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 Symptoms: all the symptoms are only suggestive for the disorders 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
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 ovulation: Before
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)
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.
• • 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 the cervical mucus 3-Changes in cervical mucus
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
The secretory pattern of the endometrium starts to be definite 4 days after ovulation. P.E.B. can be carried out on unanesthetized women through undilated cervix using Novak’s, Sharman or Randall’s curette
Premenstrual endometrial biopsy P.E.B
Premenstrual endometrial biopsy P.E.B biopsy are: The values of premenstrual endometrial
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.
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
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 310 ng/ml indicates ovulation with luteal phase defect.
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
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
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
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)
1- Anovulation due to central defect (hypothalamic or pituitary causes
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 [gigantismacromegaly], Basophil adenoma [Cushing’s syndrome] or Chromophobe adenoma [either non functioning or prolactinoma].
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
Clinical picture of anovulation:
- Infertility. oligohypomenorrhea. - Irregular bleeding. - Amenorrhea or - 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.
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.
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).
12 - 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 induction of ovulation Clomiphene citrate (clomid)
Drugs for Ovarian. clomphineStimulation. citrate
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 (!?)
Closely related to diethylstilboesterol.
Clomiphene citrate (clomid) compound. Nature: It is a synthetic non-steroidal
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.
Dose and administration: 50-100 mg [1-2
Clomiphene citrate (clomid)
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)
increases 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
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.
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.
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 maturation of the follicles.
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.
• • • • • CC. CC ± FSH or ± HMG. Gn. Standard step-up protocol. Gn. Low dose step-up protocol. Gn. Low dose step-up, stepdown protocol.
Combination of clomiphene and In some resistantHMG to clomiphene cases
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.
Regression of Corpus luteum
Clomiphene 100 mg day2 for 5 days Gonadotrophin stimulation from day 4 to day of 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.
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.)
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.
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
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.
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.
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)Progesterone luteal phase defect: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
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.
Definition: failure of rupture of the mature