Transcript Klinefelters

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 hypothalamicpituitary- 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
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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