Rise In Testosterone Research Articles

8696 Whole Exome Sequence Analysis in a Naïve Cohort of Congenital Hypopituitarism in a Single Center

Abstract Disclosure: F.Q. Aratani: None. D.P. Di Matteo: None. I.P. de Magalhães: None. P. Frudit: None. L.S. Motomia: None. S.K. Beeby: None. L.R. Barros: None. D.D. Bissegatto: None. L.R. Carvalho: None. Background: Deficiency of one or more pituitary hormones is defined as hypopituitarism. In the literature, molecular diagnosis (MD) is defined in 12% by the Sanger sequencing and large scale sequencing increased this number to 15%. Aim: To perform whole exome sequencing (WES) in a cohort of patients with congenital hypopituitarism (CH) naïve to MD approach. Patients: Nine patients with CH followed in a single Brazilian tertiary center were included. Methods: Libraries were prepared with kits from Agilent and sequenced on Hi-Seq (Illumina). The variants were called following GATK best practices, using the Haplotypecaller and genome version hg38. They were classified in the Franklin by genoox (https://franklin.genoox.com/clinical-db/home). WES that did not pass the platform's initial quality control and variants that did not reach an adequate confidence level (low/medium confidence: VAF < 50%) were excluded. The remaining variants were classified according to ACMG criteria. Results: Three among 9 patients presented allelic variants and aredescribed here. Case 1: A 22-year-old female presented height of 143 cm (-3,13 SDS) at the first visit without signs of puberty, had delayed bone age (DBA), hypoplastic adenohypophysis, interrupted pituitary stalk (IPS) and ectopic neurohypophysis (ENH) at the magnetic resonance imaging (MRI). Hormonal profile showed low E2, GH, FSH and LH. Twoheterozygous missense variants in the ALMS1 gene (c.5450G>A : p.Arg1817GIn; and ALMS1:c.4225G>C: p.Ala1409Pro) were seen in the exome; both classified as VUS according to ACMG criteria. This allelic variant is related to Alstrom Syndrome. Case 2: A 7-year-old female presented with short stature and was diagnosed with GH followed by LH/FSH, TSH and ACTH deficiencies. At MRI presented IPS and ENH. A heterozygous variant in the PROK2 gene c.364C>T p.R122 with a premature stop codon and truncated protein was present and classified as probably pathogenic according to ACMG criteria. This variant was already described with hypogonadotropic hypogonadism (HH) with or without anosmia. Case3: A 15-year-old male was referred with growth hormone deficiency (GHD), DBA, and HH. Growth hormone replacement was started followed by testosterone. Despite delayed puberty, the testes were normal in size. WES showed a variant c.629G>A:p.Trp210*, in hemizygosity in IGSF1 gene and was classified as probably pathogenic according to ACMG criteria. Loss-of-function mutations in IGSF1 may cause an X-linked syndrome of central hypothyroidism, macroorchidism and delayed puberty (delayed rise of testosterone, but normal timing of testicular growth). Conclusion: WES in a cohort of patients with congenital hypopituitarism naïve to molecular diagnosis revealed 33% (3/9) with positive genetic findings, two of them with clinical significance and family segregation according to the genetic inheritance. Presentation: 6/3/2024

Identification of a Novel IGSF1 Variant in Two Malaysian Male Siblings with Central Hypothyroidism and Macroorchidism.

IGSF1 mutation is the commonest cause of mild to moderate isolated central congenital hypothyroidism and has an X-linked recessive inheritance, primarily affecting males. Other notable clinical features are macroorchidism with delayed pubertal testosterone rise, large birth weight, increased body mass index, low prolactin, transient growth hormone deficiency and low prolactin. Two male siblings with central hypothyroidism were found to have a novel IGSF1 c.3467T>A variant that was likely pathogenic based on the family segregation study. The proband, aged 3 years presented at 18 days old with prolonged jaundice while his 16-year-old brother was only detected to have central hypothyroidism after the proband's genetic analysis result was known. Both siblings were obese, had large birth weights, macroorchidism and low prolactin. The proband's brother had intellectual disability while the proband had normal development. This case study highlights the importance of evaluation for the IGSF1 variant in patients with unexplained central hypothyroidism, especially when accompanied by X-linked inheritance and macroorchidism. Family segregation analysis allows detection of other affected family members or carriers who may also benefit from thyroxine treatment.

Salivary testosterone and cortisol response in acute stress modulated by seven sessions of mindfulness meditation in young males

Stress is an established risk factor for negative health outcomes. Salivary cortisol and testosterone concentrations increase in response to acute psychosocial stress. It’s crucial to reduce stress for health and well-being through evidence-based interventions. Body-mind interventions such as meditation and Tai Chi have shown reduced cortisol levels but mixed results in testosterone concentration after stress. To address this research gap, we conducted a pilot randomized controlled trial to examine the modulating effects of a short-term (seven 20-minute sessions) mindfulness meditation on testosterone and cortisol in response to acute stress. Using one form of mindfulness meditation – Integrative Body-Mind Training (IBMT) and an active control–relaxation training (RT), we assessed salivary cortisol and testosterone concentrations at three stages of stress intervention – rest, stress, and an additional 20-min IBMT or RT practice. We found increased cortisol and testosterone concentrations after acute stress in both groups, but testosterone rise was not associated with cortisol rise. Moreover, an additional practice immediately after stress produced higher testosterone concentrations in the IBMT group than the RT group, whereas cortisol concentration increased in the RT group than in the IBMT group at the same time point. These findings indicate that brief mindfulness intervention modulates a dual-hormone profile of testosterone and cortisol in response to acute stress presumably via the co-regulation of hypothalamus-pituitary-adrenal and hypothalamus-pituitary-testicular axes.

Neuroplastin Expression in Male Mice Is Essential for Fertility, Mating, and Adult Testosterone Levels.

Male reproduction depends on hormonally driven behaviors and numerous genes for testis development and spermatogenesis. Neuroplastin-deficient (Nptn-/-) male mice cannot sire offspring. By immunohistochemistry, we characterized neuroplastin expression in the testis. Breeding, mating behavior, hormonal regulation, testicular development, and spermatogenesis were analyzed in cell-type specific neuroplastin mutant mice. Leydig, Sertoli, peritubular myoid, and germ cells express Np, but spermatogenesis and sperm number are not affected in Nptn-/- males. Neuroplastin lack from CNS neurons or restricted to spermatogonia or Sertoli cells permitted reproduction. Normal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) blood levels in Nptn-/- males support undisturbed hormonal regulation in the brain. However, Nptn-/- males lack mounting behavior accompanied by low testosterone blood levels. Testosterone rise from juvenile to adult blood levels is absent in Nptn-/- males. LH-receptor stimulation raising intracellular Ca2+ in Leydig cells triggers testosterone production. Reduced Plasma Membrane Ca2+ ATPase 1 (PMCA1) in Nptn-/- Leydig cells suggests that Nptn-/- Leydig cells produce sufficient testosterone for testis and sperm development, but a lack of PMCA-Np complexes prevents the increase from reaching adult blood levels. Behavioral immaturity with low testosterone blood levels underlies infertility of Nptn-/- males, revealing that Np is essential for reproduction.

SAT649 Org43553, The First Low-molecular-weight Agonist Of The Human Luteinizing Hormone Receptor Induces Leanness And Energy Expenditure In Mice

Abstract Disclosure: D. Lizneva: None. A. Gumerova: None. K. Ievleva: None. O. Barak: None. F. Korkmaz: None. J. Gimenez Roig: None. T. Frolinger: None. G. Pevnev: None. F. Sultana: None. N. Kramskiy: None. S. Wizman: None. M. Orloff: None. A.R. Pallapati: None. S. Rojekar: None. V. Ryu: None. O. Moldavski: None. T. Yuen: None. M. Zaidi: None. We provide compelling evidence that LH is a pro–lean hormone, and that ORG43553, the first low-molecular-weight agonist of the luteinizing hormone receptor (LHCGR) induces leanness and promotes energy expenditure in mice. We detected Lhcgr transcripts in white adipose tissue (WAT) depots in male and female C57BL/6 mice (qPCR, IHC, RNAscope, Sanger sequencing), but not in Lhcgr-/- mice. Intraperitoneal AlexaFluor-488–labeled hCG bound to gonadal and subcutaneous fat pads in wild type mice, but not in Lhcgr-/- mice. Following i.v. 89Zr–LH injection, radioactivity was detected in mesenteric, inguinal and gonadal WAT. LH, hCG and ORG43553 rapidly induced ERK1/2 phosphorylation in differentiated 3T3.L1 cells. Female and male Lhcgr+/- mice on normal chow and high–fat diet, respectively, became obese, importantly, without changes in sex steroids. The gene–dosage effect of Lhcgr depletion suggests a dominant physiologic action of LH on body composition. 14–week–old male C57BL/6 mice were fed on high–fat diet and injected, i.p., with LH, hCG or vehicle, twice–a–week, for 6 weeks. Both LH and hCG markedly reduced body fat accrual (qNMR) but triggered a rise in serum testosterone. The hCG–induced lean phenotype persisted despite androgen receptor blockade by flutamide—confirming that the pro–lean actions of LH and hCG were largely independent of testosterone. Furthermore that LH failed to inhibit fat accrual in Lhcgr-/- mice testified to its action via the LHCGR. Injection of ORG43553 into male C57BL/6 mice for 9 weeks caused a significant reduction in fat mass (qNMR), with reduced WAT weight in fat depots. Remarkably, serum testosterone remained unchanged confirming that the anti–adiposity effect of ORG43553 was independent of testosterone. To study the mechanism of LHCGR activation on body fat, 3T3.L1 adipocytes were treated with hCG or ORG43553 for 12 hours. This resulted in reduced oil droplet accumulation. 3T3-L1–derived organoids treated with LH, hCG or ORG43553 also displayed a substantial reduction in the differentiated layer compared to vehicle–treated organoids. To study whether, in addition to reducing adipocyte differentiation, LHCGR agonism also enhanced thermogenesis, 3T3-L1 adipocytes were pretreated with ORG43553 for 1 hour before measuring oxygen consumption rate (OCR) on a Seahorse Xf96 Analyzer. ORG43553 increased OCR at baseline and upon oligomycin exposure, indicating mitochondria proton leak (thermogenesis). To confirm increased energy expenditure in vivo, mice were injected, s.c., with ORG43553 or vehicle. Oxygen consumption (VO2) and energy expenditure (EE) increased acutely in ORG43553–treated mice, with no change in locomotor activity. The findings suggest that ORG45335, which has been tested in humans for infertility, can potentially become a candidate drug for obesity. Presentation: Saturday, June 17, 2023

Pyridoxamine protects human granulosa cells against advanced glycation end-products-induced steroidogenesis disturbances.

Ovarian advanced glycation end-products (AGEs) accumulation is associated with ovarian granulosa cells (GCs) dysfunction. Vitamin B6 derivatives positively affected reproduction. The current study was conducted to elucidate the AGEs effects on human luteinized mural GCs steroidogenesis in the presence or absence of pyridoxamine (PM). Isolated GCs of 50 healthy women were divided into four parts and treated with media alone (Control), PM alone, or human glycated albumin (HGA) with/without PM. Main steroidogenic enzymes and hormones were assessed by qRT-PCR and ELISA. The AGE receptor (RAGE) protein was also determined using Western blotting. The non-toxic concentration of HGA increased the expression of RAGE, StAR, 3β-HSD, and 17β-HSD (P < 0.0001 for all) but decreased the expression of CYP19A1 at mRNA levels. The increased RAGE protein expression was also confirmed by western blot analysis. These effects resulted in declined estradiol (E2), slightly, and a sharp rise in progesterone (P4) and testosterone (T) levels, respectively. PM, on its own, ameliorated the HGA-altered enzyme expression and, thereby, corrected the aberrant levels of E2, P4, and T. These effects are likely mediated by regulating the RAGE gene and protein expression. This study indicates that hormonal dysfunctions induced by the AGEs-RAGE axis in luteinized GCs are likely rectified by PM treatment. This effect is likely acquired by reduced expression of RAGE. A better understanding of how AGEs and PM interact in ovarian physiology and pathology may lead to more targeted therapy for treating ovarian dysfunction.

Excluded and ashamed: Shame proneness interacts with social exclusion and testosterone reactivity to predict behavioral aggression

Exclusion from social relationships is a painful experience that may threaten an individual’s status and dominance. The steroid hormone testosterone, which fluctuates rapidly in response to such threats, may be implicated in subsequent behavioral action (e.g., aggressive or prosocial responses) that aims to protect or enhance one’s status after exclusion. Past research, however, indicates that the link between acute changes in testosterone and behavior depend on context-relevant individual dispositions. In the context of social exclusion, an individual’s level of shame proneness—characterized by a tendency to experience shame and to react submissively—is theoretically relevant to the testosterone-induced aggression relationship but has yet to be examined empirically. Here, men (n = 167) were randomly assigned to be socially included or excluded in the virtual ball-tossing game, Cyberball, after which aggressive behavior was examined using the Point Subtraction Aggression Paradigm (PSAP). Testosterone reactivity was measured via salivary hormone samples collected pre- and post-game. Moderated multiple regression analyses were run to examine the extent to which testosterone reactivity and shame proneness moderated the effect of Cyberball condition on aggression. Results revealed a significant two-way interaction between Cyberball condition and testosterone reactivity, as well as a three-way interaction including shame proneness. For individuals low in shame proneness, exclusion was associated with higher post-cyberball aggression among those who experienced a rise in testosterone but was associated with lower post-cyberball aggression among those who experienced a decrease in testosterone. For individuals high in shame proneness, however, exclusion did not meaningfully affect aggressive responses, regardless of whether they experienced an increase or decrease in testosterone. These findings extend our understanding of the moderating roles of context and disposition on the neuroendocrinology of aggression in social interaction

Hepatomegaly and fatty liver disease secondary to central hypothyroidism in combination with macrosomia as initial presentation of IGSF1 deficiency syndrome.

IGSF1 deficiency syndrome (immunoglobulin superfamily member 1) is considered the most common sex-linked cause of secondary congenital hypothyroidism and is characterized by a wide variety of other clinical and biochemical features, including hypoprolactinemia, transient and partial growth hormone deficiency, early/normal timing of testicular enlargement but delayed testosterone rise in puberty, and adult macro-orchidism. Congenital central hypothyroidism is a rare disease (1:65,000 births); the detection of which may be delayed and missed by neonatal screening programs since most neonatal screening programs are based on TSH determination in dried blood spots only. Untreated hypothyroidism may cause abnormal liver biochemistry and non-alcoholic fatty liver disease. Our aim is to report a case of secondary hypothyroidism in an infant with an uncommon initial presentation. A 3-month-old male baby was referred to our hospital due to elevated alpha-fetoprotein levels, hypercholesterolemia, and macrosomia. Initial investigations revealed enlarged fatty liver and central hypothyroidism. Pituitary insufficiency was biochemically excluded and a pituitary MRI showed normal findings. Upon genetic analysis, a hemizygous variant NM_001170961.1:c.2422dup, p.(His808Profs*14), in IGSF1 gene was detected, establishing the diagnosis of the IGSF1 deficiency syndrome. In our patient, no other clinical findings were identified. Treatment with levothyroxine led to the remission of liver disease. Liver disease may be the initial presentation of secondary hypothyroidism in neonates and infants. Macrosomia in patients with isolated secondary central hypothyroidism is a strong indicator of IGSF1 syndrome.

Effects of Exogenous Human Chorionic Gonadotropin Administration on Plasma Testosterone and Semen Production in the Veiled Chameleon (Chamaeleo calyptratus)

Gamete collection, gamete preservation, hormone analysis, and artificial insemination have become integral parts of in situ and ex situ conservation programs for threatened and endangered species, and while these methods have been used to assist conservation in many different vertebrate groups, limited work has been done in reptiles. For example, semen collection in lizards has only recently been described and determined to be safe. The purpose of this study was to determine effective doses of human chorionic gonadotropin (hCG) for increasing plasma testosterone concentrations in the veiled chameleon (Chamaeleo calyptratus), as well as to determine whether the rise in testosterone impacts semen collection. A cross-over design was used. Chameleons were given injections of 100 IU, 200 IU, and 300 IU of hCG/animal and serial plasma testosterone measurements were collected over 24 hours. 100 IU/animal was determined to increase plasma testosterone concentrations similar to 200 IU, and 300 IU/animal. Following this, we determined weekly injections of hCG (100 IU/animal) would maintain elevated testosterone concentrations over 30 days. Additionally, we determined that elevated testosterone secondary to repeated injections of hCG decreased testicular size as determined by ultrasound. Repeated hCG injections and long-term elevation of plasma testosterone concentrations did not increase the likelihood to collect a semen sample with electroejaculation or improve ejaculate quality. Further research is needed to exogenously stimulate spermatogenesis and increase ejaculate quality to perform timed semen collections in male reptile species.

Polycystic Ovarian Syndrome In Some Sample Of Iraqi Adolescents: Implementation Of Consensus Guidelines

Background: The diagnosis of polycystic ovarian syndrome (PCOS) in adolescent girls can be difficult because symptoms are shared with normal pubertal development. The updated consensus guideline for PCOS diagnosis in adolescents sought to encourage accurate and timely diagnosis, optimize therapy, and improve health outcomes. Aim: the present study aims to implement an updated consensus criteria in the diagnosis of PCOS in adolescents complaining of clinical features of hyperandrogenism or menstrual abnormalities. Methods: A total of 60 patients with clinical features of hyperandrogenism and/or menstrual abnormalities were studied. A detailed history followed by clinical examination was taken. Serum Thyroid Stimulating Hormone, Cortisol, Total Testosterone, Dehydroepiandrosterone, Luteinizing Hormone (LH), and Prolactin were performed for all patients. Consensus criteria were used for PCOS diagnosis. Results: Menstrual irregularity was reported by 20 (33.3%) and hyperandrogenism features in 21(35%) of the participants. PCOS was confirmed in 14 (23%) participants. Patients diagnosed with PCOS were shown to have substantially higher rates of menstrual irregularity, hirsutism, elevated serum testosterone, and LH (P0.001, P0.001, P=0.002, and P0.002 respectively). Seven patients (50%) had both clinical and biochemical hyperandrogenism. Association between testosterone rise was more significant with hirsutism (P&lt;0.001) than with acne (P=0.001). Morbid obesity was observed in 21% of patients, 7% had their diastolic blood pressure 90mm Hg, and 39% had and fasting blood sugar ≥100 mg/dL. Conclusion: PCOS was diagnosed in 23% of adolescent girls who had features of hyperandrogenism and menstrual irregularities. Obesity and family history were more frequent in PCOS adolescents. Concordant clinical and biochemical hyperandrogenism was confirmed in only half of PCOS patients. PCOS patients may be at higher risk of metabolic syndrome.

Associations between serum copper, zinc, selenium level and sex hormones among 6-19 years old children and adolescents in NHANES 2013-2016.

Copper, zinc, and selenium are essential trace elements for human and have important effects on sex hormones. There are few studies on the relationships between the three trace elements and sex hormones. Therefore, our study aimed to investigate the relationships between serum copper, zinc, selenium and testosterone, estradiol, SHBG using data from the National Health and Nutrition Examination Survey (NHANES) 2013-2016 in participants 6-19 years. 1097 participants were enrolled and stratified into male/female children and adolescents. Weighted linear regression models combined regression diagnosis were used to estimate the relationships between trace elements and sex hormones according to the different stratifications. Our results showed that copper was inversely associated with testosterone and estradiol but positively correlated with SHBG. Zinc had positive relationships with testosterone in male adolescents and female children but an inverse relationship with testosterone in female adolescents. Furthermore, a negative association was observed between zinc and SHBG. With the rise of selenium level, testosterone and estradiol were increased but SHBG was decreased. In general, this study used more standardized statistical methods to investigate the relationships between copper, zinc, selenium and testosterone, estradiol, SHBG. Further study should pay attention to some details in statistical methods.

Changes in sex differences in neuroanatomical structure and cognitive behavior across the life span.

Sex differences occur in the structure and function of the rat cerebral cortex and hippocampus, which can change from the juvenile period through old age. Although the evidence is incomplete, it appears that in at least some portions of the cortex these differences develop due to the rise of ovarian hormones at puberty and are potentially not dependent on the perinatal rise in testosterone, which is essential for sexual differentiation of the hypothalamus and sexual behavior. During aging of female rats, the presence of continued ovarian hormone secretion after cessation of the estrous cycle also influences sex differences in neuroanatomical structure and cognitive behavior, resulting in nullification or reversal of sex differences seen in younger adults. Sex differences can be altered by experience in a stimulating environment during the juvenile/adolescent period, and sex differences in performance even can be affected by the parameters of a task. Thus, broad generalizations about differences such as "spatial ability" are to be avoided. It is clear that to understand how the brain produces behavior, sex and hormones have to be taken into account.

Seasonal but not sex-biased gene expression of the carotenoid ketolase, CYP2J19, in the sexually dichromatic southern red bishop (Euplectes orix).

Intense red colours in birds are often owing to ketocarotenoids (KCs). In many land birds, KCs are oxidized from dietary yellow precursors, presumably by the avian carotenoid ketolase CYP2J19, the regulation and constraints of which have important implications for condition-dependence and honest signalling of carotenoid colour displays. We investigated hepatic CYP2J19 gene expression in the seasonally and sexually dichromatic southern red bishop (Euplectes orix) in relation to season, sex, progression of the prenuptial moult, testis size, body condition, redness and circulating sex steroids. A coloration function of CYP2J19 is supported by a seasonal upregulation prior to and during the carotenoid-depositing stage of the male prenuptial moult. However, CYP2J19 expression was similarly high in females (which do not moult prenuptially), and remained high in males after moult, suggesting additional or alternative roles of hepatic CYP2J19 or its products, such as detoxification or antioxidant functions. In males, the CYP2J19 upregulation preceded and was unrelated to the rise in plasma testosterone, but was correlated with androstenedione, probably of adrenal origin and compatible with luteinizing hormone-induced and (in females) oestrogen-suppressed moult. Finally, contrary to ideas that carotenoid ketolation rate mediates honest signalling of male quality, CYP2J19 expression was not related to plumage redness or male body condition.

The onset of puberty in colony-housed male and female titi monkeys (Plecturocebus cupreus): Possible effects of oxytocin treatment during peri-adolescent development

Oxytocin has been used to treat neurodevelopmental conditions in adolescent patients but possible effects on reproductive development have not been well investigated. The effects of daily intra-nasal oxytocin treatment (12–18 months of age) on puberty and fertility were studied in colony-housed, male and female titi monkeys (Plecturocebus cupreus). Body weight, urinary conjugated pregnanes and estrogens (defining cyclicity) in females, and androgens and sperm in urine of in males, were measured from 1 to 3 years of age to detect puberty. Serum testosterone was also measured in males at 13, 23 and 33 months of age and hemi-castration at 3 years of age enabled assessment of testicular morphometry and oxytocin receptor expression. An oxytocin treatment*time interaction suggested a minor, transient suppression in weight gain after treatment ended. Note that females weighed 10% less across all ages. Oxytocin-treated females exhibited early, spurious ovulations but neither regular cyclicity (≈30 months) nor pregnancies were affected by treatment. Oxytocin did not affect the pubertal increase in urinary androgen or the first appearance of sperm, which occurred as early as 15 months of age. Treatment did delay the puberty-associated rise in serum testosterone in males. All males were pubertal by 22 months and all females by 32 months of age. Although no major male or female fertility outcome was observed, oxytocin demonstrated some physiological effects through a delay of testosterone secretion in males, induction of precocious ovulation in females, and a suppression of general weight gain for the months following treatment.

Double-Blind, Placebo-Controlled Trial of Cyproterone Acetate to Prevent Flare-Up Effect on Dogs Implanted With Deslorelin.

Deslorelin slow-released implants are registered in Europe for the reversible suppression of fertility in male dogs. After administration, a time-limited increase in sex hormones concentration and related behavioral problems may be observed. The aim of this work was to assess whether cyproterone acetate, a synthetic progestogen, can prevent this flare-up effect. Eighteen privately-owned entire male dogs were enrolled in this double-blind, placebo-controlled, randomized clinical trial. All subjects received a 4.7 mg deslorelin implant by SC route and 1–3 capsules containing either cyproterone acetate 2 mg/kg (N = 9) or a placebo (N = 9), by oral route BID for 14 days, depending on the dog's weight. The dogs were followed for 28 days. An increase in the blood testosterone concentration was observed in respectively 9/9 and 7/9 dogs of the control and cyproterone groups (p = 0.47). However, a worsening of the sex hormone related problems (i.e., urinary marking, mounting, aggressiveness toward other dogs and/or escape) was only observed in the placebo group, in 56 or 66% of the dogs as measured by respectively the veterinarian and the owners. Our study suggests that cyproterone acetate is effective and safe to supress the deslorelin induced behavioral flare-up effect, but not the rise in testosterone.

Childhood reproductive hormone levels after pediatric hematopoietic stem cell transplantation in relation to adult testicular function.

ObjectivesLongitudinal assessment of testicular function after pediatric hematopoietic stem cell transplantation (HSCT) is needed to guide clinical follow-up. We investigated dynamics in male reproductive hormones after pediatric HSCT, focusing on pubertal timing and associations with testosterone deficiency and azoospermia in adulthood.MethodsThis retrospective, longitudinal study included 39 survivors median 19 years after pediatric HSCT. Serum concentrations of LH, testosterone, FSH, and inhibin B from the time of HSCT, during puberty, and into adulthood were analyzed. Pubertal timing (rise in LH and testosterone) was compared to a reference cohort of 112 healthy boys. Associations between reproductive hormone levels during puberty and adult testicular function (including semen quality) were investigated.ResultsPubertal induction with testosterone was needed in 6/26 patients who were prepubertal at HSCT. In the remaining patients, pubertal timing was comparable to the reference cohort. However, 9/33 patients (without pubertal induction) developed testosterone deficiency in early adulthood, which was associated with higher LH levels from age 14 to 16 years. Azoospermia in adulthood was found in 18/26 patients without testosterone substitution. Higher FSH and lower inhibin B levels from mid-pubertal age were associated with azoospermia in adulthood, in patients being prepubertal at HSCT.ConclusionOur results indicate a substantial risk of deterioration in testicular function after pediatric HSCT, despite normal pubertal timing. Although reproductive hormone levels from mid-puberty indicated adult testicular function, prolonged follow-up into adulthood is needed in these patients, including clinical examination, reproductive hormone analysis, and semen sample for patients interested in their fertility potential.

Development of a single-dose intranasal testosterone administration paradigm for use in men and women

For over two decades, researchers in the field of human social neuroendocrinology have been using single-dose pharmacological challenge protocols to determine the causal effects of testosterone on psychological, behavioural, and neural processes. Most of these single-dose administration studies have so far used (1) single-sex samples and (2) varying modes of testosterone administration (intramuscular, transdermal, sublingual, and intranasal) that produced vastly different dose-response curves. Moreover, whereas studies with male participants increased men's testosterone concentrations within the high normal physiological range, studies with women typically increased testosterone concentrations to supraphysiological levels. The purpose of this study was to develop a single-dose administration protocol using intranasal testosterone that would produce a proportionally similar rise in testosterone for both sexes. We found that an 11 mg intranasal testosterone dose in men and a 0.3 mg dose in women raised testosterone concentrations to the high normal physiological range for each sex, producing similar dose-response dynamics in both sexes. This paradigm will allow researchers to design studies with mixed-sex samples that test physiologically plausible sex differences/similarities in the causal effects of testosterone. It will also provide a replicable protocol to examine the possible adaptive functions of acute increases in testosterone in both sexes.

Management of Fully Pubertal Girls With Nonclassical Congenital Adrenal Hyperplasia: Glucocorticoids Versus Oral Contraceptives

ObjectiveTo compare clinical outcomes of 3 treatment regimens—glucocorticoids (GCs), oral contraceptives (OCs), or a combination of both—administered to adolescents and young women diagnosed in childhood with nonclassical congenital adrenal hyperplasia (NCCAH), who had been treated with GCs until their adult height was achieved. MethodsA retrospective study of medical records of 53 female patients with NCCAH followed in 3 tertiary pediatric endocrinology institutes. The 3 treatment groups were compared for the prevalence of hirsutism and acne, standardized body mass index (BMI)-standard deviation score (SDS), and androgen levels at the attainment of adult height (baseline), 1-year later, and at the last documented visit. ResultsAt baseline, there were no significant differences among groups in BMI-SDS, androgen levels, hirsutism prevalence, acne, or irregular menses. From baseline to the last visit, the rate of hirsutism declined significantly only in the OC group (37.5% vs 6.2%, respectively; P = .03). The rate of acne declined in the combined group (50% vs 9%, respectively; P = .03) with a similar tendency in the OC group (50% vs 12.5%, respectively; P = .05). No significant changes were observed in BMI-SDS for the entire cohort or any subgroup during follow-up. A significant rise in androstenedione (P < .001), testosterone (P < .01), and 17-hydroxyprogesterone (P < .01) levels was observed only in the OC group. ConclusionIn girls diagnosed in childhood with NCCAH, who require treatment for hyperandrogenism following completion of linear growth, management should be tailored individually using a patient-centered approach. Treatment with OCs might be better than that with GCs for regression of hirsutism and acne. The long-term effects of elevated levels of androgens associated with this treatment regimen should be further studied.

Equisetum arvense L. Extract Ameliorates Oxidative Stress, Inflammation and Testicular Injury Induced by Methotrexate in Male Rats

Methotrexate (MTX) is a cytotoxic drug used to treat a wide range of cancers and non-cancerous conditions. However, it can cause unfavorable acute toxic effects in several organs, including the testis. Equisetum arvense L. (E. arvense) extract is effective in counteracting oxidative stress-related disorders. This study assessed the preventive effect of E. arvense extract against MTX-induced testicular toxicity. Gas chromatography-mass spectroscopy (GC-MS) was used to analyze the active constituents of E. arvense extract. Testicular toxicity was induced via MTX injection (0.5 mg/kg/ twice a week for 4 weeks). Forty male albino rats were divided into 4 groups: I- control (Cont); II: MTX; III: E. arvense (500 mg/kg/daily for 10 weeks); and IV: E. arvense + MTX. E. arvense main active constituents were squalane (15%), ascorbic acid per methyl (9.55%), phytol (8.69%), 2-pyrroline 1,2-dimethyl (8.63%), and octacosane (8.23%). Treatment of MTX injected rats with E. arvense produced a significant rise in body weight, serum testosterone and luteinizing hormone. E. arvense significantly increased the sperm counts, viability, and motility relative to the MTX injected rats. The levels of testicular oxidative stress and inflammation significantly reduced in the MTX rats treated with E. arvense. Furthermore, E. arvense markedly improved the testicular tissue and seminiferous tubules’ pathologic features in MTX-treated rats. E. arvense significantly decreased lipid peroxidation products, interleukin-1 beta, tumor necrosis factor-alpha while increasing superoxide dismutase levels. E. arvense prevented MTX-induced testicular damage via anti-inflammatory and antioxidant activities.

A longitudinal investigation of bidirectional and time-dependent interrelationships between testosterone and training motivation in an elite rugby environment

In sport, testosterone has been positioned as a substrate for motivation with both directional and time dependencies. However, evidence is scarce when considering the complexities of competitive sport and no work has explicitly modeled these dependencies. To address these gaps, we investigated the bidirectional and time-dependent interrelationships between testosterone and training motivation in an elite rugby environment. Thirty-six male athletes were monitored across training weeks before and after eight international rugby matches. Pre-breakfast measures of salivary testosterone and training motivation (1–10 rating) were taken on training, competition, and recovery days (up to 40 tests). Using a continuous-time (CT) model, within-person estimates of autoregressive effects (persistence) and cross-lagged effects (relationships) were derived. A stronger, more persistent temporal association was identified for testosterone than for motivation. Cross-lagged effects verified that training motivation was positively related to testosterone at latter time points (p < 0.001). Discrete-time analyses revealed a non-linear association; increasing in strength from a zero-time lag to peak after 2.83 days (standardized effect = 0.25), before dissipation over longer lagged intervals. The testosterone relationship with ensuing training motivation was also positive, but non-significant. Match effects also appeared (p < 0.001) with a predicted decline in training motivation, but a rise in testosterone, at match onset. In summary, a positive within-person association emerged between fluctuations in self-appraised motivation to train and testosterone concentration in an elite rugby environment. The lagged, non-linear nature of this relationship and match predictions on both outcomes support, and extend, theoretical models linking testosterone and competitive behaviors.