European Review for Medical and Pharmacological Sciences 2018; 22: 2502-2512 Vitamin D: a steroid hormone with progesterone-like activity G. MONASTRA1, S. DE GRAZIA2, L. DE LUCA3, S. VITTORIO3, V. UNFER4 1Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy 2Department of Research and Development, Lo.Li. Pharma, Rome, Italy 3Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, Polo Universitario SS. Annunziata, University of Messina, Messina, Italy 4Faculty of Medicine and Psychology, Department of Developmental and Social Psychology, Sapienza University of Rome, Rome, Italy Abstract. – OBJECTIVE: This review is aimed Abbreviations at demonstrating the progesterone-like activity 1,25(OH)2D = 1α,25-dihydroxyvitamin D; 1α-OHase: exerted by the active form of vitamin D, or cal- 1α-hydroxylase; CL = corpus luteum; CRF = corticotro- citriol (1,25(OH)2D). To achieve this outcome, we pin-releasing factor; CSF = colony-stimulating factor; compared the effects in vivo and in vitro exert- CYP24A1 = Cytochrome P450 family 24 subfamily A ed by progesterone and vitamin D, with a spe- member 1; CYP27A1 = Cytochrome P450 Family 27 cial focus on the female reproductive system Subfamily A Member 1; CYP27B1 = Cytochrome P450 and pregnancy. Family 27 Subfamily B Member 1; DBP = vitamin D MATERIALS AND METHODS: This is a litera- Binding Protein; FGF = Fibroblast growth factor; IL = ture review of the most important articles pub- interleukin; TNF-α = tumour necrosis factor alpha; Treg lished in English on vitamin D as a hormone, cells = T regulatory cells; VDR = vitamin D receptor; mainly found by MEDLINE. Furthermore, a sec- VEGF = Vascular endothelial growth factor. tion of our review contains some unpublished data, concerning the analysis in silico of the sim- ilarities between the steric structure of proges- terone and calcitriol, based on the availability of the experimental structures of progesterone and Introduction vitamin D3 receptors in complex with their phys- iological ligands in the RCSB Protein Data Bank. A Story Coming from the Thirties RESULTS: Vitamin D was shown to exert ma- Between the end of sixties and the beginning ny physiological activities during the very ear- ly stages of gestation in perfect synchrony with of seventies some advanced researches and stu- progesterone. Both the molecules mutually help dies brought out to understand much better the and reinforce the activity exerted by each one. A activity of calcitriol or 1,25(OH)2D, two names little bit later than progesterone is released, vita- referred to the active form of vitamin D (in our min D secretion rises, but only if pregnancy oc- paper “vitamin D” will be used with the same curs. Calcitriol contributes to prepare the endo- meaning of them). They offered a wider picture metrium to be receptive. Moreover, it supports of this very intriguing molecule, until then consi- the implantation process and the course of preg- nancy through different but similar pathways to dered only an essential vitamin for bone growth those used by progesterone, giving rise to a sig- and for fighting rickets. In that period vitamin D nificant synergy of action. It is increasingly ev- was defined, for the first time, as a new steroid ident that vitamin D gives an essential support hormone and its chemical structure was characte- from the luteal phase onwards. rized1,2. In 1971 Norman et al3 published a semi- CONCLUSIONS: Based on the evidence dis- nal paper where they stated that “It is possible that played in this review we may define appropriate- ly vitamin D as a steroid hormone with proges- 1,25- dihydroxycholecalciferol should be reclassi- terone-like activity. fied as a steroid hormone. Certainly, its secretion by the kidney followed by its selective accumula- Key Words: tion in the target intestinal mucosa where it exerts Calcitriol, CYP24A1, CYP27A1, CYP27B1, Embryo its characteristic physiological effect on calcium implantation, Inflammation, Osteopontin, Pregnancy, metabolism satisfies the minimal definitions of Progesterone, Progesterone receptor, Vitamin D, Vita- min D receptor. a hormone”. Furthermore, in the same years, its nuclear receptor was identified4,5. Vitamin D 2502 Corresponding Author: Vittorio Unfer, MD; e-mail: [email protected] Vitamin D: a steroid hormone with progesterone-like activity started to be considered a hormone, even thou- photoconversion of 7-dehydrocholesterol and gh many years had to pass before this concept subsequent thermosensitive but noncatalytic iso- became established in the scientific community, merization to cholecalciferol. Then, cholecalci- as stated in 1997 by the Nutritional Committee ferol is hydroxylated by liver mitochondrial and Report for both North America and Europe6. De- microsomal 25-OHase CYP27A1. The resultant spite this and other authoritative opinions and de- 25-hydroxycholecalciferol (calcidiol) is 1α-hyd- clarations7, some scholars still do not accept this roxylated in the kidney by CYP27B1 (a mito- classification8, but they are a minority. It is worth chondrial 1α-OHase). This reaction yields the of note that a couple of decades before the six- secosteroid 1α,25(OH)2D (calcitriol). Therefore, ties, some studies (1934) demonstrated the hor- CYP27A1 and CYP27B1 are key enzymes invol- monal properties exerted by a group of molecules ved in the synthesis of vitamin D, whereas the having the cyclopentanoperhydrophenanthrene inactivating enzyme CYP24A1 determines the ring, with seventeen-carbon tetracyclic hydro- rate-limiting step for calcitriol catabolism12. In carbon. Ovariectomized rats (Wistar strain) were physiologic conditions at least the 80% of this injected with 100 mg of each compound dissolved vitamin is produced by the skin, whereas the re- in sesame oil and the treatment was able to induce maining 20% or less is taken up from dietary estrus in these animals, showing that such effect sources. In areas rich in sunlight, this endoge- is due to the presence of the classic steroid skele- nous production provides enough quantity of ton9. A marked activity was shown by ergosterol vitamin D, at least in healthy young subjects. and its irradiation product calciferol (crystalline However, among people with darker skin, a se- vitamin D), and still greater activity by neo-ergo- vere and widespread deficiency may be found sterol9. Later, Feyel-Cabanes (1949) and Chambon as seen in the US especially among blacks and (1951) highlighted that ergosterol and 7-dehydro- Hispanics13. Moreover, subjects who are obese, cholesterol, administered at non-estrogenic nor have hypertension, low high-density lipoprotein progestogenic doses, act synergically with proge- cholesterol level, do not drink milk daily, are all sterone in sustaining the pregnancy10 or obtaining significantly, independently associated with vi- implantation of ovariectomized rabbits11. These tamin D deficiency13. interesting results were then forgotten. The times Besides the chemical structure, there are other were not yet ripe to go ahead in that direction of very convincing connections between vitamin D research. and the class of (steroid) hormones. These last ones are bound to transport proteins in plasma, howe- Vitamin D and Steroid Hormones ver only the free molecule can spread into its target In fairly recent years, the studies on calci- cells. These hormones are chemical messengers in triol had a revival, even under the impulse of a wide number of species and tissues to transmit the discovery of areas, in developed countries, signals. Obviously, the ability of steroid hormones with deficiency and widespread rickets. Another to give rise to biological message depends on the cause for this renewed interest in the field came presence of their receptors on their specific targets. from the finding that many vitamin D receptors Unlike the growth factors and peptide hormones (VDR) in tissues and cells are not connected which bind only to receptors on cell membrane, with its effects on bone, being linked to other, the fat-soluble steroid hormones can pass through before unknown, benefits for health. Nowa- the lipid bilayer surrounding the cell and interact days, vitamin D and its metabolites, from the also with their related receptors on the cell nucleus, structural point of view, are called secosteroids, inducing a genomic response. The receptor-hor- i.e., compounds whose structure shows the abo- mone complex binds to DNA and triggers or re- ve-cited steroid skeleton with seventeen-carbon presses the transcription of one or more genes14. tetracyclic hydrocarbon, that is not joined at the Furthermore, steroid hormones bind to a variety of level of the bond located in position 9-10 of the receptor types located near or associated with the ring B. Therefore, chemically they are like the plasma membrane15-17. In this way, they activate sy- mineralocorticoids, glucocorticoids, testoste- stems of second messengers, with rapid cellular re- rone, progesterone, estrogens, chorionic gona- sponses that may range from seconds (e.g., opening dotropin. By now, both calcidiol and calcitriol of ion channels) to 10-60 min (e.g., activation of are considered respectively pre-hormone and phosphatidylinositol-3’-kinase or endothelial nitric hormone. Indeed, they are synthetized endoge- oxide synthase). Instead, the genomic responses nously in the skin by means of UVB stimulated commonly need from some hours to days before 2503 G. Monastra, S. De Grazia, L. De Luca, S. Vittorio, V. Unfer becoming entirely manifest; they may be stopped