Credits

• Section Writer: Dr. Om J Lakhani
• Section Editor: Dr. Om J Lakhani

Q. What is the definition of male hypogonadism?

• Defect in one of the two functions of the testis
  • Sperm production
  • Testosterone production

Q. What are the two main groups of causes of hypogonadism in males?

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Causes of primary hypogonadism in males

Q. What are major clinical differences between primary and secondary hypogonadism?

• Primary hypogonadism is more likely to be associated with defective sperm production than  Leydig cell function
• Primary hypogonadism is more likely to be associated with gynecomastia because of increase FSH and LH increasing the aromatase activity
• FSH >8 IU/l is suggestive of primary hypogonadism

Q. Enlist the causes of primary hypogonadism?

• Congenital causes
  • Klinefelter's syndrome- most common
  • Gonadal dysgenesis
  • FSH and LH receptor defect- Leydig cell hypoplasia
  • Testosterone synthesis defect
  • Cryptorchidism
  • Congenital anorchia
  • Varicocele
  • Myotonic dystrophy
• Acquired causes
  • infection- mump orchitis
  • HIV
  • Testicular tumor
  • Drugs – glucocorticoids, cyclophosphamide, cisplatin, other chemotherapeutic agents, ketoconazole
  • Autoimmune
  • Testicular torsion
  • Testicular trauma
  • Surgery
  • Chronic systemic disorder –CRF and CLD
  • Environmental toxins
  • Radiotherapy
  • Surgical orchidectomy

Q. Why is the timing of testosterone defect important in congenital abnormalities of primary hypogonadism?

• Defect in 1st trimester of pregnancy- male external genitalia would not be appropriately formed – ambiguous genitalia or female external genitalia
• Normal Testosterone in the first trimester but defective in 3rd-trimester  micropenis at birth
• Normal Testosterone in utero, Testosterone defect before puberty- absent secondary sexual characteristic, Eunhacnoid proportions, gynecomastia
• Testosterone defect after puberty – normal virilization, gynecomastia, testicular atrophy, reduced libido, infertility

**Other congenital causes of Primary hypogonadism in males (other than Klinefelter syndrome) **

Q. Which other chromosomal abnormalities are associated with primary hypogonadism in males?

• 46 XY/XO- mixed gonadal dysgenesis
• Yq microdeletion- azoospermia or severe oligospermia

Q. What is AZF?

• AZF is a region on the long arm of chromosome Y which is associated with infertility in men
• This produces a condition called Y Chromosome infertility
• There are three regions - AZFa, AZFb, AZFc
• Deletion in AZFa and AZFb produce azoospermia
• Deletion in AZFc produce severe oligospermia - however, enough sperms are produced for sperm extraction using TESE and use for Intracytoplasmic sperm injection (ICSI)

Q. What are the features of mixed gonadal dysgenesis?

• Patient will have a Turner like phenotype – e.g.: short stature, etc
• Variable gonads- streak, dysgenetic or normal
• Phenotype ranging from normal female to normal male
• High to intermediate risk of gonadoblastoma hence gonadectomy generally advised

Q. What does mutation in LH receptor lead to?

• It leads to Leydig cell hypoplasia
• This produces 46 XY DSD and ambiguous genitalia

Q. What are the clinical features of myotonic dystrophy?

• Muscle atrophy
• Hypogonadism
• Detected later in adulthood

Q. What happens in congenital anorchia?

• Here, the testicular regression occurs after 20 weeks
• Hence there is normal male external genitalia but absent testis

Q. What is Sertoli cell-only syndrome?

• This is a histological syndrome.
• This is typically seen in young males between 20-40 years
• On Semen analysis, they have azoospermia or severe oligospermia
• On Histopathology- the seminiferous tubules are lined with Sertoli cells only, and little or no spermatogenesis takes place
• the testis may be slightly atrophied
• Inhibin B levels may be low
• FSH is elevated with normal LH
• The male is otherwise normally virilized
• The likely etiology is likely to be Y Chromosome infertility due to AZF microdeletions
• Similar situation can also be acquired due to toxins which damage the sperm production

Acquired causes of primary hypogonadism

Q. Tell me something about mumps orchitis?

• Hypogonadism In mumps orchitis occurs when it occurs in adulthood and not in childhood
• There is swelling and pain of the testis followed by regression
• Seminiferous tubule more damaged, but Leydig damage can also occur

Causes of secondary hypogonadism in males

Q. What are the features of congenital secondary hypogonadism?

• Normal external male phenotype
• Micropenis at birth
• Normal growth in childhood
• Delayed / absent puberty
• Eunuchoid proportions

Q. What are features of eunachoid propotions?

• Arm spam > height by 5 cm
• Pubis to floor > pubis to crown
• This is because of delayed closure of epiphysis due to low testosterone and lack of estrogen

Q. What are congenital causes of hypogonadotropic hypogonadism?

• Idiopathic hypogonadotropic hypogonadism
• Part of MPHD (Multiple pituitary hormone deficiencies) – LHX3, LHX4, PROP1, HESX1
• Prader Willi syndrome
• Leptin deficiency / Leptin receptor defect
• Mutation in LH beta and FSH beta

Q. What are the acquired causes of secondary hypogonadism?

• Defect at the level of Hypothalamus
  • Drugs
    • Glucocorticoids
    • GnRH analog
    • Exogenous sex steroids
  • Trauma
  • Obesity
  • Diabetes
  • Sleep apnea
  • Aging
  • Critical illness
  • Hyperprolactinemia
  • Anorexia nervosa
  • Chronic systemic illness
• Defect at the level of the pituitary
  • Pituitary adenoma
  • Suprasellar mass
  • Pituitary apoplexy