The Retardation of Myometrial Infiltration, Reduction of Uterine Contractility, and Alleviation of Generalized Hyperalgesia in Mice With Induced Adenomyosis by Levo-Tetrahydropalmatine (l-THP) and Andrographolide

Abstract

Adenomyosis is a tough disease to manage nonsurgically. Levo-tetrahydropalmatine (l-THP), a known analgesic, and andrographolide, a nuclear factor kappa B (NF-κB) inhibitor, are both active ingredients extracted from Chinese medicinal herbs. We sought to determine whether treatment of l-THP, andrographolide, and valproic acid (VPA) would suppress the myometrial infiltration, improve pain behavior, and reduce uterine contractility in a mice model of adenomyosis. Adenomyosis was induced in 55 female ICR mice neonatally dosed with tamoxifen, while another 8 (group C) were dosed with solvent only. Starting from 4 weeks after birth, hotplate test was administrated to all mice every 4 weeks. At the 16th week, all mice with induced adenomyosis were randomly divided into 6 groups, each receiving different treatment for 3 weeks: low- or high-dose l-THP, andrographolide, low-dose l-THP and andrographolide jointly, VPA, and untreated. Group C received no treatment. After treatment, the hotplate test was administered and all mice were killed. The depth of myometrial infiltration of ectopic endometrium and uterine contractility were measured and compared across groups. We found that induction of adenomyosis resulted in progressive generalized hyperalgesia, along with elevated amplitude and irregularity of uterine contractions. Treatment with either l-THP, andrographolide, VPA, or l-THP and andrographolide jointly suppressed myometrial infiltration, improved generalized hyperalgesia, and reduced the amplitude and irregularity of uterine contractions. These results suggest that increased uterine contractility, in the form of increased contractile amplitude and irregularity, may contribute to dysmenorrhea in women with adenomyosis. More importantly, l-THP, andrographolide, and VPA all seem to be promising compounds for treating adenomyosis.

Epigallocatechin-3-Gallate Reduces Myometrial Infiltration, Uterine Hyperactivity, and Stress Levels and Alleviates Generalized Hyperalgesia in Mice Induced With Adenomyosis

“…Starting from 4 weeks after birth, hot plate test was administered to all mice every 4 weeks, as described previously. 9,13 At the 16th week after birth, all mice dosed with tamoxifen were randomly divided into 3 groups of roughly equal size, each group receiving a different treatment by daily intraperitoneal administration for 3 weeks: group L (n ¼ 9) received a low-dose (5 mg/kg body weight) EGCG treatment; group H (n ¼ 10) received a high-dose (50 mg/kg body weight) EGCG treatment; and group U (n ¼ 9), the untreated group, received the vehicle only. The mice in group C received no treatment at all and served as a blank control.…”

“…Following Parrott et al, 11,12 and as reported previously, 9,13 adenomyosis was induced by orally dosing female neonatal mice with 1 mg/kg tamoxifen suspended in peanut oil/ lecithin/condensed milk mixture (2:0.2:3, by volume) at a dose volume of 5 mL/g body weight from day 2 to day 5 after birth. Female control neonatal mice, selected randomly, were similarly fed with the same amount of solvent, without tamoxifen.…”

“…9,13 If endometrial glands and stroma were seen to be infiltrated into the myometrium, adenomyosis was diagnosed.…”

“…9 Briefly, grade 1 was defined as the penetration of the ectopic endometrium into superficial myometrium; grade 2, the penetration into mid-myometrium; and grade 3, the penetration beyond mid-myometrium. For ease of statistical analysis, grade 0 was recorded when there was a complete absence of any ectopic endometrium in the myometrium.…”

“…Remarkably, it shares many similarities with endometriosis in terms of estrogen dependency, progesterone resistance, symptomology, and many molecular aberrations. 9 Similar to endometriosis, our current knowledge of the mechanisms underlying adenomyosis-caused pain is still woefully inadequate. As a result, treatment of adenomyosis has been a challenge, 10 with hysterectomy being the treatment of choice for severe adenomyosis.…”