Unusual hypocalcaemia in breast cancer relapse with multiple bone metastasis

Severe hypocalcaemia in breast cancer with bone metastasis is a rare finding usually associated with an advanced stage of the disease. We report a case of a 45-year-old woman with a history of local ductal carcinoma in situ (DCIS) of the breast, who presented with muscle tremors and general weakness. Hypocalcaemia was evident, with a positive Chvostek sign and a serum calcium level of 5.9 mg/dL (1.47 mmol/L), phosphorus 5.9 mg/dL (normal range: 2.3–4.7 mg/dL) with normal levels of albumin, magnesium and parathyroid hormone. High oral doses of alpha calcitriol and calcium with i.v. infusion of high calcium doses were instituted, altogether sufficient to maintain only mild hypocalcaemia. A whole-body CT revealed bone lesions along the axial skeleton. A biopsy from a bone lesion revealed a metastasis of breast carcinoma. With this pathological finding, leuprolide (GNRH analogue) and chlorambucil (alkylating agent) were initiated, followed by prompt tapering of infused calcium down to full discontinuation. Serum calcium was kept stable close to the low normal range by high doses of oral alpha calcitriol and calcium. This course raises suspicion that breast metastases to the skeleton caused tumour-induced hypocalcaemia by a unique mechanism. We assume that hypocalcaemia in this case was promoted by a combination of hypoparathyroidism and bone metastasis. Learning points Severe hypocalcaemia can a presenting symptom for breast cancer relapse.

Should Skeletal Maturation Be Manipulated for Extra Height Gain?

Skeletal maturation can be delayed by reducing the exposure to estrogens, either by halting pubertal development through administering a GnRH analogue (GnRHa), or by blocking the conversion of androgens to estrogens through an aromatase inhibitor (AI). These agents have been investigated in children with growth disorders (off-label), either alone or in combination with recombinant human growth hormone (rhGH). GnRHa is effective in attaining a normal adult height (AH) in the treatment of children with central precocious puberty, but its effect in short children with normal timing of puberty is equivocal. If rhGH-treated children with growth hormone deficiency or those who were born small-for-gestational age are still short at pubertal onset, co-treatment with a GnRHa for 2-3 years increases AH. A similar effect was seen by adding rhGH to GnRHa treatment of children with central precocious puberty with a poor AH prediction and by adding rhGH plus GnRHa to children with congenital adrenal hyperplasia with a poor predicted adult height on conventional treatment with gluco- and mineralocorticoids. In girls with idiopathic short stature and relatively early puberty, rhGH plus GnRHa increases AH. Administration of letrozole to boys with constitutional delay of growth puberty may increase AH, and rhGH plus anastrozole may increase AH in boys with growth hormone deficiency or idiopathic short stature, but the lack of data on attained AH and potential selective loss-of-follow-up in several studies precludes firm conclusions. GnRHas appear to have a good overall safety profile, while for aromatase inhibitors conflicting data have been reported.

Regulation of FSH Synthesis by Differentially Expressed miR-488 in Anterior Adenohypophyseal Cells

Gonadotropin-releasing hormone (GnRH), which is synthesized and released by the hypothalamus, promotes the synthesis and secretion of follicle-stimulating hormone (FSH), thereby regulating the growth and reproduction of animals. GnRH analogues have been widely used in livestock production. MiRNAs, which are endogenous non-coding RNAs, have been found to play important roles in hormone regulation and other physiological processes in recent years. However, the roles of miRNAs in GnRH-mediated regulation of FSH secretion have rarely been studied. Herein, we treated bovine anterior adenohypophyseal cells with an exogenous GnRH analogue and found that miR-488 was differentially expressed. Through a combination of TargetScan prediction and dual luciferase reporter analysis, miR-488 was confirmed to be able to target the FSHB gene. Based on this finding, we verified the expression of Fshβ and Lhβ mRNA in the rat adenohypophysis before and after exogenous GnRH treatment in vivo and in vitro. Experiments on rat anterior adenohypophyseal cells showed that overexpression of miR-488 significantly inhibited Fshβ expression and FSH synthesis, while knockdown of miR-488 had the opposite effects. Our results demonstrate that GnRH relies on miR-488 to regulate FSH synthesis, providing additional useful evidence for the significance of miRNAs in the regulation of animal reproduction.

​Induction of Postpartum Oestrus in Lakhimi Cows through Hormonal and Nutritional Interventions

Background: Postpartum anoestrus is the most devastating cause of the dairy farming which causes more economic losses to the farmers. The present study was conducted to record the incidence of postpartum anoestrus and to evolve a suitable therapeutic regime for addressing postpartum anoestrus in Lakhimi cows. Methods: A total of 1000 Lakhimi cows maintained in different villages of Assam were selected and the incidence rate was recorded on the basis of breeding records provided by the farmers, per-rectal examination and ultrasonography screening of genital organ. To study the effect of hormonal and nutritional interventions in post partum anoestrus cows, the cows were divided randomly into seven groups comprising twelve animals in each group. The different treatment regimes were Hydroxyprogesterone caproate + eCG, Clomiphene citrate alone, Clomiphene citrate + Mineral mixture, GnRH analogue alone, GnRH analogue + Mineral mixture, Mineral mixture alone and control. The response to different treatment regimes was based on oestrus response, mean interval from the end of treatment to onset of oestrus and conception rate. Result: The incidence of postpartum anoestrus was found to be 20.60%. Clomiphene citrate + Mineral mixture administration regime brought about the highest oestrus induction response (100.00%) and conception rate (66.67%).

Case Report: Lipoma of the Tuber Cinereum Mimicking a Pituitary Gland Abnormality in a Girl With Central Precocious Puberty

IntroductionMagnetic Resonance Imaging (MRI) is the best approach to investigate the hypothalamic-pituitary region in children with central precocious puberty (CPP). Routine scanning is controversial in girls aged 6-8 year, due to the overwhelming prevalence of idiopathic forms and unrelated incidentalomas. Cerebral lipomas are rare and accidental findings, not usually expected in CPP. We report a girl with CPP and an unusually shaped posterior pituitary gland on SE-T1w sequences.Case DescriptionA 7.3-year-old female was referred for breast development started at age 7. Her past medical history and physical examination were unremarkable, apart from the Tanner stage 2 breast. X-ray of the left-hand revealed a bone age 2-years ahead of her chronological age, projecting her adult height prognosis below the mid parental height. LHRH test and pelvic ultrasound were suggestive for CPP. Routine brain MRI sequences, SE T1w and TSE T2w, showed the posterior pituitary bright spot increased in size and stretched upward. The finding was considered as an anatomical variant, in an otherwise normal brain imaging. Patient was started on treatment with GnRH analogue. At a thorough revaluation, imaging overlap with adipose tissue was suspected and a new MRI scan with 3D-fat-suppression T1w-VIBE sequences demonstrated a lipoma of the tuber cinereum, bordering a perfectly normal neurohypophysis. 3D-T2w-SPACE sequences, acquired at first MRI scan, would have provided a more correct interpretation if rightly considered.ConclusionThis is the first evidence, to our knowledge, of a cerebral lipoma mimicking pituitary gland abnormalities. Our experience highlights the importance of considering suprasellar lipomas in the MRI investigation of children with CPP, despite their rarity, should the T1w sequences show an unexpected pituitary shape. 3D-T2w SPACE sequences could be integrated into standard ones, especially when performing MRI routinely, to avoid potential misinterpretations.

Effectiveness of modified downregulation for women with moderate and severe adenomyosis of the uterus prior to frozen thawed embryo transfer (MODA) study protocol: a pragmatic randomised-controlled trial

IntroductionAdenomyosis can adversely reduce chances of pregnancy in couples undergoing assisted conception. We aim to evaluate the effect of two different downregulation protocols on the reproductive outcomes in women with moderate and severe adenomyosis undergoing frozen-thawed embryo transfer (FTET).Methods and analysisWe will conduct a two-armed pragmatic randomised clinical trial comparing modified downregulation with gonadotrophin-releasing hormone (GnRH) analogue for 6 weeks to standard downregulation with GnRH analogue for 1 week prior to FTET. Our primary outcome is clinical pregnancy, defined as a viable intrauterine pregnancy confirmed by ultrasound at greater than 6 weeks gestation, with other secondary reproductive, neonatal and safety outcomes. We aim to randomise 162 patients over 3 years to achieve 80% power for detecting a 20% difference in the primary outcome at 5% significance.Ethics and disseminationTo date there is no consensus on the optimal protocol for management of subfertile women with adenomyosis. Modified downregulation could improve the clinical pregnancy rate by reducing the endometrial inflammatory reaction and/or myometrial contractility and their impact on uterine receptivity in women with moderate and severe adenomyosis of the uterus undergoing FTET. The MODA trial is designed to offer pragmatic, real-life evaluation of the optimal protocol for downregulation for this population during assisted conception treatments. Our findings will be published in peer-reviewed journals and presented at national and international scientific meetings and congresses. Ethical approval was granted by the NHS Research Ethics Committees (19/LO/1567).Trial registration numberNCT03946722.

Effect of Treatment With Gonadoreline at the Embryo Transfer on Pregnancy Outcomes in Bovine.

The aim of this study was to assess whether administration of the gonadotropin-releasing hormone (GnRH) agonist gonadorelin would increase conception rates at 30 (P / ET 30) and 60 (P / ET 60) days of gestation and reduce pregnancy losses (PL) in embryo recipients and what would be the correlation between the animal category and the season of the year in which the embryo transfer would occur. The experiment was conducted on 11 commercial farms in the state of Minas Gerais, Brazil. Recipients were randomly divided into groups: treated (n = 624), cows that received 0.1 mg gonadorelin on the day of FTET, and control (n = 687), untreated cows. All embryos were produced in vitro from oocyte donors of different races. Recipients were classified as heifers, dry cows or lactating cows. Higher conception rate was observed at 30 days (p = 0.03) and 60 days (p = 0.01) in the treated group (45.8%; 43.0%, respectively). Dry and lactating cows had less pregnancy loss (p = 0.001) compared to heifers (2.70% and 2.47% vs 10.42%, respectively). During spring/summer, there was less P/FTET at 30 days (0.024). Embryo transfer carried out in the warmer seasons of the year reduced the pregnancy rate to 60 days and increased pregnancy loss. As an implication, the use of the GnRH analogue can be used as a tool to increase fertility in embryo recipients.

The Diagnostic Utility of the Basal Luteinizing Hormone Level and Single 60-Minute Post GnRH Agonist Stimulation Test for Idiopathic Central Precocious Puberty in Girls

ObjectiveThe present study aimed to assess the diagnostic utility of the Luteinizing hormone (LH) levels and single 60-minute post gonadotropin-releasing hormone (GnRH) agonist stimulation test for idiopathic central precocious puberty (CPP) in girls.MethodsData from 1,492 girls diagnosed with precocious puberty who underwent GnRH agonist stimulation testing between January 1, 2016, and October 8, 2020, were retrospectively reviewed. LH levels and LH/follicle-stimulating hormone (FSH) ratios were measured by immuno-chemiluminescence assay before and at several timepoints after GnRH analogue stimulation testing. Mann–Whitney U test, Spearman’s correlation, χ2 test, and receiver operating characteristic (ROC) analyses were performed to determine the diagnostic utility of these hormone levels.ResultsThe 1,492 subjects were split into two groups: an idiopathic CPP group (n = 518) and a non-CPP group (n = 974). Basal LH levels and LH/FSH ratios were significantly different between the two groups at 30, 60, 90, and 120 minutes after GnRH analogue stimulation testing. Spearman’s correlation analysis showed the strongest correlation between peak LH and LH levels at 60 minutes after GnRH agonist stimulation (r = 0.986, P < 0.001). ROC curve analysis revealed that the 60-minute LH/FSH ratio yielded the highest consistency, with an area under the ROC curve (AUC) of 0.988 (95% confidence interval [CI], 0.982–0.993) and a cut-off point of 0.603 mIU/L (sensitivity 97.3%, specificity 93.0%). The cut-off points of basal LH and LH/FSH were 0.255 mIU/L (sensitivity 68.9%, specificity 86.0%) and 0.07 (sensitivity 73.2%, specificity 89.5%), respectively, with AUCs of 0.823 (95% CI, 0.799–0.847) and 0.843 (95% CI, 0.819–0.867), respectively.ConclusionsA basal LH value greater than 0.535 mIU/L can be used to diagnose CPP without a GnRH agonist stimulation test. A single 60-minute post-stimulus gonadotropin result of LH and LH/FSH can be used instead of a GnRH agonist stimulation test, or samples can be taken only at 0, 30, and 60 minutes after a GnRH agonist stimulation test. This reduces the number of blood draws required compared with the traditional stimulation test, while still achieving a high level of diagnostic accuracy.

Administration of GnRH at Onset of Estrus, Determined by Automatic Activity Monitoring, to Improve Dairy Cow Fertility during the Summer and Autumn

We examined gonadotropin-releasing hormone (GnRH) administration at onset of estrus (OE), determined by automatic activity monitoring (AAM), to improve fertility of dairy cows during the summer and autumn. The study was performed on two dairy farms in Israel. The OE was determined by AAM recorded every 2 h, and a single im dose of GnRH analogue was administered shortly after OE. Pregnancy was determined by transrectal palpation, 40 to 45 d after artificial insemination (AI). Conception risk was analyzed by the GLIMMIX procedure of SAS. Brief visual observation of behavioral estrus indicated that about three-quarters of the events (n = 40) of visually detected OE occurred within 6 h of AAM-detected OE. Accordingly, the GnRH analogue was administered within 5 h of AAM-detected OE, to overlap with the expected endogenous preovulatory LH surge. Overall, pregnancy per AI (P/AI) was monitored over the entire experimental period (summer and autumn) in 233 first, second or third AI (116 and 117 AI for treated and control groups, respectively). Least square means of P/AI for treated (45.8%) and control (39.4%) groups did not differ, but group-by-season interaction tended to differ (p = 0.07), indicating no effect of treatment in the summer and a marked effect of GnRH treatment (n = 58 AI) compared to controls (n = 59 AI) on P/AI in the autumn (56.6% vs. 28.5%, p < 0.03). During the autumn, GnRH-treated mature cows (second or more lactations), and postpartum cows exhibiting metabolic and uterine diseases, tended to have much larger P/AI than their control counterparts (p = 0.07–0.08). No effect of treatment was recorded in the autumn in first parity cows or in uninfected, healthy cows. In conclusion, administration of GnRH within 5 h of AAM-determined OE improved conception risk in cows during the autumn, particularly in those exhibiting uterine or metabolic diseases postpartum and in mature cows. Incorporation of the proposed GnRH treatment shortly after AAM-detected OE into a synchronization program is suggested, to improve fertility of positively responding subpopulations of cows.

Late presentation of extrauterine adenomyomas after laparoscopic morcellation at hysterectomy: a case report

Background An adenomyoma is a well circumscribed form of adenomyosis and can be located within the myometrium, in the endometrium as a polyp, or extrauterine with the last being the rarest presentation amongst the three. With the ongoing advancement in gynecological surgery, the use of electromechanical morcellators have made the removal of large and dense specimens possible with minimally invasive techniques. However, it has also caused an increase in complications which were previously rare. Whilst the tissue is being grinded within the abdominal cavity, residual tissue can spread and remain inside, allowing for implantation to occur and thereby giving rise to recurrence of uterine tissue as a new late postoperative complication. Case presentation A 45-year-old woman presented with worsening constipation and right iliac fossa pain. Her past surgical history consists of laparoscopic supra-cervical hysterectomy that was indicated due to uterine fibroids. Computerized tomography and magnetic resonance imaging were done, which showed an irregular lobulated heterogeneous mass seen in the presacral space to the right, located on the right lateral aspect of the recto-sigmoid, measuring 4.5 × 4.3 × 4.3 cm in size. A transvaginal ultrasound revealed a cyst in the left ovary. The patient had a treatment course over several months that included Dienogest (progestin) and Goserelin (GnRH analogue) with add-back therapy. In line with the declining response to medications, the patient was advised for a laparoscopic ovarian cystectomy. During the surgery, an additional lesion was found as a suspected fibroid and the left ovarian cyst was identified as pockets of peritoneal fluid which was sent for cytology. The surgical pathology report confirmed adenomyosis in both specimens, namely the right mass and the initially suspected fibroid. Conclusion In this case report, we showcase a rare occurrence of an extrauterine adenomyoma presenting two years post laparoscopic morcellation at hysterectomy. This poses questions regarding the benefits versus risks of power morcellation in laparoscopic hysterectomy.