Secondary hypogonadism following hand, foot, and mouth disease in an adult: a case report and review of literature

Background Previous reports have described hypogonadism associated with virus infection such as hantavirus, human immunodeficiency virus (HIV) or severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). However, to our best knowledge there has been no case report of secondary hypogonadism following hand, foot, and mouth disease (HFMD). Case presentation A previously healthy 28-year-old man with no history of major physical and psychological trauma, presented with bilateral gynecomastia and erectile dysfunction 2 weeks after HFMD. Laboratory testament showed the level of gonadotropin hormones declined. Imaging examination demonstrated no major abnormal change in pituitary or reproductive system. The diagnosis of hypogonadism was established. Then the patient was ordered to maintain mental health outward of hospital without drug intervention. One month after presentation, his gonadotropin hormone level and sexual desire had recovered, while bilateral gynecomastia and erectile dysfunction symptoms disappeared. Conclusions Physicians should notice the possibility for hypogonadism in adult patients with a recent history of HFMD.

Primary and Secondary Hypogonadism in Male Persons with Diabetes Mellitus

Aims. To characterize hypogonadism in male persons with diabetes mellitus. Patients and Methods. 184 consecutive male persons with diabetes were studied. Besides the usual care, total testosterone (TT), estradiol (E2), FSH, and LH were measured in the last appointment and in 40 patients, also in the next two appointments. Statistical analysis compared groups and explored factors for TT and LH levels. Results. TT levels were stable and highly correlated (r > 0.750, p < 0.001 ) over a 6–12-month period. 20% of the patients presented secondary hypogonadism (SH) and 18% presented primary hypogonadism (PH). SH was inversely related to HbA1 (partial r (rp) = 0.229, p < 0.005 ), while PH was directly related to age (r = 0.356, p < 0.001 ). TT levels were reduced independently by metformin (364 ± 160 vs. 431 ± 242 ng/dL, t = 2.241, p < 0.05 ) and statins (359 ± 156 vs. 424 ± 230 ng/dl, t = 2.224, p < 0.05 ). TT levels were inversely related to microvascular disease (rp = −0.169, p < 0.05 ). Discussion. TT levels were stable over time and hypogonadism was common. SH, generally clinically, is related to the diabetic state, while PH, generally subclinically, is an age-dependent process unrelated to diabetes. Low TT levels were related to older age, poor metabolic control, metformin and statins use, and microvascular disease.

Optimal injection interval for testosterone undecanoate treatment of hypogonadal and transgender men

Objective: To define the optimized inter-injection interval of injectable testosterone undecanoate (TU) treatment for hypogonadal and transmen based on individual dose titration in routine clinical practice. Design and Methods: Prolective observational study of consecutive TU injections in men undergoing testosterone replacement therapy for pathological hypogonadism or masculinization of female-to-male transgender (transmen) subject to individual dosing titration to achieve a stable replacement regimen. Results: From 2006 to 2019, 6899 injections were given to 325 consecutive patients. After excluding the 6-week loading dose, 6300 injections were given to 297 patients who had at least three and a median of 14 injections. The optimal injection interval (mean of last three injection intervals), had a median of 12.0 weeks (interquartile range 10.4–12.7 weeks). The interval was significantly influenced by age and body size (body surface area, BSA) but not by diagnosis or trough serum LH, FSH and SHBG. Longer (≥14 weeks; 68/297, 23%), but not shorter (≤10 weeks; 22/297, 7.4%), intervals were weakly correlated with age but not diagnosis or other covariables. Low blood hemoglobin increased with trough serum testosterone to reach plateau once testosterone was about 10 nmol/L or higher. Conclusion: Optimal intervals between TU injection after individual titration resulted in the approved 12-week interval in 70% of patients with only minor influence for clinical application of age and body size (BSA) and not of trough serum LH, FSH and SHBG. Individually optimised inter-injection interval did not differ between men with primary or secondary hypogonadism or transmen.

Biochemical predictors of structural hypothalamus–pituitary abnormalities detected by magnetic resonance imaging in men with secondary hypogonadism

Purpose Organic conditions underlying secondary hypogonadism (SH) may be ascertained by magnetic resonance imaging (MRI) of the hypothalamic–pituitary region that could not be systematically proposed to each patient. Based upon limited evidence, the Endocrine Society (ES) guidelines suggest total testosterone (T) < 5.2 nmol/L to identify patients eligible for MRI. The study aims to identify markers and their best threshold value predicting pathological MRI findings in men with SH. Methods A consecutive series of 609 men seeking medical care for sexual dysfunction and with SH (total T < 10.5 nmol/L and LH ≤ 9.4 U/L) was retrospectively evaluated. An independent cohort of 50 men with SH was used as validation sample. 126 men in the exploratory sample and the whole validation sample underwent MRI. Results In the exploratory sample, patients with pathological MRI findings (n = 46) had significantly lower total T, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prostate specific antigen (PSA) than men with normal MRI (n = 80). Receiver Operating Characteristics analysis showed that total T, LH, FSH and PSA are accurate in identifying men with pathologic MRI (accuracy: 0.62–0.68, all p < 0.05). The Youden index was used to detect the value with the best performance, corresponding to total T 6.1 nmol/L, LH 1.9 U/L, FSH 4.2 U/L and PSA 0.58 ng/mL. In the validation cohort, only total T ≤ 6.1 nmol/L and LH ≤ 1.9 U/L were confirmed as significant predictors of pathologic MRI. Conclusion In men with SH, total T ≤ 6.1 nmol/L or LH ≤ 1.9 U/L should arise the suspect of hypothalamus/pituitary structural abnormalities, deserving MRI evaluation.

The Hypothalamic-Pituitary-Testicular Axis in Exceptionally Old Men

Introduction: As life expectancy continues to increase and more men reach the extremes of age, it is important to understand the physiology of the aging hypothalamic-pituitary-testicular (HPT) axis and its role in health. While prior studies primarily focused on men younger than age ninety, we studied a unique cohort enriched for men with exceptional longevity to characterize the age-related trends in male sex-hormones, the etiology of the observed changes in the HPT axis, and its relationship with metabolic dysfunction and survival at the extremes of age. Methods: This is a cross-sectional study of community-dwelling Ashkenazi Jewish men (n = 427), age range 50-106 years. Longitudinal follow-up for vital status was conducted for men age ≥ 88 at enrollment (n = 86). Measurements included serum total testosterone (TT) by LC/MS, LH, SHBG, lipids, glucose and BMI. Free testosterone (FT) was calculated according to Vermeulen et. al. A change-point linear regression model was applied to describe the age trend of TT. Multivariable linear regression adjusted for comorbidities tested the associations between metabolic parameters and TT. The association between survival and TT was evaluated with the age-adjusted Cox proportional hazards model. Age-specific cutoffs for TT and LH were used to define primary and secondary hypogonadism. Results: The change point model was a significantly better fit for the data compared to the straight-line model (p = 0.004), indicating that TT significantly declines after age 88 years. Men age &lt; 88 years had higher average TT (401 ± 162 vs. 278 ± 178 ng/dL, p &lt; 0.001), FT (6.3 ± 2.0 vs. 3.3± 2.1 pg/mL, p &lt; 0.001), and lower LH (4.3 [3.0 - 6.1] vs. 14.6 [7.2 - 25.5] mIU/mL, p &lt; 0.001), compared to men age ≥ 88 years. The prevalence of primary and secondary hypogonadism was 2% and 11%, respectively, in men age &lt; 88 years, and 30% and 11%, among men age ≥ 88 years (p &lt; 0.001). A multivariable linear regression analysis revealed interactions between age, dichotomized at the change-point of 88 years, and metabolic parameters. Models stratified at age 88 demonstrated an inverse association between TT and BMI (p = 0.02), serum triglycerides (p = 0.007), and random glucose levels (p = 0.02) among men age &lt; 88; whereas a positive association was noted between TT and HDL cholesterol (p = 0.009) in this group. In men age ≥ 88 years, TT was not associated with any of the metabolic parameters or overall survival. Conclusions: Low testosterone in men with exceptional longevity is largely a result of primary testicular failure that occurs around age 88 and is accompanied by preserved hypothalamic-pituitary response with no associated metabolic dysfunction or effect on survival. This is in contrast to younger men, whose low T typically results from hypothalamic-pituitary dysfunction and is associated with metabolic derangements.

Safety and Efficacy of Clomiphene Citrate in the Treatment of Secondary Hypogonadism. A Retrospective Study

“Introduction: Clomiphene (Clomid) has an off-label indication to treat hypogonadism in select populations. “Based on clinical practice, this medication in certain types of hypogonadism is equally effective as testosterone in treating hypogonadism. It will lead to less side effects, lower treatment cost, and will decrease rates of infertility in the male veteran population.” Secondary hypogonadism can be most often caused by opioid use, obesity, sleep apnea, and diabetes.” “Aim of Study: To evaluate the safety and efficacy of Clomiphene Citrate in Treatment of Secondary Hypogonadism in comparison with testosterone. “Study Population: Data was obtained from the Veterans Administration Data Warehouse through the Veterans Administration Informatics and Computing Infrastructure. Data was extracted using SQL. There were 405,824 male patients with a diagnosis of hypogonadism (87.1%)and infertility (12.9%). nationally at the VA. Of these, 9566 patients have been treated with clomiphene citrate and 232,123 with various testosterone therapy. “ The two groups were then matched by propensity method to controls at a ratio of about 1:1 for Age, race, BMI and time for follow-up as potential confounding factors hat could have affected inclusion in the study controls. Patients without either Clomiphene or testosterone treatment were excluded. Statistical Analysis: SAS was used for propensity matching (PSM, greedy near) Categorical variables were evaluated as frequency counts with percentage within group, as well as ODDS ratio (OR) and differences were evaluated by a chi-square method. Comparisons of continuous variables were done were done by simple and paired t-test. Kaplan Meier plots and Cox Hazard ratio calculations were used to examine time dependent risk between treatments. Actual p-values are shown and p-values lower than 0.0001 are shown as such. All comparisons used a two-sided assumption. Measurements: Testosterone laboratory measures were recorded for start and end of trial. Survival was taken as the difference in days between start date and date of death. New diagnosis of Osteoporosis and Polycythemia was that which occurred after initiation of therapy. “Results: Clomid treatment normalized testosterone levels in 53.2% versus 46.8% in the testosterone group (OR 1.32 P&lt;0.005). All-cause mortality was in the clomid group 0.16% and 1.62%in the testosterone group (OR 0.16 P&lt;0.001). The incidence of new Osteoporosis for clomid was 3.9 % versus 5.9% for testosterone (OR 0.65 P&lt;0.001)” Conclusion: This is a retrospective study comparing the efficacy and side effects of clomiphene versus testosterone for treatment of hypogonadism. The study showed that clomiphene is more effective than testosterone to treat secondary hypogonadism. We also found decreased overall mortality and incidence of polycythemia and osteoporosis.

Hormonal Replacement Therapy in Premenopausal Women With Hypogonadism: An Analysis of Prescriber Practices

Introduction: Estrogen replacement therapy in premenopausal women with hypogonadism is important for reducing risk of osteoporosis, cardiovascular disease, and urogenital atrophy. Numerous formulations of estrogen are available and there is limited evidence to guide management. We conducted a preliminary retrospective study to determine prescribing practices of hormonal replacement therapy (HRT) in premenopausal women with hypogonadism and frequency of DEXA scan screening. Methods: Using ICD 10 and billing codes, females ages 18-51 with a diagnosis of hypogonadism were identified. Patients with a diagnosis of prolactinoma, breast or endometrial cancer, and significant thrombotic disease as well as patients without clinical data were excluded. Information regarding etiology of hypogonadism, age of diagnosis, type/dose of estrogen and progesterone prescribed, prescriber specialty [obstetrics and gynecology (OB/GYN), endocrinology (ENDO), primary care (PCP), or other], and DEXA results was recorded. Prescriptions for estrogen and progesterone were compared in women with primary vs secondary hypogonadism and among specialties. For bone density, we analyzed the frequency of DEXA scan ordering. Statistical analysis was performed using Fisher’s Exact Test. Results: Out of 1,306 patients identified, 150 met criteria for analysis. 99 (66%) had primary hypogonadism, 47 (31%) had secondary hypogonadism, and 4 (3%) had mixed or unknown type. OB/GYN was the most common prescriber (n=88, 59%) followed by ENDO (n=39, 26%) and PCP/other (n=23, 15%). For all patients, type of estrogen prescribed differed by specialty (p=0.041) with ENDO most commonly prescribing transdermal estradiol (47%), OB/GYN either transdermal estradiol (30%) or oral ethinyl estradiol (30%), and PCP/other oral estradiol (45%). Patients with primary, but not secondary hypogonadism, were prescribed more transdermal estradiol by ENDO as compared to OB/GYN (68% vs 27%, p=0.039). In patients with secondary hypogonadism on oral ethinyl estradiol, mean daily dose (mcg) differed among providers ((ENDO 27 ± 6, OB/GYN 35 ± 8, PCP/other 10 ± 0, p=0.04). There was no difference in dosing of other types of estrogen, prescribing practices for progesterone, or frequency of DEXA scans among providers. DEXA scans were performed at least once in 59 (39%) and more than once in 20 (13%) patients. Conclusions: Overall, premenopausal women with hypogonadism seeing ENDO as compared to other providers were more frequently prescribed transdermal estradiol as compared to oral estradiol and/or other types of estrogen. Only dosages of oral ethinyl estradiol differed by provider. Despite an increased risk of osteoporosis, a minority of patients underwent DEXA scans. This study highlights heterogeneity in prescribing practices and underscores the need for further research to guide management of premenopausal women with hypogonadism.

Diagnostic Threshold for Postoperative Secondary Adrenal Insufficiency After Transsphenoidal Resection of Pituitary Adenomas

Transsphenoidal surgery (TSS) is the first line treatment for pituitary adenomas. A well-known complication of TSS is secondary adrenal insufficiency with a reported risk of 4-9% after TSS. Currently, glucocorticoid replacement is recommended if postoperative AM cortisol is &lt; 3 ug/dL. Postoperative adrenal insufficiency is ruled out if AM cortisol is &gt; 15 ug/dL. However, further evaluation of the adrenal axis with ACTH stimulation test is recommended for intermediate cortisol levels 3-15 ug/dL. Other studies have proposed postoperative cortisol threshold of &lt; 4-14 ug/dL for glucocorticoid replacement. Retrospective analysis of all patients undergoing TSS at a tertiary center from January 2013 through April 2016 was performed. ACTH producing adenomas (Cushing’s disease) were excluded. Of the 97 patients included, 17.5% (n=17) had secondary adrenal insufficiency requiring glucocorticoid replacement at 1 year post operatively. Mean age at presentation was 56 ± 16 years and 52% were female. Mean adenoma size was 25.3 ± 11.3 mm. Factors associated with adrenal insufficiency at 1 year post operatively were preoperative secondary adrenal insufficiency (AM cortisol 4.5 ± 1.9 vs 11.0 ± 1.0 µg/dL; p = 0.03), and preoperative adenoma contact with optic chiasm (15.7% vs 2.1%; p = 0.01). Day 1-7 postoperative cortisol was lower in the group with adrenal insufficiency at 1 year (5.6 µg/dL (IQR 1.9-11.5) vs 19.8 µg/dL (IQR 12.75-43.2); p=0.02). Age, gender, adenoma size, and cavernous sinus involvement were not associated with adrenal insufficiency at 1 year. A day 1-7 postoperative cortisol concentration of ≥8.0 µg/dL had a sensitivity of 75% and specificity of 92% in predicting adrenal insufficiency at 1 year. In patients with secondary adrenal insufficiency at 1 year (n=17), there was a higher frequency of concomitant loss of other pituitary hormone function at 1 year: secondary hypothyroidism 82% (n=14), secondary hypogonadism 70.6% (n=12) and diabetes insipidus 17.7% (n=3). A lower postoperative cortisol threshold of 8 µg/dL can be adopted for glucocorticoid replacement on discharge after TSS.

Immune checkpoint inhibitor-related hypogonadism and infertility: a neglected issue in immuno-oncology

Despite a significant amount of data on incidence and therapy of immune-related adverse events affecting virtually all organ systems, the potential impact of immune checkpoint inhibitors (ICIs) on gonadal function has not been sufficiently studied. The limited evidence available suggests that ICI-related primary hypogonadism due to orchitis as well as secondary hypogonadism due to hypophysitis are a potential risk for infertility. A systematic investigation of gonadal function under ICIs is warranted given the increasing application of ICIs in the adjuvant setting, among young adults and children and the possible influence of sex hormone levels on the efficacy and toxicity of ICIs.