Age and the Regula-on of Testosterone Synthesis

Transcription

1 Sensitivity to T Feedback GNRH Oestrogens GH Mean LH Pulse Amplitude Age and the Regula-on of Testosterone Synthesis DHEA Testicular Degeneration Modified from Nussey,S.S., Whitehead, S.A. 2001

2 Actions of Testosterone on Cell Differentiation and Activity Neural Progenitor Cell Neurone Testosterone Deficiency Carruthers, Trinick, Jankowska, Traish 2007

3 Links between adipocytes and diseases making up the metabolic syndrome. Carruthers, Trinick, Jankowska, Traish 2007 Testosterone Deficiency Promotes Adipocyte Produc-on and Ac-vity Axis of Evil

4 Alcohol Testosterone Related Effects Binge drinking Las-ng damage due to acetaldehyde and LHRH Increased E2 produc-on Phyto-estrogens Increased adipose -ssue Increased T-resistance to stress (cor-sol, PRL and Catecholamines) Raised FFA Pancrea-c Damage Acute and chronic pancrea--s Most common in men age Raises blood sugar but can also cause hypoglycaemia.

5 Heredity Gene-cs and T-Resistance Steroid hormone receptor superfamily - includes anabolic steroids hormone binding and DNA-binding domains similar but n-terminal domain is different Variations in CAG and GGN domains Gene-cs and Insulin Resistance Steroid hormone receptor superfamily includes glucocorticoids hormone binding and DNA-binding domains similar but n-terminal domain is different.

6 AR Polymorphism Conclusions Gene-c muta-ons in the androgen receptor have been shown to affect genital development, prostate -ssue, spermatogenesis, bone density, hair growth, cardiovascular risk factors, psychological factors, and even testosterone levels. As in diabetes mellitus, in the regula-on of androgen ac-on, it is a balance between hormone levels and -ssue sensi-vity or resistance that decides whether homeostasis is maintained or dysfunc-on results. Minor varia-ons in the AR gene can have major consequences in deciding the structure and func-on of androgen responsive -ssues throughout life. Gene-c, racial and individual varia-ons in androgen resistance can render even the most accurate measurements of androgen and gonadotrophin levels in the blood largely irrelevant in deciding whether or not a par-cular pa-ent is androgen deficient, and would benefit from testosterone treatment. Glutamine-Proline-Glycine

7 Stress Stress and Testosterone Wide variety of stresses shown to reduce Testosterone. Stress hormones such as cor-sol, catecholamines, and prolac-n oppose testosterone ac-on Stress and Diabetes Cor-sol and adrenaline raise glucose. Noradrenaline raises FFA and cholesterol levels. Stress related anxiety can raise weight by increasing alcohol and carbohydrate intake.

8 Xeno-Estrogens and An--Androgens There is currently concern about environmental influences on fer-lity, par-cularly in rela-on to xeno-estrogens and an--androgens. We need to consider the evidence in rela-on to the impact of such hormonal havoc on endocrine balance in both the developing male foetus, and in men throughout their lives. Many agro-chemicals are shown to have estrogenic or an--androgen effects, eg DDT

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10 Infec-ons Tes-s Mumps, mainly post-pubertal. An autoimmune condi-on triggered by a failure of the undeveloped immune defences of the testes, causes further persistent damage. Other viruses such as glandular fever can also cause autoimmune damage. Severe orchi-s from any cause can also cause damage. Pancreas 'one or more immuneresponse genes associated with HLA-A8 and/or W15 might be responsible for an altered T-lymphocyte response. The gene-cally determined host response could fail to eliminate an infec-ng virus (eg Coxsackie B4 and others) which in turn might destroy the pancrea-c beta-cells or trigger an autoimmune reac-on against the infected organ'.

11 Changes in Tes-s in TDS Compensatory hypertrophy of the Leydig cells is seen in some infertile men. Leydig cell micronodules were associated with significantly increased total Leydig cell volume, and showed evidence of functional Leydig cell failure, shown by vacuolisation and a decreased T/Leydig cell volume ratio. The T/LH and T/FSH ratios were also significantly decreased, indicating impaired testicular function at the endocrine as well as the spermatogenic level (Holm,M. et al, J. Pathol 2003:199: ) Vasectomy was also originally undertaken in the 1920 s to promote hypertrophy of the aging Leydig cells (Freud) An interesting example of experimental autoimmunity

12 Changes in Pancreas in Diabetes Type 2 diabetes can be associated with raised and then lowered insulin levels, combined with insulin resistance. This is due to failure of beta-cell compensatory hypertrophy or hyperplasia. Prolonged stimulation of the beta-cells depletes the insulin granule stores, and causes amyloid deposition in the islets (glucotoxicity). Beta-cells are unable to secrete pulses of insulin and become blind to changes in glucose concentration. Hyperglycaemia also contributes to insulin resistance as a result of down-regulation (decreased numbers of GLUTS) in peripheral tissues.

13 Insulin Resistance and Diabetes 70 years ago Sir Harold Himsworth devised a standardised insulin glucose tolerance test, the forerunner of modern glucose insulin clamp techniques, and used this to distinguish between insulin-sensitive and insulin-insensitive types of diabetes. He also noted the association of obesity, hypertension and arteriosclerosis with insulin-insensitive diabetes. Sir Harold Himsworth MD FRS ( ) Himsworth HP (1939) Mechanism of diabetes mellitus (The Goulstonian Lectures). Lancet 65:

14 Measuring Testosterone Resistance A Therapeu-c TRIal Testosterone Resistance Index In pa-ents with AMS Total score in Moderate (37-49) and Severe Ranges (>50): If Total Testosterone < 15nmol/l (430ng/dl) - Give Usual Testosterone Treatment If in range of nmol/l (860ng/dl) give IG Testosterone Undecanoate Injec-on (Nebido), followed by usual TRT. Testosterone Resistance Index = 10/Number of weeks symptoms are relieved. Eg Low Resistance - Injec-on lasts 10 weeks TRI 1.0 High Resistance Injec-on lasts 5 weeks TRI 2.0

15 Conclusions and Treatment Testosterone Deficiency Diagnose on clinical history and symptoms TRT usually needed to start recovery Lifestyle modifica-on: Weight loss, exercise Stress reduc-on, eg medita-on Drug reduc-on or change Treat co-existent diabetes Type 2 Diabetes Be aware of symptoms of TDS Insulin enhancers eg me`ormin usually needed Lifestyle modifica-on: Weight loss, exercise Stress reduc-on, eg medita-on Drug reduc-on or change Treat complica-ons with testosterone

16 Syndrome-Y Because of similar causa-on and co-existence of resistance to these two hormones in metabolic syndrome, it is suggested that this may be new facet of the condi-on which with its associa-on with the male chromosome could be re-named as Syndrome-Y.