Hypothalamic Reproductive Endocrine Pulse Generator Activity Independent of Neurokinin B and Dynorphin Signaling.

CONTEXT: Kisspeptin-neurokinin B (NKB)-dynorphin neurons are critical regulators of the hypothalamic-pituitary-gonadal axis. NKB and dynorphin are hypothesized to influence the frequency of GnRH pulses, whereas kisspeptin is hypothesized to be a generator of the GnRH pulse. How these neuropeptides interact remains unclear. OBJECTIVE: To probe the role of NKB in GnRH pulse generation and to determine the interactions between NKB, kisspeptin, and dynorphin in humans and mice with a complete absence of NKB. DESIGN: Case/control. SETTING: Academic medical center. PARTICIPANTS: Members of a consanguineous family bearing biallelic loss-of-function mutations in the gene encoding NKB and NKB-deficient mice. INTERVENTIONS: Frequent blood sampling to characterize neuroendocrine profile and administration of kisspeptin, GnRH, and naloxone, a nonspecific opioid receptor antagonist used to block dynorphin. MAIN OUTCOME MEASURES: LH pulse characteristics. RESULTS: Humans lacking NKB demonstrate slow LH pulse frequency, which can be increased by opioid antagonism. Mice lacking NKB also demonstrate impaired LH secretion, which can be augmented with an identical pharmacologic manipulation. Both mice and humans with NKB deficiency respond to exogenous kisspeptin. CONCLUSION: The preservation of LH pulses in the absence of NKB and dynorphin signaling suggests that both peptides are dispensable for GnRH pulse generation and kisspeptin responsiveness. However, NKB and dynorphin appear to have opposing roles in the modulation of GnRH pulse frequency.

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.

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. DESIGN: We retrospectively analysed the GH and IGF-I data from a large multicentre study in which patients' biochemical response to treatment with the depot somatostatin analogue Sandostatin LAR as primary and adjuvant therapy was assessed. We used GH and IGF-I levels at diagnosis as baseline values to eliminate any preselection bias. PATIENTS AND RESULTS: In 91 patients (42 male) studied, mean serum GH fell from 36.2 +/- 3.3 micro g/l (SEM) at diagnosis to 2.2 +/- 0.2 micro g/l after 48 weeks of treatment (P < 0.0001). In the primary (n = 34) and adjuvant (n = 57) therapy groups, mean GH fell from 30.7 +/- 5.7 to 2.6 +/- 0.4 micro g/l (P < 0.0001) and from 39.5 +/- 4.1 to 2.0 +/- 0.2 micro g/l (P < 0.0001), respectively. Sixty-two percent of patients in the primary therapy group and 70% in the adjuvant therapy group achieved GH < 2 micro g/l. Serum IGF-I levels were available in 67 patients (34 male). In the primary therapy group (n = 25) mean IGF-I fell from 764 +/- 68 to 414 +/- 31 micro g/l (P < 0.0001) at 48 weeks. In the adjuvant therapy group (n = 42) mean IGF-I was 666 +/- 50 micro g/l, falling to 384 +/- 30 micro g/l (P < 0.0001) at 48 weeks. 72% of patients achieved normal age-related IGF-I-values. There were no statistically significant differences in GH or IGF-I levels between the primary and adjuvant therapy groups at diagnosis, pre Sandostatin LAR or after 48 weeks of treatment. CONCLUSION: This retrospective study demonstrates that in a group of patients with similar diagnostic GH and IGF-I levels, Sandostatin LAR was equally effective as primary therapy in acromegalic patients as in patients previously treated with surgery and/or radiotherapy.

Long-term safety and efficacy of depot long-acting somatostatin analogs for the treatment of acromegaly.

Depot somatostatin analogs are now increasingly being prescribed as adjuvant and primary therapy for the treatment of acromegaly. Previous studies have shown them to be both effective and safe, suppressing GH levels to less than 2 micro g/liter in 50-65% of cases and normalizing serum IGF-I levels in 65%. However, published data on their long-term efficacy and safety is scanty. We analyzed data from 22 patients (16 female and 6 male) treated with Sandostatin LAR or Lanreotide for an average of 41 months (range 12-89). Three patients had previously been treated with surgery, two with radiotherapy, and seven with both. Ten patients had received primary medical therapy. Mean pretreatment GH levels were 13.1 +/- 3.4 micro g/liter, and IGF-I levels were 592.9 +/- 53.9 micro g/liter. Results after 12 months of therapy indicated reduction in GH (3.2 +/- 0.7 micro g/liter; P < 0.0001) and IGF-I (321.9 +/- 33.9 micro g/liter; P < 0.001) concentrations, and this was sustained at latest follow-up. Using GH criteria (serum GH < 2 micro g/liter), 46% of subjects achieved a cure at 12 months, and 36% achieved a cure long-term. Fifty-two percent achieved normal IGF-I values at 12 months, and 67% long-term. Mean fasting and 2-h plasma glucose concentrations were similar at latest follow-up and at 12 months to baseline values. Three patients developed impaired glucose tolerance within 12 months of treatment, one going on to develop frank diabetes mellitus. However, glucose tolerance improved in five patients. Five patients developed gallstones while on treatment. In summary, this study reports the long-term efficacy of the depot somatostatin analogs as either adjuvant or primary therapy. Although overall glucose tolerance did not change, the development of impaired glucose tolerance in three patients at a time when GH levels were not changing highlights the ongoing need to monitor the long-term safety of these preparations.