This document defines infertility and its causes. It discusses male and female factors of infertility in detail. For male factors, it covers pre-testicular, testicular, and post-testicular causes and evaluates male factor infertility through history, examination, semen analysis, and assessment of sperm function. For female factors, it discusses ovarian causes of anovulation including physiological and pathological causes. It also describes the treatment of ovulatory disorders, focusing on clomiphene citrate as a first-line induction of ovulation treatment.

1. Presented by
Shaymaa EL-Naggar
Lecturer of Obstetrics & Gynecology
Qena Faculty of Medicine
َSouth Valley University

2. Definitions:
● Infertility: non occurrence of pregnancy despite free unopposed
intercourse. Includes:
1ry infertility: non occurrence of pregnancy after one year of free
unopposed intercourse.
2ry infertility: non occurrence of pregnancy after two years or
more after a previous pregnancy (even if abortion or ectopic) despite
free unopposed intercourse.
● Fecundability: is the ability of achieving pregnancy within a
single menstrual cycle.
● Monthly fecundity rate (MFR): total no. of
pregnancies/no. of months of exposure.
● Sterility: infertility beyond treatable causes.

3. Causes of infertility:
1. Male factor (25-40%).
2. Female factor (40-55%):
a) ovarian factors (30-40%).
b) tubal factors (20-30%).
c) peritoneal factors (10-20%).
d) cervical factors ( 5-10%).
e) uterine factors ( ≤ 5%).
f) multi-factorial ( 25-35%).
3. Both male & female factor (10%).
4. Sexual error (30%).
5. Unexplained (10%): when all previous are
proved not to be the cause.

4. 1. Male factor (25-40%):
a) pre-testicular causes:
1. Gonadotrophin deficiency (hypothalamic or
pitutary causes): Congenital deficiency, tumors ,
granulomatous infections ,drugs.
2. Endocrine excess syndroms:
● Tumors secreting sex steroids ( estrogen or
androgen).
● Exogenous steroid intake.
● Excess corticosteroids; Cushing S or steroid ttt.
3. 0thers:D.M., hypothyroidism, sperm agglutinatio
Ab in the serum.

5. b) Testicular causes:
1. Congenital :aplasia, dysplasia, hypoplasia,
androgen receptor defect.
2. Trauma : surgical or accidental.
3. Infammatory : mumps, granulomatous
(T.B., S, Bilharziasis).
4. Increased testicular temp. : undesended
testis, varicocele, haematocele,
chylocele.
5. Toxins :e.g. cytotoxins or lead poisoning.
6. Tumorrs : destroying testicular tissue.
7. Gonadotrophin resistant testis.

6. c) post-testicular causes:
1. Obstruction of the duct system:
a) congenital : aplasia, atresia.
b) traumatic : hernia operation, correction
of varicocele, vasectomy.
c) inflammation: gonorrhea.
d) tumors: rare.
2. Failure of sperm deposition:
a) penile hypoplasia, epispadius.
b) impotence.
c) premature ejaculation.
d) retrograde ejaculation.

7. Evaluation of male factor:
1. History
2. Examination
3. investigations:
I. semin analysis.
II. Assessment of sperm function.

8. Semin analysis
» It is a basic laboratory study assessing male factor .
» Should be done routinely.
» Can be omitted if the husband has young kids within the
past few years and has no recent significant events.
» Pre-requisits and methods:
1. Done twice in 2 reliable labs 2 weeks apart.
2. Done at least 6 weeks after stopping any
hormonal ttt.
3. Abstinence for 2-3 days.
4. Sample collected by masturbation or coitus
interruptus.
5. Contraceptive condoms should never be used for
semen collection as they contain spermicides.
6. Sample is transported in clean, dry, plastic or glass bottle
within 2 hours and protected from heat and direct
sunlight.

9. Standard normal values ;
(WHO,1992)1. Volume: ≥ 2ml.
low volume: retrograde ejaculation.
high volume: inflammation of acc. Gland.
2. Colour: grey yellow.
(d.t. high protein content & sperms).
3. PH: 7.2 – 7.8.
(acidic by time d.t.metabolism of sperm).
4. Liquifaction time: ‹ 20 min.
(fail d.t. deficiency of prostatic proteolytic enzy)
5. Viscocity : assessed visually by time needed for one drop
to leave a standard pipette.
(hyperviscoid infertility & affect count)
6. Sperm conc.: ≥ 20 million/ml.
(N.B. count is nothing except after being combined with
motility)

10. 7. Motility : sperm motility is classified into 5 grads:
i) Grade 0: no movement .
( we use live-dead stain to diff dead sperm from
alive but immotile sperm).
ii) Grade 1: poor= weak or sluggish movement.
iii) Grade 2: moderate = definite forward progressive.
iv) Grade 3: good = forward movement with progression.
v) Grade 4: excellent = vigorous rapid forward with
progression.
» normally ≥ 50 % with grade 2.
25 % with grade 3.
» practically : the total motile sperm count is the most
useful measure. Calculated as follow:
Motile sperm count= sperm count/ml×%motility×semin vol
/ 100

11. 8. Morphology: ≥ 30 % of normal morphology.
Abnormal forms (teratospermia) may be:
- large oval head . - small oval head.
- pyriform head . - tapering head.
- double head . - double tail.
9. Additional measures: (done when needed)
a) fractose: secreted by seminal vesicle.
normally=200-300mg/dl.
absent=i) ejaculatory duct obst.
ii) seminal vesicle destruction.
iii) incr fractolysis-decr angrogen.
b) WBCs: >1 million/ml is abnormal.
c) RBCs : normally not present.
d) micro-organisms : normally semin is sterile.

12. Assessment of sperm function
1. Sperm penetration assay/Hamster egg
penetration test.
( golden hamesters are superovulated, eggs retreaved,
treated with enzymes to remove cumulus & zona
pellucida to prevent immunologic effect on human
sperm. Sperm incubated in rich protein media to
promot incapacitation). Normally 14-100% are
successffully penetrated.
2. Human zona-binding assay. (Hemi-zona test)
( test ability of sperm to bind to zona)
3. The hypo-osmotic swelling test.
4. Acrosome reaction assay.

13. Treatment of male factor:
1. Clomiphene citrate: cases of idiopathic origin.
Increase level of LH, FSH and testosterone.
Empirical addition of vit. C and tonics.
2. Pure FSH : sever idiopathic male factor.
3. Pulsatile GnRH therapy: in cases of
hypothalamic dysfunction
4. Adrenergic agonists as phenylephrine: to
strenght internal urethral sphincter tone
5.Glucocorticoids : for antisperm antibodies.
6. Low dose testosterone : for decreased motility.
7. Surgical ttt: varicocele, reversal of vasectomy
8. ART

14. 2.Ovulatory factors:
Anovulation
● Definition: failure of expulsion of an ovum out of an
ovarian follicle.
● Incidence: 20-30% of cases of 1ry infertility.
● Causes:
I. Physiological : before puberty, during lactation,
sporadically and after menopause.
II. Pathological :
hypothalamic causes of amenorrhea.-:. Central causes1
- hyperprolactinaemia.
- abnormal GnRH pulse in PCO.
:. Abnormal feedback signals2

15. a) Estogen is not enough to stimulate LH surge ( bad
quality follicle).
b) Estogen not fall enough to stimulate FSH needed
For early follicular growth:
i. Abnormal peripheral conversion (obesity).
ii. Extra-gonadal estrogen production.(tumors, estrogen
containing drugs).
iii. Decreased estrogen binding d.t. SHBG (Obesity).
(obesity recorded in 35-60% of cases of anovulation)
iv. Abnormal estrogen clearance (hepato-renal disorders).
: (ovarian causes of amenorrhea). Local ovarian causes3
ovarian destruction or removal.
. Abnormal increase in androgen4

16. Obesity
Estrogen excess
Anovulation
Insulin excess
Androgen excess

17. ● Clinical presentation:
1. Amenorrhea .
2. Infertility .
3. Abnormal uterine bleeding.
● Diagnosis: (detection of ovulation)
I. Signs of ovulation:
1. regular cycles .
2. premenstrual symptoms .
3. spasmodic dysmenorrhea .
4. ovulatory bleeding(midcyclic) .
5. ovulatory pain (mittelelschmerz).
6. ovulatory discharge.

18. II. Tests to detect ovulation:
1. Basal body temperature (BBT):
- Earliest & least expensive.
- Depend on progestrone thermogenic effect.
C.°0.5-0.2~Biphasic pattern rise in temp.-
2. Cervical mucus study:
- before ovulation : thin, watery, +ve fern (cx.
mucus on flame) , +ve spinnbarkheit .
- after ovulation : thick, scanty, -ve fern, -ve
spinnbarkheit.
3. Hormonal assay:
a) midluteal seum progestrone:> 3ng/ml (day
21-23).
b) LH monitoring: only prospective test.

19. ovulation occur 24-36 hrs after LH surge.
(5-20mIU/ml). Elevation 2-3 folds of LH level
indicate ovulation.
c) Serum E² (estrione) level:>200pg/ml
or E²/E¹(estradiol):>2:1
4. Endometrial biopsy: secretory end. Indicate
ovulation.
5. Serial U/S monitoring: ovulation characterized
by: - Dominant follicle diameter=17-29mm.
- Fluid in Cul-de-sac.
6. Direct method:
- occurance of pregnancy.
- during laparoscopy: ovulation stigma.

20. Treatment of ovulatory factors:
-Treatment of the cause.
- Induction of ovulation:
TTT
Anti-estrogen(1st line)
1. clomid.
2. tamoxifen.
3. cyclofenil
Gn.
HMG. GnRH
1. MEDICAL
2. SURGICAL
( DRILLING/RESECTION)

21. a) Clomaphine citrate
» It is a synthetic compound related chemically to di-ethyl-
stilbesterol (tri-phenyl-etthylene citrate derivative).
» It has both anti-esttrogenic & weak estrogenic actions.
» Mechanism of action:
1. In the hypothalamus:
It binds to estrogen receptor for long period.
Decrease ovarian-hypothalamic estrogen feedback.
Increase GnRH pulse freq & amplitude.
Increase both FSH & LH during the typical 5 days of
administration.
2. Direct action on the pituitary or the ovary.

22. Selection of patients:
1. Functional anovulation. (no organic
hypothalamic, pituitary, ovarian disease).
2. Un-explained infertility. (to increase no.
of ova available).
3. No hypo-eestrogenism.
4. No increase LH. (PCO).
5. No hyper-prolactinaemia.
6. No liver dysfunction.

23. Dose & administration:
● Starting dose= 50mg/day (one tab), from 2nd or
5th day of a spontaneous or progestrone-induced
menses, for 5 days.
● Ovulation is expected to occur 5-12 days after
the last day of therapy, detected by;
- BBT chart,
- US folliculometry,
- mid-cycle LH assay= 2-3 folds normal (5-
20mIU/ml,
- luteal phase progestrone measurment=
>3ng/ml.

24. Results :
- Ovulation rate: 80- 85 %.
- Conception rate: 40%.
- If ovulation not occur at the initial dose,
increase the dose by 50 mg/day in
subsequent cycles,
- FDA recommend max. dose =250
mg/day.
- If no ovulation for 3- 4 cycles= clomid
failure.

25. Additional to clomiphene therapy:
a) HCG (pregyl / profassi)=5000-10,000 IU, IM.
Indicated only when LH is not detected in urine
(i.e.<40IU/L) or follicle =20mm.
b) Metformin= 500-850mg, 2-3 timees daily ,in
cases with hyper-insulinaemia.
Rosiglitazone maleate (avanda)=4mg twice daily.
c) Glucocorticoids (dexamethasone)=0.5mg at
night, few weeks before clomid.
d) Bromocriptine (or dopaminergic drugs)
e) Aromatase inhibitors as letrazole
(femara)=2.5mg daily. Inhibit peripheral
estrogen synthesis

26. b) Cyclofenil:=100-200mg / day. Max. is=400mg.
II. Gonofadotrophines: 2nd line of ttt
1. Human menopausl gonadotrophines:
(HMG, pergonal, humegon) each ampoule =
75IU FSH & 75IU LH, prepared from urine of
menopausal women.
2. Purified urinary FSH: (Metrodin, normegon,
orgafol) each ampoule = prepared 75IU purified
FSH & <1 IU LH, prepared from human urine
3. Highly purified urinary FSH: (metrodin HP).
4. Recombinant FSH: as follitropin-α (gonal-F) &
follitropin-β (puregon).

27. Tubal factor
Causes:
a) Congenital: aplasia, atresia, hypoplasia, diverticulae &
accessory ostia.
b) Trauma: after pelvic surgery or rarely accident.
c) Inflammations (most important cause):
1. Acute inflammation
PID: clamydia and gonorrhea.
Purperal or post aportive infection
Post operative infection
2. Chronic inflammation: TB, syphilis, bilharziasis.
d) Functional anomalies:
(tubal spasm or abnormal peristalsis )
e) Tumours :destroying tubal cells or obstructing the
lumen.

28. Diagnosis
» Depends on diagnosis of tubal patency only.
» No tubal function is currently available.
» Available tubal patency test are:
Injection of detectable material as in HSG.
Direct visualization of the tube through endoscopy
or open laborotomy
» Special investigation
1. HSG
2. Rubin insufflation (CO² insufflation)
3. Simple insufflation (pushing 80 ml of air)
4. Sherman kymography (cotrolled delivery of
CO² with continous pressure monitoring &
representing pressure on a graph.

29. Treatment:
I. Surgical treatment: therapy for tubal factor was
entirly surgical but the success of art limited the
surgery
II. Medical treatment:
a) Treatment of PID.
b) Short wave therapy: (200mA for 10-20 min)
through 12-24 sessions (lysis mild adhesions)
c) Repeated insufflation
d) Repaeted hydro-tubation using:
hydrocortisone + streptomycin + chemotrypsin
III. Outpatient tubal canalization by hystroscopic
or fluoroscopic guidance
IV. ART.

30. Peritoneal factor
Causes:
I. Peritoneal inflammation: septic, aseptic
inflammations
II. Abdominal or pelvic surgical procedures
III. Endometriosis
IV. Organized pelvic haematoma
V. Pelvic irradiation
Grades:
- Involving outer 1/3 of the tube.
- Involving the whole tube.
- Frozen pelvis (no plane of cleavage between
pelvic organs.

31. Treatment :
1. Ttt of PID.
2. Conservative surgery of endometriosis.
3. Micro – surgery or laparoscopic adheisolysis.
4. ART.

32. Cervical factors
Composition of cervical mucus:
- Mucin :glycoprotein responsible for viscosity.
- Mucus plasma: albumin, globulin, Igs, enzymes.
- Electrolytes.
- Tubular & endometrial cellular debris.
Causes:
1. Congenital :hypoplasia, elongation, pin point os.
2. Trauma :obst.lacerations, surgical trauma.
3. Infammation :chronic non-specific, TB, S, B.
4. Tumours .
5. Anti-sperm antibodies :IgG, IgA.

33. Special investigations:
» done at time of ovulation.
» done after one another; cx. Mucus, post-coital,
sperm penetration, cross compitabity
1. Evaluation of cervical mucus:
- Done at time of ovulation by a pipette .
- No vag. Douches or medications for 2 days.
- Moghissi scoring:

34. Moghissi scoring:
3210
ml0.3>0.1-0.2ml<0.1ml0amount
normalviscousmoremostviscosity
rt3>
angle
2rt angle1rt anglenonefern
cm8>5-8cm1-4 cmnoneSpinnbarkat
none1-5/hpf6-10/hpf/hpf11>cells
Score 10-15= normal cervical mucus.
Score 5-10= relatively abnormal cx.mucus.
Score <5= hostile cx.mucus

35. .2. Post-coital test(Sims-Huhner, 1866):3 sample taken
diagnosisresultspecimen
Failure of deposition
azoospermia
No spemsPost.vag.
wall.
Without
prior PV
Necrospermia
Hostile vag.sec.
Dead sperms
Anti-sperm AbShaking mov.
Normally accepted>20 /HPFLower
cx.canal satisfactory10-20/HPF
Asthenospermia.
Hostile cx.mucus.
<5 active motile
sperm/HPF
satisfactoryAny active spermUpper
cx.canal

36. 3. In vitro sperm-mucus penetration test:
a) Slide test (Miller-Kurzrok test):
At of ovulation, a drop of cx.mucus & semen
on a clean dry slide.
b) Capillary tube test:
A capillary tube filled with cx.mucus put in a
semen container.
4. Cross compatibility test (Kremer test):
Depend on in-vitro sperm mucus interaction.
a) Husband semen against donor mucus.
b) Wife’s mucus against donor semen.

37. Uterine factor
Causes:
1. Uterine anomalies: recurrent pregnancy loss
2. Uterine fibroids (infrequent cause of infertility)
3. Infections: destroying the endometrium
4. Intrauterine adhesions interfering with embryo
implantation
Special investigations:
1. Sounding (clinical test).
2. HSG,
3. Endometrial hystopathology

38. Treatment:
1. Cyclic E & P (doubtful results)
2. Myomectomy
3. Treatment of endometritis:
- imperically by;
tetracuclin/erythromycin
for 14 days (better in follicular phase to
avoid accidental pregnancy)
- D & c before starting treatment to
remove infected endometrium
4. Treatment of Asherman syndrome.