Mandy Donaldson

Subcutaneous Injection of Kisspeptin-54 Acutely Stimulates Gonadotropin Secretion in Women with Hypothalamic Amenorrhea, But Chronic Administration Causes Tachyphylaxis

BACKGROUND Kisspeptin is a critical regulator of normal reproductive function. A single injection of kisspeptin in healthy human volunteers potently stimulates gonadotropin release. However, the effects of kisspeptin on gonadotropin release in women with hypothalamic amenorrhea (HA) and the effects of repeated administration of kisspeptin to humans are unknown. AIM The aim of this study was to determine the effects of acute and chronic kisspeptin administration on gonadotropin release in women with HA. METHODS We performed a prospective, randomized, double-blinded, parallel design study. Women with HA received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline (n = 5 per group) for 2 wk. Changes in serum gonadotropin and estradiol levels, LH pulsatility, and ultrasound measurements of reproductive activity were assessed. RESULTS On the first injection day, potent increases in serum LH and FSH were observed after sc kisspeptin injection in women with HA (mean maximal increment from baseline within 4 h after injection: LH, 24.0 +/- 3.5 IU/liter; FSH, 9.1 +/- 2.5 IU/liter). These responses were significantly reduced on the 14th injection day (mean maximal increment from baseline within 4 h postinjection: LH, 2.5 +/- 2.2 IU/liter, P < 0.05; FSH, 0.5 +/- 0.5 IU/liter, P < 0.05). Subjects remained responsive to GnRH after kisspeptin treatment. No significant changes in LH pulsatility or ultrasound measurements of reproductive activity were observed. CONCLUSION Acute administration of kisspeptin to women with infertility due to HA potently stimulates gonadotropin release, but chronic administration of kisspeptin results in desensitization to its effects on gonadotropin release. These data have important implications for the development of kisspeptin as a novel therapy for reproductive disorders in humans.

Oral cholecalciferol decreases albuminuria and urinary TGF-β1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition.

The anti-inflammatory, antifibrotic, and antiproteinuric properties of vitamin D have been defined in studies using active vitamin D analogs. In this prospective observational study we determined whether nutritional vitamin D repletion can have additional beneficial effects in patients with type 2 diabetic nephropathy already established on renin-angiotensin-aldosterone system inhibition. During a 7-month period, 63 patients were enrolled and those with low levels of 25(OH)D were treated with oral cholecalciferol for 4 months. Baseline serum 25(OH)D and 1,25(OH)(2)D showed no significant correlation with baseline urinary MCP-1, TGF-β1, or albuminuria measured as the urinary albumin-to-creatinine ratio. Of the 63 patients, 54 had insufficient or deficient levels of serum 25(OH)D and 49 complied with cholecalciferol therapy and follow-up. Both 25(OH)D and 1,25(OH)(2)D were significantly increased at 2 and 4 months of treatment. Albuminuria and urinary TGF-β1 decreased significantly at both time points compared to their baseline values, while urinary MCP-1 did not change. Thus, in the short term, dietary vitamin D repletion with cholecalciferol had a beneficial effect in delaying the progression of diabetic nephropathy above that due to established renin-angiotensin-aldosterone system inhibition.

Twice‐Weekly Administration of Kisspeptin‐54 for 8 Weeks Stimulates Release of Reproductive Hormones in Women With Hypothalamic Amenorrhea

Kisspeptin is a novel therapeutic target for infertility. A single kisspeptin‐54 (KP‐54) injection acutely stimulates the release of reproductive hormones in women with hypothalamic amenorrhea (HA), a commonly occurring condition characterized by absence of menstruation; however, twice‐daily administration of KP‐54 results in tachyphylaxis. We determined the time course of desensitization to twice‐daily KP‐54 injections, compared the effects of twice‐daily and twice‐weekly administration regimens of KP‐54, and studied the effects of long‐term twice‐weekly administration of KP‐54 on the release of reproductive hormones in women with HA. When KP‐54 was administered twice daily, responsiveness to luteinizing hormone (LH) diminished gradually, whereas responsiveness to follicle‐stimulating hormone (FSH) was nearly abolished by day 2. Twice‐weekly KP‐54 administration resulted in only partial desensitization, in contrast to the complete tolerance achieved with twice‐daily administration. Women with HA who were treated with twice‐weekly KP‐54 injections had significantly elevated levels of reproductive hormones after 8 weeks as compared with treatment with saline. No adverse effects were observed. This study provides novel pharmacological data on the effects of KP‐54 on the release of reproductive hormones in women with HA.

Utility of the urine calcium-to-creatinine ratio to diagnose primary hyperparathyroidism in asymptomatic hypercalcaemic patients with vitamin D deficiency.

Background Primary hyperparathyroidism (PHP) is the most common cause of hypercalcaemia, and often requires surgical treatment. Familial hypocalciuric hypercalcaemia (FHH) has similar biochemical features to PHP, but requires no treatment. The most common biochemical method used to distinguish between PHP and FHH is the urine calcium-to-creatinine ratio (UCCR). Vitamin D deficiency may alter the renal excretion of calcium, but it is unclear how vitamin D deficiency affects the diagnostic performance of UCCR. Aim To examine the reliability of UCCR to detect PHP in patients presenting with asymptomatic hypercalcaemia, in the presence or absence of vitamin D deficiency. Methods One hundred and eighteen UCCR measurements from 97 asymptomatic hypercalcaemic patients diagnosed with PHP presenting to a single specialist endocrine unit were analysed retrospectively. Results A significantly higher proportion of UCCR measurements were <0.010 in patients with serum vitamin D <25 nmol/L when compared with patients with serum vitamin D >25 nmol/L, thus incorrectly suggesting the presence of FHH (proportion of measurements with UCCR >0.010: 11/48 [22.9%], vitamin D <25 nmol/L; 4/70 [5.7%], vitamin D >25 nmol/L; P < 0.001). Urine calcium concentration was 26% lower and serum parathyroid hormone (PTH) was 27% higher in patients with vitamin D deficiency when compared with patients without vitamin D deficiency. Conclusions These data suggest that the presence of vitamin D deficiency is associated with worsened PTH hypersecretion, impairment of urinary calcium excretion and reduced sensitivity of UCCR measurement with respect to the detection of PHP. These data have important clinical implications for the investigation and management of patients with asymptomatic hypercalcaemia.

Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception

Testosterone (T), alone or in combination with progestin, provides a promising approach to hormonal male contraception. Its principle relies on enhanced negative feedback of exogenous T to suppress gonadotropins, thereby blocking the testicular T production needed for spermatogenesis, while simultaneously maintaining the extragonadal androgen actions, such as potency and libido, to avoid hypogonadism. A serious drawback of the treatment is that a significant proportion of men do not reach azoospermia or severe oligozoospermia, commensurate with contraceptive efficacy. We tested here, using hypogonadal luteinizing hormone/choriongonadotropin receptor (LHCGR) knockout (LHR–/–) mice, the basic principle of the T‐based male contraceptive method, that a specific T dose could maintain extragonadal androgen actions without simultaneously activating spermatogenesis. LHR–/– mice were treated with increasing T doses, and the responses of their spermatogenesis and extragonadal androgen actions (including gonadotropin suppression and sexual behavior) were assessed. Conspicuously, all dose responses to T were practically superimposable, and no dose of T could be defined that would maintain sexual function and suppress gonadotropins without simultaneously activating spermatogenesis. This finding, never addressed in clinical contraceptive trials, is not unexpected in light of the same androgen receptor mediating androgen actions in all organs. When extrapolated to humans, our findings may jeopardize the current approach to hormonal male contraception and call for more effective means of inhibiting intratesticular T production or action, to achieve consistent spermatogenic suppression.—Oduwole, O. O., Vydra, N., Wood, N. E. M., Samanta, L., Owen, L., Keevil, B., Donaldson, M., Naresh, K., Huhtaniemi, I. T. Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception. FASEB J. 28, 2566–2576 (2014). www.fasebj.org

Combination of Peptide YY3–36 with GLP-17–36 amide Causes an Increase in First-Phase Insulin Secretion after IV Glucose

Context: The combination of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) has been proposed as a potential treatment for diabetes and obesity. However, the combined effects of these hormones, PYY3–36 and GLP-17–36 amide, on glucose homeostasis are unknown. Objective: This study sought to investigate the acute effects of PYY3–36 and GLP-17–36 amide, individually and in combination, on insulin secretion and sensitivity. Setting and Design: Using a frequently sampled iv glucose tolerance test (FSIVGTT) and minimal modeling, this study measured the effects of PYY3–36 alone, GLP-17–36 amide alone, and a combination of PYY3–36 and GLP-17–36 amide on acute insulin response to glucose (AIRg) and insulin sensitivity index (SI) in 14 overweight human volunteers, studied in a clinical research facility. Results: PYY3–36 alone caused a small but nonsignificant increase in AIRg. GLP-17–36 amide alone and the combination of PYY3–36 and GLP-17–36 amide did increase AIRg significantly. No significant differences in SI were observed with any intervention. Conclusions: PYY3–36 lacks any significant acute effects on first-phase insulin secretion or SI when tested using an FSIVGTT. Both GLP-17–36 amide alone and the combination of PYY3–36 and GLP-17–36 amide increase first-phase insulin secretion. There does not seem to be any additive or synergistic effect between PYY3–36 and GLP-17–36 amide on first-phase insulin secretion. Neither hormone alone nor the combination had any significant effects on SI.

Serum Parathyroid Hormone Is Not an Accurate Predictor of Postthyroidectomy Hypocalcemia in Vitamin D–Deficient Patients: A Pilot Study

To the Editor: Transient hypoparathyroidism resulting in temporary hypocalcemia is the most frequent complication of total thyroidectomy and affects up to one third of patients. The ability to accurately predict hypocalcemia after thyroidectomy allows timely intervention and facilitates early discharge of patients. The postoperative decline in serum parathyroid hormone (PTH) is currently regarded as the gold standard biochemical predictor of postthyroidectomy hypocalcemia. Although the value of PTH in predicting postthyroidectomy hypocalcemia has been extensively studied, its predictive accuracy in vitamin D–deficient patients is unclear. This is of particular importance because there is a high prevalence of vitamin D deficiency in patients with thyroid nodules, malignancy, and Graves disease, the major indications for thyroidectomy (1, 2). We retrospectively examined the value of serum PTH as a predictor of postthyroidectomy hypocalcemia in patients with and without vitamin D deficiency. We identified 74 consecutive patients who had undergone total/completion thyroidectomy. Serum 25-hydroxyvitamin D concentration was measured preoperatively, and serum PTH and calcium concentrations were measured in all patients 8–10 h after surgery. Serum calcium …

Comparison of the overnight metyrapone and glucagon stimulation tests in the assessment of secondary hypoadrenalism

The insulin tolerance test (ITT) is contraindicated in a proportion of patients with suspected ACTH deficiency. The aim of this study was to investigate the diagnostic accuracy of the glucagon stress test (GST) compared with the overnight metyrapone test (OMT) in patients with contraindications to ITT.

Adrenal venous sampling as a diagnostic procedure for primary hyperaldosteronism: experience from a tertiary referral centre

CONTEXTAdrenal vein sampling (AVS) is recommended in all patients with hyperaldos-teronism to whom surgery would be offered if the results indicated unilateral hypersecretion.OBJECTIVETo assess the performance of AVS against radiological findings and to evaluate the Endocrine Society’s Practice Guidelines for diagnostic cut-offs.PATIENTSRetrospective study of 41 patients with hyperaldosteronism who underwent both AVS and computed tomography (CT) imaging.RESULTSCT and AVS results were concordant in 73.7%. Unilateral lesions on CT had a greater positive predictive value (85%) than non-unilateral lesions (50%). In patients with subsequently confirmed adrenal adenomas, a lateralisation ratio >2 when comparing cortisol-corrected aldosterone ratios from the affected versus unaffected side was 100% sensitive. Patients who were managed surgically experienced significant reductions in blood pressure and medication burden and 46% were cured.CONCLUSIONSAVS is important in establishing unilateral or bilateral adrenal secretion of aldosterone in patients with primary hyperaldosteronism. However, it may not be essential for the work-up in patients below the age of 40, in whom adrenal incidentalomas adrenal incidentalomas are known to be rarer, and a unilateral lesion on CT therefore has a greater positive predictive value.

Dexamethasone-Suppressed Corticotrophin-Releasing Hormone–Stimulation Test Does Not Reliably Diagnose or Predict Recurrence of Cushing Disease

First-line treatment for Cushing disease is surgical removal of the adrenocorticotrophin-secreting pituitary tumor. Because of the high risk of relapse, it is essential that patients receive long-term postoperative follow-up for disease recurrence through expert clinical evaluation and biochemical assessment of hypercortisolism, including the use of dexamethasone suppression (1). However, no gold-standard test has been shown to accurately predict recurrence(1). The dexamethasone-suppressed corticotropin-releasing hormone–stimulation (LDDST-CRH)1 test was initially proposed to be more accurate in confirming hypercortisolism than the standard low-dose dexamethasone-suppression test (LDDST) for the diagnosis of Cushing syndrome(2). The underlying principle of this test is that patients with true hypercortisolism demonstrate suboptimal cortisol suppression by dexamethasone, yet remain responsive to exogenous CRH. More recent studies have challenged the diagnostic accuracy of this test in the diagnosis of Cushing syndrome by demonstrating suboptimal specificity(3)(4)(5). The utility of the LDDST-CRH test for postoperative surveillance in patients with previously diagnosed Cushing disease who have been treated with transsphenoidal hypophysectomy has not been assessed. Therefore, we investigated the performance of the LDDST-CRH test in this setting. We identified a subset of 21 patients who had undergone pituitary surgery for Cushing disease and had remained at our center for postoperative surveillance. Each patient had undergone at least 1 postoperative LDDST and LDDST-CRH test as previously …