Kallmann syndrome


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Kallmann syndrome

  1. 1. Chris Redford ST3
  2. 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. 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
  4. 4. FSH/LH,Testosterone, Oestrogen, Prolactin,TSH, FT4, IGF-1 Karyotype KAL-1/2/3 Mutation, GnRH1, CHD7 (CHARGE),TAC3,TACR3
  5. 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
  6. 6. GnRH pulsing hCG/FSH Testosterone Oestrogen/progesterone Bone Health – ( 3 vs 5 year DEXA) Vit D/Calcium ? Bisphosphonate
  7. 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. 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.
  9. 9. http://www.gnrhnetwork.eu http://emedicine.medscape.com/article/ 255152-treatment