Susan E. Stewart

TAC3/TACR3 Mutations Reveal Preferential Activation of Gonadotropin-Releasing Hormone Release by Neurokinin B in Neonatal Life Followed by Reversal in Adulthood

CONTEXT Mutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH), but broader populations have not yet been tested and genotype-phenotype correlations have not been established. OBJECTIVE A broad cohort of normosmic IHH probands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. DESIGN AND SETTING The study consisted of sequencing of TAC3/TACR3, in vitro functional assays, and neuroendocrine phenotyping conducted in tertiary care centers worldwide. PATIENTS OR OTHER PARTICIPANTS 345 probands, 18 family members, and 292 controls were studied. INTERVENTION Reproductive phenotypes throughout reproductive life and before and after therapy were examined. MAIN OUTCOME MEASURE Rare sequence variants in TAC3/TACR3 were detected. RESULTS In TACR3, 19 probands harbored 13 distinct coding sequence rare nucleotide variants [three nonsense mutations, six nonsynonymous, four synonymous (one predicted to affect splicing)]. In TAC3, one homozygous single base pair deletion was identified, resulting in complete loss of the neurokinin B decapeptide. Phenotypic information was available on 16 males and seven females with coding sequence variants in TACR3/TAC3. Of the 16 males, 15 had microphallus; none of the females had spontaneous thelarche. Seven of the 16 males and five of the seven females were assessed after discontinuation of therapy; six of the seven males and four of the five females demonstrated evidence for reversibility of their hypogonadotropism. CONCLUSIONS Mutations in the neurokinin B pathway are relatively common as causes of hypogonadism. Although the neurokinin B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time.

Long‐term therapy with long‐acting octreotide (Sandostatin‐LAR®) for the management of acromegaly

To evaluate the efficacy and safety of a long‐acting preparation of the somatostatin analogue octreotide, Sandostatin‐LAR® (SMS‐LAR) for the treatment of acromegaly.

Efficacy of Sandostatin LAR (long-acting somatostatin analogue) is similar in patients with untreated acromegaly and in those previously treated with surgery and/or radiotherapy.

background and objectives  Somatostatin analogues have been used as an adjunct to surgery and radiotherapy in the treatment of acromegaly for over 15 years, but debate surrounds their use as primary therapy. Newman suggested that octreotide was equally effective as primary or adjuvant therapy, but the effects of previous surgery/radiotherapy may have led to a preselection bias. In an attempt to eliminate this bias, the efficacy of the depot somatostatin analogue Sandostatin® LAR® as primary and adjuvant therapy has been assessed using GH and IGF‐I levels at diagnosis as baseline values.

Clinical and biochemical response following withdrawal of a long-acting, depot injection form of octreotide (Sandostatin-LAR).

Monthly injections of Sandostatin‐LAR® have been shown to be an effective therapy for patients with acromegaly. Because of an ongoing need to assess a patients response to definitive therapy such as surgery and/or radiotherapy, we aimed to evaluate GH levels and acromegaly symptom scores in patients withdrawing from Sandostatin‐LAR®.