Download Male Sex Hormones and Related Disorders

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.
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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)
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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.
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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]