BioEssays Vol. 4, No. 2 65 REVIEW ARTICLES antithrombin I11 gene and an immunoglobu- 21 BARSH,G. S., SEEBURG,P. H. &GELINAS, 26 ROBINS,D. M., PAEK,I., SEEBURG,P. H. lin light-chain gene enhancer. Nature 316, R. E. (1983). The human growth hormone & AXEL,R. (1982). Regulated expression of 845-848. gene family: structure and evolution of the human growth hormone genes in mouse 16 ROGERS, B. L., SOBNOSKY,M. G. & chromosomal locus. Nucl. Acidr Res. 11, cells. Cell 29, 623-631. SAUNDERS,G. F. (1985). Transcriptional 3939-3958. 27 MOORE,D. D., MARKS,A. R., BUCKLEY, enhancer within the human placental lacto- 22 KIDD,V. J. & SAUNDERS,G. F. (1982). D. I., KAPLEO,G., PAYVAR,F. & GOODMAN, gen and growth hormone multigene cluster. Linkage arrangement of human placental H. M. (1985). The first intron of the human J. Biol. Chem. (in press). lactogen and growth hormone genes. J. Biol. growth hormone gene contains a binding site 17 PICARD,D. & SCHAFFNER,W. (1984). A Chem. 257, 10673-10680. for glucocorticoid receptor. Proc. Natl. lymphocyte-specific enhancer in the mouse 23 BARRERA-SALDANA,H. A., SEEBURG, Acad. Sci. USA 82, 699-702. immunoglobulin gene. Nature 307, 80-82. P. H. & SAUNDERS, G. F. (1983). Two 28 ROGERS, B. L., WHITE,J., SOBNOSKY, 18 EPHRUSSI,A., CHURCH,G. M., TON- structurally different genes produce the same M. G. & SAUNDERS,G. F. Characterization EGAWA, S. & GILBERT,W. (1985). Science secreted human placental lactogen hormone. and sequence of the human placental 227, 134-140. J. Biol. Chem. 258,3787-3793. lactogen enhancer. J. Biol. Chem. (in 19 CHANDLER,V. L., MALER, B. A. & 24 SELVANAYAGAM,C. S., TSAI,S. Y., TSAI, preparation). YAMAMOTO,K. R. (1983). DNA sequences M.-J., SELVANAYAGAM,P. & SAUNDERS, bound specifically by glucocorticoid receptor G. F. (1984). Multiple origins of transcrip- in oitro render a heterologous promoter tion for the human placental lactogen genes. I I hormone responsive in uivo. Cell 33, J. Biol. Chem. 259, 14642-14646. BRUCE L ROGERS and GRADY F. 48-99. 25 SPINDLER, S. R., MELLON, S. H. & SAUNDERS are in the Department of 20 BARRERA-SALDANA,H. A., ROBBERSON, BAXTER,J. D. (1982). Growth hormone gene Biochemistry and Molecular Biology, D. L. & SAUNDERS,G. F. (1 982). Transcrip- transcription is regulated by thyroid and University of Texas M. D. Anderson tional products of the human placental glucocorticoid hormones in cultured rat Hospital and Tumor Institute, Houston, lactogen gene. J. Biol. Chem. 257, pituitary tumor cells. J. Biol. Chem 257, Texas 77030, USA. 12399-12404. 11627-1 1632. I I

Newly Discovered Activities for Calcitriol (I ,25=-Dihydroxyvitamin D,) : Implications for Future Pharmacological Use Robert U. Simpson and Ronald Weishaar

gene transcription and the translation of Summary Introduction mRNA. Initially, investigators exten- Recent studies have yielded new insights Studies of the function and endocrin- sively characterized a specific receptor into the critical importance of adequate ology of vitamin D, over the last 80 for 1,25dihydroxyvitaminD3in intestine vitamin D, intake and metabolism. years have elucidated the role of this and bone. Recently, calcitriol receptors Investigations of the actions of 1,25- prohormone in regulating calcium and have been characterized in tissues not dihydroxyvitamin D, (calcitriol) on novel phosphate concentrations in blood. originallyrecognized ascalcitriol respon- target tissues has revealed that this During this period, great increases in ~ive.l-~Subsequent in vivo and in vitro hormone has functions other than its our understanding of the significance of studies have to some extent corroborated recognized action in regulating blood vitamin D have taken place. First the receptor studies and demonstrated pre- calcium and phosphate levels. Reports identification of the antirachitic factor viously unappreciated functions for have characterized calcitriol receptors and its importance in controlling blood calcitriol. Current data now suggest that and activities in organs and tissues as calcium and phosphate levels was a 1,25-dihydroxyvitamin D, affects the diverse as pancreas, skeletal and heart major insight in basic physiology and functioning of organ systems that are muscle, blood cells, brain, skin, pituitary, had important therapeutic application. not directly responsible for regulation of parathyroid, kidney, bone and intestine. Secondly, studies on the metabolism of blood calcium and phosphate. We refer These studies suggest functions for vitamin D led to the identification of the to excellent reviews on the vitamin D calcitriol as varied as the regulation of hormone, 1,25-dihydroxyvitaminD, or system as sources of reference for much insulin and prolactin secretion, muscle calcitriol. This discovery resulted in the of the discussion in this text.4” It is the contractility, immune cell metabolism, rationale for clinical use of calcitriol in intention of this report to review the melanin synthesis and diferentiation of renal disease and increased our under- recent studies and summarize the in- blood cells. This information may ulti- standing of the basic mechanisms and formation that pertains to our expanded mately help us to understand the etiologies action of this steroid hormone. The view of calcitriol for health. Our inten- of several kinds of organ dysfunction and expression of vitamin D action is now tion is also to suggest future possible lead to the development of tissue-specific known to involve the functioning of pharmacologically important uses for agents for new therapies. intracellular receptors, the regulation of the vitamin D hormone. 66 BioEssays Vol. 4, No. 2 REVIEW ARTICLES vitamin D, metabolites and synthetic Regulation of Vitamin D3 vitamin D analogueshave been described Metabolism in detail by Stern6 Vitamin D, + Pre-vitamin D + 7-keto-cholesterol The observation that a time lag exists To date, no compound has been iden- between vitamin D, administration in tified which exerts a classic antagonist viuo and changes in bone and intes- effect (high-affinity binding, no intrinsic tinal metabolism, together with the activity) on the intracellular vitamin D finding that vitamin D, lacks activity receptor. However, a number of agents in vitro, suggested that vitamin D, have been shown to impair calcitriol required bioactivation to produce its synthesis and may, therefore, be con- effects. Subsequent studies established sidered to ‘antagonize’ the response to that a metabolite of vitamin D,, 1,25- vitamin D,. Such agents include inhibi- 25(OH) vitamin D3 dihydroxyvitamin D, (calcitriol), is the 25(OH) vitamin D3 v tors of 25-hydroxylase such as 24-nor- functionally active form of the vita- 25-hydroxy vitamin D,, which also lacks min, and that its metabolism is tightly intrinsic vitamin D receptor ‘agonist’ controlled. a~tivity.*-~Several metabolites of vita- The bioactivation of vitamin D, can min D, have been shown to inhibit 1- be influenced by a number of factors, a-hydroxylase activity; however, these including serum calcium and phosphate metabolites also possessed intrinsic re- levels, calcitriol itself, parathyroid hor- ceptor ‘agonist’ a~tivity.~-~ mone, estradiol and prolactin. Circula- Fig. 1. Organs involved in metabolism of vitamin D. ting levels of calcitriol are increased in response to reductions in serum levels of I ntest ine calcium and phosphate. This response is chronically via oral administration, 25 Our greatest understanding of the apparently mediated in part by para- hydroxyvitamin D, is more effective mechanism of action of calcitriol on thyroid hormone, since it has been than calcitriol for maintaining serum subcellularprocesses comes from studies shown that parathyroid hormone exerts calcium and in promoting bone miner- of its effects on the intestine. Vitamin D, a direct stimulatory effect on l-a- alization. These observations likely acting via its metabolite, calcitriol, hydroxylase activity.’ In addition, para- indicate that calcitriol is subject to rapid stimulates Ca2+ transport from the thyroidectomy has been shown to blunt inactivation or elimination; an im- lumen of the intestine through the cell the increase in circulating calcitriol portant consideration when attempting and into the blood. Along with the levels observed during lactation in to develop useful therapeutic agents intestinal transport of Ca2+, calcitriol rat^.^-^ Estradiol and prolactin also which act as ‘vitamin D agonists’. In stimulates the transport of PO,2- from stimulate the bioactivation of calcitriol, this regard, it has been shown that intestinal lumen to blo~d.~-~It is now and the dopamine agonist bromo- fluorination of calcitriol to produce recognized that calcitriol induces the cryptine - which decreases prolactin 24,24-difluoro-calcitriol increased the synthesis of a cytosolic CaBP.l0 This secretion - has been shown to lower biopotency and serum half-life of this action most likely does not account for plasma levels of calcitriol in rat^.^-^ analogue.*It has also been reported that all the processes activated by calcitriol Organs involved in regulating 1,25- 1-fluoro-vitaminD, possesses a selective and required for calcium transport dihydroxyvitamin D, metabolism in stimulatory effect on bone calcium across the intestinal epithelia. There- vivo are illustrated in Fig. 1. mobilization, compared to intestinal fore, many studieshave concerned them- calcium tran~port.~ selves with identifying other proteins or A number of analogs of calcitriol Pharmacokinetics, factors that are synthesized in intestine have been evaluated for biological Structure-Activity Relationships and under the control of calcitriol. For activity and/or therapeutic utility. and ’Vitamin D Receptor example, a membrane-bound calcium- Several recent studies have employed Agonists and Antagonist’ binding protein complex possessing competitive binding experiments to phosphatase activity has been reported Vitamin D, can enter the circulation in identify structural features which en- to be under the direct control of vitamin two ways. In the skin, ultraviolet light hance the activity of various vitamin D, D.” A different mechanism of action - catalyzes the conversion of 7-keto- congeners as calcitriol receptor agonists. alteration of membrane phospholipid cholesterol to pre-vitamin D,, which For such studies the ability of these composition - for calcitriol has been then thermally equilibrates to vitamin congeners to compete with [3H]calcitriol supported by Rasmussen and co- D,. Vitamin D, is also readily absorbed for binding sites on the intracellular workers.12 These data suggest that the from the small intestine. Vitamin D, and receptor binding protein is evaluated. activity of calcitriol might not be its metabolites are transported in the Such experiments have demonstrated explained entirely by the activation of circulation bound to a 52,000 molecular that the 1-a-OH group contributes nuclear transcription of specific genes. weight protein which has been termed substantially to the potency of vitamin Clearly, much work remains to be done the serum vitamin D binding D,. Activity is also enhanced consider- before a clear understanding of how Like vitamin D,, calcitriol is also ably by the presence of a 25-OH group, calcitriol affects intestinal cell processes orally active, and absorption occurs in with calcitriol being 100 to 1,000-fold is reached. the proximal portion of the small more potent than la-hydroxyvitamin intestine. The absorption of calcitriol D,. The presence of two adjacent appears to require complex formation hydroxyl groups, e.g. 1,24R-25-tri- Osteoporosis with bile salts, and such absorption can hydroxyvitamin D,, impairs interaction Vitamin D-dependent rickets was cured be impaired by biliary cirrhosis. Studies with the vitamin D receptor, and lowers with the therapeutic application of the have demonstrated that when given potency. Structural considerations for anti-ricket factor vitamin D. Recently, it BioEssays Vol. 4, No. 2 67 REVIEW ARTICLES was also shown that calcitriol is of great ever, these in viuo studies could not Recent discoveries Well- therapeutic use in treatment of such eliminate the possible secondary action and documented diseasesasrenalosteodystrophy, vitamin of other renal active agents to elicit speculative effects effects D-resistant rickets due to an inborn these effects. In spite of this, calcitriol error of vitamin D metabolism, and receptors have been demonstrated in certain hypoparathyroid disorder^.^" distal renal tubule cells, cultured kidney Osteoporosis is an age-related disorder cells and kidney h~mogenates.~-~ Parathyroid that affects over 15 million persons in Further evidence that calcitriol has a Blood cells the United States. The bone wasting direct effect on kidney functions comes associated with this disease suggests the in the data showing that a specific possible therapeutic usefulness of calci- vitamin D-dependent calcium-binding trio1 for the treatment of osteoporosis. protein is present in kidney tubule cells. Initial clinical studies focused on the action of the prohormone, vitamin D, on postmenopausal osteopor~sis.~~Vitamin D and Skeletal Muscle These studies did not demonstrate a Several authors have suggested a poten- therapeutic use of vitamin D for tial role for vitamin D in the regulation Skin \ I\ treatment of osteoporosis. It has been of skeletal muscle contractile function. I argued that use of vitamin D for the Such involvement is based upon the treatment of postmenopausal osteo- observation that vitamin D deficiency is porosis has not been effective due to associated with skeletal muscle myo- decreased metabolism of vitamin D to pathy and muscle fibre atrophy, condi- the active metabolite calcitriol in the tions which are reversible upon adminis- aged.14 Analysis of serum calcitriol tration of vitamin D or its metab01ites.l~ Fig. 2. Target tissues for calcitriol. supports this contention, showing that In addition, Curry et al. have shown postmenopausal women have a signifi- that the rate of calcium uptake by skele- cant decrease in serum calcitriol levels. tal muscle sarcoplasmic reticulum isola- Studies using 0.25 pg calcitriol showed ted from vitamin D-deficient rabbits Vitamin D and Cardiac Muscle that calcitriol was ineffective in treating is significantly reduced compared with It has been known for many years that this disease.15 Others, however, using that of sarcoplasmic reticulum isolated administration of pharmacological higher concentrations of calcitriol, have from normal rabbits.'* This reduction quantities of vitamin D can produce demonstrated significant improvement is apparently not related to any change myocardial failure, presumably due to of bone parameters in osteoporetic in the ATPase activity of the sarco- hypercalcemia and calcification of car- patients.I6 Further clinical testing of plasmic reticulum. We reported that diac muscle. Such hypercalcemia can calcitriol for the treatment of postmeno- receptors for calcitriol exist in skeletal persist for months following discon- pausal osteoporosis is on-going and muscle myoblasts and at significantly tinuation of vitamin D administration. essential for establishing the therapeutic lower concentrations in excised muscle Furthermore, vitamin D has been usefulness of calcitriol. tissue.lg Others have demonstrated that reported to alter the ultra-structure of calcitriol stimulated calcium transport cardiac muscle endoplasmic in cultured muscle myoblasts.20A pos- Kidney A physiological role for vitamin D in sible dihydroxyvitamin 1,25D, specific influencing myocardial calcium homeo- A major action of calcitriol is to regu- effect on muscle myoblasts is currently stasis has been suggested by the recent late renal 25-hydroxyvitamin D,-l-a- being studied in our laboratory. observation of Simpson et al. that hydroxylase (la(0H)ase). It has been In a recent study, Wassner and cardiac cells grown in culture contain a shown that calcitriol brings about a co-workers reported that weight gain specific receptor for ~alcitriol.~,This suppression of la(0H)ase concomitant and skeletal muscle mass were reduced receptor has also been identified in with an increase in 25-hydroxyvitamin in vitamin D-deficient rats, and that whole left ventricular muscle from D3-24-hydroxylase (24(OH)ase). These myofibrillar protein degradation was adult rats. In addition, Thomassett observations have been supported by in increased.21 According to the authors, and co-workers have shown that the vivo and in vitro This action these changes were associated with the 10K vitamin Ddependent calcium- of calcitriol is analogous to the action of onset of hypocalcemia and could be binding protein, but not the 28K other steroid hormones to effect a reversed by the addition of vitamin D to calcium binding protein, is present in rat feedback inhibition of their synthesis. the diet or by feeding the vitamin heart muscle.24 The relevance of this The feedback inhibition of la(0H)ase is D-deficient rats diets that contained latter observation is not known at the dependent on blood calcium concentra- sufficient quantities of calcium to restore present time. tions since it has been observed that circulating calcium to normal levels. Receptors for calcitriol have also calcitriol will, in fact, stimulate its own Thus, although vitamin D repletion been identified in uterine muscle.25 synthesis in hypocalcemic animals. leads to improved muscle protein ana- Possible actions of calcitriol on renal bolism and an increase in skeletal Cancer Cells calcium and phosphate handling are not muscle mass and weight gain, these at present fully characterized. Studies effects have yet to be proved to be a The initial observation that cancer cells have shown that vitamin D increases result of the direct action of vitamin D possess calcitriol receptors was that of renal retention of calcium. Also, it has or a vitamin D-derived metabolite on Eisman and collaborators.2e Since this been shown that vitamin D increases skeletal muscle. report, a number of malignant tumors renal absorption of phosphate. How- and cell lines have been characterized as 68 BioEssays Vol. 4, No. 2 REVIEW ARTICLES possessing calcitriol receptors. Further- melanin synthesis in B16 mouse mela- tions imply a physiological role for more, calcitriol has been shown to noma cells.31This stimulatory effect was vitamin D in modulating calcium inhibit proliferation of breast and apparently the result of an increase in metabolism in the pancreas, and indicate melanoma cell lines and to initiate the activity of tyrosinase, a key enzyme that vitamin D may exert an influence terminal differentiation of myeloid involved in regulating melanin synthesis. on insulin secretion as well. However, leukemia cells.27 According to the authors, since pig- vitamin D deficiency also leads to de- Possible clinical usefulness of calci- mentation of the skin prevents the creased food intake and hypocalcemia. triol for control of certain malignant penetration of sunlight to the dermis, The direct action of calcitriol on insulin cancers was supported by studies that stimulation of melanin synthesis by secretion therefore remains to be firmly correlated 1,25-dihydroxyvitamin D, calcitriol may represent a negative feed- established. receptor concentrations and potency back mechanism for suppressing the of supra-physiological levels of 1,25- conversion of pre-vitamin D, to Parathyroid dihydroxyvitamin D, action to inhibit vitamin D,. cancer cell proliferation.28 Further- The existence of a brain-pituitary axis There is in vivo and in vitro evidence to more, it has been shown that survival for calcitriol effects was suggested by support a direct action of calcitriol in time of mice injected with leukemia cells autoradiographic studies of Stumpf et regulating secretion of parathyroid hor- was greater in animals dosed with calci- al.32Specific localization of [3H]calcitriol mone (PTH) from the parathyroid triol than control mice.29Obvious dis- in neurons of rat forebrain, hindbrain gland. Evidence has been presented advantages are present in the use of and spinal cord was demonstrated. showing that a calcitriol receptor exists calcitriol for control of endocrine-as- Receptors have also been identified for in excised parathyroid tissue from avian sociated malignancies. Hypercalcemia calcitriol in ovaries and testes; however and mammalian species.34Furthermore, and bone wasting induced by this agent no clear functional role for calcitriol in immunochemical vitamin D-dependent would be prevalent side-effects. How- these tissues has as yet been CaBP have been localized to the ever, the use of calcitriol in concert identified.1-3.33 parathyr~id.~~Functional studies have with hypocalcemic agents (e.g. diphos- suggested that calcitriol in normal calcemia can suppress the secretion of phonates, glucocorticoids) may prove Exocrine Function of Calcitriol useful. Future development of vitamin PTH. However, in vitro studies designed D analogs that possess cancer-inhibitory The presence of calcitriol receptors in to demonstrate a direct action of activities but are devoid of calcium- parathyroid, pancreas, testes, ovaries calcitriol on parathyroid tissue have mobilizing actions may permit thera- and pituitary has raised the possibility yielded ambiguous data. It has been peutic application of calcitriol. of a direct action of this hormone in the shown that calcitriol inhibited, stimu- The observations that calcitriol recep- regulation of hormone synthesis and lated or had no effect on release of PTH tors exist in leukemia cells and that secretion. We will review the data from parathyroid cells dosed in vitro (for calcitriol stimulates differentiation of presented to support a functional role of review see ref. 3). These discrepancies these cells into mature monocytes calcitriol in exocrine cell processes. in results might be explained by the suggests that the hormone may be nutritional status of tested animals or in terms of the in vitro incubation con- involved in the regulation of monocyte Pancreas differentiation. Recently, this work has ditions for PTH release. Recent studies, been extended to show that calcitriol Recent studies have provided evidence however, do support an in uiuo role stimulates the aggregation of precursor that vitamin D plays a role in regulating for calcitriol in regulation of PTH cells into poly-nuclear osteoclastic-like pancreatic metabolism. Such an involve- secretion^.^' cells. This process was suggested as a ment is supported by several obserya- possible mechanism for calcitriol- tions, including the presence of a Pituitary induced osteoclastic bone reabsorption. receptor for calcitriol in the pancreas, Receptors for calcitriol have also been and of a vitamin D-dependent calcium- Pituitary cells have been shown to characterized in activated T cells.30 binding protein (CaBP).34-35Kadowaki possess specific calcitriol receptors and Therefore, a function for calcitriol in the and Norman have shown that the pan- the vitamin D-dependent calcium- immune response may exist. creatic CaBP is homologous with the binding protein.l*34 It has recently been intestinal CaBP.5 In addition, changes shown that calcitriol has a specific and in dietary calcium and phosphorus, as selective action to increase prolactin Skin, Brain and Sex Tissue well as changes in circulating levels of synthesis and secretion from pituitary Calcitriol receptors have been demon- calcitriol, produce comparable changes cells.38This has been shown measuring strated in mammary and skin in pancreatic and intestinal CaBP levels the peptide and specific mRNAs A possible role of calcitriol in calcium (for review see ref. 5). for prolactin. The effect of 1,25-dihy- handling by skin, sweat glands and In 1980, Norman and co-workers droxyvitamin D, on prolactin mRNA mammary glands is suggested. However, demonstrated that vitamin D deficiency synthesis was diminished in low- little data on hormone action have been inhibited insulin secretion from the calcium-containing media. These find- presented. An increase in 7-dehydro- perfused pancreas, whereas vitamin D ings demonstrate that calcitriol stimu- cholesterol levels in skin due to calcitriol repletion improved insulin ~ecretion.,~ lates prolactin gene expression and that has been identified. This suggests that An involvement of vitamin D with calcium is involved in this expression. calcitriol may have a feedback-inhibi- insulin secretion is also implicated by In addition, autoradiography and im- tory action on the synthesis of vitamin the observation that although pancreatic munohistochemistry techniques have D, in skin (see ref. 3 for review). levels of CaBP are low compared with provided evidence that calcitriol specifi- Recently, Hosoi et al. demonstrated levels in the intestine or the kidney, cally localizes in those cells that that calcitriol exerted a time- and pancreatic CaBP is present exclusively secrete thyroid-stimulating hormone.39 dose-dependent stimulatory effect on in the B-cek5 Together these observa- These data indirectly suggest that calci- BioEssays Vol. 4, No. 2 69 REVIEW ARTICLES triol may modulate thyroid hormone 2 COLSTON,K., HIRST,M. & FELDMAN,D. 17 SCHOT,G. D. & WILLIS,M. R. (1976). secretion. (1980). Organ distribution of the cytoplasmic Muscle weakness in osteomalacia. Lancet 1, The presence of receptors for calcitriol 1,25dihydroxycholecalciferol receptor in 626-629. in exocrine tissues suggests a functional various mouse tissues. Endocrinology 107, 18 CURRY,0. B., BASTEN,J. F., FRANCIS, role for calcitriol in endocrine-controlled 1916-1 920. M. J. &SMITH,R. (1974). Calcium uptake by processes. However, with the exception 3 FRANCESCHI,R.T., SIMPSON,R.U. & sarcoplasmic reticulum of muscle from DELUCA,H. F. (1982). Binding proteins for vitamin D deficient rabbits. Nature 249, of the action of calcitriol on PTH vitamin D metabolites: serum carriers and 83-84. secretion,aclear picture of the regulation intracellular receptors. Arch. Biochem. Bio- 19 SIMPSON,R. U., THOMAS,G. A. & of hormone secretion by calcitriol phys. 210, 1-13. ARNOLD,A. J. (1985). Identification of 1,25 remains to be established, and further 4 DELUCA,H. F. & SCHNOES,H. K. (1983). dihydroxyvitamin D, receptors and activities studies are required to translate in vitro Vitamin D: recent advances. Annu. Rev. in muscle. J. Biol, Chem. 270, 8882. observations of calcitriol secretory con- Biochem. 52,411439. 20 GIULIANI, D. L. & BOLAND, R.L. trol to in viva relevance. 5 NORMAN,A. W., ROTH,J. & ORCI, L. (1984). Effects of vitamin D, metabolites on (1982). The vitamin D endocrine system. calcium fluxes in intact chicken muscle and Endocr. Rev. 3, 331-366. myoblasts cultured in vitro. Calcg Tissue Conclusions 6 STERN,P. H. (1980). The D vitamins and Inr. 36,20&205. bone. Pharmacol. Rev. 32,47-80. 21 WASSNER,S. J., LI, J. B., SPERDUTO,A. During the last two decades the im- 7 FRASHER,D. R., KODICEK,E. (1973). & NORMAN, M. E. (1983). 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Human Choriogonadotropin David Puett

Summary hCG exhibits LH-like effects and is corpus luteum and stimulation of prog- responsible for maintenance of the esterone production during the first 6-8 Human choriogonadotropin, a hormone derived from the syncytiotrophoblast cells of the placenta, is a member of the glycoprotein hormone family which also contains the pituitary hormones lutropin, follitropin and thyrotropin. These four hormones are comprised of two dissimilar + subunits, one (a)being common to allfour and the other (J) conferring hormonal specificity. Information is rapidly accum- ulating on rhe nature and regulation of the genes for these subunits, as well as the structural aspects, mechanism-of-action and physiological roles of these complex (Y P 4 (hCG) hormones. This mini review considers some of the recent advances in our understanding of human choriogonado- M, (PI 10.2 K 15.5 K 25.7 K tropin.

M, (C) 4.3 K 6.7 K 11.0 K The Glycoprotein Hormones There are four characterized members of the human (h) glycoprotein hormone 22.2 K family :choriogonadotropin (CG, gener- M, (t) 14.5 K 36.7 K ally designated as hCG), lutropin (LH, luteinizing hormone), follitropin (FSH, follicle-stimulating hormone) and thyro- No. of Res 92 145 237 tropin (TSH, thyroid-stimulating hor- mone). hCG is a product of the syn- NO.of S-S 5 6 11 cytiotrophoblast cells of the placenta, 2 2 4 and the other hormones are synthes- NO. of N-l ized in and secreted by specific cell types NO. of 0-1 0 4 4 of the adenohypophysis (i.e. the anterior lobe of the pituitary). There has also Fig. 1. Schematic representation of the reversible formation of hCG from the constituent subunits; the Kd is about 0.1 p~.The a subunit is common to the four human glycoprotein hormones, and the p subunit been a suggestion of an hCG-like confers hormonal specificity. Characteristics of the a and p subunits and the ap dimer are provided. Mr(P), material in human pituitary, and hCG Mr(C) and M,(t) denote the respective molecular weights (K = kilodaltons) of the polypeptide portion, and subunits are secreted by certain the carbohydrate (CHO)portions (the subunits are heterogenous, and the values given are averages) and tumors. Each hormone contains a com- the total (i.e.polypeptide plus carbohydrate). The number of amino acid residues (Res), disulfides (S-S), N-linked oligosaccharides (N-c) and 0-linked oligosaccharides (0-0are also given. The disulfide pairings mon a subunit and hormone-specific are controversial, but there is general agreement of disulfide bonh between half-cystines 7-31 and 1&32 B subunit; only the a/3 complex (Fig. 1) in the a-subunit and between 23-72,26110 and 93-100 in the$ subunit. Additional information is provided exhibits significant biological activity. in refs. 4-6.