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

2018 ◽  
Vol 115 (4) ◽  
pp. E715-E724 ◽  
Author(s):  
David Møbjerg Kristensen ◽  
Christèle Desdoits-Lethimonier ◽  
Abigail L. Mackey ◽  
Marlene Danner Dalgaard ◽  
Federico De Masi ◽  
...  
Keyword(s):  
Sertoli Cells ◽  
Transcriptional Repression ◽  
Endocrine System ◽  
Western World ◽  
Fetal Life ◽  
Reproductive Disorders ◽  
Elderly Men ◽  
Steroidogenic Cell ◽  
Physical Disorders ◽  
Mild Analgesics

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.

scholarly journals The Role of Fetal, Infant, and Childhood Nutrition in the Timing of Sexual Maturation

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 419
Author(s):  
Valeria Calcaterra ◽  
Hellas Cena ◽  
Corrado Regalbuto ◽  
Federica Vinci ◽  
Debora Porri ◽  
...  
Keyword(s):  
Sexual Maturation ◽  
Pubertal Development ◽  
Endocrine System ◽  
Metabolic Adaptation ◽  
Fetal Life ◽  
Critical Periods ◽  
Important Indicator ◽  
Prenatal Growth ◽  
Adaptation Response ◽  
Healthy Growth

Puberty is a crucial developmental stage in the life span, necessary to achieve reproductive and somatic maturity. Timing of puberty is modulated by and responds to central neurotransmitters, hormones, and environmental factors leading to hypothalamic-pituitary-gonadal axis maturation. The connection between hormones and nutrition during critical periods of growth, like fetal life or infancy, is fundamental for metabolic adaptation response and pubertal development control and prediction. Since birth weight is an important indicator of growth estimation during fetal life, restricted prenatal growth, such as intrauterine growth restriction (IUGR) and small for gestational age (SGA), may impact endocrine system, affecting pubertal development. Successively, lactation along with early life optimal nutrition during infancy and childhood may be important in order to set up timing of sexual maturation and provide successful reproduction at a later time. Sexual maturation and healthy growth are also influenced by nutrition requirements and diet composition. Early nutritional surveillance and monitoring of pubertal development is recommended in all children, particularly in those at risk, such as the ones born SGA and/or IUGR, as well as in the case of sudden weight gain during infancy. Adequate macro and micronutrient intake is essential for healthy growth and sexual maturity.

scholarly journals Molecular mechanisms underlying AMH elevation in hyperoestrogenic states in males

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Clara Valeri ◽  
María M. Lovaisa ◽  
Chrystèle Racine ◽  
Nadia Y. Edelsztein ◽  
Marina Riggio ◽  
...  
Keyword(s):  
Sertoli Cells ◽  
Oestrogen Receptor ◽  
Molecular Mechanisms ◽  
Follicle Stimulating Hormone ◽  
Androgen Insensitivity Syndrome ◽  
Fetal Life ◽  
Complete Androgen Insensitivity Syndrome ◽  
Peutz Jeghers Syndrome ◽  
Clinical Conditions ◽  
Sertoli Cell Line

Abstract Anti-Müllerian hormone (AMH) is secreted by Sertoli cells of the testes from early fetal life until puberty, when it is downregulated by androgens. In conditions like complete androgen insensitivity syndrome (CAIS), AMH downregulation does not occur and AMH increases at puberty, due in part to follicle-stimulating hormone (FSH) effect. However, other conditions like Peutz-Jeghers syndrome (PJS), characterised by low FSH, also have increased AMH. Because both CAIS and PJS may present as hyperoestrogenic states, we tested the hypothesis that oestradiol (E2) upregulates AMH expression in peripubertal Sertoli cells and explored the molecular mechanisms potentially involved. The results showed that E2 is capable of inducing an upregulation of endogenous AMH and of the AMH promoter activity in the prepubertal Sertoli cell line SMAT1, signalling through ERα binding to a specific ERE sequence present on the hAMH promoter. A modest action was also mediated through the membrane oestrogen receptor GPER. Additionally, the existence of ERα expression in Sertoli cells in patients with CAIS was confirmed by immunohistochemistry. The evidence presented here provides biological plausibility to the hypothesis that testicular AMH production increases in clinical conditions in response to elevated oestrogen levels.

scholarly journals RNA Binding Protein Musashi1 Is Expressed in Sertoli Cells in the Rat Testis from Fetal Life to Adulthood

2002 ◽  
Vol 66 (2) ◽  
pp. 500-507 ◽  
Author(s):  
P.T.K. Saunders ◽  
S.M. Maguire ◽  
S. Macpherson ◽  
M.C. Fenelon ◽  
S. Sakakibara ◽  
...  
Keyword(s):  
Sertoli Cells ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Fetal Life ◽  
Rat Testis

Effect of thyroid hormone on the pre- and post-natal development of the rat testis

1991 ◽  
Vol 129 (1) ◽  
pp. 35-NP ◽  
Author(s):  
S. Francavilla ◽  
G. Cordeschi ◽  
G. Properzi ◽  
L. Di Cicco ◽  
E. A. Jannini ◽  
...  
Keyword(s):  
Germ Cells ◽  
Sertoli Cells ◽  
Serum Levels ◽  
Seminiferous Tubules ◽  
Testicular Development ◽  
Postnatal Life ◽  
Fetal Life ◽  
Newborn Rats ◽  
Total Thyroxine ◽  
Delayed Maturation

ABSTRACT The relationship between thyroid function and testicular development in the rat was investigated. Hypothyroidism was induced during fetal or postnatal life by adding methimazole (MMI) to the drinking water of pregnant or lactating mothers. A group of newborn rats was treated with MMI and i.p. injections of l-tri-iodothyronine (l-T3). Hypothyroidism was shown by the reduced serum levels of total T3 and of total thyroxine (T4) in pregnant mothers and in pubertal rats. Testes were studied using light microscopy at 18 and 21 days post coitum or during puberty (21, 35 and 50 days after birth); serum levels of gonadotrophins were also evaluated in pubertal rats. Hypothyroidism had no effect on testicular development during fetal life and when induced in newborn rats it was associated at puberty with reduced serum levels of FSH and LH and with delayed maturation of the testis compared with control rats. The delay in maturation consisted of a reduction in the diameter of seminiferous tubules, and a reduction in the number of germ cells per tubule; this was associated with increased degeneration and arrested maturation of germ cells. In addition, Sertoli cells demonstrated retarded development, as indicated by a delay in the appearance of cytoplasmic lipids and in the development of a tubule lumen. Hormonal and morphological abnormalities were absent in rats treated with MMI plus l-T3. In conclusion, hypothyroidism occurring soon after birth caused reduced levels of gonadotrophins in the serum and a delay in pubertal spermatogenesis, possibly due to retarded differentiation of the Sertoli cells. Journal of Endocrinology (1991) 129, 35–42

scholarly journals Endocrine and molecular influences on testicular development in Meishan and White Composite boars

2003 ◽  
Vol 178 (3) ◽  
pp. 405-416 ◽  
Author(s):  
SA McCoard ◽  
TH Wise ◽  
JJ Ford
Keyword(s):  
Thyroid Hormone ◽  
Sertoli Cells ◽  
Plasma Concentrations ◽  
Testicular Development ◽  
Postnatal Life ◽  
Morphological Development ◽  
Fetal Life ◽  
Early Maturation ◽  
Protein Levels ◽  
Inhibin Subunits

The aim of this study was to evaluate developmental changes in thyroid hormone and other key endocrine hormones/molecular markers produced by testicular cells, in relation to breed differences in proliferation and maturation of Sertoli cells and general testicular morphological development in Meishan (MS) and White Composite (WC) boars. Blood samples and testes were collected on days 60, 75, 90 and 105 post coitum (dpc) and days 1, 7, 14 and 25 post partum (dpp). Testes were immunostained for thyroid hormone receptor-beta1 (THRbeta1), GATA4, Mullerian-inhibiting substance (MIS), 17-alpha-hydroxylase (P450(c17)) and inhibin subunits (alpha, betaA, betaB). In addition, protein levels were determined by densitometry. Plasma concentrations of free triiodothyronine (T(3)) were greater in MS (hyperthyroid) compared with WC (hypothyroid) boars (P<0.01) during fetal life, but the reverse was evident postnatally. Elevated levels of free T(3) during fetal life were associated with increased levels of THRbeta1, suggesting increased thyroid responsiveness of the testis during this time, contrasting with observations during early postnatal life. Localization patterns of THRbeta1, MIS, GATA4 and the inhibin subunits were consistent with previous studies. MIS protein levels declined more rapidly (P<0.001) in MS compared with WC Sertoli cells postnatally, consistent with earlier maturation of Sertoli cells as indicated by our previous study. In this study, transient neonatal hyperthyroidism in MS boars during late gestation was associated with a decline in proliferation and early maturation of Sertoli cells, followed by early onset of puberty in this breed. These observations indicate a possible role for thyroid hormone in the modification of Sertoli cell development, thereby influencing growth and differentiation of the testis in pigs.

Regulation of aromatase expression by 1α,25(OH)2 vitamin D3 in rat testicular cells

2011 ◽  
Vol 23 (5) ◽  
pp. 725 ◽  
Author(s):  
Leila Zanatta ◽  
Hélène Bouraïma-Lelong ◽  
Christelle Delalande ◽  
Fátima R. M. B. Silva ◽  
Serge Carreau
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Vitamin D3 ◽  
Sertoli Cells ◽  
Endocrine System ◽  
Aromatase Gene ◽  
Testicular Cells ◽  
Pka Pathway ◽  
Aromatase Gene Expression

It is well known that the vitamin D endocrine system is involved in physiological and biochemical events in numerous tissues, especially gut, bone and kidney but also testis. Therefore, in this study the effect and mechanisms of action of 1α,25(OH)2 vitamin D3 (1,25D) on aromatase gene expression in immature rat Sertoli cells were evaluated. Vitamin D receptor transcripts were present in immature Sertoli cells as well as in adult testicular germ cells and somatic cells. The treatment of immature Sertoli cells with 100 nM 1,25D increased the amount of aromatase transcript, mainly in 30-day-old rats. The protein kinase A (PKA) blocker, H89, partially inhibited the 1,25D effect. The stimulation of aromatase gene expression in 30-day-old Sertoli cells by the agonist 1α,25(OH)2 lumisterol3, and the suppression of the 1,25D effect by the antagonists 1β,25(OH)2 vitamin D3 and (23S)-25-dehydro-1α (OH)-vitamin D3-26,23-lactone suggested, besides a genomic effect of 1,25D, the existence of non-genomic activation of the membrane-bound vitamin D receptor involving the PKA pathway.

Differentiation of Fetal Sertoli Cells in the Adult Testis

Reproduction ◽  
2021 ◽  
Author(s):  
Tetsuhiro Yokonishi ◽  
Blanche Capel
Keyword(s):  
Sertoli Cell ◽  
Sertoli Cells ◽  
Developmental Process ◽  
Ips Cells ◽  
Cell Maturation ◽  
Seminiferous Tubules ◽  
Fetal Life ◽  
Adult Testis ◽  
Testicular Cells

Sertoli cells proliferate and construct seminiferous tubules during fetal life, then undergo differentiation and maturation in the prepubertal testes. In the adult testes, mature Sertoli cells maintain spermatogonia and support spermatogenesis during the entire lifetime. Although Sertoli-like cells have been derived from iPS cells, they tend to remain immature. To investigate whether Sertoli cells can spontaneously acquire the ability to support spermatogenesis when transferred into the adult testis, we transplanted mouse fetal testicular cells into a Sertoli-depleted adult testis. We found that donor E12.5, E14.5 and E16.5 Sertoli cells colonized adult seminiferous tubules and supported host spermatogenesis two months after transplantation, demonstrating that immature fetal Sertoli cells can undergo sufficient maturation in the adult testis to become functional. This technique will be useful to analyze the developmental process of Sertoli cell maturation, and to investigate the potential of iPS-derived Sertoli cells to colonize, undergo maturation, and support spermatogenesis within the testis environment.

scholarly journals Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood

Reproduction ◽  
2003 ◽  
pp. 769-784 ◽  
Author(s):  
RM Sharpe ◽  
C McKinnell ◽  
C Kivlin ◽  
JS Fisher
Keyword(s):  
Sertoli Cell ◽  
Sertoli Cells ◽  
Cell Cancer ◽  
Abnormal Development ◽  
Fetal Life ◽  
Protein Markers ◽  
Testicular Germ Cell ◽  
Testicular Dysgenesis Syndrome ◽  
Functional Maturation ◽  
Testicular Germ Cell Cancer

Disorders of testicular function may have their origins in fetal or early life as a result of abnormal development or proliferation of Sertoli cells. Failure of Sertoli cells to mature, with consequent inability to express functions capable of supporting spermatogenesis, is a prime example. In a similar way, failure of Sertoli cells to proliferate normally at the appropriate period in life will result in reduced production of spermatozoa in adulthood. This review focuses on the control of proliferation of Sertoli cells and functional maturation, and is motivated by concerns about 'testicular dysgenesis syndrome' in humans, a collection of common disorders (testicular germ-cell cancer, cryptorchidism, hypospadias and low sperm counts) which are hypothesized to have a common origin in fetal life and to reflect abnormal function of Sertoli (and Leydig) cells. The timing of proliferation of Sertoli cells in different species is reviewed, and the factors that govern the conversion of an immature, proliferating Sertoli cell to a mature, non-proliferating cell are discussed. Protein markers of maturity and immaturity of Sertoli cells in various species are reviewed and their usefulness in studies of human testicular pathology are discussed. These markers include anti-Mullerian hormone, aromatase, cytokeratin-18, GATA-1, laminin alpha5, M2A antigen, p27(kip1), sulphated glycoprotein 2, androgen receptor and Wilms' tumour gene. A scheme is presented for characterization of Sertoli-cell only tubules in the adult testis according to whether or not there is inherent failure of maturation of Sertoli cells or in which the Sertoli cells have matured but there is absence, or acquired loss, of germ cells. Functional 'de-differentiation' of Sertoli cells is considered. It is concluded that there is considerable evidence to indicate that disorders of maturation of Sertoli cells may be a common underlying cause of human male reproductive disorders that manifest at various life stages. This recognition emphasizes the important role that animal models must play to enable identification of the mechanisms via which failure of proliferation and maturation of Sertoli cells can arise, as this failure probably occurs in fetal life.

scholarly journals High Radiosensitivity of Germ Cells in Human Male Fetus

2007 ◽  
Vol 92 (7) ◽  
pp. 2632-2639 ◽  
Author(s):  
Romain Lambrot ◽  
Hervé Coffigny ◽  
Catherine Pairault ◽  
Charlotte Lécureuil ◽  
René Frydman ◽  
...  
Keyword(s):  
Germ Cells ◽  
Sertoli Cells ◽  
Specific Inhibitor ◽  
Genotoxic Stress ◽  
First Trimester ◽  
Fetal Life ◽  
Mrna Levels ◽  
Γ Irradiation ◽  
P53 Pathway ◽  
Induced Apoptosis

Abstract Context: Germ cells formed during human fetal life are essential for fertility of the adult, and several studies have described an increasing frequency of male reproductive disorders, which may have a common origin in fetal life and which are hypothesized to be caused by endocrine disruptors. However, factors inducing a genotoxic stress may also be implicated. Objectives: We investigated the effect of γ-irradiation on the functions of human fetal testis during the first trimester of gestation by using an organ culture system. Then we focused on the role of the p53 pathway in the observed effects. Results: Germ cells were highly sensitive to irradiation even at doses as low as 0.1 and 0.2 Gy. Indeed, for these doses, one third of germ cells died by apoptosis. Other germ cells were blocked in their cycle, but no repair seemed to occur, and longer culture with the highest dose used showed that they were destined to die. Sertoli cells were less affected, although their proliferation and the level of anti-Müllerian hormone were reduced. Irradiation had no effect on testosterone secretion or on the expression of steroidogenic enzymes by Leydig cells. After irradiation, p53 phosphorylated on serine 15 was detected from 1–24 h in all cell types. This activation of p53 was accompanied by an increase in mRNA levels of proapoptotic factors Bax and Puma, whereas that of antiapoptotic Bcl-2 remained unchanged. P21, which is responsible for cell cycle arrest, was also up-regulated 6, 30, and 72 h after irradiation. Finally, when we added pifithrin-α, a specific inhibitor of p53 functions, a significant decrease in irradiation-induced apoptosis in both germ and Sertoli cells was observed, indicating the involvement of the p53 pathway in irradiation-induced apoptosis. Conclusions: This study demonstrated here for the first time the great sensitivity of human fetal germ cells to genotoxic stress caused by ionizing radiation.

Inactivation of Wt1 causes pre-granulosa cell to steroidogenic cell transformation and defect of ovary development†

2020 ◽  
Vol 103 (1) ◽  
pp. 60-69
Author(s):  
Changhuo Cen ◽  
Min Chen ◽  
Jingjing Zhou ◽  
Lianjun Zhang ◽  
Shuguang Duo ◽  
...  
Keyword(s):  
Granulosa Cell ◽  
Granulosa Cells ◽  
Sertoli Cells ◽  
Cell Transformation ◽  
Ovary Development ◽  
Marker Genes ◽  
Cell Marker ◽  
Lineage Specification ◽  
Steroidogenic Cell ◽  
Steroidogenic Cells

Abstract Wt1 gene encodes a nuclear transcription factor which is specifically expressed in ovarian granulosa cells and testicular Sertoli cells. Our previous studies demonstrated that Wt1 is required for the lineage specification of supporting cells and inactivation of Wt1 results in Sertoli cells to Leydig-like cells transformation. To test whether Wt1 is also involved in lineage maintenance of granulosa cells during ovary development, Wt1 was specifically deleted in pre-granulosa cells using Foxl2-cre. We found that the female Wt1−/flox; Foxl2-cre mice were infertile with atrophic ovaries and no growing follicles with multiple layers of granulosa cells were observed. A large number of 3β-HSD-positive steroidogenic cells were detected in ovaries of Wt1−/flox; Foxl2-cre mice during embryonic stage and these cells were derived from Foxl2-expressing pre-granulosa cells. The quantitative results showed the expression of granulosa cell marker genes (Foxl2, Follistatin) was downregulated and steroidogenic cell marker genes (3β-HSD, Cyp11a1, Star and Sf1) was dramatically increased in Wt1−/flox; Foxl2-cre ovaries. We also found that the meiosis of germ cells in Wt1−/flox; Foxl2-cre ovaries was delayed but not arrested. This study demonstrates that Wt1 is required for lineage maintenance of granulosa cells and inactivation of Wt1 results in pre-granulosa cells to steroidogenic cells transformation which in turn causes the defect of ovary development.

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