Follicle-Stimulating Hormone (FSH) and the Onset of Puberty

Girls begin puberty earlier and have as much as a 5-fold increase in incidence of precocious
puberty as do boys, while boys are more likely to have delayed adolescence compared to girls.

The reasons for sex differences in the timing of puberty and sex-based variation in
expression of pubertal disorders are not known.

Puberty is heralded by an increase in the episodic release of luteinizing hormone (LH) under
the control of increased gonadotropin-releasing hormone (GnRH) release. It has been thought
that sex differences in central nervous system restraint of GnRH and subsequently of LH
secretion account for the differences in timing of onset of puberty in boys and girls.

Follicle-stimulating hormone (FSH) secretion is readily detected prior to the onset of
puberty and exhibits sexual dimorphism in basal and GnRH-stimulated concentrations. Thus,
assessment of factors regulating FSH secretion during childhood may enhance our understanding
of sex differences in pubertal development and the pathogenesis of precocious puberty.

Although FSH is secreted under the control of GnRH, FSH is also secreted constitutively under
the control of a group of peptides collectively known as the FSH-regulatory proteins. These
peptides include activins, peptides that increase FSH secretion and inhibins and
follistatins, peptides that suppress FSH secretion.

Gonadal inhibins inhibit FSH via endocrine negative feedback, but their production during
puberty is only beginning to be understood. Activin and follistatin have been thought to have
a principle paracrine role in FSH regulation but recent data have demonstrated these peptides
have an endocrine role as well.

We hypothesize that differences in elaboration of activins, inhibins, and follistatin that
alter FSH constitutive secretion underlie precocious and delayed puberty in boys and girls
and account, in part, for sex differences in pubertal timing.

Specifically we expect that the inhibitory regulators, inhibins and/or follistatins, will be
lower while the stimulatory regulator, activin, will be higher in early compared to delayed
puberty.

FSH and the Onset of Puberty is a case control study comparing boys with precocious puberty
to boys with delayed adolescence and girls with precocious puberty to girls with delayed
adolescence.

Hypothesis: Basal and GnRH agonist-stimulated activin concentrations will be greater and
inhibin concentrations lower in children with early puberty than in children with delayed
adolescence, and the GnRH antagonist, ganirelix, will decrease activin concentrations in
children with early puberty but not in delayed adolescence.

Specific Aim 1: Determine the degree to which FSH-regulatory peptides, compared to
gonadotropin-releasing hormone (GnRH), control FSH secretion in children by suppressing GnRH
with ganirelix in children with early and delayed adolescence.

Specific Aim 2: Determine the role of FSH-regulatory peptides in control of timing of onset
of puberty by comparing their concentrations with and without GnRH stimulation of FSH in
children with precocious puberty and delayed adolescence.

Specific Aim 3: Determine the role of GnRH in control of the FSH-regulatory peptides by
comparing activin, inhibin and follistatin concentrations in children with delayed
adolescence due to constitutional growth delay to those with delayed adolescence from
hypogonadotropic hypogonadism

Inclusion Criteria:

Early Puberty Children who have early puberty may participate in this study. Children must
be between 6 and 10 years of age and be healthy with the exception of having early puberty.
For early puberty, girls should have had the onset of breast development prior to 8 years
of age and boys should have the onset of pubic hair growth or genital growth prior to 9
years of age.

Inclusion Criteria for Delayed Puberty Children who have late (delayed) puberty may
participate in this study. Children must be between 12 and 17 years of age and be healthy
with the exception of having late puberty. In order to have late puberty, boys and girls
should have short stature compared to their family with at least one year delay in bone age
as determined by bone age x-ray and/or have the onset of secondary sexual characteristics
(breast and pubic hair growth) at 12 years of age or later for a girl or 13 years of age or
later for a boy.

Exclusion Criteria:

Early Puberty Children with known genetic disorders, chronic medical conditions requiring
the use of steroids, and use of medication for puberty within the last 3 months are
excluded.

Delayed Puberty Children with known genetic disorders with the exception of possible
hypogonadotropic hypogonadism, chronic medical conditions requiring the use of steroids,
and use of medication for puberty within the last 3 months are excluded.