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

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  2. 2.  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
  3. 3. Hypothalamic-Pituitary-Testicular Axis
  4. 4. 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
  5. 5. 2. Interstitial Compartment  Leydig cells: Produce testosterone (dihydrotestosterone, DHEA and androstenedione) by respond to luteinizing hormone (LH) with steroid production (primarily testosterone).
  6. 6. 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
  7. 7. DHT &Estradiol
  8. 8. ***This will be a hard task for someone with hypogonadism due to fatigue and loss of strength*** I’VE GOT THE ‘T’ FOLKS
  9. 9. 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
  10. 10. 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
  11. 11. Vasomotor and nervous – Hot flushes – Sweating Androgen Deficiency Symptoms cont’d
  12. 12. – Diminished muscle mass – Loss of body hair – Abdominal obesity – Gynecomastia – Testes frequently normal, occasionally small Physical Signs Androgen Deficiency Symptoms
  13. 13. 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
  14. 14. MALE HYPOGONADISM: Definition  A decrease in either of the two major functions of the testes: – sperm production – testosterone production
  15. 15. Types of Male Hypogonadism Secondary hypogonadism Primary hypogonadism
  16. 16. 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
  17. 17. Secondary hypogonadism  Hypothalamic/pituitary cause (often presents as delayed puberty or infertility)  Genetic, structural or environmental causes Possible aetiologies
  18. 18. 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
  19. 19.  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.
  20. 20. 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.
  21. 21. 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
  22. 22. 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)
  23. 23. 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
  24. 24. 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
  25. 25. Signs:  Eunuchoidal body habitus  Variable androgenization  Long extremities (LS>US)  Karyotype: XXY Klinefelter’s Syndrome
  26. 26. NB: So the klinefactor is having 47 chromosomes instead of 46 Trisomy
  27. 27.  Low testosterone  Elevated LH/FSH  Azospermia  Definitive diagnosis is based on karyotyping – 47XXY or 46XY/47XXY (mosaic)  Counselling – Klinefelter’s Syndrome Association UK []  Androgen replacement therapy
  28. 28. 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
  29. 29.  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
  30. 30.  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
  31. 31.  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
  32. 32.  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
  33. 33. 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
  34. 34. REFERENCES  Greenspan’s Basic &Clinical Endocrinology, 8th edition  Per Williams Textbook of Endocrinology 11th edition  []  Wikipedia []: kallman’s, klinefecter’s, Nooman’s syndrome, XX males, etc....