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DR/ ADEL FAROUK M.D.

ASSISTANT PROFFESOR of
Obstetrics & Gynecology
Cairo university
Infertility II
Ovarian factor of

infertility
Definition of ovulation:
 It is the rupture of a fully mature Graafian follicle with
release of the oocyte surrounded by the crona radiata and
the zona pelluicda to the peritoneal cavity, to be picked up
by the fimbrial end of the tube.
 Mechanism: Ovulation is controlled by 2 mechanisms.
 Central:
 The secretion of F.S.H. and a little amount of L.H. from the anterior
pituitary under the control of hypothalamus causes follicles in the
ovary to ripe and to secrete estrogen.
 The resulting high level of estrogen by a positive
feedback mechanism on L.H. secretion causes L.H. surge,
which causes ovulation and corpus luteum formation
(acts through prostaglandins).
 Local:
 Increased tension of the fluid inside the follicle.
 Increased enzymatic activity of the follicular fluid (proteolytic
activity).
infertility
Ovulation and its

disorders
Symptoms: all the symptoms are only suggestive for the
occurrence of ovulation
 1- Regular cycle: it is strongly suggestive of monthly
ovulation
 2- Ovulation pain (mittelschmerz):
 It is a dull aching pain experienced in one illiac fossa at time
of ovulation, it is caused by irritation of the peritoneum by the
fluid of the Graafian follicle.
 3- Ovulatory bleeding: (ovulatory spotting):
 Spotting vaginal bleeding may occur at time of ovulation.
 4- Ovulatory discharge (cascade):
 Some females develop increase in the normal vaginal
discharge at the time of ovulation due to increase of the level
of estrogen hormone to maximum just before ovulation with
activation of the cervical glands.
Ovarian factor of infertility
• 5- Premenstrual tension:
• The presence of premenstrual tension
especially mastalgia (breast pain and
tenderness) is a reliable evidence that ovulation
has occurred during that particular cycle.
• 6- Spasmodic dysmenorrhea: occurs only
with ovulatory cycles.
Ovarian factor of infertility
• Assessment of ovarian factor:
• A- To assess ovarian reserve, an early follicular
(day 1-3 of the cycle) gonadotropin level by
serum FSH and LH is essential, an LH: FSH
ratio of 2:1 or more indicated underlying PCOS.
• B- Assessment of the thyroid functions,
prolactin level and androgen profile is
necessary in women with irregular cycles.
Investigations to diagnose ovulation
 1- Basal body temperature
 2- Changes In the vaginal smear: Progesterone
effect.
 3-Changes in cervical mucus:-ve thread &
ferning test
 4- Premenstrual endometrial biopsy P.E.B.:
secretory changes, detection of L.P.D and T.B
endometritis.
 5- Hormonal assay: serum progesterone in the
2nd half, pregnandiol in urine, detection of L.H.
peak.

Basal body temperature
chart
Simplest test to detect

A ovulation
 Progesterone has a
thermogenic effect.
 the patient is instructed to
record daily oral
temperature prior to getting
B out of bed
 During the follicular
phase the temperature
is relatively tow, rise of
the body temperature
by 0.2 to 0.5 °c during
the luteal phase is an
indication of ovulation.
 A biphasic temperature
chart suggesting
Changes In the vaginal
smear
 Before ovulation:
A Estrogenic smear: cells
polyhedral, flat edges, small
pyknotic nuclei and acidophylic
cytoplasm (stains pink).
(Superficial cells). Maturation
index 0, 30 and 70 (parabasal,
intermediate and superficial
cells)
 After ovulation:
B  Progesterone effect: Cells
collected in clusters, folded
edges, vesicular nuclei, the
cytoplasm is basophilic with
lecuocytic infiltration in-between
(intermediate cells) Maturation
index 0, 70 and 30.
Changes In the cervical
• mucus
3-Changes in cervical mucus
• Before ovulation
• Positive thread test (spinnebarkeit test): the cervical
mucus can be thrown to a thread that reach maximum
of 7-10 cm. This test is carried by putting one drop of
the cervical mucus between two glass slides and then
separates them.
Positive ferning test (Arborization test): the cervical
mucus when left to dry; deposits of crystals of sodium
and potassium chloride arrange in a characteristic
pattern which is similar to palm leav
• After ovulation: Negative thread and ferning test.
Changes in cervical
mucous
 + ve thread
(spinbarkiet) test just
before ovulation

 Palm leaf appearance


of the cervical mucus
on drying before
ovulation arborization
(ferrning) test
Premenstrual endometrial
biopsy P.E.B
 The secretory pattern of the endometrium
starts to be definite 4 days after
ovulation. P.E.B. can be carried out on un-
anesthetized women through undilated
cervix using Novak’s, Sharman or
Randall’s curette
Premenstrual endometrial
biopsy P.E.B
The values of premenstrual endometrial biopsy are:
 Detection of ovulation, [typical secretory
endometrium].
 Detection of Luteal phase defect: At least 2 days
delay or lag of the biopsy from the normal date of
the lady is needed to diagnose L.P.D.
 Detection of tuberculous endometritis: Part of the
sample should be sent for bacteriological
evaluation to detect tuberculous endometritis,
such a sample should be preserved in saline,
stained by Zeil Nelesen stain and cultured on
Lovenstein- jenssen medium and the sample
should be taken premensturally to allow
reinfection from the tube which is the commonest
site of affection in genital tuberculosis.
P.E.B
 The optimum time for P.E.B. is 2-3
days before menstruation. Some prefer to
obtain the biopsy on the 1st day of
menstruation as:
 The cycles may be irregular and to
avoid disturbing an already present
pregnancy.
 However the necrotic endometrium of the
1st day of menstruation is difficult to
detect evidence of L.P.D.
 The premenstrual endometrial biopsy is
Hormonal assay
 It is estimated at
the midluteal
phase of the cycle
on day 22.
 Levels less than 3
ng/ml indicates
anovulation.
Nanogram (1/1000
microgram)
 Levels between 3-
10 ng/ml indicates
ovulation with
luteal phase
defect.
Hormonal assay
 B- Detection of pregnandiol in urine [pregnandiol is a
metabolic product of progesterone and it is excreted in
urine]. A level of 3-5 mg/24 hours urine is detected in the
2nd half of the ovulatory cycle.
 C- L.H. peak in the middle of the cycle The LH peak is
defined as 3 times the basal level and it occurs in serum 12
to 24 hours prior to ovulation, while it occurs in urine 6-12
hours later than in plasma.
 Measurement of LH peak by radioimmunoassay (RIA)
methods is a difficult method to detect ovulation as it
needs frequent blood samples at 2-4 hours intervals
between 1 to 4 days to be complete, recently more rapid
RIA takes about 2 hours have been developed (ovulation
occurs 28-36 hours after L.H. surge). Recently L.H. peak
can be detected by repeated urinary estimation using
dipsticks (ovu stick or ovu Quick).
 D- Maximum estradiol plasma level is reached 1-2 days
before LH surge & serum estradiol level can be measured
Ultrasonography
 Can detect dominant
follicle 3-5 days.
Before ovulation, it
increases by rate of
2-3 mm/day to reach
19-26 mm at time of
ovulation (average
of 20mm).
 After ovulation,
there is follicular
collapse of the
dominant follicle,
increase amount of
fluid in Douglas
pouch. The pattern
Laparoscopy
 detect stigmata of
ovulation and fresh
corpus luteum
formation at the
surface of the ovary
The sure evidence of
ovulation
 8- Pregnancy: occurrence of pregnancy is a definite
8- Pregnancy: occurrence of pregnancy is a definite
indication that ovulation has occurred in the previous
cycle.
 The sure evidence of ovulation is one of the following:
 Serial ultrasound follow up of the dominant
follicle.
 Laparoscopy detecting stigmata of ovulation.
 Oocyte retrieval as in I.V.F. programs.
 Occurrence of pregnancy
Anovulation
 It is a condition of failure of ovulation.
 Etiology

Physiological: All causes of physiological amenorrhea.


 - Before puberty. - After menopause.
 - During pregnancy. - Sometimes during lactation.
 - Short period after the age of puberty and before the
age of menopause
Iatrogenic causes: contraceptive pills and large doses of
Estrogen
 Pathological

 - Central defect -Abnormal feedback signals


- peripheral defect (ovarian)
Anovulation
 1- Anovulation due to central defect (hypothalamic or pituitary causes
of amenorrhea):
A-Hypothalamic factors
Psychological causes (stress or psychiatric disease, anorexia
nervosa and pseudocyesis (see amenorrhea for details).
Organic lesions: (destructive lesions, tumors and scarring).
Functional lesions: either congenital as Kallmann’s
syndrome, drugs (as phenothiazine or reserpine),
hyperprloctinemia (Chiari Frommel syndrome) and Polycystic
ovarian disease.
B- Pituitary factors
Pituitary insufficiency (Sheehan’s syndrome or Simmond’s
disease), empty sella syndrome
Pituitary adenoma (Acidophil adenoma [gigantism-
acromegaly], Basophil adenoma [Cushing’s syndrome] or
Chromophobe adenoma [either non functioning or
prolactinoma].
Anovulation
 C -Abnormal feedback signals
Estradiol level may not fall enough to release FSH from
negative feedback signals as in:
 Estrogen secreting tumors.
 Abnormal Estrogen metabolism in thyroid or hepatic disease.
 Obesity due to increase peripheral conversion of
androstenedione to Estrone.
 Anovular types of dysfunctional bleeding as metropathia
hemorrhagica or estrogen threshold bleeding.
Estradiol level may not increase enough to trigger LH surge
as in:
 Absolute failure: gonadal dysgenesis or primary ovarian failure.
 Relative failure: it can be seen in pre-menopausal females
due to intrinsic follicular weakness.
D –Idiopathic anovulation: thought to be due to
functional hypothalamic disturbance
Anovulation
 Clinical picture of anovulation:
 - Infertility. - Amenorrhea or
oligohypomenorrhea.
 - Irregular bleeding. - Hirsutism.
 Diagnosis of anovulation:
 1- Basal body temperature: monophasic thermal curve.
 2- Vaginal smear: superficial (estrogenic) smear. Cells are
separate flat edges, esinophilic cytoplasm, small dark
nuclei and no leucocytic infiltration, Maturation index 0, 30,
70 in the second half of the cycle.
 3- Cervical mucus: +ve thread or arborization test.
 4- Hormonal studies: plasma progesterone level at day
22v<3ng/ml, absence of LH peak. No pregnandiol in urine.
Anovulation
 5- Premenstrual endometrial biopsy: shows
atrophic or proliferative endometrium no
evidence of secretory changes.
 6-Ultrasound: detection of a mature follicle
or corpus luteum after ovulation.
 N.B: Failure of ovulation may be temporary
and repeated investigations may thus be
required.
Anovulation
 Once anovulation is diagnosed try to find a cause
by detailed history, clinical examination and
number of investigations as:
 1- Serum FSH, LH and prolactin (high FSH >40
mIU/ml indicates ovarian failure, Low FSH
<5mIU\ml indicates hypothalamic or pituitary
cause. LH: FSH ratio 3 or more is diagnostic of
PCO.
 2- Serum androgen levels (high in PCO), thyroid
function tests and 17α hydroxyl progesterone (for
late onset adrenal hyperplasia).
Treatment of
 Correction of anovulation
the general condition (adequate nutrition,
weight reduction)
 Treatment of the cause (correction of diabetes, thyroid
or adrenal abnormalities).
 Induction of ovulation.
 Methods of induction of ovulation: either medical (by
use of drugs), surgical or general
 A) General lines:
 Weight reduction for obese patients help to correct
abnormal hormonal pattern in this group. Stopping
vigorous exercise in athletic patients can correct the
disturbance in the level of the brain endorphins.
 B) Drugs
 C) Surgical treatment (wedge resection of the ovary or
Ovarian drilling).
Drugs for induction of
1-
ovulation
Clomiphene citrate (clomid)
2 - Tamoxifen (Nolvadex)
3- Cyclofenil (Ondogen)
4 –Gonadotropins
5- Combination of clomiphene and HMG
6 -Purified F.S.H. ( pureagon -Metrodin)
7- Gonadotropic releasing hormone
(Gn.R.H.)
8- Gondotropic releasing hormone
analogue
9 -Bromocryptine
10-Thyroid extract.
Drugs for Ovarian.
 clomphineStimulation
citrate .
Gonadotrophins:
 HMG
 highly purified ur FSH

Rec. FSH

Rec LH

 GnRH (pulsatile).
 GnRHa (intranasal-S.C- I.M)

 GnRH ant (involved in final steps of


oocyte maturation).
 HCG & Bromocripitine (!?)
Clomiphene citrate

(clomid)
Nature: It is a synthetic non-steroidal compound.
Closely related to diethylstilboesterol.

 Mode of action: It competes with estrogen for estrogen


receptors in the hypothalamus thus hypothalamus is
relieved from negative feedback mechanism of estrogen
and it produces its Gonadotropin releasing hormone
leading to production of pituitary gonadotropins.

 Selected cases: It is the first drug to be used for cases


with anovulation infertility with no other infertility problems
due to hypothalamic-pituitary or ovarian dysfunction with
retained power of all to secrete their own hormones as in
cases of hypothalamic dysfunction, P.CO, post pills
amenorrhea and selected cases of luteal phase defect.
Clomiphene citrate
(clomid)
 Dose and administration: 50-100 mg [1-2
tab] given orally for 5 days starting from the
5th day of menstruation sometimes started
on the 2nd or 3rd day (large number of
follicles and less effect on cervical mucus).
In cases of amenorrhea it is preferable to
give clomid on the 5th day of progesterone
withdrawal bleeding. Significant correlation
has been made between body weight and
the dose of clomiphene citrate which can
induce ovulation. Ovulation is expected 5-10
days after treatment.
Clomiphene citrate (clomid)
 Side effects
 Itincreases the risk of multiple pregnancy,
abortion.
 Ovarian hyperstimulation syndrome (see later)
start by the smallest effective dose.
 Minor side effects: Vasomotor flushes, abdominal
distention, breast discomfort, nausea, vomiting,
headache, visual disturbances (Mydriatic) and
mild loss of hair.
 Luteal phase defect due to antiestrogenic effects
treated by giving H.C.G.
 Low quality of cervical mucus due to anti-estrogenic
effects treated by small dose of estrogen (e.g. ethinyl
estradiol 0.01 - 0.02 mg daily) may be given for 5 days
before the expected time of ovulation to improve the
quality of the cervical mucus.
Clomiphene citrate (clomid)
 Patients with hyperandrogenism may be
resistant to clomiphene citrate therapy.
Dexamethazone 0.5 mg orally is given at
bed time (in addition to the clomid therapy)
to suppress the adrenal androgen
production and this improves the results
regarding the occurrence of ovulation this
regimen may be used in selected cases of
P.C.O.
 Sometimes H.C.G 10000 I.U. is given 5-7
days after clomid therapy (or better when
the ultrasonographic measurement of the
follicle is 18 mm or more) to enhance the
mid-cycle LH peak and to prevent the
Tamoxifen [Nolvadex]
 Nature: Anti-estrogenic preparation similar to clomiphene
citrate.
 Mode of action: It competes with estrogen for the binding
sites in the target organs. It induces ovulation in a similar
way to clomiphene citrate.
 Selected cases: same cases as clomiphene it is used for
induction of ovulation and correction of luteal phase defect
(L.P.D).
It has advantages over clomiphene being.
- Less coast - No hyperstimulation syndrome.
-Less anti-estrogenic effect on cervical mucus.
 Dose and administration: The dose may be increased from
10-40 mg orally twice daily for 5 days starting on the 2nd
day from onset of menstruation.
 Side effects: No toxicity is reported however hot flushes
are more.
Cyclofenil (Ondogen)
 Nature: It is chemically related to clomiphene,
although mildly estrogenic.
 Mode of action: It has a similar effect to
clomiphene as regards induction of ovulation
 Selected cases: The same indications as
clomiphene citrate.
 Dose and administration: It is given in a dose of
400 mg orally twice daily for 5 days starting on the
5th day from the onset of menstruation.
 Side effects: Less incidence of hyperstimulation
and few multiple birth.
Gonadotropins
    Nature : They are naturally occurring
compounds. They are obtained from.
 1-Human menopausal Gonadotropins
(H.M.G): taken from the urine of
postmenopausal women it has F.S.H Like
action with minimal LH activity Pergonal.
 2-Human chorionic Gonadotropins (H.C.G)
taken from the urine of pregnant women.
It has LH like action available in
ampoules (5000 I.U) Preganel, Choragon
and Profassi.
Mode of action
 H.M.G is injected to induce
maturation of the follicles.
Gonadotropins
 Selected cases
 Gonadotropins are used for induction of ovulation in
women who have healthy ovaries and responsive uterus
with low pituitary gonadotropins, the best example is
cases of Sheehan’s syndrome.
 Dose and administration: 75-300 IU of H.M.G (having
F.S.H action) is given I.M. for 5-10 days starting from the 7th
day until the Graafian follicle becomes mature as evident by:
- A mature follicle measures 20-22 mm in diameter by ultrasound
(the best).
- When plasma Estradiol level is 1000-1500 pg/ml.
- Total urinary estrogen is about 100 microgram /24 hours urine,
then:
 Human chorionic gonadotropins (HCG) having LH
action is injected in one or two injections of 10000 I.U by I.M
route to induce rupture of the mature follicle. Frequent sexual
intercourse in the same day and for 2 days after HCG injection
so as fertilization of the released ovum can occur.
Monitoring ovarian
stimulation

Transvaginal ultrasound scanning :


. No. & size of follicles
. Pattern & thickness of endometrium
Estrogen blood level
Gonadotropins
(continued)
Side effects
 Hyperstimulation syndrome.
 Expensive.
 Multiple pregnancies:10-30% which
increase the risk of abortion and
preterm labor.
protocols
• CC.
• CC ± FSH or ± HMG.
• Gn. Standard step-up protocol.
• Gn. Low dose step-up protocol.
• Gn. Low dose step-up, step-
down protocol.
Combination of clomiphene and
 In some resistantHMG
cases to clomiphene
therapy this combination may be used to
reduce the dose needed of
gonadotrophines and consequently the
cost of treatment by H.M.G alone.
 Dose and administration
 Clomiphene citrate is given in a dose of
100 mg daily for 5 days starting from the
3rd day of onset of menstruation and 150
I.U. H.M.G. is given I.M daily for 5 days
starting on the 6th day of the cycle.
 Follicular maturation is monitored by
ultrasound and estrogen level.
Unripe follicle Ripening Ovulation Corpus luteum Regression of
follicle Corpus luteum

Oocyte mature
Clomiphene Gonadotrophin 38 hrs
100 mg day2 stimulation from
for 5 days day 4 to day of
HCG
HCG Leading follicle > 18mm
Purified F.S.H. ( pureagon
-Metrodin)
 Specially used in cases of P.C.O. having
abnormally high L.H so the use of
unpurified F.S.H may lead to premature
luteinization of the follicle.
 One ampoule contains 75 I.U of F.S.H. 1 I.U.
L.H. Recently highly purified (Recombinant
F.S.H) containing F.S.H only is available.
  Gonadotropic releasing
hormone (Gn.R.H.) or
(L.H.R.H.)
 Nature: It is a decapeptide synthetic GnRH.
 Mode of action: it increases gonadotropine
secretion from the pituitary.
 Selected cases
 Hypogonadotropic hypogonadism of
hypothalmic origin e.g Kallman’s syndrome.
 Failure of ovulation or occurrence of
complications in response to clomiphene or
H.M.G.
Gonadotropic releasing
hormone (Gn.R.H.) or
 (L.H.R.H.)
Dose and administration
 Pulsatile administration by I.V or S.C routes
through the use of a portable infusion pump.
 The inter-pulse time intervals are 60-120 minutes
(90 minutes on the average), when the follicle
become mature 10.000 I.U of HCG is given I.M or
change the inter-pulse interval of (G.N.R.H) to
every 4 hours.
Gonadotropic releasing
hormone (Gn.R.H.) or
(L.H.R.H.)
 Side effects
 Minimal and generally confined to local
phenomena (irritation or inflammation).
 Allergic reaction being a synthetic
protein.
 No hyperstimulation as Gn-Rh
produces down regulation of its own
receptors.
Gondotropic releasing hormone
[Gn-R.H or LH-RH] analogue
 Given continuously
subcutaneous every day or
intranasal every 4 hours causes
suppression of endogenous
gonadotropic secretion (in cases
of with persistent high LH level
or in cases with premature LH
peak as cases of P.C.O) then,
H.M.G and H.C.G are given to
induce ovulation.
Bromocryptine
 Nature: lysergic acid derivative,
dopamine agonist.
 Mode of action: Binds to dopamine
receptors in the anterior pituitary thus
decreasing prolactin.
 Selected cases: Cases associated with
galactorrhea or hyperprolactinaemia.
 Dose and administration: 2.5 mg one to
two times orally daily with meals.
 Side effects: G.I.T irritation (common),
Faintness, Hallucination, dizziness and
fatigue
Other drugs
 Thyroid extract: In cases of
hypothyroidism.
 Cortisone: In cases of Addison’s disease,
adrenogenital syndrome and in some
cases of P.C.O. especially associated with
Hirsutism.
Hyper stimulation
 syndrome
Excessive enlargement of the ovary with multiple cystic
formation. It occurs with H.C.G injection after clomid or F.S.H.
therapy especially in young and lean P.C.O cases.
 Clinical manifestations: abdominal pain (ovarian
enlargement), abdominal distension (ascites), nausea,
vomiting, edema, oliguria and chest pain (pleural effusion
and arrhythmias)
 Signs: weight gain, edema, hypotension, abdominal
enlargement
 Risks: D.V.T, rupture of the ovarian cyst causing acute
abdomen, liver dysfunction, respiratory distress, renal
failure and adnexal torsion.
 Prevention: avoid giving H.C.G if the ovaries are cystic
or Estradiol level above 2000pg/ml, follicular aspiration
 Treatment: bed rest, avoid rough abdominal or pelvic
examination, correction of hypovolemia and electrolyte
imbalance, I.V albumin, anti-coagulant therapy in DVT,
diuretics are contraindicated and may be aspiration of the
peritoneal and pleural fluid.
Surgical treatment
 Bilateral wedge resection of the ovaries
in cases of P.C.O .This operation is usually
followed by periovarian and peritubal
adhesions that may result in infertility itself
(out of use). It can be done laparoscopically to
decrease post-operative adhesions.
 Ovarian electrocautery (ovarian drilling)
can be done laparoscopically in cases of
P.C.O., it consists of multiple cauterization of
the external surface of the ovary. It is associated
with decline in testosterone and L.H. levels, increase in F.S.H.
levels, resumption of ovulation and increase chances of
pregnancy But carries the risk of ovarian failure
or the development of peritubal adhesions in
some cases.

Ovarian drilling
 Multiple puncture
made to the surface of
the ovary.
Luteal phase defect
 Definition: it is inadequate secretory endometrium
due to insufficient secretion of progesterone by
the corpus luteum or premature cessation of
corpus luteum activity (short luteal phase less
than 11 days).
 Etiology: Inadequate release of F.S.H., abnormal
F.S.H./L.H. ratio at time of ovulation,
hyperprolactinemia and during induction of
ovulation or the use of synthetic progestogen
 Symptoms: Infertility or Habitual abortion in the
1st trimester (may be silent early abortion).
Luteal phase defect
Diagnosis: (continued)
1- Dated premenstrual endometrial biopsy
shows lag of 2 days or more.
2- Serum progesterone on day 22 of the
cycle (between 3-10 ng/ml). Estimate serum
prolactin at the same time (normally 4-20 nanogram /ml) as
some cases are associated with hyperprolactinanemia.
3- Basal body temperature may denote a
short luteal phase (8 days or less).
Luteal phase defect
 Treatment of (continued)
luteal phase defect:- Progesterone
1.25 mg I.M daily (or progesterone vaginal
suppositories 25 mg twice daily) in the 2nd half
of the cycle (2-3 days after ovulation). If
pregnancy occurs as detected by estimation of
serum beta subunit of human chorionic
Gonadotropin before the expected time of
menstruation, progesterone treatment should
continue during the first trimester until the
placental formation.
 H.C.G in the second half of the cycle 5000 I.U.
I.M every 3 days for 5 doses.
 Bromocreptin: in cases of hyperprolactinemia
Luteinized unruptured follicle syndrome
 Definition: failure of rupture of the mature
follicle followed by luteinization of its cells
with progesterone secretion
 This is a rare cause of infertility. Basal
body temperature, endometrial biopsy and
serum progesterone are similar to those
found in ovulatory cycle but the follicle
does not rupture and the oocyte is still
inside the un-ruptured follicle. This is
diagnosed by laparoscopy and ultrasound
performed 3-5 days after the L.H. peak.
These cases are treated by clomiphene
citrate and H.C.G. or H.M.G. and H.C.G.