Hypogonadism Syndrome Research Articles

Efficient differentiation of human iPSCs into Leydig-like cells capable of long-term stable secretion of testosterone.

Late-onset hypogonadism (LOH) syndrome is characterized by age-related testosterone deficiency and negatively affects the quality of life of older men. A promising therapeutic approach for LOH syndrome is transplantation of testosterone-producing Leydig-like cells (LLCs) derived from human induced pluripotent stem cells (hiPSCs). However, previous studies have encountered obstacles, such as limited cell longevity, insufficient testosterone production, and inefficiency of differentiation. To address these issues, we developed a novel protocol that includes forced NR5A1 expression, a cytokine cocktail promoting mesoderm differentiation, and a transitional shift from 3D to 2D cultures. The resultant cells survived on culture dishes for over 16weeks, produced 22-fold more testosterone than the conventional method, and constituted a homogeneous population of LLCs with a differentiation efficiency exceeding 99% without purification. Furthermore, these LLCs were successfully engrafted subcutaneously into mice, resulting in increased serum testosterone levels. Our study will facilitate innovative therapeutic strategies for LOH syndrome.

Клиническое обоснование значимости оценки уровня эстрадиола у мужчин с синдромом гипогонадизма на фоне терапии по стабилизации уровня тестостерона.

Introduction. A significant reason for the decrease in the effectiveness of testosterone replacement therapy (TRT) in men is the increased activity of the aromatase enzyme in overweight and obese patients, when under its influence estrogens are converted from androgens (the transition of testosterone to estradiol) mainly in adipose tissue, leading to an increase in estradiol levels. That is, with exogenous administration of testosterone, estradiol becomes overabundant, thereby the positive effects of TRT are weakened and even often leveled, dangerous side effects of hyperestradiolemia appear, that is, without careful monitoring and normalization of estradiol levels, the effectiveness of TRT turns out to be low, and the side effect of therapy, due to high estrogens, on the body is high. The aim of research was to increase the effectiveness of testosterone replacement therapy for hypogonadism in obese patients. Material and methods. A two-center prospective study was conducted to study TRT for hypogonadism. The results of examination and treatment of 106 men aged 35-59 years (average age 45.9±7.2 years) with hypogonadism syndrome, who were prescribed TRT Omnadren 250 mg 1 ml/m, were analyzed. The levels of total testosterone, estradiol, and prolactin were monitored 48 hours after injection (Omnadren pharmacokinetics: Cmax of testosterone in blood plasma occurs within 24-48 hours), as well as level of hormones on day 10 with Aging Male Screening (AMS) control. Results. In patients with TRT, on the second day after 48 hours, as well as after 10 days inclusive, an increase in testosterone and estradiol was statistically significant (p<0.01), but in overweight and obese individuals, the aromatization of testosterone into estradiol was significantly higher than in patients with normal body mass index (BMI), with at the same time, according to the scores of the AMS questionnaire, there was an improvement clinically, however, in patients with obesity it was clinically less significant due to significantly increased level of estradiol at the time of treatment. Conclusions. It was found that patients with increased BMI have worse treatment results with elevated estradiol, which requires monitoring of estradiol starting from 2-3 days and later on day 10 in order to titrate the frequency of injections of testosterone preparations and correct the level of estradiol to physiological ones.

Woodhouse-Sakati syndrome: genotype–phenotype review and case of intra-familial heterogeneity

Woodhouse-Sakati syndrome (WSS) is a rare eponymous disease described by Drs. Woodhouse and Sakati in 1983 as a syndrome of hypogonadism, alopecia, diabetes mellitus, intellectual disability, and ECG abnormalities. A couple of years later, a variant in the gene DCAF17 (DDB1 and CUL4-associated factor 17) was labeled as the founder mutation in most cases of WSS in the Arabian Peninsula and the Middle East. Reports around the world started to emerge on variable presentations of the syndrome, expanding its phenotypic spectrum. In addition, the discovery of new variants in the same gene grew our understanding of this multi-systemic syndrome. Genotype and phenotype expansion is increasing with the growing number of diagnosed cases owing to the availability and advances in clinical genetic testing. This review describes the current understanding of the DCAF17 gene with its molecular implication in WSS. We also provide an extensive analysis of the documented genetic changes associated with the syndrome, describing the geographical prevalence of these genetic variations. Additionally, we examine the disorder’s extensive manifestations and clinical presentations and describe a case of intra-familial phenotypic heterogeneity.

O-263 The risk of hypogonadism after microdissection testicular sperm extraction (micro TESE) in non-obstructive azoospermia (NOA) patients with various etiologies

Abstract Study question What is the risk factor of hypogonadism after micro TESE in NOA patients? Summary answer Klinefelter syndrome (KS), past history of cryptorchidism, preoperative testicular volume <8 ml or testosterone <287 ng/dL are significant risk factors of hypogonadism after micro TESE. What is known already Micro TESE combined with intracytoplasmic sperm injection (ICSI) is currently standard procedure to treat infertility in cases of NOA. Although many studies have reported the effectiveness of the treatment concerning about sperm retrieval rates (SRR) and the live birth rates, data on safety, especially on the risk of hypogonadism, are limited. Most previous studies, including our past study, regarding the risk of hypogonadism after TESE have been limited to relatively few in number of patients and the investigations only of the changes of mean serum testosterone levels. Study design, size, duration This study retrospectively investigated 535 NOA patients including 336 cases of unexplained NOA, 91 KS, 16 other chromosomal abnormalities, 31 azoospermia factor (AZF)c deletions, 31 past history of cryptorchidism, and 30 post anticancer chemotherapy, who had undergone micro TESE at our institution from September 2013 to August 2018. All of them had been examined serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels before and at least once in 1-3 months after micro TESE. Participants/materials, setting, methods In this study, hypogonadism was defined as total testosterone <250 ng/dL, which is established by the Japanese Society of Men’s Health as diagnostic criteria for late onset hypogonadism syndrome, and/or starting testosterone replacement therapy (TRT). We assessed risk factors of hypogonadism after micro TESE using indicators such as age, preoperative testicular volume and testosterone levels, past medical history, unilateral or bilateral, first time or not micro TESE. Main results and the role of chance In total of 535 men, FSH and LH after micro TESE significantly increased vs baseline (26.2 vs 29.9 IU/L, 9.6 vs 12.8 IU/L, respectively). On the other hand, testosterone levels significantly decreased after surgery (351.2 vs 297.5 ng/dL). Although postoperative hypogonadism was found in 42% (227/535), many of whom were cases of KS or preoperative testosterone levels <250 ng/dL. Sixteen men with KS, 3 men with unexplained NOA, and 2 men with past history of cryptorchidism started TRT because they complained clinical symptoms after micro TESE. Of the 21 men who started TRT, only 5 had new-onset low testosterone levels after micro TESE. According to the assessment of any association of various indicators and low postoperative total testosterone levels using multiple logistic regression analysis, significant risk factors of hypogonadism early after micro TESE were cases of KS (OR 11.4, 95% CI 4.4-29.9), preoperative testosterone levels <287 ng/dL (OR 7.5, 95% CI 4.7-12.0), preoperative testicular volume <8 ml (OR 3.9, 95% CI 2.3-6.4), past history of cryptorchidism (OR 2.9, 95% CI 1.1-7.8). Limitations, reasons for caution Most examinations of postoperative hormone levels were performed in short-term period after micro TESE, so we could only assess the risk of postoperative hypogonadism in a short time course in this cohort study. Wider implications of the findings The strength of the current study is that the risk factors of hypogonadism after micro TESE was assessed in a large population of NOA men with various etiologies. The results of this study provide useful clinical information about the risk of postoperative hypogonadism for NOA patients considering micro TESE. Trial registration number not applicable

(192) Evaluating Effect of hCG and hCG+rFSH Therapy on Ejaculation Disorders in Middle-Aged Men: A Case Study

Abstract Introduction The prevalence of various ejaculation disorders affecting middle-aged and older men has gained increasing attention due to their significant impact on quality of life. One of them, Late-Onset Hypogonadism (LOH) syndrome, can result in a decline in overall well-being. Testosterone replacement therapy (TRT) is commonly used to address LOH; however, it presents challenges such as diminishing endogenous testosterone secretion and incomplete symptom relief. Objective This study aimed to investigate the effects of human chorionic gonadotropin (hCG) or hCG plus recombinant follicle-stimulating hormone (rFSH) therapy in patients experiencing ejaculation disorders characterized by low semen volume and decreased pleasure during ejaculation. Methods Four male patients, aged 55 to 59 years, complaining of decreased ejaculatory pleasure and low semen volume, were enrolled in the study. One patient received hCG+rFSH therapy, while three patients received hCG alone. The initial dose of hCG was 5,000 units administered twice a week, and if deemed insufficient, it was increased to three times a week. rFSH was administered at a dosage of 150 units three times a week. Levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and estradiol (E2) were measured monthly. Anastrozole (1 mg) was added for patients exhibiting elevated E2 levels. Results Case 1: A 58-year-old male. Prior to treatment, testosterone and E2 levels were 4.84 ng/mL and 34.2 pg/mL, respectively. hCG+rFSH therapy resulted in increased testosterone levels (10.2 ng/mL) and elevated E2 levels (109.0 pg/mL) after three months of treatment. Addition of anastrozole resulted in testosterone levels of 10.90 ng/mL and E2 levels of 57.9 pg/mL in the following month. The patient experienced improved sexual desire, increased semen volume, and hair loss as a side effect. Treatment was discontinued after six months. Case 2: A 57-year-old male with diabetes mellitus. Pre-treatment testosterone and E2 levels were 2.19 ng-mL and 21.9 pg/mL, respectively. After changing the hCG dosage to 5,000 units three times a week, testosterone levels reached 5.33 ng/mL and E2 levels increased to 72.8 pg/mL after two months. With the addition of anastrozole four months into treatment, E2 levels were 44.4 pg/mL after five months. The patient reported improved morning erections, increased libido, increased semen volume, and improved glycemic control (HbA1c decreased from 9.0 to 7.0). Case 3: A 55-year-old male. Pre-treatment testosterone and E2 levels were 4.99 ng/mL and 32.3 pg/mL, respectively. In the first month of hCG therapy, testosterone levels increased to 13.6 ng/mL, while E2 levels rose to 75.5 pg/mL. Then, despite testosterone remaining in the 9.0–10.0 ng/mL range, E2 levels increased to 100 pg/mL. With the addition of anastrozole in the fifth month, the patient reported increased semen volume thereafter. Case 4: A 59-year-old male with a history of bipolar disorder. Prior to treatment, testosterone and E2 levels were 2.45 ng/mL and 23.0 pg/mL, respectively. hCG therapy resulted in testosterone levels of 6.71 ng/ml and E2 levels of 51.0 pg/mL after two months. Conclusions This case study highlights the outcomes of hCG or hCG+rFSH therapy in middle-aged men experiencing ejaculation disorders. Disclosure No.

Clinical and laboratory features of rheumatoid arthritis in men depending on testosterone levels

It has been suggested that the presence of chronic immunoinflammatory rheumatic disease (CIRD) may be a factor that increases the likelihood of developing hypogonadism syndrome, and conversely, the presence of uncompensated testosterone deficiency may predispose to a greater risk of developing or more severe course of ICRD. To study the incidence of hypogonadism in men with rheumatoid arthritis (RA) and evaluate its impact on the course of RA and concomitant diseases. A one-time continuous study included 170 men with RA who were undergoing inpatient treatment at the Federal State Budgetary Institution NIIR named after.V.A.Nasonova.Patients were assessed for total testosterone levels and subsequently divided into subgroups with normal (>12 nmol/l) and reduced levels.An intergroup comparison was carried out on the main indicators used in clinical rheumatological practice to assess the stage, activity and other medical and demographic characteristics of RA, as well as the state of purine and carbohydrate metabolism.A correlation analysis was performed between the level of total testosterone and some clinical and laboratory parameters. The frequency of detected testosterone deficiency in the study group was 24.1%. Significant correlations were noted between the level of total testosterone and body mass index (r=-0.29), the level of blood uric acid (r=-0.19) and C-reactive protein (r=-0.18). Patients with hypogonadism compared to the group with normal testosterone levels were characterized by higher body mass index (29.3±5.6 vs 26.3±4.0 kg/m2; p<0.001), glucose levels (6.95±7 .85 mmol/l vs5.42±1.13 mmol/l; p=0.034) and uric acid (354.6±110.7 vs 317.5±84.8 µmol/l; p=0.03) blood. In addition, patients with hypogonadism were more likely to suffer from obesity (41.6% vs 15.7%; p=0.001) and diabetes mellitus (21.6% vs 10.2%; p=0.075) without a statistically significant difference, and also had higher ESR (46.5±42.2 vs 31.0±30.9 mm/h; p=0.012). A more frequent occurrence of anemia was noted in hypogonadism (32.4% vs 16.7%; p=0.041). Testosterone levels and the presence of hypogonadism were not associated with the stage and activity of RA, however, testosterone deficiency was accompanied by a more frequent development of overweight and obesity, and adeterioration in purine and carbohydrate metabolism.

Epigenetics of Hypogonadotropic Hypogonadism: Molecular Mimicry between Severe Acute Respiratory Syndrome Coronavirus 2 and KISSR

AbstractThis study analyzed KISS1 and its receptor KISSR for peptide sharing with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was found that SARS-CoV-2 shares numerous minimal immune pentapeptide determinants with KISSR only. The peptide sharing has a high immunologic potential since almost all the common peptides are present in 101 SARS-CoV-2-derived immunoreactive epitopes. Data are in favor of configuring molecular mimicry as an epigenetic factor that can alter KISSR thus causing the hypogonadotropic hypogonadism syndrome with which altered KISSR associates.

Clinical and epidemiological characteristics of male hypogonadism in type 2 diabetes in Russia: combined analysis of study data for the period 2005–2022

Background: Male hypogonadism is associated with type 2 diabetes mellitus (T2DM), therefore, it is of interest to study its clinical and epidemiological characteristics. These data are published, but their fragmentation and small sample sizes are a problem. A summary assessment of the combined primary data of the conducted studies will provide sufficient representativeness and will allow to extrapolate the results to the general Russian population with T2DM.Aim: Assessment of the clinical and epidemiological characteristics and aggravating factors of male hypogonadism in T2DM in Russia.Materials and methods: A Combining primary data (anamnesis, anthropometric indicators, laboratory tests) of full-design, cross-sectional, screening studies of hypogonadism in men with T2DM conducted on the territory of the Russian Federation in the period from 2005 to 2022. The groups were compared using the Mann-Whitney U-test for quantitative indicators and χ² with Yates’ correction for qualitative ones. Differences were considered statistically significant with p <0,05. The groups were compared using the Mann-Whitney U-test and χ² with Yates correction. Differences were considered statistically significant at p<0.05.Results: Hypogonadism was detected in 893 of 1576 men (56,7%) with T2DM. Patients with hypogonadism were statistically significantly older, had higher body mass index (BMI), worse glycemic control than eugonadal men. There was ­statistically significantly higher prevalence of macroangiopathies and polyneuropathy in hypogonadal patients.Conclusion: The prevalence of male hypogonadism in T2DM 56,7%. Its development is due to age, obesity, worse glycemic control. Hypogonadism syndrome is associated with the development of diabetic macroangiopathy and polyneuropathy. Severe violation of glycemic control (glycated hemoglobin (HbA1c) 10% or more) significantly reduces testosterone production and increases the prevalence of hypogonadism.

ODP418 Late-Onset Hypogonadism Detected in Young Male Patients Suffering From Post COVID-19 Condition

Abstract At least one-third of post COVID-19 patients suffer from various chronic symptoms, defined by WHO as "post COVID-19 condition". However, the pathogenesis of post COVID-19 condition and its clinical course remain unclear. In February 2021, we set up an outpatient clinic specialized for COVID-19 after care (CAC) in Okayama University Hospital in Japan and we have investigated the clinical characteristics of patients with post COVID-19 condition. Our recent study revealed that general fatigue is the most common symptom in the post COVID-19 condition. Direct effects of viruses on each organ and conditions such as post-intensive care syndrome, post-traumatic stress disorder, and myalgic encephalomyelitis / chronic fatigue syndrome have been considered as possible etiologies. Recently, it has been suggested that endocrine disruption including the hypothalamic damage might be involved in the underlying mechanism. In the present study, we focused on male hypogonadism, called late-onset hypogonadism (LOH) syndrome. LOH syndrome causes fatigue and metabolic syndrome in middle-aged males. The aim of this study was to clarify the clinical characteristics of patients with LOH syndrome who visited our CAC outpatient clinic. We retrospectively reviewed medical records of all 39 male patients in whom serum free testosterone (FT) level was measured between February 2021 and November 2021 in our CAC outpatient clinic. As a result, 19 patients (48.7%) met the criteria for LOH syndrome (FT < 8.5 pg/mL; LOH group), and 14 (73.6%) of those patients were under the age of 50 years. A weak negative correlation was found between age and serum FT level (R=-0.301, p=0. 0624). A comparison of the LOH group with the non-LOH group showed that there were no significant differences in the patients’ background factors including age (36. 0 vs. 37.5 years), acute hospitalization (9 patients, 47.4% vs. 5 patients, 25. 0%), and number of days between COVID-19 onset and CAC outpatient clinic visitation (71 vs. 81 days). There were also no significant differences in various laboratory parameters between the two groups. However, symptoms including anxiety, cough and hair loss were more frequent in the LOH group. Compared to the incidence of LOH syndrome in the general population, the present study revealed that there is a relatively high incidence of LOH syndrome in young patients with post COVID-19 condition. Although it is known that gonadal functions are impaired in the acute phase of COVID-19, hypogonadism is also thought to be related to the chronic phase of COVID-19. Leydig cells in the testis may be susceptible to damage by SARS-CoV-2 virus because of the high level of ACE2 receptor expression; however, the underlying mechanisms of LOH syndrome due to post COVID-19 condition have yet to be elucidated. Presentation: No date and time listed

Eunuchoid skeletal proportions in male hypogonadism: a comparative analysis of anthropometric measures between men with congenital hypogonadotropic hypogonadism (CHH) and Klinefelter Syndrome (KS)

Eunuchoid skeletal proportions in male hypogonadism: a comparative analysis of anthropometric measures between men with congenital hypogonadotropic hypogonadism (CHH) and Klinefelter Syndrome (KS)

Long-term outcomes of testosterone replacement therapy for patients with late-onset hypogonadism syndrome

ABSTRACT Introduction and Objective Testosterone replacement therapy (TRT) is effective for patients with late onset hypogonadism (LOH) syndrome. However, treatment compliance of long-term TRT for LOH syndrome patients remains unclear. We investigated the long-term outcomes of TRT for patients with LOH syndrome. Methods Forty-two patients (age: mean 55.9, SD 10.2) were diagnosed and then underwent TRT using testosterone enanthate between January 2010 and December 2014 at our hospital. We investigated long-term compliance of TRT, changes of subjective data, i.e. aging male symptom (AMS score) and, international index of erectile function (IIEF5), and objective data, i.e. free testosterone level and, serum PSA level, retrospectively. This study was approved by the Ethics Committee of our facility (Approval No.3043). Results At the time of TRT initiation, AMS score (mean, as mentioned below) was 55.1 (SD 10.1) points, IIEF5 was 7.9 (SD 3.8) points, free testosterone level was 5.8 (SD 1.9) pg/ml, and serum PSA level was 1.3 (SD 1.6) ng/ml. The duration of TRT was 27.7 (SD 29.4) months. Dose of testosterone enanthate was 183.1 (SD 69.2) mg/4weeks. AMS score and IIEF5 were significantly improved after TRT. Adverse events (AE) occurred in 9.6% of the patients, but these were no severe AE. TRT continuation rate was 50.0% at 12 months, 40.5% at 24 months, 35.7% at 36 months, and 33.3% at 48 months. In addition, there was a significantly higher rate in the group with severe AMS scores than in mild-moderate groups. In the discontinuation group of 25 patients (59.5%), the duration of treatment was significantly longer in the improvement group than in the ineffective group. Conclusions Testosterone replacement therapy for late onset hypogonadism syndrome is a safe and effective long-term treatment. The treatment continuation analysis showed that patients with severe AMS scores and better effect of TRT requested long-term treatment. Disclosure Work supported by industry: no.

A Case of late-onset hypogonadism syndrome with rapidly elevated prostate specific antigen

ABSTRACT Introduction Cases of developing prostate cancer during hormone therapy for late-onset hypogonadism syndrome are rare. Objective We report a case of prostate cancer that developed and died during hormone therapy for late-onset hypogonadism syndrome. Case A 63-year-old man was diagnosed with depression around 2010. In 2011, he visited a private urologic clinic with complaints of depression and decreased libido, and was started on androgen replacement therapy (ART) with a diagnosis of late-onset hypogonadism (LOH) syndrome. His PSA was 0.87 ng/mL in 2012, but was 3.335 ng/mL at the time of his 2017 municipal checkup. He continued to receive hormone injections every 1-2 months, but his PSA was not retested. In August 2018, he had difficulty in urination and visited his local physician, who referred him to our hospital because of a markedly elevated PSA of 213.3 ng/mL. Prostate biopsy showed adenocarcinoma, Gleason score 5+4, and CT scan showed supraclavicular, mediastinal, and retroperitoneal lymph node metastases. He underwent maximal androgen blockade therapy with castration and bicalutamide. He died after PSA failure despite chemotherapy and other treatments. Conclusions There is no evidence that ART, which is the main treatment for LOH syndrome, directly causes prostate cancer. In this case, a rapid increase in PSA was observed during ART treatment, which may indicate that the treatment caused latent prostate cancer to become apparent, resulting in a rapid increase in PSA. However, in this case, the detection of prostate cancer might have been delayed because PSA levels, which were required during ART treatment, were not measured regularly. In addition, the psychiatric symptoms of LOH syndrome are similar to those of depression, and it is difficult to differentiate them. When there is a history of depression, as in this case, a more careful diagnosis and treatment strategy are required. Disclosure Work supported by industry: no.

Clinical efficiency of combination therapy using testosterone replacement therapy, phosphodiesterase 5 inhibitors and Kampo herbal medicine for eugonadal patients with late-onset hypogonadism syndrome

ABSTRACT Introduction Late-onset hypogonadism (LOH) syndrome is an endocrine disorder that is characterized by low levels of androgen and a subsequent decline in various physical functions. Regarding the treatment of LOH syndrome, the use of several agents, primarily testosterone replacement therapy (TRT), has been reported. In addition to TRT, certain therapies for LOH syndrome commonly include counseling, antidepressants, PDE5i and herbal medicine (Kampo). Objective In the present study, the effectiveness of initial treatment by combination therapy using TRT, herbal medicine and PDE5i in male patients with LOH were determined. The patients’ clinical background, changes in symptom scores and clinical parameters were analyzed to verify the effectiveness of the treatment intervention. Methods Between April 2017 and September 2018, 21 patients with LOH-associated symptoms, including chief complaints of decreased libido, ED, depression and general fatigue, visited the menopausal outpatient clinic. At their first visit, the patients were evaluated by reviewing their medical history, a physical examination and detection of clinical parameters, and their general LOH symptoms were judged according to Heinemann's Ageing Males’ Symptoms (AMS) scale. Voiding function was evaluated by the International Prostate Symptom Score (IPSS) and sexual function was evaluated by the International Index of Erectile Function-5 (IIEF-5) score. Blood screening, including hemoglobin (Hb), aspartate transaminase, alanine transaminase, creatinine, total cholesterol (T-Cho), triglyceride, blood sugar and PSA, and endocrinological variables including FT, LH and FSH were determined prior to monitoring endocrinological variables for any treatment of LOH. TRT or an oral treatment, such as herbal medicines or PDE5i, was provided for each symptom. For the TRT, T enanthate was administered via intramuscular injection every four weeks for a total of 12 weeks or testosterone ointment was applied. The most appropriate herbal medicine was administered to the patients according to their pathogenic alterations. A total of three traditional Japanese herbal medicines were candidates for LOH treatment in the present study. Total of 21 patients were enrolled and after 12 weeks, the clinical efficacy was evaluated based on improvement of LOH symptoms via same laboratory parameters and questionnaires. Results The overall AMS scores, as well as the psychological, physical and sexual AMS factors prior to and after treatment in the TRT, testosterone enanthate (T enanthate) monotherapy and T enanthate + PDE5i treatment groups were significantly improved. In the herbal medicine group, only the AMS physiological factors were significantly improved after treatment compared with the baseline. The improvement of the overall AMS scores, as well as the physiological and sexual AMS factors, were significantly negatively correlated with the free testosterone (FT) value prior to treatment. Conclusions Treatment with combination therapy using TRT, herbal medicine and PDE5i improved AMS scores in patients with LOH syndrome. Particularly in patients with LOH syndrome and low FT, the symptoms were significantly improved following combination therapy. Disclosure Work supported by industry: no.

Clinical outcomes of testosterone replacement therapy in Japanese patients with late onset hypogonadism (LOH) syndrome

ABSTRACT Objectives The Japanese late-onset hypogonadism (LOH) guideline is using serum free testosterone (FT) level for diagnosis of LOH syndrome. On the other hand, the European and American guidelines are using total testosterone level (TT) for diagnosis of LOH syndrome. Serum total testosterone levels below 8 nmol/L (231 ng/dL) require substitution of testosterone in the E.A.U. recommendations. In this study, we compared serum free testosterone level and total testosterone level in patients who visited our LOH syndrome out-patient department. We also investigate clinical outcomes of testosterone replacement therapy (TRT) in patients with LOH syndrome. Material and Methods Two hundred thirty male patients who visited our LOH syndrome out-patient department from January, 2008 to September, 2017 were targeted at this study. The patient's average age was 55.1 years old. Average of AMS score in patients was 51.7 points. Results Only 20 patients (8.7%) were low value (less than 2.31ng/ml) and 86 (37.4%) patients were low and borderline value (less than 3.46ng/ml) in serum total testosterone (TT) level. On the other hand, 99 patients (43.1%) were low values (less than 8.5pg/ml), and also 175 examples (76.1%) were low and borderline value (less than 11.8pg/ml) in serum free testosterone (FT) level. Testosterone replacement therapy (TRT) was carried out for 3 months in 84 patients with patient with LOH syndrome. Sixty nine patients (82.1%) were effective for ART. Only four patients dropped out TRT because of dysuria and plethora. Fifty four patients (83%) with patients who were low value (l less than 8.5pg/ml) in serum free testosterone (FT) were effective for ART in 53 patients. Also 25 patients (80.6༅) who was borderline value (less than 11.8pg/ml) in serum free testosterone (FT) level were effective for TRT in 31 patients. Conclusions Including borderline case, high frequency patient is suited at the diagnostic criteria of LOH syndrome using serum FT value compared to TT value. It might be necessary to also consider measurement of the auxiliary total testosterone, and compensation of the isolation testosterone by age. Testosterone replacement therapy (TRT) was also effective in patients with LOH syndrome not only low value but also borderline value in serum free testosterone (FT). Disclosure Work supported by industry: no.

Androgenic status in men during COVID-19

COVID-19 is a disease that has a negative systemic effect on the human body, including the male gonads. Therefore, the androgenic status in men with COVID-19 needs to be studied. To evaluate the levels of total testosterone, sex hormone binding globulin (SHBG) and free testosterone in men in the acute phase of COVID-19 and during convalescence. A continuous dynamic prospective study of 70 men with moderate to severe COVID-19 at the age of 50[44; 64] years. During the study, the levels of total testosterone, SHBG were determined with further calculation of the level of free testosterone by Vermeullen. The data were collected twice - at the patient's hospitalization and at his discharge. The differences between the groups were considered statistically significant at p <0.05. At the time of hospitalization for COVID-19, hypogonadism syndrome was observed in 61 people - 87%. Patients with hypogonadism did not statistically significant differ in age and severity of COVID-19 disease compared to men without hypogonadism. Inpatient treatment lasting 12[10;14] days resulted in a statistically significant increase in the levels of total testosterone from 4,7[2,96;8,48] to 12,85[8,62;19,2] nmol/l, p<0,001; SHBG from 27,87[20,78;36,57] to 33,76[26,27;52,60] nmol/l, p<0,001 and free testosterone from 107[65;174] to 235[162;337] pmol/l, p<0,001. This led to the elimination of hypogonadism in 28 patients - 40%. Patients with persistent hypogonadism were statistically significantly older than men with normalized testosterone, there were no statistically significant differences in the initial levels of total testosterone, SHBG and free testosterone, and there were also no differences in the prevalence of severe COVID-19 (3,97[2,86;7,46] vs 4,26[2,93;5,96] nmol/l, p=0,100; 28,76[20,78;48,59] vs 24,63[18,85;31,70] nmol/l, р=0,994; 100[58;118] vs 96[64;143] pmol/l, p=0,522; 24 против 18%, p=0,754, respectively). COVID-19 has a pronounced negative effect on the production of testosterone in men, leading to the development of laboratoric hypogonadism, which is potentially reversible. The reversibility of laboratoric hypogonadism is typical for younger patients.

Late-Onset Hypogonadism in a Male Patient with Long COVID Diagnosed by Exclusion of ME/CFS

After the acute phase of COVID-19, some patients have been reported to have persistent symptoms including general fatigue. We have established a COVID-19 aftercare clinic (CAC) to provide care for an increasing number of these patients. Here, we report the case of a 36-year-old man who developed post-COVID fatigue after acute infection with SARS-CoV-2. In the acute phase of COVID-19, the patient’s fever resolved within four days; however, general fatigue persisted for three months, and he visited our CAC 99 days after the initial infection. Examination revealed a high Aging Male’s Symptoms (AMS) score of 44 and low free testosterone (FT) level of 5.5 pg/mL, which meet the Japanese criteria of late-onset hypogonadism (LOH) syndrome. Imaging studies revealed an atrophic pituitary in addition to fatty liver and low bone mineral density. Anterior pituitary function tests showed a low follicle-stimulating hormonelevel and delayed reaction of luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) stimulation, indicating the possibility of hypothalamic hypogonadism in addition to primary hypogonadism seen in patients with post-COVID-19 conditions. After the initiation of Japanese traditional medicine (Kampo medicine: hochuekkito followed by juzentaihoto), the patient’s symptoms as well as his AMS score and serum FT level were noticeably improved. Furthermore, follow-up tests of GnRH stimulation revealed improvements in LH responsiveness. Although many patients have been reported to meet the criteria of ME/CFS such as our case, we emphasize the possibility of other underlying pathologies including LOH syndrome. In conclusion, LOH syndrome should be considered a cause of general fatigue in patients with post-COVID-19 conditions and herbal treatment might be effective for long COVID symptoms due to LOH (264 words).

Low-grade inflammation in survivors of childhood cancer and testicular cancer and its association with hypogonadism and metabolic risk factors

BackgroundIn childhood (CCS) and testicular cancer (TCS) survivors, low-grade inflammation may represent a link between testosterone deficiency (hypogonadism) and risk of metabolic syndrome. We aimed to study levels of inflammatory markers in CCS and TCS and the association with hypogonadism and future cardio-metabolic risk factors.MethodsSerum levels of inflammatory markers and testosterone were analyzed in CCS (n = 90), and TCS (n = 64, median time from diagnosis: 20 and 2.0 years, respectively), and in controls (n = 44). Differences in levels between patients and controls were calculated using univariate analysis of variance. T-test and logistic regression were applied to compare levels of cardio-metabolic risk factors and odds ratio (OR) of hypogonadism and metabolic syndrome in low and high inflammatory marker groups after 4–12 years of follow up. Adjustment for age, smoking, and active cancer was made.ResultsTCS and CCS, as compared to controls, had 1.44 (95%CI 1.06–1.96) and 1.25 (95 CI 1.02–1.53) times higher levels of IL-8, respectively. High IL-6 levels were associated with hypogonadism at baseline (OR 2.83, 95%CI 1.25–6.43) and the association was stronger for high IL-6 combined with low IL-10 levels (OR 3.10, 95%CI 1.37–7.01). High IL-6 levels were also associated with higher BMI, waist circumference, insulin, and HbA1c at follow up. High TNF-α was associated with higher diastolic blood pressure. No individual inflammatory marker was significantly associated with risk of metabolic syndrome at follow up. High IL-6 combined with low IL-10 levels were associated with risk of metabolic syndrome (OR 3.83, 95%CI 1.07–13.75), however not statistically significantly after adjustment.ConclusionTCS and CCS present with low-grade inflammation. High IL-6 levels were associated with hypogonadism and cardio-metabolic risk factors. Low IL-10 levels might reinforce the IL-6 mediated risk of developing metabolic syndrome.

Differentiation of Human Induced Pluripotent Stem Cells Into Testosterone-Producing Leydig-like Cells.

Late-onset hypogonadism (LOH) syndrome, due to a partial lack of testosterone, decreases the quality of life of older men. Testosterone is mainly secreted by Leydig cells in the testes. Leydig cell transplantation is expected to be a promising alternative to conventional testosterone replacement therapy for LOH syndrome. We herein report a simple and robust protocol for directed differentiation of human induced pluripotent stem cells (hiPSCs) into Leydig-like cells by doxycycline-inducible overexpression of NR5A1 and treatment with a combination of 8-bromoadenosine-3',5'-cyclic monophosphate (8-Br-cAMP) and forskolin. The differentiated cells expressed the steroidogenic enzyme genes STAR, CYP11A1, CYP17A1, and HSD3B2 and the specific markers of adult Leydig cells HSD17B3, INSL3, and LHCGR. Furthermore, we confirmed the secretion of functional testosterone from the cells into the culture supernatant by a testosterone-sensitive cell proliferation assay. These findings showed that the hiPSCs were able to be differentiated into Leydig-like cells, supporting the expectation that hiPSC-derived Leydig-like cells can be novel tools for treating LOH syndrome.

Clinical efficiency of combination therapy using testosterone replacement therapy, phosphodiesterase 5 inhibitors and Kampo herbal medicine for eugonadal patients with late-onset hypogonadism syndrome.

In the present study, the initial treatment efficiency of combination therapy using testosterone replacement therapy (TRT), herbal medicine and phosphodiesterase 5 inhibitors (PDE5i) in male patients with late-onset hypogonadism (LOH) were assessed. A total of 21 patients were enrolled and after 12 weeks, the clinical efficacy was evaluated based on improvement of LOH symptoms via laboratory parameters and several questionnaires, including the Ageing Males' Symptoms (AMS) scale. The overall AMS scores, as well as the psychological, physical and sexual AMS factors prior to and after treatment in the TRT, testosterone enanthate (T enanthate) monotherapy and T enanthate + PDE5i treatment groups were significantly improved. In the herbal medicine group, only the AMS physiological factors were significantly improved after treatment compared with the baseline. The improvement of the overall AMS scores, as well as the physiological and sexual AMS factors, were significantly negatively correlated with the free testosterone (FT) value prior to treatment. In conclusion, treatment with combination therapy using TRT, herbal medicine and PDE5i improved AMS scores in patients with LOH syndrome. Particularly in patients with LOH syndrome and low FT, the symptoms were significantly improved following combination therapy.

Change of preoperative symptoms of the late-onset hypogonadism syndrome after robot-assisted radical prostatectomy.

Background:As prostate cancer (PCa) is a common cancer among older men, patients with PCa often show aging male symptoms (AMSs). This study aimed to investigate the preoperative AMSs of the late-onset hypogonadism (LOH) syndrome and the effects on them after robot-assisted radical prostatectomy (RARP).Materials and methods:One hundred eighty-eight patients who underwent RARP without androgen deprivation therapy were measured for serum free and serum total testosterone, and were preoperatively assessed for symptoms of the LOH syndrome using a questionnaire containing an AMS score. Patients with a preoperative AMS score higher than 37 and a serum free testosterone level lower than 8.5 pg/mL were classified as Group A, with the remaining classified as Group B. AMS scores were measured at 1, 3, 6, 9, and 12 months after surgery.Results:Of the 188 patients, 49 and 139 patients were classified as Groups A and B, respectively. Preoperative AMS scores were 44.5 ± 8.2 in Group A and 28.6 ± 5.3 in Group B (p < 0.0001). AMS scores in Group A significantly improved 1 month after RARP (30.6 ± 8.4, p < 0.0001) compared with their preoperative scores and remained at the same level from 3 to 12 months postoperatively, whereas those in Group B became significantly worse (32.0 ± 7.8, p < 0.0001) than their preoperative ones. There were no differences between AMS scores in Groups A and B at every postoperative period (p = 0.3259, 0.2730, 0.2429, 0.4629, 0.1771 at 1, 3, 6, 9, and 12 months after surgery, respectively).Conclusions:Our results indicate that AMSs in PCa patients with the LOH syndrome can expect the same level of improvement as patients without it.