Follicle-Stimulating Hormone (FSH) and the Onset of Puberty
Condition: Delayed Puberty; Precocious Puberty
MeSH terms: Puberty, Precocious; Puberty, Delayed
Study type: Interventional
Phase: Early Phase 1

Summary: 
      The purpose of this study is to determine if the timing of the onset of puberty may be
      affected by FSH-regulatory peptides.

      We will determine how these peptides relate to FSH production in prepubertal and pubertal
      children by comparing the regulation of FSH control in children with precocious (early)
      puberty and delayed puberty.

      In this pilot study, we will stimulate the pubertal axis using an agonist of GnRH to
      determine the pubertal response of activin-A, inhibin-A and -B and follistatin.

      To determine baseline FSH secretion and FSH-regulatory peptide tone, we will block GnRH with
      a specific antagonist.

      These studies should lead to a better understanding of the role of FSH in controlling the
      onset of puberty and the pathogenesis of pubertal disorders.
    

Detailed description: 
      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
    

Intervention name(s): Leuprolide Acetate - Early Puberty Leuprolide Visit; Ganirelix - Early Puberty Ganirelix Visit; Ganirelix - Delayed Puberty Ganirelix Visit; Leuprolide Acetate- Delayed Puberty Leuprolide Visit
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Dose of 10 mcg/kg Sub cutaneous once at 0800 on day 2 of the Early Puberty Luprolide Visit; Dose of 2.5 mcg/kg Sub-cutaneous once at 17:30 on day 1 of the Early Puberty Ganirelix Visit and once at 08:00 on day 2 of the Early Puberty Ganirelix Visit; Ganirelix is administered at a dose of 2.5 mcg/kg sub cutaneous at 17:30 on day 1 and once at 08:00 on day 2 of the Ganirelix Delayed Puberty Visit; Leuprolide acetate is given at a dose of10 mcg/kg at 0800 on day 2 of the Delayed Puberty Leuprolide Visit
Other intervention name(s): Leuprolide Injection; Lupron; Lupron SQ; Lupron Injection; Leuprolide SQ; Ganirelix SQ; Ganirelix Acetate; Ganirelix SQ; Ganirelix Acetate; Leuprolide Injection; Lupron; Lupron SQ; Lupron Injection; Leuprolide SQ
Intervention MeSH terms: Leuprolide; Ganirelix
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Puberty; Delayed; Early; Precocious; Peripubertal; Gonadotropin; FSH; LH