cdgp versus hypogonadism
DESCRIPTION
DifferencesTRANSCRIPT
How to differentiate between
Constitutional delay of puberty
and hypogonadism in male
adolescents
Ashraf T Soliman MD, PhD, FRCP
Professor of Pediatrics and
EndocrinologyHMC- Doha-Qatar
Contents
• A case presentation of delayed puberty in a
boy?
• How to differentiate CDGP from HH ?
• Shall we treat CDGP, Why?
• Can we simulate normal pubertal
physiology?
• Androgen therapy? Present protocols and
outcomes?
• Testosterone Vs HCG ?
• Other treatment options ?
Case • A 14.5 year-old boy was referred because of short stature and
lack of signs of puberty.
• Height is on 3rd percentile.
• Normal weight for height (25th percentile)
• There were no signs of puberty (Tanner I genitalia and pubic hair)
• Testicular volume 3 ml.
• Bone age of 12 years
• Normal birth size ( L = 50.5 cm, wt = 3.2 kg)
• Good school performance
• Not actively exercising
• His past medical history was unremarkable.
• His mother's menarche was at 12 years and his dad vaguely
remembered that he was almost the shortest one in the class when he was 13 years. But now he his height is on the 75th percentile.
Biochemistry
• Normal renal and hepatic functions, ESR
• Normal hemogram
• LH = 0.5 IU/L
• FSH = 0.7 IU/L
• Testosterone = 1.8 nmol/L ( 10 – 35 nmol/L)
• Normal free T4, TSH , prolactin.
• IGF-I = 65 ng/ml (low for age and bone age)
• Bone age = 12 years
• What is the Dx ??
How to differentiate
between
CDGP and HH ?
Question 1 ?
How to differentiate between
CDGP and HH • 1. Clinical (Family Hx, pattern of
growth)
• 2 Basal LH, FSH, Testosterone (6 AM)
• 3. Stimulation Tests :
A. HCG test
B. GnRH test/ GnRHa tests
• 4. Therapeutic tests ( Testosterone,
HCG)
Test CDGP HH
Testicular Vol > 4 ml < 4 ml
Basal T > 1.7 nmol/L < 1.7 nmol/L
T response to HCG
(1500 U EOD IM X 3)
> 8 nmol/L < 3 nmol/L
LH after GnRH test ( 0.1
mg/m2)
> 6 – 8 U/L < 2 U/L
LH (4 h) GnRHa (0.1
mg/m2)
T after HCG X 3 (72h)
LH > 14 U/L
T > 9 nmol/L
LH < 14 U/L
T < 9 nmol/L
Low dose HCG (15
U/kg/once IM) T after 24
h
T > 6 nmol/L < 6 nmol/L
Low dose GnRH
10 mcg iv
++ response No response
Question 4 ?
• What is their peak bone mass vs boys with normal pubertal onset ?
• Osteopenia in men with a history of delayed puberty +/-
• Reduced total-body bone mass
JS Finkelstein, NEJM 1992, 326
V Rochira,Eur J Endo 2006,154
Fabian Yap, JCEM 2004, 89.
Question 5 ?
• What is the effect of delayed
puberty on spermatogenesis?
What is the effect of therapy?
NOT KNOWN
Question 6 ?
Is CDGP associated with • Sense of incompetence and vulnerability
• Impaired self-esteem
• Reluctance to participate in athletic activities
• Social isolation
• Impaired academic performance
• Substance abuse and disruptive and suicide behavior
+/- YES
GraberJA, J Am Acad Adolesc Psyciatry 2004,43
Lee PD, Pediatr Clin N Am 1987;34:851
Question 7 ? What R we
treating? 1. Treating a hypogonadal state for 2-3 years ?
• To simulate the pattern of increasing T gradually and for this long time (buying time till onset of puberty) OR
2. Inducing puberty by sensitizing the HPG axis by androgen ?
• Using low dose of T for a short time OR
3. BOTH
Question 8? Do we have evidence of accelerating
puberty with androgens ? • Yes • Undertreated boys and girls with CAH have
early puberty.
• Some boys with CDGP have increased
testicular volume during the months following
cessation of T therapy.
• However, some boys need repeated T courses
( 6 months X 2 ) to respond.
Androgen Therapy ?many ???
• What is the ideal drug?
• What is the blood level that should be achieved?
(fixed monthly small dose vs increasing dose)
• For how long to prime/stimulate normal HPG
axis? ( 3 months vs 18 months)
• What are the short term results?
• What are the long term results (Safety) on final
adult height and fertility??
Question?
Can we simulate normal T
secretion?
Normal Physiology of Male
Puberty
1. Amount of circulating T (gradual increase to
simulate (Tanner II, III, then IV) levels
2. Intra-testicular T X 50-100 circulating T.
3. Rhythm of T secretion (high AM)
4. T + FSH are necessary for beginning
spermatogenesis
1. What is the
appropriate T blood
level for starting
puberty ?
Question ??
Androgen Therapy:
Is it safe for
spermatogenesis for 12-18
months ???
Unknown
Normal -Spermarche
• Spermarche occurred early in puberty
• Before the peak growth spurt
• Secondary sexual characteristics are at an early stage of development
• May occur when little or no pubic hair & testes growth.
• T secretion did not reach maximum levels
• At Tanner I : 6% & at V: 96% had sperms in AM urine
• Associated with age-appropriate gonadotropin production.
Nielsen CT Acta Endocrinol Suppl (Copenh). 1986;279:98-106.
Hirsch M, J Adolesc Health Care. 1985 :35-9.
Schaefer F1: Arch Dis Child. 1990:1205-7
Kulin HE Am J Dis Child. 1989 Feb;143(2):.
Normal Spermatogenesis
• For spermatogenesis to be initiated
concentrations of T, well in excess of
those needed to maintain androgen
effects in other regions of the body. (LH
induced)
• FSH is important for Sertoli cell
function necessary for beginning of
spermatogenesis
Different Protocols of Treating CDGP ?
Do they achieve the goals?
Which one is more physiologic?
Question ?
Can we achieve the desired (physiologic) blood level of
testosterone with these doses ???
Question ?
Testosterone VS
HCG
therapy
OTHER FORMS
OF
TREATMENT
Are short boys
with CDGP
candidates for
GH therapy ??
Nutritional Support for CDGP
• CDGP have relative deficiencies in
testosterone and lower IGF-I concentrations
associated with greater rates of total energy
expenditure, suggesting that this relatively
hormone-insufficient state is associated with a
hyper-metabolic state. • Whether added nutritional supplements, alone
or in combination with GH, could improve the
growth pattern and final height of these children
deserves further study.
Nelly Mauras. Horm Res 2006;66 (Suppl. 1):42-48