Primary Testicular Failure Research Articles

P-069 The expression patterns of ALOX15 and GPX4 in the seminiferous epithelium of men with non-obstructive azoospermia (NOA) due to primary testicular failure

Abstract Study question Does the expression of ALOX15 and GPX4 differ in NOA men with a history of cryptozoospermia from NOA who never had sperm in their ejaculate? Summary answer There was no significant difference between these 2 groups of patients. What is known already Oxidative stress (OS) has been investigated as a prime suspect for many unexplained pathologies, including primary testicular failure (PTF). The fact that male germ cells are rich in polyunsaturated fatty acids (PUFAs) but have a limited amount of cytoplasmic scavenging enzymes, is the reason behind their extreme vulnerability to OS. The accumulation of lipid peroxidation markers leads to the inactivation of glutathione peroxidase 4 (GPX4), the lipid repair enzyme, and the exacerbation of arachidonate 15-lipoxygenase (ALOX15), a lipoxygenase enzyme that promotes lipid degradation. This study investigates the activity of these antagonizing enzymes in the testicular tissue of NOA patients. Study design, size, duration This observational study was conducted in the period from May 2020, following the Ethics Committee of the University of Split School of Medicine approval, to October 2023. The testicular tissue from 57 patients diagnosed with NOA (according to WHO criteria) and referred to their first microTESE as a part of fertility treatment was collected and processed. Participants/materials, setting, methods Samples were prepared for histological evaluation and immunodetection (fixation; embedding in paraffin; H&E staining; and staining with anti-ALOX15 and anti-GPX4 antibodies). Two groups of NOA patients were observed: Crypto-NOA and NOA group. The main outcome measure was the number of ALOX15 positive germ cells per 1 mm² of the seminiferous tubule surface (N/ mm²) and the percentage (%) of GPX4 positive surface per surface of the tubule measured by the ImageJ program. Main results and the role of chance Spermatozoa were retrieved in 37 of 57 (64,91 %) men; samples of 4 patients had to be excluded due to poor fixation. There were 18 patients in the Crypto-NOA group, and 10 in the NOA group, while 5 patients were diagnosed with obstructive azoospermia (OA) and were used as controls. For comparison of the baseline data of Crypto-NOA and NOA patients, we used the Mann-Whitney test, and with statistical significance set at the level of P < 0.05, we found that there were significantly more patients with cryptorchism in the NOA group. As a tool for histological evaluation, we used the diagnostic code designed by McLachlan et al. and found similar spermatogenic phenotypes between Crypto NOA and NOA patients. The most represented phenotype was hypospermatogenesis with a moderate reduction in late spermatid number mixed with normal tubules (38,8 % in Crypto-NOA; 40% in NOA), following the phenotype where late spermatids are present in some tubules but mixed with tubules showing no progression past the spermatocyte stage. Using the Mann-Whitney test, we did not find a significant difference in the expression of ALOX15 and GPX4 in the seminiferous epithelium of Crypto-NOA and NOA patients. Limitations, reasons for caution The testicular tissue of NOA patients is characterized by focal or patchy spermatogenesis which led to the exclusion of several samples due to the fixation of tissue with a homogenous pattern of Sertoli cell-only or germ-cell arrest. Wider implications of the findings This study will provide additional information regarding the cause of impaired spermatogenesis and help to determine if the patient is a potential candidate for antioxidant therapy. Our next step is to associate the expression patterns of ALOX15 and GPX4 with the success rates of in vitro fertilization procedure outcomes. Trial registration number not applicable

Impact of varicocelectomy on sperm parameters and hormone levels in infertile patients with sickle cell disease

Purpose: This study analyzes the semen parameters and gonadal hormone levels in infertile patients with sickle cell disease (SCD) and palpable varicoceles who underwent varicocelectomy for impaired semen parameters. Patients and methods: Improvements in the semen parameters—serum levels of total testosterone, follicle-stimulating hormone (FSH), and inhibin B—and testicular volume (TV) in 18 infertile patients with SCD were evaluated before and at 6 months after varicocelectomy. Results: Before varicocelectomy, all sperm parameters were affected, with high rates of low sperm concentration (83.3%), poor motility (88.9%), and abnormal morphology (77.8%). All sperm parameters were altered in 61.1%. On follow-up at 55.5 months after varicocelectomy, improvement in all the semen parameters was successful and complete in 22.2% but was not significant in 77.8%. The median follow-up period for sperm recovery was relatively long at 60.3 months. Total testosterone, FSH, and inhibin B were not significantly different before and after treatment (P > 0.05). However, testosterone, FSH, and TV significantly correlated with the semen parameters (P < 0.05). Moreover, a significant positive correlation was found between TV and inhibin B (P < 0.05), and the improvement in the semen parameters was significantly correlated with primary hypogonadism (P < 0.05). Conclusion: In adult men with SCD, varicocelectomy had a positive impact on the impaired seminal parameters and may be an option before sperm cryopreservation to improve future male fertility. Furthermore, primary testicular failure may be a feature of reversible spermatogenesis recovery in these patients.

FRI432 An Interesting Case Of Primary Hypogonadism In A Patient With Multiple Sclerosis

Abstract Disclosure: S. Ahsun: None. P. Lekprasert: None. K.K. Win: None. Introduction: As per the recent data there is an association between low levels of testosterone in men and the risk for multiple sclerosis (MS). Most recent practice involves checking testosterone levels for male patients with newly developed MS and treating with testosterone supplementation if levels are low. CASE PRESENTATION: A 65-year-old male with medical history of multiple sclerosis, prediabetes, hypogonadism, squamous cell carcinoma of left ear, thyroid cancer (unknown type) status post total thyroidectomy and radioiodine therapy; presented to our endocrine office for an initial visit. Patient had been following with Endocrinologist at different state in the past and did not have much of his prior records since that practice closed. He has been on 150 mcg of levothyroxine and his TSH was stable at 1.2 (0.4-4.5 mIU/L). He also had a history of hypogonadism and had been on testosterone supplementation since the age around 50. Patient did not know the underlying cause for his hypogonadism. He has 3 biological children and the youngest one is 26 years old. He had been off of testosterone therapy for 3 months prior to our initial visit. We did some workup which showed total testosterone level of <20 (250-1100 ng/dL). Free testosterone 2.2 (46-224 pg/mL). FSH and LH levels were elevated at 27.1 (1.6-8 mIU/mL) and 17.3 (1.6-15.2 mIU/mL). Prolactin level was 5.1 (5.2-26.5) ng/mL. These labs were consistent with Primary hypogonadism. Repeat testing was done and the patient had redemonstration of very low testosterone levels. Further checking of the karyotype analysis revealed normal male karyotype testing. His physical exam showed normal sized testicles at 20 cc and no gynecomastia. Body hair distribution was normal but there was decreased shaving frequency with decreased muscle strength. Patient never had any chemotherapy or the radiation therapy to the pelvic area. No known history of chronic infection or trauma. Currently, he is on Ocrelizumab for Multiple Sclerosis. His testosterone level is now in the normal range with the testosterone therapy after the work up. CONCLUSION: As per the above case, our patient has an interesting presentation of primary hypogonadism with multiple sclerosis. He has no known reason for his primary testicular failure. We know that testosterone deficiency has been linked to development of MS and MS can lead to secondary hypogonadism. But Primary hypogonadism has not yet been seen with MS although autoimmunity can be postulated to lead to primary testicular failure in these patients, but more studies and investigation will need to be done to establish this cause and effect relationship. REFERENCE: Chitnis T. The role of testosterone in MS risk and course. Mult Scler. 2018 Jan;24(1):36-41. doi: 10.1177/1352458517737395. PMID: 29307293 Presentation: Friday, June 16, 2023

THU098 Gonadotropin Secreting Pituitary Tumor Presenting As Primary Hypogonadism

Abstract Disclosure: J.N. Shapiro: None. T.X. Lu: None. J. Eapen: None. J.G. Karam: None. Gonadotroph adenomas are the most common subtype of nonfunctional pituitary adenomas, with 35 percent secreting enough LH or FSH to raise serum gonadotropin levels, but clinical syndromes due to hypersecretion of gonadotropins are rare. A low testosterone level with high FSH or LH can mislead to a diagnosis of concomitant primary hypogonadism rather than a secreting pituitary adenoma. We present a case of a patient with an FSH-secreting pituitary macroadenoma presenting with low testosterone levels. The patient is a 67-year-old man incidentally found to have a pituitary macroadenoma measuring 12 x 13 x 12 millimeters, impinging upon the optic chiasm on MRI of the brain obtained for headaches. Visual field tests revealed abnormalities compatible with glaucoma, but not chiasm compression. He has no symptoms of hormonal excess or deficit, although his wife reported decreased erectile function. Physical examination was unremarkable except for an atrophic left testicle. Pituitary hormone function tests (ACTH, AM cortisol, IGF-1, prolactin, thyroid function tests, and 24-hour urine free cortisol) were within normal range, except for an elevated FSH 14.8-18.1 mIU/mL and decreased testosterone in range of 185-256 ng/dL, with normal LH at 7.0 mIU/mL, for which he was referred for urology for evaluation of primary hypogonadism. The patient underwent transsphenoidal resection of the pituitary adenoma. Postoperative pathology revealed a pituitary adenoma, gonadotroph cell type, with immunohistochemical staining scattered positive FSH, and rare positive LH. Postoperative MRI showed post-surgical changes with no residual nodular enhancement. Following surgery, the patient suffered from severe clinical hypogonadism with episodes of profuse diaphoresis and extreme fatigue. Postoperative laboratory values revealed panhypopituitarism with undetectable testosterone level, and low LH and FSH levels. The patient was successfully treated with hydrocortisone, levothyroxine, and testosterone, with resolution of his symptoms. Our patient presented with a pituitary macroadenoma, low testosterone, and high FSH suggestive initially of primary hypogonadism, but found ultimately to have an FSH-secreting adenoma. He likely had underlying hypogonadism, primary or secondary, and although his adenoma secreted FSH, it was not enough to maintain testosterone level in normal range, possibly in part due to biologically inactive FSH molecules or to primary testicular failure. The extremely low testosterone levels postoperatively suggest that his testicular function was mostly stimulated by the adenoma secreted FSH and was therefore drastically lost after surgery. This case increases awareness to consider a gonadotropin-secreting tumor in the differential diagnosis of a pituitary adenoma with high FSH or LH, even when testosterone level is unexpectedly low. Presentation: Thursday, June 15, 2023

Hypergonadotropic hypogonadism and chromosomal aberrations: clinical heterogeneity and implications on the health of elderly men, case series

BackgroundHypogonadism in older men is often considered as late onset hypogonadism. However, this clinical condition results from primary testicular failure which could be of genetic origin with Klinefelter syndrome being the most common chromosomal abnormality associated with it.Case presentationWe report a heterogeneous group of cases who were diagnosed with hypergonadotropic hypogonadism in their adulthood and were found to have rare chromosomal aberrations. All were elderly men (in their 70 s and 80 s) for whom the diagnosis was made during the evaluation of incidental symptoms suggestive of endocrinopathy. The first had hyponatremia; the other two had gynaecomastia and features of hypogonadism noted during admission for various acute medical problems. With respect to their genetic results; the first had a male karyotype with balanced reciprocal translocation between the long arm of chromosome 4 and the short arm of chromosome 7. The second case had a male karotype with one normal X chromosome and an isochrome for the short arm of the Y chromosome. The third case was an XX male with unbalanced translocation between the X & Y chromosomes with retention of the SRY locus.ConclusionHypergonadotrophic hypogonadism in the elderly, may be due to chromosomal aberrations, resulting in heterogeneous and diverse clinical phenotypes. Vigilance must be exercised when seeing cases with subtle clinical findings. This report suggests that in selected cases of adult hypergonadotropic hypogonadism, chromosomal analysis may be indicated.

A Clinical Trial Evaluating the Efficacy of Prolistem? Supplement in Men with Non-Obstructive Azoospermia (Primary Testicular Failure)

A Clinical Trial Evaluating the Efficacy of Prolistem? Supplement in Men with Non-Obstructive Azoospermia (Primary Testicular Failure)

Hypoparathyroidism and late-onset hypogonadism in an adult male with familial 22q11.2 deletion syndrome: a case report with 3-year follow-up and review of the literature

Background22q11.2 deletion syndrome (DiGeorge syndrome) is associated with multiple organ dysfunctions such as cardiac defects, immunodeficiency, and hypoplasia of parathyroid glands. Moreover, the phenotype of 22q11.2 DS has clinical variability and heterogeneity.Case presentationIn this report, we present the case of a 35-year-old patient with a past medical history that included recurrent infections, mild learning difficulties in childhood, pediatric obesity, and cataract. He was admitted to the endocrinology department for the management of hypogonadism and hypocalcemia. During the 3-year follow-up, the patient gradually developed primary hypoparathyroidism, hypogonadism, chronic renal failure, and heart failure, and his medical condition deteriorated. Meanwhile, in order to improve clinicians’ awareness of the endocrine manifestations of adult 22q11.2 DS and reduce missed diagnoses, we reviewed 28 case reports of adult 22q11.2 DS to analyze the clinical characteristics.DiscussionHere, we report the case of a young man diagnosed with 22q11.2 DS presented a rare combination of multiple endocrine disorders. This is the first time that a patient with 22q11.2DS had late-onset hypogonadism caused by primary testicular failure combined with decreased pituitary gonadotropin reserve in a patient with 22q11.2DS.

ODP381 Changes in Perceptions of Pediatric Endocrinologists (PE) and Urologists (PU) to Infants and Children regarding care of individuals with 46,XY DSD

Abstract Introduction Over recent decades, controversy regarding standards of care has contributed to questioning past management recommendations for infants and children with a 46,XY DSD. Surveys conducted in 3 waves (2003, 2010, 2020) provide evidence of changes in recommendations for care have changed over this period. Methods Online surveys of the members of the Pediatric Endocrine Society (PE) and Societies for Pediatric Urology (PU) included case vignettes representing partial androgen insensitivity syndrome (PAIS), micropenis resulting from primary testicular failure, and penile ablation (non-DSD). Survey items included questions regarding recommended gender of rearing (GoR), genital surgery (and timing), and disclosure of diagnostic details to patient. Results The newborn PAIS vignette included elevated LH and FSH and a 1.2 cm. phallus that increased to 1.7 after exogenous testosterone. Male GoR was chosen by 47, 55 & 55% PE and 81, 83 & 69% of PU in waves 1 to 3, respectively; 27 PE and 28% PU chose an added "non-binary" option in 2020. The recommendation that parents, rather than patients, should decide about perineal hypospadias repair was chosen by 70, 60 & 50% of PE and 93, 90 & 79% of PU. Recommending against surgery were 25, 22 & 10% PE and 23, 13 & 8% PU. Recommending surgery be completed at <1 year of age: 56, 59, 66% PE and 69, 78, 84% PU. Recommendation against disclosure of the underlying condition to the patient 12, 17 & 28% PE and 17, 19 & 22% PU, while 35, 28 to 32% PE and 34, 43 & 30% PU recommended that disclosure occur by 11 years of age. For the penile ablation vignette, 78, 92 & 92% PE and 98, 95 & 97% PU recommended male GoR. The 2020 non-binary option was chosen by 4 and 2% PE and PU. The majority of both groups recommended male GoR for the micropenis vignette with testicular failure; 94, 94 & 89% PE and 96, 97 & 88% PU. The decline in 2020 resulted from the recommendation of the non-binary option by 9% PE and 8% PU. Conclusions It seems clear that a female GoR recommendation is currently rare across 46,XY vignettes with evidence of testicular function during at least some of fetal life. It is also apparent that the current emphasis/controversy regarding GoR has resulted in confusion as to how to apply this poorly understood concept. The resulting shift of delaying decisions regarding surgery until the patient can decide is inconsistent with the recommendation that hypospadias repair occur before age 1 year. Finally, lack of or delayed disclosure is inconsistent with patient centered care recommendations. Presentation: No date and time listed

Untoward Azoospermia by absurd testosterone therapy

The established role of the male partner in overall infertility is almost 50%.1 The most significant cause is degraded number as well as the quality of sperms.2 Spermatogenesis is governed by gonadotropin-releasing hormone (GnRH) then follicle-stimulating hormone (FSH) and finally by testosterone, which is linked with puberty, and essentially required well controlled hypothalamic-pituitary axis leading the Leydig cells along with Sertoli cells.3 In Pakistan incidence of azoospermia is 12.32%, and another study reported it to be 16%, this incidence is comparable to infertility in the USA at 10% while 11.35% in Kenya.4The non-obstructive azoospermia (NOA) is mostly treated with testicular sperm extraction and then intracytoplasmic sperm injection (ICSI), but only a small percentage can afford it, and mostly it requires multiple attempts. So, most couples end up with adaptation or sperm donation.5,6 One percent of all men and 10% of infertile are azoospermic. In non-obstructive azoospermia primary testicular failure occur, testosterone therapy (TTh) negative feedback mechanism can cause suppression of luteinizing hormone (LH).7 In 30% of infertile men, the cause cannot be established, but genetics, chronic infection, prostatitis, anti-sperm antibodies, and persistent obesity can lead to it.8Unfortunately, in Pakistan, most of our physicians are fond of prescribing a high dosage of testosterone for the long term, to infertile male patients. Patients become satisfied due to the positive characteristics of testosterone, but the most painful aspect is that high TTh leads to complete azoospermia. Moreover, in most such cases, it is permanent due to damage to the germinal layer. More than six-month high TTh is contraceptive.9 In 2018 the Endocrine Society and the American Urological Association recommend testosterone therapy to treat infertility and preserve fertility.10 The first management of such cases is the cessation of TTh. An integrated analysis of 1549 men on high TTh was reported as the median time to recover was 3.4 months, to a sperm concentration of 20 million/ mL and the median time to recover to baseline sperm concentration was 5.4 months.10 According to this analysis, 90% of men recovered in 12-month time after stopping TTh with 20 million/ml sperms, and 100% recovered after 24 months, all of them were on average 31.8 years of age. They were on TTh for 9.5 months.11 Hypothalamic-pituitary-gonadal (HPG) axis is almost terminated by testosterone replacement therapy (TRT) and anabolic androgenic steroids (AAS) resulting in very much suppressed or even the complete arrest of the spermatogenesis. Spontaneous cessation of such overwhelming male infertility treatments can recover spermatogenesis depending upon the length and strength of such treatments.12,13 The Prime concern is the weightage of the decision by a physician to start such therapies, which have an abusive role in treating infertility. Most physicians are unfortunately causing such azoospermia.Many very reputed international guidelines and recommendations are against such TTh, TRT, and even AAS for the treatment of male infertility. Clomiphene citrate (CC) and human chorionic gonadotropin (HCG) along with the revival of the hypothalamic-pituitary-gonadal axis can help to restore spermatogenesis in these men, after 1-2 years of the cessation of the TTh.14

Non-Obstructive Azoospermia with Hypergonadotropic Hypogonadism without a Significant Abnormalities in the Physical Examination

Background: Around 10 % of infertile men and 1 percent of all males have azoospermia. There are two types of azoospermia, which are obstructive and non-obstructive azoospermia. Non-obstructive azoospermia's main mechanism is because the testes fail to produce the sex hormone and induce spermatogenesis (primary testicular failure).
 Case: A patient is 28 years old and has a job as a car paint worker. He came with the chief complaint of infertility since two and a half years ago. He and his wife were having intercourse 3-4 times a week. Past medical history is unremarkable. His wife’s medical history is also unremarkable. Physical examination and ultrasound of the testes are normal. The semen analysis in this patient was azoospermia for 2 different times in the span of 2 weeks with no abnormalities in the accessory gland. Hormonal profiles results are testosterone level 2,32 ng/mL and FSH 15,03 mIU/mL, which indicatehypergonadotropic hypogonadism. The patient was suggested to evaluate further (complete hormonal profile, karyotyping analysis, and Y-Chromosome microdeletion) and educate about the possibility to conceive with assisted reproductive technology (ART).
 Discussion: Hypergonadotropic hypogonadism is a challenging case that needs a complete assessment such as complete hormonal profile, karyotyping analysis, Y-chromosome microdeletion analysis, and also, in this case, the paint thinner exposure in the workplace is needed to be considered. The chance of normal conception is very small, and the assisted reproductive procedure is necessary.
 Conclusion: Some abnormalities are usually present in the physical examination of azoospermia patients. This case convinces us of the importance of thorough history taking and other investigations. Managing this patient will be challenging, with the goal of the therapy is to achieve spermatogenesis to be able to use the spermatozoa available for ICSI.

Abstract 101: A case of CYP11A1 enzyme deficiency with unambiguity

We hereby present a 20 years old boy who presented at 14 years of age with generalized hyperpigmentation, bilateral breast enlargement, loose stools and fever. He was born out of second-degree consanguinity with uneventful birth and childhood history. On examination he had generalized hyperpigmentation, gynecomastia, no genital ambiguity with normal sexual maturity ratings. Blood biochemistry was suggestive of primary adrenal insufficiency and primary testicular failure. The computerized tomography imaging showed normal adrenal glands. With involvement of both adrenal glands and gonads, differential diagnosis including autoimmune polyglandular syndrome, NR5A1 and NR0B1 mutations were considered. Clinical exome sequencing was done which showed a novel homozygous missense variation in exon 4 of the CYP11A1 gene (chr15:g.74343895G>C). A diagnosis of side chain cleavage enzyme (CYP11A1) deficiency unusually presenting with genital unambiguity was made.

Chronic exposure to delta-9-tetrahydrocannabinol impacts testicular volume and male reproductive health in rhesus macaques

To determine the dose-dependent effect of delta-9-tetrahydrocannabinol (THC) exposure on male testes and reproductive health in a nonhuman primate model. Research animal study. Research institute. Adult male rhesus macaques 8-10 years of age (n = 6). Daily edible THC at medically and recreationally relevant doses. Testicular volume and epididymal head width, serum levels of inhibin B, albumin, total testosterone, prolactin, follicle-stimulating hormone, estradiol, and luteinizing hormone; semen volume; and sperm motility, morphology, and concentration. For each 1 mg/7 kg/day increase in THC dosing, there was a marked loss in total bilateral testicular volume of 11.8 cm3 (95% confidence interval [CI]: 8.3-15.4). In total, average bilateral testicular volume decreased by 58%. Significant dose-response decreases in mean total testosterone level by 1.49 ng/mL (95% CI: 0.83-2.15) and in estradiol level by 3.8 pg/mL (95% CI: 2.2-5.4) were observed, but significant increases in the levels of follicle-stimulating hormone by 0.06 ng/mL (95% CI: 0.02-0.10), luteinizing hormone by 0.16 ng/mL (95% CI: 0.08-0.25), and prolactin by 7.4 ng/mL (95% CI: 3.4-11.3) were observed. There were no statistically significant changes in semen parameters. In rhesus macaques, chronic exposure to THC resulted in significant dose-response testicular atrophy, increased serum gonadotropin levels, and decreased serum sex steroids, suggestive of primary testicular failure. Further studies are needed to determine if reversal of these observed adverse effects would occur if THC was discontinued and for validation of thefindings in a human cohort.

Endocrine aberrations of human nonobstructive azoospermia.

Nonobstructive azoospermia (NOA) refers to the failure of spermatogenesis, which affects approximately 1% of the male population and contributes to 10% of male infertility. NOA has an underlying basis of endocrine imbalances since proper human spermatogenesis relies on complex regulation and cooperation of multiple hormones. A better understanding of subtle hormonal disturbances in NOA would help design and improve hormone therapies with reduced risk in human fertility clinics. The purpose of this review is to summarize the research on the endocrinological aspects of NOA, especially the hormones involved in hypothalamic–pituitary–testis axis (HPTA), including gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, estradiol, sex hormone binding globulin, inhibin B, anti-Müllerian hormone, and leptin. For the NOA men associated with primary testicular failure, the quality of currently available evidence has not been sufficient enough to recommend any general hormone optimization therapy. Some other NOA patients, especially those with hypogonadotropic hypogonadism, could be treated with hormonal replacement. Although these approaches have succeeded in resuming the fertility in many NOA patients, the prudent strategies should be applied in individuals according to specific NOA etiology by balancing fertility benefits and potential risks. This review also discusses how NOA can be induced by immunization against hormones.

Endocrine Dysfunction in Patients With Myotonic Dystrophy.

Myotonic dystrophy is a dominantly inherited multisystem disorder that results from increased CTG repeats in the 3' region of the myotonic dystrophy protein kinase gene (DMPK). The mutant DMPK mRNA remains in the nucleus and sequesters RNA-binding proteins, including regulators of mRNA splicing. Myotonic dystrophy is characterized by a highly variable phenotype that includes muscle weakness and myotonia, and the disorder may affect the function of many endocrine glands. DMPK mRNA is expressed in muscle, testis, liver, pituitary, thyroid, and bone; the mutated form leads to disruption of meiosis and an increase in fetal insulin receptor-A relative to adult insulin receptor-B, resulting in adult primary testicular failure and insulin resistance predisposing to diabetes, respectively. Patients with myotonic dystrophy are also at increased risk for hyperlipidemia, nonalcoholic fatty liver disease, erectile dysfunction, benign and malignant thyroid nodules, bone fractures, miscarriage, preterm delivery, and failed labor during delivery. Circulating parathyroid hormone and adrenocorticotropic hormone levels may be elevated, but the mechanisms for these associations are unclear. This review summarizes what is known about endocrine dysfunction in individuals with myotonic dystrophy.

Secondary azoospermia after sleeve gastrectomy: a case report

ObjectiveTo report the first case of secondary azoospermia after sleeve gastrectomy.DesignCase report.SettingAcademic male infertility clinic.Patient(s)A 33-year-old man with secondary azoospermia and primary testicular failure with testosterone deficiency after laparoscopic sleeve gastrectomy.Intervention(s)Hormonal therapy with anastrozole for 10 months and diagnostic testicular biopsy.Main Outcome Measure(s)Semen analyses and testicular histopathology.Result(s)Non-obstructive azoospermia persisted at 20 months after surgery despite hormonal therapy with anastrozole. Testicular histopathology revealed the presence of Sertoli cells only.Conclusion(s)Although further research is need to determine the relationship between sleeve gastrectomy and secondary infertility, men should be informed of the potentially deleterious effects of this surgery on semen parameters.

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 < 88 years had higher average TT (401 ± 162 vs. 278 ± 178 ng/dL, p < 0.001), FT (6.3 ± 2.0 vs. 3.3± 2.1 pg/mL, p < 0.001), and lower LH (4.3 [3.0 - 6.1] vs. 14.6 [7.2 - 25.5] mIU/mL, p < 0.001), compared to men age ≥ 88 years. The prevalence of primary and secondary hypogonadism was 2% and 11%, respectively, in men age < 88 years, and 30% and 11%, among men age ≥ 88 years (p < 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 < 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.

Genetics of Azoospermia

Azoospermia affects 1% of men, and it can be due to: (i) hypothalamic-pituitary dysfunction, (ii) primary quantitative spermatogenic disturbances, (iii) urogenital duct obstruction. Known genetic factors contribute to all these categories, and genetic testing is part of the routine diagnostic workup of azoospermic men. The diagnostic yield of genetic tests in azoospermia is different in the different etiological categories, with the highest in Congenital Bilateral Absence of Vas Deferens (90%) and the lowest in Non-Obstructive Azoospermia (NOA) due to primary testicular failure (~30%). Whole-Exome Sequencing allowed the discovery of an increasing number of monogenic defects of NOA with a current list of 38 candidate genes. These genes are of potential clinical relevance for future gene panel-based screening. We classified these genes according to the associated-testicular histology underlying the NOA phenotype. The validation and the discovery of novel NOA genes will radically improve patient management. Interestingly, approximately 37% of candidate genes are shared in human male and female gonadal failure, implying that genetic counselling should be extended also to female family members of NOA patients.

Long-term follow-up of boys who have undergone a testicular biopsy for fertility preservation.

Long-term follow-up of boys who have undergone a testicular biopsy for fertility preservation.

Testicular Function of childhood cancer survivors: Who is worse?

This cross-sectional study evaluated morpho-volumetric development of the testis, endocrine function and sperm parameters in 102 young adult childhood cancer survivors (CCS). About 1/3 of patients showed low testicular volume (<24 ml); the Hodgkin disease group showed significantly lower total testicular volumes, compared to the rest of the group. CCS who underwent hematopoietic stem cell transplantation (SCT) showed significantly lower total testicular volume, followed by those who received chemotherapy plus radiotherapy. Eighty-seven CCS underwent hormonal evaluation; 3/87 showed low LH levels, 5/87 high LH levels, 8/87 high FSH values. Twenty-eight out of 84 patients (33.3%) had suboptimal testosterone values (<3.5 ng/ml), while 5/84 showed frankly reduced levels (<2.3 ng/ml). AMH levels were measured in 17 CCS and were normal in all of them. Thirty-four patients accepted to undergo sperm analysis; sperm count was reduced in 7/34 patients (20.6%), while azoospermia was found in 6/34 patients (17.7%). All patients with azoospermia had a primary testicular failure (FSH levels >8 UI/l and low testicular volume) and had received radiotherapy or SCT. History of Hodgkin’s disease, SCT, and non-cranial irradiation associated with chemotherapy were risk factors for reduced sperm concentration. Patients treated during puberty showed lower total testicular volume than patients treated before puberty, probably due to a more aggressive treatment in older patients. Sperm concentration was more closely related to testicular volume than to FSH levels, while AMH values were unrelated to testicular function. In this study, only one third of patients accepted to undergo sperm analysis. The same reluctance has been described by other authors. This common attitude among CCS has prompted the search for surrogate markers of spermatogenesis to be used in infertility screening. Inhibin B has proved to be a better marker for spermatogenesis than FSH. Surprisingly, inhibin B was not analysed in this study, while as expected, AMH was not useful in the evaluation of testicular function. Similarly, the cumulative dose of alkylating agents, already identified as a detrimental factor affecting gonadal function in these patients, was not evaluated.

Primary Testicular Failure with Unilateral Cryptorchidism

Background: Primary Testicular Failure (PTF) in men with unilateral cryptorchidism is a rare case, which might be the first time reported. Case: A 34-year-old man came with infertility and azoospermia. Signs of secondary sex found. FSH levels: 60.68 mIU / ml, LH levels: 15.96 mIU / ml, T levels: 336.14 ng / dl, E2 levels: 27.81 ng / dl. Ultrasound showed the left testis in the left inguinal +/- 2,4x1,1x3,6 cm in size, with decrease vascularization; +/- 4.1 cm from the base of the penis. The right testis size +/- 2,8x1,1x2,2 cm in the right scrotum accompanied by spermatocele. The patient was referred to the Urology department for orchidopexy of the left testis in the inguinal. Discussion: Primary testicular failure, in this case, may occur due to idiopathic but does not rule out the mosaic type of Klinefelter syndrome. The patient has unilateral cryptorchidism for 20 years, there will be a risk of testicular cancer. Management of cryptorchidism must be performed orchidopexy the first year after birth. After orchidopexy, monitoring is needed every year until at least 5 years. Conclusion: PTF occurs when the parenchymal tissue contained in the testes is no longer able to produce sperm or testosterone. PTF diagnosis is only possible through pathology and testicular cytology, but the combination of FSH and Inhibin B examination remains the best recommendation as a biomarker for patients with PTF.