Infertility is defined as a state in which a
couple, desirous of a child cannot conceive after 12 months of
unprotected intercourse. But, if a couple approaches a doctor
for infertility, they should be evaluated to see that they do not
have any major problems.
Initial evaluation of the
Infertility, the inability to conceive after 1 year of unprotected
intercourse, is estimated to affect one in six couples at some point
in their life. Investigations should be normally be instigated as
soon as the couple seeks help, as gross irregularities that one
could come across during history taking or examination can be
corrected immediately. There are many situations unique to the
Indian set up, like couples staying separately, or working for long
hours with no time for intimacies, interference from overbearing
family members, being just some of them. Social stigma attached to
infertility is also peculiar to the subcontinent.
It is important to try and start counselling in the presence of only
the husband and wife, without interference from relatives or
friends. . In India, the male partner quite often refuses to be
involved in discussions. If the male partner refuses to meet the
gynaecologist, it would be better to talk to the female partner
alone, confidentially, as this would bring out many points in the
history, which may be masked, in the presence of parents or
friends. For example, H/O medical termination of pregnancy before
marriage, or the presence of children by another marriage, are
quite often suppressed unless the woman is interrogated separately.
Investigations include careful history taking, examination, blood
investigations and other specialised investigations focused to
determine if the woman has any of the eitiological factors
responsible for infertility.
Initial evaluation of a patient:
A careful history should include questions to know :
Whether the couple are staying together, and the frequency of
There is pain during intercourse
Regularity of menstruation
Associated History of any medical disorders
BMI:Determination of body mass index(BMI) is important, as both
obesity as well as being too underweight can be causes of disorders
of ovulation and pregnancy wastage. Determination of BMI is made
from the height and weight (Kg/m2). The normal range is
20-25kg/m2. BMI of >30 falls in the obesity range.
A cursory examination can reveal stigmata of hyperandrogenism, like
acne, hirsuitism, and male pattern of balding , which are
suggestive of Poycystic ovarian syndrome(PCOS). Hirsuitism can be
graded and given a “Ferriman Gallway” score.
Virilisation is a higher grade of androgenism with very high
circulating androgen levels and causes deepening of the voice,
increase in muscle bulk,cliteromegaly and breast atrophy beside the
other signs of hyperandrogenism. Other than severe PCOS,it could
also be seen in congenital adrenal hyperplasia(CAH) , androgen
secreting tumors and Cushing’s syndrome.
Acanthosis nigricans is a sign of profound insuin resistance and is
usually visible as hyperpigmented thickening of the skin folds of
the axilla and neck, associated with PCOS and obesity.
Any thyroid swelling should be noted.
Breasts should be examined to look for galactorrhoea. It is
important to know that examination of breasts, vagina, or even
stress can elevate prolactin levels and therefore, blood tests
should never immediately follow examination of the patient.
It is mandatory to do a per vaginal (PV) and per speculum
examination as it can give a lot of valuable information. The
advent of Utrasonography has led to a reluctance to do vaginal
examination. However, a PV has, quite often led to the discovery
that the couple are not even aware of the need for proper penile
insertion into the vagina for completion of intercourse. Some such
couple who have not even consummated their marriage have been known
to undergo expensive investigations for infertility. Acute
retroversion and retroflexion of the uterus with the cervix lying
almost close to the urethra will need proper counselling. The
average gynaecologist asks the patient to lie for half an hour in
the supine position with a pillow under her buttocks so that the
cervix dips into the pool of semen in the vagina. However, in the
retroflexed uterus, the supine position may not serve that purpose.
Irregularities in the fornices , specially the posterior fornix is
suggestive of either endometriosis or post infective adhesions, and
such findings on initial evaluation should prompt the clinician to
start evaluating and treating the patient straight away. Acute
pelvic infection is another finding which can be missed if one
solely relies on ultrasound reports. These “misses” are more likely
in the patient who comes with reports from many doctors and more so
when some investigative reports show gross abnormalities like
resistant PCOD or Azoospermia in the male, just to name a few. The
doctor who sees the patient with many reports, may just omit Per
vaginal examination, thus missing out a recent infection or polyp or
A per speculum examination can sometimes reveal cervicitis or
endometrial polyps, or even simple trichomonal infection and if
they are detected and treated after proper examination it can
improve results in a fertility clinic.
Endocervical swabs and tests for Chlamydia detection:
Chlamydia trachomatis can cause cervicitis , salpingitis and
endometritis in women, although symptoms can be mild and
non-specific1. Antibodies can be tested in serum and
antigens in endocervical swabs. Some clinics routinely test serum
for anti chlamydial antibodies. The presence of chlamydial
antibodies predicts tubal damage in 90% of cases. Chlamydial
antigen can be detected by enzyme linked immunosorbent assy in
(ELISA) of endocervical swabs. A sensitive urinary assay also has
been developed for the screening of past chlamydial infection.
However, Chlamydia detection tests may be negative in the presence
of upper genital infection.
Bacterial vaginosis causes up to 50% of vaginal infections. It is
associated with infective complications following gynaecological
surgery, first and second trimester miscarriage and premature
labor/delivery. There is also an increased risk of miscarriage
after IVF in women found to have bacterial vaginosis. Screening for
bacterial vaginosis can be useful in the investigation of
Investigating the female further, should be target oriented, to
determine if the woman has ovulatory disorder, tubal factor,
cervical factor or immulogical cause for infertility. As against
semen analysis for the male, which is a simple test, most of the
investigations for dertermining female factor of infertility are
cumbersome and some invasive, so one has to be careful in deciding
which patient should undergo the investigation, and the frequency
with which she has to undergo the tests.
Oligo ovulation or anovulation is the commonest female factor of
infertility. Empirical treatment for infertility is most often
targeted at correcting ovulatory disorders. Documenting ovulation
before starting therapy for oligo/Anovulation would be ideal instead
of empirical treatment, which can have draw backs, like reduced
cervical mucus with the use of prolonged clomiphene therapy. The
following investigations can help ascertain if a woman is
History: Irregular periods are suggestive of anovulation. Women who
are having regular menstrual cycles (frequency of 23-35days, with no
more than 2-3 days variation each month) have a greater than 95%
chance that they are ovulating.
Basal body temperature chart: The temperature of the woman is taken
every day before rising from bed and noted. Just after ovulation
the temperature rises by 0.2-0.50 C due to a rise in
progesterone levels and remains higher than the preovulatory phase.
It is a retrospective diagnosis and can strain the patient, though
it is a fairly good method of documenting ovulation. However, a
flat BBT chart does not necessarily mean anovulation, as 10-75% of
ovulatory cycles fail to show a rise in BBT.
Serum progesterone measurements:A serum progesterone value greater
than 30nmol/L in the luteal phase suggests ovulation. However, in
a woman with an erratic cycle, it is difficult to know when to do a
progesterone measurement. In such patients, if the progesterone
level is 15-30, it need not mean anovulation as it may be in the
proliferative phase of menstruation. Thus the progesterone value
has to be co-related with the onset of menstruation. Progesterone
levels combined with USG is more useful.
Endometrial biopsy: A secretory endometrium in the second half of
the cycle suggests ovulation. It is an invasive method and is not
resorted to in current day practice.
Urinary LH kits: Urinary LH is measured using reagent strips by the
patient herself . In response to a preovulatory surge in estradiol,
LH levels surge in the bloodstream and spill into the urine. The
kit measures the LH as it accumulates in the urine and a midcycle
surge predicts ovulation.
Ovulation induction kits can help couples to time intercourse. The
testing should be carried out at the same time every day starting
two to three days before expected ovulation. 3 drops of urine is put
on the kit. A colour change predicts ovulation in 12-24 hours.
The true window of fertilization is actually short (usually <24
hours), but the sperm can remain in the cervical mucus for 72
hours. Thus even if the monitor predicts several days of LH surge,
the sperm in the mucus can still reach the ovum in case of
ovulation, on any one of these days.
However, this is a prospective test and ovulation cannot be
confirmed , as increase in LH levels may not always end in
ovulation. In patients with elevated LH levels, like in PCOD, the
LH levels may remain high, the kits showing positive surge every day
of the month.
Ultrasound: Ultrasonography as an investigative tool is basically
used for detecting ovulation and timing ovulation. By and large,
transvaginal sonography is preferred over the older method of
transabdominal sonography. Rarely, wives with vaginismus, or whose
husbands have erectile dysfunction or premature ejaculation may find
transvaginal sonography painful. In such patients, abdominal
sonography may be needed to monitor ovulation.
Abdominal vs Vaginal sonography: Transabdominal ultrasound does not
allow adequate visualization in patients with obesity, scars of
abdominal surgery, or patients with ovaries fixed in the deep
pelvis. Follicle structures are better seen on Trans-vaginal
ultrasonography. Follicle diameter measured by transabdominal
ultrasound are greater by an average 3.2mm .
Assessment of follicles: A baseline scan should be done on day 3-5
of the cycle, to rule out ovarian cysts or persisting corpus luteal
cysts from the previous cycle. If a cyst is detected, it would be
apt to commence ovarian stimulation only after the patient has had
another spontaneous menstrual bleed, which indicates that the
endogenous secretion of ovarian hormones has returned to baseline
levels. This can be corroborated by the finding of a thin
endometrial lining (<5mm). A baseline scan also can rule out the
presence of hydrosalpinges,or submucous fibroids.
In the diagnosis of PCOD, calculating the ovarian volume is
important. It is calculated by the formula, for a prolate
The preovulatory follicle grows at a rate of 2-3 mm per day and is
17-25mm at the time of ovulation. Inner diameter of the follicle is
measured, in 2 dimensions,Anteroposterior and longitudinal, and the
Pregnancy is associated with follicles of larger size at the time of
ovulation are usually those greater than 20mm. Largest diameter of
the preovulatory follicle is 16-18mm in normal or clomiphene
Ultrasound features of ovulation are:
Reduction in size of the follicle
Loss of definition of the folllicular wall,
Presence of fluid in the pouch of Douglas
Multiple echoes in the follicle.
Change in texture of endometrium.
Timing of ultrasound: Beside the base line scan, for monitoring
follicular growth, Ultrasound assessment is usually carried out one
or two days before expected ovulation and repeated every one or two
days till after ovulation. In stimulated cycle, where HCG or GnRh
analogues are given to stimulate ovulation, the trigger injection is
given when the dominant follicle is 18mm, and insemination timed 36
Evaluation of endometrium: The sonographic appearance of the
endometrium may reflect an adequately receptive tissue and may be
related to the success or failure to achieve pregnancy. Endometrial
thickness, measured in the plane through the central longitudinal
axis of the uterus between the interfaces of the endometrium and
myometrium represents the estrogenic activity of the uterus. In the
normal cycle, the endometrial thickness ranges from 6-12mm in the
late follicular phase and is usually 10-12mm at around the time of
ovulation. Periovulatory endometrium has a characteristically three
line pattern. The middle layer represents the lumen of the
endometrial cavity. The mucus in the lumen makes the cavity
echogenic, represented as the middle line. A thin or homogenous
endometrium in the pre-ovulatory phase may be associated with poor
fertility outcome. Endometrium becomes hyperechoic in the luteal
Colour Doppler sonography in infertility: Poor uterine flow
is a cause for infertility7. Measuring uterine bloodflow
using resistance index and pulsatility index
In the uterine artery has been useful in predicting success in IVF
cycles. Sustained diastolic flow in the uterine artery during early
and midsecretory phase is associated with a high chance of success
in IVF cycles8. Women with poor uterine perfusion could
have their embryos preserved for transfer at a later date, when
their endometrial receptivity is better.
A baseline endocrine profile quite often is helpful in evaluating
and monitoring treatment of anovulation.
Endocrine profile is optimally performed during the first 3 days of
the cycle. The initial workup should include measurement of thyroid
stimulating hormone, prolactin, and cycle day 3 FSH and estradiol
Thyroid disease is found very commonly in reproductive age women and
should be assessed by doing a Thyroid Stimulation test,(TSH) which
is the most sensitive test of thyroid function- an elevation
suggesting hypothyroidism. Hypothyroidism can also elevate
Prolactin levels fluctuate throughout the day, reaching a nadir in
the morning, and therefore, testing should be done in the morning6.
Women with hyperandrogenism should in addition undergo determination
of testosterone, dehydroepiandrosterone sulphate (DHEAS), and 17-
hydroxyprogesterone (17OHP) levels. Women with PCOS should have a
fasting glucose or 2-hour glucose tolerance test. Some workers use
glucose to insulin ratio or simply insulin level to gauge the degree
of insulin resistance.
Luteal phase deficiency used to be assessed by measuring
progesterone levels, but progesterone is secreted in pulses every
2-3 hours, and therefore may not indicate actual levels.
Tests for Ovarian reserve:
In every woman, there is a resting follicle pool, which represents
the ovarian reserve, from which follicles will be recruit
ed for maturation. The term "ovarian reserve" refers to a woman's
current supply of oocytes and is associated with reproductive
potential. A diminished ovarian reserve greatly decreases a
patient's chances for conception.
results may predict a lower pregnancy rate, but the possibility of
pregnancy cannot be totally ruled out. Ovarian reserve can be
assessed by Biochemical tests, Dynamic tests, Sonography and Ovarian
FSH: Basal (Day 3) FSH levels indicate ovarian responsiveness. An
FSH level>15IU/ml indicates that ovarian activity is minimal.
Estradiol: In older women, a more advanced follicular recruitment
by cycle day 3 results in high serum estradiol concentrations in the
early follicular phase. Basal levels of Estradiol >80pg/ml is
associated with higher cancellation rates in IVF.
Inhibin: Inhibin is a polypeptide produced by granulose cells of the
ovary. Inhibin levels below 45pg/ml demonstrated a poorer response
to ovulation induction in ART cycles.
Serum Mullerian hormone (AMH): AMH is produced by granulosa cells
and it regulates the transition from resting primordial follicles
into growing follicles. Levels decline with advancing female age.
The advantage is that levels do not fluctuate with menstrual
Dynamic tests for ovarian reserve:
Clomiphene challenge test: Clomiphene is administered at the oral
dose of 100mg between days 5 and 9 and FSH levels measured twice,
once on the 2ND and 3rd day and again on the 9-11th
day. A total FSH level >26IU indicates poor ovarian reserve.
However, basal FSH levels have been found to correlate better than
clomiphene challenge test to know ovarian reserve.
Gonadotropin Analogue Stimulation Test (GAST): GAST evaluates the
estradiol serum concentration change from cycle day 2 to day 3 after
the administration of a supraphysiological dose of a GnRH agonist.
The prompt response of E2 levels, reflect the ovarian reserve.
Exogenous FSH Ovarian Reserve test (EFORT): In this test, following
the measurement of basal FSH and estradiol levels, estradiol
respose 24 hours following a 300IU FSH injection on day 3 is
determined. However, it is a costly test and therefore, not
Antral follicle count (AFC): AFC is the number of follicles smaller
than 10mm in diameter, detected by TVS, in early follicular phase.
A count of 8-12
indicates good ovarian reserve and a normal response to IVF. A count
of 6 or less suggests the need for higher stimulation protocols.
In one study, AFC< 3 had 68.8% cancellation rates in IVF.
Ovarian volume: In women with small ovaries(<3cm3) the
cancellation rate of IVF is higher.
Colour Doppler sonography in ART: Ovarian blood flow,
Endometrial blood flow, etc can be assessed with colour Doppler.
Good flow indicates good endometrial receptivity. If endometrium is
non receptive as per Doppler studies, in ART cycles, precious
embryos can be stored till another cycle, where the endometrium has
been made receptive.
Tests to assess tubal patency:
All patients who seek evaluation of fertility need to have their
tubes evaluated at some point of time. Even patients with obvious
anovulation or azoospermia, will need tubal evaluation, if pregnancy
is not achieved after treatment for a few cycles. Patients with
prior pelvic inflammatory disease, sexually transmitted diseases
such as gonorrhoea or Chlamydia trachomatis, or a history of septic
abortions are most likely to have tubal disease. Patients with
positive antichlamydial antibodies are likely candidates for tubal
Tubal patency can be evaluated through hysterosalpingography,
sonosalpingogram,ultrasound contrast hysterosalpingography and
involves the X-ray imaging of the pelvis while a contrast medium is
injected into the uterus through a cannula positioned in the
cervical canal. The uterine cavity and tubes can be imaged in real
time and the spill of the radioactive medium into the pelvis noted.
X-rays are taken while the dye passes through the uterus and after
it spills into the pelvis .
Cannulas used: In India, either metal cannulae that can be screwed
into the cervical canal, or balloon catheters that are passed into
the uterine cavity itself are used.
Contrast medium:A water soluble medium is usually used and will be
absorbed after an hour. Sometimes the cause of an apparent blockage
is a mucus plug, which might be flushed through the tube by the
contrast medium. Thus there are reports of an increased chance of
pregnancy in the 2 or 3 months that follow either an HSG.
Timing: An HSG should be performed optimally within 10 days of a
menstrual period when there should be no risk of a pregnancy. The
HSG can be uncomfortable, especially if there is either tubal spasm
or a tubal obstruction. Tubal spasm can occur and antispasmodics
have been employed. A slow injection of dye can prevent tubal
Antibiotic prophylaxis: Routine antibiotic prophylaxis is
recommended with a 3-5 day course of doxycyclin to treat silent
pelvic infection, particularly, chlamydia.
Characteristic findings: The cavity of the body of the uterus is
usually triangular, sometimes with a concave or convex fundus.
Filling defects that are in the uterine cavity can sometimes be due
to air bubbles. These defects have to be distinguished from
Irregular filling defects could be caused by intrauterine adhesions,
which could be a cause of recurrent abortions.
Submucous fibroids can show as filling defects.
Partial or complete septum can be diagnosed on HSG by seeing the
contrast free longitudinal filling defect in the centre.
Unicornuate uterus will show the dye filling only one side of the
uterus with the tube.
Tubal blocks and the site of block can be diagnosed on HSG. A free
spill of dye into the peritoneal cavity indicates patent tubes.
Hydrosalpinx can , often with multiple strictures and a beaded
appearance; occasionally the tube is rigid, with a “pipe stem”
Pelvic tuberculous may lead to calcification, which can be seen on
An 8f foley’s urinary catheter is inserted into the uterine cavity
and 2.5-3.0ml saline is injected into the bulb to stabilise it.
While concentrating on scanning the space between the cornu and the
ovary on either side, 20ml saline along with air is pushed through
the Foleys catheter . Patent tubes distend with the mixture of
agitated saline and air-bubbles gush past the ovary. As an
extension,in a procedure called hydrogynecography, after giving
Atropine and antispasmodics orally half an hour before, 300 ml of
normal saline is injected to flood the pelvis, delineating all sorts
of adhesions, flimsy and dense. However, one has to be sure there
is no active pelvic infection before doing the procedure.
Ultrasound contrast hysterosalpingography : It is now possible to
perform an HSG using ultrasonography and an ultrasound contrast
medium which contains galactose microparicles(“Echovist”) and is
therefore free of the possible risks of radiation.
Caution: Both Sonosalpingogram and hysterosalpingography should not
be performed in the presence of active pelvic infection. These
investigations are contraindicated in the presence of adnexal
Advanntages of hysterosalpingography:
gives a permanent pictorial record of the findings.
Tubal pathologies like hydrosalpinx and beaded tubes can be seen
Uterine pathologies like unicornuate uterus, septate uterus/bicornuate
uterus,T-shaped uterus, etc, are better delineated on
the presence of air bubbles, intrauterine adhesions cannot be
Advantages of Sonosalpingogram: Since most infertility clinics
have an ultrasound machine in their clinic, with just an addition of
facilities to detect tubal patency, tubal patency test can be done
immediately with the evaluation of infertility.
Additional findings like fibroids, uterine polyps,etc can be
diagnosed more accurately on sonosalpingogram.
In hydrosalpinx, tubal flow may give a false impression of tubal
2..Expertise in ultrasonography has a higher learning curve compared
Spill of fluid has to be detected immediately, while the liquid
flows out. However, the site of the block cannot be pinpointed, as
cornual, fimbrial, etc. This can affect planning of management.
Cornual blocks are better managed hysteroscopically, while fimbrial
blocks or midtubal blocks due to external adhesions need
Findings of the fluid coming out of the tube may be subjective and
objective reports cannot be given.
Laparoscopy and hysteroscopy:
Laparoscopy is not done as an initial investigative tool, unless
there are obvious stigmata of endometriosis clinically.
Hysteroscopy should always accompany laparoscopy for infertility, as
many findings like incidental polyps can be detected on
hysteroscopy. Laparoscopy can ascertain tubal patency, presence of
adhesions or endometriosis which can alter the tubo-ovarian
anatomy. Peri-hepatic adhesions, pathognomonic of chlamydial
infection, should be looked for in all laparoscopies for
infertility. Laparoscopy is usually resorted to after many failed
cycles of treatment of infertility. Laparoscopy should always be
done in centres where operative corrections are possible in cases
where there are detrimental anatomical factors for infertility.
Cervical factor of infertility and Immune factor of infertility
Cervical receptivity was tested by doing the post coital test, where
live sperms were quantified in the cervical mucus after
intercourse. However, this test is no longer performed.
Presence of antisperm antibodies in the serum of the infertile
couple and in the cervical mucus also used to be looked for, but the
utility of this test is currently being questioned.
Initial evaluation of the
The simplest evaluation in male infertility is the
semen evaluation. Semen should be collected after two days
abstinence into a wide bore container and preferably examined within
half an hour of collection. If the semen parameters are
abnormal, the male should be examined to see if the testes are of
normal size and for the presence of varicocoele. Grossly big
varicocoeles should undergo surgical correction. If the count is
very low and if the hair growth on the face is low there could be
Klinefelter-s syndrome. Estimation of serum FSH and
Testosterone could be helpful in planning treatment in patients with
very low counts.
A semen analysis report contains macroscopic and
microscopic evaluation. Macroscopic evaluation includes an
assessment of semen color, volume, and viscosity.
Colour-Normal semen has a pearly, opalescent
colour. Blood tinged or purulent semen is abnormal.
Volume: The mean normal volume suggests incomplete
sample collection. But if repeated semen analyses shows low
volume, it is abnormal. If it is less than 0.5ml,and there are
no sperms in the ejaculate, one must think in terms of retrograde
ejaculation and examine the urine for sperms immediately after
ejaculation. If the volume is low and the ejaculate contains
sperms, a post coital test should be done to see if adequate sperms
reach the cervical mucus. If not, the couple may benefit from
intrauterine insemination with husband-s sperms.
Viscosity and liquefaction: Many laboratories in
rural areas do not evaluate this parameter at all. If the
woman does not liquefy within half an hour on standing, even with a
good count, the couple may not achieve conception.
Sperm density: Sperm density should be 20 million
or more sperm per milliliter. Normally 40% or more sperms are
motile. Azoospermia is defined as absence of spermatozoa in the
ejaculate. The ananlysis should be repeated twice to confirm the
diagnosis. Motility is a more important parameter of sperm
function compared to count.
Abnormal forms should be less than 40% .
Presence of pus-cells could be indicative of
prostatitis and may need prolonged antibiotic therapy.
Treatment of male
General advice:Men with
oligospermia should be advised to abstain from alcohol and smoking
as both have deleterious effects on spermatogenesis. Heat can
have a detrimental effect and sitting hot baths and wearing
tight-fitting underpants and trousers should be avoided.
Diabetes, chronic renal failure or thyrotoxicosis should be looked
for and treated. As simple an acute illness as a streptococcal
sore throat requiring penicillin can result in a temporary
azoospermia. It is therefore important to note any such
illness in the past 3 months when reviewing the results of semen
Frequency of intercourse: The
concentration of motile sperm in sequential ejaculates decreases in
normospermic men. But men with oligozoospermia or asthenozoospermia
appear to benefit from sequential ejaculations and they should be
advised to have intercourse at least daily, if not twice daily,
around the time of ovulation rather than follow the usual advice
given to normospermic men of alternate day intercourse.
Pus-cells in the semen should be treated
with doxycyclin(100mg/day)_ or ciprofloxacin (500mg/day) for 4-6
weeks. If the condition recurs in 3 months-s time,long-term
antibiotic therapy may be tried until a pregnancy has been
Low motility:Low doses of oral
androgens,e.g. fluoxymesterone,10mg twice a week for at least 6
weeks, may be helpful in some cases. The improvement
usually last for several months and treatment may be repeated.
Injections of hCG(5000IU once or twice a week) have also been used
to enhance motility.
Low count: In men with
hypogonadotropic hypogonadism as proved by low or low normal
range of FSH<LH and Testosterone values will benefit from
gonadotropin therapy. Treatment with either hCG alone(In the
dose mentioned above) or hMG one amp.IM on alternate days for 45
injections combined with hCG will benefit the patient.
The effect of Clomiphene citrate (in the dose of
25mg/day for 3 months) in idiopathic oligoasthenospermia is
controversial. A Cochrane review has mentioned that the
endocrine parameters may be improved with Clomiphene,but the
reviewers are not convinced about it-s effect in improving pregnancy
rates. Other studies have found it to be quite useful.
Testosterone administration may be ineffective and may be
Use of anti-oxidants:
Reactive oxygen species are highly reactive oxidising agents
belonging to the class of free radicals. Excessive production
of ROS in semen can overwhelm the antioxidant defense mechanisms of
spermatozoa and seminal plasma causing oxidative stress.
Antioxidants are a broad group of compounds that destroy free
radicals in the body, thereby protecting against oxidative damage to
1. Zinc in the dose of 66 mg along with folic
acid 5mg per day, was shown to increase sperm count in a randomised
controlled study. Biological zinc administratio was shown to
improve sperm count in patients with chronic prostatitis in another
2.Scott et al concluded in a double blind
placebo controlled study that men with placebo controlled study that
men with low sperm motility could improve their sperm motility with
selenium in the dose of 100umg/day or selenium with vitaminA
1mg, with vitamin C 10mg with vitamin D 15mg for 3
3.Carnitine: :L-Carnitine and acetyl-L
carnitine are highly concentrated in the epididymis and play a
crucial role in sperm metabolism and maturation. They are
related to sperm motility and have antioxidant properties.
Carnitine enhances sperm energy production and therefore,
motility. In a multicentre study of 100 patients treated with
3 gma carnitine for 4 months significant improvement in sperm
motility was reported by Lewin et al, particularly in patients with
4.Con-enzyme Q10: Balercia et al used
Co-enzyme Q10 in the dose of 200mg twice daily for 6 months in
patients with sperm count >20mill/ml with forward motility
<50% with good results. Other than this, there are not many
clinical reports on this antioxidant. In India, many
pharmaceutical companies market this drug in the dose of 30-50
mg/day for asthenospermia. We still do not know if it is of
any use, especially in this dose.
5.Glutathione: Injectable Glutathione 600mg
IM on alternate days for a period of 2 months in a study by Lenzi et
al resulted in significant improvements in overall motility,
progressive motility , velocity, linearity and amplitude of
lateral head displacement. Oral Glutathione is of limited
value in male infertility.
6. Lycopene: Gupta and Kumar treated 30
infertile men with 4 mg lycopene for 3 months and found a
significant improvement in sperm counts and motility with no
significant changes in sperm morphology. A 20% pregnancy rate
was seen during the course of the study.
Surgical treatment:If a
varicocoele is present, it may be ligated. The effect of varicocoel
ligation on fertility has been controversial. But if the semen
parametres are abnormal and the female factors are either not there
or corrected, it is reasonable to get this abnormality corrected, as
the presence of varicocele is often associated with a decline in
spermatogenesis and testosterone production and elevation in serum
Treatment of female
The five cardinal causes of
female infertility, viz: ovulatory dysfunction, tubal blocks,
cervical factors , endometriosis and immunological infertility
should be evaluated and treated. Usually, a patient comes with
multiple causes and each cause should be evaluated and
treated. Quite often, the clinician falls into the pitfall of
trying to treat one cause of infertility, and forgetting other
factors which may be co-existing. For example, if a woman has
irregular periods, caused by ovulatory dysfunction, the onus of
treatment my be in trying to treat anovulation and co-existing
vaginal infections or tubal blocks may get overlooked. Thus,
it is necessary to try and look at each factor every time the
patient visits the doctor.
The commonest factor for female
infertility is irregular ovulation and quite often, empiric
treatment to correct ovulatory dysfunction is given by the doctor,
without any evidence of impaired ovulation. Management of
anovulation is given in the section named anovulation
and the readed is directed to read it there
Evaluation and treatment of tubal
The old method of diagnosing tubal block was to do
a tube testing where air is injected into the uterine cavity.
Patency is confirmed by hearing a gurgling sound in the lower
abdomen as heard through a stethescope.This has been found to be an
inaccurate method, but is still practised in many centres in India,
where patients cannot afford any costlier methods.
Hysterosalpingogram; A radio opaque dye is
injected into the uterus and an X-ray taken.The uterus,tube and
spillage of dye into the abdomen can be seen. Anatomical
abnormalities of the uterus can be evaluated along with any blocks
in the tubes. The procedure can be painful. The author sometimes
does it under I-V Ketamine in the operation theatre under C-Arm
control, but the films are not as clear as the routine
Sonosalpingogram: Under sonographic control,
saline is forced into the uterus through a foley-s bulb and the
spillage of fluid in the pouch of Douglas evaluated. Additional
information like fibroid uterus can be picked up, but the tube
cannot be delineated properly.
Laparoscopy: Ringer lactate with or without the
dye methylene blue is injected into the uterus and the spillage of
dye into the abdomen noted. There is the added advantage of
the chance for evaluating the entire pelvis and correcting any
adhesions or endometriotic patches. The disadvantage is the
necessity for anaesthesia and the increased cost in private set
Many types of intrauterine catheters have
come iin the market for the release of proximal tubal obstruction.
Using cannulae and guide wires, proximal tubal block can be
negotiated under sonographic control, fluoroscopic control or
through the hysteroscope. The patient should be aggressively managed
to achieve a pregnancy soon after as many of the blocks removed in
this fashion tends to recur after some time.
Fimbrial blocks can usually be removed
laparoscopically. For patients with totally blocked tubes,
IVF-ET may be the only recourse.
Laparoscopy in infertility: Indications:
In the 1980-s there was a tendency to post all
infertile patients for routine laparoscopy. However,
considering the low yield of positive findings when such an approach
is taken, and the morbidity involved in anesthesia, we do not
routinely advocate laparoscopy for all infertile patients. If
the patient gives history of congestive dysmenorrhoea and there is
nodularity in the pouch of Douglas, she probable is suffering from
external endometriosis. In such cases, laparoscopic evaluation
should not be delayed and should be done as soon as the patient
presents herself to the clinician. For patients in whom uterus
appears normal on pelvic examination, laparoscopy could be delayed
for a few cycles. For patients with polycystic ovarian
disease, where treatment with clomiphene citrate has failed, before
going in for treatment with gonadotropins, laparoscopic ovarian
drilling would be a better option. It is not only cost effective,
but also gives an opportunity to evaluate the rest of the
pelvis. If medical treatment of infertility does not yield
results after five or six months laparoscopic evaluation should be
done as it will detect asymptotic adhesions and endometriotic
patches. In patients undergoing artificial insemination with
donor-s semen (AID) if there is no pregnancy after 3-4 attempts a
laparoscopic assessment should be done before trying further
Cervical factor of infertility:
Cervical factors account for about 10% of the
cases of female infertility. Cervical factor can be detected by a
post-coital test. Postcoital test or PCT should be done in the
preovulatory phase of the cycle. The couple should abstain
from intercourse for 2 days prior to the test, since it takes 48
hours to replete sperm reserves. It could be done between 1-12
hours after intercourse. A normal PCT is defined as good
quality cervical mucus and 10 or more progressively motile sperm per
hpf. The mucus component should also be evaluated. Cervical mucus
acts like a ladder on which the sperm climbs up to reach the uterus
It is usually clear, mucoid and copious in midcycle . Lack of
adequate cervical mucus or hostility in the cervical mucus can lead
When the quality of mucus is poor, the cause could
be infection. Infection with Chlamydia trachomatis can be detected
with cervical mucus cultures. In India, where health care is not
insured, the usual practice is to give empiric therapy with
Doxycyclin 100mg daily for 7 days in suspected cases. Besides
chlamydia other agents, which could cause vaginitis and secondary
cervicitis, should be sought for and treated. There could be
vagainal mycosis, Trichomoniasis, or gardnerella vaginitis.These
should be treated apporopriately as mentioned in the chapter on
leucorrhoea. If the culture is negative, or if empiric
therapy with antibiotics fail, there could be either estrogen
deficiency or to failure of endocervical cells to respond to
normal levels of estrogen. Empiric therapy with Estrogen (Ethinyl
estradiol, 0.01mg per day on days 6 to 9,increased to 0.02mg per day
on days 10-13 of a 28 day cycle), gonadotropins or cryosurgery for
may help. When the PCT is abnormal
inspite of good quality mucus, an immulogic cause should be sought
for. When medical therapy fails, intra uterine insemination is
the next option.
An abnormal postcoital test with scant cervical
mucus, a poor cervical score, cervical stenosis or an endocervix
that is friable and bleeds in response to gentle manipulation may
indicate cervical factor with an anatomical basis.
When cervical stenosis is suspected, one can try
passing a 2-4mm dilator through the cervical os. If it does not pass
or passes with difficulty, a true stenosis should be dagnosed.
Application of estrogen vaginal cream (Refer to chapter on
menopause) twice daily for 3-4 weeks may soften the stenotic cervix
and allow the small dilator to pass. Such patients are difficult to
treat and may need intrauterine insemination.
When the cervix appears friable and causes
bleeding on passing a dilator. Cervical varicosities should be
suspected. Cryosurgery of the cervix may help.
Intra Uterine Insemination is one of the simplest
procedures among the procedures called the Artificial reproductive
technologies or ART. Semen is washed with special media and
centrifuged. The motile sperms from the sample is separated and
introduced into the uterine cavity along with a little (0.3-0.6ml)
media using special intrauterine cannulae. The common indications
are cervical factor infertility & male infertility. But it can
be performed in any woman with patent tubes, where all other factors
of infertility have been treated and she has what can be termed
intractable infertility. The ovaries are usually
hyperstimulated with clomiphene citrate and gonadotropins to produce
a lot of follicles. The ovulation is monitored using ultrasonography
on alternate days and insemination is done on the day previous to
the day of expected ovulation. Ovulation is timed by giving
HCG injections on the day the follicle reaches the size of 18mm on
ultrasonography.Ovulation is expected to occur 36 hors later.
Pregnancy rates can vary from 16% to 25% and varies from centre to
centre. It is high in cervical factor infertility (50%) and low in
male factor infertility where husband-s sperms are used for
infertility. Patients expect a lot, almost 100% result, when
they come for IUI as it is very stressful having to come for serial
ultrasonography and to collect semen in an alien atmosphere.
Patients should be told that even a newly married couple who are
fertile take 3 or 4 months to conceive and even though one makes
sure that ovulation, tubal factor, and cervical factor have been
taken care of , there still may be failures at the point where the
sperm enters the ovum or at implantation.
IVF-ET is In Vitro Fertilisation and Embryo
Transfer. The gametes (ovum and sperm) are taken out of the body and
fertilisation done outside the body in vitro. The fertilised
embryo is transferred into the uterus. The chance of pregnancy is
about 30% in larger units. This procedure was started for patients
with blocked tubes, but now the indications have widened to almost
all cases of infertility where conventional treatments have
failed. The cost of therapy is about Rs.50, 000 to Rs.75, 000
The full forms and short details of modern ART
procedures are listed below:
ICSI: Intracytoplasmic sperm injection: In IVF-ET
the sperms and ova are incubated together in a petridish and the
sperms are expected to penetrate the ova by themselves. As against
this, in ICSI, a single sperm is taken into a micropipette and
injected directly into the ovum. With this procedure fertilisation
rates are higher. It has another advantage that not only men with
profound oligospermia(low count) or asthenoteratospermia (low
motility with increased number of abnormal forms), but also
those with obstructive azoospermia, after microsurgical or direct
aspiration of sperm from either the epididymis or testis can be
benefitted. Sperms need to be alive, but need not be motile
for this procedure.
TESA: Testicular Sperm Aspiration:Sperms are
directly taken from the seminiferous tubules and ICSI
PESA: Per Epididymal Sperm Aspiration. Sperms are
aspirated from the epididymis and ISCI performed.
Ovum donation: Oocyte donation can be used to
treat women with premature ovarian failure of whatever cause and
those who do not wish to use their oocytes for genetic
reasons. The ovum from a donor is inseminated with the sperm
of the patient-s husband and the resultant embryo introduced into
the uterus of the infertile woman. As the embryo might genetically
be the donor mother-s recently another procedure has been
developed. Here the ovum of the infertile woman is taken and
the cytoplasm replaced with that of the donor ovum.
Blastocyst transfer:It was found that a lot of
failures in ART procedures occurred at the implantation stage,
because at the time that the embryo was transferred (In the 4
cell stage) the endometrium was not adequately prepared. Hence, the
embryo is grown to reach the blastocyst stage before it is
transferred into the uterus.
Preimplantation diagnosis: In women with repeated
pregnancy losses, the embryo is developed in vitro. One of the cells
is aspirated and chromosomal study performed to see if the embryo is
genetically normal. Embryo transfer is done only if the embryo is