This trial has a randomized, single-blind, single-center, parallel-controlled design, with participant screening and trial implementation conducted at Guangdong Provincial People's Hospital. The study evaluate the efficacy of oral magnesium L-threonate supplementation on improving menopausal symptoms and quality of life among peri/post-menopausal women.

This trial aims to explore whether oral magnesium L-threonate supplementation could alleviate menopausal syndromes.

Participants will randomly assigned to conduct oral magnesium L-threonate supplementation or placebo for 8 weeks. Face-to-face and internet follow up will be conducted once per 2 weeks.

The peri-menopausal period is a crucial transitional stage for women from middle age to old age. During this period, there is a dramatic and continuous decline in estrogen levels in women's bodies. The rapid change in estrogen levels triggers a series of complex physiological and pathological changes, leading to many clinical symptoms in perimenopausal women. The menopausal syndrome encompasses osteoporosis and joint-muscle pain, hot flashes and night sweats in terms of vasomotor symptoms, mood swings and memory loss, etc. It greatly troubles women physically and mentally and affects their daily lives. Currently, the main treatment methods for menopausal syndrome include hormone replacement therapy (HRT) and selective serotonin reuptake inhibitors (SSRI). However, both of these treatment methods are accompanied by significant side effects. Hormone replacement therapy may increase the risk of diseases such as breast cancer, endometrial cancer, and venous thrombosis. Therefore, there is an urgent need to explore safe and effective new therapies to improve the health of perimenopausal women.

Magnesium ions, as important cations in the human body, play an indispensable role in maintaining the normal physiological functions of the body. In perimenopausal women, due to the decrease in estrogen levels, the level of magnesium is greatly decreased. Magnesium deficiency not only aggravates the symptoms of menopausal syndrome but also may increase the risk of chronic diseases such as cardiovascular diseases and osteoporosis.

However, traditional magnesium supplements, such as magnesium sulfate and magnesium oxide, have obvious limitations in practical applications. After oral administration, traditional magnesium supplements cannot effectively increase the intracellular magnesium concentration, and cannot cross the blood-brain barrier and are difficult to act on the nervous system to improve pain, hot flashes, and other menopausal symptoms.

Magnesium L - threonate is a new magnesium supplement with unique advantages. It is an oral preparation that can effectively supplement intracellular magnesium. Its greatest feature is that it can smoothly cross the blood-brain barrier and directly act on the central nervous system. Although it has been proven to be relatively safe, currently, the randomized controlled trials related to magnesium L - threonate have only confirmed its improvement effects on pain and cognitive function [23,24], and the research on its effect on improving overall menopausal symptoms is rare.

This study aims to deeply explore whether magnesium L-threonate can effectively improve the menopausal symptoms of perimenopausal women and improve their quality of life.

Participants will be randomly divided into an intervention group and a control group, and medications are administered according to the following protocols:

Intervention group: Magnesium L-threonate, 1740 mg, taken orally, twice a day, for 8 weeks.

Control group: Placebo of magnesium L-threonate, 1740 mg, taken orally, twice a day, for 8 weeks.

The face-to-face questionnaire surveys, physical examinations, and biological sample collections will be conducted during the study screening period and at the end of the study (8 weeks completed) ± 1 day. The online questionnaire surveys will be carried out on the 3rd week ± 1 day, 5th week ± 1 day, and 7th week ± 1 day of the intervention period.

Inclusion Criteria:

1. Women aged 40-60 years;
2. Postmenopausal status or in the late menopausal transition stage. 3. Postmenopausal status is defined as: natural menopause with no menstruation in the past 12 months. The late menopausal transition stage will be defined as: amenorrhea for at least 60 days within the past 12 months;

4. MRS score ≥15 points based on symptoms in the past 1 month; 5. Willing to complete the required follow-up visits during the trial period. 6. Voluntarily sign the informed consent form.

Exclusion Criteria:

1. History of bilateral oophorectomy or hysterectomy;
2. Current or past use of magnesium L-threonate preparations or similar nutrient formulations within the last 3 months;
3. Definite history of gastrointestinal diseases that may affect the absorption of the investigational drug;
4. Definite history of liver diseases that may affect the metabolism of the investigational drug;
5. Definite history of kidney diseases that may affect the excretion of the investigational drug, with serum creatinine levels > 2 mg/dL (88.4 μmol/L);
6. Current or recent use of hormone replacement therapy: vaginal or transdermal estrogen within the past 4 weeks; oral estrogen or progesterone within the past 8 weeks; intrauterine progesterone therapy within the past 8 weeks; progesterone implants or estrogen injection therapy within the past 3 months; estrogen pellet therapy or progesterone injection therapy within the past 6 months; or intention to use these medications during the intervention period;
7. Current or past use of medications such as clonidine, methyldopa, gabapentin, pregabalin, and selective serotonin or norepinephrine reuptake inhibitors (SSRIs/SNRIs) within the past 1 month, or intention to use these medications during the intervention period;
8. Current or past use of phosphodiesterase inhibitor medications within the past 1 month, or intention to use these medications during the intervention period;
9. Autoimmune diseases requiring medication, current or past treatment with glucocorticoids, antirheumatic drugs, or biologics within the past 6 months, or intention to use these medications during the intervention period;
10. Depression or anxiety requiring medication, current or past use of antidepressants within the past 3 months, or intention to use these medications or treatments during the intervention period;
11. Current or past use of hypnotic medications such as diazepam or triazolam within the past 2 weeks, or intention to use these medications during the intervention period;
12. Osteoarthritis, osteoporosis, or other musculoskeletal diseases requiring medication;
13. Known allergy to magnesium L-threonate;
14. History of malignancy, or life expectancy less than 1 year;
15. Major surgery within the past 6 months, or intention to undergo surgery during the intervention period, including but not limited to cardiac surgery or joint replacement;
16. Currently pregnant, having given birth within the past 3 months, planning pregnancy during the study period, or unwilling to use conventional barrier contraception or abstain from sexual activity to prevent pregnancy if not fully menopausal;
17. Currently breastfeeding, having breastfed within the past 3 months, or planning to breastfeed during the study period;
18. Unable or unwilling to provide informed consent, complete questionnaires, or attend study visits;
19. Participation in other interventional studies;
20. Other conditions judged by the investigator as unsuitable for trial participation. These conditions may make potential participants highly unlikely to adhere to the study protocol, including plans to relocate, substance abuse, severe psychiatric issues, or severe dementia.