Male infertility

Male factor contribute wholly or in part of 40-50% causes

of infertility.

Regulation of the testis:

The testes have two distinct components –
(i) seminiferous tubules (site of spermatogenesis).
(ii) Leydig cells (source of testosterone)

The function of these components is regulated by pituitary

gonadotropin (FSH; LH).
The primary effect of LH is to stimulate the synthesis and
secretion of testosterone by the Leydig cells (about 5-
10mg per day), an effect that is enhanced by FSH, which
also bind to Leydig cells and increase the number of LH
receptors on the cells.

Increasing levels of testosterone, in turn, inhibit LH

secretion (negative feedback), acutely through the
hypothalamus and chronically at the level of the pituitary.
This negative feedback action does not require
aromatization to oestrogen.
In men virtually all the oestrone and oestradiol present are
derived from androstenedione and testosterone; there is
essentially no direct secretion of oestrogen.
FSH, in conjunction with testosterone, acts on the
seminiferous tubules to stimulate spermatogenesis. This
effect may be mediated by sertoli cell function, which is
controlled by both FSH and testosterone.
FSH binds to sertoli cells and stimulates the production of
several proteins, one of which is Androgen binding protein
(ABP).
Spermatogenesis requires a very high local concentration
of testosterone and dihydrotestosterone (50 times higher
than the level of testosterone in the circulation and
greater than the amount of testosterone that can be
administered exogenously).
The ABP is secreted into the tubule lumen, where they
bind testosterone and dihydrotesterone as they diffuse
into the tubule lumen, concentrating the androgens in the
seminiferous epithelium for spermatogenesis and as well
in the epididymis for sperm maturation.
Steroid hormones at physiological levels do not suppress
FSH secretion. Inhibin B is synthesized in the sertoli cells
in response to FSH, it specifically inhibits FSH secretion in
the pituitary.
Inhibin has been found in seminal fluid, spermatozoa,
sertoli cells, and Leydig cells. Inhibin A is absent in the
circulation of males. The secretion of inhibin B by the
sertoli cells is further modulated by LH, human chorionic
gonadotropin, and testosterone.

Note: The sertoli cells of the testis are analogous to the

granulosa cells of the ovary, and the Leydig cells are
comparable to the theca cells.

Leydig cells contain receptors for prolactin. Prolactin at

normal levels stimulate testosterone secretion, where
hyperprolactinaemia leads to reduced testosterone
secretion.

The seminiferous tubules and the intraluminal

environment are controlled by the sertoli cells. Tight
junctions between the sertoli cells effectively seal off the
tubules, creating the blood-testis barrier.
The seminiferous tubules, therefore, are essentially
avascular, and regulatory substances must enter by
diffusion. The blood-testis barrier protects the germ cells
from antigens, antibodies, and environmental toxins. The
Leydig cells are in the connective tissue between the
seminiferous tubules.
Developing sperm are enveloped by sertoli cells that
influence the sequential process of spermatogenesis.
Spermatogonia undergo mitotic division to form the
primary spermatocytes, which undergoes meiotic division
to form secondary spermatocytes (i.e haploid [23
chromosomes]). The secondary spermatocytes proceed
through maturation process to the spermatid stage, which
ultimately becomes the spermatozoa.
Note: One X chromosome in the somatic cell of the female
is inactivated; in the oocyte both X-chromosomes are
genetically active.
In the male, the single X-chromosome in the somatic cell
(XY) is genetically active, while that in the spermatocytes
is inactive. Normal spermatogenesis is directed by the
genes on the Y-chromosome.

Most of the testis is composed of the tightly coiled

seminiferous tubule (each tubule, if uncoiled reaches a
length of 70cm). A spermatozoa takes approximately 74
days to reach maturity, about 50 days are spent in the
seminiferous tubule. After leaving the testes, sperm takes
12-21 days to travel the epididymis (which is 5-6 metres
long) and appear in the ejaculate. The vas deferens is 30-
35cm in length, begins at the cauda epididymis and
terminates in the ejaculatory duct near the prostate.
Semen is composed of secretions contributed in a
sequential fashion, first the prostatic fluid and contents of
the distal vas deferens, followed by seminal vesicle
secretions.

Semen Analysis:
1. Abstinence from coitus of 2-3 days prior to collection
of semen sample for analysis.
2. specimen should be collected directly into a clear
container with wide bore.
3. the recommended method of production is
masturbation – collection of a specimen by
withdrawal (coitus interruptus) runs the risk of losing
the first part of the specimen that contains the
highest concentration of sperm. Ideally, the specimen
should be collected in a private room near the
laboratory. If collected at home, the specimen should
be protected from the cold and delivered to the
laboratory within 1 hour of collection for analysis.

The world health organisation suggested values for semen

analysis.

Volume 2.0ml or more

Sperm concentration 20 million/ml or more
Motility 50% or more with
forward progression or
25% or more with rapid
progression within 60
minutes of ejaculation.
Morphology 30% or more normal
forms
White blood cells Fewer than 1 million/ml
Immunobead test Fewer than 20%
spermatozoa with
adherent particles
Sperm Mar test Fewer than 10%
spermatozoa with
adherent particles.

Note: At least 2 samples or preferably 3 samples of semen should be

screened before an individual is diagnosed as fertile, subfertile or
infertile.

Investigation and treatment of male infertility:

If the semen analysis is abnormal, enquiries should be made about –
(i) History of testicular injury, surgery or mumps.
(ii) Exposure to excessive heat – chimney sweeper, long distance
truck driving.
(iii) Severe allergic reactions
(iv) Exposure to radiation, or to industrial or environmental toxins
(v) Heavy marijuana and alcohol use can depress sperm count and
testosterone levels – marijuana inhibits the secretion of GnRH
and can suppress reproductive function in both men and women
and cocaine use is known to reduce spermatogenesis.

There is good evidence that fecundity is reduced in women who smoke.

Certain drugs, including cimetidine, spironolactone, nitrofurans,
sulfasalazine, erythromycin, tetracycline, anabolic steroids, and
chemotherapeutic agents, can depress sperm quantity and quality.
Cephalosporins, penicillins, quinolones, and the combination of
sulphamethoxazole and trimethoprim are relatively safe to use when there
is concern about effects on sperm.
Neurologic ejaculatory dysfunction can be caused by α-blockers,
phentolamine, methyldopa, guanethidine, and reserpine.
(vi) Coital frequency – counts at the lower level of the normal range
may be depressed to below normal levels by more frequent
ejaculation.
 (vii) Exposure to diethylstilbesterol in utero.

Urologic evaluation:
1. Anatomic abnormalities – hypospadia, epispadia, retrograde
ejaculation into the bladder (as in diabetic neuropathy, pelvic
lymphadenectomy or prostatectomy); obstruction or absence of the
vas deferens (fructose which is produced in the seminal vesicles
will be absent from the semen).

Note: Kartagener syndrome includes sperm immobility, bronchiectasis,

sinusitis, and situs inversus.

Genetic causes of male infertility:

- Karyotyping – Klinefelter syndrome (47XXY) as with azospermia
or severe oligospermia.
- Endocrine disorders – are rare cause of male infertility – testing for
thyroid, gonadotropins, prolactin and testosterone may
occasionally reveal an unsuspected abnormalities. FSH levels are
elevated with germ cell aplasia, testosterone levels are decreased in
men who are hypogonadotropic. Hyperprolactinaemia is commonly
associated with impotence.

Varicocele:
A varicocele is an abnormal tortuosity and dilatation of the veins of the
pampiniform plexus within the spermatic cord.
The varicocele usually occurs on the left side because of the direct
insertion of the spermatic vein into the left renal vein.

Reactive Oxygen species:

Increased levels of reactive oxygen species can cause damage to the
sperm membrane. Substances such as peroxidase and hydrogen peroxide
can be released by abnormal sperm and by white blood cells, and when
elevated levels of leukocytes are present in the semen (with a negative
culture), treatment with vitamin E and glutathione is advocated.

Management of male factor infertility:

Due to reaction to whole semen insemination (potential reactions to the
proteins, prostaglandins, and bacteria in semen) there is the need to use
washed sperm for intrauterine insemination (IUI).

Indications for IUI:

(i) Failure of sperm to penetrate cervical mucus.
 (ii) Unexplained infertility with superovulation with clomiphene/
gonadotropin.

Methods of washing sperm

(i) swin-up (allow sperm to swim-up hyaluronic acid).
(ii) Separation of sperm on density gradients.

At least 1 million sperm should be inseminated to increase the pregnancy

rate.
The multiple pregnancy rate increased when more than 20 million motile
sperm was inseminated.

Therapeutic donor insemination (TDI):

TDI must never be done without the consent of both partners.

Donor insemination do not guarantee pregnancy, the success rate with

fresh semen is higher than with frozen semen.

Before TDI, the donor should be screened for HIV and the semen
quarantined for 6 months, only to be used after the donor is screened after
6 month, if still negative and has not be practising risky behaviour, its
only then it can be inseminated.
The donor is also screened to exclude family history of thalassaemia in
Mediterranean races, Tay-sachs heterozygosity in Jews, and sickle cell
disease in blacks.
Donor inseminations are useful in azospermia, severe oligospermia, or
asthenospermia refractory to treatment.
Donor insemination is also useful for the rare woman, who has a history
of fetal loss due to Rhesus sensitization. In this case a Rh-negative donor
is used.

Timing of insemination:
(i) The basal body temperature change (inseminate a day or 2
before temperature rise).
(ii) The woman’s perception of vaginal wetness, and ovulatory
pain.
(iii) Monitoring LH surge with LH urine kits (inseminate a day after
a positive LH test).
(iv) USS monitoring of preovulatory follicle growth.
(v) Inseminate approximately 36 hours after HCG administration.

Intracytoplasmic sperm injection (ICSI):

Direct injection of a single spermatozoon or spermatid into the cytoplasm
of an oocyte. Today in-vitro fertilization with ICSI can overcome even
the most grievous cases.