Introduction
Foeniculum vulgare seed is used to treat infertility because of phytoestrogenic properties.
Aim
The present study was conducted to compare the effects of F. vulgare plus oestrogen and oestrogen alone on Endometrial Thickness (ET) in infertile women.
Materials and Methods
In this study, 92 people with infertility were enrolled by convenience sampling and randomly divided into treatment case (45 women) and control (47 women) groups. Both groups were administered with oestradiol valerate 2 mg tablet three times a day since the third day of the menstrual cycle. Treatment group was also administered with F. vulgare tea on a daily basis. Then, ultrasound was conducted once every three days to determine ET. Other data such as serum β-hCG level and increase in oestrogen dose were recorded in a checklist. The data were analysed by independent t-test and Chi-square in SPSS version 17.0.
Results
There were no significant differences in mean age, BMI, number of years of infertility, number of children, cause of infertility, positive β-hCG, failure to achieve adequate endometrial thickness, and increase in oestradiol dose between the treatment and control groups (p>0.05). The mean number of days to achieve ET of at least 8 mm was 13.1±3.2 in the treatment group and 14.2±3.5 in the control group with no significant difference (p>0.05).
Conclusion
F. vulgare seed tea was not significantly effective in increasing the ET as compared to oestradiol valerate 6 mg alone.
Introduction
Infertility is one of the common healthcare issues that many couples worldwide are facing [1]. In Iran, infertility is a common issue associated with several outcomes such as aggression, social stigma, exclusion, and emotional-psychological problems that lead ultimately to adverse effects on quality of life [2,3]. In addition, infertility brings stupendous health care costs for women and their families and leads to economic instability in the health care system [4]. ET is one of the factors that plays an important role in infertility. Women with 6 mm<ET≤10 mm endometrial thickness have greater chance of pregnancy [5].
To achieve successful implementation in Assisted Reproductive Technologies (ARTs), ET should be taken into account to increase fertility likelihood [6,7]. This issue is not considered to deserve much investigation by fertility specialists in treating infertility [8]. Oestrogen therapy is an effective and side effect free approach to treat inadequate ET in folliculogenesis and ovulation [9], because it has been recommended to increase ET using oestrogen supplements in women without adequate ET. Oestrogen supplements have also been investigated for their effects in preventing the complications of ET-reducing infertility drugs such as clomiphene citrate [9,10].
In addition to synthetic drugs, plants are used to treat problems due to infertility including fennel (Foeniculum vulgare Mill). F. vulgare is from family Apiaceae (Umbelliferae) that occurs perennially in temperate regions and Mediterranean Basin. Because F. vulgare seeds have pleasant smell and taste, they are abundantly used in food industries. This seed is used as stimulant, carminative, anti cancer, and anti-inflammatory in different organs of the body [11,12]. F. vulgare aromatic seeds have also certain properties such as dysmenorrhea reducing, menstruation symptoms reducing, delivery facilitating, milk secretion increasing, libido increasing, and premenstrual syndrome symptoms reducing properties. In addition, they are used to treat different gynaecological disorders because they have oestrogenic properties [13-15].
Given that F. vulgare is a phytoestrogen, can be a potentially suitable alternative to oestrogen because of being economical and causing fewer side effects, and has many uses in Iranian traditional medicine; hence, we conducted this study to comparatively investigate the effects of oestrogen plus F. vulgare and oestrogen alone on ET in infertile women.
Materials and Methods
The study population of this randomised clinical trial that was conducted in April 2014 to December 2014 consisted of 98 infertile women with indication of Frozen Embryo Transfer (FET) protocol. Randomisation was done with 92 labeled cards, selected by the patients randomly. Participants were enrolled according to convenience sampling if they met the inclusion criteria including being diagnosed with infertility irrespective of having previous fertility and FET indication. The exclusion criteria were patients suffering from chronic systemic diseases, incidence of severe side effects, failing to follow up the patient carefully, and not volunteering to participate in the study. The patients provided informed consent to participate in the study after the study protocol was registered in Iranian Registry of Clinical Trials (registration code: IRCT2014120210617N2) and ethical permission was obtained from Hamedan University of Medical Sciences with approval number 16.935.699. Then, they were randomly assigned to two groups, treatment and control, according to random number table [Table/Fig-1].
Flowchart of allocation of participants to treatment group and control group.
Both groups were administered with oestradiol valerate 2 mg tablet (Aburaihan Pharmaceutical Co., Tehran, Iran) three times a day since the third day of the menstrual cycle. Treatment group was also administered with F. vulgare tea on a daily basis.
To prepare the tea, 50 mL of boiling water was added to 10 gm of F. vulgare seed and the resulting solution brewed for 20 minutes [16]. After starting treatment with oestrogen, the patients underwent vaginal ultrasound (Samsung Medison, SonoAce R3, Seoul, South Korea, 6-MHz vaginal transducer) and ET of approximately 1 cm below the the fundus from the external margin of the endometrium contact surface with the myometrium to endometrial stripe outer margin [17] was measured by an experienced radiologist. If the endometria of the patients did not respond to the treatment appropriately based on the findings of the two ultrasounds, the dose of administered oestrogen increased to four, five, or six 2 mg tablets a day, but the amount of the administered F. vulgare tea did not change. When ET reached 8 mm or over, FET was conducted by the same protocol and instruments for the patients of the two groups and the parents were followed up for two weeks after the FET to investigate β-hCG result. Serum β-hCG level of over 50 milli-international unit/mL was considered to represent chemical pregnancy [18].
The data on each patient were recorded in a separate checklist including demographic characteristics, the day when ET reached 8 mm, failure to achieve ET of 8 mm, and β-hCG results two weeks after the FET. The data were analysed by descriptive statistics, independent t-test, and Chi-square in SPSS version 17.0.
Results
There was no significant difference in age, body mass index, the number of years of infertility, the number of children, and the mean number of days to achieve adequate (8 mm) ET between the two groups [Table/Fig-2].
Comparison of demographic features between the two groups.
| Variables | Oestradiol valerate plus Foeniculum vulgare (n=45) Mean±Standard deviation | Oestradiol valerate (n=47) Mean±Standard deviation | p-value |
|---|
| Age (year) | 30.7±5.4 | 30.1±6.3 | 0.716 |
| BMI (kg/m2) | 25.95±3.25 | 26.9±2.6 | 0.627 |
| Number of years of infertility | 6.00±2.80 | 6.4±1.1 | 0.649 |
| Number of children | 0.13±0.50 | 0.06±0.25 | 0.522 |
| Number of days to achieve adequate ET | 13.10±3.20 | 14.2±3.5 | 0.591 |
BMI: Body mass index
ET: Endometrial thickness
Chi-square test indicated no significant difference in cause of infertility, previous surgery (any previous invasive vaginal or abdominal surgery on upper genital tract), positive β-hCG, and failure to achieve adequate ET (p>0.05) [Table/Fig-3].
Comparison of cause of infertility, previous surgery, positive β-hCG, and failure to achieve adequate endometrial thickness between two groups.
| Variables | Oestradiol valerate plus Foeniculum vulgare | Oestradiol valerate | p-value(Chi-square) |
|---|
| No. (%) | No. (%) |
|---|
| Cause of infertility | 0.765 |
| Male infertility | 27 (60) | 31 (66) |
| Tubular | 5 (11.1) | 3 (6.4) |
| Ovular | 4 (8.9) | 5 (10.6) |
| Combined | 7 (15.6) | 6 (12.7) |
| Miscellaneous | 2 (4.4) | 2 (4.2) |
| Previous surgery | 9 (20) | 8 (17.0) | 0.565 |
| β-hCG Positive | 6 (13.3) | 5 (10.6) | 0.718 |
| Failure to achieve ET* of 8 mm | 1 (2.2) | 2 (4.2) | 0.674 |
* Endometrial thickness.
In addition, no significant difference in the number of oestradiol doses was seen between the two groups (p=0.648) [Table/Fig-4].
Comparison of the number of patients requiring increased dose of oestradiol between two groups.
| Oestradiol valerate dose | Oestradiol valerate plus Foeniculum vulgare | Oestradiol valerate | p-value(Chi-square) |
|---|
| No. (%) | No. (%) |
|---|
| 6 mg (baseline dose) | 19 (42.2) | 15 (31.9) | 0.648 |
| 8 mg | 11 (24.5) | 11 (23.4) |
| 10 mg | 8 (17.8) | 10 (21.3) |
| 12 mg | 7 (15.5) | 11 (23.4) |
Discussion
The present study was conducted to investigate the effect of F. vulgare seed on infertile women's ET to achieve a thickness adequate for fertility. To the best of our knowledge, no study has yet been done to investigate this issue. This study demonstrated that taking 200 mg/dL of F. vulgare seed tea per day decreased the mean number of days required to achieve at least 8 mm ET (though statistically insignificant). Sadr Fozlaee S et al., study indicated that treatment with F. vulgare helped to regulate the secretion of oestrogen and progesterone and therefore led to increase in ET and decrease in epithelium [19]. A study on menopausal women indicated that phytoestrogens prevented endometrial tissue atrophy and could be used as safe herbal compounds [20]. Studies shows that medicinal plant like Cimicifuga racemosa [21] and Aspalathus linearis [22] and plant derivatives such as klimadynon [23] and icariin [24] can increase endometrial thickness. Also some of plant formulations such as Xiaoyao powder have oestrogenic effect and can increase cell proliferation in endometrial layer [25].
F. vulgare seed contains certain phytoestrogens such as isoflavones, prenylated flavonoids, and coumestans [26]. F. vulgare's oestrogenic activity is attributed to a compound named anatole. Trans-anatole comprises over 80% of F. vulgare compounds [27-29]. Oestrogenic compounds (like phytoestrogens) increases endometrial thickness by affecting glands and endometrial cells and increasing the blood flow of the functional layer [30,31]. A small amount of alcoholic F. vulgare extract causes increase in alkaline phosphatase activity and therefore cell growth and proliferation [31,32].
Inconsistency in the findings of the current study and other studies can be explained by the fact that phytoestrogens (such as isoflavones) largely bind to beta-type oestrogen receptor [33] but alpha-type oestrogen receptor represents the main oestrogen receptor in the endometrium [34,35]. Therefore, low doses of phytoestrogens are likely to be influenced by the method of brewing F. vulgare (F. vulgare tea), and the bioavailability of F. vulgare active compounds (anatole and oestragole) may be affected by the route of administration (oral or local) or the extract type. Consistently, a number of studies have reported that phytoestrogens have no effect on ET in menopausal women [35-37].
Although, more patients in the treatment group needed increase in dose compared to the control group, the difference was not statistically significant. Besides that, treatment with F. vulgare caused increase in the mean rate of chemical pregnancy yet insignificantly. F. vulgare antioxidant properties have been reported to cause increase in fertility in mice through destroying cells and facilitating cell growth and folliculogenesis [38].
A study demonstrated that low ET caused difficulty for endometrial glandular growth, disrupted angiogenesis process, and subsequently decreased secretion of vascular endothelial growth factor. More clearly, inadequate endometrial bed leads to weak implantation and vascularisation and therefore early abortion [39]. However, it is not sufficient to determine and exclusively consider ET and prescribe human chorionic gonadotropin to treat infertility, and other factors such as appropriate endometrial tissue (triple-line) and embryo quality should be taken into account [7] as well.
Limitation
Not determining the active dose of F. vulgare and not isolating phytoestrogenic compounds of this plant are some limitations of the current study. It is recommended to conduct studies with larger sample size and longer follow-up as well as considering molecular, genetic, and histopathological characteristics. Although, there were no clinical side effect in treatment group, but it is recommended that this can be considered in future studies.
Conclusion
F. vulgare seed tea caused no significant effect on ET compared to oestradiol valerate 6 mg tablet alone. However, further studies are needed to investigate this issue.
BMI: Body mass indexET: Endometrial thickness* Endometrial thickness.
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