IS THERE A ROLE OF MEDICAL TREATMENT IN MALE INFERTILITY?

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IS THERE A ROLE OF MEDICAL TREATMENT IN MALE
INFERTILITY?

• PROF. DR. BÜLENT SEMERCI
• EGE UNIVERSITY SCHOOL OF MEDICINE
• DEPARTMENT OF UROLOGY

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MEDICAL TREATMENT IN MALE INFERTILITY

• 1- Specific Therapy
• 2- Empiric Therapy

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MEDICAL TREATMENT IN MALE INFERTILITY

• 1- Specific Therapy
• A- Endocrine Disorders
• B- Leucospermia
• C- Immunological Infertility
• D- Gonadotoxins
• E- Ejaculatory Dysfunction

4
A- Endocrine Disorders

• Hypogonadotropic Hypogonadism
• Accounts for less than 1 of all cases of male
  infertility
• Gonadotropin replacement is the rational
  treatment and is the only clearly accepted and
  effective management of associated infertility
• Endocrinol Metab Clin North Am. 2007
  Jun36(2)313-31.

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A- Endocrine Disorders

• Normal male fertility
• Adequate levels of intratesticular testosterone
• Adequate levels of follicle-stimulating hormone
  (FSH)
• FSH has been shown to initiate and maintain
  spermatogenesis

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A- Endocrine Disorders

• Gonadotropin Replacement
• FSH administration in men with hypogonadotropic
  hypogonadism increases sperm count, motility,
  morphology and testicular volume
• J Androl. 2003 Jul-Aug24(4)604-11.

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A- Endocrine Disorders

• Gonadotropin replacement treatment
• hCG
• LH analog
• hMG
• mimics LH and FSH
• Purified FSH
• Pulsatile GnRH
• Normal Physiology
• Kallman Syndrome
• Infrequent, a portable minipump, an inconvenient,
  costly practice

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A- Endocrine Disorders

• Gonadotropin Replacement
• Initial management hCG
• IM or SC 3000-6000 IU/week,
• until adequate serum testosterone levels detected
• If sperm undetected after 6 months concomitant
  treatment
• hMG (75-150 IU 2-3 times/week)
• FSH (50-150 IU 3 times/week)
• Contraception. 2005 Oct72(4)314-8.
• Up to 1-2 years

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A- Endocrine Disorders

• Predictive factors of gonodotropin replacement
  response
• Larger testicular volume
• Prior gonadotropin therapy
• Postpubertal status
• Absence of bilateral maldescended testes

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A- Endocrine Disorders

• Gonadotropin Replacement
• hCG/hMG effective in anabolic steroid-induced
  azoospermia
• Fertil Steril. 2003 Jun79 Suppl 31659-61.

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A- Endocrine Disorders

• Gonadotropin Replacement
• 24 men with isolated hypogonadotropic
  hypogonadism
• 92 became fertile
• 40 pregnancies
• 71 sperm concentrations below 20 million/mL
• Fertil Steril. 1988 Aug50(2)343-7

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A- Endocrine Disorders

• Gonadotropin Replacement
• Gonadotropins have proven highly effective in
  inducing fertility
• Eur J Endocrinol. 1998 Sep139(3)298-303.
• Int J Androl. 1994 Oct17(5)241-7
• Int J Androl. 1992 Aug15(4)320-9

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A- Endocrine Disorders

• Androgens
• Exogenous testosterone therapy is detrimental for
  sperm production and has a contraceptive effect
• Fertil Steril 199665(4)821-9
• Meta-analyses testosterone and mesterolone
• no effect on sperm production
• no increase in pregnancy rates

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B- Leucospermia

• Antibiotics
• The incidence of genital tract infections among
  men with infetility varies 10-20
• Organization WH. WHO labaratory manual for the
  exmination of human semen and semen-cervical
  mucus interaction. Cambridge (UK) Cambridge
  University Press 1992.
• Often asymptomatic and difficult to diagnose

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B- Leucospermia

• Antibiotics
• When leukocytospermia, defined as greater than
  one million WBC/mL, is present in an asymptomatic
  infertile male on semen analysis, an evaluation
  for a genital tract infection is recommended
• Hum Reprod 10. (7) 1736-1739.1995

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B- Leucospermia

• Antibiotics
• In asymptomatic infertile men with
  leukocytospermia or in cases of truly unexplained
  infertility, semen cultures can be considered and
  appropriate antibiotic treatment instituted
  depending on the organism isolated

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C- Immunological Infertility

• Corticosteroids
• Treatment of antisperm antibodies
• Inconsistent and incomplete meta-analysis of four
  of six randomized, available controlled studies
  revealed no significant enhancement of fertility
• Hum Reprod. 1999 Sep14 Suppl 11-23.

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C- Immunological Infertility

• Corticosteroids
• Using before ICSI is a choice for patients with
  high antisperm antibody titers
• Statistical significance is lacking
• Hum Reprod Update. 2001 Sep-Oct7(5)450-6.
• Int J Fertil Womens Med. 1998 May-Jun43(3)165-70
  

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D- Gonadotoxins

• Often depend on the job
• Prevention from exposure to industrial and
  agricultural gonadotoxin (lead, manganese etc.,)

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E- Ejaculatory Dysfunction

• Failure of emission
• Retrograde ejaculation

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E- Ejaculatory Dysfunction

• Causes
• Spinal-cord injury
• DM
• Retroperitoneal surgery
• Multiple sclerosis
• Bladder neck and prostate surgery

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E- Ejaculatory Dysfunction

• Medical Therapy
• a- sympathomimetic medications
• Ephedrine
• Pseudoephedrine
• Imipramine
• Phenylpropanolamine
• If these agents contraindicated or unsuccesful
• Vibratory simulation
• Electroejaculation (90 of patients producing a
  semen specimen
• J Urol 163. (6) 1717-1720.2000
• Int J Androl 25. (6) 324-332.2002

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MEDICAL TREATMENT IN MALE INFERTILITY

• Empiric Therapy
• A- Antiestrogens
• B- Aromatase inhibitors
• C- Gonadotropins
• D- Alternative therapy

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A- Antiestrogens

• Clomiphene citrate, a synthetic antiestrogen, is
  the most commonly used drug in the treatment of
  idiopathic oligospermia.
• Binding estrogen receptors
• Inhibition of estrogen at the hypothalamic and
  pituitary levels
• Increasing GnRH, LH, and FSH secretion and
  stimulating testosterone production and
  spermatogenesis
• Peripheral conversion of testosterone

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A- Antiestrogens

• Clomiphene citrate
• The first study yielded poor results in 1966
• Within the past 40 years studies have
  demonstrated conflicting results in sperm counts,
  morphology, motility and pregnancy rates

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A- Antiestrogens

• In a meta-analysis of 10 controlled studies
  involving 738 men
• Positive hormonal effect
• No improvement in pregnancy rate
• Vandekerckhove P., et al  Clomiphene or
  tamoxifen for idiopathic oligo/asthenospermia.
   Cochrane Database Syst Rev . (2) 2000CD000151 

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A- Antiestrogens

• More advantageous in men who have mild
  oligospermia and low serum gonadotropins or
  increased estrogen
• Less likely to be efficacious in men who have
  elevated baseline gonadotropins and in men who
  have remarkably abnormal semen analyses or
  testicular biopsies

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A- Antiestrogens

• With the advancement of assisted reproduction
  techniques the goal may be to augment
  spermatogenesis so that in vitro fertilization
• 42 patients who had nonobstructive azoospermia
• After 3 to 9 months of therapy with dose
  titration to achieve testosterone levels of
  600-800 ng/dl
• 64.3 of patients demonstrated semen analyses
  containing sperm
•  J Androl 26. (6) 787-791.2005discussion
  7923

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A- Antiestrogens

• Self-limited, common side effects
• weight gain
• blurred vision
• hypertension
• gastrointestinal disturbances
• insomnia

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B- Aromatase inhibitors

• Aromatase inhibitors have been used to block the
  conversion of androgens to estrogen and therefore
  increase testosterone with the hopes of improving
  male infertility.
• Steroidal (eg, testolactone)
• Nonsteroidal (eg, anastrazole)
• Highly potent and less likely to cause
  interruption of the adrenal axis beyond aromatase
  inhibition
• Lowering serum estradiol and increasing
  testosterone/estradiol ratio
• Only in men with Klinefelter syndrome was
  anastrozole not significantly effective
• J Urol 167. (2 Pt 1) 624-629.2002

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B- Aromatase inhibitors

• Semen parameters and testosterone/estradiol
  ratios improved in a study of 63
  hypergonadotropic hypogonadic infertile men
• J Urol 165. (3) 837-841.2001
• Controlled studies looking at pregnancy rates
  using aromatase inhibitors are lacking
• Patients who have hepatic disease, and liver
  function tests should be monitored

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C- Gonadotropins

• Treatment of idiopathic infertility
• Randomized controlled trials have observed no
  significant effect of hCG, hMG, or rhFSH on
  pregnancy rates or seminal parameters
•  Hum Reprod 13. (3) 596-603.1998
• Clin Endocrinol Metab 65. (6) 1081-1087.1987

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C- Gonadotropins

• FSH may be beneficial subsets of patients, such
  as those who have normal plasma levels of FSH and
  inhibin B and a testicular tubular appearance of
  hypospermatogenesis without maturation
  disturbances
• FSH 100 IU on alternate days increased
  stimulation of spermatogenesis
• Significant increases in testicular volume and
  sperm parameters were detected with doses of 150
  IU
• Fertil Steril 80. (6) 1398-1403.2003

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C- Gonadotropins

• FSH may be useful in infertile men who have
  certain defects in sperm structure, such as those
  who have apoptotic or immature sperm, because
  treatment seems to improve the quality of sperm
  micro-organelles
• Increase in spontaneous pregnancies
• Hum Reprod 12. (9) 1955-1968.1997
• Fertil Steril 73. (1) 24-30.2000

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C- Gonadotropins

• Several controlled studies have found better
  quality embryos and implantation rates after
  pretreatment of infertile men undergoing in vitro
  fertilization (IVF)/intra-cytoplasmic sperm
  injection (ICSI)
•  Fertil Steril 80. (6) 1398-1403.2003
• Fertil Steril 72. (4) 670-673.1999

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C- Gonadotropins

• The role of FSH in treating idiopathic
  oligospermia
• In patients who have hypospermatogenesis
• Patients attempting IVF/ICSI

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D- Alternative therapy

• 30 of men presenting for infertility evaluation
  use alternative therapies
• tocopherol (vitamin E)
• ascorbic acid (vitamin C)
• acetylcysteine
• glutathione
• pentoxifiline
• Urology 63. (1) 141-143.2004

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D- Alternative therapy

• Tocopherol improved sperm function (spermzona
  pellucida binding capacity) and IVF rates
• Fertil Steril 64. (4) 825-831.1995
• Fertil Steril 66. (3) 430-434.1996

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D- Alternative therapy

• Acetylcysteine and retinol (vitamin A) together
  with tocopherol and essential fatty acids
• increased sperm count,
• decreased ROS,
• augmented acrosome reaction
• Prostaglandins Leukot Essent Fatty Acids 63. (3)
  159-165.2000

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D- Alternative therapy

• Folic acid and zinc supplements
• Increase sperm concentration
• No effect in seminal and hormonal parameters
• Int J Androl 29. (2) 339-345.2006
• Fertil Steril 77. (3) 491-498.2002

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D- Alternative therapy

• L-carnitine
• a vital component of sperm metabolism and
  maturation
• improvement sperm concentration and motility
• Reprod Biomed Online 8. (4) 376-384.2004

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D- Alternative therapy

• Pentoxifiline
• Phosphodiesterase inhibitor
• Augmenting the fertilizing potential of
  asthenozoospermic sperm samples, presumably by
  improving sperm movement
• Commonly used doses 400mg / 3 times a day

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D- Alternative therapy

• Results are encouraging
• Side effects are minimal
• Recommended as adjunctive therapy

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RECOMMENDATIONS

• Medical treatment of male infertility can only be
  advised in cases of hypogonadotrophic
  hypogonadism
• Medical treatment of male infertility can be
  valuable in conjuction with advanced assisted
  techniques
• Drugs are usually ineffective in the treatment of
  idiopathic male infertility