A comparative study between Dydrogesterone alone and combined with Non-Steroidal Anti-Inflammatory Drugs in the treatment of Mild Endometriosis

Objective: To evaluate the clinical efficacy of dydrogesterone combined with non-steroidal anti-inflammatory drugs(NSAIDs) in the treatment of patients with mild endometriosis. Methods: This was a clinical comparative study. Eighty patients with mild endometriosis were recruited at Affiliated Hospital of Hebei University, randomly divided experimental group (n=40) and control group (n=40) from March 2022 to March 2023. Both groups started treatment with dydrogesterone on the 5th day of menstruation. Patients in the control group were treated with dydrogesterone monotherapy, while those in the experimental group were treated with mefenamic acid the basis of the therapy of the control group. The clinical efficacy, differences in the levels of humoral immune indexes, the levels of inflammatory factor and the incidence of adverse drug reactions of the two groups was compared and analyzed. Results: The efficacy of the experimental group was significantly higher than the control group, with a statistically significant difference(P=0.02). The levels of C3 and C4 in the experimental group after treatment were significantly lower than those in the control group, with a statistically significant difference(P=0.00). After treatment, TNF-a, CRP, IL-6 and other indexes in the experimental group were significantly lower than those in the control group, with statistically significant differences(P=0.00). The incidence of adverse reactions after treatment had no statistically significant difference(P=0.45). Conclusion: Dydrogesterone combined with non-steroidal anti-inflammatory drugs is a safe and effective treatment for patients with endometriosis. It can improve various obvious curative effects, such as marked relief of pain symptoms, reduction of complement and inflammatory factor levels without a significant increase in adverse reactions.


INTRODUCTION
Endometriosis is a disease in which the endometrial tissue with growth function appears in other places of the uterus, causing a series of symptoms and signs in patients. 1It tends to make inroads on women of childbearing age.Studies suggest that about 5-10% 2 of women of reproductive age worldwide have suffered from the disease.Endometriosis is prone to occur in the ovary and peritoneum, often accompanied by various degrees of pelvic adhesions.It has a certain impact on patients' daily life and study, with clinical manifestations such as progressive dysmenorrhea, pelvic pain and dyspareunia. 3Clinically, surgery and drugs are usually preferred for the treatment of endometriosis, but postoperative lesions are easy to spread and infiltrate and have a high recurrence rate.Fertility-sparing patients have a disease recurrence rate of approximately 20% within two years after surgery, 4,5 and are more likely to damage the urinary system and

Original Article
A comparative study between Dydrogesterone alone and combined with Non-Steroidal Anti-Inflammatory Drugs in the treatment of Mild Endometriosis rectal function of patients.Therefore, patients with mild endometriosis are often treated with conservative drugs. 6onadotropin-releasing hormone agonist (GnRHa) has been widely used in the treatment of endometriosis. 7espite the exact curative effect, long-term medication may cause a series of symptoms of low estrogen such as vaginal dryness, low-grade fever, and osteoporosis.Dydrogesterone is oral progesterone that is effective in treating endometriosis, such as decreasing endometrial lesions and controlling pain intensity. 8Mefenamic acid is a non-steroidal anti-inflammatory drug with a strong analgesic effect and low adverse reactions and risks. 9In this study, dydrogesterone combined with mefenamic acid was used to treat patients with mild endometriosis, and certain clinical efficacy was achieved.• Patients with cognitive dysfunction or mental diseases who could not cooperate with the study.Both groups started treatment with dydrogesterone on the fifth day of menstruationon.Patients in the control group were treated with dydrogesterone monotherapy as follows: 10mg of dydrogesterone twice a day for six months.Those in the study group were combined with oral mefenamic acid on the basis of the control group as follows: 0.25 g of mefenamic acid twice a day, from the first day to the seventh day of menstruation as a course of treatment, usually repeated two to three courses. 11oth groups were observed before and after treatment to judge the clinical efficacy 12 : Markedly effective: all pelvic masses decreased after treatment, and symptoms such as dysmenorrhea and pelvic pain completely disappeared or improved significantly; Effective: all pelvic masses without obvious change after treatment, and symptoms such as dysmenorrhea and pelvic pain improved; Ineffective: all pelvic masses did not shrink or even increased after treatment, and symptoms such as dysmenorrhea and pelvic pain did not improve.

RESULTS
The comparative analysis of clinical efficacy showed that the efficacy of the experimental group was 90%, which was significantly higher than 70% of the control group, with a statistically significant difference (P=0.02)(Table-II).
No statistically significant difference was observed in the levels of IgG and IgM before and after treatment between the two groups (P>0.05);The levels of C3 and C4 in the experimental group after treatment were significantly lower than those in the control group, with a statistically significant difference (P=0.00)(Table-III).
No statistically significant difference was observed in the comparison of TNF-a, CRP, IL-6 and other indexes between the experimental group and the control group before treatment (P>0.05).After treatment, TNF-a, CRP, IL-6 and other indexes in the experimental group were significantly lower than those in the control group, with statistically significant differences (P=0.00)(Table-IV).The incidence of adverse reactions after treatment in the experimental group was 30%, while that in the control group was 22.5%, with no statistically significant difference (P=0.45)(Table-V).

DISCUSSION
It has been confirmed in our study that the efficacy of the experimental group was 90%, which was significantly higher than 70% of the control group, with a statistically significant difference (P=0.02);The levels of C3 and C4 in the experimental group after treatment were significantly lower than those in the control group, with a statistically significant difference (P=0.00).After treatment, TNF-a, CRP, IL-6 and other indexes in the experimental group were significantly lower than those in the control group, with statistically significant differences (P=0.00).The incidence of adverse reactions after treatment in the experimental group was 30%, while that in the control group was 22.5%, with no statistically significant difference (P=0.45).
Endometriosis (EMs) refers to ectopic endometrial tissue that occurs outside the uterine cavity.It is a common benign inflammatory disease in women of childbearing age 13 characterized by dysmenorrhea, chronic pelvic pain, and infertility, which seriously affects the quality of life of patients. 14Presently, endometriosis is still unclear in terms of pathogenesis, and there are mainly several theories about it: excessive estrogen biosynthesis, estrogen-dependent inflammation, and insufficient production and action of vitamin A 15 , among which inflammatory factors are the key factors in the occurrence and development of the disease.In past clinical practice, laparoscopic surgery is a commonly used treatment for endometriosis.Despite being a benign disease, it has the biological behavior of malignant tumors. 16Surgery on patients with endometriosis removes only the visible lesions but does not address the underlying cause of the disease.Therefore, such patients can be temporarily relieved of symptoms, but have a high postoperative recurrence rate.The long-term control of endometriosis still relies on drugs, so drug therapy is the first choice for treatment. 17Therefore, how to effectively relieve pain and reduce recurrence has become a clinical research hotspot. 18Ms is an estrogen-dependent disease that if treated with high-dose progesterone alone, the release of pituitary gonadotropin will be inhibited, resulting in a decrease in estrogen levels; On the other hand, progesterone can also directly act on the endometrium and ectopic endometrium to make endometrium atrophy, resulting in high progesterone amenorrhea and endometrium decidualization. 19Studies have shown 20 that progesterone also has a variety of antiinflammatory effects in vitro and in vivo, which inhibit the implantation and growth of the endometrium in the retrograde menstrual blood, and inhibit the expression of matrix metalloproteinases and angiogenesis, thus reducing the inflammatory state caused by the metabolic activity of the ectopic endometrium.It was reported that progesterone treatment of EMs 21 also affects bone metabolism and reduces bone density, but it is far less effective than GnRHa drugs.It has also been shown in a study that dydrogesterone evidently improved the symptoms of pelvic pain caused by EMs. 22ormone therapy for EMs-related pain is only effective in a subset of patients, who often experience recurrence of these symptoms after discontinuation of the drug. 23EMs has been shown to potentially induce a local inflammatory response with the recruitment of macrophages, release of cytokines, and production of reactive oxygen species, resulting in a pro-oxidant peritoneal microenvironment.These changes may be systematically reflected to affect the follicular microenvironment. 24Cycloxygenase (COX), also known as prostaglandin synthetase, is a key enzyme that catalyzes the conversion of arachidonic acid to prostaglandin.Under the activation of various physical, chemical and biological damage factors, phospholipase A2 hydrolyzes cell membrane phospholipids to generate arachidonic acid, which is catalyzed by COX-2 and oxygenated to generate prostaglandins. 25In endometriotic tissues, the expression level of COX-2 is increased. 26Studies have shown that non-steroidal antiinflammatory drugs (NSAIDs) are effective in relieving pain caused by endometriosis 27 , mainly by inhibiting COX-2 and thereby inhibiting prostaglandin synthesis.But at the same time, a variety of adverse reactions may also be caused, such as gastric ulcers, and inhibition of  ovulation when taken in the middle of menstruation.In recent years, an increasing number of studies have been carried out on the use of COX-2-specific inhibitors for the treatment of endometriosis pain.

Treatment of Mild Endometriosis
Limitations: It includes a small number of cases were included, the follow-up time was short, and some other non-steroidal anti-inflammatory drugs such as ibuprofen were not included in the study for analysis.In response to this, more samples will be included in future studies, the follow-up time will be extended, and the research content of other non-steroidal antiinflammatory drugs will be increased.It is hoped that with the help of this type of research, more women will be relieved of pain, and their quality of life and fertility will be improved.

CONCLUSION
Dydrogesterone combined with non-steroidal antiinflammatory drugs is a safe and effective treatment for patients with endometriosis.It boasts various obvious curative effects, such as marked relief of pain symptoms, and reduction of complement and inflammatory factor levels without a significant increase in adverse reactions.

Source of funding:
This studuy is supported by Hebei University Affiliated Hospital Youth Scientific Research Fund Project (No.:2021Q029).
was a clinical comparative study.Eighty patients with mild endometriosis were included at Affiliated Hospital of Hebei University.They were randomly divided experimental group(n=40) and control group(n=40) from March 2022 to March 2023.Patients in the study group were aged 23-57 years, with an average of 37.53±11.42,while those in the control group were aged 22-60 years, with an average of 38.33±12.06.No significant difference was observed in the comparison of general data between the two groups, which were comparable (Table-I).

Table - I
: Comparative analysis of the general data of the experimental group and the control group ( )n=40.

Table -
II: Comparative analysis of clinical efficacy of the two groups ( ) n=40..

Table -
IV: Comparative analysis of changes in inflammatory factors before and after treatment between the two groups ( ) n=40.

Table - V
: Comparative analysis of the incidence of complications between the two groups ( ) n=40.