The Effects of Signaling-Selective Parathyroid Hormone Analogs on Osteoporotic Osteocyte Apoptosis

Objectives: To compare the effects of signaling-selective parathyroid hormone analogs [G1, R19]hPTH(1–28) [GR(1–28)] and [G1, R19]hPTH(1–34) [GR(1–34)] on osteoporotic osteocyte apoptosis, and to explore the mechanism of the anti-osteoporotic difference. Methods: The osteoporosis model was established in eighty adult female C57BL/6 mice aged 12 weeks. The mice were subcutaneously administered with GR(1–28) and GR(1–34) 5 days per week for 8 weeks. Bilateral femur samples were collected at 4 and 8 weeks, and micro-computed tomography (CT), H&E staining and immunohistochemical staining analyses were performed. Results: From micro-CT analysis, GR(1–34) increased proximal femoral bone mineral density (BMD) and relative bone volume (BV/TV), which was higher than GR(1–28) did. In addition, more trabecular number (Tb.N), thinner trabecular thickness (Tb.Th) and wider trabecular separation (Tb.Sp) were measured at week 8 using GR(1–34). From H&E and immunohistochemical staining, a stronger apoptosis inhibition was induced by GR(1–34) with more Bcl-2 secretion but less Bax expression, as opposed to GR(1–28). Conclusions: GR(1–34) shows better anti-osteoporotic effects than GR(1–28), which appears to be attributed to the activation of the PLC-independent PKC signaling pathway triggered by the former, inhibiting osteocyte apoptosis through up-regulation of Bcl-2 and down-regulation of Bax to increase bone mass and improving trabecular bone microstructure to enhance bone quality by reducing trabecular number, increasing trabecular thickness and trabecular space.

Gonadotropin Suppression for 7 Years after a Single Histrelin Implant for Precocious Puberty

Gonadotropin releasing hormone analogs (GnRHas) are an effective treatment to address the compromise in height potential seen in patients with central precocious puberty. There is no evidence in the literature of a single GnRHa used for longer than 2 years before being removed or replaced. We describe a patient who was on continuous gonadotropin suppression for 7 years and despite this, achieved a height potential within one standard deviation of mid-parental height. A boy aged 10 years and 3 months presented to endocrine clinic with signs of precocious puberty and advanced bone age. Initial labs showed random LH 9.4 mIU/mL, FSH 16.3 mIU/mL, DHEAS 127 mcg/dl, and testosterone 628 ng/dL. He was initially started on Lupron injections before transitioning to a Histrelin implant. Follow-up laboratory results 5 months post-suppression showed pre-pubertal random LH 0.2 mIU/mL, FSH 0.1 mIU/mL, and testosterone 5 ng/dL. The patient was lost to follow-up and returned 5 years later presenting with gynecomastia and delayed bone age. He had continuous gonadotropin suppression with random LH 0.10 mIU/mL, FSH 0.16 mIU/mL, and testosterone 8 ng/dL. The Histrelin implant was removed and 4 months after removal labs showed random pubertal hormone levels with LH 5.6 mIU/mL, FSH 4.3 mIU/mL, and testosterone 506 ng/dl. The patient’s mid-parental height was 175.3 cm and the patient’s near final height was 170.6 cm which is within one standard deviation of his genetic potential. Further studies are needed to explore continuous gonadotropin hormone suppression with a single Histrelin implant beyond 2 years.

Assessment of gonadotropin concentrations stimulated by gonadotropin-releasing hormone analog by electrochemiluminescence (ECLIA) in girls with precocious puberty and premature thelarche

Objective: The aim of this study is to determine the cutoff values of gonadotropin response to gonadotropin-releasing hormone analogs (GnRHas) corresponding to the activation of the hypothalamic–pituitary–gonadal axis that could differentiate central precocious puberty (CPP) from premature thelarche (PT) and using the electrochemiluminescence assay method. Methods: A total of 49 girls underwent the stimulation test with the intramuscular injection of 3.75 mg leuprolide acetate. Based on the clinical and laboratory characteristics, they were divided into two groups: CPP (n = 22) and PT (n = 27). Baseline estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were collected before GnRHa administration, and LH and FSH at 60 and 120 min, respectively, after GnRHa administration. Results: The girls with CPP presented an increased height Z-score, advanced bone age, and higher baseline LH, FSH, estradiol, and LH/FSH ratio in relation to PT (p < 0.001). Stimulated LH differed significantly between the two groups, and the LH cutoff values were ≥4.29 IU/L (p < 0.001) and ≥3.95 IU/L at 60 and 120 min, respectively (p < 0.001). LH peak was found at 60 min after stimulation. Conclusions: The GnRHa test is effective in distinguishing CPP from PT, and a single sampling, at 60 min, with LH concentrations above 4.29 may be the parameter of choice with the advantage of greater convenience and practicality.

The Comparison of Juvenile Hormone and Transcriptional Changes between Three Different Juvenile Hormone Analogs Insecticides on Honey Bee Worker Larval’s Development

Juvenile hormones (JHs) play a crucial role in the development of honey bee (Apis mellifera) worker larvae. Juvenile hormone analogs (JHAs), insecticides widely used in pest control, have been reported to affect the health and survival of honey bee worker larvae. However, the molecular mechanisms of JHAs in the honey bee remain unclear. In this study, we treated honey bee worker larvae with pyriproxyfen, fenoxycarb, and methoprene, three different JHAs. We monitored the changes in the transcription of genes encoding major JH response enzymes (CYP15A1, CYP6AS5, JHAMT, and CHT1) using RT-qPCR and analyzed the transcriptome changes in worker larvae under JHA stress using RNA-seq. We found that the enrichment pathways differed among the treatment groups, but the classification of each pathway was generally the same, and fenoxycarb affected more genes and more pathways than did the other two JHAs. Notably, treatment with different JHAs in the honey bee changed the JH titers in the insect to various extents. These results represent the first assessment of the effects of three different JHAs on honey bee larvae and provide a new perspective and molecular basis for the research of JH regulation and JHA toxicity in the honey bee.

Clinical aspect, pathogenesis and therapy options of alopecia induced by hormonal therapy for breast cancer

Adjuvant hormonal therapy is one of the most important treatments of hormone-receptor-positive breast cancer and includes selective estrogen receptor modulators, aromatase inhibitors, and luteinizing hormone-releasing hormone analogs. In patients receiving these drugs, a progressive recession of frontal-temporal hairlines is often observed, such as a certain grade of hair miniaturization in the same areas and the central scalp area, producing a pseudo-female androgenic alopecia, which has to be considered oncotherapy-induced alopecia. The aim of this work, is to describe the clinical aspects and pathogenesis of this type of alopecia and to analyze the different drugs which have been proposed until now. The authors concude that topical hormones should not be considered as a therapeutic approach because of their direct or indirect oncogenic potential. A therapeutic approach that could be both safe and effective is proposed.

GnRHa protects the ovarian reserve by reducing endoplasmic reticulum stress during cyclophosphamide-based chemotherapy

Chemotherapy-induced ovarian dysfunction is a serious adverse effect in premenopausal patients with cancer. Gonadotrophin-releasing hormone analogs (GnRHa) protect ovarian function, but its molecular mechanisms have not yet been determined. In this study, we attempted to determine the previously unknown molecular mechanism by which such protection occurs. Serum anti-Müllerian hormone (AMH) levels were tested in tumor-bearing nude mice, a series of exploratory experiments were conducted. We discovered that GnRHa protects granulosa cells from chemotherapeutic toxicity in vivo and in vitro. We also showed that CTX-induced endoplasmic reticulum stress inhibits the secretion of AMH, and treatment with GnRHa relieves ER stress and the subsequent unfolded-protein response by modulating mTOR signaling to induce autophagy. The results of mechanistic studies indicated that GnRHa-modulated mTOR signaling to induce autophagy, which alleviated CTX-induced ER stress and promoted the secretion of AMH.

Age of diabetes onset in the mutant proinsulin syndrome correlates with mutational impairment of protein foldability and stability

Diverse heterozygous mutations in the human insulin gene cause a monogenic diabetes mellitus (DM) syndrome due to toxic misfolding of the variant proinsulin. Whereas mutations that add or remove cysteines (thereby leading to an odd number of thiol groups) generally lead to neonatal-onset DM, non-Cys-related mutations can be associated with a broad range of ages of onset. Here, we compare two mutations at a conserved position in the central B-chain α-helix: one neonatal in DM onset (ValB18→Gly) and the other with onset delayed until adolescence (AlaB18). The substitutions were introduced within a 49-residue single-chain insulin precursor optimized for folding efficiency (Zaykov, A., et al. ACS Chem. Biol. 9, 683-91 (2014)). Although mutations are each unfavorable, GlyB18 (a) more markedly perturbs DesDi folding efficiency in vitro than does AlaB18 and (b) more severely induces endoplasmic reticulum (ER) stress in cell-based studies of the respective proinsulin variants. In corresponding two-chain hormone analogs, GlyB18 more markedly perturbs structure, function and thermodynamic stability than does AlaB18. Indeed, the GlyB18-insulin analog forms a molten globule with attenuated α-helix content whereas the AlaA18 analog retains a nativelike cooperative structure with reduced free energy of unfolding (ΔΔGu 1.2(±0.2) kcal/mole relative to ValB18 parent). We propose that mutations at B18 variably impede nascent pairing of CysB19 and CysA20 to an extent correlated with perturbed core packing once native disulfide pairing is achieved. Differences in age of disease onset (neonatal or adolescent) reflect relative biophysical perturbations (severe or mild) of an obligatory on-pathway protein folding intermediate.

Anthropometric, metabolic, and reproductive outcomes of patients with central precocious puberty treated with leuprorelin acetate 3-month depot (11.25 mg)

Objectives Longer-acting gonadotropin-releasing hormone analogs (GnRHa) have been widely used for central precocious puberty (CPP) treatment. However, the follow-up of patients after this treatment are still scarce. Our aim was to describe anthropometric, metabolic, and reproductive follow-up of CPP patients after treatment with leuprorelin acetate 3-month depot (11.25 mg). Methods Twenty-two female patients with idiopathic CPP were treated with leuprorelin acetate 3-month depot (11.25 mg). Their medical records were retrospectively evaluated regarding clinical, hormonal, and imaging aspects before, during, and after GnRHa treatment until adult height (AH). Results At the diagnosis of CPP, the mean chronological age (CA) was 8.2 ± 1.13 year, and mean bone age (BA) was 10.4 ± 1.4 year. Mean height SDS at the start and the end of GnRHa treatment was 1.6 ± 0.8 and 1.3 ± 0.9, respectively. The mean duration of GnRHa treatment was 2.8 ± 0.8 year. Mean predicted adult heights (PAH) at the start and the end of GnRH treatment was 153.2 ± 8.6 and 164.4 ± 7.3 cm, respectively (p<0.05). The mean AH was 163.2 ± 6.2 cm (mean SDS: 0.1 ± 1). All patients were within their target height (TH) range. There was a decrease in the percentage of overweight and obesity from the diagnosis until AH (39–19% p>0.05). At the AH, the insulin resistance and high LDL levels were identified in 3/17 patients (17.6%) and 2/21 patients (9.5%), respectively. The mean CA of menarche was 12.2 ± 0.5 years. At the AH, PCOS was diagnosed in one patient (4.8%). Conclusions Long-term anthropometric, metabolic, and reproductive follow-up of patients with CPP treated with longer-acting GnRHa revealed effectivity, safety, and favorable outcomes.