Infertility management-Treatment catogories

TREATMENT CATEGORIES OF
MALE INFERTILITY
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai
1

Moderators:
Professors:
• Prof. Dr. G. Sivasankar, M.S., M.Ch.,
• Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
• Dr. J. Sivabalan, M.S., M.Ch.,
• Dr. R. Bhargavi, M.S., M.Ch.,
• Dr. S. Raju, M.S., M.Ch.,
• Dr. K. Muthurathinam, M.S., M.Ch.,
• Dr. D. Tamilselvan, M.S., M.Ch.,
• Dr. K. Senthilkumar, M.S., M.Ch.
Dept of Urology, GRH and KMC, Chennai. 2

Distribution of Etiology of Male
Infertility
• Varicocele
• Idiopathic
• Obstruction
• Female factor
• Cryptorchidism
• Immunologic
• Ejaculatory dysfunction
• Testicular failure
• Drug/radiation
• Endocrinopathy
• Others - <1%
3
Dept of Urology, GRH and KMC, Chennai.

Varicocele
• Abnormal dilation and tortuosity of the internal
spermatic veins within the pampiniform plexus of
the spermatic cord.
• Incidence -
15% --- general population,
35% -- men with primary infertility
75% to 81% - men with secondary infertility.
4

Etiology
• Anatomic variance
• Increased pressure in the left renal vein
• Incompetent or congenitally absent valves
5

• Varicocele -
more common in left testicle than right
Because of several anatomic factors
- right angle at which left testicular vein enters left
renal vein
- Long left testicular vein (8 - 10 cm)
- lack of effective antireflux valves at juncture of
testicular vein and renal vein
- increased renal vein pressure due to its
compression between the superior mesenteric artery and
the aorta
Nutcracker PHENOMENON
6

• Secondary varicocele - due to compression of
the venous drainage of the testicle.
• Pelvic or abdominal malignancy suspects -
when a right-sided varicocele is newly diagnosed
in a patient older than 40 years of age
• Most common cause - Renal cell carcinoma
Others -- retroperitoneal fibrosis or adhesions.
7

Pathologic effects of varicocele
• Abnormal spermatogenesis, and infertility
Semen analysis shows
- Decreased motility,
- Decreased sperm density
- Increased number of pathologic sperm
forms
8

• Histologic studies shows
- Leydig cell hyperplasia,
- Decreased number of spermatogonia per
tubule
- Decreased spermatogenesis and
maturation arrest,
- Sloughing of germinal epithelium
interstitial fibrosis
9

Mechanism of varicocele-induced
IMPAIRMENT OF SPERMATOGENESIS
• Lead theory postulates - that testicular
cellular processes are temperature
dependent.
• Venous pooling from a varicocele produces
- Elevated intrascrotal temperature
resulting in reductions in testosterone
- Injury to germinal cell membranes,
- Altered protein metabolism, and
reduced Sertoli cell function
10

• Free reflux of renal and adrenal metabolites
from the left renal vein - directly
gonadotoxic.
• Spermatic cord blood catecholamine and
prostaglandin levels - appear elevated in
varicocele
11

• Other proposed mechanisms for
Varicocele induced subfertility
 Include impaired venous drainage
with results - hypoxia
 Poor clearance of gonadotoxins
 Elevated levels of oxidative stress.
• Mechanism of varicocele damage -
Multifactorial
12

Indications
• Current guidelines in 2008 by the Best Practice
Committee of American Society for
Reproductive Medicine
• Recommend treatment of a varicocele in the
infertile patient
 Varicocele - palpable on physical examination
 Couple has known infertility
13

 Female partner has normal fertility or a
potentially treatable cause of infertility;
 Male partner has abnormal semen
parameters or abnormal results from sperm
function tests
• Sense of heaviness or hemiscrotal discomfort
• Clinical varicoceles with testicular
hypotrophy
14

• Patients with subclinical varicoceles are
not candidates - varicocele treatment
Prophylactic surgery - not advisable
15

OUTCOMES
• Significant improvement
Semen analysis - 60% to 80% of men.
Mean increases in sperm density - 9.7million/mL
Motility increases - 9.9%
Sperm morphology improvement - 3%
Semen quality - improve in 51% to 78%
16

• Spontaneous pregnancy rates after varicocele
treatment have reported - between 30% and
50%
• Microsurgical varicocelectomy results -return
of sperm ejaculate - up to 60% of
azoospermic men with palpable varicoceles
• Repair of bilateral varicoceles - increased
benefit over unilateral varicoceles
17

• Repair of large varicoceles results in - greater
improvement semen quality than repair of
small varicoceles
• Infertile men with low serum testosterone
levels, microsurgical varicocelectomy results
 substantial improvement in serum
testosterone levels
18

Cryptorchidism
• Relatively common condition -2.7% -newborns
0.8% -1 year
• Well -known etiology for subfertility
• Associated with reduced testicular size and
sperm concentration
• Reductions in serum inhibin
Elevations in serum FSH levels
19

• Reductions in semen quality
• Suggested mechanisms for cryptorchidism-
induced subfertility
Testicular dysgenesis
 Impaired endocrine axis
 Immunologic damage
Obstruction
20

• Studies shows significant detrimental effects
on semen parameters with even unilateral
cryptorchidism
• Studies suggested that orchiopexy younger
than 4 years of age - associated with
improved fertility outcomes
21

Endocrinopathies
• Occur at hypothalamic, pituitary, or gonadal levels.
• Primary hypogonadism (primary testicular failure)
Hypergonadotrophic hypogonadism
- defined as low serum testosterone and elevated
gonadotropin level consistent with organ function
failure at the level of the testes.
• Secondary hypogonadism (hypogonadotropic
hypogonadism)
low testosterone levels in conjunction
low gonadotropin levels
22

Hypogonadotropic Hypogonadism
• Relatively rare cause of subfertility <1%
• May be congenital or acquired
Acquired Causes of Hypogonadotropic Hypogonadism
• Central nervous system (CNS)
CNS developmental abnormalities
Head trauma
Pituitary tumors
• Autoimmune disease
• Parasitic diseases
• Crohn disease
• Beta-thalassemia/hemoglobinopathy
• Hemochromatosis
• Disorders of lipid metabolism 23

Congenital Hypogonadotropic
Hypogonadism
• Congenital idiopathic hypogonadism
Anosmic (Kallman syndrome)
Nonanosmic
• Congenital adrenal hypoplasia
• Fertile eunuch syndrome
• Genetic defects of the gonadotropin subunits
Follicle-stimulating hormone–β mutations
Luteinizing hormone–β mutations
Mutations in leptin and leptin receptor genes
• Syndromes associated with hypogonadotropic hypogonadism
Prader-Willi syndrome
Congenital spherocytosis
Moebius syndrome
Cerebellar ataxia
Retinitis pigmentosa
24

Androgen Excess
• Excess systemic levels of androgen paradoxically
inhibit spermatogenesis
• Due to direct feedback inhibition of
gonadotropin secretion at the level of the
hypothalamus and pituitary.
• Results in low intratesticular levels of
testosterone, inadequate for the maintenance of
spermatogenesis
25

• Excess states may result from either endogenous
production or exogenous administration of androgens
• Congenital adrenal hyperplasia (CAH) most common
endogenous etiology of androgen excess
 specific enzyme defects in cortisol and aldosterone
synthesis.
 Inadequate systemic cortisol levels result in excessive
pituitary release of ACTH leading to hyperstimulation
of the adrenal gland
 subsequent release of adrenal androgens and
suppression of pituitary gonadotropin release.
26

• Deficiency in the 21-hydroxylase enzyme
accounts - 90% of cases of CAH
• Present neonatal period with salt wasting, milder
deficiencies with phallic enlargement, precocious
puberty, and advanced skeletal maturation
• Elevated levels of serum 17-
hydroxyprogesterone and urinary pregnanetriol
- diagnosis of 21-hydroxylase deficiency
• Treatment – glucocorticoid replacement, reduces
ACTH levels and adrenal androgen production
27

Hyperprolactinemia
• Hyperprolactinemia - associated with medications,
physiologic stress, and pituitary tumors
• Elevated prolactin levels – confirmed
(>18 ng/dL),
• Anatomic imaging of the sella turcica - required,
usually with magnetic resonance imaging with
gadolinium contrast.
• Macroadenomas - require surgical excision,
Microadenomas - usually responsive to dopamine
agonist therapy with bromocriptine or cabergoline.
28

Disorders of Internal Ductal
Development
• Congenital Bilateral Absence of the Vas
Deferens
- Mildest presentation of cystic fibrosis
transmembrane conductance regulator (CFTR)
dysfunction
- One CF allele - mutated, patient present
with CBAVD without the pulmonary and
pancreatic manifestations
29

Congenital Bilateral Absence of the
Vas Deferens
• 6% cases of obstructive azoospermia
• Associated anomalies - prominent caput with
absence of the distal two thirds of the
epididymis, atrophy, or hypoplasia of the
seminal vesicles.
• Absence of seminal vesicle contributions
- ejaculate will be azoospermic with
- low volume (typically <0.5 mL)
- acidic pH (6.5) unbuffered scant prostatic
secretions
30

• TRUS - confirm the seminal vesicle anomalies
• Diagnosis of CBAVD - basis of clinical and
semen findings
• Spermatogenesis - usually normal,
• TREATMENT
- Sperm retrieval techniques via a
percutaneous or open surgical route from
either the caput epididymis or testis
31

Ultrastructural Sperm Anomalies
• Primary Ciliary Dyskinesia.
immotile cilia syndrome
- encompasses a spectrum disorders
involving ultrastructural abnormalities of the
flagellum affecting all ciliated cells including
the lining of the respiratory and sinus tracts,
as well as sperm motility.
32

• Electron microscopy demonstrated
abnormalities in PCD - absence of outer and
inner dynein arms, radial spokes, and central
doublet.
• Affected patients - rarely present with
infertility, initially present in childhood with
chronic bronchiectasis and sinusitis
33

• Kartagener syndrome - variant of PCD with
chronic sinusitis and bronchiectasis, situs
inversus, and infertility manifested by low or
absent sperm motility
• No cure for the ultrastructural defects,
• Sperm have been used successfully for ICSI
with resulting normal births
• Genetic counseling - highly recommended
before pursuing ICSI
34

Globozoospermia
• Round headed sperm syndrome
• 0.1% of infertile males
• Sperm concentration and motility – normal,
spermatozoa have a characteristic circular head
due to the absence of the acrosomal cap and
enzyme package including acrosin
• This deficiency prevents the sperm from
penetrating the zona pellucida and outer
investment of the oocyte and from obtaining
fertilization.
• ICSI - Treatment
35

Ejaculatory Dysfunction
• Functional
• Neurogenic
• Retrograde
36

Functional Ejaculatory Dysfunction
• Include premature and delayed ejaculation.
• Premature ejaculation - common form of male
sexual dysfunction,
• Occurs in more than 30% of men between ages
18 and 60
• Cause significant emotional distress in couples
• If ejaculation- consistently occurring before
intromission, semen may be collected by the
couple and used for intravaginal insemination
37

• Delayed ejaculation - defined as persistent
difficulty or inability to ejaculate despite the
presence of sexual desire and erection
• Believed to be psychogenic issue
• Benefit from sex therapy or vibratory
stimulation , electroejaculation or surgical
sperm retrieval
38

Neurogenic Anejaculation
• Usually the result of a spinal cord injury
• Also have erectile dysfunction and deficiencies
in spermatogenesis, & stasis of spermatozoa
• Most require penile vibratory stimulation
(PVS), electroejaculation (EEJ)
• Surgical sperm retrieval via either
percutaneous or open biopsy of the
epididymis or testis - remains an effective
option for management
39

Retrograde Ejaculation
• Occurs when seminal fluid preferentially flows into
the bladder, instead of the normal antegrade direction
due to failure of the bladder neck to close
Causes
• Incompetence of the bladder neck from prior surgery
such as transurethral resection of the prostate gland,
• Medications such as α blockers and antidepressants,
• Neurologic pathology such as diabetes and multiple
sclerosis.
Diagnosis - confirmed by identification of
10 to 15 sperm per HPF in a centrifuged specimen of
postejaculation urine
40

Treatment
• Reversible etiologies such as medications should be
removed
• Trial of sympathomimetic medication therapy useful
in increasing sympathetic tone of the bladder neck and
vas deferens
Phenylpropanolamine Ephedrine
Pseudoephedrine Imipramine
• Who do not respond to medical therapy - sperm
recovered from the bladder for use in intrauterine
insemination
41

Immunologic Infertility
• Antisperm antibodies (ASA) results from a
variety of conditions cause disruption of the
blood-testis immune barrier, results in exposure
of sperm antigens to the systemic immune
system
• Elevated levels of ASA - associated with gonadal
trauma, testicular torsion, cryptorchidism,
varicocele, genital infections, and prior testicular
biopsy
• Prior vasectomy - leading cause of clinically
significant immunologic infertility
vasectomized men - 34% to 74%
42

• Effects of ASA -
 Impaired sperm motility,
 Reduced binding & penetration of the zona
pellucida,
 Inhibition of the acrosome reaction, and
 Reduced sperm survival in the female
reproductive tract.
43

• Current treatment strategies
 Immunosuppression using corticosteroid
therapy
 Assisted reproduction
IUI & Intracytoplasmic sperm injection -
an effective treatment for ASA -mediated
infertility
44

Idiopathic Infertility
• > 30% of patients - still have no discernible
cause for abnormal semen analysis
• At present they are considered idiopathic
disorders
• In absence of other causes, therapy involves
employment of empiric medical therapy or
assisted reproductive techniques
45

Empiric Pharmacologic Therapy
• Gonadotropin-releasing hormone
• Gonadotropins
Luteinizing hormone (human chorionic gonadotropin)
Follicle-stimulating hormone (human menopausal gonadotropin)
• Antiestrogens
Clomiphene citrate
Tamoxifen citrate
• Aromatase inhibitors
Testolactone
Anastrozole
• Other
• Antioxidant vitamins
L-carnitine
Kallikrein
Thyroid hormone
Dopamine agonist for hyperprolactin-associated infertility
Bromocriptine
Cabergoline
46

Gonadotropin-Releasing Hormone Agonists
• Effective for treatment of hypogonadotropic
hypogonadism
• Stimulation of FSH elevation may be
beneficial even in the absence of known
deficiency
47

Antiestrogens
• Most commonly employed medical therapy for
idiopathic male infertility.
• Clomiphene citrate and tamoxifen citrate -
nonsteroidal selective estrogen receptor
modulators.
By blocking the estrogen receptors at the
hypothalamus and pituitary levels,minimizes the
estrogenic-mediated inhibition of gonadotropin
release, results in - elevation of gonadotropin
levels.
48

• More recent study shows combination
therapy with tamoxifen (20 mg/day) and
testosterone replacement (120 mg/day) for
patients with idiopathic oligoteratospermia -
noting improvements in semen parameters
and pregnancy rates
49

Aromatase Inhibitors
• Suppress the activity of aromatase, a
cytochrome P-450 enzyme concentrated in
the testes, liver, brain, and adipose tissue.
• Aromatase - responsible for the conversion
of testosterone to estradiol, so blockade
produces functional effects similar to the
antiestrogen class of medications
50

• Testolactone and anastrozole - two main
agents used for the treatment of idiopathic
infertility.
• Study shows noted improvement in semen
parameters in men with severe idiopathic
oligospermia
51

Antioxidant Therapy
• Antioxidant supplementation - common form
of empiric therapy.
• Antioxidant vitamins
α-tocopherol(vitamin E), ascorbic acid(vitaminC)
retinoids (vitamin A), L-carnitine,
amino acid - important for mitochondrial
metabolism, shows therapeutic benefit for
male subfertility
52

• Various studies shows - antioxidant vitamin
supplementation L-carnitine have shown
improvement
semen parameter and pregnancy rate results
53

THANK YOU
54

Anatomy
• Testicular veins form highly anastomotic
channels that surround the testicular artery
forms pampiniform plexus.
• Arrangement allows countercurrent heat
exchange, which cools the blood in the testicular
artery.
• Testicular veins may anastomose with the
external pudendal, cremasteric, and vasal veins
55

• At the level of the
inguinal canal, veins join
to form two or three
channels
• Then a single vein that
drains into
Right - Inferior vena cava
Left - Renal vein
56

• Examined in a warm room -standing and supine
positions, with and without a Valsalva
maneuver.
• Grade I - detectable only during the
Valsalva maneuver
• Grade II - can be palpated without Valsalva
• Grade III - visible through the scrotal skin
classically described as feeling like a “bag
of worms”
57

Physical examination - Testis
• Assess - testicular consistency & volume.
• Simultaneous comparison of both testes
• Several methods are available to measure the
size of testis
- visual comparison
- calipers like Prader orchidometer
Takahi orchidometer
- Ultrasound.
58

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