In Vitro Generation of Haploid Germ Cells from Human XY and XXY Immature Testes in a 3D Organoid System.

Increasing survival rates of children following cancer treatment have resulted in a significant population of adult survivors with the common side effect of infertility. Additionally, the availability of genetic testing has identified Klinefelter syndrome (classic 47,XXY) as the cause of future male infertility for a significant number of prepubertal patients. This study explores new spermatogonia stem cell (SSC)-based fertility therapies to meet the needs of these patients.

Male contraception development: monitoring effective spermatogenesis suppression utilizing a user-controlled sperm concentration test compared with standard semen analysis.

Objective: To determine whether a user-controlled sperm concentration test compared with standard semen analysis can effectively monitor spermatogenesis suppression for male contraception.

Design: Single center, prospective sub study of the ongoing clinical trial: "Study of daily application of Nestorone and testosterone combination gel for male contraception."

Setting: Research institute at an academic medical center.

propagation of XXY human Klinefelter spermatogonial stem cells: A step towards new fertility opportunities.

Klinefelter Syndrome (KS) is characterized by a masculine phenotype, supernumerary sex chromosomes (47, XXY), and impaired fertility due to loss of spermatogonial stem cells (SSCs). Early testicular cryopreservation could be an option for future fertility treatments in these patients, including SSCs transplantation or spermatogenesis. It is critically essential to adapt current SSCs propagation systems as a fertility option for KS patients.

In Vitro Propagation of XXY Undifferentiated Mouse Spermatogonia: Model for Fertility Preservation in Klinefelter Syndrome Patients.

Klinefelter syndrome (KS) is characterized by a masculine phenotype, supernumerary sex chromosomes (usually XXY), and spermatogonial stem cell (SSC) loss in their early life. Affecting 1 out of every 650 males born, KS is the most common genetic cause of male infertility, and new fertility preservation strategies are critically important for these patients. In this study, testes from 41, XXY prepubertal (3-day-old) mice were frozen-thawed.

The emerging role of mitochondrial derived peptide humanin in the testis.

The discovery of mitochondrial derive peptides (MDPs) has spotlighted mitochondria as central hubs in control and regulation of cell viability and metabolism in the testis in response to intracellular and extracellular stresses. MDPs (Humanin, MOTS-c and SHLP-2) are present in testes. Humanin, the first MDP, is predominantly expressed in Leydig cells, and moderately in germ cells and seminal plasma.

The IL-27 component EBI-3 and its receptor subunit IL-27Rα are essential for the cytoprotective action of humanin on male germ cells†.

Humanin (HN) is a mitochondrial-derived peptide that protects many cells/tissues from damage. We previously demonstrated that HN reduces stress-induced male germ cell apoptosis in rodents. HN action in neuronal cells is mediated through its binding to a trimeric cell membrane receptor composed of glycoprotein 130 (gp130), IL-27 receptor subunit (IL-27R, also known as WSX-1/TCCR), and ciliary neurotrophic factor receptor subunit (CNTFR).

The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan.

Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. It is conserved in animals and is both neuroprotective and cytoprotective. Here we report that in the overexpression of humanin is sufficient to increase lifespan, dependent on .

Age-related presence of spermatogonia in patients with Klinefelter syndrome: a systematic review and meta-analysis.

Background: Klinefelter syndrome (KS) has been defined by sex chromosome aneuploidies (classically 47, XXY) in the male patient. The peripubertal timeframe in KS patients has been associated with the initiation of progressive testicular fibrosis, loss of spermatogonial stem cells (SSC), hypogonadism and impaired fertility. Less than half of KS patients are positive for spermatozoa in the ejaculate or testis via semen analysis or testicular sperm extraction, respectively.

The humanin analogue (HNG) prevents temozolomide-induced male germ cell apoptosis and other adverse effects in severe combined immuno-deficiency (SCID) mice bearing human medulloblastoma.

Subfertility is a major concern of long-term cancer survivors at the reproductive age. We have previously demonstrated that a potent humanin analogue, HNG, protected chemotherapy-induced apoptosis in germ cells but not cancer cells in a metastatic melanoma allograft model. In this study, we utilized severe combined immuno-deficiency (SCID) mice bearing human medulloblastoma to study the effect of HNG in Temozolomide (TMZ) induced male germ cell apoptosis and white blood cell (WBC) suppression.

Humanin analog enhances the protective effect of dexrazoxane against doxorubicin-induced cardiotoxicity.

The chemotherapeutic effect of doxorubicin (Dox) is limited by cumulative dose-dependent cardiotoxicity in cancer survivors. Dexrazoxane (DRZ) is approved to prevent Dox-induced cardiotoxicity. Humanin and its synthetic analog HNG have a cytoprotective effect on the heart.

Testosterone protects high-fat/low-carbohydrate diet-induced nonalcoholic fatty liver disease in castrated male rats mainly via modulating endoplasmic reticulum stress.

We previously showed that testosterone (T) deficiency enhanced high-fat/low-carbohydrate diet (HFD)-induced hepatic steatosis in rats independent of insulin resistance and that T replacement reduced hepatic macrovesicular fat accumulation and inflammation. The present report explores the mechanism of T's protective effects on HFD-induced steatohepatitis. Adult male rats were randomized into four treatment groups for 15 wk: intact rats on regular chow diet or HFD, and castrated rats on HFD with or without T replacement.

The Potent Humanin Analogue (HNG) Protects Germ Cells and Leucocytes While Enhancing Chemotherapy-Induced Suppression of Cancer Metastases in Male Mice.

Humanin is a peptide that is cytoprotective against stresses in many cell types. We investigated whether a potent humanin analogue S14G-humanin (HNG) would protect against chemotherapy-induced damage to normal cells without interfering with the chemotherapy-induced suppression of cancer cells. Young adult male mice were inoculated iv with murine melanoma cells.

The effects of humanin and its analogues on male germ cell apoptosis induced by chemotherapeutic drugs.

Human (HN) prevents stress-induced apoptosis in many cells/tissues. In this study we showed that HN ameliorated chemotherapy [cyclophosphamide (CP) and Doxorubicin (DOX)]-induced male germ cell apoptosis both ex vivo in seminiferous tubule cultures and in vivo in the testis. HN acts by several putative mechanisms via binding to: an IL-12 like trimeric membrane receptor; BAX; or insulin-like growth factor binding protein-3 (IGFBP-3, a proapoptotic factor).

Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies.

Murine sex chromosome aneuploidies (SCAs) provide powerful models for charting sex chromosome influences on mammalian brain development. Here, building on prior work in X-monosomic (XO) mice, we use spatially non-biased high-resolution imaging to compare and contrast neuroanatomical alterations in XXY and XO mice relative to their wild-type XX and XY littermates. First, we show that carriage of a supernumerary X chromosome in XXY males (1) does not prevent normative volumetric masculinization of the bed nucleus of the stria terminalis (BNST) and medial amygdala, but (2) causes distributed anatomical alterations relative to XY males, which show a statistically unexpected tendency to be co-localized with and reciprocal to XO-XX differences in anatomy.

Pharmacokinetics and tissue distribution of humanin and its analogues in male rodents.

Humanin (HN) is a novel 24-amino acid mitochondrial-derived peptide that has demonstrated diverse cytoprotective effects, including an emerging role in diabetes. The purpose of this study was to examine the pharmacokinetics of humanin analogues, which show great potential as therapeutic agents (HNG and the non-IGFBP-3 binding, HNGF6A). 11-week-old male IGFBP-3(-/-) and wild type (WT) mice were divided into 3 groups: WT mice treated with HNG, WT mice treated with HNGF6A, and IGFBP-3(-/-) mice treated with HNG.

Functional role of progestin and the progesterone receptor in the suppression of spermatogenesis in rodents.

Synthetic progestins such as levonorgestrel (LNG) are used in combination with testosterone (T) in male contraceptive clinical trials to suppress gonadotropins secretion, but whether progestins have additional direct effects on the testis are not known. This study aimed to examine the effect of a potent progestin, (LNG), alone or in combination with testosterone (T) on spermatogenesis in adult rats, and to evaluate the functional role of the progesterone receptors (PRs) in the testis. In comparison with a low dose of LNG treatment in adult rats for 4 weeks, T and T + LNG treatment decreased testicular sperm count to 64.

Integrity of the blood-testis barrier in healthy men after suppression of spermatogenesis with testosterone and levonorgestrel.

Study Question: Do exogenous male hormonal contraceptives that suppress intratesticular testosterone and spermatogenesis interfere with the blood-testis barrier integrity in men?

Summary Answer: When spermatogenesis was suppressed by testosterone alone or combined with levonorgestrel (LNG) treatment in men, the structural appearance of Sertoli cell tight junctions remained intact in the human testis.

What Is Already Known: Testosterone promotes the integrity of the blood-testis barrier. Intratesticular androgen deprivation induced by exogenous testosterone plus a progestin to suppress spermatogenesis in a contraceptive regimen may disturb the structural and functional integrity of the blood-testis barrier.

Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model.

Klinefelter syndrome (47, XXY male) is the most common sex chromosome disorder in men. To study the underlying mechanisms of XXY phenotypes and design specific and novel therapeutic regimens for KS men, an experimental mouse model (41, XXY) was established. This manuscript compares the phenotypes of XXY men and mice and discusses the possible contributions of low androgen levels and extra X chromosome genes to the XXY phenotypes.

Mouse model for men with klinefelter syndrome: a multifaceted fit for a complex disorder.

Unlabelled: 41XXY mouse models share many characteristics of the human 47XXY Klinefelter syndrome (KS). This manuscript discusses the relative role of androgen deficiency and X chromosome genes resulting in the XXY mouse phenotype. The similarities in phenotype between 47XXY men and 41XXY mice suggest that the clinical manifestations in XXY men may be because of gene-dosage effect from genes that escape X inactivation in mouse.

Proteomic analysis of testis biopsies in men treated with transient scrotal hyperthermia reveals the potential targets for contraceptive development.

Mild testicular heating safely and reversibly suppresses spermatogenesis. In this study, we attempted to clarify the underlying molecular mechanism(s) involved in heat-induced spermatogenesis suppression in human testis. We conducted global proteomic analyses of human testicular biopsies before, and at 2 and 9 wk after heat treatment.

Genetic, hormonal, and metabolomic influences on social behavior and sex preference of XXY mice.

XXY men (Klinefelter syndrome) are testosterone deficient, socially isolated, exhibit impaired gender identity, and may experience more homosexual behaviors. Here, we characterize social behaviors in a validated XXY mouse model to understand mechanisms. Sociability and gender preference were assessed by three-chambered choice tasks before and after castration and after testosterone replacement.

Genetic and hormonal control of bone volume, architecture, and remodeling in XXY mice.

Klinefelter syndrome is the most common chromosomal aneuploidy in men (XXY karyotype, 1 in 600 live births) and results in testicular (infertility and androgen deficiency) and nontesticular (cognitive impairment and osteoporosis) deficits. The extent to which skeletal changes are due to testosterone deficiency or arise directly from gene overdosage cannot be determined easily in humans. To answer this, we generated XXY mice through a four-generation breeding scheme.