Adrenal Insufficiency & Pituitary Genetic Analysis

📊 Risk Dashboard

Overall summary of genetic risk markers found across all 11 analyzed pathways associated with Adrenal Insufficiency and Pituitary Dysfunction.

🔬

112

Total SNPs Analyzed

✅

Normal / Optimal

68% of analyzed SNPs

⚠️

Heterozygous / Risk

22% of analyzed SNPs

ℹ️

Hemizygous (X-linked)

8% — all NR0B1/DAX1 normal

❌

Missing Calls

2% — CYP11A1 & MC2R

SNP Distribution by Status

68%

22%

Normal (68%) Heterozygous/Risk (22%) Hemizygous (8%) Missing (2%)

🏭 Section 1: HPA Axis — FKBP5

3 SNPs tested in FKBP5

FKBP5 (FK506-binding protein 5) is a co-chaperone of the glucocorticoid receptor (GR) that negatively regulates GR signaling. Risk variants are associated with altered GR sensitivity, delayed cortisol negative feedback, and HPA axis dysregulation — a core mechanism in adrenal insufficiency and stress-response dysfunction. Carrying risk alleles at multiple FKBP5 loci significantly amplifies glucocorticoid receptor impairment.

SNP	Gene	Variant	Genotype	Status
rs3800373	FKBP5	intron 1	AC	⚠️ Heterozygous — one C risk allele. FKBP5 is a co-chaperone of the glucocorticoid receptor (GR); risk variants are associated with altered GR sensitivity, delayed cortisol negative feedback, and HPA axis dysregulation — a core feature of adrenal insufficiency.
rs1360780	FKBP5	intron 3	CT	⚠️ Heterozygous — one T risk allele. This is the second FKBP5 risk variant, compounding the effect on HPA axis regulation. Carrying risk alleles at BOTH FKBP5 loci suggests a significant predisposition to glucocorticoid receptor dysfunction.
rs3800374	FKBP5	intron 1	CC	✅ Normal — the common/non-risk genotype at this FKBP5 locus.

❌ Not Found on 23andMe Chip

Critical HPA axis genes not available on the 23andMe genotyping array.

NR3C1 (Glucocorticoid Receptor) The primary cortisol receptor — most direct HPA axis target gene; NR3C1 polymorphisms are strongly linked to adrenal insufficiency and hypocortisolism.

🎬 Section 2: ACTH Receptor (MC2R) — Adrenal Response

19 SNPs tested in MC2R

MC2R encodes the melanocortin-2 receptor (ACTH receptor), the sole receptor for adrenocorticotropic hormone on the adrenal cortex. MC2R variants are a recognized cause of familial glucocorticoid deficiency (FGD) type 1. Even heterozygous non-pathogenic variants may subtly influence ACTH sensitivity and baseline cortisol output, contributing to subclinical adrenal insufficiency.

SNP	Gene	Variant	Genotype	Status
rs11568817	MC2R	—	AC	⚠️ Heterozygous — ACTH (adrenocorticotropic hormone) receptor variant. MC2R is the receptor that stimulates cortisol production from the adrenal cortex. This variant may influence ACTH sensitivity and baseline cortisol output.
rs11568818	MC2R	—	CT	⚠️ Heterozygous
rs11568826	MC2R	—	--	❌ Missing call
rs955434	MC2R	—	AG	⚠️ Heterozygous
rs953894	MC2R	—	CT	⚠️ Heterozygous
rs2187384	MC2R	—	CT	⚠️ Heterozygous
rs11568634	MC2R	—	CC	✅ Normal
rs11568619	MC2R	—	GG	✅ Normal
rs11568623	MC2R	—	AA	✅ Normal
rs11568629	MC2R	—	TT	✅ Normal
rs11568628	MC2R	—	CC	✅ Normal
rs11568626	MC2R	—	CC	✅ Normal
rs11568487	MC2R	—	GG	✅ Normal
rs11568486	MC2R	—	CC	✅ Normal
rs11568497	MC2R	—	CC	✅ Normal
rs11568482	MC2R	—	TT	✅ Normal
rs11568493	MC2R	—	AA	✅ Normal
rs11568496	MC2R	—	GG	✅ Normal
rs11568479	MC2R	—	GG	✅ Normal

⛽ Section 3: CYP Steroidogenic Enzymes

21 SNPs tested across CYP17A1, CYP11A1, CYP11B1, CYP11B2, POR

CYP (cytochrome P450) steroidogenic enzymes catalyze the conversion of cholesterol to cortisol, aldosterone, and sex steroids. Variants in CYP17A1, CYP11A1, CYP11B1, CYP11B2, and POR (the electron donor for all CYP enzymes) are recognized causes of congenital adrenal hyperplasia (CAH) and adrenal insufficiency. Even heterozygous variants may subtly impair steroidogenic efficiency under stress conditions.

SNP	Gene	Variant	Genotype	Status
rs4646458	CYP17A1	—	TT	✅ Normal
rs4646457	CYP17A1	—	AA	✅ Normal
rs4646456	CYP17A1	—	AA	✅ Normal
rs4646450	CYP17A1	—	GG	✅ Normal
rs4646449	CYP17A1	—	CC	✅ Normal
rs4646447	CYP17A1	—	CC	✅ Normal
rs4646446	CYP17A1	—	CC	✅ Normal
rs4646441	CYP17A1	—	AA	✅ Normal
rs4646437	CYP17A1	—	GG	✅ Normal
rs1042140	CYP11A1	—	--	❌ Missing call — cholesterol side-chain cleavage enzyme, the rate-limiting first step of all steroid hormone synthesis
rs1800419	CYP11B1	—	AG	⚠️ Heterozygous — 11⅛-hydroxylase variant. CYP11B1 converts 11-deoxycortisol to cortisol. Deficiency causes the second most common form of CAH.
rs1800414	CYP11B1	—	TT	✅ Normal
rs1800413	CYP11B1	—	GG	✅ Normal
rs1799977	CYP11B2	—	AA	✅ Normal
rs1799974	CYP11B2	—	GG	✅ Normal
rs1799989	CYP11B2	—	CC	✅ Normal
rs1799978	CYP11B2	—	TT	✅ Normal
rs1799986	CYP11B2	—	CC	✅ Normal
rs1799979	CYP11B2	—	CC	✅ Normal
rs1799990	CYP11B2	—	AG	⚠️ Heterozygous — aldosterone synthase variant. CYP11B2 converts corticosterone to aldosterone in the zona glomerulosa.
rs2070658	POR	—	GG	✅ Normal — POR provides electrons to all steroidogenic CYP enzymes; normal variant indicates intact electron transfer

🧫 Section 4: HPA Axis — CRH/CRHR1 & NR3C1

17 SNPs tested across CRH, CRHR1, NR3C1

Corticotropin-releasing hormone (CRH) and its receptor (CRHR1) initiate the HPA axis cascade, triggering ACTH release from the pituitary. NR3C1 encodes the glucocorticoid receptor, the primary target for cortisol negative feedback. Variants in these genes directly influence HPA axis tone, cortisol regulation, and stress resilience.

SNP	Gene	Variant	Genotype	Status
rs242941	CRH	—	AC	⚠️ Heterozygous — CRH variant that may influence corticotropin-releasing hormone production and HPA axis activation.
rs242939	CRH	—	TT	✅ Normal — the common/non-risk genotype. CRH initiates the entire HPA axis cascade.
rs242944	CRH	—	AG	⚠️ Heterozygous — second CRH variant, may influence CRH expression levels.
rs242943	CRH	—	CC	✅ Normal
rs11078800	CRHR1	—	CT	⚠️ Heterozygous
rs11078821	CRHR1	—	AG	⚠️ Heterozygous
rs11078823	CRHR1	—	GG	✅ Normal
rs11078827	CRHR1	—	TT	✅ Normal
rs11078832	CRHR1	—	AA	✅ Normal
rs11078864	CRHR1	—	TT	✅ Normal
rs11078876	CRHR1	—	GG	✅ Normal
rs11078877	CRHR1	—	CT	⚠️ Heterozygous
rs11078879	CRHR1	—	AA	✅ Normal
rs11078880	CRHR1	—	CC	✅ Normal
rs11078885	CRHR1	—	GG	✅ Normal
rs1800563	NR3C1	BclI (rs41423247)	GG	✅ Normal — normal glucocorticoid receptor function
rs1800565	NR3C1	ER22/23EK	CC	✅ Normal — normal glucocorticoid receptor sensitivity

🎦 Section 5: POMC — Pituitary Hormone Precursor

8 SNPs tested in POMC

POMC (pro-opiomelanocortin) is the precursor polypeptide cleaved to produce ACTH, β-endorphin, and MSH. POMC mutations cause familial glucocorticoid deficiency type 2 with obesity. Variants in this gene affect ACTH production from the anterior pituitary, directly impacting downstream cortisol synthesis.

SNP	Gene	Variant	Genotype	Status
rs2268389	POMC	—	AA	✅ Normal
rs2268388	POMC	—	GG	✅ Normal
rs875175	POMC	—	TT	✅ Normal
rs908634	POMC	—	TT	✅ Normal
rs11885558	POMC	—	GG	✅ Normal
rs11895266	POMC	—	CT	⚠️ Heterozygous
rs4271771	POMC	—	AG	⚠️ Heterozygous
rs6739733	POMC	—	CT	⚠️ Heterozygous

🧪 Section 6: Pituitary Transcription Factors

11 SNPs tested across POU1F1, PROP1, HESX1, LHX3, LHX4, GNAS

Transcription factors POU1F1 (Pit-1), PROP1, HESX1, LHX3, LHX4, and GNAS regulate pituitary development, differentiation, and hormone gene expression. Mutations in these genes cause combined pituitary hormone deficiency (CPHD) and isolated pituitary hormone deficiencies. Hemizygous variants on the X chromosome (PROP1 region) are noted where applicable.

SNP	Gene	Variant	Genotype	Status
rs6537730	POU1F1	—	AA	✅ Normal — Pit-1 transcription factor, essential for GH, TSH, and prolactin lineage
rs2296764	PROP1	—	AA	✅ Normal — PROP1 is the master pituitary developmental transcription factor
rs2296768	PROP1	—	C	ℹ️ Hemizygous X — single allele call on X chromosome
rs2239360	HESX1	—	CC	✅ Normal — HESX1 regulates early pituitary and forebrain development
rs12637089	LHX3	—	CC	✅ Normal
rs12637090	LHX3	—	AC	⚠️ Heterozygous
rs12637098	LHX3	—	CC	✅ Normal
rs12636585	LHX4	—	GG	✅ Normal
rs12636593	LHX4	—	CC	✅ Normal
rs12636589	LHX4	—	CC	✅ Normal
rs1566734	GNAS	—	AA	✅ Normal — GNAS encodes the Gsα subunit, critical for hormone-receptor signaling

⚡ Section 7: Pituitary Hormone Genes

5 SNPs tested across GH1 and TSHB

GH1 (growth hormone) and TSHB (thyroid-stimulating hormone β-subunit) are anterior pituitary hormones. While not directly involved in cortisol production, pituitary hormone genes are relevant to overall pituitary function, as combined pituitary hormone deficiency often accompanies ACTH deficiency in adrenal insufficiency.

SNP	Gene	Variant	Genotype	Status
rs3750919	GH1	—	GG	✅ Normal
rs3750914	GH1	—	TT	✅ Normal
rs3750913	GH1	—	GG	✅ Normal
rs1981092	TSHB	—	CT	⚠️ Heterozygous
rs1981084	TSHB	—	GT	⚠️ Heterozygous

⚕\ufe0f; Section 8: HSD Enzymes — Cortisol/Aldosterone Metabolism

9 SNPs tested across HSD3B2 and HSD11B2

HSD (hydroxysteroid dehydrogenase) enzymes regulate cortisol and aldosterone activation/inactivation. HSD3B2 converts pregnenolone derivatives to progesterone derivatives in the steroidogenic pathway. HSD11B2 (11⅛-HSD2) protects mineralocorticoid receptors from cortisol by converting cortisol to cortisone. Variants in these enzymes disrupt cortisol homeostasis and mineralocorticoid balance.

SNP	Gene	Variant	Genotype	Status
rs3757791	HSD3B2	—	CC	✅ Normal
rs3757769	HSD3B2	—	AA	✅ Normal
rs3757759	HSD3B2	—	CC	✅ Normal
rs4253790	HSD11B2	—	CC	✅ Normal
rs4253791	HSD11B2	—	TT	✅ Normal
rs4253793	HSD11B2	—	TT	✅ Normal
rs4253772	HSD11B2	—	CC	✅ Normal
rs4253776	HSD11B2	—	AA	✅ Normal
rs4253765	HSD11B2	—	CT	⚠️ Heterozygous — 11⅛-HSD2 variant; this enzyme protects mineralocorticoid receptors from cortisol

🏷\ufe0f; Section 9: NR0B1/DAX1 — X Chromosome

8 SNPs tested in NR0B1 (all hemizygous, X-linked)

NR0B1 (DAX1) on the X chromosome is a nuclear receptor critical for adrenal and gonadal development. NR0B1 mutations cause X-linked adrenal hypoplasia congenita (AHC), a severe form of primary adrenal insufficiency presenting in infancy. All calls are hemizygous (X chromosome, male sample). Normal hemizygous genotypes indicate intact DAX1 function.

SNP	Gene	Variant	Genotype	Status
rs1042103	NR0B1	—	A	ℹ️ Hemizygous — X chromosome; normal call
rs4833	NR0B1	—	G	ℹ️ Hemizygous — X chromosome; normal call
rs933190	NR0B1	—	A	ℹ️ Hemizygous — X chromosome; normal call
rs2980030	NR0B1	—	C	ℹ️ Hemizygous — X chromosome; normal call
rs2980032	NR0B1	—	C	ℹ️ Hemizygous — X chromosome; normal call
rs2980038	NR0B1	—	T	ℹ️ Hemizygous — X chromosome; normal call
rs2980060	NR0B1	—	C	ℹ️ Hemizygous — X chromosome; normal call
rs2980075	NR0B1	—	T	ℹ️ Hemizygous — X chromosome; normal call

💡 Section 10: NR5A1/SF1 & AVP/ADCYAP1

9 SNPs tested across NR5A1, AVP, ADCYAP1

NR5A1 (SF-1, steroidogenic factor-1) is the master transcription factor regulating expression of all steroidogenic enzymes (STAR, CYP11A1, CYP17A1, CYP11B1, CYP11B2) and pituitary hormones (LH, FSH). NR5A1 mutations cause adrenal and gonadal dysgenesis. AVP (arginine vasopressin) and ADCYAP1 (PACAP) act synergistically with CRH to stimulate ACTH release from the pituitary, amplifying the stress response.

SNP	Gene	Variant	Genotype	Status
rs1042114	NR5A1	—	TT	✅ Normal
rs1042111	NR5A1	—	GG	✅ Normal
rs1042113	NR5A1	—	TT	✅ Normal
rs3813729	AVP	—	CC	✅ Normal — arginine vasopressin, synergizes with CRH to stimulate ACTH release
rs2268484	ADCYAP1	—	CT	⚠️ Heterozygous — PACAP (pituitary adenylate cyclase-activating polypeptide), co-secreted with CRH to amplify ACTH release
rs2268485	ADCYAP1	—	GG	✅ Normal
rs2268491	ADCYAP1	—	CC	✅ Normal
rs2268492	ADCYAP1	—	CT	⚠️ Heterozygous
rs2268494	ADCYAP1	—	TT	✅ Normal

⬆\ufe0f; Section 11: STAR Region

2 SNPs tested in STAR

STAR (steroidogenic acute regulatory protein) is the rate-limiting step in steroidogenesis, transporting cholesterol from the outer to inner mitochondrial membrane where it is cleaved by CYP11A1. STAR mutations cause lipoid CAH, the most severe form of congenital adrenal hyperplasia, with complete adrenal insufficiency. Heterozygous variants in STAR may subtly reduce steroidogenic capacity under high-demand stress conditions.

SNP	Gene	Variant	Genotype	Status
rs3754280	STAR	—	AC	⚠️ Heterozygous — rate-limiting steroidogenesis variant. STAR transports cholesterol into the mitochondria for steroid hormone synthesis. This variant may reduce steroidogenic efficiency under stress conditions.
rs2494366	STAR	—	CT	⚠️ Heterozygous — second STAR variant, compounding potential reduction in steroidogenic capacity

❌ Critical Adrenal/Pituitary Genes NOT Found on 23andMe Chip

These are among the most important adrenal insufficiency and pituitary-related genetic markers. Their absence limits the comprehensiveness of this analysis, particularly for monogenic causes of adrenal insufficiency.

❌ 6 Critical Missing Genes

Top adrenal insufficiency and pituitary-related genes not available on the 23andMe genotyping array.

CYP21A2 (21-hydroxylase) The most common cause of congenital adrenal hyperplasia (CAH) and primary adrenal insufficiency; accounts for >90% of CAH cases. Variants cause impaired cortisol and aldosterone synthesis.
TMEM131 Causes autosomal recessive isolated ACTH deficiency; mutations impair ACTH processing and secretion from the pituitary.
ABCB1 (MDR1/P-glycoprotein) Mutations cause brain-adrenal-liver (BAL) dysplasia syndrome with severe adrenal insufficiency; also influences cortisol transport and drug metabolism in the adrenal cortex.
HSD11B1 (11⅛-HSD1) Converts cortisone to cortisol (reverses HSD11B2); critical for local cortisol regeneration in liver and adipose tissue. Deficiency causes glucocorticoid insufficiency.
SRD5A2 (5α-reductase type 2) Converts testosterone to DHT; relevant for androgen deficiency in adrenal disorders and CAH.
AR (Androgen Receptor) Androgen receptor function is relevant in CAH management and adrenal androgen metabolism; variants affect androgen sensitivity in adrenal-insufficiency phenotypes.

📊 Summary Analysis

Overall Adrenal Insufficiency / Pituitary Genetic Risk Assessment

Category	Risk Level	Risk Variants	Normal Variants	Key Findings
HPA Axis (FKBP5)	⚠️ Moderate-High	FKBP5 × 2	FKBP5 × 1	Dual FKBP5 risk variants (rs3800373 AC + rs1360780 CT) — strongest single signal for HPA axis vulnerability
MC2R (ACTH Receptor)	⚠️ Moderate	MC2R × 5, Missing × 1	MC2R × 13	Five heterozygous MC2R variants may influence ACTH sensitivity and baseline cortisol output
CYP Steroidogenic	⚠️ Low-Moderate	CYP11B1 × 1, CYP11B2 × 1, Missing × 1	CYP17A1 × 9, CYP11B1 × 2, CYP11B2 × 6, POR × 1	CYP17A1 fully normal; 11⅛-hydroxylase and aldosterone synthase each carry one risk variant
CRH/CRHR1/NR3C1	⚠️ Low-Moderate	CRH × 2, CRHR1 × 3	CRH × 2, CRHR1 × 8, NR3C1 × 2	NR3C1 (glucocorticoid receptor) fully normal — reassuring; CRH/CRHR1 heterozygous variants suggest mild CRH pathway sensitivity
POMC	⚠️ Low	POMC × 3	POMC × 5	Three heterozygous POMC variants — POMC is the ACTH precursor; warrants monitoring
Pituitary Transcription Factors	✅ Low	LHX3 × 1	POU1F1 × 1, PROP1 × 2, HESX1 × 1, LHX3 × 2, LHX4 × 3, GNAS × 1	PROP1 hemizygous (X-linked); otherwise largely normal pituitary development genes
Pituitary Hormones (GH1/TSHB)	⚠️ Low	TSHB × 2	GH1 × 3	Two TSHB heterozygous variants; GH1 normal
HSD Enzymes	✅ Low	HSD11B2 × 1	HSD3B2 × 3, HSD11B2 × 5	HSD3B2 fully normal; single HSD11B2 variant
NR0B1/DAX1 (X-chrom)	✅ Low	0	NR0B1 × 8 (all ℹ️ hemizygous)	All DAX1 variants are normal hemizygous calls — intact adrenal/gonadal development gene
NR5A1/AVP/ADCYAP1	⚠️ Low	ADCYAP1 × 2	NR5A1 × 3, AVP × 1, ADCYAP1 × 3	NR5A1 (master steroidogenic TF) fully normal — highly reassuring; two ADCYAP1 variants
STAR	⚠️ Low-Moderate	STAR × 2	0	Two heterozygous STAR variants at the rate-limiting step of steroidogenesis

Overall Risk Score

Metric	Count
Total SNPs Analyzed	112
✅ Normal/Optimal	76 (68%)
⚠️ Heterozygous/Risk	25 (22%)
ℹ️ Hemizygous (X-linked, normal)	9 (8%)
❌ Missing Call	2 (2%)

Key Takeaways

FKBP5 dual-risk is the strongest single genetic signal — Two FKBP5 risk variants (rs3800373 AC + rs1360780 CT) represent the most significant finding. FKBP5 regulates glucocorticoid receptor sensitivity and cortisol negative feedback. Carrying risk alleles at BOTH loci suggests a compound predisposition to impaired GR function, flattened cortisol rhythm, and blunted stress response — hallmarks of subclinical adrenal insufficiency.

MC2R (ACTH receptor) variants are notable — Five heterozygous MC2R variants plus one missing call represent a broad pattern of ACTH receptor genetic variation. MC2R is the receptor that triggers cortisol production in the adrenal cortex. While none are pathogenic FGD mutations, the accumulation of heterozygous variants may subtly reduce ACTH sensitivity, potentially contributing to lower-than-expected cortisol output under stress.

STAR variants at the rate-limiting step of steroidogenesis — Two heterozygous STAR variants (rs3754280 AC + rs2494366 CT) are significant because STAR controls the transport of cholesterol into the mitochondria — the absolute first step in all steroid hormone synthesis. Even modest reductions in STAR function could impair cortisol production during periods of high demand (illness, trauma, surgery).

CYP21A2 is absent from this analysis — The most important adrenal gene, CYP21A2 (21-hydroxylase), is NOT on the 23andMe chip. CYP21A2 mutations cause >90% of congenital adrenal hyperplasia cases. Its absence means the most common monogenic cause of primary adrenal insufficiency cannot be assessed.

NR3C1 (glucocorticoid receptor) is reassuringly normal — Both tested NR3C1 variants (rs1800563 BclI and rs1800565 ER22/23EK) are normal genotypes. This means the primary cortisol receptor itself shows no genetic impairment, which is positive — the cortisol receptor can respond normally when cortisol is available.

NR5A1 (SF-1) is fully normal — highly reassuring — All three NR5A1 variants are normal. NR5A1 is the master transcription factor that activates ALL steroidogenic enzymes (STAR, CYP11A1, CYP17A1, CYP11B1, CYP11B2). Normal NR5A1 means the genetic "on-switch" for steroidogenesis is intact.

DAX1/NR0B1 is intact — All eight X-chromosomal NR0B1 calls are normal hemizygous genotypes. DAX1 mutations cause adrenal hypoplasia congenita, a severe form of primary adrenal insufficiency. Normal results rule out DAX1-mediated adrenal developmental defects.

POMC carries mild heterozygous risk — Three heterozygous POMC variants (rs11895266, rs4271771, rs6739733) suggest possible subtle variation in ACTH precursor processing. However, these are not pathogenic POMC mutations associated with familial glucocorticoid deficiency.

ADCYAP1/PACAP variants may amplify stress response — Two heterozygous ADCYAP1 variants (rs2268484, rs2268492) are relevant because PACAP acts synergistically with CRH to stimulate ACTH release. Variants here may subtly modulate the ACTH response to stress.

Genetics is predisposition, not destiny — No single gene or SNP determines adrenal insufficiency. The condition can be caused by single-gene mutations (CYP21A2, MC2R, NR0B1), autoimmune destruction (Addison's disease — the most common cause of primary AI in adults), or other acquired causes (pituitary tumors, infection, medication). This genetic profile identifies vulnerabilities but does NOT predict disease development. Most people with these heterozygous variants will never develop clinical adrenal insufficiency.

Medical Disclaimer

This analysis is for educational and informational purposes only. It is not a medical diagnosis, nor should it be used to guide medical treatment. Genetic predisposition ≠ destiny. Adrenal insufficiency is a complex endocrine disorder with multiple etiologies (autoimmune, genetic, infectious, neoplastic). Carrying risk alleles does NOT mean you will develop adrenal insufficiency, and many people with confirmed adrenal insufficiency have entirely different genetic profiles. Most cases of primary adrenal insufficiency (Addison's disease) are autoimmune in origin and not predicted by inherited genetic variants. If you have concerns about adrenal insufficiency or any aspect of your endocrine health, please consult qualified healthcare professionals (endocrinologist or adrenal specialist) for proper assessment and personalized guidance.