Autoimmune diseases such as rheumatoid arthritis (RA) and Sjögren syndrome (SS) ameliorate during pregnancy, through dampening (immunotolerance) of the maternal immune system which protects the fetus from rejection. A large number of studies have shown that human chorionic gonadotropin (hCG) contributes to this tolerance. Studies on animal models have reaffirmed that hCG treatment mimics the benefits of pregnancy. Based on the scientific evidence, randomized clinical trials comparing hCG with current therapies and/or placebo are recommended for RA, SS, and for other autoimmune diseases such as, type 1 diabetes and ankylosing spondylitis, which also get better during pregnancy and hCG treatment seems to help.
MikulsTRSaagKG. Comorbidity in rheumatoid arthritis. Rheum Dis Clin North Am. 2001;27(2):283–303.
4.
HelmickCGFelsonDTLawrenceRC. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15–25.
5.
MyasoedovaECrowsonCSKremersHMTherneauTMGabrielSE. Is the incidence of rheumatoid arthritis rising? Results from Olmsted Country, Minnesota, 1955-2007. Arthritis Rheum. 2010;62(6):1576–1582.
6.
WolfeFMitchellDMSibleyJT. The mortality of rheumatoid arthritis. Arthritis Rheum. 1994;37(4):481–494.
GabrielSECrowsonCSCampionMEO’FallonWM. Direct medical costs unique to people with arthritis. J Rheumatol. 1997;24(4):719–725.
9.
GabrielSECrowsonCSCampionMWO’FallonWM. Indirect and nonmedical costs among people with rheumatoid arthritis and osteoarthritis compared with nonarthritic controls. J Rheumatol. 1997;24(1):43–48.
10.
MaetzelALiLCPencharzJTomlinsonGBombardierC. The economic burden associated with osteoarthritis, rheumatoid arthritis, and hypertension: a comparative study. Ann Rheum Dis. 2004;63(4):395–401.
11.
WhitacreCC. Sex differences in autoimmune disease. Nat Immunol. 2001;2(9):777–780.
12.
FritzMCSperoffL. Endocrinology of pregnancy. In: FrtizMCSperoffL, eds. Clinical Gynecologic Endocrinology and Infertility. 8th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011:269–330.
13.
LichtPCaoHLeiZMRaoChVMerzWM. Novel self-regulation of human chorionic gonadotropin biosynthesis in term pregnancy human placenta. Endocrinology. 1993;133(6):3014–3025.
14.
ShiQJLeiZMRaoChVLinJ. Novel role of human chorionic gonadotropin in differentiation of human cytotrophoblasts. Endocrinology. 1993;132(3):1387–1395.
15.
LeiZMRaoCV. Endocrinology of the trophoblast tissue. In: BeckerK, ed. Principles and Practice of Endocrinology and Metabolism. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:1096–1102.
16.
YangMLeiZMRaoChV. The central role of human chorionic gonadotropin in the formation of human placental syncytium. Endocrinology. 2003;144(3):1108–1120.
17.
RaoCV. Nongonadal actions of LH and hCG in reproductive biology and medicine. Sem Reprod Med. 2001;19(1):1–119.
18.
RaoCVLeiZM. The past, present and future of nongonadal LH/hCG actions in reproductive biology and medicine. Mol Cell Endocrinol. 2007;269(1-2):2–8.
19.
RahmanNRaoCV. Recent progress in luteinizing hormone/human chorionic gonadotropin hormone research. Mol Human Reprod. 2009;15(11):703–711.
20.
AbdallahMALeiZMLiX. Human fetal nongonadal tissues contain human chorionic gonadotropin/luteinizing hormone receptors. J Clin Endocrinol Metab. 2004;89(2):952–956.
21.
LinJLojunSLeiZMWuWXPeiperSCRaoChV. Lymphocytes from pregnant women express human chorionic gonadotropin/luteinizing hormone receptor gene. Mol Cell Endocrinol. 1995;111(1):R13–R17.
22.
ZhangYMLeiZMRaoChV. Functional importance of human monocyte luteinizing hormone and chorionic gonadotropin receptors. J Soc Gynecol Invest. 1999;6:Abstract #46.
23.
ZhangYMRaoChVLeiZM. Macrophages in human reproductive tissues contain luteinizing hormone/chorionic gonadotropin receptors. Am J Reprod Immunol. 2003;49(2):93–100.
24.
YoshimuraTInabaMSuguiraK. Analyses of dendritic cell subsets in pregnancy. Am J Reprod Immunol. 2003;50(2):137–145.
25.
TicconiCZicariABelmonteARealacciMRaoChVPiccioneE. Pregnancy-promoting actions of hCG in human myometrium and fetal membranes. Placenta. 2007;28(suppl A):S137–S143.
26.
ZuoJLeiZMRaoChV. Human myometrial chorionic gonadotropin/luteinizing hormone receptors in preterm and term deliveries. J Clin Endocrinol Metab. 1994;79(3):907–911.
27.
AmbrusGRaoChV. Novel regulation of pregnant human myometrial smooth muscle cell gap junctions by human chorionic gonadotropin. Endocrinology. 1994;135(6):2772–2779.
28.
EtaEAmbrusGRaoChV. Direct regulation of human myometrial contractions by human chorionic gonadotropin. J Clin Endocrinol Metab. 1994;79(6):1582–1586.
29.
KurtzmanJTSpinnatoJTGoldsmithLJ. Human chorionic gonadotropin exhibits potent inhibition of preterm delivery in a small animal model. Am J Obstet Gynecol. 1999;181(4):853–857.
30.
KayeMDJonesWR. Effect of human chorionic gonadotropin on in vitro lymphocyte transformation. Am J Obstet Gynecol. 1971;109(7):1029–1031.
31.
JenkinsDMAcresMGPetersJRileyJ. Human chorionic gonadotropin and the fetal allograft. Am J Obstet Gynecol. 1972;114(1):13–15.
32.
AdcockEWIIITeasdaleTAugustCS. Human chorionic gonadotropin: its possible role in maternal lymphocyte suppression. Science. 1973;181(4102):845–847.
33.
HanT.Human chorionic gonadotropin. Its inhibitory effect on cell-mediated immunity in vivo and in vitro. Immunology. 1975;29(3):509–515.
34.
HammarstromLFuchsTSmithCI. The immunodepressive effect of human glycoproteins and their possible role in the nonrejection process during pregnancy. Acta Obstet Gynecol Scand. 1979;58(5):417–422.
35.
FuchsTHammasrtromLSmithCIEBrundinJ. In vitro induction of human suppressor T cells by a chorionic gonadotropin preparation. J Reprod Immunol. 1981;3(2):75–84.
36.
FuchsTHammarstromLSmithCIBrundinJ. Sex-dependent induction of human suppressor T cells by chorionic gonadotropin. J Reprod Immunol. 1982;4(4):185–190.
37.
ReinischNSitteBAKahlerCMWiedermannCJ. Human chorionic gonadotropin: a chemoattractant for human blood monocytes, neutrophils and lymphocytes. J Endocrinol. 1994;142(1):167–170.
38.
Teodorezykj-InjeyanJAKellenJA. Chorionic gonadotropin-induced cell proliferation and polyclonal immunoglobulin synthesis in human mononuclear cells. Biomed Pharmacother. 1988;42(1):49–54.
39.
SchumacherAHeinzeKWitteJ. Human chorionic gonadotropin as a central regulator of pregnancy immune tolerance. J Immunol. 2013;190(6):2650–2658.
40.
Mohamed AliAFFateenBEzzetABadawyHRamadanAEl-tobgeA. Treatment of preterm labor with human chorionic gonadotropin: a new modality. Obstet Gynecol. 2000;95(4-Suppl 1):S61.
41.
KurtzmanJWilsonHRaoChV. A proposed role for hCG in clinical obstetrics. Sem Reprod Med. 2001;19(1):63–68.
42.
TothP. Clinical data supporting the importance of vascular LH/hCG receptors of uterine blood vessels. Sem Reprod Med. 2001;19(1):55–61.
LorzadehNDehnooriAMomennasabM. hCG versus magnesium sulfate in prevention of preterm labor. J Ostet Gynecol Infertil Iran. 2003;2(2):12–19.
45.
TutunaruDVladareanuRIosupD. Therapeutic administration of hCG in pregnant women with preeclamptic risk. Int Congr. 2004;1271:367–371.
46.
LorzadehNDehnooriAMomennasabM. Human chorionic gonadotropin (hCG) versus magnesium sulfate to arrest preterm. Yafteh. 2004;5(3):41–46.
47.
TicconiCPiccioneEBelmonteARaoCh V. HCG—a new kid on the block in the prematurity prevention. J Matern Fetal Neonatal Med. 2006;19(11):687–692.
48.
SakhavarNMirteimooriMTeimooriB. Magnesium sulfate versus hCG (human chorionic gonadotropin) in suppression of preterm labor. Shiraz E-Med J. 2008;9(3):134–140.
49.
JarvelaIYTapanainenJSMartikainenH. Improved pregnancy rate with administration of hCG after intrauterine insemination: a pilot study. Reprod Biol Endocrinol. 2010;8:18.
50.
NorrisWNeversTSharmaSKalkunteS. Review: hCG, preeclampsia and regulatory T cells. Placenta. 2011;32(suppl 2):S182–S185.
51.
MansourRTawabNKamalO. Intrauterine injection of human chorionic gonadotropin before embryo transfer significantly improves the implantation and pregnancy rates in in vitro fertilization/intracytoplasmic sperm injection: a prospective randomized study. Fertil Steril. 2011;96(6):1370–1374.
52.
RaniVUReddyAMSinghAMalathiP. Role of hCG in preventing preterm labour in comparison with vaginal progesterone. Indian Pract. 2012;65:1–6.
53.
RacicotKEWunscheVAuerbachBAldoPSilasiMMorG. Human chorionic gonadotropin enhances trophoblast–epithelial interaction in an in vitro model of human implantation. Reprod Sci. 2014;21(10):1274–1280.
54.
SantibanezAGarciaJPashkovaO. Effect of intrauterine injection of human chorionic gonadotropin before embryo transfer on clinical pregnancy rates from in vitro fertilization cycles: a prospective study. Reprod Biol Endocrinol. 2014;12:9.
55.
PersellinRH. The effect of pregnancy on rheumatoid arthritis. Bull Rheum Dis. 1976;27(9):922–927.
56.
HazesJMWDijkmansBACVandenbrouckeJPde VriesRRPCatsA. Pregnancy and the risk of developing rheumatoid arthritis. Arthritis Rheum. 1990;33(12):1770–1775.
57.
Da SilvaJASpectorTD. The role of pregnancy in the course and aetiology of rheumatoid arthritis. Clin Rheumatol. 1992;11(2):189–194.
58.
NelsonJLHughesKASmithAGNisperosBBBranchaudAMHansenJA. Maternal–fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis. N Engl J Med. 1993;329(7):466–471.
59.
WilderRL. Hormones, pregnancy, and autoimmune diseases. Ann N Y Acad Sci. 1998;840:45–50.
60.
KaajaRJGreerIA. Manifestations of chronic disease during pregnancy. J Am Med Assoc. 2005;294(21):2751–2757.
61.
SilmanAKayABrennanP. Timing of pregnancy in relation to the onset of rheumatoid arthritis. Arthritis Rheum. 1992;35(2):152–155.
62.
TsampalasMGrideletVBerndtSFoidartJ-MGeenenVd’HauteriveSP. Human chorionic gonadotropin: a hormone with immunological and angiogenic properties. J Reprod Immunol. 2010;85(1):93–98.
63.
SongXYZengLJinWPiloCMFrankMEWahlSM. Suppression of streptococcal cell wall-induced arthritis by human chorionic gonadotropin. Arthritis Rheum. 2000;43(9):2064–2072.
64.
LiNShigiharaTTzioufasAGNotkinsALYoonJWJunHS. Human chorionic gonadotropin prevents Sjogren’s syndrome-like exocrinopathy in mice. Arthritis Rheum. 2007;56(7):2211–2215.
65.
KayisliUASelamBGuzeloglu-KayisliODemirRAriciA. Human chorionic gonadotropin contributes to maternal immunotolerance and endometrial apoptosis by regulating Fas-Fas ligand system. J Immunol. 2003;171(5):2305–2313.
66.
WanHVersnelMACheungWY. Chorionic gonadotropin can enhance innate immunity by stimulating macrophage function. J Leukocyt Biol. 2007;82(4):926–933.
67.
SherwinJRSharkeyAMCameoP. Identification of novel genes regulated by chorionic gonadotropin in baboon endometrium during the window of implantation. Endocrinology. 2007;148(2):618–626.
68.
LeiZMYangMLiXTakikawaORaoChV. Upregulation of placental indoleamine 2,3-dioxygenase by human chorionic gonadotropin. Biol Reprod. 2007;76(4):639–644.
69.
UenoAChoSChengL. Transient upregulation of IDO in dendritic cells by human chorionic gonadotropin downregulates autoimmune diabetes. Diabetes. 2007;56(6):1686–1693.
70.
MunnDHZhouMAttwoodJT. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281(5380):1191–1193.
71.
DongMDingGZhouJWangHZhaoYHuangH. The effect of trophoblasts on T lymphocytes: possible regulatory effector molecules—a proteomic analysis. Cell Physiol Biochem. 2008;21(5-6):463–472.
72.
KoldehoffMKatzorkeTWisbrunNC. Modulating impact of human chorionic gonadotropin hormone on the maturation and function of hematopoietic cells. J Leukoc Biol. 2011;90(5):1017–1026.
73.
SchumacherABrachwitzNSohrS. Human chorionic gonadotropin attracts regulatory T cells into the fetal–maternal interface during early human pregnancy. J Immunol. 2009;182(9):5488–5497.
74.
RolleLTehranMMMorell-GarciaA. Cutting edge: IL-10-producing regulatory B cells in early human pregnancy. Am J Reprod Immunol. 2013;70(6):448–453.
75.
MuzzioDZygmuntMJensenF. The role of pregnancy-associated hormones in the development and function of regulatory B cells. Front Endocrinol. 2014;5:39.
76.
WanHVersnelMALeijtenLME. Chorionic gonadotropin induces dendritic cells to express a tolerogenic phenotype. J Leukocyt Biol. 2008;83(4):894–901.
WeiQOuyangYZengWDuanLGeJLiaoH. Pregnancy complicating systemic lupus erythematosus: a series of 86 cases. Arch Gynecol Obstet. 2011;284(5):1067–1071.
79.
Tapia-SerranoRJimenez-BalderasFJMurrietaSBravo-GarciaCGuerraRMintzG. Testicular function in active ankylosing spondylitis: therapeutic response to human chorionic gonadotropin. J Rheumatol. 1991;18(6):841–848.
80.
JunHSKhilLYKwonHKimSYoonJWNotkinsALYooJK. Human choriogonadotropin can prevent autoimmune diabetes in NOD mice. Diabetologia. 2007;50(10):2147–2155.
81.
KhanNAKhanASavelkoulHFBennerR. Inhibition of diabetes in NOD mice by human pregnancy factor. Hum Immunol. 2001;62(12):1315–1323.
82.
KhilLYJunHSKwonH. Human chorionic gonadotropin is an immune modulator and can prevent autoimmune diabetes in NOD mice. Diabetologia. 2007;50(10):2147–2155.
83.
LinJLeiZMLojunSRaoChVSatyaswaroopPGDayTGJr. Increased expression of luteinizing hormone/human chorionic gonadotropin receptor gene in human endometrial carcinomas. J Clin Endocrinol Metab. 1994;79(5):1483–1491.
84.
KonishiIKoshiyamaMMandaiM. Increased expression of LH/hCG receptors in endometrial hyperplasia and carcinoma in anovulatory women. Gynecol Oncol. 1997;65(2):273–280.
85.
MandaiMKonishiIKurodaH. Messenger ribonucleic acid expression of LH/hCG receptor gene in human ovarian carcinomas. Eur J Cancer. 1997;33(9):1501–1507.
86.
CasadesusGMillikenELWebberKM. Declines in cognitive performance are associated with increased luteinizing hormone levels in mice. Mol Cell Endocrinol. 2007;269(1-2):107–111
87.
LinJLiXYuanFP. Genetic ablation of luteinizing hormone receptor improves the amyloid pathology in a mouse model of Alzheimer disease. J Neuropathol Exp Neurol. 2010;69(3):253–261.
88.
ArcangeliANociIFortunatoAScarselliGF. The LH/hCG axis in endometrial cancer: A new target in the treatment of recurrent or metastatic disease. Obstet Gynecol Int. 2010;2010:1–5.
89.
CuiJMinerBMEldredgeJB. Regulation of gene expression in ovarian cancer cells by luteinizing hormone receptor expression and activation. BMC Cancer. 2011;11:280.
