Abstract
Objective: Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting folliculogenesis and endometrial receptivity. PCOS causes low fertility due to failures in folliculogenesis and ovulation. Electroacupuncture (EA) may help improve folliculogenesis and endometrial receptivity. EA can decrease tonic activity in the sympathetic vasoconstrictor pathway to the uterus. This study was conducted to determine the effect of the addition of EA therapy on folliculogenesis and endometrial receptivity in women with PCOS.
Materials and Methods: This case-control study was conducted at the Dr. Moewardi General Hospital, in Jawa Tengah, Indonesia. The subjects were women with PCOS, ages 20–45, who were infertile. They were divided into a control group (17 women) and an experimental group (17 women). The control group received letrozole therapy, and the experimental group received EA + letrozole therapy. Folliculogenesis is determined by measuring the growth of follicle diameter on days 2, 6, 8, 10, and 12 of the menstrual cycle. Endometrial receptivity is determined by resistance index (RI) and pulsatility index (PI) examinations on days 19 and 21; endometrial thickness is measured on day 12.
Results: There was a significant difference in folliculogenesis on days 2, 6, 8, 10, and 12. Folliculogenesis with letrozole versus EA + letrozole, respectively, were: day 2 = 5.59 ± 1.06 versus 7.01 ± 1.53, P = 0.004; day 6 = 6.71 ± 1.59 versus 9.11 ± 1.23, P < 0.001; day 8 = 9.51 ± 2.68 versus 12.44 ± 1.49, P < 0.001; day 10 = 11.30 ± 3.08 versus 15.53 ± 2.34, P < 0.001; and day 12 = 13.92 ± 3.61 versus 19.86 ± 0.75, P < 0.001. RI value with letrozole versus EA + letrozole were, respectively, day 19 = 0.91 ± 0.07 versus 0.88 ± 0.07, P = 0.150; day 21 = 0.88 ± 0.07 versus 0.79 ± 0.09, P < 0.001. PI value with letrozole versus EA + letrozole were respectively, day 19 = 3.00 ± 0.89 versus 2.30 ± 0.65, P = 0.009; and day 21 = 2.72 ± 0.88 versus 2.02 ± 0.55, P = 0.009. Endometrial thickness with letrozole versus EA + letrozole were, respectively, day 12 = 6.95 ± 1.82 versus 8.22 ± 1.76, P = 0.005.
Conclusions: The addition of EA to letrozole therapy improved folliculogenesis, RI, PI, and endometrial thickness in patients with PCOS. Further studies are needed to gain a better understanding of the dosage and timing of this therapy and its potential synergy with other current treatments.
Keywords: electroacupuncture, folliculogenesis, letrozole, endometrial receptivity, polycystic ovary syndrome
INTRODUCTION
Polycystic Ovary Syndrome (PCOS) is a complex and heterogeneous endocrine disorder associated with decreased fertility and endometrial receptivity.1,2 Infertility treatment with ovulation-induction agents such as clomiphene citrate (CC) has shown disappointing results, with low pregnancy rates. However, the success rate of in vitro fertilization (IVF) is also not high, although the quality of the embryos transferred is good. This suggests that anovulation is not the only cause of infertility. Endometrial receptivity also has a vital role in pregnancy success in women with PCOS.3 Adequate endometrial thickness is an essential element in endometrial receptivity and implantation. Ultrasonography (USG) is one of the easiest ways to check endometrial receptivity. Several parameters for checking receptivity include endometrial thickness, pattern, and volume; uterine arteries; and endometrial blood flow. Endometrial blood flow is expressed as both a pulsatility index (PI) and a resistance index (RI).4 A study reported that color Doppler USG showed the variability of blood flow in PI and RI from the ovaries and uterine arteries in patients with PCOS.5
One of the therapies used to treat infertility in women with PCOS is to induce ovulation by using letrozole. Letrozole, a third-generation aromatase inhibitor, is a better treatment option for PCOS because this agent produces a higher pregnancy rate than CC.6
Previous studies have shown that acupuncture therapy can reduce PI in the uterine arteries. The most likely causes are decreased tonic activity in the sympathetic vasoconstrictor pathway to the uterus and the involvement of central mechanisms, with a general inhibition of sympathetic outflow after acupuncture.7 However, despite these various studies, there still is not enough evidence to support using acupuncture to treat ovulation disorders in women with PCOS.8 The current study was conducted to determine the effect of adding electroacupuncture (EA) to letrozole therapy for improving folliculogenesis, the RI, the PI, and endometrial thickness in women with PCOS.
MATERIALS AND METHODS
This was a case-control study conducted at the Dr. Moewardi General Hospital, in Jawa Tengah, Indonesia. The study subjects were women with PCOS ages 20–45. The subjects were randomized by number generation and allocated into either the control group (17 subjects) or the experimental group (17 subjects). The control group received letrozole therapy alone, and the experimental group received EA + letrozole therapy. The inclusion criteria were infertile women with PCOS who met 2 of the following 3 Rotterdam criteria: (1) oligo-ovulation and anovulation, defined by <9 menstrual cycles per year; (2) hirsutism or hyperandrogenemia, defined clinically by >8 in the Ferriman–Galleway scoring system; and (3) polycystic ovaries, defined by >12 follicles in each ovary noted on USG examination. Exclusion criteria were: (1) use of hormonal birth control; (2) malignant disease; (3) use of hormone-replacement therapy; (4) hyperprolactinemia disease; (5) hyperthyroidism; and (6) pregnancy.9
In both groups, folliculogenesis was determined by measuring the growth of follicle diameter on days 2, 6, 8, 10, and 12 of the menstrual cycle. Endometrial receptivity was determined based on RI and PI results on days 19 and 21, and endometrial thickness on day 12 of the menstrual cycle. Measurements were carried out pre- and post-EA + letrozole treatment. EA was performed twice per week, up to 12 times.
For the experimental group, the EA points used were based on the meridian system and included CV 3 (Zhongji), CV 6 (Qihai), ST 29 (Guilai) bilateral, SP 6 (Sanyinjiao) bilateral, LI 4 (Hegu) bilateral, and ST 36 (Zusanli) bilateral. For the EA, stainless-steel, sterile, single-use acupuncture needles were used; they were 0.25 × 25 mm or 0.25 × 40 mm (Huanqiu, China) depending on the patient's body mass index (BMI). Stimulation was performed to reach De Qi (the sensation of matchmaking) in each experimental group patient, after which, the needle was connected to the stimulator electrode (Hwato SDZ V, Shanghai, China) for 15 minutes, at a continuous wave and a frequency of 2 Hz. Acupuncture points used were based on the research of Li et al.9 and Johansson and Stener-Victorin.10 (CV 3, CV 6, ST 29, and ST 36 correspond to meridians that affect ovarian and endometrial perfusion.) Letrozole was given on days 2–6 of menstruation for 5 days at a dose of 5 mg per day, given after EA was completed 12 times.
Outcome Measures/Assessment
Folliculogenesis was measured on days 2, 6, 8, 10, and 12 of the menstrual cycle by selecting the largest follicle, then the average follicle diameter of the 2 perpendicular measurements in mm in women with PCOS, and measured using transvaginal USG (TVUS; Voluson P6, General Electric Healthcare). Uterine artery PI and RI were quantified electronically when at least 3 consecutive good-quality waveforms were obtained, then the mean values were calculated using transabdominal color Doppler ultrasound (Voluson P6) and performed on days 19 and 21 of the menstrual cycle.
Figure 1 shows a PCOS uterine artery on Doppler ultrasound.
FIG. 1.
Doppler ultrasound of uterine-artery polycystic ovary syndrome. Pulsatility index (PI) = 2.10 and resistance index (RI) = 0.84. The uterine artery was seen notching with a systolic/diastolic ratio of 6.12. Ut, Uterus.
Endometrial thickness was measured in mm using TVUS (Voluson P6) on day 12 of the menstrual cycle. Data were analyzed using the Mann–Whitney-U test using IBM-SPSS, version 24, statistical application.
Ethical Clearance
Ethical clearance was obtained from the health research ethics committee of Dr. Moewardi General Hospital and the medical faculty of Universitas Muhammadiyah Surakarta, both in Jawa Tengah, Indonesia. Number 137/I/HREC/2020 dated January 24, 2020 and Number 3320/B.2/KEPK-FKUMS/I/2021.
RESULTS
The variables age, height, weight, BMI, and duration of infertility had P-values >0.05, which meant that no differences or data characteristics were homogeneous (Table 1).
Table 1.
Correlations of Age, Height, Weight, Body Mass Index, and Duration of Infertility between Letrozole Therapy + Electroacupuncture and Letrozole Therapy
| Variables | n | Min | Max | Mean | SD | P |
|---|---|---|---|---|---|---|
| Age (yrs) | ||||||
| Letrozole | 17 | 26 | 44 | 31.12 | 4.88 | 0.493 |
| EA + letrozole | 17 | 26 | 44 | 30.06 | 4.53 | |
| Height (cm) | ||||||
| Letrozole | 17 | 150 | 167 | 157.88 | 3.82 | 0.743 |
| EA + letrozole | 17 | 150 | 163 | 156.24 | 4.06 | |
| Weight (kg) | ||||||
| Letrozole | 17 | 40 | 99 | 64.53 | 14.85 | 0.686 |
| EA + letrozole | 17 | 40 | 105 | 65.33 | 15.93 | |
| BMI (kg/m2) | ||||||
| Letrozole | 17 | 17 | 36 | 25.65 | 5.30 | 0.243 |
| EA + letrozole | 17 | 17 | 39 | 25.76 | 5.30 | |
| Duration of infertility (yrs) | ||||||
| Letrozole | 17 | 2 | 10 | 4.88 | 2.21 | 0.899 |
| EA + letrozole | 17 | 1 | 8 | 4.53 | 2.49 |
Min, minimum; Max, maximum; SD, standard deviation yrs, years; EA, electroacupuncture; BMI, body mass index.
There were no statistical differences (P > 0.05) in folliculogenesis, RI, PI, and endometrial thickness between the control and experimental groups before treatment (Table 2).
Table 2.
Results Before Letrozole Therapy and Before Electroacupuncture + Letrozole Therapy
| Variables | Mean ± SD |
P | |
|---|---|---|---|
| Before letrozole therapy | Before EA + letrozole therapy | ||
| Follicle day 2 (mm) | 5.56 ± 1.12 | 5.61 ± 1.11 | 0.676 |
| Follicle day 6 (mm) | 5.59 ± 1.06 | 6.40 ± 0.99 | 0.498 |
| Follicle day 8 (mm) | 7.48 ± 1.88 | 7.27 ± 1.27 | 0.703 |
| Follicle day 10 (mm) | 8.87 ± 1.93 | 8.67 ± 1.67 | 0.749 |
| Follicle day 12 (mm) | 10.58 ± 2.46 | 9.97 ± 2.28 | 0.460 |
| RI day 19 | 0.94 ± 0.06 | 0.93 ± 0.07 | 0.786 |
| RI day 21 | 0.93 ± 0.07 | 0.91 ± 0.07 | 0.760 |
| PI day 19 | 3.79 ± 1.22 | 3.64 ± 1.28 | 0.953 |
| PI day 21 | 3.64 ± 1.36 | 3.30 ± 1.09 | 0.677 |
| Endometrial thickness day 12 | 5.74 ± 1.76 | 5.76 ± 1.41 | 0.227 |
SD, standard deviation; EA, electroacupuncture; RI, resistance index; PI, pulsatility index.
The P-value was <0.05 on days 8, 10, and 12 for folliculogenesis; on days 19 and 21 for PI, and on day 12 for endometrial thickness (Table 3).
Table 3.
Results Before Letrozole Therapy and After Letrozole Therapy
| Variables | Mean ± SD |
P | |
|---|---|---|---|
| Before letrozole therapy | After letrozole therapy | ||
| Follicle day 2 (mm) | 5.56 ± 1.12 | 5.59 ± 1.06 | 0.921 |
| Follicle day 6 (mm) | 5.59 ± 1.06 | 6.71 ± 1.59 | 0.149 |
| Follicle day 8 (mm) | 7.48 ± 1.88 | 9.51 ± 2.68 | <0.001* |
| Follicle day 10 (mm) | 8.87 ± 1.93 | 11.30 ± 3.08 | 0.001* |
| Follicle day 12 (mm) | 10.58 ± 2.46 | 13.92 ± 3.61 | <0.001* |
| RI day 19 | 0.94 ± 0.06 | 0.91 ± 0.07 | 0.113 |
| RI day 21 | 0.93 ± 0.07 | 0.88 ± 0.07 | 0.209 |
| PI day 19 | 3.79 ± 1.22 | 3.00 ± 0.89 | <0.001* |
| PI day 21 | 3.64 ± 1.36 | 2.72 ± 0.88 | 0.001* |
| Endometrial thickness day 12 | 5.74 ± 1.76 | 6.95 ± 1.82 | <0.001* |
p < 0.05.
SD, standard deviation; RI, resistance index; PI, pulsatility index.
There were statistically significant differences in folliculogenesis in between the groups on days 2, 6, 8, 10, and 12 before and after the intervention. Likewise, there was a significant difference in RI on days 19 and 21. There was a significant difference in PI on days 19 and 21. There was also a significant difference in endometrial thickness on day 12. See Table 4.
Table 4.
Results Before Electroacupuncture + Letrozole Therapy and After Electroacupuncture + Letrozole Therapy
| Variables | Mean ± SD |
|
|
|---|---|---|---|
| Before EA + letrozole therapy | After EA + letrozole therapy | P | |
| Follicle day 2 (mm) | 5.61 ± 1.11 | 7.01 ± 1.53 | 0.003* |
| Follicle day 6 (mm) | 6.40 ± 0.99 | 9.11 ± 1.23 | <0.001* |
| Follicle day 8 (mm) | 7.27 ± 1.27 | 12.44 ± 1.49 | <0.001* |
| Follicle day 10 (mm) | 8.67 ± 1.67 | 15.53 ± 2.34 | <0.001* |
| Follicle day 12 (mm) | 9.97 ± 2.28 | 19.86 ± 0.75 | <0.001* |
| RI day 19 | 0.93 ± 0.07 | 0.88 ± 0.07 | 0.002* |
| RI day 21 | 0.91 ± 0.07 | 0.79 ± 0.09 | 0.001* |
| PI day 19 | 3.64 ± 1.28 | 2.30 ± 0.65 | <0.001* |
| PI day 21 | 3.30 ± 1.09 | 2.02 ± 0.55 | <0.001* |
| Endometrial thickness day 12 | 5.76 ± 1.41 | 8.22 ± 1.76 | 0.003* |
p < 0.05.
SD, standard deviation; EA, electroacupuncture; RI, resistance index; PI, pulsatility index.
There were statistically significant differences between the control and experimental groups in folliculogenesis on days 2, 6, 8, 10, and 12. Likewise, there was a significant difference in RI on day 21. There was a significant difference in PI on days 19 and 21. There was also a significant difference in endometrial thickness on day 12. However, RI results on day 19 did not show a statistically significant difference between the 2 groups. See Table 5.
Table 5.
Results After Letrozole Therapy and after Electroacupuncture + Letrozole Therapy
| Variables | Mean ± SD |
P | |
|---|---|---|---|
| After letrozole therapy | After EA + letrozole therapy | ||
| Follicle day 2 (mm) | 5.59 ± 1.06 | 7.01 ± 1.53 | 0.004* |
| Follicle day 6 (mm) | 6.71 ± 1.59 | 9.11 ± 1.23 | <0.001* |
| Follicle day 8 (mm) | 9.51 ± 2.68 | 12.44 ± 1.49 | <0.001* |
| Follicle day 10 (mm) | 11.30 ± 3.08 | 15.53 ± 2.34 | <0.001* |
| Follicle day 12 (mm) | 13.92 ± 3.61 | 19.86 ± 0.75 | <0.001* |
| RI day 19 | 0.91 ± 0.07 | 0.88 ± 0.07 | 0.150 |
| RI day 21 | 0.88 ± 0.07 | 0.79 ± 0.09 | <0.001* |
| PI day 19 | 3.00 ± 0.89 | 2.30 ± 0.65 | 0.009* |
| PI day 21 | 2.72 ± 0.88 | 2.02 ± 0.55 | 0.009* |
| Endometrial thickness day 12 | 6.95 ± 1.82 | 8.22 ± 1.76 | 0.005* |
p < 0.05.
SD, standard deviation; EA, electroacupuncture; RI, resistance index; PI, pulsatility index.
Figure 2 shows these results.
FIG. 2.
Comparison of folliculogenesis, resistance index, pulsatility index, and endometrial thickness between letrozole therapy alone and electroacupuncture (EA) + letrozole therapy.
DISCUSSION
This study showed a significant effect of the addition of EA on folliculogenesis at days 2, 6, 8, 10, and 12. This is in line with previous studies by Budihastuti et al.,11 which stated that EA also significantly affected follicular-size growth on days 2, 6, 8, 10, and 12. Several therapies have been investigated for assisting ovulation in women with PCOS. These include antiestrogens, gonadotropins, aromatase inhibitors, and surgical interventions.9 Letrozole is a nonsteroidal aromatase inhibitor that can induce ovulation in women suffering from infertility. This agent inhibits estrogen production by suppressing the aromatase enzyme.12,13 One of the advantages of letrozole therapy for patients with PCOS is that it does not result in excess estrogen production, which would lead to thinning of the endometrium.14 A well-developed endometrium is essential for successful implantation.15
EA has been shown to increase β-endorphins and reduce sympathetic activity.16 These changes may be postulated to lead to changes in ovarian neurogenic control. Thus, EA + letrozole therapy may have some synergistic activity with respect to PCOS physiology. Letrozole prevents the hypothalamic–pituitary axis from negative estrogenic feedback. As such, this agent increases gonadotropin secretion and stimulates ovarian follicles.17 Letrozole is also a desirable PCOS therapy because it obviates the use of antiestrogenic agents such as clomiphene.18 However, a previous retrospective study did not find that letrozole was superior to clomiphene.19
According to research by Ozdemir et al.,20 the uterine-artery PI and RI values were higher in patients with PCOS as seen on polycystic USG evidence, whereas PI and RI ovarian-artery values were lower. These results were similar to the current study, which also found significant reductions in RI and PI after EA + letrozole therapy. A PI value >3 indicates that endometrial receptivity is not good, leading to possible failed implantation.21 In addition, the results of this study suggested that EA + letrozole can significantly increase endometrial thickness and reduce RI value. The current results supported a previous study by Zhong et al.,7 which stated that acupuncture increases pregnancy success effectively, thickens the endometrium, and reduces RI value.
Acupuncture has been shown to modulate β-endorphins, reduce excess plasma β-endorphin levels, and decrease sympathetic-nerve activity. The sympathetic nervous system (SNS) and ovarian neurogenic control are involved in PCOS etiology.16 Women with anovulatory PCOS have high plasma β-endorphin levels and low skin temperature and have increased sympathetic-nerve activity that can be repaired by EA.22,23 In EA, acupuncture points are stimulated by electrical means. Stimulation with the insertion of acupuncture needles can activate muscle-afferent pathways to the spinal cord and central nervous system (CNS).24
The difference between EA and manual acupuncture is that EA induces electrically continuous stimulation by applying an electric field that conducts an electric current to 2 needles that are inserted at acupoints. EA with a low-frequency intensity (1–15 Hz) can stimulate contractions. This mechanism will activate and modulate nerve pathways in the peripheral (local) nervous system, segmental nervous system (spinal cord), and CNS.10 EA can also release β-endorphins via 2 mechanisms: (2) by using the hypothalamus and inhibiting the SNS; and (2) via the β-endorphins and adrenocorticotropic hormone (ACTH) in the blood. Both can reduce sympathetic effects, thereby increasing blood flow to the endometria of women with PCOS.25 EA also has a greater stimulus intensity, compared to manual acupuncture, so it is necessary to consider several factors including the severity of the patient's symptoms and her medical history.
EA is safe at commonly clinically delivered parameters. These include the following characteristics: frequency (2–200 Hz); voltage below 12 mA; waveform (biphasic or balanced charge); needle-insertion time (20–30 minutes); and needle diameter (0.25–0.30 mm).26 Side-effects of EA include peripheral- or central-nerve irritation or injury, cardiac-conduction block, burns, and pneumothorax, although these side-effects are rare and are likely caused by negligence or malpractice. All of this can be avoided.27–29
EA therapy can increase ovulation in patients with PCOS by affecting the secretion of β-endorphins in the CNS and inhibiting sympathetic tone.22 EA can increase uterine blood flow by reducing uterine vasoconstriction and increasing endometrial receptivity. Reproductive function is regulated by central endorphin and gonadotropin-releasing hormone (GnRH). GnRH also affects the release of luteinizing hormone and follicle-stimulating hormone.30
This study suggests that addition of EA to letrozole therapy can increase folliculogenesis, increase endometrial receptivity, and lower RI and PI. Further studies are needed to explore the improvement in these physiologic markers on pregnancy and healthy neonate delivery.
There were several limitations to the current study. First, EA cannot be blinded. Thus, the recipients of the treatment were aware of their treatment assignments. Second, EA was performed for a total of 12 times in each participant. This treatment regimen represents a significant treatment burden for patients and providers and may be difficult to replicate in clinical care. Finally, it was not possible to measure estrogen and progesterone levels on Days 18 and 21; thus, it was not possible to determine the correlation between RI/PI and hormone levels.
CONCLUSIONS
The addition of EA to letrozole therapy improves folliculogenesis, RI, PI, and endometrial thickness in patients with PCOS. Further studies are needed to understand the dosage and timing of this therapy better as well as potential synergy with other current treatments.
ACKNOWLEDGMENTS
The authors thank Cahyono Hadi, the director of the Dr. Moewardi General Hospital, MD, PhD, for permission and cooperation in conducting this research.
AUTHOR DISCLOSURE STATEMENT
No financial conflicts of interest exist.
FUNDING INFORMATION
There is no funding for this research.
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