Impact of biomimetic electrical stimulation combined with Femoston on pregnancy rate and endometrium characteristics in infertility patients with thin endometrium: a prospective observational study

Abstract

Objective

To explore the impact of biomimetic electrical stimulation combined with Femoston (estradiol tablets/estradiol and dydrogesterone tablets) on pregnancy rate and endometrium characteristics (endometrial thickness and type) in patients with infertility and a thin endometrium.

Methods

This prospective study enrolled patients with infertility and a thin endometrium admitted to Urumqi Maternal and Child Health Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China, between May 2021 and January 2022. The patients received Femoston alone (Femoston group) or Femoston combined with biomimetic electrical stimulation (electrotherapy group). The outcomes were the pregnancy rate and endometrium characteristics.

Results

Finally, 120 patients were enrolled (60/group). Before treatment, the endometrial thickness (p = 0.515) and the percentages of patients with endometrial types A + B and C (p = 0.769) were comparable between the two groups. After treatment, the endometrium of the patients in the electrotherapy group was thicker than those in the Femoston group (6.48 ± 0.96 mm vs. 5.27 ± 0.51 mm, p < 0.001). Furthermore, the percentages of patients with endometrial types A + B and C in the electrotherapy group were larger than in the Femoston group (p = 0.027). In addition, the pregnancy rates between the two groups (28.33% vs. 16.67%, p = 0.126) were similar.

Conclusions

The results suggest the possibility that biomimetic electrical stimulation combined with Femoston could improve endometrial type and thickness in patients with infertility and thin endometrium compared with Femoston alone, but the pregnancy rate showed no significant improvement. The results need to be confirmed.

Keywords:

• Thin endometrial
• infertility
• Femoston
• endometrial thickness
• pregnancy rate

Introduction

Infertility is the inability to conceive after 1 year of unprotected sexual intercourse. Infertility occurs in about 15% of reproductive-aged couples worldwide and is more common in developing countries. The cause of infertility is often multifactorial [1].

The endometrium is the basis for embryo implantation [2]. Endometrial thickness in the mid-luteal phase (6–10 days after ovulation) is one of the very important quality indicators for embryo implantation [3]. Inflammation and iatrogenic injury are the most common causes of a thin endometrium [4]. The endometrial and ovarian blood perfusion in patients with a thin endometrium is lower than in those with a normal endometrium [5]. Hypoperfusion results in decreased endometrial vascular endothelial growth factor expression and endometrial growth restriction [6].

The available treatments have a poor effect in patients with a thin endometrium caused by severe or extensive injury, and the difficulty of increasing endometrial thickness has become a common intractable problem in clinical treatment [7]. Therefore, based on exogenous high-dose estrogen therapy, clinical studies examined low-dose aspirin [8], sildenafil [9], granulocyte colony-stimulating factor [10], and stem cell transplantation [11], which have conflicting results regarding fertility improvement but confirmed side effects [12].

In recent years, biomimetic electrical stimulation therapy has received increasing attention for managing stress urinary incontinence, pelvic pain, sexual dysfunction, low back pain, and constipation [13]. A preliminary study suggested that biomimetic electrical stimulation therapy could increase endometrial thickness [14].

Therefore, this study investigated the impact of biomimetic electrical stimulation combined with Femoston (Complex Packing Estradiol Tablets/Estradiol and Dydrogesterone Tablets) on endometrial thickness, endometrial type, and pregnancy rate in patients with infertility and a thin endometrium.

Methods

Study design and patients

This prospective study enrolled patients with infertility and a thin endometrium admitted to Urumqi Maternal and Child Health Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China, between May 2021 and January 2022. This study was approved by the Ethics Committee of Urumqi Maternal and Child Health Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China. All participants signed the informed consent form.

Most patients had a history of targeted treatment after preliminary observation and follow-up (up to 2 years) after excluding other causes of infertility and considering causes such as thin endometrial and poor endometrial receptivity. The treatments included ovulation stimulation, artificial insemination, IVF/ICSI, and other methods approved by the National Health and Family Planning Commission. Considering the possibility of thin endometrium and poor endometrial receptivity, B-mode ultrasound examinations for the detection of thin endometrium were performed during patient management. The inclusion criteria were 1) women of childbearing age (28–40 years), 2) endometrial thickness of <7 mm in the mid-luteal phase (6–10 days after ovulation), 3) regular menstrual cycle and period (menstrual cycles of 21 to 35 days, menstruation lasting 2 to 8 days, and a median volume of 20–60 ml), 4) no organic lesions in the uterus, 5) exclusion of male infertility factors, and 6) normal ovarian function (the normal blood levels were 5–40 mIU/ml for FSH, 5–25 mIU/ml for the luteinizing hormone (LH) in the non-ovulatory period, and 25–45 pg/ml for E2).

The exclusion criteria were 1) low-frequency electrical stimulation treatment contraindications (e.g. cardiac pacemakers, neurostimulators, etc.), 2) acute infectious diseases, epilepsy, or other neurological diseases, 3) contraindications to oral estrogen and progesterone drugs, 4) known or suspected estrogen-dependent malignancy (e.g. endometrial cancer and breast cancer), 5) unexplained genital tract bleeding, untreated endometrial hyperplasia, previous idiopathic or existing venous thromboembolism (deep vein embolism or pulmonary embolism), active or recent arterial thromboembolic disease (such as angina pectoris or myocardial infarction), acute liver disease, or a history of liver disease, 6) abnormal liver function, 7) porphyria (indications not limited to postmenopausal women), 8) known or suspected pregnancy, or 9) other uterus organic disease.

Procedures

All participants received Femoston (estradiol tablets/estradiol and dydrogesterone tablets) 2/10 orally on the 2^nd to 3^rd day of the menstrual cycle, once a day, 28 days as a course of treatment, for a total of two courses. The participants received Femoston alone (Femoston group) or Femoston combined with biomimetic electrical stimulation (electrotherapy group).

The patients meeting the eligibility criteria were randomized by blocks of six participants according to age and course of the disease. The randomization sequence was prepared by a third-party biostatistician. Due to the nature of the interventions, the patients and physicians could not be blinded, but the sonographers were blind to grouping.

For the biomimetic electrical stimulation therapy, the PHENIX-8 neuromuscular stimulation therapeutic apparatus (Guangzhou Shanshan medical apparatus and instruments industry Co., Ltd., Guangzhou, China) was used. In the follicular phase (2–3 days after menstruation finished), the electrode sheet (50 × 50 mm) was attached to the abdominal aorta area below the navel, and the back electrode was placed and aligned with the front one. The dorsal pedis artery and the inguinal artery on one side of the lower extremity were grouped together; the foot was connected to the positive electrode, the groin was connected to the negative electrode, and the other lower extremity was connected in the same way. Appropriate bioelectrical stimulation was given to the patient according to her comfort. The first stage was hemodynamic activation for 20 min, and the second stage was electrodynamic acceleration for 20 min, for a total of 40 min. The treatment was applied every other day, and it could be applied three or five times per cycle. The patient’s age, duration of the disease, and treatment outcome were collected.

Outcomes

The outcomes were 1) the pregnancy rate (the embryonic primordial cardiac tube pulsation could be seen in the intrauterine gestational sac) and 2) endometrium characteristics, including the thickness and types of the endometrium monitored by color Doppler ultrasound in each cycle (double-layer) and endometrial type which included type A (three-line type), type B (no obvious midline echo in the uterine cavity), and type C (strong homogeneous echo) [15].

Statistical analysis

SPSS 20.0 (IBM, Armonk, NY, USA) was used for statistical analysis. The continuous data were expressed as means ± standard deviation. The paired t-test was used for comparison within a group before and after treatment. Student’s t-test was used for comparison between the two groups. The categorical data were expressed as n (%) and analyzed using the chi-square test. Two-sided P-values < 0.05 were considered statistically significant.

Results

A total of 120 participants were included. There were 60 participants in the electrotherapy group, with a mean age of 31.3 ± 2.7 years, 36 participants with a disease course of 1–6 months, and 24 participants with a course of 7–12 months. There were 60 patients in the Femoston group, with a mean age of 31.1 ± 2.9 years, 37 patients with a disease course of 1–6 months, and 23 patients with a course of 7–12 months. There were no significant differences in patient characteristics between the two groups (all p > 0.05) (Table 1).

Table 1. Characteristics of the participants.

	Electrotherapy group (n = 60)	Femoston group (n = 60)
Age, years, mean ± SD	31.25 ± 2.68	31.10 ± 2.85
Course of disease
1-6 months, n (%)	36 (60.0)	37 (61.7)
7-12 months, n (%)	24 (40.0)	23 (38.3)
E2, mIU/ml	136.7	144.4
ESH level, mIU/ml	8.91	9.23
LH level, mIU/ml	4.68	4.00

Before treatment, the endometrial thickness (p = 0.515) and the percentages of patients with endometrial types A + B and C (p = 0.769) were comparable between the two groups. After treatment, the endometrium of the patients in the electrotherapy group was thicker than those in the Femoston group (6.48 ± 0.96 mm vs. 5.27 ± 0.51 mm, p < 0.001). Furthermore, the percentages of patients with endometrial types A + B and C in the electrotherapy group were larger than in the Femoston group (p = 0.027). The pregnancy rates between the two groups were similar (28.33% vs. 16.67%, p = 0.126) (Table 2).

Table 2. Outcomes of biomimetic electrical stimulation therapy on endometrial thickness, type, and pregnancy rate in female patients.

	Group, n	Endometrial thickness (mm)	Type A, B	Type C	Pregnancy rate
Before treatment	Electrotherapy group n = 60	4.66 ± 0.33	6 (10.00)	54 (90.00)	–
	Femoston group (n = 60)	4.68 ± 0.32	7 (11.67)	53 (88.33)	–
	P	0.515	0.769		–
After treatment	Electrotherapy group n = 60	6.48 ± 0.96	40 (66.67)	20 (33.33)	17 (28.33)
	Femoston group (n = 60)	5.27 ± 0.51	28 (46.67)	32 (53.33)	10 (16.67)
	P	< 0.001	0.027		0.126

Discussion

The results suggest that, after treatment, the endometrium and the percentages of patients with endometrial type A + B and C in the electrotherapy group were significantly thicker and larger than in the Femoston group. The pregnancy rates between the two groups were similar. These findings might support the favorable outcomes of biomimetic electrical stimulation combined with estradiol/dydrogesterone therapy on endometrial thickness and endometrial type in patients with infertility due to thin endometrium.

Studies showed that a thin endometrium could adversely affect the embryo’s implantation, causing infertility; even if pregnancy is achieved, the risk of miscarriage is high [16–19]. Infertility caused by various reasons leads to different degrees of psychological and reproductive pressure on the patients, and their physical and mental health is greatly threatened, which may lead to the breakdown of family relationships and seriously affect social harmony [20]. Patients with many previous miscarriages have a high risk of endometrial thinning, and the pregnancy outcomes of patients with a thin endometrial can be improved by increasing estrogen use time and dosage [22]. Determining methods to improve endometrial thickness should improve pregnancy outcomes.

Bioelectricity is a kind of physicochemical change in life activities, a basic feature of living organisms, and a manifestation of normal physiological activities. Electrophysiology has developed rapidly in different disciplines in recent years. Electrophysiology research can help understand the functional status of the body. It can be used to diagnose diseases (e.g. electrocardiogram), but it can also help intervene for function regulation intervention, and it is possible to use it for disease prevention and treatment clinically. Biomimetic electrical stimulation acts on pelvic floor muscles and nerves through low-frequency currents, promotes lymphatic and blood circulation by stimulating the nerve-muscle-visceral reflex axis, improves endometrial blood flow and tissue nutrition, accelerates the healing of damaged tissue, and promotes endometrial repair [23,24]. A study enrolled 41 patients with a thin endometrium (≤ 7 mm) and undergoing assisted reproductive technology; they received intermittent vaginal electrical stimulation for 20–30 min on treatment days. The results showed that pelvic floor nerve stimulation significantly increased uterine endometrial thickness in patients with a thin endometrium [14]. By stimulating the repeated contraction and relaxation of uterine smooth muscle, the blood supply to the entire endometrial and subendometrial region can be increased, resulting in better nourishment of the endometrial tissues [14].

PHENIX-8 can selectively act on vascular smooth muscles, make the vascular smooth muscle contract, and promote blood microcirculation and lymphatic return, as previously observed [14]. The first stage of hemodynamic activation is mild. In the second stage, the hemodynamics are accelerated, and the arterial blood flow resistance is reduced, thereby increasing the blood circulation of the ovary and the endometrium and promoting the growth of the endometrium. The results of this study showed that after treatment, the endometrial thickness and the proportion of endometrial types A + B in the electrotherapy group were higher than in the Femoston group (p < 0.05), while the proportion of type C was lower than in the Femoston group (p < 0.05), suggesting that the application of bioelectrical stimulation therapy could effectively improve endometrial thickness. At the same time, there were no safety-related events, side effects, or adverse patient experiences in the electrotherapy group.

There were no significant differences in the pregnancy rates between the two groups in this study because the inclusion criteria of this study were strict, and the follow-up was limited. This lack of differences was also observed by Bodombossou-Djobo et al. [14], whose study also suffered from a small number of patients and a short follow-up. Still, the literature is scarce regarding the use of electrotherapy in patients with infertility. Additional studies are necessary.

Nevertheless, the selection of the hormonal treatment for a thin endometrium is mostly unknown. Shao [25] pointed out, regarding a thin endometrium, that ‘Comprehensive treatment can be attempted from the aspects of increasing estrogen, improving endometrial circulation, promoting endometrial proliferation, etc. Estrogen administration needs to stimulate the endometrial and inhibit the growth of dominant follicles at the same time’. In addition, it is pointed out that ‘Pelvic floor muscle contraction and relaxation caused by electrical stimulation of pelvic floor nerve muscle may promote pelvic floor blood circulation, increase intima and subintima blood perfusion, and promote intima growth’. [26]. A recent paper by Di Guardo & Palumbo [27] discusses the approaches to restoring a functional endometrium in women with Asherman syndrome. Insights could be gleaned from those approaches but will have to be examined in future studies.

This study had limitations. The sample size was small, and the statistical power was probably insufficient to confirm the presence or absence of an effect of electrotherapy on pregnancy. In addition, the follow-up was short, and whether the effects remain for some time after treatment is unknown. Furthermore, using a mock treatment in the Femoston group would be a more robust experimental design. Follow-up in pregnancy rate was an assumption in the cumulative outcome that was not necessarily reflected in cases of infertile women with thin endometrium. Finally, all enrolled patients actively sought fertility treatments; therefore, a control group without any treatment (i.e. no electrotherapy and no Femoston) could not be included in the study design for ethical reasons.

In conclusion, the results suggest the possibility that biomimetic electrical stimulation combined with Femoston could improve endometrial type and thickness in patients with infertility and thin endometrium compared with Femoston alone, but the pregnancy rate showed no significant improvement. The results need confirmation by a multicenter, randomized controlled trial with a larger sample size.

Data availability statement

Data sharing does not apply to this article as no datasets were generated or analyzed during the current study.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Science and Technology Planning Project of the Urumqi Health Commission (No. 202012)