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Transcript
Male Sex Hormones and Related Disorders Hormone Measurement T estosterone measurement is routinely used in the initial assessment of the hypothalamic/pituitary/testicular axis. Blood should be taken at 8am-9am as there is a diurnal variation with peak levels between 4am-8am. (Reference ranges are based on morning blood levels.) Most testosterone is tightly bound to Sex Hormone Binding Globulin (SHBG) and is thus inactive; the measurement of SHBG allows the free testosterone, which is biologically active, to be calculated and routinely reported. As SHBG levels can vary markedly with hormone therapy, obesity, thyroid status and illness, total testosterone levels may be misleading when measured alone. Free testosterone is a more reliable measure of androgen status than total testosterone or the free androgen index and SHBG should thus be routinely included in testosterone requests. If a low free testosterone is found, it is advisable to request a repeat 8am-9am specimen for testosterone, SHBG, Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH) to confirm the low testosterone and to assess whether the hypogonadism is: • Hypergonadotrophic (high LH and/or FSH due to testicular failure) • Hypogonadotrophic (low or normal LH and FSH due to pituitary/ hypothalamic factors) • Combined as commonly seen in older men. The measurement of FSH, LH and testosterone should be on the same sample to assist interpretation. PBS authority for testosterone therapy requires at least 2 morning samples with testosterone less than 8 nmol/L, or in the range 8-15 nmol/L with LH increased more than 1.5 times the upper reference limit. Delayed Puberty in Boys Puberty in boys is delayed if there is no sexual development by age 14. Usually this is due to constitutional delay and a family history of delayed puberty will assist with this diagnosis. Page 1 of 3 Less commonly, systemic illness, excessive exercise or malnutrition account for about 20% of cases; pituitary/hypothalamic defects (prolactinoma, trauma, congenital defects) for about 10%; and testicular defects about 15% of cases. Testicular defects (e.g. Klinefelters, post orchitis etc) have low testosterone and elevated LH and FSH levels for age and are thus usually biochemically obvious, however, constitutional delay and pituitary/hypothalamic defects both have low testosterone and low or normal LH and FSH levels and are thus difficult to differentiate from each other biochemically. Further testing for such cases would include prolactin, TSH and T4, growth hormone and IGF1 and morning cortisol and ACTH levels. Delayed bone age may also be helpful in the differential diagnosis of constitutional delay; puberty usually ensues once a bone age of 12-14 years has been attained in this condition. Endocrinologist referral is advisable if sexual and biochemical parameters fail to progress after monitoring suspected cases of constitutionally delayed puberty. Adult Male Hypogonadism Hypogonadism is a clinical syndrome defined as low (free) testosterone and consequent signs and symptoms e.g. fatigue, low libido, reduced energy levels and vitality, depression, erectile dysfunction, reduced muscle, osteoporosis, loss of sex hair and anaemia1. Hypogonadism responds well to testosterone therapy and testosterone should thus be measured when any of the above clinical features are present. The use of testosterone therapy when symptoms are not accompanied by low free testosterone is, however, controversial. Andropause is a controversial and potentially misleading term as unlike the female menopause, many men do not experience this “climacteric” and maintain normal sex hormone levels into old age (the mean testosterone level at 80 years is approximately 60% of that of men aged 20-40 years) and the normal reduction of testosterone levels with age is a very gradual process that occurs over decades. Hypogonadotrophic Hypogonadism: (low free testosterone, low or inappropriately normal FSH and LH) Common acquired causes include: • suppression of the pituitary hypothalamic axis by stress, illness (diabetes, especially if poorly controlled), • malnutrition, • extreme exercise, • opiates, marijuana • previous testosterone therapy. Generalised pituitary damage due to prolactinoma or other pathology is less common but should be excluded by measuring prolactin, 8-9am cortisol, and iron studies to exclude haemochromatosis. Congenital causes are rare; Kallman’s syndrome is Gonadotropin Releasing Hormone (GnRH) deficiency with anosmia. The lack of GnRH from the hypothalamus causes low FSH, LH and testosterone in these patients. Male Sex Hormones and Related Disorders continued Obesity reduces the SHBG level and this may result in low total testosterone levels with normal FSH and LH, however, the free testosterone levels are usually normal and these patients are not really hypogonadal, (apart from a subset of massively obese individuals with hypothalamic suppression and low free testosterone levels.) Hypergonadotrophic Hypogonadism (low free testosterone, high FSH and LH). Causes include Klinefelters syndrome (XXY) which presents with hypogonadism, gynaecomastia, and azoospermia; uncorrected cryptorchidism, chemotherapy/ radiation, trauma, and post orchitis e.g. mumps. Further investigation in these cases would include semen analysis and karyotyping. Erectile Dysfunction (ED) This is defined as the inability to attain or maintain an erection adequate for intercourse and is a common problem, with approximately 20% of males aged 40-49 years and 50% of males 70-79 years moderately to severely affected. Previously it was believed that most cases of ED were psychogenic. The mechanism of erection is via neural control of penile vascular smooth muscle and today we appreciate that most cases of ED are in fact organic and vasculogenic2. The presence of early morning erections is helpful to differentiate psychogenic ED from organic causes; if they do occur, the neurologic and vascular mechanisms required for erection are intact and a psychogenic aetiology is likely. Atheroma is a major cause; ED is commoner in metabolic syndrome, cigarette smokers and in diabetics the risk of ED is proportional to duration and the HbA1c elevation. Between 35%-75% of diabetic men have ED. More than two thirds of patients with coronary artery disease have ED before the onset of coronary symptoms. Neurogenic causes include Parkinson’s, stroke, multiple sclerosis and spinal cord lesions; peripheral neuropathy is the cause in alcoholics and a contributory cause in diabetics. After standard (non nerve-sparing) Page 2 of 3 radical prostatectomy, between 65 percent and 90 percent of men will experience erectile dysfunction, depending on their age. This figure is reduced by nerve-sparing techniques. Endocrinopathies Testosterone increases libido but is not, per se, essential for erection. Hypogonadal males have improved erectile function in response to testosterone but testosterone is not helpful for ED when free testosterone is normal. High prolactin, (prolactinoma, many medications) reduces libido by inhibiting hypothalamic GnRH release and also testosterone release. Medications are frequently implicated in ED including: • Diuretics especially thiazides, • Antihypertensives especially beta blockers, • Antidepressants especially tricyclics and SSRIs, • Tranquilisers, • H2 antagonists • Anticonvulsants. • Alcohol and illicit drugs especially marijuana, opiates and cocaine may also cause ED. Initial investigations should include fasting glucose, lipids & HDL, LFTs, U&Es, FBC, prolactin, testosterone and SHBG. Medical treatment: The Phosphodiesterase type-5 (PDE5) inhibitors e.g. sildenafil (Viagra) are effective for most causes of ED including psychogenic, vasculogenic and neurogenic causes however these drugs should never be used in patients taking nitrates (risk of profound hypotensive shock) and are contraindicated in patients with high and intermediate coronary artery disease risk. Perversely many such patients suffer from ED as mentioned above. Gynaecomastia Gynaecomastia (the presence of glandular breast tissue which clinically is concentric with the nipple and is felt as a firm, rubbery mound of tissue) must be differentiated from pseudogynaecomastia due to adipose tissue and rarely, breast cancer. Mammography or ultrasound may be helpful if there is clinical doubt as to the diagnosis. Long-standing gynaecomastia is usually painless, consists largely of fibrotic tissue and is resistant to hormonal therapy. Acute gynaecomastia is tender or painful and usually responds to hormonal therapy. Causes of gynaecomastia: The underlying cause of most cases of gynaecomastia is an increase in the Oestrogen/Testosterone ratio or responsiveness3. Increased oestrogen levels are the cause of physiological gynaecomastia which is seen in: • neonates due to transplacental oestrogen transfer • pubertal boys due to higher oestrogen synthesis by the pubertal testis • ageing and obese males due to increased conversion of testosterone to oestrogens (aromatisation) by increased adipose tissue. Male Sex Hormones and Related Disorders continued Gynaecomastia due to increased oestrogen is also seen with: • liver disease, • re-feeding post starvation or illness, • certain testicular (Sertoli and Leydig cell) tumours, • some adrenal tumours and HCG secreting tumours, as HCG stimulates the testis to produce oestrogens. Increased aromatisation of testosterone to oestrogens with resultant gynaecomastia occurs in bodybuilders using testosterone and anabolic steroids, in thyrotoxicosis and (rarely) in some individuals due to a familial or sporadic defect. Reduced testosterone is the mechanism of gynaecomastia in hypogonadism (see above) e.g. patients with Klinefelter’s Syndrome typically have low testosterone and gynaecomastia, as do patients being treated for prostate cancer using antiandrogen therapy. Page 3 of 3 Drugs causing gynaecomastia include those with intrinsic oestrogenic activity e.g. digoxin and phytoestrogens, and those which reduce testosterone e.g. androcur or block its action e.g. spironolactone. Initial laboratory tests should include LFTs, TFTs, serum testosterone, SHBG, androstenedione, oestradiol, HCG, and LH. Karyotype should be checked if the free testosterone is low, however, more than half of cases have no demonstrable biochemical abnormality (idiopathic gynaecomastia). Treatment consists of testosterone and a Selective Oestrogen Receptor Modulator (SERM) e.g. tamoxifen, and up to 80% of idiopathic gynaecomastia cases will respond to this. Tamoxifen is also effective for prostate cancer patients on androgen suppressive therapy. Surgery may be required in some cases which are resistant to medical therapy. References 1.Rhoden et al, N Engl J Med 2004; 350: 482-92 2.McVary, N Engl J Med 2007; 357: 2472-81 3.Braunstein, N Engl J Med 2007; 357: 1229-37 Dr Sydney Sacks Chemical Pathologist T:9476 5211 E: [email protected]