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