Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
Sci-tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, China.
BMC Complement Med Ther. 2022 Oct 13;22(1):268. doi: 10.1186/s12906-022-03739-2.
The WHO recommends artemisinin-based combination regimens for uncomplicated Plasmodium falciparum malaria. One such combination is artemisinin-piperaquine tablets (ATQ). ATQ has outstanding advantages in anti-malarial, such as good efficacy, fewer side effects, easy promotion and application in deprived regions. However, the data about the reproductive and endocrine toxicity of ATQ remains insufficient. Thus, we assessed the potential effects of ATQ and its individual components artemisinin (ART) and piperaquine (PQ) on the reproductive and endocrine systems in Wistar rats.
The unfertilized female rats were intragastric administrated with ATQ (20, 40, and 80 mg/kg), PQ (15, 30, and 60 mg/kg), ART (2.5, 5, and 10 mg/kg), or water (control) for 14 days, respectively. The estrous cycle and serum levels of estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), prostaglandin (PG), and adrenocorticotropic hormone (ACTH) were determined. The weights of the kidney, adrenal gland, uterus, and ovaries were measured. The histopathological examinations of the adrenal gland, ovary, uterus, and mammary gland were performed.
Compared with the control group, there were no significant differences in the examined items of female rats in the ART groups, including general observation, estrous cycle, hormonal level, organ weight, and histopathological examination. The estrous cycle of female rats was disrupted within 4-7 days after ATQ or PQ administration, and then in a persistent dioestrus phase. At the end of administration, ATQ and PQ at three doses induced decreased PG, increased ACTH, increased adrenal weight and size, and pathological lesions in the adrenal gland and ovary, including vasodilation and hyperemia in the adrenal cortex and medulla as well as hyperplasia and vacuolar degeneration, ovarian corpus luteum surface hyperemia, numerous but small corpus luteum, and disordered follicle development. But the serum levels of E2, FSH, LH, and PRL did not change obviously. These adverse effects in ATQ or PQ treated rats could not completely disappear after 21 days of recovery.
Based on the results of this study, ART had no obvious reproductive and endocrine effects on female rats, while ATQ and PQ caused adrenal hyperplasia, increased ACTH, decreased PG, blocked estrus, corpus luteum surface hyperemia, and disrupted follicle development in female rats. These events suggest that ATQ and PQ may interfere with the female reproductive and endocrine systems, potentially reducing fertility.
世界卫生组织推荐青蒿素类复方疗法治疗无并发症的恶性疟原虫疟疾。其中一种复方药物是青蒿琥酯-哌喹片（ATQ）。ATQ 在抗疟方面具有显著优势，如疗效好、副作用少、在贫困地区易于推广和应用。然而，关于 ATQ 及其单体成分青蒿素（ART）和哌喹（PQ）对生殖和内分泌系统的生殖和内分泌毒性的数据仍然不足。因此，我们评估了 ATQ 及其单体成分青蒿素（ART）和哌喹（PQ）对 Wistar 大鼠生殖和内分泌系统的潜在影响。
未受精卵的雌性大鼠分别灌胃给予 ATQ（20、40 和 80mg/kg）、PQ（15、30 和 60mg/kg）、ART（2.5、5 和 10mg/kg）或水（对照）14 天。测定动情周期和血清雌二醇（E2）、卵泡刺激素（FSH）、黄体生成素（LH）、催乳素（PRL）、前列腺素（PG）和促肾上腺皮质激素（ACTH）水平。测量肾脏、肾上腺、子宫和卵巢的重量。对肾上腺、卵巢、子宫和乳腺进行组织病理学检查。
与对照组相比，ART 组雌性大鼠的一般观察、动情周期、激素水平、器官重量和组织病理学检查均无显著差异。ATQ 或 PQ 给药后 4-7 天，雌性大鼠的动情周期紊乱，然后进入持续的间情期。给药结束时，ATQ 和 PQ 在三个剂量下诱导 PG 降低、ACTH 增加、肾上腺重量和大小增加以及肾上腺和卵巢的病理损伤，包括肾上腺皮质和髓质的血管扩张和充血、以及增生和空泡变性、卵巢黄体表面充血、黄体数量多但体积小、卵泡发育紊乱。但血清 E2、FSH、LH 和 PRL 水平无明显变化。ATQ 或 PQ 治疗大鼠的这些不良反应在 21 天恢复期后并未完全消失。
根据本研究结果，ART 对雌性大鼠的生殖和内分泌系统无明显影响，而 ATQ 和 PQ 可导致雌性大鼠肾上腺增生、ACTH 增加、PG 减少、动情周期阻断、黄体表面充血、卵泡发育紊乱。这些事件表明，ATQ 和 PQ 可能干扰女性生殖和内分泌系统，潜在降低生育能力。
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