first 30 bottles were fennel and the second 30 were placebo.

Intervention

The subjects were randomly assigned to either the fennel or the placebo group. Those in the fennel group were orally administered fennel three times per day (once in the morning, once at noon and once at night) with 100-mg soft capsules containing 30% fennel (standardized to 21–27 mg anethole) combined with sunflower oil. The fennel administered was commercially provided by Barij Essence Company (Iran) under the name Fennelin.¹⁵ The placebo and fennel capsules were identical in terms of shape and size (as ensured by Barij Essence Company), but the placebo capsules were filled with sunflower oil only. The subjects were screened every four weeks for side-effects and were asked to bring their medication bottles with them to each visit in order to ensure their medical compliance by counting the remaining capsules.

Outcome measures

A pelvic examination was performed on the subjects by the fourth author. Their vaginal pH was measured using a pH indicator strip (Macherey Nagel, Germany). After inserting a vaginal speculum without lubrication or water soluble gel, 2 cm of the strip was held directly against the lateral vaginal wall. The colour change in the strip was compared with the colorimetric scale. After measuring their vaginal pH, an Ayre’s spatula was used to take vaginal smears from the lateral vaginal wall.

The epithelial cells were smeared on a glass slide, immediately fixed with 95% alcohol and then stained by the Papanicolaou method before being sent to the central laboratory. All the slides were examined by the same cytopathologist, who was blinded to the patients’ information. The Maturation Vaginal Index (MVI) provides the percentages of parabasal, intermediate and superficial cells. The maturation value (MV) was calculated using the following formula: MV (0 × % parabasal cells) + (0.5 × % intermediate cells) + (1.0 × % superficial cells).

Sample size

To the authors’ best knowledge, the present research is the first study to compare orally administered fennel with a placebo. The required sample size was estimated by reference to a study conducted by Yaralizadeh on the effect of using 5% fennel vaginal cream on the MV; the study had reported differences between the administration of 5% fennel vaginal cream and the administration of placebo vaginal cream in terms of improvements in the superficial cells (mean in the fennel group = 76.1 ± 15.3; mean in the placebo cream group = 11.8 ± 8), intermediate cells (fennel = 21.2 ±15.2; placebo cream = 75.2 ± 8.7) and parabasal cells (fennel = 2.3 ± 2.5; placebo cream = 12.7 ± 6.6). The NCSS-PASS software was also used in the estimation of the sample size. Ultimately, sample sizes of 3, 4 and 7 were obtained for the superficial, intermediate and parabasal cells, with an alpha error of 0.05 and a statistical power of 80%. The sample size was increased to 30 subjects per group.

Statistical analysis

The data obtained were analyzed in SPSS-11 (SPSS Inc., Chicago, IL). The normal distribution of the data was analyzed by the Kolmogorov–Smirnov test. Differences between the two groups were evaluated using the Chi-square test and the independent t-test. The paired sample t-test was used to draw a comparison between the baseline and the three-month follow-up results. All the statistical tests were two-sided. The level of statistical significance was set at P < 0.05.

Results

Consort flow diagram for the trial is shown in Figure 1. The 60 participants were randomly assigned to either the fennel or the placebo groups. A total of eight participants withdrew from the study, including three who withdrew in the follow-up and five who were excluded because they reported side-effects. The subjects receiving the placebo did not report any side-effects, but five subjects from the fennel group experienced side-effects. Some of the participants in the fennel group complained of frequent urination (n = 2), rash (n = 1) and spotting (although it was not related to any malignancies or endometrial proliferation). The mean age of the patients was 55.6 years (SD = 5.2) in the fennel group and 54.9 years (SD = 6.4) in the placebo group. The mean duration of menopause was 5.52 ± 3.45 years in the fennel group and 5.91 ± 4.9 years in the placebo group, and the subjects had a mean BMI of 29.9 ± 3.5 and 30.77 ± 5.2. The two groups were similar with regard to their socio-demographic characteristics (as shown in Table 1).There were no significant differences in the percentages of the parabasal (P = 0.191), intermediate (P = 0.219) and superficial (P = 0.82) cells, which was also the case for the MV (P = 0.64). The vaginal pH remained unchanged in all the participants (as shown in Table 2). Also the paired t-test showed that the changes induced in the MVI (i.e. the decline in parabasal and the increase in intermediate and superficial cells), and the MVs were all statistically significant at the end of the trial compared to at baseline in both the fennel and placebo groups.

Figure 1.

CONSORT 2010 flow diagram.

Table 1.

The socio-demographic characteristics of the participants in the fennel and control groups.

Variables	Placebo (n = 27)	Fennel (n = 25)
Variables	Mean ± SD	Mean ± SD
Age	54.9 ± .6.04	55.6 ± 5.2
Body mass index (BMI, kg/m²)	29.9 ± 3.5	30.77 ± 5.2
Months since menopause	70.96 ± 59.9	66.32 ± 41.4
Smoking n (%)	1 (3)	1 (3)
Marital status
Married	22 (81.5%)	21 (84%)
Divorced/widowed	5 (18.5%)	4 (16%)
Level of education
Illiterate	6 (22%)	2 (8%)
Primary school	14 (51.9%)	11 (44%)
Junior high school	2 (7.4%)	1 (4%)
High school	3 (11.1%)	8 (32%)
University	2 (7.4%)	3 (12%)

Table 2.

The effect of fennel on vaginal cytology and vaginal pH.

Variable	Fennel (n = 25)	Placebo (n = 27)	P value (between groups)
Variable	Mean ± SD	Mean ± SD	P value (between groups)
Vaginal pH
Baseline	5.6 ± 0.7	5.8 ± 0.87	0.35
After intervention	5.3 ± 0.94	5.7 ± 1.1	0.12
P value (within groups)	0.2	0.86
Vaginal cytology (primary endpoint)
Maturation value (%)
Baseline	43.1 ± 7.6	45.1 ± 4.5	0.25
After intervention	47.1 ± 4.3	47.6 ± 4.4	0.64
P value (within groups)	<0.001	<0.001
Superficial cells (%)
Baseline	10.1 ± 3.5	10 ± 62	0.62
After intervention	12.3 ± 4.1	12.1 ± 4.09	0.82
P value (within groups)	<0.001	<0.001
Intermediate (%)
Baseline	66 ± 13.3	68.9 ± 6.7	0.31
After intervention	69.5 ± 4.5	71.14 ± 4.8	0.21
P value (within groups)	0.124	0.039
Parabasal cells (%)
Baseline	21.2 ± 4.7	20.33 ± 6.9	0.59
After intervention	18.44 ± 4.1	16.5 ± 5.7	0.19
P value (within groups)	<0.001	<0.001

Discussion

To the authors’ best knowledge, this research is the first study to evaluate the effect of oral fennel on vaginal atrophy in postmenopausal women. The results of the study showed no significant positive effects for this treatment on vaginal atrophy over the three-month period examined.

Despite the researchers’ efforts, no human studies were found on the effects of orally administered fennel on vaginal atrophy; however, there was one animal study that had examined the effect of the oral administration of fennel seed extract on the genital organs of female rats.

Adult female Wistar rats (3–4 months old, weighing 150 ± 20 g) were ovariectomized bilaterally and their vaginal smears were taken after 15 days. The rats were randomly assigned to either the control or intervention groups.

From day 16, the fennel extract was administered orally on a daily basis at doses of 50, 150 and 250 µg/100 g for a period of 10 days. The control group received 1% ethanolic solution. Twenty hours after the last dose was administered, the animals were put down. The high and medium doses of the extract were found to have increased the weight of the endometrium, cervix and vagina¹⁶; however, given that phytoestrogen was an active biological compound of fennel, the present findings were compared with the results of studies that had evaluated the phytoestrogen effect of vaginal atrophy. Phytoestrogens are plant compounds with properties similar to those of estrogen. Phytoestrogens can be divided into four main groups: Isoflavones, lignans, flavonoids and coumestans.¹⁷ Isoflavones are common components of soy and red clover extract.¹⁸ Lignans are found in flaxseed.¹⁹ Fennel serves as a major source of flavonoids.²⁰

Only in one trial, fennel was topically used to relieve vaginal atrophy; according to the results of this study, both the fennel cream and the placebo groups showed an increase in their superficial cells and a decline in their parabasal and intermediate cells after eight weeks; however, these changes were more prominent in the cream fennel group compared to the placebo group (P < 0.001). Symptoms including itching (P = 0.017), dryness (P < 0.001), pallor (P < 0.001) and dyspareunia (P < 0.001) and excluding burning (P = 0.14) improved significantly.¹⁴ Based on the results of the discussed studies, it can be concluded that phytoestrogens have more positive effects when administered topically. The findings of previous animal studies and human data regarding the effect of fennel are inconsistent with the present findings. There are two reasons for which to believe that the enhanced therapeutic effect of the topical form of the treatment may be related to the moisturizing effect of vaginal cream: first, in the study of Yaralizadeh et al.,¹² the placebo vaginal cream improved vaginal dryness and dyspareunia significantly; second, in a study by Lima et al., a 64% improvement in vaginal dryness was reported after the administration of vaginal placebo gel.²¹ To further confirm this finding, the administration of placebo as transdermal patches did not yield any positive effects. Present study showed a positive change in its placebo group that may have been caused by the subjects’ accidental or deliberate consumption of phytoestrogen-rich foods in the placebo group. There are several reasons for which to believe that the results were not indicative of any significant changes: first, the dosage and duration of treatment were not sufficient to lead to any effects on vaginal atrophy; second, no inclusion criteria were set for the cases of vaginal atrophy (superficial cells ≤5% or MVI <40%) and the baseline data in the present study were normal in both groups. The loss to follow-up was 17% in fennel group, the sample size was small and intent to treat analysis was not performed, so the result must be interpreted with caution.

Conclusion

The oral administration of fennel did not lead to a significant positive effect on vaginal atrophy in postmenopausal women. Further studies with longer durations, higher doses of the administered extract and larger sample sizes are required in order to verify the present findings.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by Mashhad University of Medical Sciences in Mashhad, Iran (Grant Number 4946004).

Ethical approval

The ethics committee of “The effect of Foeniculum vulgare (fennel) on vaginal atrophy in post-menopausal women: a double-blind randomized placebo-controlled trial” approved this study (REC number: IR.MUMS.REC.1392.151).

Guarantor

Masumeh Ghazanfarpour

Contributorship

Masumeh Ghazanfarpour, Talat Khadivzadeh, Khadijeh Mirzaii Najmabadi and Paymaneh Shokrollahi were involved in protocol development, gaining ethical approval. Nosrat Baharian Sharghi and Talat Khadivzadeh were involved in patient recruitment. Masumeh Ghazanfarpour and Paymaneh Shokrollahi were involved in data analysis. Masumeh wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript. All slides were examined by Amir Hossine Jafarian. Masoudeh Babakhanian edited the manuscript.

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