Gonadal function and dysfunction

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 2 o C 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

Male hypogonadism with effects before and after puberty Normal body proportions Eunachoid stature Osteoporosis Delayed bone age Normal hair distribution but poor growth Decreased body and facial hair Central fat distribution Gynaecomastia Gynaecomastia Voice broken High pitched voice Normal penis length Penis <5cm Testes volume <145ml Testes volume <5ml After puberty Before 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

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)
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
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

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Gonadal function and dysfunction

by PeninsulaEndocrine on Aug 12, 2011

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