Characteristics of Secondary, Primary, and Compensated Hypogonadism in Aging Men: Evidence from the European Male Ageing Study

Tajar, Abdelouahid; Forti, Gianni; O'Neill, Terence W; Lee, David M.; Silman, Alan J.; Finn, Joseph D.; Bártfai, György; Boonen, Steven; Casanueva, Felipe F.; Giwercman, Aleksander; Han, Thang S.; Kula, Krzysztof; Labrie, Fernand; Lean, Michael E. J.; Pendleton, Neil; Punab, Margus; Vanderschueren, Dirk; Huhtaniemi, Ilpo; Wu, Frederick C. W.

doi:10.1210/jc.2009-1796

Cited by 528 publications

(556 citation statements)

References 39 publications

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“…defined as normal/reduced blood testosterone in the face of elevated LH and thus, an altered LH to testosterone ratio (7,60). Because adult Leydig cells develop from the stem cells, this finding implies that the stem cells are modified functionally as well as numerically because of reduced fetal androgen exposure, and this ultimately translates in adulthood into compromised steroidogenesis.…”

Section: -Hsd3mentioning

confidence: 99%

“…This suggested connection has widespread implications, because one in six young men in northern European countries has a low sperm count (<20 million/mL) (68), and testosterone levels in men of all ages are declining (4-6). Moreover, it has implications for morbidities associated with aging and the aging-related decline in testosterone levels (3,(7)(8)(9)69), because ∼10% of aging men exhibit compensated Leydig cell failure (7). Our findings also provide a pathway through which fetal growth/birth weight could influence testosterone levels in adult men (13), because no explanation for this association is currently available.…”

Section: -Hsd3mentioning

confidence: 99%

“…Large studies from the United States (4) and Europe (5,6) also show that testosterone levels in men of all ages are declining with later year of birth. Aging is itself associated with declining testosterone levels and a high incidence of primary/compensated hypogonadism (7)(8)(9). Because low testosterone levels are also associated with generalized proinflammatory changes (10,11), frailty, and risk of dying in aging men (12), what determines an adult man's testosterone level is of fundamental importance.…”

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confidence: 99%

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Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Kilcoyne

Smith

Atanassova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

160

135

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Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk.adult Leydig stem/progenitor cells | compensated Leydig cell failure | GATA4 | ethane dimethane sulfonate

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Section: -Hsd3mentioning

confidence: 99%

Section: -Hsd3mentioning

confidence: 99%

mentioning

confidence: 99%

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Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Kilcoyne

Smith

Atanassova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

160

135

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“…According to EMAS (172), total T concentrations <8 nmol/L (230 ng/ dL) confirms the diagnosis of LOH; if total T is between 8 and 11 nmol/L (230-320 ng/dL), free T <220 pmol/L (63.5 pg/mL) supports the diagnosis. A novel diagnostic entity is that of compensated hypogonadism, defined as low normal T (>10.4 nmol/L-300 mg/dL) and elevated LH concentrations (>9.4 IU/L) (173). Proper classification of LOH and exclusion of other causes of hypogonadism in the aging male is established through history, clinical evaluation (digital rectal examination) and additional laboratory (hematocrit (Ht), prostate-specific antigen (PSA), follicle-stimulating hormone (FSH), prolactin, SHBG, ferritin and drug screen) and imaging studies (pituitary MRI, bone densitometry), as needed.…”

Section: Late-onset Hypogonadismmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Aging and anti-aging: a Combo-Endocrinology overview

Diamanti-Kandarakis

Dattilo²,

Macut

et al. 2017

European Journal of Endocrinology

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Aging and its underlying pathophysiological background has always attracted the attention of the scientific society. Defined as the gradual, time-dependent, heterogeneous decline of physiological functions, aging is orchestrated by a plethora of molecular mechanisms, which vividly interact to alter body homeostasis. The ability of an organism to adjust to these alterations, in conjunction with the dynamic effect of various environmental stimuli across lifespan, promotes longevity, frailty or disease. Endocrine function undergoes major changes during aging, as well. Specifically, alterations in hormonal networks and concomitant hormonal deficits/excess, augmented by poor sensitivity of tissues to their action, take place. As hypothalamic-pituitary unit is the central regulator of crucial body functions, these alterations can be translated in significant clinical sequelae that can impair the quality of life and promote frailty and disease. Delineating the hormonal signaling alterations that occur across lifespan and exploring possible remedial interventions could possibly help us improve the quality of life of the elderly and promote longevity.

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“…While primary and compensated hypogonadism are a concomitant problem of aging, secondary hypogonadism may be correlated to obesity and such other, above-mentioned risk factors. 21 Studies evaluating the basis of age-dependent changes in T levels have identified pathophysiological dysfunctions to be central, at the hypothalamo-pituitary axis, 8 together with secondary changes in the testes, 22 In a step-wise pattern, hypothalamic dysfunction will lead to downregulation of the anterior pituitary and decline in the levels of gonadotropins and T. 8 In contrast to primary testicular failure due to gonadal pathology, the continued aromatisation to E 2 and the gonadotropin-suppressant effect of E 2 would modulate the ratio of free T to E 2 , 23,24 accompanied by further decrements in luteinizing hormone, follicle-stimulating hormone and T levels, 8 and contribute to the age-related alterations in E 2 /T ratio and the decline of serum T levels.…”

Section: Endogenous Cross-talk With Oestrogenmentioning

confidence: 99%

Endocrine milieu and erectile dysfunction: is oestradiol–testosterone imbalance, a risk factor in the elderly?

Srilatha

Adaikan²

2011

Asian J Androl

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Oestrogens are not exclusive to the female gender but occur in moderate circulating levels of 25-70 pg ml 21 in men, compared to 44-153 pg ml 21 in women. Arising from aromatisation of testosterone (T), oestrogen is considered to have many opposing physiological functions and the progressive T decline in the aging male is associated with relative and/or absolute increase in serum oestradiol (E 2 ). Sexual disinterest and erectile dysfunction (ED) in the elderly may well be due to pathophysiological E 2 -T imbalance; the altered hormonal ratio may also explain the higher incidence of ED in hyperestrogenism or following exposure to environmental/plant oestrogens. Keywords: aging; erectile dysfunction; hormone imbalance; oestradiol; phytoestrogen; testosterone INTRODUCTIONThe last two decades have witnessed the change in the scientific outlook of erectile dysfunction (ED) which is now regarded as a multifactorial and predominantly an organic disorder. Since the erectile process is a coordinated function with neurologic, vascular, endocrine and ionic inputs, successful therapeutic outcome for ED envisages recognition and delineation of the precipitating causes. An important premise is the increased prevalence of ED with aging 1 coupled with the possibility that the present population of men older than 65 years will double by the year 2025. 2 ED in the elderly is a pertinent clinical issue.Aging is associated with a number of comorbid conditions and risk factors for ED, including central and peripheral nervous system disorders, cardiovascular dysfunctions and side-effect profile of prescription medications. In addition to the wide range of general physical complaints in the elderly, it is imperative to address age-related affective alterations arising possibly from hormonal and lifestyle adjustments. 3 With the multifactorial symptoms and evidence for the missing correlation of testosterone (T) levels in the clinical features of hypogonadism, 4 further complexities have to be considered. For instance, not all aging males present with sexual deterioration and in some, a non-hormonal background to the precipitating conditions affecting sexuality may coexist. These include depression, fragility, decreased vitality, endothelial dysfunction, chronic diseases, cancer, incontinence, cognitive impairment and concurrent problems of the aging partner. At the cellular level too, decreased expression and activation of endothelial nitric oxide (NO) synthase with aging and the subsequent blunting of the physiological actions of NO, may have a non-hormonal basis. Therefore, caution should be used while associating hormonal, particularly oestradiol (E 2 )-T imbalance, to ageassociated ED.Nevertheless, steroid hormone secretion conforms to overall health status in men and understanding the dynamics of endocrine

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Characteristics of Secondary, Primary, and Compensated Hypogonadism in Aging Men: Evidence from the European Male Ageing Study

Cited by 528 publications

References 39 publications

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

MECHANISMS IN ENDOCRINOLOGY: Aging and anti-aging: a Combo-Endocrinology overview

Endocrine milieu and erectile dysfunction: is oestradiol–testosterone imbalance, a risk factor in the elderly?

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