Emma O. Billington

Endocrine Aspects of 4H Leukodystrophy: A Case Report and Review of the Literature

Introduction. 4H leukodystrophy is an autosomal recessive RNA polymerase III-related leukodystrophy, characterized by hypomyelination, with or without hypodontia (or other dental abnormalities) and hypogonadotropic hypogonadism. Case Presentation. We describe a 28-year-old female who presented with primary amenorrhea at the age of 19. She had a history of very mild neurological and dental abnormalities. She was found to have hypogonadotropic hypogonadism, and magnetic resonance imaging of the brain showed hypomyelination. The diagnosis of 4H leukodystrophy was made. She was subsequently found to have mutations in the POLR3B gene, which encodes the second largest subunit of RNA polymerase III. She wished to become pregnant and failed to respond to pulsatile GnRH but achieved normal follicular growth and ovulation with subcutaneous gonadotropin therapy. Discussion. Patients with 4H leukodystrophy may initially present with hypogonadotropic hypogonadism, particularly if neurological and dental manifestations are subtle. Making the diagnosis has important implications for prognosis and management. Progressive neurologic deterioration is expected, and progressive endocrine dysfunction may occur. Patients with 4H leukodystrophy should be counseled about disease progression and about this diseases autosomal recessive inheritance pattern. In those who wish to conceive, ovulation induction may be achieved with subcutaneous gonadotropin therapy, but pulsatile GnRH does not appear to be effective.

Anti-Mullerian hormone levels do not predict response to pulsatile GnRH in women with hypothalamic amenorrhea

Abstract Pulsatile GnRH is used to induce ovulation in women with hypothalamic amenorrhea (HA), but tools to predict response are lacking. We assessed whether baseline AMH levels are associated with response to pulsatile GnRH in 16 women with HA. AMH levels were compared between non-responders and women who achieved follicular development or pregnancy. Median AMH for the cohort was 2.2 ng/mL. AMH levels were undetectable or low in four women, normal in nine and high in three. Follicular development was observed in 13 (81%) women (82% of cycles) and pregnancy achieved in 10 (63%) women (29% of cycles). All four women with low or undetectable AMH had follicular response and three achieved pregnancy. Of the 12 women with normal or high AMH, 10 had a follicular response and seven achieved pregnancy. Median AMH levels were comparable in those who achieved follicular development and those who did not (2.2 ng/mL versus 1.3 ng/mL, p = 0.78) and in those who became pregnant and those who did not (2.2 ng/mL versus 1.9 ng/mL, p = 0.52). In summary, low AMH does not preclude response to ovulation induction in women with HA, suggesting that ovarian potential may not be the primary determinant of AMH concentrations in this population.

Reasons for discrepancies in hip fracture risk estimates using FRAX and Garvan calculators

OBJECTIVES Both the FRAX and Garvan calculators are used to estimate absolute risk of fracture, but they sometimes produce different estimates. We sought to determine which patient characteristics contribute to these discrepancies. STUDY DESIGN Ten-year hip fracture risk was estimated for 122 women, using both FRAX and Garvan with bone mineral density (BMD). MAIN OUTCOME MEASURES Differences in estimates of hip fracture were assessed, both in absolute terms and with respect to a treatment threshold of 3%. RESULTS Garvan estimates were higher than FRAX estimates across the range of ages and BMDs studied. A history of falls or of multiple fractures increased risk calculated by Garvan 3-6-fold, but did not account for all differences between calculators. Discrepancies around a 3% treatment threshold occurred in 31/122 (25%). Women aged 70-74 years, and women with osteopenia were most likely to have discordant estimates. Most discordant estimates (29/31) had a Garvan estimate ≥ 3% and FRAX <3%. Falls, multiple fractures, ethnicity and a history of parental hip fracture contributed to some discordant estimates. CONCLUSIONS Hip fracture risk estimates are usually higher with Garvan than FRAX, and these differences could impact on treatment decisions in about a quarter of patients. Falls and multiple fractures have a strong influence on Garvan risk estimates, when present. Clinically important discrepancies tend to occur in patients who are at borderline fracture risk. In patients with hip fracture risks near the treatment threshold with one calculator, use of the other calculator should be considered to help guide treatment decisions.

Serum phosphate is related to adiposity in healthy adults

Inorganic phosphate is a crucial component of cellular energy metabolism. We have identified an inverse relationship between serum phosphate concentration and fat mass in a cohort of healthy men. This study reports those data and determines whether this association is present in two female populations.

Parathyroid hormone reflects adiposity and cardiometabolic indices but not bone density in normal men

Hyperparathyroidism may be associated with skeletal and cardiovascular abnormalities, but it is unclear whether these associations exist for high-normal levels of parathyroid hormone (PTH). We assessed relationships between PTH and anthropometric, skeletal and cardiometabolic indices in normal men. Body composition, blood pressure, biochemistry and bone mineral density (BMD) were evaluated in 151 healthy men. BMD was reassessed at 2 years, and coronary artery calcium (CAC) was measured at 3.5 years. Relationships between PTH and other baseline characteristics, CAC scores and change in BMD were evaluated. PTH correlated positively with baseline body mass index, fat mass, diastolic blood pressure, triglycerides, total and low-density lipoprotein (LDL) cholesterol, (r=0.19-0.25, P=0.02-0.002), and with category of CAC score. Relationships between PTH and cardiometabolic indices remained significant after adjustment for age, 25-hydroxyvitamin D and estimated glomerular filteration rate. Men in the top PTH tertile (⩾4.4 pmol l-1, n=51) were more likely to have LDL cholesterol ⩾3.5 mmol l-1, diastolic blood pressure ⩾85 mm Hg, and CAC score >0 than men in lower tertiles. PTH was not associated with history of fracture, baseline BMD, or change in BMD over 2 years. In summary, in this cohort of healthy men, PTH levels are linearly related to adiposity and to cardiometabolic indices, but not to BMD or bone loss. These findings suggest that adiposity should be considered as an independent cause of secondary hyperparathyroidism, and they may be relevant to patients with normocalcemic hyperparathyroidism, in whom high PTH levels may be a marker of adiposity and cardiometabolic risk rather than always indicating parathyroid autonomy.

Pathogenesis of Osteoporosis

Skeletal strength and resilience to fracture is dependent upon a multitude of factors, including peak bone mass, subsequent bone loss, bone turnover, skeletal micro- and macro-architecture, and the condition of the bone matrix. Any condition that influences these factors has the potential to promote the development of osteoporosis and increase the risk of fragility fracture. This article reviews the many determinants of skeletal strength and highlights the various scenarios in which skeletal fragility can develop, including both postmenopausal and secondary osteoporosis.

Methods and procedures for: A randomized double-blind study investigating dose-dependent longitudinal effects of vitamin D supplementation on bone health

The optimum dose of vitamin D and corresponding serum 25-hydroxyvitamin D (25OHD) concentration for bone health is still debated and some health practitioners are recommending doses well above the Canada/USA recommended Dietary Reference Intake (DRI). We designed a three-year randomized double-blind clinical trial investigating whether there are dose-dependent effects of vitamin D supplementation above the Dietary Reference Intake (DRI) on bone health. The primary aims of this study are to assess, whether supplementation of vitamin D3 increases 1) volumetric bone mineral density measured by high-resolution peripheral quantitative computed tomography (HR-pQCT); 2) bone strength assessed by finite element analysis, and 3) areal bone mineral density by dual X-ray absorptiometry (DXA). Secondary aims are to understand whether vitamin D3 supplementation improves parameters of bone microarchitecture, balance, physical function and quality of life. Participants are men and women aged 55-70 years, with women at least 5-years post-menopause. The intervention is daily vitamin D3 supplementation doses of 400, 4000 or 10,000 IU. Participants not achieving adequate dietary calcium intake are provided with calcium supplementation, up to a maximum supplemental dose of 600 mg elemental calcium per day. Results from this three-year study will provide evidence whether daily vitamin D3 supplementation with adequate calcium intake can affect bone density, bone microarchitecture and bone strength in men and women. Furthermore, the safety of high dose daily vitamin D3 supplementation will be explored.