8 Klinefelter Syndrome

Suggested citation:  Endocrine Society. Endocrine Facts and Figures: Reproduction and Development. First Edition. 2017

Klinefelter syndrome (KS) is a sex chromosome abnormality characterized by supernumerary sex chromosomes. Those who have KS typically possess additional X chromosome, which result in a 47,XXY karyotype. As is true with TS, there are a number of variations on this karyotype, such as those including additional X chromosomes (e.g., 48,XXXY) and mosaicism with 46,XY 184.

Data suggest that boys with KS have similar sex hormone concentrations as normal boys until puberty beings, although some researchers have recently challenged this notion 184.

T production decreases midpuberty, resulting in various degrees of hypergonadotropic hypogonadism, which might contribute to some characteristics observed in KS patients, which include small testes, tall stature, azoospermia, and symptoms related to hypogonadism (including female habitus and body-hair distribution and gynaecomastia 184.

Table 28. Reported physiological and cognitive–behavioral features of Turner syndrome, Klinefelter syndrome, and XYY syndrome.
  Klinefelter syndrome Turner syndrome XYY syndrome


Deep vein thrombosis, mitral valve prolapse Aortic coarctation, bicuspid aortic valve, increased risk of aortic dissection, hypertension Data not available


Micro-orchidism, gynaecomastia, hypogonadism, infertility Gonadal dysgenesis, delayed or absent pubertal development, infertility Possible macro-orchidism


Oncological Breast cancer, mediastinal germ-cell tumors


Data not available


Data not available




Seizures; tremor; non-specific motor impairments, including hypotonia


Conductive hearing loss (childhood), sensorineural hearing loss (adulthood)


 Seizures, tremor, hypotonia




Risk of pulmonary embolism




Data not available


Risk of asthma


Intelligence Normal FSIQ* (5-10 points below siblings), PIQ higher than VIQ


Normal FSIQ* (5-10 points below siblings), VIQ higher than PIQ


Similar to findings for KS




Data not available


Deficits in visuomotor skills, mental rotation, spatial orientation


Data not available


Social Impairments in assessment of trustworthiness of faces and classification of emotions and difficulties with social withdrawal, communication, and emotion regulation Impairments in face recognition and classification of negative emotions, parent-rated difficulties with social reciprocity and communication (for children)


Similar to findings for KS
Executive function


Similar to findings for KS, particularly response- inhibition impairments


Impairments in attention, processing speed, working memory, cognitive flexibility, and sequencing or planning Similar to findings for KS


Other endocrine Insulin resistance or diabetes, MetS, hypothyroidism Hypothyroidism Data not available


Orthopedic Tall stature, osteoporosis (related to hypogonadism) Short stature, characteristic craniofacial features, scoliosis, osteoporosis (related to hypogonadism) Tall stature, macrocephaly
Immunological Systemic lupus erythematosus Autoimmune thyroiditis, coeliac disease Data not available


Renal Data not available Collecting system malformations, horseshoe kidney Data not available


Lymphatic Data not available


Lymphoedema in infancy and early childhood Data not available
Language Deficits in oral fluency, written language, reading comprehension, verbal memory Reports of hyperlexia Similar to findings for KS, although deficits can be more severe
Speech Delay in early childhood Possible speech issues related to hearing loss Similar to findings for KS
Arithmetic Mixed evidence: some reports of arithmetic problem-solving deficits by contrast with normal mathematic-achievement scores compared with controls Difficulties with calculation and subitising Similar to findings for KS
Psychiatric Increased risk for ADHD, reading disability or dyslexia, autism- spectrum disorders, depression, schizophrenia Risk for ADHD and dyscalculia; equivocal evidence of autism-spectrum disorders Risk of ADHD, reading disability or dyslexia, and autism-spectrum disorders; case reports of schizophrenia
Abbreviations: KS, Klinefelter syndrome; FSIQ, full-scale intelligence quotient; MetS, metabolic syndrome; VIQ, verbal intelligence quotient. PIQ; performance intelligence quotient; ADHD, attention-deficit hyperactivity disorder.
Note: *, Normal FSIQ is defined as around 100.

Source: Hong et al. 2014 184

Table 29. Abnormalities associated with Klinefelter syndrome and their frequencies.
Feature Frequency
Infertility (adults) 202,203 91-99
Small testes (bi-testicular size <6 ml) 202 >95
Increased gonadotropin levels 203 >95
Azoospermia (adults) 203 >95
Learning disabilities (children) 204 >75
Decreased T levels 203 63-85
Decreased facial hair (adults) 203 60-80
Decreased pubic hair (adults) 203 30-60
Gynecomastia (adolescents, adults) 202,204,205 38-75
Delay of speech development (children) 204 40
Increased height (prepubertal, adults) 204,206 30
Abdominal adiposity (adults) 207 ∼50
MetS (adults) 207 46
Osteopenia (adults) 208,209 5-40
T2DM (adults) 207,210 10-39
Cryptorchidism 202,204 27-37
Decreased penile size (children) 204 10-25
Psychiatric disturbances (children) 204 25
Congenital malformations, cleft palate, inguinal hernia 211 ∼18
Osteoporosis (adults) 209 10
Mitral valve prolapse (adults) 212,213 0-55
Breast cancer (adults) 214, 215 Increased risk (∼50 fold)
Mediastinal cancers (children) 216 increased risk (∼500 fold)
Fractures 217,218 Increased risk (2-40 fold)
Abbreviations: T, testosterone; MetS, metabolic syndrome, T2DM, type 2 diabetes mellitus.

Source: Groth et al. 2013 219


The first paper on KS, published in 1942, called it “not uncommon” 220. Later, after technology made it possible for large-scale chromosome analyses in newborns, the actual prevalence surfaced with a wide range of variation.

A 2013 review by Groth et al. 219 reported that KS is the most frequent male chromosomal aberration, with a prevalence of approximately 150 per 100,000 live-born males 219,221.

Morris et al. proposed that the prevalence of KS is increasing 222, and also that the prevalence may differ between populations.

Table 30. Prevalence of Klinefelter syndrome (47,XXY) in studies of newborns,
spontaneous abortions, prenatal diagnoses, and perinatal deaths.
  Years of data collection Number of cases 47,XXY Prevalence per 1,000 (95% CI) 47, XXY
Newborn studies
Early 1967-1971 41 1.09 (0.80-1.47)
Late 1971-1988 58 1.72 (1.33-2.23)
Prenatal diagnoses series
Amniocentesis series all women >35 1976-1981 112 3.08 (2.54-3.71)
CAD series 1980-2006 542  Data not available
Spontaneous abortions
Culture 1975-2005 17 4.2 (2.4-6.7)
CVS 1987-2005 10 13.1 (6.3-24.0)
Perinatal deaths Data not available 3 4.6 (0.9-13.4)

Source: Morris et al. 2008 222


Data from epidemiological studies in KS in the UK and Denmark indicate that KS individuals will live approximately 1.5 to 2 years less than comparable non-KS individuals. Increased mortality in KS results from a range of disorders, including: cerebrovascular disease, diabetes, epilepsy, lung diseases, and intestinal vascular insufficiency 207,208,210,214,217,218,223.

In Danish populations, the risk of breast cancer in KS individuals was not increased. However there was a large increase in the risk of mediastinal tumors 216. In addition, there was a 70% increased risk of being hospitalized, with the highest risk of hospitalization associated with congenital malformations and psychiatric, endocrine, and metabolic disorders 207,210.

In the UK study mentioned above, 163 deaths occurred among 646 KS patients with a 47,XXY constitution. Diabetes and diseases of the cardiovascular, respiratory and digestive systems were primarily responsible for the increased mortality. In addition, this cohort saw a significantly increased risk of lung cancer and breast cancer incidence and mortality 188.


KS tend to present with language-related disorders. Speech delays can exist in early development, and by early school age (roughly 5-13 years), KS children can exhibit prominent language-related learning disabilities, such as difficulties with writing and reading. Up to 80% of those with KS meet learning disorder criteria (related mainly to language). School-age children often need special-needs education and speech therapy services, and usually experience persistent difficulties throughout adulthood 184.

There are mixed results regarding treatment for neurocognitive and psychiatric symptoms. Most data come from studies examining T-replacement therapies. Some studies suggest T treatment might improve verbal fluency, concentration, motor function, and general wellbeing. However, we need more placebo-controlled prospective studies to better address this question 184.

Table 31. Some available testosterone preparations and suggested dosages for adults with Klinefelter syndrome.
Substance  Brand name (manufacturer) Suggested dose  Route of administration  Format 
T-undecanoate Andriol© (Organon: Oss, The Netherlands) 120-160 mg/d TID Oral 40-mg capsule
T-undecanoate Nebido© (Schering: Berlin, Germany) 750 mg every 9-16 wk Intramuscular 750 mg injection
T Androgel©1 1% (Abbvie Pharmaceuticals) 50 mg to 100 mg, daily Skin Gel
T Androgel©2 1.62%(Abbvie Pharmaceuticals) 20.25 mg to 81 mg, daily Skin Gel


Testim©3 (Endo Pharmaceuticals, Malvern, PA) 50 mg/d Skin Gel


Axiron©4 (Lilly, Indianapolis, IN) 30-120 mg/d Skin Gel


Fortesta©5 (Endo Pharmaceuticals, Malvern, PA) 10-70 mg/d Skin Gel
T Implants© (Organon: Oss, The Netherlands) 400-800 mg every 4-6 mo Subcutaneous Pellets


Striant© (Columbia Laboratories, Livingston, NJ) 60 mg/d Buccal Buccal adhesive


Androderm©6 (Allergan USA, Inc. Irvine, CA) 2-6 mg/d Skin Transdermal patch
Abbreviations: d, day; wk, week; TID, three times a day; mo, month; UK, United Kingdom. T, testosterone.
Notes: 1, Abbvie 49; 2, Abbvie 49; 3,  Endo 224; 4,  Lilly 225; 5,  Endo 224; 6,  Allergan 226

Source: Groth et al. 2012 219

Table 32. Outpatient program for patients with Klinefelter syndrome.
At baseline 
    Fasting glucose, lipids, and HbA1c
    Thyroid status, hemoglobin, hematocrit
Information about the syndrome
    Physical examination including BP, height, weight, waist, testes, gynecomastia, and varicose veins
                 Sex hormones: T, estrogen, SHBG, FSH, and LH
                Confirmation of karyotype, if necessary
    Initiation of androgen treatment (injections, transdermal, or oral)
    Questions about well-being, physical activity, energy, sexual activity, libido, socioeconomic situation
    Bone densitometry (DEXA scan) and vitamin D status, p-calcium
    Echocardiography if deemed necessary
    Discussion of fertility issues often resulting in referral to a fertility clinic
    Consider referral to plastic surgeon for correction of gynecomastia
    Consider referral to psychologist
Annual (every 3 months initially) 
    Questions about well-being, physical activity, energy, sexual activity, libido
    Physical examination including BP, height, weight, waist, and gynecomastia
    Fasting glucose, lipids, and HbA1c
    Sex hormones: total or FT, estrogen, SHBG, FSH, and LH (nadir values)
    Thyroid status, hemoglobin, hematocrit
Every 2nd year or up to every 10th year 
    Bone densitometry (DEXA scan) and vitamin D status, p-calcium
Abbreviations: HbA1c, glycosylated hemoglobin; BP, blood pressure; DEXA, dual-energy x-ray absorptiometry; SHBG, sex hormone-binding globulin; FSH, follicle-stimulation hormone and LH, luteinizing hormone; T, testosterone; FT, free testosterone.

Source: Groth et al. 2012219

Table 33. Major issues in Klinefelter syndrome and potential solutions.
Problem  Potential solution 
Late diagnosis and non-diagnosis Examination of dried blood spots with new molecular genetic techniques
Will early diagnosis lead to better outcome? Prospective screening studies with health technology assessment with reference to medical ethics
Poor learning in school Early diagnosis leading to better learning schemes and perhaps early treatment with T
Effect of T Randomized clinical trials with T and placebo with study of numerous variables
Poor socioeconomic outcome Improvements in schooling and possibly early treatment
T2DM Randomized clinical trials with T and placebo
Increased morbidity Improvements in adult care with multidisciplinary approach
Infertility Improved understanding of pathophysiology of germ cell loss through animal models; better testicular sperm extraction techniques
Abbreviations: T, testosterone; T2DM, type 2 diabetes mellitus.

Source: Groth et al. 2012 219


  1. Gold EB, Crawford SL, Avis NE, et al. Factors Related to Age at Natural Menopause: Longitudinal Analyses From SWAN. American Journal of Epidemiology. 2013;178(1):70-83.
  2. Avis NE, Ory M, Matthews KA, Schocken M, Bromberger J, Colvin A. Health-Related Quality of Life in a Multiethnic Sample of Middle-Aged Women. Medical Care. 2003;41(11):1262-1276.
  3. Blümel JE, Chedraui P, Baron G, et al. A large multinational study of vasomotor symptom prevalence, duration, and impact on quality of life in middle-aged women. Menopause. 2011;18(7):778-785.
  4. Williams RE, Levine KB, Kalilani L, Lewis J, Clark RV. Menopause-specific questionnaire assessment in US population-based study shows negative impact on health-related quality of life. Maturitas. 2009;62(2):153-159.
  5. Freeman EW, Sammel MD, Sanders RJ. Risk of long-term hot flashes after natural menopause. Menopause. 2014;21(9):924-932.
  6. Woods NF, Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women’s lives. The American Journal of Medicine. 2005;118(12):14-24.
  7. Gold EB, Colvin A, Avis N, et al. Longitudinal Analysis of the Association Between Vasomotor Symptoms and Race/Ethnicity Across the Menopausal Transition: Study of Women’s Health Across the Nation. American Journal of Public Health. 2006;96(7):1226-1235.
  8. Williams RE, Kalilani L, DiBenedetti DB, Zhou X, Fehnel SE, Clark RV. Healthcare seeking and treatment for menopausal symptoms in the United States. Maturitas. 2007;58(4):348-358.
  9. Nicholson WK, Ellison SA, Grason H, Powe NR. Patterns of ambulatory care use for gynecologic conditions: A national study. American Journal of Obstetrics and Gynecology. 2001;184(4):523-530.
  10. Crandall CJ, Tseng C-H, Crawford SL, et al. Association of menopausal vasomotor symptoms with increased bone turnover during the menopausal transition. Journal of Bone and Mineral Research. 2011;26(4):840-849.
  11. Thurston RC, Sutton-Tyrrell K, Everson-Rose SA, Hess R, Matthews KA. Hot Flashes and Subclinical Cardiovascular Disease: Findings From the Study of Women’s Health Across the Nation Heart Study. Circulation. 2008;118(12):1234-1240.
  12. Thurston RC, Sutton-Tyrrell K, Everson-Rose SA, Hess R, Powell LH, Matthews KA. Hot flashes and carotid intima media thickness among midlife women. Menopause. 2011;18(4):352-358.
  13. Sarrel P, Portman D, Lefebvre P, et al. Incremental direct and indirect costs of untreated vasomotor symptoms. Menopause. 2015;22(3):260-266.
  14. Utian WH. Health and Quality of Life Outcomes. 2005;3(1):47.
  15. Avis NE, Crawford SL, Greendale G, et al. Duration of Menopausal Vasomotor Symptoms Over the Menopause Transition. JAMA Internal Medicine. 2015;175(4):531.
  16. Cooper GS, Sandler DP. Age at Natural Menopause and Mortality. Annals of Epidemiology. 1998;8(4):229-235.
  17. Wise PM, Krajnak KM, Kashon ML. Menopause: The Aging of Multiple Pacemakers. Science. 1996;273(5271):67-70.
  18. Snowdon DA, Kane RL, Beeson WL, et al. Is early natural menopause a biologic marker of health and aging? American Journal of Public Health. 1989;79(6):709-714.
  19. Ossewaarde ME, Bots ML, Verbeek ALM, et al. Age at Menopause, Cause-Specific Mortality and Total Life Expectancy. Epidemiology. 2005;16(4):556-562.
  20. Jacobsen BK. Age at Natural Menopause and All-Cause Mortality: A 37-Year Follow-up of 19,731 Norwegian Women. American Journal of Epidemiology. 2003;157(10):923-929.
  21. Jansen SC, Temme EHM, Schouten EG. Lifetime estrogen exposure versus age at menopause as mortality predictor. Maturitas. 2002;43(2):105-112.
  22. Jacobsen BK, Knutsen SF, Fraser GE. Age at Natural Menopause and Total Mortality and Mortality from Ischemic Heart Disease. Journal of Clinical Epidemiology. 1999;52(4):303-307.
  23. de Kleijn MJJ. Endogenous Estrogen Exposure and Cardiovascular Mortality Risk in Postmenopausal Women. American Journal of Epidemiology. 2002;155(4):339-345.
  24. van der Schouw YT, van der Graaf Y, Steyerberg EW, Eijkemans MJC, Banga JD. Age at menopause as a risk factor for cardiovascular mortality. The Lancet. 1996;347(9003):714-718.
  25. Jacobsen BK, Nilssen S, Heuch I, Kvåle G. Does age at natural menopause affect mortality from ischemic heart disease? Journal of Clinical Epidemiology. 1997;50(4):475-479.
  26. Hu FB, Grodstein F, Hennekens CH, et al. Age at Natural Menopause and Risk of Cardiovascular Disease. Archives of Internal Medicine. 1999;159(10):1061.
  27. Atsma F, Bartelink M-LEL, Grobbee DE, van der Schouw YT. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause. 2006;13(2):265-279.
  28. Cui R, Iso H, Toyoshima H, et al. Relationships of Age at Menarche and Menopause, and Reproductive Year with Mortality from Cardiovascular Disease in Japanese Postmenopausal Women: The JACC Study. Journal of Epidemiology. 2006;16(5):177-184.
  29. Lokkegaard E, Jovanovic Z, Heitmann BL, Keiding N, Ottesen B, Pedersen AT. The association between early menopause and risk of ischaemic heart disease: influence of Hormone Therapy. Maturitas. 2006;53(2):226-233.
  30. Lisabeth LD, Beiser AS, Brown DL, Murabito JM, Kelly-Hayes M, Wolf PA. Age at Natural Menopause and Risk of Ischemic Stroke: The Framingham Heart Study. Stroke. 2009;40(4):1044-1049.
  31. Joakimsen O, Bønaa KH, Stensland-Bugge E, Jacobsen BK. Population-based study of age at menopause and ultrasound assessed carotid atherosclerosis. Journal of Clinical Epidemiology. 2000;53(5):525-530.
  32. Parashar S, Reid KJ, Spertus JA, Shaw LJ, Vaccarino V. Early menopause predicts angina after myocardial infarction. Menopause. 2010;17(5):938-945.
  33. Kritz-Silverstein D, Barrett-Connor E. Early menopause, number of reproductive years, and bone mineral density in postmenopausal women. American Journal of Public Health. 1993;83(7):983-988.
  34. Parazzini F, Bidoli E, Franceschi S, et al. Menopause, menstrual and reproductive history, and bone density in northern Italy. Journal of Epidemiology & Community Health. 1996;50(5):519-523.
  35. van der Voort DJM, van der Weijer PHM, Barentsen R. Early menopause: increased fracture risk at older age. Osteoporosis International. 2003;14(6):525-530.
  36. de Graaff J, Stolte LAM. Age at menarche and menopause of uterine cancer patients. European Journal of Obstetrics & Gynecology and Reproductive Biology. 1978;8(4):187-193.
  37. Franceschi S, La Vecchia C, Booth M, et al. Pooled analysis of 3 european case-control studies of ovarian cancer: II. Age at menarche and at menopause. International Journal of Cancer. 1991;49(1):57-60.
  38. Kelsey JL, Gammon MD, John EM. Reproductive Factors and Breast Cancer. Epidemiologic Reviews. 1993;15(1):36-47.
  39. Monninkhof EM, van der Schouw YT, Peeters PHM. Early age at menopause and breast cancer: are leaner women more protected? A prospective analysis of the Dutch DOM cohort. Breast Cancer Research and Treatment. 1999;55(3):285-291.
  40. Gray A, Feldman HA, McKinlay JB, Longcope C. Age, Disease, and Changing Sex Hormone Levels in Middle-Aged Men: Results of the Massachusetts Male Aging Study*. The Journal of Clinical Endocrinology & Metabolism. 1991;73(5):1016-1025.
  41. Orwoll E, Lambert LC, Marshall LM, et al. Testosterone and Estradiol among Older Men. The Journal of Clinical Endocrinology & Metabolism. 2006;91(4):1336-1344.
  42. Wu FCW, Tajar A, Pye SR, et al. Hypothalamic-Pituitary-Testicular Axis Disruptions in Older Men Are Differentially Linked to Age and Modifiable Risk Factors: The European Male Aging Study. The Journal of Clinical Endocrinology & Metabolism. 2008;93(7):2737-2745.
  43. Snyder PJ. Hypogonadism in Elderly Men — What to Do Until the Evidence Comes. New England Journal of Medicine. 2004;350(5):440-442.
  44. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010;363(2):123-135.
  45. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
  46. Fink HA, Ewing SK, Ensrud KE, et al. Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. J Clin Endocrinol Metab. 2006;91(10):3908-3915.
  47. Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013;173(15):1465-1466.
  48. Antonio L, Wu FC, O’Neill TW, et al. Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone. J Clin Endocrinol Metab. 2016;101(7):2647-2657.
  49. Abbvie. Highlights of Prescribing Information Androgel 1%. US Prescribing Information 2016; http://www.rxabbvie.com/pdf/androgel_PI.pdf. Accessed August 11, 2017.
  50. Health A. Androgel 50mg. 2017; http://amazon4health.com/product/androgel-50mg/. Accessed August 11, 2107.
  51. Pfizer. Product Monogropah. 2015; https://www.pfizer.ca/sites/g/files/g10017036/f/201505/Depo-Testosterone_PM_E_181380_25_March_2015.pdf. Accessed August 10, 2017.
  52. MyThyroidShop. 2017; https://www.myroidshop.net/buy-injectable-steroids/Buy-Test-E. Accessed August 11, 2017.
  53. Handelsman DJ. Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse. Med J Aust. 2013;199(8):548-551.
  54. Rohrmann S, Nelson WG, Rifai N, et al. Serum estrogen, but not testosterone, levels differ between black and white men in a nationally representative sample of Americans. J Clin Endocrinol Metab. 2007;92(7):2519-2525.
  55. Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92(11):4241-4247.
  56. Araujo AB, O’Donnell AB, Brambilla DJ, et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 2004;89(12):5920-5926.
  57. Liu PY, Swerdloff RS, Veldhuis JD. Clinical review 171: The rationale, efficacy and safety of androgen therapy in older men: future research and current practice recommendations. J Clin Endocrinol Metab. 2004;89(10):4789-4796.
  58. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109-122.
  59. Farias JM, Tinetti M, Khoury M, Umpierrez GE. Low testosterone concentration and atherosclerotic disease markers in male patients with type 2 diabetes. J Clin Endocrinol Metab. 2014;99(12):4698-4703.
  60. Tibblin G, Adlerberth A, Lindstedt G, Bjorntorp P. The pituitary-gonadal axis and health in elderly men: a study of men born in 1913. Diabetes. 1996;45(11):1605-1609.
  61. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care. 2000;23(4):490-494.
  62. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and Sex Hormone-Binding Globulin Predict the Metabolic Syndrome and Diabetes in Middle-Aged Men. Diabetes Care. 2004;27(5):1036-1041.
  63. Tsai EC, Matsumoto AM, Fujimoto WY, Boyko EJ. Association of Bioavailable, Free, and Total Testosterone With Insulin Resistance: Influence of sex hormone-binding globulin and body fat. Diabetes Care. 2004;27(4):861-868.
  64. Orwoll E, Lambert LC, Marshall LM, et al. Testosterone and estradiol among older men. J Clin Endocrinol Metab. 2006;91(4):1336-1344.
  65. Tajar A, Forti G, O’Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab. 2010;95(4):1810-1818.
  66. Araujo AB, Kupelian V, Page ST, Handelsman DJ, Bremner WJ, McKinlay JB. Sex steroids and all-cause and cause-specific mortality in men. Arch Intern Med. 2007;167(12):1252-1260.
  67. Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015;36(40):2706-2715.
  68. Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. Jama. 2013;310(17):1829-1836.
  69. Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. Jama. 2017;317(7):708-716.
  70. Roy CN, Snyder PJ, Stephens-Shields AJ, et al. Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial. JAMA Intern Med. 2017;177(4):480-490.
  71. Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial. JAMA Intern Med. 2017;177(4):471-479.
  72. Mohr BA, Guay AT, O’Donnell AB, McKinlay JB. Normal, bound and nonbound testosterone levels in normally ageing men: results from the Massachusetts Male Ageing Study. Clin Endocrinol (Oxf). 2005;62(1):64-73.
  73. Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2011;34(4):828-837.
  74. Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369(11):1011-1022.
  75. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611-624.
  76. Zitzmann M, Mattern A, Hanisch J, Gooren L, Jones H, Maggi M. IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. J Sex Med. 2013;10(2):579-588.
  77. Chang AY, Ayers C, Minhajuddin A, et al. Polycystic ovarian syndrome and subclinical atherosclerosis among women of reproductive age in the Dallas heart study. Clin Endocrinol (Oxf). 2011;74(1):89-96.
  78. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004;89(6):2745-2749.
  79. March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25(2):544-551.
  80. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41-47.
  81. Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(12):4565-4592.
  82. Zawadzki JK DA. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A GJ, Haseltine FP, Merriam GR,, ed. Polycystic Ovary Syndrome. Boston: Blackwell Scientific; 1992:377-384.
  83. Azziz R, Carmina E, Dewailly D, et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab. 2006;91(11):4237-4245.
  84. Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007;370(9588):685-697.
  85. Azziz R, Marin C, Hoq L, Badamgarav E, Song P. Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span. J Clin Endocrinol Metab. 2005;90(8):4650-4658.
  86. Engmann L, Jin S, Sun F, et al. Racial and ethnic differences in the polycystic ovary syndrome metabolic phenotype. Am J Obstet Gynecol. 2017;216(5):493.e491-493.e413.
  87. Chang AY, Oshiro J, Ayers C, Auchus RJ. Influence of race/ethnicity on cardiovascular risk factors in polycystic ovary syndrome, the Dallas Heart Study. Clinical Endocrinology. 2016;85(1):92-99.
  88. Wild RA, Carmina E, Diamanti-Kandarakis E, et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab. 2010;95(5):2038-2049.
  89. Gambineri A, Pelusi C, Vicennati V, Pagotto U, Pasquali R. Obesity and the polycystic ovary syndrome. Int J Obes Relat Metab Disord. 2002;26(7):883-896.
  90. Zimmermann S, Phillips RA, Dunaif A, et al. Polycystic ovary syndrome: lack of hypertension despite profound insulin resistance. J Clin Endocrinol Metab. 1992;75(2):508-513.
  91. Dahlgren E, Janson PO, Johansson S, Lapidus L, Oden A. Polycystic ovary syndrome and risk for myocardial infarction. Evaluated from a risk factor model based on a prospective population study of women. Acta Obstet Gynecol Scand. 1992;71(8):599-604.
  92. Dahlgren E, Johansson S, Lindstedt G, et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones. Fertil Steril. 1992;57(3):505-513.
  93. Wild RA, Vesely S, Beebe L, Whitsett T, Owen W. Ferriman Gallwey self-scoring I: performance assessment in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90(7):4112-4114.
  94. Holte J, Gennarelli G, Berne C, Bergh T, Lithell H. Elevated ambulatory day-time blood pressure in women with polycystic ovary syndrome: a sign of a pre-hypertensive state? Hum Reprod. 1996;11(1):23-28.
  95. Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, Ghazzi MN. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91(1):48-53.
  96. Talbott EO, Zborowski JV, Boudreaux MY, McHugh-Pemu KP, Sutton-Tyrrell K, Guzick DS. The relationship between C-reactive protein and carotid intima-media wall thickness in middle-aged women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004;89(12):6061-6067.
  97. Christian RC, Dumesic DA, Behrenbeck T, Oberg AL, Sheedy PF, 2nd, Fitzpatrick LA. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88(6):2562-2568.
  98. Shroff R, Kerchner A, Maifeld M, Van Beek EJ, Jagasia D, Dokras A. Young obese women with polycystic ovary syndrome have evidence of early coronary atherosclerosis. J Clin Endocrinol Metab. 2007;92(12):4609-4614.
  99. Orio F, Jr., Palomba S, Spinelli L, et al. The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study. J Clin Endocrinol Metab. 2004;89(8):3696-3701.
  100. Yarali H, Yildirir A, Aybar F, et al. Diastolic dysfunction and increased serum homocysteine concentrations may contribute to increased cardiovascular risk in patients with polycystic ovary syndrome. Fertil Steril. 2001;76(3):511-516.
  101. Tiras MB, Yalcin R, Noyan V, et al. Alterations in cardiac flow parameters in patients with polycystic ovarian syndrome. Hum Reprod. 1999;14(8):1949-1952.
  102. Schmidt J, Landin-Wilhelmsen K, Brannstrom M, Dahlgren E. Cardiovascular disease and risk factors in PCOS women of postmenopausal age: a 21-year controlled follow-up study. J Clin Endocrinol Metab. 2011;96(12):3794-3803.
  103. Iftikhar S, Collazo-Clavell ML, Roger VL, et al. Risk of cardiovascular events in patients with polycystic ovary syndrome. Neth J Med. 2012;70(2):74-80.
  104. Wild S, Pierpoint T, McKeigue P, Jacobs H. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study. Clin Endocrinol (Oxf). 2000;52(5):595-600.
  105. Haoula Z, Salman M, Atiomo W. Evaluating the association between endometrial cancer and polycystic ovary syndrome. Hum Reprod. 2012;27(5):1327-1331.
  106. Chittenden BG, Fullerton G, Maheshwari A, Bhattacharya S. Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review. Reprod Biomed Online. 2009;19(3):398-405.
  107. Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012;97(1):28-38 e25.
  108. Dokras A. Mood and anxiety disorders in women with PCOS. Steroids. 2012;77(4):338-341.
  109. de Niet JE, de Koning CM, Pastoor H, et al. Psychological well-being and sexarche in women with polycystic ovary syndrome. Hum Reprod. 2010;25(6):1497-1503.
  110. Elsenbruch S, Hahn S, Kowalsky D, et al. Quality of life, psychosocial well-being, and sexual satisfaction in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88(12):5801-5807.
  111. Matsunaga H, Sarai M. Elevated serum LH and androgens in affective disorder related to the menstrual cycle: with reference to polycystic ovary syndrome. Jpn J Psychiatry Neurol. 1993;47(4):825-842.
  112. Rasgon NL, Altshuler LL, Fairbanks L, et al. Reproductive function and risk for PCOS in women treated for bipolar disorder. Bipolar Disord. 2005;7(3):246-259.
  113. Joffe H, Cohen LS, Suppes T, et al. Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism in women with bipolar disorder. Biol Psychiatry. 2006;59(11):1078-1086.
  114. Isojarvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla VV. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med. 1993;329(19):1383-1388.
  115. Nelson-DeGrave VL, Wickenheisser JK, Cockrell JE, et al. Valproate potentiates androgen biosynthesis in human ovarian theca cells. Endocrinology. 2004;145(2):799-808.
  116. Franks S, Webber LJ, Goh M, et al. Ovarian morphology is a marker of heritable biochemical traits in sisters with polycystic ovaries. J Clin Endocrinol Metab. 2008;93(9):3396-3402.
  117. Legro RS, Driscoll D, Strauss JF, 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(25):14956-14960.
  118. Sir-Petermann T, Ladron de Guevara A, Codner E, et al. Relationship between anti-Mullerian hormone (AMH) and insulin levels during different tanner stages in daughters of women with polycystic ovary syndrome. Reprod Sci. 2012;19(4):383-390.
  119. Sir-Petermann T, Codner E, Perez V, et al. Metabolic and reproductive features before and during puberty in daughters of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2009;94(6):1923-1930.
  120. Kent SC, Gnatuk CL, Kunselman AR, Demers LM, Lee PA, Legro RS. Hyperandrogenism and hyperinsulinism in children of women with polycystic ovary syndrome: a controlled study. J Clin Endocrinol Metab. 2008;93(5):1662-1669.
  121. Dumont A, Robin G, Catteau-Jonard S, Dewailly D. Role of Anti-Mullerian Hormone in pathophysiology, diagnosis and treatment of Polycystic Ovary Syndrome: a review. Reprod Biol Endocrinol. 2015;13:137.
  122. Tal R, Seifer DB, Khanimov M, Malter HE, Grazi RV, Leader B. Characterization of women with elevated antimullerian hormone levels (AMH): correlation of AMH with polycystic ovarian syndrome phenotypes and assisted reproductive technology outcomes. Am J Obstet Gynecol. 2014;211(1):59.e51-58.
  123. Dewailly D, Lujan ME, Carmina E, et al. Definition and significance of polycystic ovarian morphology: a task force report from the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update. 2014;20(3):334-352.
  124. Witchel SF, Oberfield S, Rosenfield RL, et al. The Diagnosis of Polycystic Ovary Syndrome during Adolescence. Horm Res Paediatr. 2015.
  125. Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(4):1105-1120.
  126. Rosenzweig JL, Ferrannini E, Grundy SM, et al. Primary prevention of cardiovascular disease and type 2 diabetes in patients at metabolic risk: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(10):3671-3689.
  127. Harborne L, Fleming R, Lyall H, Sattar N, Norman J. Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88(9):4116-4123.
  128. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2010(1):Cd003053.
  129. Luborsky JL, Meyer P, Sowers MF, Gold EB, Santoro N. Premature menopause in a multi-ethnic population study of the menopause transition. Human Reproduction. 2003;18(1):199-206.
  130. Coulam CB, Adamson SC, Annegers JF. Incidence of Premature Ovarian Failure. Obstetrical & Gynecological Survey. 1987;42(3):182-183.
  131. Cramer DW, Xu H. Predicting age at menopause. Maturitas. 1996;23(3):319-326.
  132. Wellons M, Ouyang P, Schreiner PJ, Herrington DM, Vaidya D. Early menopause predicts future coronary heart disease and stroke. Menopause: The Journal of The North American Menopause Society. 2012;19(10):1081-1087.
  133. Cooper GS, Ephross SA, Weinberg CR, Baird DD, Whelan EA, Sandler DP. Menstrual and Reproductive Risk Factors for Ischemic Heart Disease. Epidemiology. 1999;10(3):255-259.
  134. Sarrel PM, Sullivan SD, Nelson LM. Hormone replacement therapy in young women with surgical primary ovarian insufficiency. Fertility and Sterility. 2016;106(7):1580-1587.
  135. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. Jama. 2013;310(13):1353-1368.
  136. Benkhadra K, Mohammed K, Al Nofal A, et al. Menopausal Hormone Therapy and Mortality: A Systematic Review and Meta-Analysis. The Journal of Clinical Endocrinology & Metabolism. 2015;100(11):4021-4028.
  137. Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(9):4133-4160.
  138. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000;21(3):245-291.
  139. White PC. Neonatal screening for congenital adrenal hyperplasia. Nat Rev Endocrinol. 2009;5(9):490-498.
  140. Pearce M, DeMartino L, McMahon R, et al. Newborn screening for congenital adrenal hyperplasia in New York State. Molecular Genetics and Metabolism Reports. 2016;7:1-7.
  141. Therrell BL, Jr., Berenbaum SA, Manter-Kapanke V, et al. Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics. 1998;101(4 Pt 1):583-590.
  142. Kaye CI, Accurso F, La Franchi S, et al. Newborn screening fact sheets. Pediatrics. 2006;118(3):e934-963.
  143. Grosse SD, Van Vliet G. How many deaths can be prevented by newborn screening for congenital adrenal hyperplasia? Horm Res. 2007;67(6):284-291.
  144. Hummel SR, Sadler S, Whitaker MJ, Ara RM, Dixon S, Ross RJ. A model for measuring the health burden of classic congenital adrenal hyperplasia in adults. Clin Endocrinol (Oxf). 2016;85(3):361-398.
  145. Han TS, Walker BR, Arlt W, Ross RJ. Treatment and health outcomes in adults with congenital adrenal hyperplasia. Nat Rev Endocrinol. 2014;10(2):115-124.
  146. Pang SY, Wallace MA, Hofman L, et al. Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics. 1988;81(6):866-874.
  147. Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI. High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet. 1985;37(4):650-667.
  148. Kovacs J, Votava F, Heinze G, et al. Lessons from 30 years of clinical diagnosis and treatment of congenital adrenal hyperplasia in five middle European countries. J Clin Endocrinol Metab. 2001;86(7):2958-2964.
  149. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J Clin Endocrinol Metab. 2002;87(9):4048-4053.
  150. Porter J. A Phase III Study of Efficacy, Safety and Tolerability of Chronocort® Compared With Standard Glucocorticoid Replacement Therapy in the Treatment of Congenital Adrenal Hyperplasia. Clinical Trial Phase 3; https://clinicaltrials.gov/ct2/show/NCT02716818?term=congenital+adrenal+hyperplasia&rank=10.
  151. Merke D. A Pilot Study Assessing the use of Continuous Subcutaneous Hydrocortisone Infusion In the Treatment of Congenital Adrenal Hyperplasia. Clinical Trial Phase 2; https://clinicaltrials.gov/ct2/show/NCT01859312?term=congenital+adrenal+hyperplasia&rank=15.
  152. Millendo Therapeutics I. A Phase 2, Multicenter Study of ATR-101 for the Treatment of Congenital Adrenal Hyperplasia. Clinical Trial Phase 2; https://clinicaltrials.gov/ct2/show/NCT02804178.
  153. Auchus RJ, Buschur EO, Chang AY, et al. Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2014;99(8):2763-2770.
  154. White P. A Phase 1 Multi-Center Study to Assess the Efficacy and Safety of Abiraterone Acetate as Adjunctive Therapy in Pre-Pubescent Children With Classic 21-Hydroxylase Deficiency. Clinical Trial Phase 1; https://clinicaltrials.gov/ct2/show/NCT02574910?term=congenital+adrenal+hyperplasia&rank=14.
  155. Pang S, Clark AT, Freeman LC, et al. Maternal side effects of prenatal dexamethasone therapy for fetal congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1992;75(1):249-253.
  156. Forest MG. Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod Update. 2004;10(6):469-485.
  157. Lajic S, Wedell A, Bui TH, Ritzen EM, Holst M. Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1998;83(11):3872-3880.
  158. New MI, Carlson A, Obeid J, et al. Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab. 2001;86(12):5651-5657.
  159. Eugster EA, Dimeglio LA, Wright JC, Freidenberg GR, Seshadri R, Pescovitz OH. Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: a meta-analysis. J Pediatr. 2001;138(1):26-32.
  160. Bonfig W, Bechtold S, Schmidt H, Knorr D, Schwarz HP. Reduced final height outcome in congenital adrenal hyperplasia under prednisone treatment: deceleration of growth velocity during puberty. J Clin Endocrinol Metab. 2007;92(5):1635-1639.
  161. Dorr HG. Growth in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res. 2007;68 Suppl 5:93-99.
  162. Hoepffner W, Kaufhold A, Willgerodt H, Keller E. Patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency can achieve their target height: the Leipzig experience. Horm Res. 2008;70(1):42-50.
  163. Weintrob N, Dickerman Z, Sprecher E, Galatzer A, Pertzelan A. Non-classical 21-hydroxylase deficiency in infancy and childhood: the effect of time of initiation of therapy on puberty and final height. Eur J Endocrinol. 1997;136(2):188-195.
  164. New MI, Gertner JM, Speiser PW, Del Balzo P. Growth and final height in classical and nonclassical 21-hydroxylase deficiency. J Endocrinol Invest. 1989;12(8 Suppl 3):91-95.
  165. Urban MD, Lee PA, Migeon CJ. Adult height and fertility in men with congenital virilizing adrenal hyperplasia. N Engl J Med. 1978;299(25):1392-1396.
  166. Cabrera MS, Vogiatzi MG, New MI. Long term outcome in adult males with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2001;86(7):3070-3078.
  167. Jaaskelainen, Voutilainen R. Long-term outcome of classical 21-hydroxylase deficiency: diagnosis, complications and quality of life. Acta Paediatr. 2000;89(2):183-187.
  168. Reisch N, Flade L, Scherr M, et al. High prevalence of reduced fecundity in men with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2009;94(5):1665-1670.
  169. Jaaskelainen J, Kiekara O, Hippelainen M, Voutilainen R. Pituitary gonadal axis and child rate in males with classical 21-hydroxylase deficiency. J Endocrinol Invest. 2000;23(1):23-27.
  170. Hagenfeldt K, Janson PO, Holmdahl G, et al. Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod. 2008;23(7):1607-1613.
  171. Finkielstain GP, Kim MS, Sinaii N, et al. Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2012;97(12):4429-4438.
  172. Arlt W, Willis DS, Wild SH, et al. Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab. 2010;95(11):5110-5121.
  173. Carmichael P RP. Telling children about a physical intersex condition. Dialogues in Pediatric Urology. 2002;25:7–8.
  174. Cohen-Kettenis PT PFe. Transgenderism and Intersexuality in Childhood and Adolescence: Making Choices. SAGE Publications Inc.; 2003.
  175. DSD. 2006 Clinical Guidelines for the Management of Disorders of Sex Differentiation in Childhood. 2006; http://www.dsdguidelines.org/. Accessed Sept. 27, 2017.
  176. DSD. 2006 Handbook for Parents. 2006; http://www.dsdguidelines.org/. Accessed Sept. 27, 2017.
  177. Hughes IA, Houk C, Ahmed SF, Lee PA. Consensus statement on management of intersex disorders. Arch Dis Child. 2006;91(7):554-563.
  178. Dessens AB, Slijper FM, Drop SL. Gender dysphoria and gender change in chromosomal females with congenital adrenal hyperplasia. Arch Sex Behav. 2005;34(4):389-397.
  179. Meyer-Bahlburg HF, Dolezal C, Baker SW, New MI. Sexual orientation in women with classical or non-classical congenital adrenal hyperplasia as a function of degree of prenatal androgen excess. Arch Sex Behav. 2008;37(1):85-99.
  180. Aboutkidshealth. How The Body Works. How The Body Works 2014-2017; http://www.aboutkidshealth.ca/En/HowTheBodyWorks/Pages/default.aspx. Accessed Sept. 27, 2017.
  181. HF M-B. Treatment guidelines for children with disorders of sex development. Neuropsychiatr Enfance Adolesc. 2008; 56:345-349.
  182. J M. Sex errors of the body and related syndromes: a guide to counseling children, adolescents, and their families. 2nd ed. Baltimore, MD: Paul H. Brookes; 1994


  1. Pinsker JE. Clinical review: Turner syndrome: updating the paradigm of clinical care. J Clin Endocrinol Metab. 2012;97(6):E994-1003.
  2. Hong DS, Reiss AL. Cognitive and neurological aspects of sex chromosome aneuploidies. Lancet Neurol. 2014;13(3):306-318.
  3. Elsheikh M, Conway GS, Wass JA. Medical problems in adult women with Turner’s syndrome. Ann Med. 1999;31(2):99-105.
  4. Gravholt CH, Juul S, Naeraa RW, Hansen J. Morbidity in Turner syndrome. J Clin Epidemiol. 1998;51(2):147-158.
  5. Price WH, Clayton JF, Collyer S, De Mey R, Wilson J. Mortality ratios, life expectancy, and causes of death in patients with Turner’s syndrome. J Epidemiol Community Health. 1986;40(2):97-102.
  6. Swerdlow AJ, Hermon C, Jacobs PA, et al. Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet. 2001;65(Pt 2):177-188.
  7. Bondy CA. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab. 2007;92(1):10-25.
  8. Grynberg M, Bidet M, Benard J, et al. Fertility preservation in Turner syndrome. Fertil Steril. 2016;105(1):13-19.
  9. Karnis MF. Fertility, pregnancy, and medical management of Turner syndrome in the reproductive years. Fertil Steril. 2012;98(4):787-791.
  10. Ross J, Lee PA, Gut R, Germak J. Impact of Age and Duration of Growth Hormone Therapy in Children with Turner Syndrome. Hormone Research in Paediatrics. 2011;76(6):392-399.
  11. Linglart A, Cabrol S, Berlier P, et al. Growth hormone treatment before the age of 4 years prevents short stature in young girls with Turner syndrome. Eur J Endocrinol. 2011;164(6):891-897.
  12. Stephure DK. Impact of growth hormone supplementation on adult height in turner syndrome: results of the Canadian randomized controlled trial. J Clin Endocrinol Metab. 2005;90(6):3360-3366.
  13. Davenport ML, Crowe BJ, Travers SH, et al. Growth hormone treatment of early growth failure in toddlers with Turner syndrome: a randomized, controlled, multicenter trial. J Clin Endocrinol Metab. 2007;92(9):3406-3416.
  14. Blum WF, Cao D, Hesse V, et al. Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome. Horm Res. 2009;71(3):167-172.
  15. Chacko E, Graber E, Regelmann MO, Wallach E, Costin G, Rapaport R. Update on Turner and Noonan syndromes. Endocrinol Metab Clin North Am. 2012;41(4):713-734.
  16. Ross JL, Quigley CA, Cao D, et al. Growth hormone plus childhood low-dose estrogen in Turner’s syndrome. N Engl J Med. 2011;364(13):1230-1242.
  17. Quigley CA, Crowe BJ, Anglin DG, Chipman JJ. Growth hormone and low dose estrogen in Turner syndrome: results of a United States multi-center trial to near-final height. J Clin Endocrinol Metab. 2002;87(5):2033-2041.
  18. van Pareren YK, de Muinck Keizer-Schrama SM, Stijnen T, et al. Final height in girls with turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens. J Clin Endocrinol Metab. 2003;88(3):1119-1125.
  19. Chernausek SD, Attie KM, Cara JF, Rosenfeld RG, Frane J. Growth hormone therapy of Turner syndrome: the impact of age of estrogen replacement on final height. Genentech, Inc., Collaborative Study Group. J Clin Endocrinol Metab. 2000;85(7):2439-2445.
  20. Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter’s syndrome. Lancet. 2004;364(9430):273-283.
  21. Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med. 1998;158(12):1309-1314.
  22. Ratcliffe S. Long-term outcome in children of sex chromosome abnormalities. Arch Dis Child. 1999;80(2):192-195.
  23. Salbenblatt JA, Bender BG, Puck MH, Robinson A, Faiman C, Winter JS. Pituitary-gonadal function in Klinefelter syndrome before and during puberty. Pediatr Res. 1985;19(1):82-86.
  24. Vorona E, Zitzmann M, Gromoll J, Schuring AN, Nieschlag E. Clinical, endocrinological, and epigenetic features of the 46,XX male syndrome, compared with 47,XXY Klinefelter patients. J Clin Endocrinol Metab. 2007;92(9):3458-3465.
  25. Bojesen A, Kristensen K, Birkebaek NH, et al. The metabolic syndrome is frequent in Klinefelter’s syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care. 2006;29(7):1591-1598.
  26. Bojesen A, Birkebaek N, Kristensen K, et al. Bone mineral density in Klinefelter syndrome is reduced and primarily determined by muscle strength and resorptive markers, but not directly by testosterone. Osteoporos Int. 2011;22(5):1441-1450.
  27. van den Bergh JP, Hermus AR, Spruyt AI, Sweep CG, Corstens FH, Smals AG. Bone mineral density and quantitative ultrasound parameters in patients with Klinefelter’s syndrome after long-term testosterone substitution. Osteoporos Int. 2001;12(1):55-62.
  28. Bojesen A, Juul S, Birkebaek NH, Gravholt CH. Morbidity in Klinefelter syndrome: a Danish register study based on hospital discharge diagnoses. J Clin Endocrinol Metab. 2006;91(4):1254-1260.
  29. Stewart DA, Netley CT, Park E. Summary of clinical findings of children with 47,XXY, 47,XYY, and 47,XXX karyotypes. Birth Defects Orig Artic Ser. 1982;18(4):1-5.
  30. Fricke GR, Mattern HJ, Schweikert HU, Schwanitz G. Klinefelter’s syndrome and mitral valve prolapse. an echocardiographic study in twenty-two patients. Biomed Pharmacother. 1984;38(2):88-97.
  31. Andersen NH, Bojesen A, Kristensen K, et al. Left ventricular dysfunction in Klinefelter syndrome is associated to insulin resistance, abdominal adiposity and hypogonadism. Clin Endocrinol (Oxf). 2008;69(5):785-791.
  32. Swerdlow AJ, Schoemaker MJ, Higgins CD, Wright AF, Jacobs PA. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst. 2005;97(16):1204-1210.
  33. Hultborn R, Hanson C, Kopf I, Verbiene I, Warnhammar E, Weimarck A. Prevalence of Klinefelter’s syndrome in male breast cancer patients. Anticancer Res. 1997;17(6d):4293-4297.
  34. Hasle H, Mellemgaard A, Nielsen J, Hansen J. Cancer incidence in men with Klinefelter syndrome. Br J Cancer. 1995;71(2):416-420.
  35. Swerdlow AJ, Higgins CD, Schoemaker MJ, Wright AF, Jacobs PA. Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab. 2005;90(12):6516-6522.
  36. Bojesen A, Juul S, Birkebaek N, Gravholt CH. Increased mortality in Klinefelter syndrome. J Clin Endocrinol Metab. 2004;89(8):3830-3834.
  37. Groth KA, Skakkebæk A, Høst C, Gravholt CH, Bojesen A. Klinefelter Syndrome—A Clinical Update. The Journal of Clinical Endocrinology & Metabolism. 2013;98(1):20-30.
  38. Klinefelter JHF, Reifenstein JEC, Albright JF. Syndrome Characterized by Gynecomastia, Aspermatogenesis without A-Leydigism, and Increased Excretion of Follicle-Stimulating Hormone1. The Journal of Clinical Endocrinology. 1942;2(11):615-627.
  39. Coffee B, Keith K, Albizua I, et al. Incidence of Fragile X Syndrome by Newborn Screening for Methylated FMR1 DNA. American Journal of Human Genetics. 2009;85(4):503-514.
  40. Morris JK, Alberman E, Scott C, Jacobs P. Is the prevalence of Klinefelter syndrome increasing? Eur J Hum Genet. 2008;16(2):163-170.
  41. Graversen D, Vestergaard P, Stochholm K, Gravholt CH, Jorgensen JO. Mortality in Cushing’s syndrome: a systematic review and meta-analysis. Eur J Intern Med. 2012;23(3):278-282.
  42. Endo. Highlights of Prescribing Information: Testim. Highlights of Prescribing Information: Testim 2016; http://www.endo.com/File Library/Products/Prescribing Information/Testim_prescribing_information.html. Accessed August 26, 2017.
  43. Lilly. Highlights of Prescribing Information. Highlights of Prescribing Information 2017; https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022504s013lbl.pdf. Accessed August 26, 2017.
  44. Allergan. HIghlights of Prescribing Information. HIghlights of Prescribing Information 2016; https://www.allergan.com/assets/pdf/androderm_pi. Accessed August 26, 2017.

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