Long-Term Treatment with Bromocriptine Inhibits Endometrial Adenocarcinoma Development in Rats

Abstract

Abstract. The effects of long-term blockade of prolactin (PRL) action by bromocriptine (BRC) treatment on uterine carcinogenesis and on related ovarian physiology were investigated using a rat uterine cancer model. Ten-week-old cycling female Donryu rats, a high yield strain for uterine corpus tumors (endometrial adenocarcinomas), were treated with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG), as a tumor initiator, and injected with 1 mg/kg body weight BRC subcutaneously 4 times per week until 14.5 months of age to block the proestrus PRL surge. The study was terminated at 15 months of age, and the results showed that long-term BRC treatment significantly inhibited endometrial adenocarcinoma development in terms of both incidence (34.6% to 13.0% with significant difference at 5%) and multiplicity (0.35 to 0.18 with significant difference at 5%), which indicates the number of adenocarcinomas per animals. While BRC did not affect estrous cyclicity in the treated animals, a significant decline was evident in the serum 17β-estradiol (E2) to progesterone (P) ratio (E: P ratio), and the serum E2 level showed a decreased tendency at 15 months of age. While the precise pathway to the inhibitory effect could not be determined; the pathway by which ovarian hormonal imbalance decreases the serum E: P ratio most likely plays a crucial role. Key words: Bromocripchne, Long-term treatment, Prolactin blockade, Rat, Uteirne carcinogenesis (J. Reprod. Dev. 55: [105][106][107][108][109] 2009) varian steroidhormone imbalance contributes to uterine carcinogenesis in human beings [1]. Maekawa et al. [2][3][4] have provided evidence that a similar imbalance, especially elevated 17β-estradiol (E2) levels relative to progesterone (P) levels (the E:P ratio), plays a crucial role in promoting endometrial adenocarcinoma development in rodents. While it is well-established that E2 and estrogenic chemicals play supportive or sometimes initiative roles in uterine carcinogenesis in rats as well as women, P may exert an inhibitory influence on human uterine cancer development [5][6][7]. However, the effects of other hormones related to the pituitary or ovaries on uterine carcinogenesis are not well known.Prolactin (PRL) is one of the important regulators of the corpus luteum as well as luteinizing hormone (LH), prostaglandin and vascular endothelial growth factors and platelet derived growth factors in rats [8][9][10]. The function of PRL as a luteotrophic and luteolytic hormone, however, is very complex [11][12][13][14][15][16][17]. Repeated injection of PRL has been shown to stimulate rapid regression of the persistent corpus luteum, with a concomitant decline in total steroidogenic capacity [12,18]. These studies indicate the possibility that the modulation of P production induced by PRL or its inhibitor affect uterine carcinogenesis through ovarian hormonal imbalance. On the other hand, PRL receptors, especially long-form ones (PRLR-L) [19], are present in the uteri of rats. PRL is known to play important roles in adenomyosis formation in ...

Effects of sulpiride and ethylene glycol monomethyl ether on endometrial carcinogenicity in Donryu rats

“…Examination of the long‐term effects of sulpiride or EGME on uterine carcinogenicity was performed modifying the Donryu rat initiation–promotion assay model for uterine corpus cancer (Ando‐Lu et al, ; Yoshida et al, ). Briefly, at 10 weeks of age, all female pups were administered a single dose of 20 mg kg −1 ENNG into the uterine horn using a stainless steel catheter via the vagina.…”

“…Aged Donryu rats exhibit a high incidence of spontaneous uterine endometrial adenocarcinomas, which are similar to human cases as follows: (1) multistep development of uterine lesions from atypical hyperplasias to adenocarcinomas; (2) ovarian hormonal imbalance, in particular, elevation of the serum E 2 level relative to P4; and (3) morphologic similarities to endometrioid adenocarcinomas in humans (Maekawa et al, ). Thus, Donryu rats are a useful model for assessing endometrial adenocarcinoma in the corpus in women, particularly for endometrioid adenocarcinoma (Yoshida et al, ).…”

Modeling Endometrial Cancer: Past, Present, and Future

“…Donryu rats have been historically used for the investigation of EC etiology and they helped to elucidate that hormonal imbalance, more specifically an increased estrogen:progesterone (E:P) ratio, can be linked to EC development [76,77]. Yoshida et al and Kojima et al showed that compounds decreasing the E:P ratio, such as bromocriptine and indole-3-carbinole, have a protective effect against EC [77,78], while compounds increasing the E:P ratio have the opposite effect.…”

“…Yoshida et al and Kojima et al showed that compounds decreasing the E:P ratio, such as bromocriptine and indole-3-carbinole, have a protective effect against EC [77,78], while compounds increasing the E:P ratio have the opposite effect. These observations explain why neonatal exposure to a high dose of the estrogenic compound p-t-octylphenol increases the likelihood of EC development [79].…”

Inhibition of Oestradiol‐induced Prolactin Release in a Dual‐Cannulated Ovariectomized Rat Model by Carmoxirole, a Peripherally Restricted Dopamine Agonist

“…GBR12909), have been shown clinically to reduce prolactin levels and induce central‐mediated side effects such as nausea, vomiting, headache and hallucination . D2 receptor agonists, such as bromocriptine, are the treatment of choice for the majority of patients suffering from hyperprolactinaemia and prolactinoma; if given chronically, these agents can increase incidences of prolactin‐sensitive tumours in rats , but not in human beings .…”