Steroidogenic Factor-1 and Human Disease

Abstract

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.

Steroidogenic factor-1 (SF-1, NR5A1, Ad4BP) is a nuclear receptor that is viewed as a “master-regulator” of many aspects of adrenal and reproductive development and function. This factor was discovered in the early 1990s through the pioneering work of Keith L. Parker (United States) and Kenichirou Morohashi (Japan), who had hypothesized that a common regulator of steroidogenic enzymes must exist.^1–3 Subsequently, SF-1 was shown to play a central role in the regulation of many genes involved in adrenal and reproductive function through the study of SF-1 transcriptional activation and binding to promoter elements in these known target genes. These studies provided strong evidence to support the concept that SF-1 is a central regulator of these systems.^4–6

In addition to these numerous in vitro studies, a major advance in our understanding of the in vivo role of SF-1 was obtained following deletion of the gene encoding Sf-1 (Nr5a1) in the mouse.^7–9 Mice with complete deletion of Nr5a1 (−/−) are viable but fail to develop adrenal glands beyond the early stages of embryogenesis and have complete testicular dysgenesis, persistent Müllerian structures in XY animals, partial hypogonadotropic hypogonadism, and other features such as hyposplenism and abnormalities of the ventromedial hypothalamus. Late-onset obesity has been reported in animals rescued from adrenal failure by adrenal transplantation at birth.¹⁰ Although animals that are haploinsufficient for loss of Nr5a1 (−/+) were originally thought to be unaffected, more subtle phenotypes have been reported following more detailed characterization of these animals.^11,12 Finally, targeted deletion or overexpression of Sf-1 in a tissue-specific manner has provided further important evidence for the key role of this nuclear receptor in an animal model.¹³

The identification and characterization of SF-1 in these in vitro and in vivo systems raised the question of whether alterations in SF-1 (NR5A1) could be responsible for human adrenal and reproductive phenotypes. Initial attempts to identify disease-associated changes in SF-1 in humans focused on those rare individuals with endocrine and developmental features similar to the Nr5a1 knockout mouse. Although such cases have been reported, it has emerged in the past decade that the range of phenotypes associated with disruption of SF-1 function is considerably greater than originally thought, and that human reproductive function seems to be more sensitive to the effects of loss of SF-1 activity than the adrenal gland. In this review we provide an update on the range of phenotypes that are emerging in association with SF-1/NR5A1 variants in humans.

Adrenal and Gonadal Failure: The “Classic” SF-1 Phenotype

The first attempts to study the potential role of SF-1 in humans focused on individuals with features that were predicted from the in vivo and in vitro studies of Sf-1 function described above: namely 46,XY patients with female genitalia, Müllerian structures (uterus and upper vagina), complete gonadal dysgenesis, and primary adrenal failure. This is a very rare phenotype in humans and represents marked disruption of adrenal and testicular development and function. Only two patients with these features have been reported in the literature to date. In both cases, disruption of key DNA-binding motifs of SF-1 seemed to have occurred.

The first individual described with this phenotype was found to have a de novo heterozygous p.G35E change in SF-1 (►Fig. 1A).¹⁴ This child presented in early infancy with a severe salt-losing crisis and adrenal failure. Cortisol was detected but was inappropriately low given the child’s stressed state. The child’s karyotype was 46,XY and originally a high block in steroidogenesis affecting both adrenal and testicular function (for example, P450 side-chain cleavage (CYP11A1), steroidgenic acute regulatory protein (STAR)) was suspected. However, the presence of fibrotic testes and a uterus (Müllerian structures) was consistent with gonadal dysgenesis rather than a specific block in steroidogenesis, so disruption of a common developmental regulator such as SF-1 was then hypothesized.

Figure 1.

Overview of SF-1 mutations associated with 46,XY DSD and adrenal failure. (A) Key functional domains of SF-1 are shown as well as the position of the two SF-1 variants associated with this phenotype. (B) Representation of the zinc finger structure of the DNA-binding domain of SF-1 showing the proximal (P)-box motif and the mutated glycine residue (p.G35E mutation) found in one case. Abbreviations: DSD, disorders of sex development; SF-1, steroidogenic factor-1. (Reproduced with permission from 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;22:125–126; copyright Nature Publishing Group 1999.)¹⁴

The p.G35E change found in this patient lies within the “P-box” motif of the DNA-binding domain (►Fig. 1B). It had been known for some time that the P-box of nuclear receptors is important in facilitating DNA-binding specificity through interactions with the DNA response elements of target genes.¹⁵ Unlike most nuclear receptors, SF-1 is thought to bind target gene response elements primarily as a monomer rather than as a homo- or heterodimer. The P-box region supports binding of SF-1 to the major groove of DNA. In vitro studies of the p.G35E mutant SF-1 compared with wild-type showed variable loss of transcriptional activation in a range of target promoters and impaired DNA response element binding.¹⁶ No strong dominant negative effects were seen in most assay systems, although a mild competitive effect was seen when mutant SF-1 was cotransfected with wild-type SF-1, and in some cases a mild dominant negative effect was seen in studies where a partner protein was needed for transcriptional activation.^16,17 However, these are relatively artificial systems compared with the true in vivo effects where SF-1 likely affects multiple target gene response elements in many different genes and at different stages of development. It is also possible that altered allelic expression or even mosaicism could have played a role in this patient or that covert disruption of the nonaffected allele because of promoter dysregulation or a deep intronic change may have occurred. Nevertheless, this “P-box” mutation was certainly highly disruptive in many assay systems and was clearly an important event in causing the phenotype in this patient.

After this initial report, the aim was to find children with a similar phenotype to see whether additional alterations in SF-1 (NR5A1) could be found, which, in turn, might shed further light on the underlying mechanisms of SF-1 action. In 2002, a second report was published of a homozygous p.R92Q alteration in SF-1 in an infant with a similar phenotype (primary salt-losing adrenal failure, 46,XY DSD, Müllerian structures).¹⁸ This mutation had been inherited in a recessive manner within a consanguineous pedigree. The codon 92 change lies within the “A-box” region of SF-1 (►Fig. 1A, B). This motif is typical of the subfamily of nuclear receptors that bind to DNA as monomers and is believed to play a supportive role in stabilizing DNA binding, through an interaction between this region and the minor groove of DNA. Again, the effects of this SF-1 disruption are likely to be complex and variable but, in several different assay systems, the mean functional activity of the p.R92Q change was found to be ~30 to 40% of wild type.^16,18,19 The fact that the condition had been inherited in a recessive manner and that the mutation was present in a homozygous state in the affected child meant that other molecular mechanisms such as dominant negative effects, mosaicism, skewed allelic expression, or even a covert second mutation were not implicated. Therefore, this report provided convincing evidence for a functional gene dosage effect of SF-1 in influencing both adrenal and gonadal development and function. It is also worth noting that—to date—no complete loss of SF-1 function has been described in humans.

Disruption of SF-1 as a Cause of Adrenal Insufficiency?

Having found alterations in SF-1 in patients with adrenal and gonadal (testicular) dysgenesis, the question arose whether alterations in SF-1 might in some other cases be associated with a predominant adrenal or reproductive phenotype.

As SF-1 was not thought at the time to have such a marked effect on ovary development, it was hypothesized that SF-1 mutations could be found in girls or women with primary adrenal failure or adrenal hypoplasia of unknown etiology. In such situations, where the affected child or woman has a 46,XX karyotype, a typical female appearance and presence of a uterus would be expected, so salt-losing primary adrenal failure would be the presenting feature. Such a report was published in 2000 by Biason-Lauber and Schoenle, who described a de novo heterozygous SF-1 (NR5A1) change in a girl who had presented at 14 months of age with primary adrenal insufficiency and seizures.²⁰ The nucleotide change found was predicted to result in a p. R255L mutation, which affects a codon in the proximal part of the ligand-binding domain of SF-1 (►Fig. 2). Functional studies in this report showed that the mutant SF-1 protein was transcriptionally inactive, but without a dominant negative effect. It is also noteworthy that the child’s ovaries were detected by MRI scan and inhibin A was low normal for age, suggesting at least that early indicators of ovarian integrity were intact.

Figure 2.

Summary of reported changes in SF-1/NR5A1 in humans compared with the structure of SF-1 and to phenotype. Most changes in SF-1/NR5A1 are found in a heterozygous state. Those present in a homozygous state are underlined and an asterix shows where the p.G146A polymorphism was also detected. Missense variants shown in italics are predicted to disrupt function, but have not been studied in functional assays. Changes involving deletions within the NR5A1 locus are not shown. Abbreviations: AI, adrenal insufficiency; DSD, disorders of sex development; POI, primary ovarian insufficiency. (Modified with permission from Lin L, Philibert P, Ferraz-de-Souza B. 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;92:991–999 (copyright The Endocrine Society 2002) and Ferraz-de-Souza B, Lin L, Achermann JC. Steroidogenic factor-1 (SF-1, NR5A1) and human disease. Mol Cell Endocrinol 2011;336:198–205 (copyright Elsevier 2011).¹⁹,⁵⁴) For a complete overview of clinical and biochemical features associated with some of these changes see Köhler and Achermann, 2010.³³

This report raised the question of whether additional SF-1 (NR5A1) changes could be associated with primary adrenal failure in other (46,XX) women where the cause was not known. Although data remain limited at present, attempts to find SF-1 changes in girls with adrenal dysfunction or in adult women with primary adrenal failure of unknown etiology have been unsuccessful.²¹ Furthermore, although mutations and deletions of the related nuclear receptor dosage-sensitive sex reversal, adrenal hypoplasia congenita critical region, on chromosome X, gene 1 (DAX-1) (NR0B1) are found in a significant proportion of phenotypic males with primary adrenal hypoplasia, no descriptions of SF-1 changes associated with adrenal failure and a male phenotype have been published.²¹ Taken together, these studies suggest that alterations in SF-1 are not a common cause of primary adrenal failure in humans and—in the two cases found in 46,XY individuals to date—have always been associated with gonadal (testicular) dysgenesis or marked underandrogenization.

SF-1 and 46,XY Disorders of Sex Development

Although relatively few SF-1 mutations have been reported to cause adrenal failure in humans, it is emerging that disruption of SF-1 is a relatively frequent cause of 46,XY disorders of sex development (DSD) (►Fig. 2).^5,22 The first such case was from Berenice Mendonca’s group (Brazil) in 2004, who reported a heterozygous frameshift mutation in NR5A1 resulting in disruption of SF-1 in a 46,XY female who had presented in early adulthood with hypertension and who had marked clitoromegaly and absent gonads on laparoscopy.²³ Soon after, two additional case reports appeared from Japan and France of 46,XY DSD because of heterozygous changes in NR5A1 that are predicted to cause nonsense or frameshift changes.^24,25 In two of these cases the genetic variant had arisen spontaneously so was likely to represent a de novo event, whereas parental DNA was not available for analysis in the third case. In all three cases, adrenal function was normal when tested. It was therefore proposed that haploinsufficiency of NR5A1 could disrupt testicular development and function, while adrenal function remained intact, and that in most cases a sporadic or de novo event had occurred.

These initial studies led to a series of investigations into the role of SF-1 in human testis development and as a potential cause of 46,XY DSD. Subsequent data have shown that mutations or rare allelic variants in SF-1 (NR5A1) can be associated with a spectrum of phenotypes in humans (►Figs. 2 and 3). Here, we will describe the range of phenotypes reported, with the most typical phenotype outlined first.

Figure 3.

Variations in SF-1/NR5A1 are associated with a range of 46,XY DSD phenotypes. Abbreviation: DSD, disorders of sex development.

The “Typical” 46,XY DSD Phenotype

Since 2004, several further reports of heterozygous mutations in SF-1 (NR5A1) in association with 46,XY DSD have emerged.^{19,22,26–33} Many of these individuals have a similar phenotype of ambiguous genitalia (or “clitoral enlargement”) at birth, a urogenital sinus, small inguinal testes, and absent or rudimentary Müllerian structures. In addition, intact or rudimentary wolffian structures may be present. The biochemical profile most typically is similar to partial gonadal dysgenesis with disrupted androgen synthesis as shown by low levels of testosterone, inhibin B and anti-Müllerian hormone (AMH), and an elevation of follicle-stimulating hormone. In some cases, however, testosterone may be relatively normal at birth, and a diagnosis of partial androgen insensitivity syndrome is made. Histological features of the gonads are variable but often show relatively preserved architecture of the testis in infancy, but with reduced size or number of seminiferous tubules.¹⁹ Leydig and Sertoli cells are seen and germ cells are usually present, although they are sometimes reduced in number. Gonads that are left in an inguinal position or remain intra-abdominal may show more marked fibrosis and degeneration with time, though extensive longitudinal data are not available.

SF-1/NR5A1 changes associated with these forms of 46,XY DSD are often frameshift or nonsense changes (►Fig. 2). Several missense changes that affect DNA binding or gene transcription have also been reported, as well as deletions of several exons of NR5A1 or of the genomic locus encoding SF-1 (9q33).^34,35 In rare cases, loss of NR5A1 may occur as part of a contiguous gene deletion syndrome (involving 9q33.3-q34.11) with genitopatellar syndrome.³⁶ These findings support the hypothesis that haploinsufficiency of SF-1 (NR5A1) is the principle mechanism causing the gonadal phenotype.

In addition to individual case reports, several cohort studies looking at SF-1 (NR5A1) in 46,XY DSD have been published. To date, these studies have reported SF-1 mutations in ~10 to 15% of individuals with this phenotype.^19,22,32 Many of these heterozygous changes are de novo events but, importantly, can be inherited from the mother in a sexlimited dominant manner in about one-third of cases.³³ As described below, some of these women are at risk of developing primary ovarian insufficiency (POI) with time. If this does not occur or if they complete their family before the onset of menopause, the heterozygous SF-1 change may be passed on to several affected 46,XY children, thereby resembling an X-linked disorder such as partial androgen insensitivity syndrome.^19,27,31 In addition, a similar phenotype can sometimes result from the recessive inheritance of a homozygous mutation in SF-1 that causes partial loss of function.²⁸ This makes defining the underling basis of the defect important as inheritance patterns associated with SF-1 can be de novo (autosomal dominant), sex-limited dominant, or autosomal recessive. The counseling of individuals and families would be different in each case, which has significant implications for undiagnosed family members or for defining who in the family might be at risk of developing features such as POI.

More Severe 46,XY DSD Phenotypes

Although atypical or ambiguous genitalia are the most frequent presentations associated with SF-1 mutations, at the more severe end of the spectrum SF-1 mutations can be found in 46,XY girls who present in adolescence with absent pubertal development and primary amenorrhea. In some cases a uterus and dysgenetic or streak gonads can be found. In other cases, Müllerian structures are not present, suggesting that sufficient AMH, also known as Müllerian inhibiting substance, was produced during early fetal testis development to facilitate regression of these structures. Limited data suggest that coinheritance of the p.G146A polymorphism in SF-1 may be associated with a more severe phenotype, but at present the true significance of this is unclear.^22,26

Several reports are also emerging of women presenting with clitoromegaly and absent puberty in adolescence.^23,28 This may reflect undiagnosed clitoromegaly that was present from infancy but not discussed previously or may represent progressive clitoral enlargement and—in some cases—virilization at puberty. For example, Philibert et al recently described SF-1 mutations in 5/15 46,XY female adolescents presenting with primary amenorrhea and with low testosterone levels.³⁰ A uterus was found in one case and clitoromegaly was present in three cases. The authors concluded that SF-1 mutations are a frequent cause of this clinical phenotype. However, progressive androgenization with surprising high testosterone concentrations in adolescence has also been described.³⁷ Therefore, disruption of SF-1 should be considered a potential cause of progressive virilization in a 46, XY female at puberty, in addition to more classic diagnoses such as 5-α reductase deficiency or 17-β hydroxysteroid dehydrogenase type 3 deficiency. In such situations a detailed phenotypic, biochemical, and genetic analysis is warranted.

Hypospadias Associated with SF-1

In contrast to the rare phenotypes described above, a potential role for SF-1 in more frequent conditions such as hypospadias has been explored. The first case of an SF-1 mutation associated with severe penoscrotal hypospadias was reported in 2007 in a child who had small inguinal testes, partial gonadal dysgenesis, and reduced androgen synthesis.¹⁹ The p. L439Q alteration found affects the putative ligand-binding domain of SF-1 resulting in disruption of SF-1 function, but partial function was seen in certain assay systems or cell lines.¹⁹ Subsequently, a cohort study of 60 boys with hypospadias was reported by Köhler et al in 2009.³⁸ Heterozygous nonsense changes in SF-1 were found in three individuals from a subset of the cohort who had the most severe forms of hypospadias (penoscrotal). All these boys had at least one undescended testis, and reduced penile length was found in two of them. The prevalence of SF-1 changes in milder forms of hypospadias is currently unknown, although reports of boys with hypospadias and normally descended testes, distal hypospadias, or “microphallus” have recently been published (►Fig. 2).^32,39,40

Bilateral Anorchia

Bilateral anorchia is a rare condition where testes are absent or show progressive postnatal regression (sometimes referred to as “vanishing testes syndrome”). Although it is often thought that this condition occurs secondary to a vascular event or torsion (especially if unilateral), it is well established that bilateral testis regression can occur, that a subset of these cases are familial, and that approximately half of all cases of bilateral anorchia are associated with reduced penile length. Therefore, this may represent a form of testicular dysgenesis with an underlying genetic basis in a subset of cases.

In a study of a cohort of 24 boys with bilateral anorchia in France, one boy was found to carry a heterozygous mutation (p.V355M) in SF-1.⁴¹ One absent and one very small testis had been documented together with microphallus in early infancy, and testicular atrophy and fibrosis was seen in later childhood. Of note, his twin brother harbored the same change and is reported to have progressed through puberty normally. This finding suggests that SF-1 may also play a role in maintaining the testis, especially when signs of underandrogenization are present, but that other factors or altered expression of the mutant allele may contribute to the phenotypic variability.

Male Factor Infertility

At the least severe end of the spectrum it has been hypothesized that changes in SF-1 may be associated with male factor infertility. It is also established that a subset of men with infertility have evidence of endocrine dysfunction with suboptimal testosterone levels, and an adult form of the testicular dysgenesis syndrome has been proposed. Recently, Bashamboo et al investigated whether changes in SF-1 could be found in a cohort of 315 men with nonobstructive male factor infertility where the underlying cause was unknown.⁴² Participants in this study had been screened for Klinefelter syndrome and for Y chromosome microdeletions as well as any potential medical or environmental cause for their condition and none of the cohort had a history of hypospadias or undescended testes.

Seven men in this cohort were found to have changes in SF-1 (NR5A1). These changes were located within the hinge region of the protein and were not found in sequencing of more than 4,000 control alleles. Furthermore, no rare allelic variants in SF-1 (except the p.G146A polymorphism) were found following sequencing of the entire NR5A1 gene in more than 600 known fertile controls.⁴² The men who were found to have SF-1 changes had severe forms of infertility (azoospermia, severe oligozoospermia) and in several cases elevated gonadotropins and low testosterone were found. Testicular histology was available in one case, which showed fibrosis of the testis with reduced seminiferous tubules and isolated rare germ cells. In one patient, a serial decrease in sperm count was found. This observation suggests that heterozygous changes in NR5A1 could be transmitted in some cases, especially if a man fathers children at a reasonably young age, and may account for the prevalence of the p. G123A + p.P129L variant found in several patients from Central, West, and North Africa. In addition, paternal mosaicism for a SF-1 mutation may be compatible with fertility and transmission of a SF-1 mutation to an affected child.³⁹

This study of Bashamboo et al highlights that changes in SF-1 may be found in a small subset of phenotypically normal men with nonobstructive male factor infertility where the cause is currently unknown. These men may be at risk of developing suboptimal testosterone levels in adult life and may represent a subset of individuals with the adult testicular dysgenesis syndrome. Further studies are needed to establish the true prevalence of SF-1 mutations in male factor infertility and whether, for example, the mutated protein might be influenced differently by environmental modulators that have been proposed to affect SF-1 fucntion.⁴³ Making the specific diagnosis in this group of patients could be important for defining which group of patients needs long-term followup and monitoring of endocrine function.

SF-1 and Ovarian Function

Although most focus has been on the role of SF-1 in testis development and function, NR5A1 mutations have also now been identified in familial and sporadic forms of 46,XX POI.²⁸ These women presented with either primary or secondary amenorrhea with a variable age of onset of features. Biochemical findings were consistent with primary gonadal failure with elevated luteinizing hormone and follicle-stimulating hormone levels and low estradiol. Disruption of SF-1 can potentially affect the ovary at multiple levels, such as altering the integrity of the stroma, reducing germ cell number, impairing folliculogenesis, or disrupting steroidogenesis. Ovarian biopsy material is only available from one women, which showed extensive fibrosis with no evidence of follicles. However, this case may have represented the most severe end of the spectrum.

To date, most women have been found to have heterozygous alterations in NR5A1 and had been identified because of a history of 46,XY DSD and 46,XX POI in members of the same family. In one family a partial loss-of-function SF-1 homozygous change was found (p.D293N) that was inherited in an autosomal recessive manner.²⁸ Further evidence for an important role of SF-1 in ovarian function follows the description of heterozygous SF-1/NR5A1 changes in two girls with sporadic forms of POI and no family history from a cohort of 25 patients. However, the true prevalence of SF-1/NR5A1 changes in women with sporadic or familial forms of POI is currently unknown. Furthermore, some 46,XX women with NR5A1 mutations have normal ovarian function using standard markers and can transmit the mutation in a sex-limited dominant fashion. Some of these women may go through a stage of decreased ovarian reserve (with decreasing AMH and elevating gonadotropins) before developing clinical signs or symptoms of ovarian failure.³¹ It remains a challenge to understand why some women develop this condition and others do not. It is possible that other genetic, epigenetic, or environmental factors could modulate phenotypic expression in some cases. More work is clearly needed in this regard.

SF-1 Overexpression or Increased SF-1 Activity

While most studies initially considered the potential effects of loss of SF-1 function on human disease, several reports have now considered what role overexpression of NR5A1 or overactivity of SF-1 might have. Various clinical conditions have been hypothesized where SF-1 might have an effect.

Adrenal Tumors

SF-1 overexpression increases proliferation and decreases apoptosis of human adrenocortical cells and induces adrenocortical tumors in transgenic mice, so a potential role for SF-1 in adrenal tumorigenesis has been considered.⁴⁴ Initial studies from Brazil have shown a high prevalence of SF-1 overexpression in childhood adrenocortical tumors.^45,46 These changes have arisen following somatic copy number changes of chromosome 9q33, which contains the NR5A1 locus, and have occurred on a background of loss of heterozygosity for the tumor suppressor gene p53 (TP53). More recently, studies have investigated NR5A1 transcript levels in adult adrenocortical carcinoma and shown that increased transcript levels and SF-1 expression correlate with worse prognosis in this condition.⁴⁷

Endometriosis and Polycystic Ovarian Disease

Some studies have shown that SF-1 is expressed in endometriotic cells, whereas it is not usually detected in normal endometrium.^48,49 This aberrant expression may reflect hypomethylation of the proximal promoter. Overactivity of SF-1 has also been considered a potential cause of polycystic ovary disease in a subset of cases. A heterozygous point mutation in SF-1 (p.R365P) was reported in a single case, but the functional or clinical significance of this observation is unclear.⁵⁰

Conclusion

SF-1 continues to emerge as an important regulator of adrenal and reproductive function in humans and variations in SF-1 and in SF-1 activity have now been described in several conditions. Underactivity of SF-1 is now reported in a wide range of reproductive conditions, ranging from severe forms of gonadal dysgenesis through to male factor infertility in males, as well as a various forms of ovarian dysfunction in females. Although the adrenal phenotypes seem to be less common in this cohort of patients, it is possible that impaired adrenal function may develop with time, so it will be important to define this group of individuals well and to counsel and monitor them appropriately. Furthermore, the variable inheritance of SF-1 changes, which can occur as sex-limited dominant, recessive, or sporadic events, means that detailed genetic analysis is important in defining the condition within families and for determining whether other family members should be screened. This might be particularly important for females who could be at risk of developing infertility or men with milder SF-1 changes who might be at risk of a progressive decline in fertility. However, considerably more data are needed to define the exact time course of these conditions and the prevalence of SF-1 changes in some of the more common phenotypes, such as infertility and POI. Finally, further studies of overexpression or activation of SF-1 in reproductive dysfunction are warranted, to add to the limited data for polycystic ovary syndrome and endometriosis.

SF-1 is emerging as an important mediator of adrenal tumorigenesis and may be a target for pharmacomodulation in the future, although the systemic effects of modulating SF-1 actions are unclear.⁵¹ Newer “-omics” approaches are being used to define novel SF-1 targets, such as mediators of angiogenesis or regulators of steroid metabolism.^52,53 Such approaches may help to define the complex networks involved in SF-1 action during development as well as into postnatal and adult life.