Andropause

Testosterone levels fall with advancing age; at 40 years of age 1-2% of men have low (bioavailable) testosterone levels; by age 60, that percentage has increased to 20%.

95% of testosterone is manufactured in the testes; the remaining 5% is produced in the adrenal glands. Most of the hormone is tightly bound to a large carrier protein, called sex hormone binding globulin (SHBG), and is unable to enter the cells to exert its metabolic effect; a small percentage is bound to a much smaller protein, called albumin, and a still smaller amount is unattached or free. This fraction, plus the testosterone bound to albumin, is collectively known as bioavailable testosterone, and this is what we are interested in measuring. A person may have normal total levels of testosterone, but have high levels of SHBG, therefore very little bioavailable testosterone, and so be symptomatic…Bioavailable levels can be determined by blood or saliva testing.

When checking levels of bioavailable testosterone, we may also measure DHEA, which is an androgen precursor, manufactured in the adrenal gland, and cortisol which is the main stress hormone, and is also produced in the adrenals.

Cortisol is a catabolic hormone-it breaks down muscle and bones, elevates blood sugar and leads to fat deposition ie it has the opposite effect to testosterone, which is an anabolic hormone, which builds muscle and strengthens bones via a stimulating effect on osteoblasts, decreases insulin resistance and lowers blood glucose levels. They compete for the same receptor sites.

We may also check levels of the hormones Estradiol and DHT (Dihydrotestosterone) which are produced by metabolism of testosterone ( see section below)

• Age – related decline in production
• Too much SHBG. Causes of high SHBG- liver disease, excessive  alcohol intake, high E2 or xenoestrogens; low HGH (Growth hormone)or thyroid hormone
• High conversion rate to estradiol (E2): see below
• Stress: elevated levels of cortisol  increase abdominal obesity, insulin resistance and heightened aromatase activity ( ie increases the conversion of testosterone to estradiol); cortisol also competes with testosterone for receptor sites and blocks its effects, causing a functional deficiency.

Testosterone is metabolized to Estradiol via the aromatase enzyme, and to dihydrotestosterone (DHT), via the 5-alpha-reductase enzyme.Some of the problems that can arise as a result of  conversion of testosterone to each of these metabolites are described below.

Excess conversion of testosterone to estradiol (estrogen dominance) can lead to gynaecomastia (enlargement of breast tissue), muscle loss, and may be a causative factor in prostate cancer.  The dietary supplements Chrysin, Zinc, and indole3 carbimole (I3C) slow this conversion, as do the class of drugs known as aromatase inhibitors. A small dose of progesterone will counter the effects of excess estrogen.  Aromatase is present in fat cells , so losing weight may also help to lower estrogen production. The ratio of testosterone to estrogen is important, and should ideally be between 20-40.  Too low a ratio is a risk for prostate cancer.

High levels of DHT can be associated with hair loss and BPH (benign prostatic hypertrophy); a herbal treatment is saw palmetto, or the drugs Finasteride or Dutasteride can be used to oppose the action of 5- alpha reductase enzyme. DHT also binds to receptor sites, blocking the action of testosterone.

Low testosterone levels lead to increased BMI (body mass index) increased waist circumference and insulin resistance, higher fasting blood sugars, elevated LDL cholesterol and triglycerides, low HDL, (metabolic syndrome)… which is a risk for cardiovascular disease.  The combination of high cortisol or high estradiol levels and low testosterone further increases this risk .

Testosterone dilates coronary vessels, improves angina, and improves cardiac output; higher levels of testosterone are associated with lower systolic blood pressure, improved cerebral blood flow, and  improvements in memory and cognitive function , even in early Alzheimer’s disease.

Testosterone replacement does not cause prostate cancer; the incidence of prostate cancer rises with age, just as testosterone levels fall with age; in fact, the combination of low testosterone and high estradiol or low growth hormone, seems to be associated with a higher risk of developing prostate cancer. Estrogen dominance is associated with the oncogene BCL2; whereas progesterone and testosterone produce a protector gene p53

Testosterone replacement therapy has not been associated with increased symptoms of BPH (benign prostatic hypertrophy).Prostatic hypertrophy is affected by  estrogen; also DHT has a stimulating effect on prostate cells.

However, testosterone therapy is contra-indicated in established prostate cancer, as it may accelerate the growth of the cancer: therefore before commencing TRT, one should have a DRE (digital rectal exam) and a PSA test- with free PSA and transrectal Ultrasound if PSA is over 2.5., to investigate the possibility of pre-existent prostate cancer, which would be a contra-indication for TRTx; and once testosterone replacement therapy is started,we would normally repeat the PSA every 6 months, and do a free/total PSA ratio , transrectal ultrasound, or prostate biopsy, if the levels are rising.

Erectile Dysfunction ( the ability to get or maintain an erection)may be  caused by

• Peripheral vascular disease- ie arteriosclerosis of the vessels supplying blood flow to the penis- risk factors hypertension, hyperlipidaemia, diabetes, smoking. LeRiche syndrome- arteriosclerosis of the iliac blood vessels- presents as hip pain when walking and erectile dysfunction.  Conversely,the presence of erectile dysfunction can be the first clue to the presence of widespread vascular disease and a heightened risk of heart attack and stroke.
• Neurological disorders- eg spine or sacral plexus lesions. Diabetes can cause microvascular, macrovascular, and peripheral neurological problems.Pelvic surgery or trauma, can damage crucial nerves
• Side effect of medications- many commonly prescribed medications, eg some antihypertensives , anti -depressants, anti-anxiety drugs,anti- epileptics, anti- Parkinson drugs, drugs for prostate cancer, and even anti histamines and H 2 blockers ( used for acid suppression) can cause erectile dysfunction
• Low testosterone levels
• Chronic disease such as cirrhosis, renal failure, diabetes( see above)
• Heavy intake of alcohol, and abuse of some recreational drugs – inc marijuana,  amphetamines, opiates,. cocaine- can lead to impotence
• Psychological problems, relationship issues, and chronic stress or depression, can be a factor

• Drugs such as Cialis, Levitra, and Viagra. These are vasodilating drugs which improve blood flow to the penis, and  should be obtained only by prescription following a medical assessment to rule out the above underlying causes of impotence, never just over the internet. It is vital to NEVER COMBINE THESE DRUGS WITH NITRATES, eg sublingual nitroglycerin, oral isosorbide dinitrate, as this can lead to a FATAL PRECIPITOUS DROP IN BLOOD PRESSURE.
• If there is documented evidence of low testosterone, testosterone replacement therapy may be of value. Bioavailable levels should be checked, as total testosterone may be normal, but bioavailable levels low in the presence of high sex hormone binding globulin. If bioavailable levels are in the low normal range, a trial of TRT is in order to bring the levels to mid or upper range of normal
• Quit smoking, alcohol, and other recreational drugs. Alcohol will increase the metabolism of testosterone to estrogen, and you will end up with gynaecomastia ( breast enlargement) as well as impotence. Smoking will cause arteriosclerosis and constriction of the blood vessels to the penis; and other recreational drugs will have central nervous system side effects.
• Discuss your current medication regimen with your family doctor It could be that ED is  caused by a prescription or over-the-counter medication that you are taking, and a substitute with less sexual side effects could be prescribed. (Do not stop any of your medications without discussing it first).It could also be that optimizing your control of diabetes, hypertension or other medical conditions , could result in resolution of the problem.
• Try to minimize your stressors , and seek counselling for mood disorders or relationship problems. Chronic stress diverts steroid hormone synthesis away from the production of sex hormones towards production of the adrenal stress hormone, cortisol- leading to diminished libido (sex drive), increased metabolism of testosterone to estradiol, and competition  for hormone binding sites on cells, resulting in a functional testosterone deficiency. In addition , high levels of performance anxiety may lead to a viscous cycle of  ongoing sexual dysfunction.
• If all else fails, a penile prosthesis can be surgically implanted

These can be either rigid or inflatable.

Testosterone is available in oral, injectable or transdermal ( cream, gel or patch ) form. It is also available in  S/C pellets/implants.

• Oral testosterone is toxic to the liver, and is generally avoided; but sublingual forms of testosterone can be administered as an occasional boost prior to  sex, exercise, or  when intense mental effort is required. The effect is rapid in onset , but over quickly, so this is not a suitable form of chronic supplementation.
• Intramuscular injections of testosterone cyprionate are administered weekly; this route of administration if often associated with peaks (when it is metabolized to estradiol) and troughs, when the symptoms of low testosterone recur; one way to get around this is by administering smaller doses twice weekly as a subcutaneous injection.
• Testosterone pellets can be implanted subcutaneously, for sustained even release of testosterone over a 3-6 month period, but this is more expensive route of administration, and does not allow for dosage adjustment.
• Daily transdermal administration allows for more even release of the hormone , but is also associated with increased conversion to DHT  (with possible hair loss) Options include Androderm patches,  Androgel and Testim gels, and bioidentical testosterone cream. Creams /gels should be applied to hairless skin at the back of the neck or forearm, or rubbed into the shoulders , upper arms or flanks.  avoid applying to the scrotum, because of increased conversion to DHT, and avoid transference of the gel to females  by skin  contact (hirsuitism)

Note: Exogenous testosterone  can  temporarily, or even permanently, suppress  a man’s natural production of the hormone, and cause testicular atrophy, leading to low or zero sperm counts. Men under 45 years age, or those wishing to retain their fertility, can in the majority of cases, experience an increase in testosterone levels  by taking Clomiphene pills, or by Human Chorionic Ganadatrophin injections.

Clomiphene is an estrogen/testosterone receptor blocker in the hypothalamus and pituitary glands. It is administered in pill form on alternate days, and will result in a surge in LH (luteinizing hormone) with a subsequent rise in testosterone production in about 80% men.

Human Chorionic Ganadatrophin is chemically similar to LH, and directly stimulates the Leydig cells in the testes to produce testosterone and it is associated with an 80% response rate in men of all ages. It can also be used to preserve sperm production and fertility on young men on TRT, see link to study –http://www.ncbi.nlm.nih.gov/pubmed/23260550.

It can even be administered initially  with the weekly IM testosterone injections, by subcutaneous injections twice weekly, or even cycled every few months to reduce testicular shrinkage.

Prior to starting TRT,  the patient should have  a physical exam including a DRE for prostatic enlargement or nodules; bioavailable levels of testosterone and other hormones should be checked, as well as initial PSA levels –  a level above 2.5 should entail further assessment ie free/total PSA ratio, transrectal ultrasound etc to rule out prostatic cancer prior to commencing therapy.

When administering IM testosterone, one would expect an increase in libido within 1-2 weeks; gels/creams will take longer 4-8 weeks; if there is no response, bioavailable levels of the hormone should be rechecked , along with the metabolites estradiol and DHT, and the dose adjusted upwards as required.

Sometimes the addition of 25-50mgs DHEA can be effective in stimulating the sex drive. If no response is seen with gels or cream, a switch to IM testosterone is an option, or adding Human Chorionic Gonadotrophin injections .

Adrenal hormones can be checked; if cortisol is high ( stress) this will compete  for binding sites with testosterone, and diminish the effect; also adrenal fatigue (see separate section) can cause chronic fatigue, and loss of libido.

High Estradiol levels -( breast enlargement, prostatic enlargement with decreased urinary flow)- can be treated with the supplements DIM or Indole 3 Carbimole, or prescription aromatase inhibitors in small doses 2-3 times a week; elevated DHT , by Zinc or saw palmetto supplements, progesterone cream, or  if associated with hair loss, Finasteride or Dutasteride ( 5-alpha – reductase inhibitors).

Other routine monitoring tests- CBC – occasionally TRT can be associated with a rise in red blood cells – polycythaemia, LFTs ( liver tests) and, of course,regular PSA levels.