Male gonadal function and dysfunction (male hypogonadism). Emphasis where made on the causes, types of male hypogonadism, diagnosis and treatment methods.

2. 6936
BY:
CLASS PRESENTATION

3.  Quick Overview
 Male gonadal (Testicular) functions
 Male gonadal Dysfunction (Androgen Deficiencies)
 Male Hypogonadism
 Secondary hypogonadism-Opiates , Kallman’s syndrome and
idiopathic hypogonadotropic hypogonadism
 Primary hypogonadism-Klinefelter’s syndrome, Nooman’s
syndrome and XX males
 Questions and Answers
 References

4. Hypothalamic-Pituitary-Testicular
Axis

5. 1. Tubular compartment
 Germ cells
 Sertoli cell: also known as the nurse or mother cells or
sustentacular cells support spermatogenesis. Their
proliferation is triggered by testosterone and FSH
secretion (has FSH-receptor on its membranes) and also
Inhibited by inhibin.
 Sperm cells
Two cellular compartments involved in spermatogenesis

6. 2. Interstitial Compartment
 Leydig cells:
Produce testosterone (dihydrotestosterone, DHEA and
androstenedione) by respond to luteinizing hormone (LH) with
steroid production (primarily testosterone).

7. Functions of testosterone
 Converted to DHT (more active)in tissues e.g. prostate gland.
 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

8. DHT &Estradiol

10. ***This will be a hard task for someone with hypogonadism due to fatigue and loss of
strength***
I’VE GOT THE
‘T’ FOLKS

11. Androgen Deficiency Symptoms
Musculoskeletal
– Decreased vigour and physical energy
– Diminished muscle strength
Sexuality
– Decreased interest in sex
– Reduction in frequency of sexual activity
– Poor erectile function/arousal
– Loss of nocturnal erections
– Reduced quality of orgasm
– Reduced volume of ejaculate

12. Mood disorder and cognitive function
– Irritability & lethargy
– Decreased sense of well-being
– Lack of motivation
– Low mental energy
– Difficulty with short-term memory
– Depression
– Low self-esteem
– Insomnia
– Nervousness
Androgen Deficiency Symptoms

13. Vasomotor and nervous
– Hot flushes
– Sweating
Androgen Deficiency Symptoms cont’d

14. – Diminished muscle mass
– Loss of body hair
– Abdominal obesity
– Gynecomastia
– Testes frequently normal, occasionally small
Physical Signs
Androgen Deficiency Symptoms

15. History and Physical (Symptoms and Signs)
Exclude reversible illness, drugs,
nutritional deficiency
Do you suspect altered SHBG?
Low T
Morning Total T
Normal T, LH+FSH
Not Hypogonadism
Follow up
Normal T
Repeat T
Check LH+FSH
If altered SHBG,
Use free or bio- T
Semen
analysis
if fertility issue
Keys: ‘T’ means Testosterone
How to investigate for Androgen Deficiencies

16. MALE HYPOGONADISM: Definition
 A decrease in either of the two major
functions of the testes:
– sperm production
– testosterone production

17. Types of Male Hypogonadism
Secondary hypogonadism
Primary hypogonadism

18. Confirmed low T (Total < 300 ng/dl)
OR
Free or Bio T < normal (Free T <5 ng/dl)
Low T
Low / normal LH+FSH
Prolactin, iron salts
Other pituitary hormones
Low T
High LH+FSH
Karyotype
Klinefelter Syndrome
Other Testicular Insult
Secondary Hypogonadism
Primary Hypogonadism
MRI in certain cases

19. Secondary hypogonadism
 Hypothalamic/pituitary cause (often presents as
delayed puberty or infertility)
 Genetic, structural or environmental causes
Possible aetiologies

20. Kallman’s syndrome
 Failure of GnRH secretion and neuronal development
 Associated with anosmia (smelling disorder) and hyposmia (75%)
 1 in 10,000
 Male : female ratio 4:1
 Diagnosis
– Low/undetectable testosterone, LH and FSH
– Other pituitary functions are normal
– Normal hypothalamus/pituitary on MRI, but absence of olfactory
bulb
 Treatment
– Exogenous testosterone replacement
– Gonadotrophins if fertility required

21.  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 gonadotropin therapy.

22. Miscellaneous causes of secondary
hypogonadism
 Stress
 Systemic illness
 Structural
– Any pituitary tumour esp. prolactinomas
– Associated with other hormonal deficiencies
 Drugs
– Anabolic steroids
– Cocaine and opiates
– Any drugs causing hyperprolactinaemia
 Hemochromatosis
 Endocrine – Cushing's, prolactinoma
 Prader-Willi syndrome – 15q mutation – obesity and mental
retardation
 Laurence-Monn-Biedl syndrome – obesity and mental retardation.

23. 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

24. Opiates and hypogonadism
 Long-acting opioid analgesics suppress the hypothalamic-pituitary
gonadal axis in men and produce symptomatic androgen deficiency
(up to 74%).
 Opiates of all kinds cause reduced release of GnRH, LH, testosterone
(free testosterone).
 This usual follows a dose dependent exposure and correlates to
reduction in libido and subjective erectile dysfunction.
 Also leads to osteoporosis
 NB: **I did not find any literature on special treatment or testosterone
replacement in this group. (though I suspect using a opioid antagonist or
stopping use of opiates might work)

25. 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

26. Klinefelter’s Syndrome
 Most common endocrine cause of Primary
hypogonadism
 FSH always 
 T variably affected (T  or normal)
 Fertility rare (in mosaics only)
 Treatment: T only if needed
– Will not reverse infertility

27. Signs:
 Eunuchoidal body habitus
 Variable androgenization
 Long extremities (LS>US)
 Karyotype: XXY
Klinefelter’s Syndrome

28. NB: So the klinefactor is having 47 chromosomes instead of 46
Trisomy

29.  Low testosterone
 Elevated LH/FSH
 Azospermia
 Definitive diagnosis is based on
karyotyping
– 47XXY or 46XY/47XXY
(mosaic)
 Counselling
– Klinefelter’s Syndrome
Association UK
[http://www.ksa-uk.co.uk]
 Androgen replacement
therapy

30. Noonan Syndrome
 Autosomal dominant disorder (variable penetrance)
 Normal karyotype
 Phenotype is like 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

31.  1 in 10,000 births
 These patients have a translocation of part of the
Y chromosome with the X chromosome
 Phenotype is similar to Klinefelter's
 May also have short stature and hypospadias

33.  A 35 year old man presents with infertility & azoospermia. He was at
puberty at the age of 15, has normal libido and shaves every other day.
 He is 72” tall, 180#, with gynecomastia and small testes
 Has normal thyroid & phallus
 The Testosterone level is low, LH high, FSH high
QUESTION???
 Can you guys give me your tentative diagnosis with reasons and
also the best diagnostic test to establish your definitive diagnosis?
o
k
oCase 1

34.  A 19 year old boy presents with inability to smell his girl friends perfume &
azoospermia
 He is 175cm tall, 53kg weight, with his arm slightly than his height at
177.5cm. He had a normal voice and his pubic hair were adult like in
texture and type.
 On endoscopy his olfactory fissures were patent and MRI images shows
that the olfactory bulb is absent.
 The Testosterone level is low and other pituitary functions were found to
be normal with MRI.
QUESTION???
 Can you guys give me your tentative diagnosis with reasons and
what type of hypogonadism is this disease?
o
k
oCase 2

35.  A 54 year old man was asked by his wife of 35years old to go visit a physician
concerning his inability to perform well in bed (low libido and erectile
dysfunction). The man in addition complaint to the clinician about a long
time worsening fatigue.
 On physical examination, he is found to be obese with BMI=31.
 There is no evidence of gynecomastia
 The testicles and prostate are normal
 Lab evaluation reveals serum testosterone level of 180ng/dl
(ref. range: 249-836)
QUESTION???
 What is your tentative diagnosis and why?
o
k
oCase 3

37. Total vs. Free vs. Bioavailable
Testosterone (male)
60%
38%
2%
Affinity for SHBG
is at least 4X higher
vs. albumin
Greenspan’s Basic &Clinical Endocrinology, 8th edition

38. REFERENCES
 Greenspan’s Basic &Clinical Endocrinology, 8th edition
 Per Williams Textbook of Endocrinology 11th edition
 [http://www.ksa-uk.co.uk]
 Wikipedia [www.wikipedia.org]: kallman’s, klinefecter’s,
Nooman’s syndrome, XX males, etc....