male infertility treatment- baby joy ivf centre
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Male infertility
• Prevalence• Normal/abnormal semen• Tests • Causes• management
EXTENT OF THE PROBLEM 50% of the contribution towards infertility is by men sperm dysfunction, azoospermia or ineffective coitus is a factor in 50% of infertile couples,thus placing andrology at the core of reproductive medicine
WHO semen parameter reference values
Semen parameters 4th edition 5th edition
Volume of ejaculate(ml)
≥2 ≥1.5
Sperm concentration (x106/ml)
≥20 ≥15
Total sperm count (x106)
≥40 ≥39
Motility (%) ≥50 progressive (a + b) ≥25 a only
≥40 total motility ≥28 progressive (a+b)
Morphology by Kruger strict criteria (%)
≥15 ≥4
Vitality (%viable) ≥75 ≥58
White blood cells (106/ml)
<1 <1
Sperm motility measurement
A rapid progressive motility
B sluggish or slowly progressive motility
C nonprogressive motility
D lack of motility
Semen quality: Kruger Strict Morphology value
• Reflects the percentage of sperms with “Perfect appearance”
• Useful in assisted reproduction
• Poor predictor of genetically normal sperm
Test Method Why? Problem
WBC assay
• Pap
• flow cytometry
• peroxidase test (widely used)
Leukocyto spermia-
• Abn motility
• morphology
• defective fertilization
Unconsistent results of leucocyto sperm & infertility;
immature germ cells resemble round cells
Test Method Why? Problem
ROS Quantificaton
Chemiluminescence (luminometer)
Excess can lead to sperm damage &infertility
ROS in 40% of subfertile men
inverse relation with rate of spon pregnancy
ROS• WBC • Sperm• prolong
ed semen processing
Test method Why? Problem
DNA fragmentation tests
• TUNEL
• comet assay
• acridine orange
• sperm chromatin
ass. with infertility, early embryo death, poor embryo development & poor implantation helpful
with rec. preg. loss, varicocele & ROS level
N range <30%
ASA detection
• Mixed agglutination
• immunofluorescence
• immunobead
• 13% subfertile
• useful if isolated defects in motility
• unexplained
• poor PCT
2.5% of fertile couples also test positive
Sperm Function
Hypo –osmotic swelling
Checks for sperm viability • D/D of immotile
cilia syndrome (ultrastructural defects in dynein) to select viable sperm in ICSI
Acrosome reaction assay
• Microscopy • acrosin
enzyme assay
• electron • Microscopy • immunocyt
ochemical • triple stain
Value ltd. With IVF –ICSI & ability of Kruger strict morphology
Sperm zona binding assay
SPERM penetration assay
Pts sperm incubated with “promiscuous” hamster ova
To predict IVF will have successful outcome
Time consuming requires intact hamster ova
GENETIC
Karyotype Sperm conc. <5 x 106 /ml
5% subfertile males will have chr. abn
15% in azoospermic
MC – Klinefelter (47,XXY) 1:500 male
Sequence abn. (pt mutations frameshift mutations & other submicroscopic deletions) cannot be id
Remarks : genetic counselling to discuss impact on future generation
Aetiology
• Pretesticular-10%
• Testicular-25%
• Post-testicular-40%
• Idiopathic-25%
Testicular
– Genetic • Klinefilter syndrome ( 10-15%)• Chromosome translocations• Y –microdeletions• Immotile cilia syndrome• XYY syndrome• Mixed gonadal dysgenesis
– Varicocele• Inflammatory
• Mumps orchits• Cryptorchidism
• Testiculartorsim• Gonadotoxins
Post -Testicular
Genetic– CFTR – mutations– 5 –alpha reductase deficiency– Persistent mullerian ducts– ADPKD – Prune belly syndrome
Sperm delivery disorders– Ductal obstruction (7-12%)
• Genital infection• Latrogenic • Walffian duct malformation• Mullerian duct cyst
– Ejaculatory problems Immunologic infertility
PRE - TESTICULAR
Genetic– Kallman’s syndrome– Congenital adrenal hyperplsia– B –thalesemia – Androgen receptor mutation– FSH/LH hormone or receptor defects
Pituitary disease
Goals of evaluation of infertile male
Identify reversible conditions Irreversible conditions – ART Genetic & chromosomal abnormalities
Where is the problem !1. Hormones from Brain2. In the Tests 3. In the Tubes4. Impotence
Ques1
Normal volume azoospermia
Ques 2
• Low ph• Low volume• Azoospermia
Any other factor?????
NOA and OA
• Spermatozoa are found in about 60% of patients with NOA.
• Birth rates are lower in NOA vsOA (19% vs 28%)
• Fertilisation and implantation ratesare significantly lower
• Miscarriage rates are higher in NOAvs OA (11.5% vs 2.5%)
EUA-2010
• Men with non-obstructive azoospermia (NOA) can be offered a testicular sperm extraction with cryopreservation of the spermatozoa to be used for ICSI
• To increase the chances of positive sperm retrievals in men with NOA, TESE (single, multiple or microsurgical) should be used rather than TEFNA
Full evaluation
Endocrine evaluation Post ejaculatroy urinalysis TRUS ± seminal vesiculography Vasography Scrotal ultrasound Sperm function testing
Pct Sperm penetration/viability assay
Anti –sperm antibodies Semen culture Genetic screening
Testicular biopsy
Endocrine evaluation -indications
Sperm density < 10 million/ml Impaired sexual function Clinical findings s/o endocrinopathy
(Endocrine disorders are extremely uncommon in men with normal semen parameters)
TRUS -indications
Fructose negative azoospermia Low volume azoospremia Severe unexplained oligoasthenospremia DRE : abnormal
Genetic testing - indications
Sperm destiny < 5 million/ml Non -obstructive azoospermia Clinical suggestions
Medical therapy
• 5% of patients exhibit abnormal semen analyses for which no etiology can be identified (Greenberg et al , J.urol, 1978)
Specific/Targetted• HH• hyperprolactinemia• Infections• Ejaculatory dysfunction
HH-Causes
• Congen– Kallman
• Acquired– pituitary tumors, – pituitary trauma, – Panhypopituitarism – anabolic steroid use
• The initial evaluation of patients with suspected HGH: MRI
•
Gonadotropin for HH(<1%)
• Initial Mx : hCG ( 3000–6000 IU/wk)– until adequate serum T levels are
detected
• If sperm undetected after 6 mo • co-treatment with– hMG (75–150 U 2-3X/week) or– FSH (50–150 IU 3X/ week)
• 6 to 9 months for sperm to appear in the ejaculate, – therapy may be needed for 1 to 2 years.
• Treatment with hCG/hMG has also been reported to be effective in a patient who has anabolic steroid-induced azoospermia
• GnRH infusion pump(iv or sc): who do not respond to hCG/FSH
• effective treatment for non-pituitary Gn deficiency, both for inducing androgenization and spermatogenesis
• need for a 2-hour dosing : clinically unfeasible
• 8of 9 patients with idiopathic HGH were able to father a child with the use of pulsatile GnRH therapy (Crowley and Whitcomb 1990).
Men on anabolic steroids
• Stop Testosterone
• Full recovery can take over a year and may not return to pretreatment
• Prob: since their endogenous production is suppressed– may need some treatment
Steroid induced azoospermia
• hCG, Clomiphene, aromatase inhibitors
Testosterone/estradiol
Treatment
Normal(15:1) CC/hcg(3000IU alt day)
Altered Letrozole Blocks the aromatization
hormone replacement therapy is more cost-effective than sperm retrieval/ ICSI in these patients
Hyperprolactinemia is a form of HGH
• An excess of prolactin inhibits the hypothalamic secretion of GnRH and has been implicated as a cause of reproductive and sexual dysfunction
• Routine screening of infertile men for hyperprolactinemia has not been shown to be useful
Causes
– pituitary tumor (macroadenoma or microadenoma)
– Hypothyroidism,– stress,–Medications : phenothiazines, tricyclic
antidepressants and some antihypertensives, medical illness, and idiopathic factors
greater than 250 ng/ml, macroadenoma
between 100 and 250 ng/ml
microadenoma
between 25 and 100 ng/ml pituitary stalk compression
0 to 25 ng/ml normal
Steroids– ASA pos: results inconsistent– aseptic necrosis of femur head
• treatment of antisperm antibodies using
corticosteroids should not be prescribed routinely, but it can be considered in patients with antisperm antibodies and earlier failed fertilization during IVF or ICSI.
Androgens• contraindicated
Infections
54% of men who have leukocytospermia have no evidence of infection
positive semen cultures may be found in up to 83% of healthy men, and pathogens such as Ureaplasma urealyticum, Proteus mirabilis, Mycoplasma hominis, Escherichia coli, and Enterococcus are isolated in the same frequency in men who have leukocytospermia and men who do not
• Chlamydia trachomatis has been isolated frequently in asymptomatic men who have unexplained infertility and has been found to bind to and penetrate human sperm
• M hominis and U urealyticum :NGU; demonstrated to impair human sperm function in vitro
• E coli and U urealyticum have been reported to decrease sperm motility
• Other pathogens include Neisseria gonorrhoeae, Treponema pallidum, Mycobacterium tuberculosis, Haemophilus ducreyi, herpes simplex virus I and II, papillomaviruses, and Trichomonas vaginalis.
• MC are Streptococcus fecalis andEscherichia coli, respectively
• Also, Chlamydia trachomatis and Ureaplasma urealyticum are often involved
• antibiotic therapy acc.
• culture-negative patients should be treated with anti-inflammatory therapy and frequent ejaculation because empiric antibiotic therapy generally provides no benefit and may be harmful
When is semen culture done?
• men who have overt signs of GU infections (eg, cystitis, urethritis, or prostatitis), semen and urine cultures are performed
• In asymptomatic infertile men who have leukocytospermia or in cases of truly unexplained infertility, semen cultures can be considered and appropriate antibiotic treatment instituted depending on the organism isolated
Schiff et al, Endocrinol Metab Clin N Am (2007) 313–331
Ejaculatory dysfunction
failure of emission or retrograde ejaculation. Reported causes are
spinal-cord injury, diabetes mellitus, retroperitoneal surgery, multiple sclerosis, and bladder-neck and prostate surgeryPsychogenic idiopathic.
• α sympathomimetic medication ephedrine, pseudoephedrine, imipramine, and phenylpropanolamine.
• IF unsuccessful or C/I, vibratory simulation or electroejaculation.
• Electroejaculation- the application of transrectal electrical current to stimu- late the pelvic nerves---results in approximately 90% of patients producing a semen specimen
Emperic therapy
For empiric pharmacologic therapy---treatment should last at least 3 to 6 months to incorporate a full 74-day spermatogenic cycle
• Advise the couple: – inconsistent response to therapy – low conception rate vs. ART– Lack of a significant improvement sor no
pregnancy after at least two spermatogenic cycles may be an indication to proceed with ART.
EMPERIC Therapy
1. Antiestrogens• Clomiphene citrate MC drug for idiopathic
oligospermia. The rationale for its use is based – on the drug’s ability to bind estrogen receptors,
causing antiestrogen and, to a lesser extent, estrogen effects. This removes the negative feedback inhibition of estrogen at the hypothalamic and pituitary levels, increasing GnRH, LH, and FSH secretion and stimulating testosterone production and spermatogenesis.
–
Due to the peripheral conversion of T, estrogen levels may increase above normalTherefore, monitoring of serum testosterone and estradiol is required to make sure levels do not rise to detrimental levels.
• therapy with clomiphene may be more advantageous in men – who have mild oligospermia and – low serum gonadotropins or – increased estrogen
• Therapy is less likely to be efficacious– who have elevated baseline gonadotropins – in men who have remarkably abnormal
semen analyses or testicular biopsies
Physiological Role of ROS
• Induces acrosome reaction
• Mediates activation and capacitation
• Needed for membrane fluidity
• Bind and traverse the zona pellucida
• Fuse with the oocyte membrane
de Lamirande et al, Hum Reprod, 1995
Why Spermatozoa Susceptible to High Levels of ROS ?
• Possess significant ability to generate ROS
• Contains extremely high concentration of polyunsaturated fatty acids (PUFA)
• Exhibit no capacity for membrane repair
• Limited amount of cytoplasmic defensive enzymes
de Lamirande et al, Hum Reprod, 1995 Alvarez et al, Mol Reprod Dev, 1995 MacLeod, Am J Physiol, 1943
List of the Antioxidants• Ascorbic acid (Vit. C) • - tocopherol (Vit. E) • tocopherol (Vit. E) plus selenium • Glutathione • L-Carnitine plus L-acetyl-carnitine • Coenzyme Q10 • Lycopene • Picnogenol • N-acetyl-cysteine • Vit. A and Vit. E • Pentoxifylline • Selenium • Shao-Fu-Zhu-Yu-Tang • Astaxanthin • Lepidium meyenii • -linolenic acid and lignans • Vit. C and E, lycopene, selenium, folic acid, garlic oil plus zinc • Morindae officinalis extract
Advantages of antioxidants
• Improvement in sperm motility and motion kinetics
• Increase in sperm count in AZ or OA patients • Decrease in abnormal spermatozoa • Reduction in PUFA in sperm membrane • Suppression of ROS production • Reduction in sperm DNA fragmentation • Improvement in sperm viability • Improvement in oocyte fertilization rate • Improvement in pregnancy rate (few studies)
Cochrane Review for “Antioxidants for Male Subfertility 2011”
• Analysis of 34 RCT involving 2876 couples.
• The study evaluated the effect of oral antioxidant supplementation for male partners of couples undergoing ART
• Pooled findings support increases in live births and pregnancy rates with the use of antioxidants by the male partner (P<0.0001).
• However, the evidence for improvement in semen parameters is not substantial.
Conclusions
Antioxidants3 main issues need to be addressed before anti-oxidant therapy becomes routine medical care for the infertile couple: • Present diagnostic tests for oxidative stress are
– cumbersome and – expensive and – not available.
• Without the availability of a “quick and easy” test for OS, many doctors are unwilling/more than willing to offer empirical antioxidant therapy.
• Development of such assays for sperm OS are urgently required
• Pressing need for large multi-centre trials using a single anti-oxidant or combination therapy to confirm that pre-conception supplementation can boost live birth rates.
• Without such a definitive trial, antioxidant therapy will be relegated to the “promising but never proven” basket of medical treatments, never receiving widespread medical support
• Finally, research suggests that OS to sperm DNA may result in miscarriage and possibly even affect the health of the next generation.
• If such inter-generational effects of sperm oxidative damage are confirmed, – pre-conception antioxidant supplementation for
the male will become standard medical practice, just as pre-conception folate supplementation for the prevention of neural tube defects is standard care for women
thankyou
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