Myxedema coma secondary to levothyroxine malabsorption in a patient previously submitted to bariatric surgery

SUMMARY Treating hypothyroidism can be challenging in patients with malabsorption, as they require a higher daily dose of oral levothyroxine (L-T4). Oral L-T4 absorption occurs mainly in the jejunum and the ileum and is affected by gastric acidity. As a result, absorption can be impaired by bariatric surgery. This paper presents a case of myxedema in a young man who had previously undergone biliopancreatic diversion. He was referred to the Emergency Department with deteriorated mental state, hypotension, bradycardia and hypothermia. Laboratory tests revealed severe hypothyroidism and hypokalaemia. The clinical and biochemical profile of the patient suggested myxedema coma. The tablet-based L-T4 therapy was replaced with intravenous (iv) L-T4, oral liquid L-T4 and oral liothyronine (L-T3) and inotropic agents and supportive care were also administered, resulting in a gradual improvement in clinical condition. The patient reported taking L-T4 tablets as prescribed before hospitalization. In patients with malabsorption, impaired L-T4 absorption may lead to severe forms of hypothyroidism. This case outlines the need for more frequent monitoring of serum Thyroid Stimulating Hormone in patients submitted to bariatric surgery and suggests the benefit of using liquid L-T4 in the place of tablets in cases of malabsorption.

Autoimmune polyglandular syndrome type 4: experience from a single reference center.

Purpose: To characterize patients with APS type 4 among those affected by APS diagnosed and monitored at our local Reference Center for Autoimmune Polyglandular Syndromes. Methods: Monocentric observational retrospective study enrolling patients affected by APS diagnosed and monitored in a Reference Center. Clinical records were retrieved and analyzed. Results: 111 subjects (51 males) were affected by APS type 4, mean age at the onset was 23.1 ± 15.1 years. In 15 patients the diagnosis of APS was performed during the first clinical evaluation, in the other 96 after a latency of 11 years (range 1-46). The most frequent diseases were type I diabetes mellitus and celiac disease, equally distributed among sexes. Conclusions: The prevalence of APS type 4 is 9:100,000 people. Type I diabetes mellitus was the leading indicator of APS type 4 in 78% subjects and in 9% permitted the diagnosis occurring as second manifestation of the syndrome. Our data, showing that 50% of patients developed APS type 4 within the first ten years, don't suggest any particular follow-up time and, more importantly, don't specify any particular disease. It is important to emphasize that 5% of women developed premature ovarian failure.

Interference or Noninterference Between Soy and Levothyroxine: That Is the Question. A Narrative Review of Literature.

OBJECTIVE: To evaluate the effect of soy intake on levothyroxine (L-T4) absorption among different L-T4 formulations. METHODS: A PubMed/MEDLINE, Web of Science, and Scopus research was performed. Case reports, case series, and original studies written in English and published online up to November 30, 2022, were selected and reviewed. The final reference list was defined based on the relevance of each study to the scope of this review. RESULTS: Few data, mainly case reports, seemed to suggest a possible interference of soy products on L-T4 tablets absorption. However, the only prospective randomized cross-over study showed no differences in L-T4 absorption when L-T4 and soy isoflavones were assumed concomitantly. The very little data available on liquid L-T4 formulations did not allow for any conclusions to be made, even if a double-blind placebo-controlled trial showed no impaired L-T4 absorption. CONCLUSION: The inference of soy products on L-T4 absorption, if present, seems to have little clinical impact. Considering this fact, the Hamlet-like question whether soy milk interferes with L-T4 absorption remains unanswered.

Androgen serum levels in male patients with adrenocortical carcinoma given mitotane therapy: A single center retrospective longitudinal study.

Objective: Hypogonadism is common in male patients with adrenocortical carcinoma (ACC) who are under treatment with mitotane, but the phenomenon is underestimated, and its prevalence has been poorly studied. This single-center retrospective longitudinal study was undertaken to assess the frequency of testosterone deficiency before and after mitotane therapy, the possible mechanism involved, and the relationship between hypogonadism with serum mitotane levels and prognosis. Research design and methods: Consecutive male ACC patients followed at the Medical Oncology of Spedali Civili Hospital in Brescia underwent hormonal assessment to detect testosterone deficiency at baseline and during mitotane therapy. Results: A total of 24 patients entered the study. Of these patients, 10 (41.7%) already had testosterone deficiency at baseline. During follow-up, total testosterone (TT) showed a biphasic evolution over time with an increase in the first 6 months followed by a subsequent progressive decrease until 36 months. Sex hormone binding globulin (SHBG) progressively increased, and calculated free testosterone (cFT) progressively decreased. Based on cFT evaluation, the proportion of hypogonadic patients progressively increased with a cumulative prevalence of 87.5% over the study course. A negative correlation was observed between serum mitotane levels >14 mg/L and TT and cFT. Conclusion: Testosterone deficiency is common in men with ACC prior to mitotane treatment. In addition, this therapy exposes these patients to further elevated risk of hypogonadism that should be promptly detected and counteracted, since it might have a negative impact on quality of life.

Osteoporosis in men with hypogonadism because of ApoA-I Leu75Pro amyloidosis under long-term testosterone therapy.

BACKGROUND: Apo A-I Leu75Pro amyloidosis is a rare systemic hereditary disease, whose hallmark and earliest involvement is testicular impairment, characterized by hypogonadism and macrorchidism; renal and hepatic involvement are the other characteristics. OBJECTIVE: To evaluate for the first time the prevalence of osteopenia, osteoporosis and vertebral fractures (VFs) in men with this form of amyloidosis affected by hypogonadism and under long-term testosterone replacement therapy (TRT). MATERIALS AND METHODS: Retrospective study on 50 men >50 years (median age 64.5) with dual-energy X-ray absorptiometry (DXA), hormonal, and biochemical data available at least 3 years after the start of TRT. Serum gonadal hormones and bone markers, lumbar and femoral DXA-scan with morphometric assay for evaluation of VFs were assessed. RESULTS: At 7.5 years from start of TRT, lumbar and/or femoral osteopenia and osteoporosis were found in 54% and 10% of patients, respectively. Of the men who had the morphometric assay performed, five of 34 (14.7%) had VFs. Compared to patients with normal bone mineral density, men with osteopenia and osteoporosis were older, had lower body mass index, higher sex hormone binding globulin and showed more frequently renal involvement. Multiorgan involvement, without different TRT dosage, was associated with lower testosterone levels. DISCUSSION AND CONCLUSION: Men with hypogonadism because of Apo A-I Leu75Pro amyloidosis under long-term TRT had a high burden of low bone mass (64%) and VFs (almost 15%). Osteopenia-osteoporosis was more frequently observed in older patients with multi-organ disease, which might contribute to impair bone health beyond hypogonadism.

Endocrine system after 2 years of COVID-19 vaccines: A narrative review of the literature.

Purpose: The purpose of this study was to describe the current knowledge on the potential endocrine adverse effects post-COVID-19 vaccines. Methods: A PubMed/MEDLINE, Web of Science, and Scopus research was performed. Case reports, case series, original studies, and reviews written in English and published online up to 31 July 2022 were selected and reviewed. The final reference list was defined based on the relevance of each paper to the scope of this review. Results: The available data showed that endocrine side effects are generally rare and with favorable outcome, being thyroid disorders the most common. Conversely, data on type 1 diabetes mellitus are rare; adrenal and pituitary events are even anecdotal. Finally, the available clinical studies suggest no impact on female reproductive system and on male and couple fertility. Conclusion: Overall, these data show that, after 2 years of COVID-19 vaccines, the endocrine system is not heavily threatened.

Case Report: Hypothalamic Amenorrhea Following COVID-19 Infection and Review of Literatures.

SARS-CoV-2 infection, responsible for the coronavirus disease 2019 (COVID-19), can impair any organ system including endocrine glands. However, hypothalamic-pituitary dysfunctions following SARS-CoV-2 infection remain largely unexplored. We described a case of hypothalamic amenorrhea following SARS-CoV-2 infection in a 36-year-old healthy woman. The diagnostic workup excluded all the causes of secondary amenorrhea, in agreement to the current guidelines, whereas the gonadotropin increase in response to GnRH analogue tests was suggestive for hypothalamic impairment. Therefore, since our patient did not present any organic cause of hypothalamic-pituitary disorder, we hypothesized that her hypothalamic deficiency may have been a consequence of SARS-CoV-2 infection. This assumption, besides on the temporal consecutio, is strengthened by the fact that SARS-CoV-2 infection can impair the hypothalamic circuits, altering the endocrine axes, given that angiotensin-converting enzyme 2 receptors have also been observed in the hypothalamus. We reviewed the literature regarding hypothalamic-pituitary dysfunction in patients with SARS-CoV-2 infection. No study has previously described female hypogonadotropic hypogonadism with secondary amenorrhea following COVID-19. We suggest clinicians focusing greater attention on this possible endocrine disorder.

Testosterone, Hypogonadism, and Heart Failure.

Male hypogonadism is defined as low circulating testosterone level associated with signs and symptoms of testosterone deficiency. Although the bidirectional link between hypogonadism and cardiovascular disease has been clarified, the association between testosterone and chronic heart failure (HF) is more controversial. Herein, we critically review published studies relating to testosterone, hypogonadism, and HF and provide practical clinical information on proper diagnosis and treatment of male hypogonadism in patients with HF. In general, published studies are extremely heterogeneous, frequently have not adhered to hypogonadism guidelines, and suffer from many intrinsic methodological inaccuracies; therefore, data provide only low-quality evidence. Nevertheless, by selecting the few methodologically robust studies, we show the prevalence of testosterone deficiency (30%-50%) and symptomatic hypogonadism (15%) in men with HF is significant. Low testosterone correlates with HF severity, New York Heart Association class, exercise functional capacity, and a worse clinical prognosis and mortality. Interventional studies on testosterone treatment in men with HF are inconclusive but do suggest beneficial effects on exercise capacity, New York Heart Association class, metabolic health, and cardiac prognosis. We suggest that clinicians should measure testosterone levels in men with HF who have symptoms of a testosterone deficiency and conditions that predispose to hypogonadism, such as obesity and diabetes. These patients-if diagnosed as hypogonadal-may benefit from the short- and long-term effects of testosterone replacement therapy, which include improvements in both cardiac prognosis and systemic outcomes. Further collaborative studies involving both cardiologists and endocrinologists are warranted.

Usefulness of routine assessment of free testosterone for the diagnosis of functional male hypogonadism.

OBJECTIVE: To investigate whether routine assessment of free testosterone improves the diagnostic accuracy of functional hypogonadism. METHODS: Total and free testosterone (calculated on SHBG levels) were determined in 188 patients with sexual symptoms and 184 with infertility. RESULTS: Hypogonadism (calculated free testosterone <63 pg/ml) was found in 47/188 (25.0%) patients with sexual symptoms and in 21/184 (11.4%) with infertility. Total testosterone determination misdiagnosed hypogonadism in 8.4% (12/143) of men with sexual symptoms and in 2% (3/152) with infertility. In subjects with borderline total testosterone, only 24.7% (19/77) had hypogonadism confirmed by free testosterone levels. Free testosterone levels significantly correlated with age, haematocrit, gonadotropins, gynecomastia, BMI, and number of co-morbidities, whereas total testosterone associated only with the latter two. Furthermore, age, haematocrit, BMI, and the presence of erectile dysfunction and of low libido were significantly different between men with normal and low free testosterone, whereas only BMI and low libido were significantly different between patients with normal and low total testosterone. CONCLUSION: Routine assessment of free testosterone allows a more accurate diagnosis of functional hypogonadism, especially in men with sexual symptoms. Free testosterone levels associate with clinical and biochemical parameters of androgen deficiency better than total testosterone levels.

The impact of diabetes mellitus type 1 on male fertility: Systematic review and meta-analysis.

BACKGROUND: Some evidence suggests that diabetes mellitus type 1 (DM1) could affect male fertility, gonadal axis, semen parameters, and spermatogenesis because of effects of hyperglycemia and insulin deficiency. Anyhow, the exact impact of DM1 on male fertility is unclear. OBJECTIVES: To review the studies evaluating paternity rate, male gonadal axis, and semen parameters in men with DM1. MATERIALS AND METHODS: A review of relevant literature from January 1980 to December 2020 was performed. Only studies published in English reporting data on fatherhood (rate of children by natural fertility), hormonal and seminal parameters were included. Out of 14 retrieved articles, the eight studies evaluating semen parameters were meta-analyzed. RESULTS: The rate of children (four studies) was lower than controls among men affected by DM1, especially in men with a longer duration of disease. The data of gonadal hormonal profile in DM1 men (six studies) are very heterogeneous and a neutral effect of DM1 or a condition of subclinical hypogonadism could not be concluded. Meta-analysis showed that men with DM1 (n = 380), compared with controls (n = 434), have significantly lower normal sperm morphology [-0.36% (-0.66; -0.06), p < 0.05, six studies] and sperm progressive motility [33.62% (-39.13; -28.11), p < 0.001, two studies] and a trend toward a lower seminal volume [-0.51 (-1.03; 0.02), p = 0.06, eight studies], without difference in total sperm count and concentration. Data on scrotal ultrasound and sperm DNA fragmentation are too few. No study evaluated other factors of male infertility, such as transrectal ultrasound, semen infections, sperm auto-antibodies, and retrograde ejaculation. DISCUSSION: DM1 might impair male fertility and testis functions (endocrine, spermatogenesis), but definition of its actual impact needs further studies. CONCLUSION: Men with DM1 should be evaluated with a complete hormonal, seminal, and ultrasound workup to better define their fertility potential and need for follow up of testis functions.

Thyroid scintigraphy in the era of fine-needle aspiration cytology.

PURPOSE: To evaluate whether thyroid scintigraphy would alter the clinical management of patients referred for fine-needle aspiration cytology (FNA). METHODS: We reviewed the medical and imaging records of patients referred to our Department between 2016 and 2019. All the patients had to take a serum thyrotropin test administered in our hospital at least two months before the FNA; where the TSH level was ≤1.5 mIU/L, the patients were subjected to a scan and subsequently to FNA, where indicated. We selected only healthy patients with no previous history of thyroid disease, who were not taking any drugs and who had a TSH level of ≤1.5 mIU/L. We excluded patients with multinodular goitre. RESULTS: A total of 176 patients were analysed. A total of 67/176 patients (38%) showed a serum of TSH ≤ 0.27 mIU/L. Scintigraphy identified a hot nodule in 142 lesions (80.7%), a warm nodule in 8 lesions (4.5%) and a cold nodule in 26 lesions (14.8%). The ROC curve analysis indicated that a TSH value of ≤0.42 mIU/L identified patients with hyperfunctioning nodules with a sensitivity of 65% and a specificity of 77%. All patients with cold and warm nodules were submitted to FNA: 22/26 (85%) and 5/8 (63%) lesions showed suspected malignancy or were compatible with malignancy, respectively. CONCLUSION: Speculating on our data, if we had subjected our patients to FNA as indicated by the 2015 ATA guidelines, we would have subjected 117 patients to cytology, from whom 83 had undetected hot nodules. Conversely, by adopting scintigraphy for all patients with TSH ≤ 1.5 mIU/L, 109 patients have avoided FNA. However, our study was performed in a region with a history of mild iodine deficiency. Therefore, we cannot claim that our observation is valid for patients born and living in areas with sufficient iodine uptake. We recommend thyroid scintigraphy for treating single thyroid nodules in euthyroid patients born and living in regions with an iodine deficiency, when TSH levels are below 1.5 mIU/L before FNA.

INSL3: A Marker of Leydig Cell Function and Testis-Bone-Skeletal Muscle Network.

This article reviews the role of INSL3 as biomarker of Leydig cell function and its systemic action in testis-bone-skeletal muscle crosstalk in adult men. Insulin-like factor 3 (INSL3) is a peptide hormone secreted constitutively in a differentiation-dependent mode by testicular Leydig cells. Besides the role for the testicular descent, this hormone has endocrine anabolic functions on the bone-skeletal muscle unit. INSL3 levels are low in many conditions of undifferentiated or altered Leydig cell status, however the potential clinical utility of INSL3 measurement is not yet well defined. INSL3 levels are modulated by the long-term cytotropic effect of the hypothalamicpituitary- gonadal axis, unlike testosterone that is acutely sensitive to the stimulus by luteinizing hormone (LH). INSL3 directly depends on the number and differentiation state of Leydig cells and therefore it represents the ideal marker of Leydig cell function. This hormone is more sensitive than testosterone to Leydig cell impairment, and the reduction of INSL3 in adult men can precociously detect an endocrine testicular dysfunction. Low INSL3 levels could cause or contribute to some symptoms and signs of male hypogonadism, above all sarcopenia and osteoporosis. The measurement provided suggested that the measurement of INSL3 levels should be considered in the clinical management of male hypogonadism and in the evaluation of testicular endocrine function. The monitoring of INSL3 levels could allow an early detection of Leydig cell damage, even when testosterone levels are still in the normal range.

Testicular Involvement is a Hallmark of Apo A-I Leu75Pro Mutation Amyloidosis.

CONTEXT: Apo A-I Leu75Pro is a rare hereditary form of amyloidosis that mainly involves the kidney, the liver, and the testis. OBJECTIVE: To define the characteristics of organ damage and testis impairment in the largest cohort collected to date of men with Apo A-I Leu75Pro amyloidosis. DESIGN, SETTING, AND PATIENTS: Retrospective study from a prospectively collected database of 129 male subjects >18 years with Apo A-I Leu75Pro amyloidosis from a reference center at the University Hospital of Brescia, Italy. MAIN OUTCOME MEASURES: We evaluated liver and renal function, scrotal ultrasound, reproductive hormone levels, testis biopsy, hypogonadal symptoms, and fertility. RESULTS: Progressive involvement of testis, kidney, and liver was observed in 96/129 (74.4%) cases. Testis impairment was found in 88/129 patients (68.2%), liver in 59 (45.7%) and renal in 50 (38.8%). Testis damage was often the first manifestation of the disease and the only dysfunction in 30% of younger patients (<38 years). Testicular involvement was characterized mainly by primary (73/88 patients, 83.0%) and subclinical (8/88, 9.1%) hypogonadism. Almost all (85/88, 96.6%) also had high follicle-stimulating hormone, suggesting a primary global damage of endocrine and spermatogenic functions, and 30% of them did not conceive. Macroorchidism was found in 53/88 (60.2%) patients, especially in men <54 years (30/33, 90.9%). Apo A-I amyloid deposits were found in Sertoli cells, germinal epithelium, and vessel walls. CONCLUSION: In men with Apo A-I Leu75Pro amyloidosis, testicular involvement is the hallmark of the disease, characterized by global primary testicular dysfunction and macroorchidism due to amyloid deposits.

Positive effect of nutraceuticals on sperm DNA damage in selected infertile patients with idiopathic high sperm DNA fragmentation.

BACKGROUND: The use of nutraceuticals to improve sperm parameters and male fertility is debatable, even if evidence suggests that selected infertile patients might benefit from their use. In particular, oxidative stress might play a role in idiopathic male infertility, leading to sperm membrane damage and high sperm DNA fragmentation (SDF). The aim of this study was to evaluate, in selected idiopathic infertile men with high SDF, the effect on sperm DNA damage and on standard semen parameters of a nutraceutical formulation containing myoinositol, alpha lipoic acid, coenzyme Q10, selenium, zinc and B vitamins. METHODS: The study included 60 idiopathic infertile men with DNA fragmentation index (DFI) >20%. Semen analysis and DFI determination were assessed at baseline and after three months of nutraceutical treatment. Primary outcome was change in DFI. RESULTS: Semen volume, sperm concentration, total sperm count, sperm motility and sperm morphology did not change after treatment. Instead, sperm vitality significantly increased (65.9±11.8% pre-treatment vs. 69.4±9.4% post-treatment, P<0.05) and DFI significantly decreased (33.5±10.1% pre-treatment vs. 26.8±8.7% post-treatment, P=0.0001) after treatment. The percentage of men with normal standard sperm parameters significantly increased (15% vs. 30%, P<0.05). The mean decrease in DFI was -6.7±1.4% and the percentage of men with DFI ≤30% after treatment was 75.0% compared to 48.3% pre-treatment (P<0.005). Higher pre-treatment DFI (and no other parameters) correlated with greater DFI reduction after treatment. CONCLUSIONS: Nutraceuticals might be effective in idiopathic infertile men with high DFI to reduce SDF, increase sperm vitality and globally improve semen parameters.