Dataset Information

Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism.

ABSTRACT: Concern has been raised over increased male reproductive disorders in the Western world, and the disruption of male endocrinology has been suggested to play a central role. Several studies have shown that mild analgesics exposure during fetal life is associated with antiandrogenic effects and congenital malformations, but the effects on the adult man remain largely unknown. Through a clinical trial with young men exposed to ibuprofen, we show that the analgesic resulted in the clinical condition named "compensated hypogonadism," a condition prevalent among elderly men and associated with reproductive and physical disorders. In the men, luteinizing hormone (LH) and ibuprofen plasma levels were positively correlated, and the testosterone/LH ratio decreased. Using adult testis explants exposed or not exposed to ibuprofen, we demonstrate that the endocrine capabilities from testicular Leydig and Sertoli cells, including testosterone production, were suppressed through transcriptional repression. This effect was also observed in a human steroidogenic cell line. Our data demonstrate that ibuprofen alters the endocrine system via selective transcriptional repression in the human testes, thereby inducing compensated hypogonadism.

SUBMITTER: Kristensen DM

PROVIDER: S-EPMC5789927 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism.

Kristensen David Møbjerg DM Desdoits-Lethimonier Christèle C Mackey Abigail L AL Dalgaard Marlene Danner MD De Masi Federico F Munkbøl Cecilie Hurup CH Styrishave Bjarne B Antignac Jean-Philippe JP Le Bizec Bruno B Platel Christian C Hay-Schmidt Anders A Jensen Tina Kold TK Lesné Laurianne L Mazaud-Guittot Séverine S Kristiansen Karsten K Brunak Søren S Kjaer Michael M Juul Anders A Jégou Bernard B

Proceedings of the National Academy of Sciences of the United States of America 20180108 4

Concern has been raised over increased male reproductive disorders in the Western world, and the disruption of male endocrinology has been suggested to play a central role. Several studies have shown that mild analgesics exposure during fetal life is associated with antiandrogenic effects and congenital malformations, but the effects on the adult man remain largely unknown. Through a clinical trial with young men exposed to ibuprofen, we show that the analgesic resulted in the clinical condition ...[more]

PMID: 29311296

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Project description:Several reports in humans as well as transgenic mouse models have shown that estrogens play an important role in male reproduction and fertility. Estrogen receptor alpha (ER?) and beta (ER?) are expressed in different male tissues including the brain. The estradiol-binding protein GPER1 also mediates estrogen action in target tissues. In human testes a minimal ER? expression during prepuberty along with a marked pubertal up-regulation in germ cells has been reported. ER? expression was detected mostly in spermatogonia, primary spermatocytes, and immature spermatids. In Sertoli cells ER? expression increases with age. The aromatase enzyme (cP450arom), which converts androgens to estrogens, is widely expressed in human tissues (including gonads and hypothalamus), even during fetal life, suggesting that estrogens are also involved in human fetal physiology. Moreover, cP450arom is expressed in the early postnatal testicular Leydig cells and spermatogonia. Even though the aromatase complex is required for estrogen synthesis, its biological relevance is also related to the regulation of the balance between androgens and estrogens in different tissues. Knockout mouse models of aromatase (ArKO) and estrogen receptors (ERKO?, ERKO?, and ERKO??) provide an important tool to study the effects of estrogens on the male reproductive physiology including the gonadal axis. High basal serum FSH levels were reported in adult aromatase-deficient men, suggesting that estrogens are involved in the negative regulatory gonadotropin feedback. However, normal serum gonadotropin levels were observed in an aromatase-deficient boy, suggesting a maturational pattern role of estrogen in the regulation of gonadotropin secretion. Nevertheless, the role of estrogens in primate testis development and function is controversial and poorly understood. This review addresses the role of estrogens in gonadotropin secretion and testicular physiology in male humans especially during childhood and puberty.

Project description:BACKGROUND:This study examined the prevalence of hypogonadism, its clinical and genetic risk factors, and its relationship to adverse health outcomes (AHOs) in North American testicular cancer survivors (TCS) after modern platinum-based chemotherapy. PATIENTS AND METHODS:Eligible TCS were <55 years of age at diagnosis and treated with first-line platinum-based chemotherapy. Participants underwent physical examinations and completed questionnaires regarding 15 AHOs and health behaviors. Hypogonadism was defined as serum testosterone levels ?3.0 ng/mL or use of testosterone replacement therapy. We investigated the role of 2 single nucleotide polymorphisms (rs6258 and rs12150660) in the sex hormone-binding globulin (SHBG) locus implicated in increased hypogonadism risk in the general population. RESULTS:Of 491 TCS (median age at assessment, 38.2 years; range, 18.7-68.4 years), 38.5% had hypogonadism. Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P= .006) and body mass index of 25 to <30 kg/m2 (OR, 2.08; P= .011) or ?30 kg/m2 (OR, 2.36; P= .005) compared with <25 kg/m2. TCS with ?2 risk alleles for the SHBG SNPs had a marginally significant increased hypogonadism risk (OR, 1.45; P= .09). Vigorous-intensity physical activity appeared protective (OR, 0.66; P= .07). Type of cisplatin-based chemotherapy regimen and socioeconomic factors did not correlate with hypogonadism. Compared with TCS without hypogonadism, those with hypogonadism were more likely to report ?2 AHOs (65% vs 51%; P= .003), to take medications for hypercholesterolemia (20.1% vs 6.0%; P<.001) or hypertension (18.5% vs 10.6%; P= .013), and to report erectile dysfunction (19.6% vs 11.9%; P= .018) or peripheral neuropathy (30.7% vs 22.5%; P= .041). A marginally significant trend for increased use of prescription medications for either diabetes (5.8% vs 2.6%; P= .07) or anxiety/depression (14.8% vs 9.3%; P= .06) was observed. CONCLUSIONS:At a relatively young median age, more than one-third of TCS have hypogonadism, which is significantly associated with increased cardiovascular disease risk factors, and erectile dysfunction. Providers should screen TCS for hypogonadism and treat symptomatic patients.

Dataset Information

Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism.

Publications

Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism.

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