Causes of azoospermia

1) Hypothalamic-pituitary failure: (Hypogonadotrophic hypogonadism)

2) Primary testicular failure (nonobstructive azoospermia)

3) Obstruction of the genital tract (obstructive azoospermia)

4) Anejaculation 

5) Retrograde ejaculation

WHO reference values for semen analysis - Year 2010

Semen volume: ≥ 1.5 ml

 pH: ≥ 7.2  

Sperm concentration: ≥ 15 million spermatozoa per ml

Total sperm number: ≥ 39 million spermatozoa per ejaculate 

Total motility (percentage of progressive motility and non-progressive motility): ≥ 40% motile or ≥ 32% with progressive motility

Vitality: ≥ 58% live spermatozoa 

Sperm morphology (percentage of normal forms): ≥ 4% 

(Please note : Older values, year 2002 are different)

Causes of azoospermia - 4

4) Anejaculation: 
    - total failure of seminal emission into the posterior urethra. 
    - Rare

5) Retrograde ejaculation: 
  - substantial propulsion of seminal fluid from the posterior urethra into the bladder. 
  - Accounts for 0.3–2.0% of male fertility problems

(4) and (5) may result from:

1. Spinal cord injury
2. Transurethral prostatectomy – only 7% of men retain ejaculation
3. Retroperitoneal lymph node dissection
4. Diabetes mellitus
5. Transverse myelitis
6. Multiple sclerosis
7. Psychogenic / idiopathic disorders

Causes of azoospermia - 3

3) Obstruction of the genital tract (obstructive azoospermia): 

Prevalence < 2%

Diagnosis is based on normal testis size and normal serum FSH levels.
Causes include :
Congenital bilateral absence of vas deferens 
(associated with cystic fibrosis mutations or renal tract abnormality)

Causes of azoospermia - 2

2) Primary testicular failure (nonobstructive azoospermia): 

The diagnosis is based on reduction in testicular size and elevation of serum FSH levels. 

It is the most common cause of male infertility due to oligozoospermia. 

May be due to:

• Cryptorchidism
• Torsion
• Trauma
• Orchitis
• Chromosome disorders (Klinefelter’s syndrome, Y-chromosome microdeletions)
• Systemic disease
• Radiotherapy or chemotherapy
• Idiopathic (66%)

There is no effective treatment. 

Men undergoing treatments that cause infertility should be offered the opportunity to cryopreserve semen.

Causes of azoospermia - 1

1) Hypothalamic-pituitary failure: (Hypogonadotrophic hypogonadism). 

 Accounts for < 1% of male factor fertility.

 It results in a deficiency of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which is associated with -

failure of spermatogenesis and testosterone secretion.

Kallman Syndrome

 - X-linked recessive disease
- Reduced or complete absence of the sense of smell (anosmia-caused by the absence of the olfactory bulbs),  
- underdeveloped genitalia  - infertility
- lack of secondary sexual characteristics, 
- gynaecomastia, 
- short 4th metacarpal bone
- Males affected (1 in 10,000). 

- Presents at puberty

- Normal life-span 

- reduced or absent GnRH, with hypogonadotrophic hypogonadism. 

 - Hypothalamus is also affected

Anovulation in hyperprolactinemia

Hyperprolactinemic anovulation -

- 5-10% anovulation. 

- Anovulatory because hyperprolactinemia inhibits gonadotropin and therefore estrogen secretion. 

- Most have oligomenorrhea or amenorrhea. 

- Their serum gonadotropin concentrations are usually normal or decreased. 

- Hyperprolactinemia should always be confirmed by several measurements of serum prolactin. 

- An MRI of the head should be done in whom the cause is not obvious (eg, neuroleptic drug therapy, primary hypothyroidism).

WHO Group 3 ovulation disorders

Hypergonadotropic hypoestrogenic anovulation -

 - 10-30% cases of anovulation. 

- Primary causes :

1. POF (absence of ovarian follicles due to early menopause) or 
2. ovarian resistance (follicular form). 

- Many, but not all, of these women have amenorrhea.

- They usually do not respond to therapy for anovulation.

WHO Group 1 ovulation disorders

Hypogonadotropic hypogonadal anovulation -
(Hypothalamic pituitary Failure)

- 5 to 10 % of anovulation, usually amenorrhea 
(although a range of gonadal compromise can be seen)

- Low or low-normal FSH and low serum estradiol due to decreased hypothalamic secretion of GnRH or pituitary unresponsiveness to GnRH
(Low gonadotrophins
Normal prolactin
Low oestrogen)

- Causes of hypothalamic amenorrhea include :

1. stress-or exercise-related amenorrhea, 
2. anorexia nervosa, and 
3. Kallman's syndrome (isolated gonadotropin deficiency); approximately 5 to 10 percent have hypopituitarism. 

- Reversing the lifestyle factors that contribute to the anovulation (low weight, heavy exercise) should be attempted before considering intervention with medications.

Infertility & HIV

HIV: To prevent Male to female transmission :

1) Sperm washing is used to reduce the viral load in prepared sperm to a very low or undetectable level followed by IUI, IVF of ICSI

However, alternatives to sperm washing are now being proposed.

2) HAART treatment to reduce viral load to undetectable levels followed by timed intercourse – may be equally effective, less invasive and more cost effective for a specific cohort of patients. 

- Not appropriate in situations where any form of female infertility is diagnosed or suspected

• Where the man is HIV positive, the risk of HIV transmission to the female partner is negligible through unprotected sexual intercourse when all of the following criteria are met:

a)    The man is compliant with highly active antiretroviral therapy (HAART)

b)    The man has had a plasma viral load of less than 50 copies/ml for more than 6 months

c)    There are no other infections present

d)    Unprotected intercourse is limited to the time of ovulation

Infertility & HIV

HIV: 

To prevent Female to male transmission -

Use of assisted reproductive techniques (ART), such as IUI or IVF

Luteal phase defect

- Luteal-phase defect is a defect of progesterone secretion by the corpus luteum or a defect in endometrial response to hormonal stimulation, resulting in an inadequate endometrium for implantation

- Affects 3–20% of the infertile population and 23–60% of women with recurrent miscarriage

- Its role as a cause of infertility has been questioned and the benefit of treatment on pregnancy rates has not been established

- Women should not be offered an endometrial biopsy to evaluate the luteal phase as part of the investigation of fertility

WHO Group 2 ovulation disorders

Hypothalamic pituitary dysfunction (Normogonadotrophic-normoestrogenic)

Characterised by

• Gonadotrophin disorder
• Normal oestrogen

 

• Accounts for ~ 85% of ovulatory disorders
• Results in anovulatory oligo/amenorrhea, predominately involving women with polycystic ovaries.
• Polycystic ovaries are present in about 80–90% of women with oligomenorrhoea and 30% of women with amenorrhoea.
• In women with polycystic ovaries and clinical symptoms (menstrual disturbances, obesity and hyperandrogenism), this combination is referred to as PCOS.
• About 30% of the PCOS population is of normal weight

• The diagnosis of a polycystic ovary requires the presence of at least 12 follicles measuring 2–9 mm in diameter and/or an ovarian volume in excess of 10 cm3

The diagnosis of PCOS requires the presence at least two of the following three criteria

1. Oligo- and/or anovulation
2. Clinical and/or biochemical hyperandrogenism
3. Polycystic ovaries, with the exclusion of other aetiologies.

WHO classification of ovulation disorders

Patients are classified as :

WHO-1  - hypo-gonadotropic, hypo-estrogenic, (15%)

WHO-2  - normo-gonadotropic, normo-estrogenic, (80%) and 

WHO-3 - hyper-gonadotropic, hypo-estrogenic (5%)


( Class 1 has hypothalamic-pituitary failure
  Class 2 has hypothalamic-pituitary-ovarian axis dysfunction
  Class 3 has ovarian failure )



 The WHO criteria for classification of anovulation include :
the determination of -
- oligomenorrea (menstrual cycle >35 days) or 
- amenorrhoea (menstrual cycle > 6 months) in combination with -concentration of prolactin, follicle stimulating hormone (FSH) and estradiol (E2). 

  The vast majority of anovulation patients belong to the WHO-2 group and demonstrate very heterogeneous symptoms ranging from anovulation, obesity, biochemical or clinical hyperandrogenism and insulin resistance.

Assessing ovarian reserve

• Female fertility is related to the ovarian reserve. Ovarian reserve declines from before birth until the menopause.
• The rate of embryo implantation decreases while the rate of pregnancy loss increases with age. There is a decline in IVF success rates from around age 35 years.
• A woman’s age is therefore the most readily measured surrogate for ovarian reserve and should be used as an initial predictor of her overall chance of success through natural conception or with IVF

The following can be used to predict the likely ovarian response to gonadotrophin stimulation in IVF:

1. Total antral follicle count measured by TV scan on day 3 of cycle ≤ 4 for a low response and > 16 for a high response
2. Anti-Müllerian hormone of ≤ 5.4 pmol/l for a low response and  ≥ 25.0 pmol/l for a high response
3. FSH > 8.9 IU/l for a low response and < 4 IU/l for a high response

The following should not be used on their own to predict any outcome of fertility treatment:

1. Ovarian volume
2. Ovarian blood flow
3. Inhibin B
4. Oestradiol levels

Nonobstructive azoospermia

Primary testicular failure

The diagnosis is based on reduction in testicular size and elevation of serum FSH levels. 

It is the most common cause of male infertility due to oligozoospermia. 

May be due to:

• Cryptorchidism
• Torsion
• Trauma
• Orchitis
• Chromosome disorders (Klinefelter’s syndrome, Y-chromosome microdeletions)
• Systemic disease
• Radiotherapy or chemotherapy
• Idiopathic (66%) 

Obstructive azoospermia

Obstruction of the genital tract

• Prevalence < 2%
• Diagnosis is based on normal testis size and normal serum FSH levels.
• Causes include : Congenital bilateral absence of vas deferens (associated with cystic fibrosis mutations or renal tract abnormality).
  

Drugs affecting fertility in males

Male

• Cimetidine and sulphasalazine and long term-daily use of androgens can affect semen quality and cause oligozoospermia.

The effect is reversible after three months following withdrawal of medication

• Beta-blockers and psychotropic drugs may lead to impotence
• Chemotherapy can induce azoospermia, which is permanent in most cases
• The use of drugs such as anabolic steroids and cocaine can adversely affect semen quality.

Infertility - Effect of occupation

Occupation

• A specific enquiry about occupation should be made to people who are concerned about their fertility and appropriate advice should be offered.

• Men should be informed that there is an association between elevated scrotal temperature and reduced semen quality, but that it is uncertain whether wearing loose-fitting underwear improves fertility

Males

• Heat exposure (increased scrotal temperature): Abnormal sperm parameters
• X-ray exposure (radiotherapists): Azoospermia and reduced sperm count which may be reversible
• Exposure to vibration (engine drivers): Oligozospermia and asthenozospermia
• Chemicals
• Dibromochloropropane (pesticide – agriculture workers): Oligozospermia, azoospermia which are generally reversible; reduced fertilisation rates
• Ethylene dibromide (pesticide): Abnormal sperm parameters
• Lead, Cadmiun, Manganese (metal workers, smelters, battery factory workers): reduced fertility
• Acetone, Carbon disulphide, Glycol ethers (Chemists, lab workers, painters): Abnormal sperm parameters, reduced fecundability, oligozoospermia