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 ??

Question 1 ?

How to differentiate between CDGP and HH ?

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
Testicular Vol Basal T T response to HCG (1500 U EOD IM X 3) LH after GnRH test ( 0.1 mg/m2) LH (4 h) GnRHa (0.1 mg/m2) T after HCG X 3 (72h) Low dose HCG (15 U/kg/once IM) T after 24 h Low dose GnRH 10 mcg iv

CDGP
> 4 ml > 1.7 nmol/L > 8 nmol/L > 6 8 U/L LH > 14 U/L T > 9 nmol/L T > 6 nmol/L

HH
< 4 ml < 1.7 nmol/L < 3 nmol/L < 2 U/L LH < 14 U/L T < 9 nmol/L < 6 nmol/L

++ 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?

Yes

Do we have evidence of accelerating puberty with androgens ?

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