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Sofya Gronskaia Endocrinology Research Centre, Moscow, Russia

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Galina Melnichenko Endocrinology Research Centre, Moscow, Russia

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Liudmila Rozhinskaya Endocrinology Research Centre, Moscow, Russia

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Tatiana Grebennikova Endocrinology Research Centre, Moscow, Russia

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Elizaveta Mamedova Endocrinology Research Centre, Moscow, Russia

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Ekaterina Pigarova Endocrinology Research Centre, Moscow, Russia

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Elena Przhialkovskaya Endocrinology Research Centre, Moscow, Russia

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Larisa Dzeranova Endocrinology Research Centre, Moscow, Russia

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Ivan Dedov Endocrinology Research Centre, Moscow, Russia

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Valentin Fadeyev I.M. Sechenov First Moscow State Medical University, Moscow, Russia

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Maria Luisa Brandi University of Florence, Surgery and Translational Medicine, Piereccaini, Firenze, Italy

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Zhanna Belaya Endocrinology Research Centre, Moscow, Russia

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Hypoparathyroidism and pseudohypoparathyroidism are rare endocrine disorders, characterized by low serum calcium due to inappropriate parathyroid hormone (PTH) levels or resistance to its action. There is little epidemiological information regarding chronic hypoparathyroidism in Russia. This study aims to build a registry database of Russian patients with chronic hypoparathyroidism who were referred for hospital treatment in order to conduct initial analysis of clinical presentations and hospital management. The Italian registry model was taken to be able to integrate our data in the future. Two hundred patients with hypoparathyroidism (n = 194) and pseudohypoparathyroidism (n = 6) were enrolled over 2 years (2017–2019). The most frequent cause of hypoparathyroidism was neck surgery (82.5%, mostly females), followed by idiopathic hypoparathyroidism (10%), syndromic forms of genetic hypoparathyroidism (4.5%) and forms of defective PTH action (3%). Calcium supplements and alfacalcidol were prescribed in most cases. However, a minority of patients (n = 6) needed to receive teriparatide as the only way to maintain calcium levels and to prevent symptoms of hypocalcemia. Consequently, substitution treatment with parathyroid hormone should be available in certain cases of hypoparathyroidism. This database will be useful to estimate the potential requirement for recombinant PTH in Russia and standards for clinical and therapeutic approaches.

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Leyre Lorente-Poch Endocrine Surgery Unit, Hospital del Mar, Barcelona, Spain
Departament de Cirurgia, Universitat Autònoma de Barcelona, Barcelona, Spain

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Sílvia Rifà-Terricabras Departament de Cirurgia, Universitat Autònoma de Barcelona, Barcelona, Spain

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Juan José Sancho Endocrine Surgery Unit, Hospital del Mar, Barcelona, Spain
Departament de Cirurgia, Universitat Autònoma de Barcelona, Barcelona, Spain

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Danilo Torselli-Valladares Endocrine Surgery Unit, Hospital del Mar, Barcelona, Spain

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Sofia González-Ortiz Department of Radiology, Hospital del Mar, Barcelona, Spain

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Antonio Sitges-Serra Endocrine Surgery Unit, Hospital del Mar, Barcelona, Spain
Departament de Cirurgia, Universitat Autònoma de Barcelona, Barcelona, Spain

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Objective:

Permanent hypoparathyroidism is an uncommon disease resulting most frequently from neck surgery. It has been associated with visceral calcifications but few studies have specifically this in patients with post-surgical hypoparathyroidism. The aim of the present study was to assess the prevalence of basal ganglia and carotid artery calcifications in patients with long-term post-thyroidectomy hypoparathyroidism compared with a control population.

Design:

Case–control study.

Methods:

A cross-sectional review comparing 29 consecutive patients with permanent postoperative hypoparathyroidism followed-up in a tertiary reference unit for Endocrine Surgery with a contemporary control group of 501 patients who had an emergency brain CT scan. Clinical variables and prevalence of basal ganglia and carotid artery calcifications were recorded.

Results:

From a cohort of 46 patients diagnosed with permanent hypoparathyroidism, 29 were included in the study. The mean duration of disease was 9.2 ± 7 years. Age, diabetes, hypertension, smoking and dyslipidemia were similarly distributed in case and control groups. The prevalence of carotid artery and basal ganglia calcifications was 4 and 20 times more frequent in patients with permanent hypoparathyroidism, respectively. After propensity score matching of the 28 the female patients, 68 controls were matched for age and presence of cardiovascular factors. Cases showed a four-fold prevalence of basal ganglia calcifications, whereas that of carotid calcifications was similar between cases and controls.

Conclusion:

A high prevalence of basal ganglia calcifications was observed in patients with post-surgical permanent hypoparathyroidism. It remains unclear whether carotid artery calcification may also be increased.

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Rasmus Reinke Department of Otorhinolaryngology, Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark

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Stefano Christian Londero Department of Otorhinolaryngology, Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark

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Martin Almquist Department of Surgery, Lund University Hospital, Lund, Sweden

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Lars Rejnmark Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark

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Lars Rolighed Department of Otorhinolaryngology, Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark

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Objective

Total thyroidectomy is associated with a high risk of postoperative hypoparathyroidism, mainly due to the unintended surgical damage to the parathyroid glands or their blood supply. It is possible that surgeons who also perform parathyroid surgery see lower rates of postoperative hypoparathyroidism. In a single institution, we investigated the effects of restricting total thyroidectomy operations for Graves’ disease to two surgeons who performed both thyroid and parathyroid surgeries. We aimed to evaluate the rates of postoperative hypoparathyroidism in a 10-year period with primary attention toward patients with Graves’ disease.

Design

Retrospective cohort study from a single institution.

Methods

We defined the rate of permanent hypoparathyroidism after total thyroidectomy as the need for active vitamin D 6 months postoperatively. Between 2012 and 2016, seven surgeons performed all thyroidectomies. From January 2017, only surgeons also performing parathyroid surgery carried out thyroidectomies for Graves’ disease.

Results

We performed total thyroidectomy in 543 patients. The rate of permanent hypoparathyroidism decreased from 28% in 2012–2014 to 6% in 2020–2021. For patients with Graves’ disease, the rate of permanent hypoparathyroidism decreased from 36% (13 out of 36) in 2015–2016 to 2% (1 out of 56) in 2020–2021. In cancer patients, the rate of permanent hypoparathyroidism decreased from 30% (14 out of 46) in 2012–2014 to 10% (10 out of 51) in 2020–2021.

Conclusion

Restricting thyroidectomy to surgeons who also performed parathyroid operations reduced postoperative hypoparathyroidism markedly. Accordingly, we recommend centralisation of the most difficult thyroid operations to centres and surgeons with extensive experience in parathyroid surgery.

Significance statement

Thyroid surgery is performed by many different surgeons with marked differences in outcome. Indeed, the risk of postoperative permanent hypoparathyroidism may be very high in low-volume centres. This serious condition affects the quality of life and increases long-term morbidity and the patients develop a life-long dependency of medical treatments. We encountered a high risk of hypoparathyroidism after the operation for Graves’ disease and restricted the number of surgeons to two for these operations. Further, these surgeons were experienced in both thyroid and parathyroid surgeries. We show a dramatic reduction in postoperative hypoparathyroidism after this change. Accordingly, we recommend centralisation of total thyroidectomy to surgeons with experience in both thyroid and parathyroid procedures.

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Anping Su Department of Thyroid Surgery, West China Hospital, Sichuan University, Chengdu, China

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Yanping Gong Department of Thyroid Surgery, West China Hospital, Sichuan University, Chengdu, China

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Wenshuang Wu Department of Thyroid Surgery, West China Hospital, Sichuan University, Chengdu, China

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Rixiang Gong Department of Thyroid Surgery, West China Hospital, Sichuan University, Chengdu, China

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Zhihui Li Department of Thyroid Surgery, West China Hospital, Sichuan University, Chengdu, China

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Jingqiang Zhu
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Background

The effect of parathyroid autotransplantation on hypoparathyroidism is not fully understood. The purpose of the study was to determine the effect of autotransplantation of a parathyroid gland on the incidence of hypoparathyroidism and recovery of parathyroid function at 6 months after total thyroidectomy with central neck dissection for papillary thyroid carcinoma.

Methods

All patients with autotransplantation of a parathyroid gland (no inadvertent parathyroidectomy) (group A), in situ preservation of all parathyroid glands (no autotransplantation and inadvertent parathyroidectomy) (group B) or inadvertent removal of a parathyroid gland (no autotransplantation) (group C) who underwent first-time total thyroidectomy with central neck dissection for papillary thyroid carcinoma between January 2013 and June 2016 were included retrospectively.

Results

Of the 702 patients, 383, 297 and 22 were respectively included in the groups A, B and C. The overall rates of transient and permanent hypoparathyroidism were 37.6% and 1.0%. The incidence of transient hypoparathyroidism was 43.9, 29.0 and 45.5% (A vs B, P = 0.000; A vs C, P = 1.000), and the incidence of permanent hypoparathyroidism was 1.0, 0.7 and 4.5% (P > 0.05). The recovery rates of serum parathyroid hormone levels were 71.4, 72.2 and 66.0% at 6-month follow-up (P > 0.05).

Conclusion

Autotransplantation of a parathyroid gland does not affect the incidence of permanent hypoparathyroidism, but increases the risk of transient hypoparathyroidism when the rest of parathyroid glands are preserved in situ. At least 2 parathyroid glands should be preserved during total thyroidectomy with central neck dissection to prevent permanent hypoparathyroidism.

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A Chinoy Royal Manchester Children’s Hospital, Manchester, UK

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M Skae Royal Manchester Children’s Hospital, Manchester, UK

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A Babiker King Abdullah Specialized Children’s Hospital, Riyadh, Saudi Arabia

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D Kendall Royal Preston Hospital, Preston, UK

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M Z Mughal Royal Manchester Children’s Hospital, Manchester, UK

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R Padidela Royal Manchester Children’s Hospital, Manchester, UK

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Background

Hypoparathyroidism is characterised by hypocalcaemia, and standard management is with an active vitamin D analogue and adequate oral calcium intake (dietary and/or supplements). Little is described in the literature about the impact of intercurrent illnesses on calcium homeostasis in children with hypoparathyroidism.

Methods

We describe three children with hypoparathyroidism in whom intercurrent illnesses led to hypocalcaemia and escalation of treatment with alfacalcidol (1-hydroxycholecalciferol) and calcium supplements.

Results

Three infants managed with standard treatment for hypoparathyroidism (two with homozygous mutations in GCMB2 gene and one with Sanjad-Sakati syndrome) developed symptomatic hypocalcaemia (two infants developed seizures) following respiratory or gastrointestinal illnesses. Substantial increases in alfacalcidol doses (up to three times their pre-illness doses) and calcium supplementation were required to achieve acceptable serum calcium concentrations. However, following resolution of illness, these children developed an increase in serum calcium and hypercalciuria, necessitating rapid reduction to pre-illness dosages of alfacalcidol and oral calcium supplementation.

Conclusion

Intercurrent illness may precipitate symptomatic hypocalcaemia in children with hypoparathyroidism, necessitating increase in dosages of alfacalcidol and calcium supplements. Close monitoring is required on resolution of the intercurrent illness, with timely reduction of dosages of active analogues of vitamin D and calcium supplements to prevent hypercalcaemia, hypercalciuria and nephrocalcinosis.

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Guido Zavatta Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy

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Bart L Clarke Mayo Clinic, Rochester, Minnesota, USA

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The first adjunctive hormone therapy for chronic hypoparathyroidism, recombinant human parathyroid hormone (1–84) (rhPTH(1–84)) was approved by the FDA in January 2015. Since the approval of rhPTH(1–84), growing interest has developed in other agents to treat this disorder in both the scientific community and among pharmaceutical companies. For several reasons, conventional therapy with calcium and activated vitamin D supplementation, magnesium supplementation as needed, and occasionally thiazide-type diuretic therapy remains the mainstay of treatment, while endocrinologists and patients are constantly challenged by limitations of conventional treatment. Serum calcium fluctuations, increased urinary calcium, hyperphosphatemia, and a constellation of symptoms that limit mental and physical functioning are frequently associated with conventional therapy. Understanding how conventional treatment and hormone therapy work in terms of pharmacokinetics and pharmacodynamics is key to effectively managing chronic hypoparathyroidism. Multiple questions remain regarding the effectiveness of PTH adjunctive therapy in preventing or slowing the onset and progression of the classical complications of hypoparathyroidism, such as chronic kidney disease, calcium-containing kidney stones, cataracts, or basal ganglia calcification. Several studies point toward an improvement in the quality of life during replacement therapy. This review will discuss current clinical and research challenges posed by treatment of chronic hypoparathyroidism.

Key points:

  • Conventional therapy with calcium and activated forms of vitamin D are currently the mainstays of treatment for most patients with chronic hypoparathyroidism.

  • Hormone therapy can be administered through FDA-approved once-daily rhPTH(1–84), or off-label multiple-daily injections of teriparatide. The former is the only FDA-approved drug, with safety and efficacy supported by a randomized placebo-controlled trial and open-label long-term extension trial data.

  • Twice-daily teriparatide has been used in children safely for up to 10 years.

  • New pharmacological options that replace the deficient hormone wi ll likely be available within the next few years.

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Jean-Philippe Bertocchio Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Physiologie, Paris, France
Centre de Référence des Maladies Rares du Calcium et du Phosphore Filière de Santé Maladies Rares OSCAR, Paris, France
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, INSERM, UMRS1138, Paris, France

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Natalie Grosset Hypoparathyroïdisme France, Annecy, France

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Lionel Groussin Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Université de Paris, Paris, France

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Peter Kamenický Université Paris-Saclay, Inserm U1185, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares du Métabolisme du Calcium et du Phosphate, Le Kremlin-Bicêtre, France

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Fabrice Larceneux Université Paris-Dauphine, PSL Research University, CNRS, UMR 7088, DRM [Ermes], Paris, France

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Anne Lienhardt-Roussie CHU Dupuytren, Hôpital Mère Enfant, Endocrinologie Pédiatrique, Limoges, France

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Agnès Linglart Centre de Référence des Maladies Rares du Calcium et du Phosphore Filière de Santé Maladies Rares OSCAR, Paris, France
Université Paris-Saclay, Inserm U1185, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Service d’Endocrinologie et Diabète de l’Enfant, Centre de Référence des Maladies Rares du Calcium et du Phosphore et Filière de Santé Maladies Rares OSCAR, Hôpital Bicêtre Paris Saclay, Le Kremlin-Bicêtre, France

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Gérard Maruani Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Physiologie, Paris, France
Centre de Référence des Maladies Rares du Calcium et du Phosphore Filière de Santé Maladies Rares OSCAR, Paris, France
Assistance Publique-Hôpitaux de Paris, Institut Necker-Enfants Malades, INSERM U1151 – CNRS UMR 8253, Paris, France

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Eric Mirallie Chirurgie Cancérologique, Digestive et Endocrine, Institut des Maladies de l’Appareil Digestif, Hôtel Dieu, CHU Nantes, France
Association Francophone de Chirurgie Endocrinienne (AFCE), France

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François Pattou Université de Lille, CHU Lille, Institut Pasteur Lille, Inserm U1190, Lille, France

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Riyad N H Seervai Molecular & Cellular Biology Graduate Program, Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA

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Coralie Sido Hypoparathyroïdisme France, Annecy, France

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Caroline Silve Centre de Référence des Maladies Rares du Calcium et du Phosphore Filière de Santé Maladies Rares OSCAR, Paris, France
Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Biochimie et Génétique Moléculaires, Paris, France
INSERM, U1169, Université Paris Sud, Hôpital Bicêtre, Le Kremlin Bicêtre, France

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Aurélie Vilfaillot Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité de Recherche Clinique, Paris, France
INSERM, U1418, CIC-EC, Hôpital Européen Georges Pompidou, Paris, France

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Antoine Tabarin Service Endocrinologie Diabète et Nutrition, CHU de Bordeaux, Université de Bordeaux, Pessac, France

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Marie-Christine Vantyghem CHU Lille, Department of Endocrinology, Diabetology and Metabolism, Inserm U1190, EGID, Lille, France

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Pascal Houillier Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Physiologie, Paris, France
Centre de Référence des Maladies Rares du Calcium et du Phosphore Filière de Santé Maladies Rares OSCAR, Paris, France
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, INSERM, UMRS1138, Paris, France
CNRS, ERL8228, Paris, France

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the investigators of the Épi-Hypo study
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the investigators of the Épi-Hypo study

Context

Recent guidelines have provided recommendations for the care of patients with chronic hypoparathyroidism. Very little is known about actual physicians’ practices or their adherence to such guidelines.

Objective

To describe the physicians’ practice patterns and their compliance with international guidelines.

Design

The cohort studies included were Épi-Hypo (118 physicians and 107 patients, from September 2016 to December 2019) and ePatients (110 patients, November 2019).

Methods

Internet-based cohorts involving all settings at a nationwide level (France). Participants were (i) physicians treating patients with chronic hypoparathyroidism and patients with chronic hypoparathyroidism either participating in the (ii) Épi-Hypo study (Épi-Hypo 2019 patients), or (iii) Hypoparathyroidism France, the national representative association (ePatients).

Results

The physicians’ specialties were mainly endocrinology (61%), nephrology (28%), family medicine (2.5%), pediatrics (2.5%), rheumatology (2%), or miscellaneous (4%) and 45% were practicing in public universities. The median number of pharmaceutical drug classes prescribed was three per patient. The combination of active vitamin D and calcium salt was given to 59 and 58% of ePatients and Épi-Hypo 2019 patients, respectively. Eighty-five percent of ePatients and 87% of physicians reported monitoring plasma calcium concentrations at a steady state at least twice a year. In 32 and 26% of cases, respectively, ePatients and physicians reported being fully in accordance with international guidelines that recommend targeting symptoms, plasma calcium and phosphate values, and urine calcium excretion.

Conclusions

The care of patients with chronic hypoparathyroidism involves physicians with very different practices, so guidelines should include and target other specialists as well as endocrinologists. Full adherence to the guidelines is low in France.

Open access
Elinor Chelsom Vogt Department of Clinical Science, University of Bergen, Bergen, Norway
K.G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen, Norway
Department of Medicine, Haukeland University Hospital, Bergen, Norway

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Francisco Gómez Real Department of Clinical Science, University of Bergen, Bergen, Norway
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway

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Eystein Sverre Husebye Department of Clinical Science, University of Bergen, Bergen, Norway
K.G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen, Norway
Department of Medicine, Haukeland University Hospital, Bergen, Norway

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Sigridur Björnsdottir Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden

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Bryndis Benediktsdottir Medical Faculty, University of Iceland, Reykjavik, Iceland
Department of Sleep, Landspitali University Hospital Reykjavík, Reykjavik, Iceland

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Randi Jacobsen Bertelsen Department of Clinical Science, University of Bergen, Bergen, Norway

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Pascal Demoly University Hospital of Montpellier, IDESP, Univ Montpellier-Inserm, Montpellier, France

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Karl Anders Franklin Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden

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Leire Sainz de Aja Gallastegui Unit of Epidemiology and Public Health, Department of Health, Basque Government, Vitoria-Gasteiz, Spain

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Francisco Javier Callejas González Department of Respiratory Medicine, Albacete University Hospital, Albacete, Spain

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Joachim Heinrich Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Munich, Germany
Allergy and Lung Health Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia

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Mathias Holm Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Nils Oscar Jogi Department of Clinical Science, University of Bergen, Bergen, Norway

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Benedicte Leynaert Université Paris-Saclay, Inserm U1018, Center for Epidemiology and Population Health, Integrative Respiratory Epidemiology Team, Villejuif, France

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Eva Lindberg Department of Medical Sciences, Respiratory, Allergy and Sleep Medicine, Uppsala University, Uppsala, Sweden

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Andrei Malinovschi Department of Medical Sciences, Clinical Physiology, Uppsala University, Uppsala, Sweden

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Jesús Martínez-Moratalla Pneumology Service of the General University Hospital of Albacete, Albacete, Spain
Albacete Faculty of Medicine, Castilla-La Mancha University, Albacete, Spain

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Raúl Godoy Mayoral Department of Respiratory Medicine, Albacete University Hospital, Albacete, Spain

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Anna Oudin Section of Sustainable Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

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Antonio Pereira-Vega Juan Ramón Jiménez University Hospital in Huelva, Huelva, Spain

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Chantal Raherison Semjen INSERM, EpiCene Team U1219, University of Bordeaux, Talence, France

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Vivi Schlünssen Department of Public Health, Environment, Work and Health, Danish Ramazzini Centre, Aarhus University, Aarhus, Denmark
The National Research Center for the Working Environment, Copenhagen, Denmark

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Kai Triebner Department of Clinical Science, University of Bergen, Bergen, Norway

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Marianne Øksnes Department of Clinical Science, University of Bergen, Bergen, Norway
K.G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen, Norway
Department of Medicine, Haukeland University Hospital, Bergen, Norway

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Objective

To investigate markers of premature menopause (<40 years) and specifically the prevalence of autoimmune primary ovarian insufficiency (POI) in European women.

Design

Postmenopausal women were categorized according to age at menopause and self-reported reason for menopause in a cross-sectional analysis of 6870 women.

Methods

Variables associated with the timing of menopause and hormone measurements of 17β-estradiol and follicle-stimulating hormone were explored using multivariable logistic regression analysis. Specific immunoprecipitating assays of steroidogenic autoantibodies against 21-hydroxylase (21-OH), side-chain cleavage enzyme (anti-SCC) and 17alpha-hydroxylase (17 OH), as well as NACHT leucine-rich-repeat protein 5 were used to identify women with likely autoimmune POI.

Results

Premature menopause was identified in 2.8% of women, and these women had higher frequencies of nulliparity (37.4% vs 19.7%), obesity (28.7% vs 21.4%), osteoporosis (17.1% vs 11.6%), hormone replacement therapy (59.1% vs 36.9%) and never smokers (60.1% vs 50.9%) (P < 0.05), compared to women with menopause ≥40 years. Iatrogenic causes were found in 91 (47%) and non-ovarian causes in 27 (14%) women, while 77 (39%) women were classified as POI of unknown cause, resulting in a 1.1% prevalence of idiopathic POI. After adjustments nulliparity was the only variable significantly associated with POI (odds ratio 2.46; 95% CI 1.63–3.42). Based on the presence of autoantibodies against 21 OH and SCC, 4.5% of POI cases were of likely autoimmune origin.

Conclusion

Idiopathic POI affects 1.1% of all women and almost half of the women with premature menopause. Autoimmunity explains 4.5% of these cases judged by positive steroidogenic autoantibodies.

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Panagiotis Anagnostis Unit of Reproductive Endocrinology, 1st Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

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Irene Lambrinoudaki 2nd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Medical School, Athens, Greece

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John C Stevenson National Heart and Lung Institute, Imperial College London, Royal Brompton and Harefield Hospitals, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

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Dimitrios G Goulis Unit of Reproductive Endocrinology, 1st Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

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Cardiovascular disease (CVD) is of major concern in women entering menopause. The changing hormonal milieu predisposes them to increased CVD risk, due to a constellation of risk factors, such as visceral obesity, atherogenic dyslipidemia, dysregulation in glucose homeostasis, non-alcoholic fatty liver disease and arterial hypertension. However, an independent association of menopause per se with increased risk of CVD events has only been proven for early menopause (<45 years). Menopausal hormone therapy (MHT) ameliorates most of the CVD risk factors mentioned above. Transdermal estrogens are the preferable regimen, since they do not increase triglyceride concentrations and they are not associated with increased risk of venous thromboembolic events (VTE). Although administration of MHT should be considered on an individual basis, MHT may reduce CVD morbidity and mortality, if commenced during the early postmenopausal period (<60 years or within ten years since the last menstrual period). In women with premature ovarian insufficiency (POI), MHT should be administered at least until the average age of menopause (50–52 years). MHT is contraindicated in women with a history of VTE and is not currently recommended for the sole purpose of CVD prevention. The risk of breast cancer associated with MHT is generally low and is mainly conferred by the progestogen. Micronized progesterone and dydrogesterone are associated with lower risk compared to other progestogens.

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Marianne C Astor Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway
Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway

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Kristian Løvås Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway
Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway

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Anette S B Wolff Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway

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Bjørn Nedrebø Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway

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Eirik Bratland Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway

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Jon Steen-Johnsen Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway

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Eystein S Husebye Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway
Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway

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Primary hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal recessive disorder characterized by neuromuscular symptoms in infancy due to extremely low levels of serum magnesium and moderate to severe hypocalcemia. Homozygous mutations in the magnesium transporter gene transient receptor potential cation channel member 6 (TRPM6) cause the disease. HSH can be misdiagnosed as primary hypoparathyroidism. The aim of this study was to describe the genetic, clinical and biochemical features of patients clinically diagnosed with HSH in a Norwegian cohort. Five patients in four families with clinical features of HSH were identified, including one during a national survey of hypoparathyroidism. The clinical history of the patients and their families were reviewed and gene analyses of TRPM6 performed. Four of five patients presented with generalized seizures in infancy and extremely low levels of serum magnesium accompanied by moderate hypocalcemia. Two of the patients had an older sibling who died in infancy. Four novel mutations and one large deletion in TRPM6 were identified. In one patient two linked homozygous mutations were located in exon 22 (p.F978L) and exon 23 (p.G1042V). Two families had an identical mutation in exon 25 (p.E1155X). The fourth patient had a missense mutation in exon 4 (p.H61N) combined with a large deletion in the C-terminal end of the gene. HSH is a potentially lethal condition that can be misdiagnosed as primary hypoparathyroidism. The diagnosis is easily made if serum magnesium is measured. When treated appropriately with high doses of oral magnesium supplementation, severe hypomagnesemia is uncommon and the long-term prognosis seems to be good.

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