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.

Recent methodological advances in male hormonal contraception.

Landmark WHO-sponsored trials showed decades ago that male hormonal contraception (MHC) is an effective male-directed contraceptive approach. Considerable progress has been made particularly in the last 5 years, establishing for the first time the reversibility of MHC and its short-term safety. Methodological advances in recent years include the pooling of information and individual-level integrated analysis; the first-time use of centralized semen analysis and fluorescence to detect low sperm concentrations; the establishment of sperm quality reference ranges in fertile men; the measurement of blood steroid concentrations by gas chromatography/mass spectrometry; and the inclusion of placebo groups to delineate clearly possible adverse effects of androgens and progestins in men.

Hormonal approaches to male contraception.

Purpose Of Review: Condoms and vasectomy are male-controlled family planning methods but suffer from limitations in compliance (condoms) and limited reversibility (vasectomy); thus many couples desire other options. Hormonal male contraceptive methods have undergone extensive clinical trials in healthy men and shown to be efficacious, reversible and appear to be well tolerated.

Recent Findings: The success rate of male hormonal contraception using injectable testosterone alone is high and comparable to methods for women.

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.

Pharmacokinetics and safety of long-acting testosterone undecanoate injections in hypogonadal men: an 84-week phase III clinical trial.

Currently available testosterone (T) injections in the United States are administered at 2-3 weekly intervals. Less frequent injections with favorable serum T pharmacokinetics would benefit hypogonadal men. The objective of this study is to assess the pharmacokinetics of long-acting testosterone undecanoate (TU) intramuscular (IM) injection in hypogonadal men.

Combined transdermal testosterone gel and the progestin nestorone suppresses serum gonadotropins in men.

Context: Testosterone (T) plus progestin combinations are the most promising hormonal male contraceptives. Nestorone (NES), a progestin without estrogenic or androgenic activity, when combined with T may be an excellent candidate for male contraception.

Objective: Our objective was to determine the effect of transdermal NES gel alone or with T gel on gonadotropin suppression.

Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men.

Prior studies have demonstrated that combined treatment of testosterone with a progestin induces a more rapid and greater suppression of spermatogenesis than testosterone treatment alone. We hypothesized that the suppressive effects of the combination of testosterone undecanoate (TU) injections plus oral levonorgestrel (LNG) on spermatogenesis may be mediated through a greater perturbation of testicular gene expression than TU alone. To test this hypothesis, we performed open testicular biopsy on 12 different adult healthy subjects: 1) four healthy men as controls; 2) four men 2 wk after TU treatment; and 3) four men 2 wk after TU + LNG administration.

Simultaneous measurement of serum testosterone and dihydrotestosterone by liquid chromatography-tandem mass spectrometry.

Background: Recent reports have described inherent problems with androgen immunoassays compared with mass spectrometry analyses.

Methods: We developed a method for measuring serum testosterone (T) and 5alpha-dihydrotestosterone (DHT) simultaneously via liquid-liquid extraction followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with positive-mode electrospray ionization.

Results: The DHT and T calibrators showed a linear response from 0.

Validation of a testosterone and dihydrotestosterone liquid chromatography tandem mass spectrometry assay: Interference and comparison with established methods.

Testosterone (T) and its metabolite dihydrotestosterone (DHT) are androgens with different biologic profiles. T and DHT measurements are required for assessment of patients with ambiguous genitalia, hirsutism, during 5 alpha reductase treatment of prostate disorders, and new androgen formulations. Our laboratory has developed and validated a method to simultaneously measure serum T and DHT with liquid chromatography tandem mass spectrometry (LC-MS/MS) for use in a clinical chemistry laboratory.

Ontogenic expression of putative feeding peptides in the rat fetal brain and placenta.

The well-demonstrated "fetal programming" paradigm is based on the observation that environmental changes can reset the developmental path and thus, gene expression during intrauterine development. As appetite-regulatory neural pathways develop in utero, we sought to determine the ontogenic expression of putative orexigenic and anorexigenic feeding-regulatory peptides in the fetal rat brain and placenta during the last third of gestation. Pregnant Sprague-Dawley rats (n = 12) at D14, D16 and D18 were sacrificed and fetal whole brain and placenta removed and examined for mRNA levels of orexigenic (neuropeptide Y (NPY), agouti-related peptide (AgRP)) and anorexigenic (cocaine and amphetamine regulated transcript (CART), pro-opiomelanocortin (POMC)) peptides and leptin receptor (OB-Rb) using real-time reverse transcription polymerase chain reactions (RT-PCR).

Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis.

Background: Hormonal methods for safe, reliable, and reversible contraception based on the suppression of spermatogenesis could soon become available. We have investigated the rate, extent, and predictors of reversibility of hormonal male contraception.

Methods: We undertook an integrated multivariate time-to-event analysis of data from individual participants in 30 studies published in 1990-2005, in which sperm output was monitored every month until recovery.

Minocycline up-regulates BCL-2 levels in mitochondria and attenuates male germ cell apoptosis.

In this study, we determined the efficacy of minocycline, a second generation tetracycline, in preventing male germ cell apoptosis after withdrawal of gonadotropins and intratesticular testosterone (T). Groups of 5 male rats received one of the following treatments daily for 5 days: (i) daily sc injection of GnRH-A (1.6 mg/kg BW), (ii) oral administration of 30% gum acacia as a vehicle control, and (iii) GnRH-A + oral administration of 50 or 100 mg/kg BW of minocycline.

Advances in male hormone substitution therapy.

Increased awareness of the clinical diagnosis of male hypogonadism has resulted in the wider use of androgen substitution therapy. Clinical signs and symptoms together with a low serum testosterone level confirm the diagnosis of male hypogonadism. Androgen replacement results in improved sexual function, mood, muscle mass and bone density in most hypogonadal men.

Placental and fetal membrane Nephrin and Neph1 gene expression: response to inflammation.

Objective: Fetal and amniotic fluid (AF) proteins (eg, alpha fetoprotein [AFP]) are measurable in the maternal circulation. Elevated maternal serum AFP levels indicate a risk for fetal anomalies or for obstetrical complications that are often associated with inflammation (eg, preterm labor). However, little is known of the mechanism of protein exchange between the fetus, AF, and maternal circulation.

XXY mice exhibit gonadal and behavioral phenotypes similar to Klinefelter syndrome.

Klinefelter syndrome (XXY males) is the most common sex chromosome aneuploidy. XXY mice were generated by using a four-generation breeding scheme that involves the use of a structurally rearranged Y chromosome, Y*, yielding approximately 50% of the live-born male offspring in the fourth generation with a XXY karyotype. Adult XXY mice have small testes, decreased plasma T levels, and elevated plasma FSH levels.

The phenomenon of altered risk factor patterns or reverse epidemiology in persons with advanced chronic kidney failure.

This lecture reviews a recently described phenomenon in patients with advanced chronic renal failure who are undergoing maintenance hemodialysis or chronic peritoneal dialysis. The phenomenon is called risk factor reversal, reverse epidemiology, or altered risk factor patterns, and it has to do with altered relations between risk factors and the hazard ratio for morbidity or mortality in these persons. This risk factor reversal phenomenon has been reported for body weight-for-height measures, systolic and diastolic blood pressures, and serum total cholesterol, LDL-cholesterol, homocysteine, creatinine, and parathyroid hormone concentrations, as well as metabolic acidemia.

Functional role of caspases in heat-induced testicular germ cell apoptosis.

In the present study, we determined whether a pan caspase inhibitor could prevent or attenuate heat-induced germ cell apoptosis. Groups of five adult (8 wk old) C57BL/6 mice pretreated with vehicle (DMSO) or Quinoline-Val-Asp (Ome)-CH2-O-Ph (Q-VD-OPH), a new generation broad-spectrum caspase inhibitor, were exposed once to local testicular heating (43 degrees C for 15 min) and killed 6 h later. The inhibitor (40 mg/kg body weight) or vehicle was administered intraperitoneally (i.