Editorial: large lessons from little lactotropes.

In this issue of Endocrinology, Turgeon et al. (1) report on the localization of nuclear progestin receptors (PRs) in the pituitary of wild-type and PR knockout (PRKO) mice from the C57/6/129sv hybrid strain. To everyone’s astonishment and unlike any other previously examined species including monkey, rat, and chicken (2–5), the wild-type mice exhibited nuclear PRs in both gonadotropes and lactotropes after E treatment. No one has ever seen PR in a pituitary lactotrope before, but no one has ever looked in the mouse pituitary either. In questioning whether the mouse pituitary is like the rat pituitary, this paper highlights the “assume nothing” approach to research with genetic knockout mouse models. This issue is likely to be confronted repeatedly as we seek to confirm physiological and pharmacological observations made in other species with those made in knockout mice, but there are several other messages to take home from this observation that go beyond the actual data. Characterization of the cell biology and physiology of the mouse has become increasingly important due to the advent of transgenic and gene knockout mice as animal models. The Turgeon and Waring laboratory has been working on the functional consequences of PR activation in rat pituitary gonadotropes, particularly related to cross-talk with GnRH receptor signaling. Thus, the availability of a PRKO mouse could allow novel extensions in this line of investigation such as teasing out pathway components, both upstream and downstream, of PR activation. With due caution however, this study questioned whether the absence of PR (from conception) would affect the developmental sequelae in the pituitary and alter the proportion of gonadotropes in the PRKO pituitary. In addition, the critical, but basic (and often overlooked) question of whether the mouse gonadotropes resembled the rat gonadotropes with respect to PR localization and induction by E was addressed. The answers to these questions were encouraging for these investigators. That is, the phenotypic distribution of the different cell types were similar between the wild-type and the PRKO mouse. The percentages of the different pituitary cell types are similar to those observed in the rat as well (6). And, yes, E induced PR in gonadotropes in mice in the same manner as in rats. The big surprise emerged from the observation that there was a large number of other cells that contained E-induced PR; these cells turned out to be predominantly lactotropes. Why is this such a surprise? Perhaps a bit of history is called for. From early physiological experiments, Rothchild deduced that ovarian progesterone stimulated PRL secretion in rats (7). The development of RIAs for rat and human PRL (8, 9) led to the characterization of PRL secretion during the menstrual (10) and estrous cycles (11), during pregnancy (10, 12), pseudopregnancy (13), lactation (14, 15), and in steroid replacement models (16, 17). From these and other studies, it was accepted that PRL secretion in the rat is stimulated by E (18); that PRL did not vary significantly across the human menstrual cycle (10), but that PRL increased during gestation in humans along with the greatly elevated serum concentrations of E and progesterone from the placenta (19). The increase in PRL during human gestation was initially attributed to E until the studies of Williams et al. (20). Using nonhuman primates, the Hodgen laboratory showed that E treatment alone had little effect on PRL secretion, but addition of progesterone to the E regimen significantly stimulated PRL secretion. Subsequently, studies using more frequent sampling reported higher serum PRL concentrations during the progesterone-dominated luteal phase than in the Edominated follicular phase of the human menstrual cycle (21–23). In rats, it was further demonstrated that progesterone administration could initiate, maintain, and prolong secretion of the two daily surges of PRL that characterize pseudopregnancy, the extended luteal phase of the rat (24, 25). Moreover, progesterone administration advances the proestrous surge of PRL (11) and progesterone enhances the magnitude of an E-induced proestrous-like surge of PRL in ovariectomized rats (26). Thus, the conclusion that progesterone stimulates PRL secretion was warranted. We began to question whether progesterone acted directly at the level of the pituitary or if it acted in the hypothalamus to increase PRL secretion. At the time, it was generally accepted that E ubiquitously induced PR and then progesterone treatment decreased levels of both ER and PR. Because it was also well accepted that receptors are needed to mediate ligand-driven biological actions, it did not follow that progesterone could stimulate PRL secretion in a continuous fashion if it also eliminated its cognate receptor (as observed in the uterus). Studies of monkey pituitary cells in culture revealed that lactotropes contain ER and they respond to E with an increase in PRL secretion, but they do not contain nuclear PR (2, 27). Only gonadotropes (LHand FSH-producing cells) contained PR, and E treatment of cultures from long-term ovariectomized macaques directly increased the number of gonadotropes with PR (28). The same phenotypic distribution of PR was reported for the in vivo monkey pituitary (3), rat pituitary (4), and chicken pituitary (5). Hence, from 1988 until this paper, it has been widely concluded that the action of progesterone on PRL secretion is not due to an action at the level of the pituitary lactotrope. Rather, progesterone acts largely through PR in the central nervous system in rats and monkeys to increase pituitary PRL secretion although paracrine influence from neighboring gonadotropes is also present (29). Moreover, PR expression in the primate diencephalon is not severely down-regulated by progesterone in chronic paradigms as it is in the uterus (30, 31). Thus, the receptor remains present in the brain to transduce the action of the hormone. Abbreviations: PR, Progestin receptor; PRKO, PR knockout. 0013-7227/01/$03.00/0 Endocrinology 142(10):4170–4172 Printed in U.S.A. Copyright © 2001 by The Endocrine Society