Primate mammary development. Effects of hypophysectomy, prolactin inhibition, and growth hormone administration.

Abstract

The pituitary gland has been found to be an important factor in mammary development in primates. Hypophysectomy in 12 sexually immature monkeys caused significant inhibition of estradiol (E2)-induced mammary growth and development. A histological index of mammary development in sexually immature hypophysectomized animals was lower (0.82) than in intact E2-treated controls (3.4; P < 0.008). Hypophysectomy also inhibited growth of the mammary gland as judged by a size index. Despite the hypophysectomy, E2 stimulated some, albeit blunted, mammary growth and development, which may have been due to incomplete hypophysectomy.Selective inhibition of prolactin by ergot drugs in intact animals did not prevent full mammary development, suggesting that there may be pituitary mammogens other than prolactin, or that very low or unmeasurable concentrations of prolactin were sufficient to synergize with E2 to cause full acinar development. The mean histological index was 3.08 in E2-treated animals and 3.16 in animals treated with E2 plus pergolide. There was also no difference in the size of the glands.We evaluated the effect of growth hormone on mammary development by treating three hypophysectomized animals with pure 22,000 mol wt human growth hormone (hGH) (Genentech, Inc., South San Francisco, CA). We found that physiological or slightly supraphysiological concentrations of hGH in animals with unmeasurable prolactin were incapable of restoring the capacity of E2 to induce full mammary growth. These findings suggest that, if growth hormone is a mammary mitogen, that physiological concentrations are insufficient to synergize with E2 to induce full mammary growth or that other forms of hGH are mammogenic.Our studies suggest that the role of the pituitary gland in mammary mitogenesis in primates is more complicated than previously thought. They also raise the possibility that heretofore unidentified pituitary substances may be mammogenic.

Evidence for a nonprolactin, non-growth-hormone mammary mitogen in the human pituitary gland.

“…Subsequently, Silastic capsules providing follicular-phase levels of E2 were implanted subcutaneously (5). Mean weekly E2 concentrations in serum were 141.5 ± 10.9 pg/ml.…”

“…Although prolactin (PRL) has been assumed to be the principal mammogenic pituitary hormone, a number of indirect lines of experimental evidence have placed in doubt the role of PRL in mammary mitogenesis, inferentially supporting the possibility that the pituitary may contain other mammogenic factors (1)(2)(3)(4)(5)(6).…”

“…In recent experiments, we observed that mammary growth and development in primates occurred in the absence of PRL (5). In prepubertal monkeys, treatment with follicular-phase levels of estradiol (E2) for 2 months caused full mammary development, whereas in hypophysectomized monkeys, E2 was ineffective.…”

Mammary development

“…Triply-operated rodents require administration of oestrogen intact non-pregnant animals. In sexually immature monkeys, hypophysectomy inhibits the growth and development of the mammary gland stimulated by oestradiol, but neither prolactin nor G H was confidently identified as the pituitary factor involved (Kleinberg et al 1985). Some of the hormonal activities involved in mammary development may originate in the placenta in pregnant females.…”

Intact and amino-terminally shortened forms of insulin-like growth factor I induce mammary gland differentiation and development.

“…We found that lactogenic as well as nonlactogenic forms of GH are far more potent than PRLs from the same species in inducing mammary development in assays employing hypophysectomized, castrated, and estradiol (E2)-treated, sexually immature rats (12). Moreover, mammary development was not impaired in rhesus monkeys in which PRL secretion was maximally inhibited (13). In recent experiments, we also found that only those naturally occurring or mutant lactogens or somatogens that avidly bind to GH receptors in rat liver are potent inducers of the initial mammary differentiation and development (14).…”