Medicine:Late onset congenital adrenal hyperplasia

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Late onset congenital adrenal hyperplasia
Other namesNonclassic onset congenital adrenal hyperplasia
Frequency0.1%–2%

Late onset congenital adrenal hyperplasia (LOCAH), also known as nonclassic congenital adrenal hyperplasia (NCCAH or NCAH), is a milder form of congenital adrenal hyperplasia (CAH),[1] a group of autosomal recessive disorders characterized by impaired cortisol synthesis that leads to variable degrees of postnatal androgen excess.[1][2][3][4]

The causes of LOCAH are the same as of classic CAH, and in the majority of the cases are the mutations in the CYP21A2 gene resulting in corresponding activity changes in the associated P450c21 (21-hydroxylase) enzyme which ultimately leads to excessive androgen production. Other causes, albeit less frequent, are mutations in genes affecting other enzymes involved in steroid metabolism, like 11β-hydroxylase or 3β-hydroxysteroid dehydrogenase.[3] It has a prevalence between 0.1% and 2% depending on population,[2] and is one of the most common autosomal recessive genetic diseases in humans.[5][6][7] The pathophysiology is complex and not all individuals are symptomatic.[2]

Presentation

Patients with LOCAH usually present with signs of hyperandrogenism, rather than of glucocorticoid deficiency, a condition characterized by inadequate cortisol production.[8][9] Cortisol synthesis impairment is mild but clinically silent (asymptomatic).[10][11] LOCAH patients usually have the same baseline but lower peak cortisol levels comparing to healthy controls.[12][13] Flatter diurnal cortisol slopes contribute to stress-related dysregulation of central and peripheral circadian mechanisms with negative health outcomes.[14][15][16]

Due to hyperandrogenism, females may present with symptoms like hirsutism, oligomenorrhea, acne, infertility,[17][18] and androgenetic alopecia.[19][20][21]

Males are generally asymptomatic,[22][8] but may present with acne,[23][24][25] early balding,[26][27][28] chronic prostatitis and/or chronic pelvic pain syndrome.[29][30][31] Rare presentation of testicular adrenal rest tumors[32][18][26] which do not affect fertility and do not require regular ultrasound examinations of the scrotum[1] is also possible.

While symptoms are usually diagnosed after puberty, children may present with premature adrenarche.[8]

The degree of hormonal disorder in patients with LOCAH is relatively mild. However, alterations in the hypothalamic–pituitary–adrenal axis (HPA axis) are present even in this mild form of the disease and might contribute to psychiatric vulnerability.[11]

Molecular genetics

LOCAH is most commonly attributed to mutations in the CYP21A2 gene, which encodes the 21-hydroxylase enzyme. Cases of LOCAH due to deficiencies in other enzymes that are known causes of CAH (3β-hydroxysteroid dehydrogenase, steroid 11β-hydroxylase, etc.) are rare and have no established prevalence estimates.[33]

Several severe mutations have been associated with LOCAH: the deletion of the CYP21A2 gene, small gene conversions, the p. I172N (rs6475, c.518T>A, CYP21A2*11) mutation, the c.293-13A/C>G (rs6467, CYP21A2*9) mutation, and the p.Gln318Stop (p.Q318X, rs7755898, c.952C>T, CYP21A2*17) mutation.[34] Besides that, LOCAH due to 21-hydroxylase deficiency can be caused by duplications of CYP21A1P pseudogene and C4B gene. Due to the high degree of homology between the CYP21A2 gene and the CYP21A1P pseudogene, and the complexity of the locus, research on the sequencing level can be difficult.[35] A 2021 study showed that mild genotypes associated with LOCAH have a low concordance rate with those phenotypes, probably due to the complex characteristics of 21-hydroxylase genotyping and the limitation of using massive parallel sequencing alone without combining with other comprehensive methods.[36]

The following three mutations to the CYP21A2 gene have been found to result in a moderate reduction in enzyme activity associated with that allele (20–60% residual activity),[34] and are associated with LOCAH:[37]

  • p.V281L (rs6471, c.844G>C, CYP21A2*15);
  • p.P453S (rs6445, c.1360C>T, CYP21A2*19);
  • p.P30L (rs9378251, c.92C>T, CYP21A2*8).

A point mutation in exon 7 of CYP21A2, (p.V281L), is commonly found in LOCAH-associated alleles.[37][35][34] Carriers for this mutation retain 20%–50% of 21-hydroxylase activity,[38][22] but are at higher risk of symptoms of androgen excess than carriers of the severe mutations,[39] and had higher adrenocorticotropic hormone (ACTH) stimulated 17α-hydroxyprogesterone,[40] suggesting that the mutant protein V281L enzyme co-expressed with the wild-type (healthy) enzyme resulted in an apparent dominant negative effect on the enzymatic activity.[41]

The particularly mild clinical symptoms of LOCAH such as hyperandrogenism, hirsutism and acne or infertility overlap with other diseases such as polycystic ovary syndrome. Biochemical parameters like 17α-hydroxyprogesterone may not be elevated in very mild cases of LOCAH, and may vary between labs that makes interpretation difficult. It may not be possible to perform ACTH stimulation tests in all institutions, depending on the availability of the injectable adrenocorticotropic hormone medication. This is why a comprehensive CYP21A2 genotyping (rather than variant-specific assays alone) is a good way to exclude/confirm 21-hydroxylase deficiency and heterozygosity (carrier) status.[42] Genetic testing can be used to exclude false positive diagnosis based on biochemical parameters alone, even with ACTH stimulation, since elevated 17-OHP levels may be also caused by ovarian or adrenal tumors, rather than by the variants in the CYP21A2 gene.[43]

Diagnosis

Originally characterized in 1957 by French biochemist Jacques Decourt,[44] LOCAH differs from classic CAH in that it does not cause atypical neonatal genital morphology, is not life-threatening and presents after birth. Unlike classic CAH, LOCAH generally cannot be reliably detected with neonatal screening.[45] Many individuals (both male and female) present no symptoms during childhood and adolescence and only become aware of the possibility of LOCAH due to the diagnosis of another family member. It is thought that 90% of women with LOCAH never receive a diagnosis.[11] In young females, premature pubarche is generally the first symptom to present.[20] The earliest known diagnosis was in a 6 month old female who developed pubic hair.[46] Additional symptoms include acne, menstrual irregularities and hirsutism in females as well as alopecia in males. LOCAH is often misdiagnosed as polycystic ovarian disease (PCOS).[47]

LOCAH is often diagnosed in the context of infertility assessment in women. During the follicular phase of the menstrual cycle, progesterone accumulates along with 17α-hydroxyprogesterone which can thin the endometrium and change cervical mucus in a manner similar to the effect of progestogen contraceptives, interferes with the normal menstrual cycle, which can lead to oligomenorrhea or amenorrhea[11] and impairs sperm penetration.[48] Abnormal endometrial development leads to decreased uterine receptivity, which also contributes to infertility.[49] Once attempting to conceive, most women with LOCAH will become pregnant within a year with or without treatment, but women with LOCAH have an increased risk of miscarriage.[11]

The diagnostic procedure varies according to the specific enzyme deficiency causing LOCAH and the precise serum androgen levels required for diagnosis are the subject to variance from different measurement methods, refinement in specific cases and are under active research. Some protocols are based on measuring 17α-hydroxyprogesterone levels, with or without ACTH stimulation test.[45][50]

21-Hydroxylase deficiency

Screening

Androgen backdoor pathway

11β-Hydroxylase deficiency

Main page: Congenital adrenal hyperplasia due to 11β-hydroxylase deficiencyThe activity of 11β-hydroxylase can be determined by observing the basal 11-deoxycortisol level. A level over 10 ng/mL, indicates followup with ACTH stimulation test. The 60th minute post-stimulation 11-deoxycortisol levels higher than 18 ng/mL are diagnostic of LOCAH.[45]

3β-Hydroxysteroid dehydrogenase deficiency

Main page: Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiencyThe activity of 3β-hydroxysteroid dehydrogenase can be determined by observing the basal 17α-hydroxypregnenolone level. A level above 30 ng/mL and 17α-hydroxypregnenolone/cortisol ratio above 10 SD are diagnostic of LOCAH.[45][3]

Management

Management and treatment of LOCAH is case specific[1] and the application of glucocorticoid treatment is not standard as it is in classic CAH.[1] LOCAH is not a life-threatening medical condition and the risks of treatment given prenatally or to asymptomatic children outweigh potential benefits.[51][52][53] In appropriate cases, glucocorticoids (usually hydrocortisone in children) are administered to suppress secretion of corticotropin releasing hormone (CRH) produced by hypothalamus and of adrenocorticotropic hormone (ACTH) produced by pituitary gland. This suppression will reduce concentration in blood of sex steroids produced by adrenal glands.[1] Some of the main considerations in treatment include the watchful waiting of symptom severity as well as adverse responses to glucocorticoids administered as drugs, seen in patient bone mineral density, height and weight.[1] For women, an oral contraceptive pill and androgen blockers such as spironolactone or cyproterone acetate are alternatives to glucocorticoids for managing symptoms of androgen excess.[1] There is still debate whether miscarriage rates in women with LOCAH are influenced by hydrocortisone treatment.[1]

Prevalence

According to haplotype association studies, the prevalence of LOCAH in the US Ashkenazi Jew and Caucasian populations is estimated to be 1:500 to 1:1000, but in people with a high rate of marriage between relatives, the prevalence rate is as high as 1:50 to 1:100. A 2017 CYP21A2 genotype analysis predicted that the total frequency of LOCAH in the general population of the United States is about 1:200 (95% confidence level, from 1:100 to 1:280).[2][54]

According to a 2017 meta-analysis, the prevalence of LOCAH among women with signs and symptoms of androgen excess is 4.2% globally, and between 1% and 10% depending on the ethnicity of the population being studied.[22]

Anne Fausto-Sterling, an American sexologist, in a 2000 book "Sexing the Body" came up with an estimate that people with intersex conditions account for 1.7% of the general population.[55] This estimate is cited by a number of prominent intersex advocacy organizations.[56][57][58][59] Of these intersex individuals, according to Fausto-Sterling, 88% have LOCAH.[55] Leonard Sax, an American psychologist and a family physician, criticized these figures in a review published in 2002 in The Journal of Sex Research, stating that from the clinician's perspective, LOCAH is not an intersex condition.[60] Including LOCAH in intersex prevalence estimates has been cited as an example of misleading statistical practice.[61]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Challenges in treatment of patients with non-classic congenital adrenal hyperplasia". Front Endocrinol (Lausanne) 13: 1064024. 2022. doi:10.3389/fendo.2022.1064024. PMID 36578966. 
  2. ↑ 2.0 2.1 2.2 2.3 "Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology and Metabolism 103 (11): 4043–4088. November 2018. doi:10.1210/jc.2018-01865. PMID 30272171. 
  3. ↑ 3.0 3.1 3.2 "A case of late-onset congenital adrenal hyperplasia due to partial 3 beta-hydroxysteroid dehydrogenase deficiency". Endocrine Journal 40 (1): 107–9. February 1993. doi:10.1507/endocrj.40.107. PMID 7951484. https://www.jstage.jst.go.jp/article/endocrj1993/40/1/40_1_107/_article. 
  4. ↑ "OMIM Entry - # 202010 - ADRENAL HYPERPLASIA, CONGENITAL, DUE TO STEROID 11-BETA-HYDROXYLASE DEFICIENCY". https://www.omim.org/entry/202010. 
  5. ↑ "High frequency of nonclassical steroid 21-hydroxylase deficiency". American Journal of Human Genetics 37 (4): 650–67. July 1985. PMID 9556656. 
  6. ↑ "Genetics of congenital adrenal hyperplasia". Best Practice & Research. Clinical Endocrinology & Metabolism 23 (2): 181–92. April 2009. doi:10.1016/j.beem.2008.10.014. PMID 19500762. 
  7. ↑ "Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency". European Journal of Endocrinology 174 (5): 601–9. May 2016. doi:10.1530/EJE-15-1181. PMID 26865584. 
  8. ↑ 8.0 8.1 8.2 "Nonclassic congenital adrenal hyperplasia". International Journal of Pediatric Endocrinology 2010: 625105. 2010. doi:10.1155/2010/625105. PMID 20671993. 
  9. ↑ "The management of glucocorticoid deficiency: Current and future perspectives". Clinica Chimica Acta; International Journal of Clinical Chemistry 505: 148–159. June 2020. doi:10.1016/j.cca.2020.03.006. PMID 32145273. 
  10. ↑ "Genotype-Specific Cortisol Reserve in a Cohort of Subjects with Non-Classic Congenital Adrenal Hyperplasia (NCCAH)". J Clin Endocrinol Metab. September 2023. doi:10.1210/clinem/dgad546. PMID 37715965. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 "Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency". The New England Journal of Medicine 383 (13): 1248–1261. September 2020. doi:10.1056/NEJMra1909786. PMID 32966723. 
  12. ↑ "Cortisol response to adrenocorticotropin testing in non-classical congenital adrenal hyperplasia (NCCAH)". Journal of Pediatric Endocrinology & Metabolism 29 (12): 1365–1371. December 2016. doi:10.1515/jpem-2016-0216. PMID 27849625. 
  13. ↑ "Circadian rhythm of adrenal glucocorticoid: its regulation and clinical implications". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1812 (5): 581–91. May 2011. doi:10.1016/j.bbadis.2011.02.003. PMID 21320597. 
  14. ↑ "Glucocorticoids and the circadian clock". The Journal of Endocrinology 200 (1): 3–22. January 2009. doi:10.1677/JOE-08-0415. PMID 18971218. 
  15. ↑ "Interaction between circadian rhythms and stress". Neurobiology of Stress 6: 57–67. February 2017. doi:10.1016/j.ynstr.2016.09.001. PMID 28229109. 
  16. ↑ "Stress-Related and Circadian Secretion and Target Tissue Actions of Glucocorticoids: Impact on Health". Frontiers in Endocrinology 8: 70. 2017. doi:10.3389/fendo.2017.00070. PMID 28503165. 
  17. ↑ "Alternative androgen pathways". WikiJournal of Medicine 10: X. 2023. doi:10.15347/WJM/2023.003. 
  18. ↑ 18.0 18.1 "The "backdoor pathway" of androgen synthesis in human male sexual development". PLOS Biology 17 (4): e3000198. April 2019. doi:10.1371/journal.pbio.3000198. PMID 30943210. 
  19. ↑ "Non-classic adrenal hyperplasia due to the deficiency of 21-hydroxylase and its relation to polycystic ovarian syndrome". Frontiers of Hormone Research 40: 158–70. 2013. doi:10.1159/000342179. ISBN 978-3-318-02238-4. PMID 24002412. 
  20. ↑ 20.0 20.1 "Management of the Female With Non-classical Congenital Adrenal Hyperplasia (NCCAH): A Patient-Oriented Approach". Frontiers in Endocrinology 10: 366. 2019. doi:10.3389/fendo.2019.00366. PMID 31244776. 
  21. ↑ "Treatment of Nonclassic 11-Hydroxylase Deficiency with Ashwagandha Root". Case Reports in Endocrinology 2017: 1869560. 2017. doi:10.1155/2017/1869560. PMID 28713602. 
  22. ↑ 22.0 22.1 22.2 "Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women". Human Reproduction Update 23 (5): 580–599. September 2017. doi:10.1093/humupd/dmx014. PMID 28582566. 
  23. ↑ "Congenital adrenal hyperplasia and acne in male patients". The British Journal of Dermatology 148 (6): 1263–6. June 2003. doi:10.1046/j.1365-2133.2003.05369.x. PMID 12828760. 
  24. ↑ "The frequency of 21-alpha hydroxylase enzyme deficiency and related sex hormones in Iraqi healthy male subjects versus patients with acne vulgaris". Saudi Medical Journal 30 (12): 1547–50. December 2009. PMID 19936418. 
  25. ↑ "Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome". Endocrine 50 (1): 32–50. September 2015. doi:10.1007/s12020-015-0656-0. PMID 26082286. 
  26. ↑ 26.0 26.1 "Extensive clinical experience: nonclassical 21-hydroxylase deficiency". The Journal of Clinical Endocrinology and Metabolism 91 (11): 4205–14. November 2006. doi:10.1210/jc.2006-1645. PMID 16912124. "Loss of scalp hair in females and males is embarrassing, requiring treatment with 5α-reductase inhibitors". 
  27. ↑ "[Premature androgenetic alopecia in adult male with nonclassic 21-OH deficiency. A novel nonsense CYP21A2 mutation (Y336X) in 2 affected siblings]" (in es-es). Medicina Clinica 127 (16): 617–21. October 2006. doi:10.1016/s0025-7753(06)72688-4. PMID 17145028. 
  28. ↑ Congenital Adrenal Hyperplasia: Diagnosis and Emergency Treatment. MDText.com. April 2019. https://www.ncbi.nlm.nih.gov/books/NBK279085/. 
  29. ↑ "Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome". Urology 71 (2): 261–6. February 2008. doi:10.1016/j.urology.2007.09.025. PMID 18308097. 
  30. ↑ "Letter to the editor regarding the article "Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome"" (in English). Urology 169: 273. 2022. doi:10.1016/j.urology.2022.07.051. ISSN 0090-4295. PMID 35987379. https://www.goldjournal.net/article/S0090-4295(22)00690-2/abstract. 
  31. ↑ "AUTHOR REPLY" (in English). Urology 169: 273–274. 2022. doi:10.1016/j.urology.2022.07.049. ISSN 0090-4295. PMID 35985522. 
  32. ↑ "Prevalence and ultrasound patterns of testicular adrenal rest tumors in adults with congenital adrenal hyperplasia". Translational Andrology and Urology 10 (2): 562–573. February 2021. doi:10.21037/tau-20-998. PMID 33718059. 
  33. ↑ "Nonclassic adrenal hyperplasia". Reviews in Endocrine & Metabolic Disorders 10 (1): 77–82. March 2009. doi:10.1007/s11154-008-9097-x. PMID 18690539. 
  34. ↑ 34.0 34.1 34.2 "Genotype-phenotype correlations in children and adolescents with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency". Molecular and Cellular Pediatrics 7 (1): 8. July 2020. doi:10.1186/s40348-020-00100-w. PMID 32647925. 
  35. ↑ 35.0 35.1 "Molecular diagnosis of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency". BMC Endocrine Disorders 20 (1): 165. November 2020. doi:10.1186/s12902-020-00643-z. PMID 33168061. 
  36. ↑ "Challenges of CYP21A2 genotyping in children with 21-hydroxylase deficiency: determination of genotype-phenotype correlation using next generation sequencing in Southeastern Anatolia". Journal of Endocrinological Investigation 44 (11): 2395–2405. March 2021. doi:10.1007/s40618-021-01546-z. PMID 33677812. 
  37. ↑ 37.0 37.1 "Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians". Genetics in Medicine 19 (11): 1276–1279. November 2017. doi:10.1038/gim.2017.46. PMID 28541281. 
  38. ↑ "Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus". The Journal of Biological Chemistry 265 (34): 20916–22. December 1990. doi:10.1016/S0021-9258(17)45304-X. PMID 2249999. 
  39. ↑ "Genetic defects in the cyp21a2 gene in heterozygous girls with premature adrenarche and adolescent females with hyperandrogenemia". Georgian Medical News (210): 40–7. September 2012. PMID 23045419. 
  40. ↑ "Hyperandrogenism in carriers of CYP21 mutations: the role of genotype". Clinical Endocrinology 64 (6): 645–51. June 2006. doi:10.1111/j.1365-2265.2006.02521.x. PMID 16712666. 
  41. ↑ "Steroid 21-hydroxylase (P450c21) naturally occurring mutants I172N, V281L and I236n/V237E/M239K exert a dominant negative effect on enzymatic activity when co-expressed with the wild-type protein". J Pediatr Endocrinol Metab 16 (7): 1017–24. September 2003. doi:10.1515/jpem.2003.16.7.1017. PMID 14513879. 
  42. ↑ "EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency". European Journal of Human Genetics 28 (10): 1341–1367. October 2020. doi:10.1038/s41431-020-0653-5. PMID 32616876. 
  43. ↑ "Adrenal Tumor Mimicking Non-Classic Congenital Adrenal Hyperplasia". Frontiers in Endocrinology 11: 526287. 2020. doi:10.3389/fendo.2020.526287. PMID 33117272. 
  44. ↑ "[Clinically late virilism with excretion of pregnanetriol and insufficiency of cortisol production]" (in fr). Annales d'Endocrinologie 18 (3): 416–22. May 1957. PMID 13470408. 
  45. ↑ 45.0 45.1 45.2 45.3 "Non-Classical Congenital Adrenal Hyperplasia in Childhood". Journal of Clinical Research in Pediatric Endocrinology 9 (1): 1–7. March 2017. doi:10.4274/jcrpe.3378. PMID 27354284. 
  46. ↑ "Late-onset steroid 21-hydroxylase deficiency: a variant of classical congenital adrenal hyperplasia". The Journal of Clinical Endocrinology and Metabolism 55 (5): 817–27. November 1982. doi:10.1210/jcem-55-5-817. PMID 6288753. 
  47. ↑ "Late-onset 21-hydroxylase deficiency mimicking idiopathic hirsutism or polycystic ovarian disease". Annals of Internal Medicine 96 (2): 143–8. February 1982. doi:10.7326/0003-4819-96-2-143. PMID 6977282. 
  48. ↑ "Adrenal steroidogenesis and congenital adrenal hyperplasia". Endocrinology and Metabolism Clinics of North America 44 (2): 275–96. June 2015. doi:10.1016/j.ecl.2015.02.002. PMID 26038201. 
  49. ↑ "Androgens in Congenital Adrenal Hyperplasia". Frontiers of Hormone Research 53: 65–76. 2019. doi:10.1159/000494903. ISBN 978-3-318-06470-4. PMID 31499506. 
  50. ↑ "17-Hydroxyprogesterone Response to Standard Dose Synacthen Stimulation Test in CYP21A2 Heterozygous Carriers and Non-carriers in Symptomatic and Asymptomatic Groups: Meta-analyses". J Clin Res Pediatr Endocrinol 14 (1): 56–68. March 2022. doi:10.4274/jcrpe.galenos.2021.2021.0184. PMID 34743977. 
  51. ↑ "Prenatal treatment of congenital adrenal hyperplasia: risks outweigh benefits". American Journal of Obstetrics and Gynecology 208 (5): 354–9. May 2013. doi:10.1016/j.ajog.2012.10.885. PMID 23123167. 
  52. ↑ "Consensus statement on 21-hydroxylase deficiency from the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society". Hormone Research 58 (4): 188–95. 2002. doi:10.1159/000065490. PMID 12324718. 
  53. ↑ Joint LWPES/ESPE CAH Working Group (September 2002). "Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology". The Journal of Clinical Endocrinology and Metabolism 87 (9): 4048–53. doi:10.1210/jc.2002-020611. PMID 12213842. 
  54. ↑ "Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians". Genetics in Medicine 19 (11): 1276–1279. November 2017. doi:10.1038/gim.2017.46. PMID 28541281. 
  55. ↑ 55.0 55.1 Sexing the body : gender politics and the construction of sexuality. [New York]. 30 November 2000. ISBN 9780465077137. 
  56. ↑ "Intersex babies are perfect just as they are!". https://www.unfe.org/intersex-awareness/. "up to 1.7 percent of babies are born with sex characteristics that don't fit typical definitions of male and female. That makes being intersex almost as common as being a redhead!" 
  57. ↑ "Its Intersex Awareness Day - here are 5 myths we need to shatter" (in en). 26 October 2018. https://www.amnesty.org/en/latest/news/2018/10/its-intersex-awareness-day-here-are-5-myths-we-need-to-shatter/. "According to experts, around 1.7% of the population is born with intersex traits - comparable to the number of people born with red hair." 
  58. ↑ "What is Intersex? Frequently Asked Questions". https://interactadvocates.org/faq/#howcommon. "About 1.7% of people are born intersex. (Compare that to a ~0.3% chance of having identical twins!) 1 in 2,000 babies (0.05% of humans) are born with genital differences that a doctor might suggest changing with unnecessary surgery." 
  59. ↑ "Intersex population figures" (in en). 28 September 2013. https://ihra.org.au/16601/intersex-numbers/. "Given that intersex people only come to the attention of data collectors through chance or an apparent medical reason, the actual numbers of people with intersex variations are likely to be as much as 1.7%. Despite the limitations of the data, 1.7% seems more justifiable as an upper limit figure than alternatives, to date." 
  60. ↑ "How common is intersex? a response to Anne Fausto-Sterling". Journal of Sex Research 39 (3): 174–8. August 2002. doi:10.1080/00224490209552139. PMID 12476264. https://www.leonardsax.com/how-common-is-intersex-a-response-to-anne-fausto-sterling/. "Reviewing the list of conditions which Fausto-Sterling considers to be intersex, we find that this one condition–late-onset congenital adrenal hyperplasia (LOCAH)–accounts for 88% of all those patients whom Fausto-Sterling classifies as intersex (1.5/1.7 = 88%). From a clinician's perspective, however, LOCAH is not an intersex condition. The genitalia of these babies are normal at birth, and consonant with their chromosomes: XY males have normal male genitalia, and XX females have normal female genitalia.". 
  61. ↑ Stat-spotting : a field guide to identifying dubious data (Updated and expand ed.). Berkeley. 14 September 2013. pp. 12–13. ISBN 978-0520279988. 

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