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Gonadal function and dysfunction
Dr Thomas Fox
Endocrine SpR
Derriford Hospital
Introduction
Male gonadal function Male hypogonadism
Secondary Primary
Hypogonadism in the aging male Treatment of hypogonadism Monitoring of those on testosteroned therapy
Testes
Leydig cells (stimulated by LH) Close to blood supply Interstitial cells Produce testosterone (dihydrotestosterone, DHEA and
androstenedione)
Seminiferous tubules 90% volume of the testes Setoli cells (stimulated by FSH) – spermatogenesis occurs
here and also produce inhibin and in the embryo mullerian inhibiting factor
Germ cells
Spermatogenesis can take up to 90 days Testicular size in adults 15-30ml and
temperature is 2oC less than core temperature.
Testosterone
Converted to DHT in tissues (more active) Testosterone is also converted to oestradiol in
adipose tissue by aromatase enzyme Actions
Male sexual differentiation Maintains male secondary sexual characteristics Regulation of GnRH secretion Spermatogenesis Normal male sexual function and behaviour Maintenance of bone mineral density
Male Hypogonadism
Variety of manifestations Failure of puberty Infertility “Male menopause/andropause” Erectile dysfunction
Primary hypogonadism Secondary hypogonadism
Before puberty After puberty
Testes volume <5ml Testes volume <145ml
Penis <5cm Normal penis length
High pitched voice Voice broken
Eunachoid stature Normal body proportions
Gynaecomastia Gynaecomastia
Central fat distribution
Decreased body and facial hair
Normal hair distribution but poor growth
Delayed bone age Osteoporosis
Male hypogonadism with effects before and after puberty
Secondary hypogonadism
Hypothalamic/pituitary cause Often presents as delayed puberty or
infertility
Genetic, structural or environmental causes
Kallman’s syndrome Failure of GnRH secretion and neuronal development Associated with anosmia (75%) 1 in 10,000 Usually isolated cases but can be AD or AR inherited Male : female ratio 4:1 Investigations
Low/undetectable testosterone, LH and FSH Other pit function normal Normal hypothalamus/pit on MRI but absent olfactory bulb
Treatment Exogenous testosterone replacement Gonadotrophins if fertility required
Idiopathic hypogonadotrophic hypogonadism
Acquired or genetic (rare cases of GnRH receptor gene mutation)
In acquired cases men may have gone through normal puberty Present with low libido, erectile dysfunction or
infertility Acquired cases may go into remission after
testosterone or gonadotrophin therapy
Miscellaneous causes of secondary hypogonadism Stress Systemic illness Structural
Any pit tumour esp prolactinomas Associated with other hormonal deficiencies
Drugs Anabolic steroids Cocaine and opiates Any drugs causing hyperprolactinaemia
Haemochromatosis Endocrine – Cushings, prolactinoma Prader-Willi syndrome – 15q mutation – obesity, hypog/hypog and
mental retardation Laurence-Monn-Biedl syndrome – obesity, RP hypog/hypog, polydactyly
and mental retardation
Primary hypogonadism
Genetic Klinefelter’s syndrome XX males Noonan’s syndrome (46XY)
Acquired Trauma Orchitis Cryptorchism Post chemotherapy/radiotherapy Chronic illness Drugs- opiates, alcohol, sulfasalazine, colchicine
Opiates and hypogonadism
Opiates of all kinds cause reduced release of GnRH, LH, testosterone, free testosterone
This is dose related Correlates to reduction in libido and
subjective erectile dysfunction No literature on testosterone replacement in
this group Hypogonadism in men consuming sustained-action oral opioids. Daniell HW. J Pain. 2002
Oct;3(5):377-84.
Klinefelter’s syndrome
First described by Harry Klinefelter 1942 1:500 men affected Extra X chromosome causes primary hypogonadism
with testosterone deficiency Clinically
Reduced testicular volume Tall eunachoid stature Reduced body hair Gynaecomastia Intellectual dysfunction in 40%
20 time increased risk of carcinoma of breast
Investigations
Low testosterone Elevated LH/FSH Azospermia Diagnosed on karyotyping
47XXY or 46XY/47XXY mosaic
Management
Counselling Klinefelter’s Syndrome Association UK http://www.ksa-uk.co.uk
Androgen replacement therapy
Noonan Syndrome
Autosomal dominant disorder (variable penetrance) Normal karyotyptype Phenotype that of Turners syndrome
Low set ears Right sided congenital heart defects (left-sided in Turners) Epicanthic folds Short stature Webbed neck Cryptorchism (50% of males) Primary hypogonadism
Can affect either sex
XX males
1 in 10,000 births These patients have a translocation of part of
the Y chromosome with the X chromosome Phenotype is similar to Klinefelters May al so have short stature and
hypospadias
Hypogonadism in the aging male
Increasing interest in this area What is the evidence for
Decline in androgen production? Clinical manifestations of androgen deficiency? Accuracy of testing? Clinical benefit of androgen replacement?
Male androgens over time
60-70% testosterone bound to SHBG
30-40% testosterone bound to albumin
How to assess testosterone
Diurnal variation Measure 9am testosterone on 2 occasions Commercially available assays inaccurate at lower
end of range Testosterone reduced in –
Chronic renal, cardiac, respiratory or hepatic disease. Also reduced in Obesity
Pts on thiazides, opiates, psychotropic medications and amiodarone
Also need to measure, free testosterone LH and FSH
In a recent small 8-week study 50% (8/16) pts with mean age 69 years were both eugonadal and hypogonadal at some point in the study
In a third of men with testosterone <6.9 there are no symptoms of hypogonadism ?due to slow decline ? due to non-specific symptoms
20% men >60 years have serum testosterone below the lower limit of normal for young me
Symptoms of hypogonadism are very non-specific Do they all have testosterone deficiency?
Effects of testosterone replacement in the aging male
Effects of testosterone replacement in the aging male
Effects of testosterone replacement
Increased muscle mass 1-2kg Reduced fat mass 1.5-2.5kg
BUT no study has shown improvement in physical function Bone mineral density Improved well-being Improved libido Limited evidence for effect on erectile dysfunction
No outcome studies of morbidity or mortality, fracture risk, risk of falls
Risks of androgen replacement in the aging male
Long term risk of androgen replacement in men may include Cardiovascular disease Prostatic hypertrophy (and carcinoma?) Polycythaemia Dyslipidaemia Sleep apnoea
When to treat?
Those with 2 low 9am testosterone measurements
WITH symptoms that could be attributable to androgen deficiency
Trial period to monitor effects of treatment No real guidance provided by NICE or
Society for Endocrinology
Testosterone replacement therapy
Various choices Transdermal patches
Intrinsa 300mcg/24hrs, patch changed twice weekly (£26.91 for 8 patches)
Transdermal gel Ie Testim gel 50mg/5g (30 tube pack £32)
Intramuscular depots Nedido 1g/4ml 10-14 weekly (£76) Sustanon 250 2-3 weekly intervals (£2.50 per 1ml amp)
(Hepatic metabolism when administered orally)
Monitoring
No BES guidelines 2002 AACE
Testosterone monitoring Regular prostate examination Regular questions RE symptoms of prostatism PSA 6 monthly for 18 months then yearly Stop testosterone if PSA rises or prostatic
symptoms develop FBC/haematocrit
hCG therapy
hCG therapy hCG binds to Leydig cells LH receptor Given peripubertally in hypogonadotrophic
hypogonadism to stimulate puberty Stimulates testosterone production, testicular growth
and spermatogenesis 2-3 weekly im injections
Also given tio hypo/hypog males wanting to father children
Human menopausal gonadotrophin therapy
Required for those who have developed hypogonadotrophic hypogonadism post-pubertally for spermatogenesis if hCG alone fails
GnRH therapy
Given as a pulsatile subcutaneous pump to induce puberty and spermatogenesis in hypogonadotrophic hypogonadism
Summary
Differential diagnosis of secondary hypogonadism
Difficulties of managing primary hypogonadism in aging male
Opiates and obesity as a cause of hypogonadism
Need for surveillance of those on androgen replacement therapy
http://www.endo-society.org/guidelines/final/upload/Androgens_in_Women_CG.pdf
http://jcem.endojournals.org/cgi/content/full/86/6/2380
AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE EVALUATION AND TREATMENT OF HYPOGONADISM IN ADULT MALE PATIENTS—2002 UPDATE http://www.aace.com/pub/pdf/guidelines/hypogonadism.pdf