Summary
Hypogonadotropic hypogonadism (HH), consequent to congenital or acquired disorders of the hypothalamic–pituitary axis, presents as absent/delayed/arrested sexual maturation and infertility. ...Optimal management includes: (a) confirmation of the diagnosis and prognosis, (b) timing and choice of therapeutic intervention and (c) consideration of future fertility prospects. Therapy is usually initiated with testosterone to induce development of secondary sexual characteristics, taking the patient (often diagnosed late) through puberty. Monitoring of the impact of the condition on long‐term health and psychosocial function is necessary. Treatment is likely to be life‐long, requiring regular monitoring for its optimization and avoidance of adverse responses. Induction of spermatogenesis requires either pulsatile gonadotropin releasing hormone (GnRH) or gonadotropin administration. Gonadotropins can be self‐administered subcutaneously and are not inferior to the more costly GnRH. ‘Reversible genetic hypogonadotropic hypogonadism’ is a recently described entity which has implications for the long‐term management of patients with HH.
This review describes the major hormonal factors that determine the balance between human skeletal muscle anabolism and catabolism in health and disease, with specific reference to age-related muscle ...loss (sarcopenia). The molecular mechanisms associated with muscle hypertrophy are described, and the central role of the satellite cell highlighted. The biological dynamics of satellite cells, varying between states of quiescence, proliferation and differentiation are strongly influenced by local endocrine factors. The molecular mechanisms of muscle atrophy are examined focussing on the causes of sarcopenia and associations with systemic medical disorders. In addition, evidence is provided that the mechanisms of atrophy and hypertrophy are unlikely to be simple opposites. Novel endocrine mechanisms underpinning mechano-transduction include IGF-I subtypes that may differentiate between endocrine and mechanical signals; their interaction with classical endocrine factors is an active area of translational research. Recently acquired knowledge on the mechanism of anabolic effects of androgens is also reviewed. The increasingly recognised role of myostatin, a negative regulator of muscle function, is described, as well as its potential as a therapeutic target. Strategies to counter age-related sarcopenia thus represent an exciting field of future investigation.
GnRH and sex steroids play an important role in immune system modulation and development. GnRH and the GnRH receptor are produced locally by immune cells, suggesting an autocrine role for GnRH. ...Experimental studies show a stimulatory action of exogenous GnRH on the immune response. The immune actions of GnRH in vivo are, however, less well established. Oestrogen and androgen receptors are expressed in primary lymphoid organs and peripheral immune cells. Experimental data have established that oestrogens enhance the humoral immune response and may have an activating role in autoimmune disorders. Testosterone enhances suppressor T cell activity. Although there are some clinical studies consistent with these findings, the impact of sex steroids in autoimmune disease pathogenesis and the risk or benefits of their usage in normal and autoimmune-disordered patients remain to be elucidated. There are neither experimental nor clinical data evaluating functional GnRH-sex steroid interactions within the human immune system, and there is a paucity of data relating to GnRH analogues, hormone replacement therapy and oral contraceptive and androgen action in autoimmune diseases. However, a growing body of experimental evidence suggests that an extra-pituitary GnRH immune mechanism plays a role in the programming of the immune system. The implications of these findings in understanding immune function are discussed.
Purpose
We report the first case of an Ectopic adrenocorticotrophin (ACTH)-secreting pituitary adenoma (EAPA) located within the posterior nasal septum associated with Nelson’s syndrome, which eluded ...diagnosis for over a decade. In this report, we explore the reasons for such diagnostic difficulty and suggest ways in which an earlier diagnosis may be made.
Methods and results
A 19 years old Lebanese man presented in 2000, with overt Cushing’s syndrome confirmed with markedly elevated urine free cortisols and failed dexamethasone suppression tests. An unsuppressed ACTH and a possible 5 mm adenoma on MRI (Magnetic Resonance Imaging) pituitary suggested Cushing’s disease. The patient underwent trans-sphenoidal surgery (TSS), but histology revealed normal pituitary tissue and Cushing’s syndrome persisted. A repeat MRI pituitary showed no anomaly, and extensive investigations failed to locate an ectopic lesion. Subsequently a bilateral adrenalectomy was performed. Over the ensuing years, the patient developed Nelson’s syndrome with hyperpigmentation and markedly elevated ACTH levels. Repeated high dose dexamethasone suppression tests, corticotrophin releasing hormone (CRH) tests, and CRH stimulated inferior petrosal sinus samplings (IPSS) suggested a pituitary origin of the ACTH. Two further TSS were unsuccessful. The pituitary was irradiated. Subsequent review of his previous MRIs revealed an enlarging mass within the posterior nasal septum, which was excised in 2011. The histology confirmed the diagnosis of an EAPA within the nasal septum.
Conclusion
Ectopic ACTH-secreting pituitary adenomas can occur not only along the developmental route of Rathke’s pouch, but other aberrant locations giving a clinical and biochemical picture identical to Cushing’s disease or Nelson’s syndrome. Clinicians should suspect an EAPA, when a central ACTH source seems to be apparent with no obvious pituitary adenoma. A detailed MRI involving possible EAPA sites aids in locating these unusual lesions.
Summary
GnRH‐I and its receptor (GnRHR‐I) have previously been demonstrated and shown to be biologically active in the immune system, notably within peripheral lymphocytes. Recently however, a second ...form of GnRH (GnRH‐II) has been described in the human. The functions of both these neuropeptides in PMBCs have not been understood yet. The present study was therefore designed to investigate the effects of GnRH‐I and/or GnRH‐II on human PMBC proliferation in males. Secondly, the effects of GnRH‐I and GnRH‐II on IL‐2 dependent lymphocyte proliferation were examined. Finally, we analysed the role of GnRH‐I and GnRH‐II in IL‐2R γ‐chain expression. Peripheral venous blood samples were obtained from six male healthy volunteers (Mean age 27·75 ± 1·5). Non‐radioactive cell proliferation assay was used for proliferation studies and we used quantitative real‐time RT‐PCR to examine the role of GnRH‐I and GnRH‐II on IL‐2R γ‐chain expression in PMBCs. Treatment of PMBCs with GnRH‐I (10−9 M and 10−5 M) and with interleukin‐2 (IL‐2) (50 U/ml) resulted in a significant increase in cell proliferation compared with the untreated control. PMBCs cotreated with IL‐2 and GnRH‐I demonstrated higher proliferative responses than IL‐2 treatment alone, the enhancement of GnRH‐I on IL‐2 response being significant only at GnRH‐I concentration of 10−5 M. Co‐incubation of IL‐2+ GnRH 10−5 M with a GnRH antagonist (Cetrorelix; 10−6 M) significantly decreased the proliferation. GnRH‐II did not affect the proliferation of PMBCs alone, and did not alter the proliferative response to IL‐2. The proliferative responses to GnRH‐I (alone and with IL‐2) were significantly attenuated by GnRH‐II coincubation (each in equal molar concentrations; 10−9 M to 10−5 M). It was found that GnRH‐I increased the expression of IL‐2Rγ mRNA in a dose dependent manner, with a significant increase of percentage 162·3 ± 14 of control at 10−5 M. In contrast, IL‐2Rγ expression was significantly decreased in all concentrations of GnRH‐II (10−9 M to10−5 M), and the maximum decrease was detected at 10−5 M, with percentage 37·7 ± 6·6 of control. All these findings strongly suggest that regulation of IL‐2R expression may therefore be an important target for GnRH‐I and GnRH‐II in PMBCs in males. In summary, present study clearly demonstrates the differential effects of GnRH‐I and GnRH‐II on PMBC proliferation, IL‐2 proliferative response, and IL‐2Rγ expression in PMBCs in males. To our knowledge, our observations provide the first evidence for the interactions of these local neuropeptides at lymphocyte level. Further experimental data in human are warranted to explore the clinical implications of these data.
BACKGROUND: This is the first report of human exposure to the novel compound follicle stimulating hormone (FSH)-C-terminal peptide (CTP) `FSH-CTP' (Org 36286), a long-acting recombinant FSH like ...substance, consisting of the α-subunit of human FSH and a hybrid β-subunit. The latter is composed of the β-subunit of human FSH and the C-terminus part (CTP) of the β-subunit of human chorionic gonadotrophin (HCG). METHODS: In this phase I, non-blind, multi-centre study, 13 hypogonadotrophic hypogonadal male subjects were enrolled to test the safety of FSH-CTP in terms of antibody formation in humans. Furthermore, the pharmacokinetic profile of this new compound was determined. Subjects were injected four times with 15 μg FSH-CTP with an interval of ~4 weeks between each injection. RESULTS: No drug related (serious) adverse events occurred. No antibodies against FSH-CTP or chinese hamster ovary (CHO)-cell derived proteins were detected and measurement of local tolerance demonstrated that s.c. administration of FSH-CTP is well tolerated and no increase in intensity of injection-site responses was observed after repeated exposure to FSH-CTP. After the first and third injection, FSH-CTP serum concentrations were determined. Overall mean (± SD) Cmax was 0.426 (± 0.116) ng/ml, mean t½ and AUC0-∞ were 94.7 (± 26.2) h and 81.5 (± 18.8) ng.h/ml respectively. Compared with recFSH (Puregon®), the half life of FSH-CTP was increased 2–3 times. Following the first and third injection a clear rise in serum inhibin-B concentrations were observed. CONCLUSIONS: The use of FSH-CTP is safe and does not lead to detectable formation of antibodies. Furthermore, the pharmacokinetic and dynamic profile of FSH-CTP may lead to the development of new, more convenient regimens for the treatment of male and female infertility.
Conventional surgery and radiotherapy for acromegaly have limitations. There are few data on the use of the somatostatin analog octreotide (Oct) as primary medical therapy. An open prospective study ...of 27 patients with newly diagnosed acromegaly was conducted in nine endocrine centers in the United Kingdom. Twenty patients had macroadenomas, and 7 had microadenomas. For the first 24 wk (phase 1), patients received sc Oct in an initial dose of 100 μg, 3 times daily, increased to 200 μg three times daily after 4 wk in the 13 patients whose mean serum GH remained greater than 5 mU/liter (2 μg/liter). Five-point GH profiles were performed at 0, 4, 12, and 24 wk, and high resolution pituitary imaging using a standard protocol was performed at 0, 12, and 24 wk (magnetic resonance imaging in 25 patients and computed tomography in 2). Tumor dimensions and volumes were calculated by a central, reporting neuroradiologist, and the results were audited by a second, independent neuroradiologist. After 24 wk, 15 patients proceeded to phase 2 of the study with a direct switch to monthly injections of the depot formulation of Oct, Sandostatin long-acting release (Oct-LAR). Further GH profiles were performed at 36 and 48 wk, and pituitary imaging was performed at 48 wk.
The median pretreatment serum GH concentration was 30.7 mU/liter (range, 6.7–141.4). During sc Oct, serum GH fell to less than 5 mU/liter in 9 patients (38%), and IGF-I fell to normal in 8 patients (33%). All 27 tumors shrank during sc Oct; for microadenomas the median tumor volume reduction was 49% (range, 12–73), and for macroadenomas it was 43% (range, 6–92). After 24 wk of Oct-LAR (end of phase 2), the GH level was less than 5 mU/liter in 11 of 14 patients (79%), and IGF-I was normal in 8 of 15 patients (53%). In the 15 patients given Oct-LAR (10 macroadenomas), wk 48 scans showed a further overall median tumor volume reduction of 24%. At the end of the study 79% of patients had mean serum GH levels below 5 mU/liter, 53% had normal IGF-I levels, and 73% showed greater than 30% tumor shrinkage. Twenty-nine percent of patients achieved all 3 targets, but no patient with pretreatment GH levels above 50 mU/liter did so at any stage of the study.
Primary medical therapy with Oct offers the prospect of normalization of GH/IGF-I levels together with substantial tumor shrinkage in a significant subset of acromegalic patients. This is most likely to occur in patients with pretreatment GH levels less than 50 mU/liter (20 μg/liter).
Abstract Objective Elevated growth hormone (GH) levels lead to increased circulating insulin-like growth factor-I (IGF-I), but the effects on localised muscle IGF-I splice variant expression is not ...known. The effects of rhGH administration, with or without an acute bout of high resistance exercise, were measured on serum IGF-I and on the mRNA levels of IGF-I splice variants in the vastus lateralis muscle of healthy young men. Design The study was a randomised double blind trial with a crossover design. Seven subjects were randomly assigned to a group receiving daily injections of rhGH (0.075 IU kg−1 day−1 ) or placebo for a two week period. Following a one month washout, the groups were reversed. Results Administration of rhGH increased circulating IGF-I from 31.8 ± 3.2 to 109 ± 5.4 nmol/L ( p < 0.05). There was no effect of the exercise bout. RNA was extracted from muscle biopsies obtained from exercised and non-exercised legs 2.5 h after the cessation of the exercise. Transcript expression was measured using Real-time QPCR. There was no effect of either exercise or rhGH administration on IGF-I 5′ (Class 1 or Class 2) or 3′ (IGF-IEa, or MGF) transcripts. Conclusion Although rhGH administration has an effect on liver IGF-I expression, as shown by increase in circulating IGF-I, muscle IGF-I expression is unaffected in young healthy subjects with normal GH profile. The findings contrast with those of a previous study in which GH deficient elderly men showed higher muscle IGF-I 3′ splice variant levels following rhGH administration with and without resistance training. Unlike in the liver, muscle Class1 and 2 IGF-I expression do not change significantly following administration of rhGH.
A detailed neurological investigation of patients with Kallmann's syndrome (KS) has been performed in an attempt to relate phenotypic characterization with genotype. Twenty-seven subjects with KS ...were studied (including 12 males with X-linked disease and 3 females). Six male and 2 female normosmics with isolated GnRH deficiency, 1 male with KS variant, and 1 obligate female carrier were also imaged. Evidence for X-linked disease was derived both from analysis of pedigree and by mutation analysis at the KAL locus. The female carrier and all 8 normosmics had normal olfactory bulbs and sulci, as did 3 male KS. The study, therefore, confirms the value of magnetic resonance imaging in the diagnosis of KS, but suggests that the technique is not sufficiently sensitive to differentiate KS from the normosmic form of GnRH deficiency in all cases. Phenotypic characterization of KS was more effectively achieved by accurate estimation of olfactory status. Three new mutations at the KAL locus were identified, 2 single exon deletions and 1 point mutation. In 2 pedigrees with clear X-linked inheritance, no coding sequence mutations were detected; it may be that these harbor mutations of pKAL, the recently characterized 5'-promoter region. No clear relationship could be established between specific phenotypic anomalies and particular KAL mutations. Involuntary, mirror movements of the upper limbs were present in 10 of 12 cases of X-linked KS, but in none of the other subjects. Although this phenomenon has been ascribed to an abnormality of the corpus callosum, in the present study magnetic resonance imaging demonstrated no quantitative or qualitative morphological anomalies of this structure.
GnRH-I and its receptor (GnRHR-I) have previously been demonstrated and shown to be biologically active in the immune system, notably within T cells. Recently however a second form of GnRH (GnRH-II) ...has been described in the human. The function of both these neuropeptides in B lymphocytes has not previously been explored. The present study investigates GnRH-I and GnRH-II expression in human peripheral mononuclear blood cells (PMBCs) and B lymphoblastoid cells (B-LCLs), as well as their action in regulating B-LCL proliferation in the presence and absence of interleukin-2 (IL-2), both in GnRHR-I mutated lymphocytes and in a normal control. RT-PCR and immunocytochemistry identified locally produced GnRH-I and GnRH-II in all cell groups. Treatment of normal B-LCLs with GnRH-I (10 (-9) M and 10 (-5) M) or with interleukin-2 (IL-2) (50 IU/ml) resulted in a significant increase in cell proliferation compared with the untreated control. IL-2 and GnRH-I (10 (-7) M, 10 (-6) M, 10 (-5) M) induced greater proliferation in normal B-LCLs than IL-2 treatment alone. No significant proliferation occurred in GnRHR-I defective B-LCLs, in response to either GnRH-I (10 (-9) and 10 (-5) M) or IL-2 treatment, nor to IL-2 and GnRH-I (10 (-10) to 10 (-5) M) co-treatment when compared to controls. Co-incubation of IL-2 and IL-2 + GnRH 10 (-5) M with a GnRH antagonist (Cetrorelix; 10 (-6) M) significantly attenuated the proliferation in normal B-LCLs. GnRH-II did not affect proliferation of normal B-LCLs alone, and did not alter the proliferative response to IL-2. Further investigation is required to clarify the physiological relevance of local GnRH-I/GnRH-II in immune system responsiveness.
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