Traditional Chinese medicine can increase fertility in women with a thin endometrium

Manuscript title: Traditional Chinese medicine Dingkun pill to increase fertility in women with a thin endometrium—a prospective randomized study

The appropriate endometrium thickness (EMT) is an important single etiology of possible infertility . If the EMT is not high enough during ovulation, there is usually a poor reproductive outcome. Although there is no consensus regarding the cutoff value of EMT during ovulation, many studies have shown that the pregnancy rate will decrease significantly if the EMT measured by transvaginal ultrasound is less than 7 mm on the day of hCG or luteal support in assisted reproductive technology (ART) . Therefore, endometrium with an EMT of less than 7 mm during ovulation is considered thin, and the resulting infertility is regarded as “thin endometrium infertility”.

Proliferation of the endometrium depends on the secretion of estrogen under normal physiological conditions. Hence, there is no doubt that estrogen supplementation is the first choice for thin endometrium infertility. In most cases, estrogen supplementation can actually promote endometrium proliferation, i.e., increase EMT and consequently improve the clinical pregnancy rate . However, it is not effective for all patients, and some patients showed low response or no response to estrogen no matter whether it was used in the stimulating cycle, natural cycle, or high-dose hormone supplement cycle. The use of high-dose estrogen is limited due to the risk of hyperplasia, which could lead to endometrial cancer. Monitoring by assessing estradiol (E2) levels is difficult, because it has been shown that E2 levels were only correlated with endometrium thickness in patients with relatively low estrogen levels. Once E2 levels are >1,000 ng/mL, it has no further significant impact on endometrium thickness . Therefore, it is necessary to explore another effective alternative method to improve EMT and pregnancy rates for those patients with less or even no response to estrogen supplement.

As the exclusive tribute medicine for the imperial palace of the Qing Dynasty, the effectiveness of Dingkun pill (DKP) on hypomenorrhea and female infertility has been repeatedly verified in China.

Study design and participants

Patients attending the Department of Gynecological Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University between November 2018 and October 2022 were recruited. All patients who met inclusion criteria and exclusion criteria were randomly assigned to the control group or the experimental group in a 1:1 ratio according to the random numbers generated by the computer software and received different treatment schemes. The whole intervention process lasted three menstrual cycles. All patients were natural cycles and received treatments in the outpatient department. Since our research was not focused on evaluating the endometrial receptivity, we do not have sufficient evidence to consider if endometrial biopsies are essential or not. Thus, endometrial biopsy and/or hysteroscopy were only performed on patients who need further diagnostic procedures such as excluding polyps as reasons for bleeding problems.Inclusion criteria were as follows: (I) female infertility, (II) women aged between 20 and 40 years, and (III) EMT less than 7 mm on ovulation day in at least two natural menstrual cycles. Infertility was defined by failure to achieve a successful pregnancy after 12 months or more of appropriate, timed unprotected intercourse or therapeutic donor insemination.

Recruitment for the study

Serum endocrine hormones including follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) were measured on days 2–4 of the menstrual cycle. EMT and endometrium type on ovulation day were also measured by transvaginal ultrasound. The day when the dominant follicle (≥18 mm) disappeared was defined as ovulation day. Endometrium with an EMT of less than 7 mm on ovulation day was considered thin. Only these patients were recruited for the study, i.e., randomly selected for the experimental group or for the control group.

EMT and type assay

After the uterus was scanned by the longitudinal section and finding out that the endometrial image was the clearest, the endometrium thickness was determined by measuring the maximum anteroposterior distance between the myometrial and the endometrium interface. The endometrial pattern was assessed according to the classification proposed by Gonen (14)as follows: Type A is a multilayered endometrium consisting of prominent outer and midline hyperechogenic lines and inner hypoechogenic regions. Type B is characterized by the same reflectivity of ultrasound as the myometrium, with a non-prominent or absent central echogenic line. Type C is an entirely homogenous, hyperechogenic endometrium.

Control group

The women were treated with estradiol valerate tablets (Bayer, Guangzhou, China) 2 mg/day orally starting on the fifth day of the menstrual cycle. If the EMT was measured by transvaginal ultrasound on ovulation day > 7 mm, the intake of estradiol valerate tablets was stopped, and only dydrogesterone 10 mg/day orally (Abbott Biologicals B.V., Netherlands) was used. If EMT on ovulation day remained< 7 mm, the treatment with estradiol valerate tablets was continued and, at the same time, dydrogesterone 10 mg/day orally was added (so-called “sequential hormone replacement therapy”).

Experimental group

These women received DKP (Luwang, Jilin, China) 10.8 g twice a day orally from the fifth day of the menstrual cycle until 14 days after ovulation. The other drug regimen (hormonal treatment) was the same as that in the control group.

DKP is mainly composed of the following 30 medicinal herbs: Radix Ginseng, Cornu Cervi Pantotrichum, Radix Angelicae sinensis, Radix Rehmanniae Preparata, Stigma Croci, Caulis Spatholobi, Radix Notoginseng, Radix Paeoniae Alba, Rhizoma Atractylodis Macrocephalae, Fructus Lycii, Radix Scutellariae, Rhizoma Cyperi, Fructus Leonuri, Rhizoma Ligustici Chuanxiong, Cornu Cervi Degelatinatum, Colla Corii Asini, Rhizoma Corydalis, Flos Carthami, Herba Leonuri, Faeces Togopteri, Poria, Radix Bupleuri, Radix Linderae, Fructus Amomi Villosi, Cortex Eucommiae, Rhizoma Zingiberis, Herba Asari, Radix Cyathulae, Cortex Cinnamomi, and Radix Glycyrrhizae. The “Dingkun pill” standard is approved by the China Food and Drug Administration (CFDA).

Serum hCG levels were measured in both groups 14 days after ovulation. If hCG >10 IU/L, estradiol valerate tablets were stopped and only dydrogesterone was given until 12 weeks of pregnancy. If hCG<10 IU/L (i.e., no pregnancy), the study was continued accordingly; i.e., treatments were continued on the 5th day of the next menstrual cycle until patients became pregnant or until the end of the third cycle at the end of the study.

Results

EMT on ovulation day in the experimental group was significantly higher than that in the control group (7.88 vs. 7.15 mm; p < 0.001). The proportion of type A and type B endometrium in total was significantly higher in the experimental group than that in the control group (83.2% vs. 77.7%; p < 0.05). Progesterone levels were significantly higher in the experimental group than those in the control group (10.874 vs. 10.074 ng/mL; p < 0.001). The cumulative pregnancy rate, the main outcome of the study, was significantly higher in the experimental group than that in the control group (29.2% vs. 15.7%; p < 0.05).

Conclusion

DKP added to conventional estrogen/progestogen therapy can significantly improve EMT and luteal function in patients attending due to infertility. Because this regimen increased the cumulative pregnancy rate in our study, we conclude that DKP can be used to increase the so-called “thin endometrium infertility”.

My comments:

This study showed that one product of traditional Chinese medicine can improve uterus endometrium thickness. This is a fixed formula and according to theory of Chinese medicine, thin uterus endometrial thickness can be resulted from multiple patterns and a different formula may be more appropriate. Meanwhile, adjusting formula of Chinese herbs based on different stage of menstrual period, such as the menses, follicular, ovulation or luteal phase, can have a synergistic effect.

Reference:

Jin. F et al. Traditional Chinese medicine Dingkun pill to increase fertility in women with a thin endometrium—a prospective randomized study. Front Endocrinol (Lausanne). 2023 Sep 28;14:1168175.