Diagnosis of Delayed Puberty and Sexual Infantilism

l Signs of puberty have not yet appeared in 0.4% of normal boys by age 15 and 0.4% of normal girls by age 13.

l Thus when prepubertal girls present at age 12 or prepubertal boys present at age 14, the physician must make a clinical judgement as to which the variants of the norm and which require extensive evaluation and treatment.

l Lack of progression through the stages of puberty¡X

n a boy who has not completed secondary sexual maturation within 4.5 y after onset of puberty or a girl who does not menstruate within 5 yr after onset may have a hypothalamic, pituitary, or gonadal disorder.

Table 22-16. Differential diagnostic features of Delayed Puberty and Sexual Infantilism

Disorder	Stature	Plasma Gonadotropin Levels	LHRH Test: LH Response	Plasma Gonadal Steroid Levels	Plasma DHEAS Level	Karyotype	Olfaction
Constitutional delay in growth and adolescence	Short for chronological age, usually appropriate for bone age	Prepubertal, later pubertal	Prepubertal, later pubertal	Low, later normal	Low for chronological age, appropriate for bone age	Normal	Normal
Hypogonadotropic hypogonadism
Isolated gonadotropin deficiency	Normal, absent pubertal growth spurt	Low	Prepubertal or no response	Low	Appropriate for chronological age	Normal	Normal
Kallman syndrome	Normal, absent pubertal growth spurt	Low	Prepubertal or no response	Low	Appropriate for chronological age	Normal	Anosmia or hyposmia
Idiopathic multiple pituitary hormone deficiencies	Short stature and poor growth since early childhood	Low	Prepubertal or no response	Low	Usually low	Normal	Normal
Primary gonadal failure
Syndrome of gonadal dysgenesis and variants	Short stature since early childhood	High	Hyper-response for age	Low	Normal for chronological age	45, X or variant	Normal
Klinefelter syndrome and variant	Normal to tall	High	Hyper-response at puberty	Low or normal	Normal for chronological age	47,XXY or variant	Normal
Familial, 46,XX or 46, XY gonadal dysgenesis	Normal	High	Hyper-response for age	Low	Normal for chronological age	46,XX or 46, XY	Normal

Table 22-17. Endocrine Diagnosis of Constitutional Delayed Adolescence and Hypogonadotropic Hypogonadism

No single test reliably discriminates between the two diagnoses.

Onset of puberty in boys is indicated by

Testes > 2.5 cm in diameter

Serum testosterone concentration > 50 ng/dL

Pubertal LH response to LHRH bolus

Pubertal pattern of LH pulsatility

Table 22-18. Endocrine and Imaging Studies in Delayed Adolescence

Initial assessment

Plasma testosterone or estradiol

Plasma FSH and LH

Plasma thyroxine (and prolactin)

Bone age and lateral skull roentgenograph

Test of olfaction

Follow-up studies

Karyotype (short, phenotypic females)

MRI and/or CT scan

Pelvic sonography (females)

LHRH test

HCG test (males)

Pattern of pulsatile LH secretion

Visual acuity and visual fields

Table 22-19. Objectives in Management and Treatment and Therapy of Delayed Adolescence

Objectives

Determine site and etiology of abnormality

Induce and maintain secondary sexual characteristics

Prevent the potential short-term and long-term psychological, personality, and social handicaps of delayed puberty

Attain fertility

Therapy

Concerned but not anxious or socially handicapped adolescent:

Reassurance and follow-up (tincture of time)

Repeat evaluation (including serum testosterone or estradiol ) in 6 mo

Psychosocial handicaps, anxiety, highly concerned:

Therapy for 4 mo with

Boys: testosterone enanthate 100 mg intramuscularly every 4 wk at 14-14.5 y of age

Girls: ethinyl estradiol 5-10£gg daily by mouth or conjugated estrogen 0.3 mg daily by mouth at 13 y of age

No therapy for 4-6 mo; re-evaluate status including serum testosterone or estradiol; if indicated repeat treatment regimen

Table 22-20. Hormonal Substitution Therapy in Boys with Hypogonadism

Goal: to approximate normal adolescent development when diagnosis is established

Initial therapy: at 13 y of age, testosterone enanthate (or other long-acting testosterone ester) 50 mg intramuscularly every month for about 9 mo (6-12 mo).

Over the next 3 to 4 y: gradually increase dose to adult replacement dose of 200 mg every 2-3 wk

Begin replacement therapy in boys with suspected hypogonadotropic hypogonadism by bone age ¡Ø14 y

To induce fertility at appropriate time: pulsatile LHRH or FSH and hCG therapy

Table 22-21. Hormonal substitution therapy in Girls with Hypogonadism

When diagnosis of hypogonadism is firmly established ( e.g., girls with 45, X gonadal dysgenesis), begin hormonal substitution therapy at 12-13 y of age

Goal: to approximate normal adolescent development

Initial therapy: ethinyl estradiol 5£gg by mouth or conjugated estrogen 0.3 mg (or less) by mouth daily for 4-6 mo.

After 6 mo of therapy (or sooner if ¡§breakthrough¡¦ bleeding occurs) begin cyclic therapy:

Estrogen: first 21 d of month

Progesterone: (e.g., medroxyprogesterone acetate 5 mg by mouth) 12^th to 21 st day of mouth

Gradually increase dose of estrogen over next 2-3 y to conjugated estrogen 0.6-1.25 mg or ethinyl estradiol 10-20£gg daily for first 21 d of month

In hypogonadotropic hypogonadism: to induce ovulation at appropriate time: pulsatile LHRH or FSH and hCG therapy

Lanes R, Gunczler P, Osuna JA, Palacios A, Carrillo E, Ramirez X, Garcia C, Paoli M, Villaroel O: Effectiveness and Limitations of the use of the Gonadotropin-Releasing Hormone Agonists Leuprolide Acetate in the diagnosis of delayed puberty in males. Horm Res 1997;48:1-4.

GnRH agonist test:

Dose: leuproline acetate a single subcutaneous injection at a dose of 20mg/kg

Time: 07.00 h

Time of collection: serum LH, FSH, and testosterone at baseline, 20 min, 40 min, 60 min, 2 h, 3 h, 6 h, 12 h, and 24 h after leuprolide acetate treatment.

Results

Table. Response to leuprolide acetate (mean¡ÓSEM)

	Basal levels			Peak levels
	LH IU/l	FSH IU/l	Testosterone	LH IU/l	FSH IU/l	Testosterone
GD (n= 8)	0.4¡Ó0.1	1.1¡Ó0.3	0.6¡Ó0.2	4.5¡Ó1.6	5.1¡Ó1.5	1.0¡Ó0.4
CDP (n=14)	0.7¡Ó0.3	1.7¡Ó0.3	1.2¡Ó0.3	17.4¡Ó2.4	8.6¡Ó1.5	3.9¡Ó0.7
P	NS	NS	NS	< 0.01	NS	<0.05

l There was, however, some degree of overlap when individual peak LH responses were analyzed, so that 3 of the 8 GD subjects had peak LH responses equal to or greater than 5.7 IU/l, the lowest individual peak LH responses of the GDP group.

l Overlap was also present when the incremental LH response (¡µLH at 2 h) was analyzed in CDP and GD subjects.