Biomarkers of male hypogonadism in childhood and adolescence

AbstractObjectivesThe objective of this review was to characterize the use of biomarkers of male hypogonadism in childhood and adolescence.ContentsThe hypothalamic-pituitary-gonadal (HPG) axis is active during fetal life and over the first months of postnatal life. The pituitary gland secretes follicle stimulating hormone (FSH) and luteinizing hormone (LH), whereas the testes induce Leydig cells to produce testosterone and insulin-like factor 3 (INSL), and drive Sertoli cells to secrete anti-Müllerian hormone (AMH) and inhibin B. During childhood, serum levels of gonadotropins, testosterone and insulin-like 3 (INSL3) decline to undetectable levels, whereas levels of AMH and inhibin B remain high. During puberty, the production of gonadotropins, testosterone, and INSL3 is reactivated, inhibin B increases, and AMH decreases as a sign of Sertoli cell maturation.Summary and outlookBased on our knowledge of the developmental physiology of the HPG axis, these biomarkers can be used in clinical practice to interpret the physiopathology of hypogonadism. Additionally, these markers can have diagnostic value in different forms of hypogonadism that may appear during childhood and adolescence.

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

Journal of Endocrinology ◽

10.1677/joe.0.1290035 ◽

1991 ◽

Vol 129 (1) ◽

pp. 35-NP ◽

Cited By ~ 70

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

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Antagonistic Effects of Testosterone and the Endocrine Disruptor Mono-(2-Ethylhexyl) Phthalate on INSL3 Transcription in Leydig Cells

Endocrinology ◽

10.1210/en.2008-0310 ◽

2008 ◽

Vol 149 (9) ◽

pp. 4688-4694 ◽

Cited By ~ 49

Author(s):

Éric Laguë ◽

Jacques J. Tremblay

Keyword(s):

Androgen Receptor ◽

Leydig Cells ◽

Endocrine Disruptor ◽

Testicular Descent ◽

Postnatal Life ◽

Fetal Life ◽

Mrna Levels ◽

Androgen Response Element ◽

Ethylhexyl Phthalate

Insulin-like 3 (INSL3) is a small peptide produced by testicular Leydig cells throughout embryonic and postnatal life and by theca and luteal cells of the adult ovary. During fetal life, INSL3 regulates testicular descent in males, whereas in adults, it acts as an antiapoptotic factor for germ cells in males and as a follicle selection and survival factor in females. Despite its considerable roles in the reproductive system, the mechanisms that regulate Insl3 expression remain poorly understood. There is accumulating evidence suggesting that androgens might regulate Insl3 expression in Leydig cells, but transcriptional data are still lacking. We now report that testosterone does increase Insl3 mRNA levels in a Leydig cell line and primary Leydig cells. We also show that testosterone activates the activity of the Insl3 promoter from different species. In addition, the testosterone-stimulating effects on Insl3 mRNA levels and promoter activity require the androgen receptor. We have mapped the testosterone-responsive element to the proximal Insl3 promoter region. This region, however, lacks a consensus androgen response element, suggesting an indirect mechanism of action. Finally we show that mono-(2-ethylhexyl) phthalate, a widely distributed endocrine disruptor with antiandrogenic activity previously shown to inhibit Insl3 expression in vivo, represses Insl3 transcription, at least in part, by antagonizing testosterone/androgen receptor action. All together our data provide important new insights into the regulation of Insl3 transcription in Leydig cells and the mode of action of phthalates.

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High normal testosterone levels in infants with non-mosaic Klinefelter’s syndrome

Acta Endocrinologica ◽

10.1530/eje-07-0310 ◽

2007 ◽

Vol 157 (3) ◽

pp. 345-350 ◽

Cited By ~ 50

Author(s):

Lise Aksglaede ◽

Jørgen H Petersen ◽

Katharina M Main ◽

Niels E Skakkebæk ◽

Anders Juul

Keyword(s):

Free Testosterone ◽

Serum Levels ◽

Cross Sectional Study ◽

Inhibin B ◽

Sex Hormone Binding Globulin ◽

Klinefelter’S Syndrome ◽

Limited Information ◽

Klinefelter's Syndrome ◽

Cross Sectional ◽

Hpg Axis

Objective: Klinefelter’s syndrome (KS) is associated with hypergonadotrophic hypogonadism in adulthood. However, limited information exists about the age at which hypogonadism occurs. The hypothalamic–pituitary–gonadal (HPG) axis is transiently activated during the first months of life, offering the opportunity to study testicular function by spontaneous, basal hormone levels. The aim of this study was to evaluate the HPG axis in KS infants. Design: Cross-sectional study. Methods: Ten KS infants aged 3.1 months (range 1.8–3.8) and 613 healthy controls aged 3.0 months (range 2.0–4.5). Serum levels of total and free testosterone (T), LH, FSH, inhibin B and sex hormone-binding globulin (SHBG) were determined. Results: KS infants had significantly higher concentrations of total T (5.0 (2.2–11.2) vs 3.4 (0.7–8.3) nmol/l, P = 0.02), free T (31.6 (18.2–61.8) vs 22.1 (4.3–48.4) pmol/l, P = 0.01), LH (3.3 (1.3–4.6) vs 1.7 (0.6–4.3) IU/l, P = 0.005) and FSH (1.7 (1.1–4.1) vs 1.2 (0.4–3.0) IU/l, P = 0.007) than controls. SHBG and inhibin B did not differ from controls. LH/T and LH/free T ratios were normal, whereas the FSH/inhibin B ratio was elevated (6.5 (2.7–16.9) vs 3.0 (0.78–11.4), P = 0.005) when compared to controls. The majority of KS infants had normal bivariate hormonal combinations. Conclusion: We found increased FSH/inhibin B ratio as a possible sign of Sertoli cell dysfunction. However, serum levels of T were high normal suggesting an altered pituitary–gonadal set point.

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Insulin-like factor 3 as a monitor of endocrine disruption

Reproduction ◽

10.1530/rep-13-0486 ◽

2014 ◽

Vol 147 (4) ◽

pp. R87-R95 ◽

Cited By ~ 26

Author(s):

Ravinder Anand-Ivell ◽

Richard Ivell

Keyword(s):

Leydig Cells ◽

Mammalian Species ◽

Testicular Descent ◽

Fetal Life ◽

Adult Males ◽

Hpg Axis ◽

Testicular Dysgenesis Syndrome ◽

Endocrine Disrupting ◽

Differentiation Status ◽

The Impact

Insulin-like factor 3 (INSL3) is generated and secreted by differentiated interstitial Leydig cells of the testes in both fetal and adult males of all mammalian species so far analyzed. All evidence to date suggests that it is produced constitutively, independently of acute regulation by the hypothalamo-pituitary–gonadal (HPG) axis, in amounts which reflect the numbers and differentiation status of the Leydig cells. This Leydig cell functional capacity is otherwise monitored only by androgen output, which, however, is massively confounded by acute regulation from the HPG axis and other factors leading to substantial and irregular short-term variation. Leydig cells are a primary target of endocrine-disrupting agents in the context of the testicular dysgenesis syndrome in the fetal male, as well as in the adult. In the male fetus, INSL3 is responsible for the first phase of testicular descent, and hence is directly linked to the etiology of cryptorchidism. In this study, by measuring INSL3 production, for example, during fetal life via amniotic fluid, or as secretions from fetal testis explants, or in adult peripheral blood, we and others have shown that INSL3 represents a useful quantitative and sensitive endpoint for assessing the impact of endocrine-disrupting agents and their mechanisms of action.

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Inverse correlation between baseline inhibin B and FSH after stimulation with GnRH: a study of serum levels of inhibin A and B, pro alpha-C and activin A in women with ovulatory disturbances before and after stimulation with GnRH

Acta Endocrinologica ◽

10.1530/eje.0.1430077 ◽

2000 ◽

pp. 77-84 ◽

Cited By ~ 2

Author(s):

FW Casper ◽

RJ Seufert ◽

K Pollow

Keyword(s):

Inverse Correlation ◽

Strong Relationship ◽

Serum Levels ◽

Activin A ◽

Inhibin B ◽

Inhibin A ◽

Before And After ◽

Pituitary Secretion ◽

Objective Interest ◽

A Minor

OBJECTIVE: Interest has focused recently on the influences of the polypeptide factors inhibin and activin on the selective regulation of the pituitary secretion of gonadotropins. DESIGN: Measurement of the concentrations of inhibin-related proteins in relation to the changes in pituitary gonadotropin (FSH, LH) parameters, after GnRH stimulation with a bolus injection of 100 microg gonadorelin, in 19 women with ovulatory disturbances. METHODS: Serum levels of inhibin A and B, activin A, and pro alpha-C were measured using sensitive ELISA kits. RESULTS: Within 60 min after GnRH stimulation, FSH values doubled from 5 to 10 mU/ml (P < 0.001). LH increased 12-fold from 2 to 24 mU/ml (P < 0.001). Activin A showed a significant decrease from 0.47 to 0.36 ng/ml (P < 0.001), whereas pro alpha-C increased from 127 to 156 pg/ml (P = 0.039). The median inhibin A concentration did not show a significant change between baseline and the 60 min value, whereas inhibin B was characterized by a minor, but not significant, increase in the median from 168 to 179 pg/ml (P = 0.408). A significant inverse correlation (P = 0.014) with a mean coefficient of correlation of 0.5516 was found, demonstrating a strong relationship between high inhibin B baseline levels and a small increase of FSH after 60 min. CONCLUSION: Our results show an interesting correlation between the baseline inhibin B and the change in FSH before and after GnRH stimulation. A high baseline inhibin B implies only a minor increase of FSH after 60 min.

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In vivo acute testicular testosterone response to injection of luteinizing hormone in the rat fetus

Acta Endocrinologica ◽

10.1530/acta.0.1280268 ◽

1993 ◽

Vol 128 (3) ◽

pp. 268-273 ◽

Cited By ~ 7

Author(s):

René Habert

Keyword(s):

Plasma Concentration ◽

Luteinizing Hormone ◽

Leydig Cells ◽

Time Dependent ◽

Fetal Life ◽

Dependent Manner ◽

Adult Rats ◽

Rat Fetus ◽

Age Related

The acute in vivo testosterone response to LH stimulation and its change during late fetal life were determined in the rat. In 18.5-day-old fetuses, testicular testosterone content was increased in a dose-and time-dependent manner after fetal subcutaneous LH injection. The maximum response was small: the testicular content and plasma concentration were increased by 200% and 2 50% over basal values respectively, while they were increased 1100% and 1200% in adult rats. Similarly, comparable low responses were obtained after subcutaneously injecting the fetuses with human chorionic gonadotropin (hCG) and after injecting LH into the vitelline vein. Between days 18.5 and 21.5 of fetal life, the testosterone levels in the testis and plasma of uninjected or PBS-injected fetuses decreased and were comparable in both groups. In maximally LH-stimulated fetuses, the testicular content did not change with age, and plasma concentration was lower on day 21.5 than on day 18.5. Since the number of Leydig cells increases 1.5 to 2-fold between days 18.5 and 21.5, these results show an age-related decrease in basal and maximally LH-stimulated in vivo testosterone secretions per Leydig cell during late fetal life.

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Diagnostic Value of Vaginal Microecology, Serum miR-18a, and PD-L1 for Identifying HPV-Positive Cervical Cancer

Technology in Cancer Research & Treatment ◽

10.1177/1533033821995281 ◽

2021 ◽

Vol 20 ◽

pp. 153303382199528

Author(s):

Yumei Zhang ◽

Sujuan Qiu ◽

Yueli Guo ◽

Jiaqin Zhang ◽

Xiaoqing Wu ◽

...

Keyword(s):

Cervical Cancer ◽

Area Under The Curve ◽

Serum Levels ◽

Diagnostic Value ◽

High Serum ◽

Control Group ◽

Observation Group ◽

Positive Group ◽

Microbial Dysbiosis ◽

Programmed Death

Objective: We aimed to investigate the diagnostic value of the vaginal microecology, serum miR-18a, and programmed death ligand-1 (PD-L1) for human papillomavirus (HPV)-positive cervical cancer. Methods: Eighty-four patients with HPV-positive cervical cancer were assigned to the observation group, 107 HPV-positive patients without cervical cancer were assigned to the positive group, and 191 healthy women were assigned to the control group. Vaginal microecology and serum levels of miR-18a and PD-L1 on the surface of CD4+ and CD8+ T cells were compared among the 3 groups. The observation group was further divided into subgroups according to patients’ characteristics for comparison. The diagnostic value of miR-18a and PD-L1 for HPV-positive cervical cancer was investigated. Results: Women in the control group had better vaginal microecology and lower levels of miR-18a and PD-L1 than those in the observation and the positive groups (all P < 0.05). Compared with the positive group, the observation group had similar vaginal microecology (all P > 0.05) but higher levels of miR-18a and PD-L1 (all P < 0.05). Moreover, the patients at stage III had higher levels of miR-18a and PD-L1 than those at stage I and II (all P < 0.05). The values of area under the curve for miR-18a and PD-L1 in the diagnosis of HPV-positive cervical cancer were over 0.8 (all P < 0.001). Conclusion: Patients with HPV-positive cervical cancer have vaginal microbial dysbiosis and high serum levels of miR-18a and PD-L1. miR-18a and PD-L1 have diagnostic value for identifying HPV-positive cervical cancer.

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Impact of Clomiphene Citrate on the Steroid Profile in Dysmetabolic Men with Low Testosterone Levels

Hormone and Metabolic Research ◽

10.1055/a-1542-8763 ◽

2021 ◽

Vol 53 (08) ◽

pp. 520-528

Author(s):

Carla Pelusi ◽

Flamina Fanelli ◽

Margherita Baccini ◽

Giovanni De Pergola ◽

Vincenzo Triggiani ◽

...

Keyword(s):

Clomiphene Citrate ◽

Serum Levels ◽

Male Hypogonadism ◽

Hormonal Changes ◽

Double Blind ◽

Adrenal Steroidogenesis ◽

Steroid Profiling ◽

Corticosteroid Binding Globulin ◽

Before And After ◽

17Β Estradiol

AbstractClomiphene citrate (CC) in male hypogonadism increases testosterone (T) and estrogen levels by stimulating pituitary gonadotropin release. Our group confirmed these hormonal changes in a randomized, cross-over, double-blind trial of CC versus placebo in addition to metformin, conducted in 21 obese dysmetabolic men with low T levels. However, we hypothesize that based on its mechanism of action, CC may directly or indirectly affect adrenal steroidogenesis. The aim of this sub-study was to better understand the changes in steroid levels and metabolism induced by CC treatment. We assessed 17α-hydroxypregnelone (17αOH-P5), dehydroepiandrosterone (DHEA), progesterone (P4), 17α-hydroxyprogesterone (17αOH-P4), androstenedione (A), T, dihydrotestosterone (DHT), estrone (E1), 17β-estradiol (E2), 11-deoxycortisol (11 S), cortisol (F), and cortisone (E) by LC-MS/MS, and corticosteroid binding globulin (CBG) by ELISA, before and after each treatment. In addition, free-F and steroid product/precursor ratios were calculated. We observed a significant change in serum levels induced by CC compared with placebo for 17αOH-P4, DHT, T, E2, E1, F, E, and CBG, but not free-F. In addition, compared to placebo, CC induced higher 17αOH-P4/P4, E2/E1, 17αOH-P4/17αOH-P5, A/17αOH-P4, T/A, E1/A, F/11 S, and F/E ratios. Therefore, besides the CC stimulating effect on testis steroidogenesis, our study showed increased F, E, but not free-F, levels, indicating changes in steroid metabolism rather than adrenal secretion stimulation. The steroid profiling also revealed the CC stimulation of the Δ5 rather than the Δ4 pathway, thus indicating considerable testicular involvement in the increased androgen secretion.

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Short-term regular moderate exercise improved male hypothalamic-pituitary-gonadal axis function via the reduction of hypothalamic neurokinin B expression in adult rats

Physiology and Pharmacology ◽

10.32598/ppj.25.2.20 ◽

2021 ◽

Vol 25 (2) ◽

pp. 171-177

Author(s):

Nazli Khajehnasiri ◽

◽

Homayoun Khazali ◽

Farzam Sheikhzadeh Hesari, ◽

Hamid Reza Sadeghnia ◽

...

Keyword(s):

Molecular Mechanisms ◽

Serum Levels ◽

Moderate Exercise ◽

Short Term ◽

Neurokinin B ◽

Adult Rats ◽

Hpg Axis ◽

Intensive Exercise ◽

Reproductive Axis ◽

Gnrh Neurons

Introduction: In the arcuate nucleus, kisspeptin, neurokinin-B and pro-dynorphin (KNDy) neurons control the function of gonadotropin-releasing hormone (GnRH) neurons. Early investigations indicated that exercise with various intensities affects luteinizing hormone (LH) and testosterone (T) in different ways. Meanwhile the molecular mechanisms underlying its function not yet been fully understood. Accordingly, the present study evaluated the role of alterations in the levels of KNDy mRNA upstream of GnRH neurons in conveying the effects of various short-term exercise intensities on the male hypothermic-pituitary-gonadal (HPG) axis. Methods: Twenty-one adult Wistar rats were randomly divided into 3 groups: control, one-month regular moderate exercise (ME) and one-month regular intensive exercise (IE). In ME (22m/min) and IE (35m/min) groups, the rats were treated 5 days a week for 60min each day. Finally, we assessed serum levels of LH and T using the ELIZA technique and KNDy and Gnrh mRNA expression by the real-time PCR method. Results: The results revealed that in ME group the expression of Nkb was reduced and the expression of Gnrh mRNA and the LH and T serum levels were increased. However, intensive exercise did not change the serum levels of LH and T or the relative expression of kiss1, Nkb, Pdyn and Gnrh genes. Conclusion: The results suggested that monthly moderate exercise improved male reproductive axis function, while intensive exercise did not have an adverse effect on the reproductive axis. These various effects on the male HPG axis may be propagated by the change in hypothalamic Nkb gene expression.

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