Klinefelter’s Syndrome (KS) Rola Zamel, R5

Testoserone Therapy in Adult Men with Androgen Deficiency Syndrome An Endocrine Society Clinical Practice Guideline

Definition of hypogonadism Classification of hypogonadism Dx of androgen deficiency Further evaluation of hypogonadism Indication of testosterone therapy Contraindications of testosterone therapy

Definition of Hypogondadism in men Is clinical syndrome that results from failure of the testis to produce physiological levels of testosterone ( androgen deficiency) and a normal number of spermatozoa due to disruption of one or ore levels of the hypothalamic-pituitary- testicular axis ( HPT)

Causes of hypogonadisim in males 1- Primary testicular failure ↓ testosterone, ↓ sperm and ↑ gonadotropin 2- Secondary testicular failure; caused by a central defects of the hypothalamus or pituitary ↓ testosterone, ↓ sperm and ↓ or ↓- normal gonadotropin

3- Combined primary and secondary testicular failure ↓ testosterone, ↓ sperm and variable gonadotropin levels depending on whether primary or secondary testicular failure predominates Eg. Hemochromatosis, sickle cell disease, thalassemia, glucocorticoid , alcoholism, old age ( the average decline in serum testosterone levels with aging in men is 1-2% per year)

Classification is important for; 1- Rx, in secondary hypogonadism fertility can be achieved with appropriate hormonal stimulation, in primary options include adoption, sperm donation 2- evaluation of secondary hypogonadism my uncover a pituitary tumor or systemic illness

Men whose hypogonadism is of prepubertal onset AND who were not adequately treated will exhibit eunuchoid proportions delayed development of secondary sex characteristics and high pitched voice

Diagnosis of androgen deficiency Dx is made only in men with consistent symptoms and signs and unequivocally low serum testosterone levels Strong recommendation Level of evidence: v. low quality

Symptoms and signs suggestive of androgen deficiency in men A- More specific symptoms and signs Incomplete or delayed sexual development, eunuchoidism Reduced sexual desire and activity Decreased spontaneous erections Breast discomfort, gynecomastia Loss of body ( axillary and pubic) hair, reduced shaving Very small ( especially < 5 ml) or shrinking testes Inability to father children, low or zero sperm count Hight loss, low trauma fracture, low bone mineral density Hot flushes, sweats

Also measure serum testosterone when patients report less specific symptom and sings Decreased energy, motivation, initiatieve and self confidence Feeling sad, depressed mood Poor concentration and memory Sleep disturbance, increased sleepiness Mild anemia ( normochromic, normocytic in the female range) Reduced muscle bulk and strength Increased body fat Diminished physical or work performance

Hx 1- Sexual history ( age of puberty, erection, libido, father kids) 2- secondary sexual characteristics( hair, testes) 3- Osteoporosis in men<50 4- breast tenderness, gynecomastia, hot flashes/ 5- Mood, sleep, fatigue P/E 1- Testicular size 2- Eunuchoidism/ secondary sexual characteristics Labs anemia

Suggest measurement of morning total testosterone level as the initial diagnostic test Rationale; S. testosterone exhibit a circadian variation with peak values in the morning Level of evidence; v. low

Recommend confirmation of the diagnosis by repeating the measurement of morning total testosterone and in men with 1- T.testosterone near the lower limit of normal 2- or in whom SHBG abnormality is suspected measure free testosterone level Level of evidence low

Conditions associated with alteratins in SHBG concentrations Decreased SHBG concentration 1- Morbid obesity 2- DM 3- Hypothyroidism 4- Acromegaly 5- Nephrotic syndrome 6- use of glucocorticioids, progestins and androgenic steroids

Increased SHBG concentrations 1- Aging 2- Hyperthyroidism 3- Cirrhosis and hepatitis 4- HIV 5- Use of anticonvulsants 6- Use of Estrogens

Indication of androgen Rx 1- Men with symptomatic androgen deficiency to induce and maintain secondary sexual characteristics, improve sexual function, sense of well-being, muscle mass and strength and BMD ( recommend, LOE low) Improves all, despite improvement on BMD the effect on fracture risk is unknown

2- HIV- infected men with hypogonadism and weight loss ( as adjunctive Rx and for short term) to promote weight maintenance and gain in lean body mass and muscle strength “LOE weak, suggestion” 3- Men on glucocorticoids who have low testosterone level to maintain BMD( suggest, LOE low)

Contraindication of testosterone 1- breast cancer 2-Prostate cancer 3-prostate nodule, PSA> 4 ng/ml, PSA> 3 ng/ml in men at high risk for prostae cancer such as African Americans or men with first degree relatives with prostate cancer ( without urologic evaluation)

4- severe lower urinary tract symptoms (obstructive symptoms, IPSS >19) 5- Hematocrit >50% 6- untreated severe obstructive sleep apnea 7- uncontrolled or poorly controlled CHF As testosterone Rx may worsen these conditions 8- those desiring fertility

Goal of Rx To raise serum testosterone levels into a range that is mid-normal for health young men

What is Klinefelter’s syndrome (KS)? Seminiferous tubular dysgenesis The clinical manifestation of a male who has an extra X chromosome

Epidemiology The most common congenital abnormality causing primary hypogonadism 1 in 1000 male live births

Genotype The most common genotype is 47,XXY results from nondisjunction of the sex chromosomes of either parent during meiotic division (~ 60% of cases during oogenesis and in 40% of cases during spermatogenesis)

Mosaic forms of KS 46 XY/47 XXY represent mitotic nondisjuction within the developing zygote occur in ~ 10% of patients with KS Other chromosomal variants 48 XXXY 46,XX (the development of testes in this setting is presumably due to translocation of a small portion of chromosomal material containing the testis-determining factor to an X chromosome)

Clinical features A- Gonadal Hyalinization and fibrosis of the seminiferous and pseudoadenomatous changes of the Leyding cells develop after puberty 1- Small, firm testes <4ml in adults 2- poor androgenization at puberty 3- Severely subnormal sperm count 4- Subnormal serum testosterone concentration

5-Elevated serum FSH and LH concentrations ( before age 12 yrs gonadotropin concentration are in the prepubertal range, levels usually rise with pubertal progression 6-Infertility The damage may be increased if the patient also has cryptorchidism, the incidence of which is increased in Klinefelter's

B- Extra-gonadal - Gynecomastia ( d/t ↑ serum Estradiol) Long bone abnormality…↑ length of legs, tall stature, ( Eunuchoid proportions)

A psychosocial abnormality, unrelated to the hypogonadism *difficulty in social interactions throughout life *impairment of higher level linguistic competence but relative sparing of vocabulary and understanding of language *Deficit in the ability to sustain attention without impulsivity Severe mental retardation is uncommon

Presenting features Small testes Gynecomastia Poor androgenization Eunuchoid proportions Infertility Micropenis and hypospadias

Predisposition to develop morbidities later in life that are unrelated to testosterone deficiency 1- pulmonary diseases eg. chronic bronchitis, bronchiectasis, and emphysema 2- aortic valvular disease and ruptured berry aneurysms ( 6 times more than normal control

3- cancers, including germ cell tumors (KS should be considered in boys with hCG- secreting germ cell tumors esp if the tumor is located in the mediastinum or CNS) breast cancer ( mortality is higher than the general population) non-Hodgkin lymphoma

4- varicose veins, leading to leg ulcers 5- SLE probably due to the extra X chromosome 6- diabetes mellitus 7- thyroid disease, fatigue, essential tremor

Diagnosis Karyotype of peripheral leukocytes

Prognosis 1- The greater the number of extra X chromosomes, the greater the phenotypic consequences, both gonadal and extragonadal 2- CAG repeat length correlates inversely with transactivational activity of the androgen receptor) in one study, longer CAGn length was associated with taller stature, lower bone mineral density, gynecomastia, and employment not requiring a high level of education

The androgen receptor gene is located on the X- chromosome and encodes a ligand dependent transcription factor and has highly polymorphic CAGn trinucleotide repeats in the coding sequence of the first exon - A paternal origin of the extra X chromosome is associated with later onset of puberty and longer CAG repeats

Treatment Fertility * some cases of spontaneous fertility have been reported for mosaic forms of KS * in classic KS, fertility is poor. However, combination of testicular sperm extraction TESE with intracytoplasmic sperm injection ISCI can result in successful pregnancies in ~50% of patients with classic KS. Success of this procedure ↓ with age, risk of transmission of sex chromosome aneuploidy

Testosterone deficiency can be treated with testosterone to fully induce puberty, support sexual characteristics, libido and BMD in adult life When to start testosterone? Williams ( monitor LH and testosterone q 6 months during puberty and yearly thereafter. If LH ↑ > 2.5 SD above the mean value or testosterone ↓ below the normal range for age then start testosterone)

Testosterone does not reduce the gynecomasita but dihydrotestosterone my help. Aromatase inhibitors and estrogen antagonist don’t help If gynecomastia don’t regress then reduction mammoplasty is required

Surveillance of disorders for which they are at increased risk - Counseling

References 1- uptodate 2- Williams 3- Endocrine Society guideline for testosterone therapy in adult men