Placental Growth Hormone-Related Proteins and Prolactin-Related Proteins D. Haig * Department of Organismic and Evolutionary Biology, Harvard University, 26 Oxford Street, Cambridge, MA 02138, USA Accepted 26 September 2007 Abstract The placentas of ruminants and muroid rodents express prolactin (PRL)-related genes whereas the placentas of anthropoid primates express growth hormone (GH)-related genes. The evolution of placental expression is associated with accelerated evolution of the corresponding pitu- itary hormone and destabilization of conserved endocrine systems. In particular, placental hormones often evolve novel interactions with new receptors. The adaptive functions of some placental hormones may be revealed only under conditions of physiological stress. Ó 2007 Published by IFPA and Elsevier Ltd. Keywords: GH; PRL; Placenta; Endometrial glands; Placental lactogen 1. Introduction Placental hormones are produced by offspring, but act on receptors of mothers. As such, placental hormones and mater- nal receptors are prime candidates for the expression of parent- offspring conflict [1,2]. The placenta is selected to secrete hormones into the mother’s circulation only if the hormones modify maternal physiology in ways that benefit the fetus, but maternal responses evolve to maximize maternal fitness. This paper will examine the actions of two ancient vertebrate hor- mones, and of placental versions of these hormones that have evolved independently in at least three groups of mammals. Growth hormone (GH) and prolactin (PRL) are structur- ally-related molecules with structurally-related receptors (GHR and PRLR). GH and PRL exhibit highly divergent rates of molecular evolution in different mammalian lineages. In most mammals, these hormones are evolutionarily conserva- tive, with a slow rate of amino acid substitutions. But, in at least three lineages d anthropoid primates, muroid rodents, and ruminants d either GH, PRL, or both have undergone greatly accelerated evolutionary change. And, in all three lineages, GH-derived or PRL-derived genes are expressed in the placenta and signal via maternal GHRs or PRLRs. The accelerated evolution of GH and PRL in these lineages may reflect ongoing maternal-fetal conflict. 2. Growth hormone and prolactin Growth hormone was so named because extracts from bo- vine pituitaries accelerated growth when administered to rats. But, the name may mislead as much as it informs: mammals continue to produce GH after they have reached adult size; ex- ogenous GH suppresses rather than enhances growth in poultry [3]; and fasting elevates GH, but reduces growth, in teleost fishes [4]. In humans, basal GH is increased in kwashiorkor, marasmus, anorexia nervosa, and fasting. Growth and starva- tion are both situations in which a lipid-rich body would benefit from conserving amino acids rather than using them as sub- strates for gluconeogenesis. The primary function of GH may be to shift the body’s fuel preference from glucose to lipids [5]. Prolactin was so named because pituitary extracts induced lactation in mammals and production of ‘crop-milk’ in pi- geons [6]. PRL also stimulates secretion of ‘uterine milk’ by the endometrium of rabbits and pigs [7,8], and PRLRs are present on endometrial glands of women, baboons, and sheep * Tel.: þ1 617 496 5125; fax: þ1 617 495 5667. E-mail address: dhaig@oeb.harvard.edu 0143-4004/$ - see front matter Ó 2007 Published by IFPA and Elsevier Ltd. doi:10.1016/j.placenta.2007.09.010 Available online at www.sciencedirect.com Placenta 29, Supplement A, Trophoblast Research, Vol. 22 (2008) S36eS41