SUMMARY

The mechanism by which suckling affects the hypothalamo-pituitary-ovarian system was studied in lactating Wistar rats. Unilateral ovariectomy was carried out on day 4 post partum and the subsequent ovarian compensatory hypertrophy (OCH) was assessed on day 14 post partum. The weight of the corpora lutea (CL) of lactation, the CL of pregnancy and of the remainder of the ovary, here termed interstitial tissue, was determined for both ovaries. A clear OCH, mainly due to an increase in interstitial tissue, occurred in rats whose pups were removed on day 4 post partum. Suckling by two pups inhibited OCH, whereas suckling by six or ten pups produced significant ovarian atrophy, these effects being due to a decrease in weight of both interstitial tissue and CL of pregnancy which overcame an increase in weight of the CL of lactation. Inhibition of OCH occurred in spinal-cord transected rats suckling six pups. Suckling was suspended in unilaterally ovariectomized rats nursing ten pups on day 14 post partum, and the weight of the remaining ovary was determined 16, 32, 64 and 96 h later in four groups of rats. The weight of the remaining ovary returned to that of the control ovary 64 h after withdrawal of suckling. This effect was due to an increase in weight of interstitial tissue and of the CL of lactation. Maintenance of suckling for 64 h in rats with the galactophores ligated to prevent milk removal, inhibited OCH. By contrast, both oxytocin injections and exteroceptive stimulation provided by litters failed to block ovarian growth after suckling withdrawal. The results suggest that suckling itself is an important influence in the inhibition of OCH, but that other factors may contribute to the ovarian changes observed during lactation in the rat.

SUMMARY

Milk yield fell in a single rabbit mammary gland within 24 h after the litter had been reduced from six to eight pups to one pup. The diminished secretion lasted 2–3 days, then rebounded to the expected level over the next 1–2 days and thereafter maintained this level. During early to mid-lactation the decrease in milk secretion after reduction of the litter to one pup was prevented either by s.c. injections of prolactin or by s.c. injections of the β-adrenergic blocking drug, propranolol. These results suggest that milk secretion was reduced in the single gland as the result of sympathetic activation, triggered possibly by the turgid state which developed in the remaining glands after the litter was reduced. The results suggest also that the depression of milk secretion by the sympathetic system was due to a reduction in the effective amount of prolactin and probably of other adenohypophysial hormones reaching the mammary secretory cells rather than to an impairment of their release from the anterior pituitary.

The magnitude of the depression and rebound in milk secretion of a single rabbit mammary gland, and the effectiveness of the preventive action of either propranolol or prolactin, was considerably less during late as compared with early to mid-lactation. We postulate from these results that the mammary gland of the rabbit has a functional lability, i.e. responsiveness, which diminishes as lactation progresses and which dictates the extent to which local, neural and humoral factors may alter the milk secretory function of the mammary gland. Since suckling in the rabbit does not change from a once-a-day frequency throughout lactation, a diminishing lability may be an important factor in the decline and cessation of lactation in this species.

Milk yields were measured at 8-h intervals in rabbits during early (days 11–14) and late (days 31–34) lactation. A single injection of 1 mg bromocriptine given to rabbits 30 min before suckling on days 11 or 31 caused a significant reduction in milk yield after approximately 8 h. The depressant effect of the drug was then maintained over the next 24–36 h. Recovery of milk yield occurred in bromocriptine-treated rabbits during both early and late lactation 8-16 h after a single injection of 3 mg prolactin. The recovery accelerated more in the rabbits in the early lactating group. Attainment of the maximal stimulatory effect occurred by 24 h after prolactin injection during both early and late lactation although the improvement in milk yield lasted for a shorter period (8 h compared with 24 h) during late lactation compared with early lactation. These differences in response of the rabbit to prolactin during late lactation may contribute substantially to the declining milk yields characteristic of late lactation in this species.

Endocrine and neuroendocrine tumors comprise a highly heterogeneous group of neoplasms that can arise from (neuro)endocrine cells, either from endocrine glands or from the widespread diffuse neuroendocrine system, and, consequently, are widely distributed throughout the body. Due to their diversity, heterogeneity and limited incidence, studying in detail the molecular and genetic alterations that underlie their development and progression is still a highly elusive task. This, in turn, hinders the discovery of novel therapeutic options for these tumors. To circumvent these limitations, numerous mouse models of endocrine and neuroendocrine tumors have been developed, characterized and used in preclinical, co-clinical (implemented in mouse models and patients simultaneously) and post-clinical studies, for they represent powerful and necessary tools in basic and translational tumor biology research. Indeed, different in vivo mouse models, including cell line-based xenografts (CDXs), patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMs), have been used to delineate the development, progression and behavior of human tumors. Results gained with these in vivo models have facilitated the clinical application in patients of diverse breakthrough discoveries made in this field. Herein, we review the generation, characterization and translatability of the most prominent mouse models of endocrine and neuroendocrine tumors reported to date, as well as the most relevant clinical implications obtained for each endocrine and neuroendocrine tumor type.