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

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