2. Delayed puberty is defined clinically by the
absence or incomplete development of
secondary sexual characteristics bounded
by an age at which 95 percent of children of
that sex and culture have initiated sexual
maturation
Boys 14 (an increase in testicular size being
the first sign)
Girls 12 (breast development being the first
sign)
3. Hypogonadotrophic Hypogonadism
Estimated to be in the region of 1 in 10,000 male
births
Associated with altered sense of smell; either
totally absent or highly reduced
Isolated or associated with other pituitary
insufficiency – CHARGE
Sixteen different gene defects have so far been
described that can cause Kallmann syndrome
5. Short-term therapeutic goals include:
Attainment of age-appropriate secondary sex characteristics.
Induction of a growth spurt without inducing premature
epiphyseal closure.This goal requires frequent (eg, every six
months) longitudinal monitoring of bone age during therapy.
Potential induction of a "reversal" of their GnRH deficiency,
whether congenital or functional; sex steroid hormone therapy has
been demonstrated to induce puberty even in cases in which the
GnRH deficiency is of a genetic etiology
The long-term goals of therapy:
In GnRH deficiency-maintain the serum concentrations of sex
steroids within the normal adult range and, eventually, to induce
fertility if and when the patient desires
7. 15% to 22% of cases
Reversal appears to be associated with 14 of the
known gene defects linked to KS/CHH.
No obvious gene defect showing a tendency to allow
reversal.
? TAC3 and TACR3 mutations might allow for a
slightly higher chance of reversal but the numbers
involved are too low to confirm this.
KAL-1 least likely to allow reversal (only 1 case
report)
8. Trial of recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in
patients with congenital hypogonadotropic hypogonadism.
Dwyer AA1, Sykiotis GP, Hayes FJ, Boepple PA, Lee H, Loughlin KR, Dym M, Sluss PM, Crowley WF Jr, Pitteloud N.
Author information 1MD, Endocrine, Diabetes, and Metabolism Service, Centre Hospitalier Universitaire
Vaudois, Rue du Bugnon 46, Lausanne, Switzerland 1011.
Abstract
CONTEXT AND OBJECTIVE:The optimal strategy for inducing fertility in men with congenital
hypogonadotropic hypogonadism (CHH) is equivocal. Albeit a biologically plausible approach, pretreatment
with recombinant FSH (rFSH) before GnRH/human chorionic gonadotropin administration has not been
sufficiently assessed.The objective of the study was to test this method.
DESIGN AND SETTING:This was a randomized, open-label treatment protocol at an academic medical center.
PATIENTS AND INTERVENTIONS: GnRH-deficient men (CHH) with prepubertal testes (<4 mL), no
cryptorchidism, and no prior gonadotropin therapy were randomly assigned to either 24 months of pulsatile
GnRH therapy alone (inducing endogenous LH and FSH release) or 4 months of rFSH pretreatment followed by
24 months of GnRH therapy. Patients underwent serial testicular biopsies, ultrasound assessments of testicular
volume, serum hormone measurements, and seminal fluid analyses.
RESULTS: rFSH treatment increased inhibin B levels into the normal range (from 29 ± 9 to 107 ± 41 pg/mL,P <
.05) and doubled testicular volume (from 1.1 ± 0.2 to 2.2 ± 0.3 mL, P < .005). Histological analysis showed
proliferation of both Sertoli cells (SCs) and spermatogonia, a decreased SC to germ cell ratio (from 0.74 to
0.35), and SC cytoskeletal rearrangements.With pulsatile GnRH, the groups had similar hormonal responses
and exhibited significant testicular growth. All men receiving rFSH pretreatment developed sperm in their
ejaculate (7 of 7 vs 4 of 6 in the GnRH-only group) and showed trends toward higher maximal sperm counts.
CONCLUSIONS: rFSH pretreatment followed by GnRH is successful in inducing testicular growth and fertility in
men with CHH with prepubertal testes. rFSH not only appears to maximize the SC population but also induces
morphologic changes, suggesting broader developmental roles.
