Hypogonadotropic Hypogonadism in Males with Glycogen Storage Disease Type 1

Abstract

Background: Glycogen storage disease type 1 is an autosomal recessive disorder with an incidence of 1 in 100,000. Long-term complications include chronic blood glucose lability, lactic academia, short stature, osteoporosis, delayed puberty, gout, progressive renal insufficiency, systemic or pulmonary hypertension, hepatic adenomas at risk for malignant transformation, anemia, vitamin D deficiency, hyperuricemic nephrocalcinosis, inflammatory bowel syndrome (type 1b), hypertriglyceridemia, and irregular menstrual cycles. We describe hypogonadotropic hypogonadism as a novel complication in glycogen storage disease (GSD) type 1.Case Studies and Methods: Four unrelated patients with GSD 1a (N ¼ 1) and 1b (N ¼ 3) were found to have hypogonadotropic hypogonadism diagnosed at different ages. Institutional Research Ethics Board approval was obtained as appropriate. Participant consent was obtained. A retrospective chart review was performed and clinical symptoms and results of investigations summarized as a case series. Results: All patients were confirmed biochemically to have low luteinizing hormone (LH) and follicular stimulating hormone (FSH), and correspondingly low total testosterone. Clinical symptoms of hypogonadism varied widely. Investigations for other causes of hypogonadotropic hypogonadism were unremarkable. In addition, all patients were found to have disproportionately low bone mineral density at the lumbar spine compared to the hip. Common to all patients was erratic metabolic control, including recurrent hypoglycemia and elevated lactate levels. Discussion: Recurrent elevations in cortisol in response to hypoglycemia may be the underlying pathology leading to suppression of gonadotropin-releasing hormone (GnRH) release. Incorporating clinical and/or biochemical screening of the hypothalamic-pituitary-gonadal axis may be important in the management of this disease. Testosterone therapy however needs to be carefully considered because of the risk of hepatic adenomas.

Evaluation of Body Composition, Physical Activity, and Food Intake in Patients with Inborn Errors of Intermediary Metabolism

“…This is in line with previous reports of low BMD values in children and adults with classical galactosemia [ 51 , 52 ] and in GSD Ia and Ib, GSD II, GSD III, GSD V, and GSD IX patients [ 53 , 54 , 55 ]. The low BMD in CHD patients could be due to their particular diet, which can result in deficiencies in certain nutrients necessary for a healthy bone density (e.g., calcium and vitamin D), due to the metabolic disorder itself [ 56 , 57 ], or as a consequence of poor metabolic control, as it has been suggested in GSD type 1 [ 58 , 59 ].…”

Male hypogonadism with its systemic complications

“…Same results were found in males with glycogen storage disease type 1 that also occured with hypogonadotropic hypogonadism. Low level of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone have an impact on the occurrence of several symptoms, which also includes low BMD in the lumbar region of spine, compared to hip [10]. Studies on mice showed that via estrogen substitution OPG/RANKL (osteoprotegerin/receptor activator of NF-kappa B ligand) ratio decreases which lower bone turn-over time by slowing maturation of osteoclasts and their activation [11].…”

Bone health in patients with inborn errors of metabolism

“…In GSD type 1, factors contributing to the reduction in bone mineral density are poor metabolic control [ 71 , 74 , 75 ] and possibly the treatment with gCSF in GSD1b [ 74 ], though the latter relationship was not found in all studies [ 76 ]. In a recent study in 4 male GSD I (a and b) patients, all had either osteoporosis or osteopenia, suffered from hypogonadotropic hypogonadism and one patient had a spinal compression fracture at a very young age [ 75 ].…”