Semin Reprod Med 2012; 30(05): 374-381
DOI: 10.1055/s-0032-1324720
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Steroidogenic Factor-1 and Human Disease

Ranna El-Khairi
1   Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, University College London, London, United Kingdom
John C. Achermann
1   Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, University College London, London, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
08 October 2012 (online)


Steroidogenic factor-1 (SF-1) (Ad4BP, NR5A1) is a nuclear receptor that plays a key role in adrenal and reproductive development and function. Deletion of the gene encoding Sf-1 (Nr5a1) in mice results in severe developmental defects of the adrenal gland and gonad. Consequently, initial work on the potential effects of SF-1 disruption in humans focused on individuals with primary adrenal failure, a 46,XY karyotype, complete gonadal dysgenesis, and Müllerian structures. This is a rare phenotype, but has been reported on two occasions, because of alterations that affect key DNA-binding domains of SF-1. Attention then turned to a potential wider role of SF-1 in human adrenal and reproductive disorders. Although changes in SF-1 only very rarely cause isolated adrenal failure, it is emerging that variations in SF-1 are a surprisingly frequent cause of reproductive dysfunction in humans. In 46,XY disorders of sex development, a spectrum of phenotypes has been reported including severe and partial forms of gonadal (testicular) dysgenesis, hypospadias, anorchia with microphallus, and even male factor infertility. In 46,XX females, alterations in SF-1 are associated with primary ovarian insufficiency. Thus, SF-1 seems be a more significant factor in human reproductive health than was first envisioned, with implications for adults as well as children.

  • References

  • 1 Rice DA, Mouw AR, Bogerd AM, Parker KL. A shared promoter element regulates the expression of three steroidogenic enzymes. Mol Endocrinol 1991; 5 (10) 1552-1561
  • 2 Lala DS, Rice DA, Parker KL. Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I. Mol Endocrinol 1992; 6 (8) 1249-1258
  • 3 Morohashi K, Honda S, Inomata Y, Handa H, Omura T. A common trans-acting factor, Ad4-binding protein, to the promoters of steroidogenic P-450s. J Biol Chem 1992; 267 (25) 17913-17919
  • 4 Parker KL, Schimmer BP. Steroidogenic factor 1: a key determinant of endocrine development and function. Endocr Rev 1997; 18 (3) 361-377
  • 5 Lin L, Achermann JC. Steroidogenic factor-1 (SF-1, Ad4BP, NR5A1) and disorders of testis development. Sex Dev 2008; 2 (4–5) 200-209
  • 6 Schimmer BP, White PC. Minireview: steroidogenic factor 1: its roles in differentiation, development, and disease. Mol Endocrinol 2010; 24 (7) 1322-1337
  • 7 Luo X, Ikeda Y, Parker KL. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 1994; 77 (4) 481-490
  • 8 Sadovsky Y, Crawford PA, Woodson KG , et al. Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. Proc Natl Acad Sci U S A 1995; 92 (24) 10939-10943
  • 9 Shinoda K, Lei H, Yoshii H , et al. Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev Dyn 1995; 204 (1) 22-29
  • 10 Majdic G, Young M, Gomez-Sanchez E , et al. Knockout mice lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity. Endocrinology 2002; 143 (2) 607-614
  • 11 Bland ML, Jamieson CA, Akana SF , et al. Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response. Proc Natl Acad Sci U S A 2000; 97 (26) 14488-14493
  • 12 Bland ML, Fowkes RC, Ingraham HA. Differential requirement for steroidogenic factor-1 gene dosage in adrenal development versus endocrine function. Mol Endocrinol 2004; 18 (4) 941-952
  • 13 Hoivik EA, Lewis AE, Aumo L, Bakke M. Molecular aspects of steroidogenic factor 1 (SF-1). Mol Cell Endocrinol 2010; 315 (1–2) 27-39
  • 14 Achermann JC, Ito M, Ito M, Hindmarsh PC, Jameson JL. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 1999; 22 (2) 125-126
  • 15 Umesono K, Evans RM. Determinants of target gene specificity for steroid/thyroid hormone receptors. Cell 1989; 57 (7) 1139-1146
  • 16 Ito M, Achermann JC, Jameson JL. A naturally occurring steroidogenic factor-1 mutation exhibits differential binding and activation of target genes. J Biol Chem 2000; 275 (41) 31708-31714
  • 17 Tremblay JJ, Viger RS. A mutated form of steroidogenic factor 1 (SF-1 G35E) that causes sex reversal in humans fails to synergize with transcription factor GATA-4. J Biol Chem 2003; 278 (43) 42637-42642
  • 18 Achermann JC, Ozisik G, Ito M , et al. Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner. J Clin Endocrinol Metab 2002; 87 (4) 1829-1833
  • 19 Lin L, Philibert P, Ferraz-de-Souza B , et al. Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function. J Clin Endocrinol Metab 2007; 92 (3) 991-999
  • 20 Biason-Lauber A, Schoenle EJ. Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency. Am J Hum Genet 2000; 67 (6) 1563-1568
  • 21 Lin L, Gu WX, Ozisik G , et al. Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (NR5A1) in children and adults with primary adrenal failure: ten years' experience. J Clin Endocrinol Metab 2006; 91 (8) 3048-3054
  • 22 Köhler B, Lin L, Ferraz-de-Souza B , et al. Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency. Hum Mutat 2008; 29 (1) 59-64
  • 23 Correa RV, Domenice S, Bingham NC , et al. A microdeletion in the ligand binding domain of human steroidogenic factor 1 causes XY sex reversal without adrenal insufficiency. J Clin Endocrinol Metab 2004; 89 (4) 1767-1772
  • 24 Hasegawa T, Fukami M, Sato N , et al. Testicular dysgenesis without adrenal insufficiency in a 46,XY patient with a heterozygous inactive mutation of steroidogenic factor-1. J Clin Endocrinol Metab 2004; 89 (12) 5930-5935
  • 25 Mallet D, Bretones P, Michel-Calemard L, Dijoud F, David M, Morel Y. Gonadal dysgenesis without adrenal insufficiency in a 46, XY patient heterozygous for the nonsense C16X mutation: a case of SF1 haploinsufficiency. J Clin Endocrinol Metab 2004; 89 (10) 4829-4832
  • 26 Reuter AL, Goji K, Bingham NC, Matsuo M, Parker KL. A novel mutation in the accessory DNA-binding domain of human steroidogenic factor 1 causes XY gonadal dysgenesis without adrenal insufficiency. Eur J Endocrinol 2007; 157 (2) 233-238
  • 27 Coutant R, Mallet D, Lahlou N , et al. Heterozygous mutation of steroidogenic factor-1 in 46,XY subjects may mimic partial androgen insensitivity syndrome. J Clin Endocrinol Metab 2007; 92 (8) 2868-2873
  • 28 Lourenço D, Brauner R, Lin L , et al. Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med 2009; 360 (12) 1200-1210
  • 29 Tajima T, Fujiwara F, Fujieda K. A novel heterozygous mutation of steroidogenic factor-1 (SF-1/Ad4BP) gene (NR5A1) in a 46, XY disorders of sex development (DSD) patient without adrenal failure. Endocr J 2009; 56 (4) 619-624
  • 30 Philibert P, Leprieur E, Zenaty D , et al. Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration. Reprod Biol Endocrinol 2010; 8: 28
  • 31 Warman DM, Costanzo M, Marino R , et al. Three new SF-1 (NR5A1) gene mutations in two unrelated families with multiple affected members: within-family variability in 46,XY subjects and low ovarian reserve in fertile 46,XX subjects. Horm Res Paediatr 2011; 75 (1) 70-77
  • 32 Allali S, Muller J-B, Brauner R , et al. Mutation analysis of NR5A1 encoding steroidogenic factor 1 in 77 patients with 46, XY disorders of sex development (DSD) including hypospadias. PLoS ONE 2011; 6 (10) e24117
  • 33 Köhler B, Achermann JC. Update—steroidogenic factor 1 (SF-1, NR5A1). Minerva Endocrinol 2010; 35 (2) 73-86
  • 34 van Silfhout A, Boot AM, Dijkhuizen T , et al. A unique 970kb microdeletion in 9q33.3, including the NR5A1 gene in a 46,XY female. Eur J Med Genet 2009; 52 (2–3) 157-160
  • 35 Barbaro M, Cools M, Looijenga LHJ, Drop SLS, Wedell A. Partial deletion of the NR5A1 (SF1) gene detected by synthetic probe MLPA in a patient with XY gonadal disorder of sex development. Sex Dev 2011; 5 (4) 181-187
  • 36 Schlaubitz S, Yatsenko SA, Smith LD , et al. Ovotestes and XY sex reversal in a female with an interstitial 9q33.3-q34.1 deletion encompassing NR5A1 and LMX1B causing features of Genitopatellar syndrome. Am J Med Genet A 2007; 143A (10) 1071-1081
  • 37 Cools M, Hoebeke P, Wolffenbuttel KP , et al. Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth. Eur J Endocrinol 2012; 166 (2) 341-349
  • 38 Köhler B, Lin L, Mazen I , et al. The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency. Eur J Endocrinol 2009; 161 (2) 237-242
  • 39 Philibert P, Polak M, Colmenares A , et al. Predominant Sertoli cell deficiency in a 46,XY disorders of sex development patient with a new NR5A1/SF-1 mutation transmitted by his unaffected father. Fertil Steril 2011; 95 (5) 1788 , e5–e9
  • 40 Paris F, De Ferran K, Bhangoo A , et al. Isolated 'idiopathic' micropenis: hidden genetic defects?. Int J Androl 2011; 34 (6 Pt 2) e518-e525
  • 41 Philibert P, Zenaty D, Lin L , et al. Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study. Hum Reprod 2007; 22 (12) 3255-3261
  • 42 Bashamboo A, Ferraz-de-Souza B, Lourenço D , et al. Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1. Am J Hum Genet 2010; 87 (4) 505-512
  • 43 Suzawa M, Ingraham HA. The herbicide atrazine activates endocrine gene networks via non-steroidal NR5A nuclear receptors in fish and mammalian cells. PLoS ONE 2008; 3 (5) e2117
  • 44 Doghman M, Karpova T, Rodrigues GA , et al. Increased steroidogenic factor-1 dosage triggers adrenocortical cell proliferation and cancer. Mol Endocrinol 2007; 21 (12) 2968-2987
  • 45 Figueiredo BC, Cavalli LR, Pianovski MA , et al. Amplification of the steroidogenic factor 1 gene in childhood adrenocortical tumors. J Clin Endocrinol Metab 2005; 90 (2) 615-619
  • 46 Almeida MQ, Soares IC, Ribeiro TC , et al. Steroidogenic factor 1 overexpression and gene amplification are more frequent in adrenocortical tumors from children than from adults. J Clin Endocrinol Metab 2010; 95 (3) 1458-1462
  • 47 Sbiera S, Schmull S, Assie G , et al. High diagnostic and prognostic value of steroidogenic factor-1 expression in adrenal tumors. J Clin Endocrinol Metab 2010; 95 (10) E161-E171
  • 48 Xue Q, Lin Z, Yin P , et al. Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5′ CpG island in endometriosis. J Clin Endocrinol Metab 2007; 92 (8) 3261-3267
  • 49 Utsunomiya H, Cheng YH, Lin Z , et al. Upstream stimulatory factor-2 regulates steroidogenic factor-1 expression in endometriosis. Mol Endocrinol 2008; 22 (4) 904-914
  • 50 Calvo RM, Asunción M, Tellería D, Sancho J, San Millán JL, Escobar-Morreale HF. Screening for mutations in the steroidogenic acute regulatory protein and steroidogenic factor-1 genes, and in CYP11A and dosage-sensitive sex reversal-adrenal hypoplasia gene on the X chromosome, gene-1 (DAX-1), in hyperandrogenic hirsute women. J Clin Endocrinol Metab 2001; 86 (4) 1746-1749
  • 51 Doghman M, Cazareth J, Douguet D, Madoux F, Hodder P, Lalli E. Inhibition of adrenocortical carcinoma cell proliferation by steroidogenic factor-1 inverse agonists. J Clin Endocrinol Metab 2009; 94 (6) 2178-2183
  • 52 Ferraz-de-Souza B, Lin L, Shah S , et al. ChIP-on-chip analysis reveals angiopoietin 2 (Ang2, ANGPT2) as a novel target of steroidogenic factor-1 (SF-1, NR5A1) in the human adrenal gland. FASEB J 2011; 25 (4) 1166-1175
  • 53 Ferraz-de-Souza B, Hudson-Davies RE, Lin L , et al. Sterol O-acyltransferase 1 (SOAT1, ACAT) is a novel target of steroidogenic factor-1 (SF-1, NR5A1, Ad4BP) in the human adrenal. J Clin Endocrinol Metab 2011; 96 (4) E663-E668
  • 54 Ferraz-de-Souza B, Lin L, Achermann JC. Steroidogenic factor-1 (SF-1, NR5A1) and human disease. Mol Cell Endocrinol 2011; 336 (1–2) 198-205