Ovulation Induction in IUI
Indications for IUI
- Failure of sperm to penetrate cervical mucus
- Poor post-coital test (anti-sperm Ab)
- Male factor infertility
Washing Procedure
- Washing medium: HTF medium
- Swim-up method
- Collection of motile sperms from the upper layer medium
- Centrifugation & collection of concentrated motile sperms
Post-washed sperms motility in IUI
- Less than 1 million motile sperms, seldom succeed
- More than 10 million motile sperms, better result
- Oligospermic Pts: combining 2 ejaculates, 4 hrs apart, increased the number of sperm available
IUI timing
- 36 hrs post-HCG injection
- Next day after urine LH surge
- Single IUI vs Multiple IUI
the same pregnancy rate
- IUI+ 同房
Induction of Ovulation — COH
Ovulation deficiencies(WHO classification)
• Group I: Hypothalamic-Pituitary Failure
• hypoganadotropic hypogonadism
• Low FSH and estrogen level
• Normal prolactin level
• Negative progesterone challenge test
• Hypothalamic amenorrhea
• Stress related amenorrhea
• Anorexia nervosa
• Kallmann ' s syndrome
• Group II:Hypothalamic Pituitary Dysfunction
• Normogonadotropic, normoestrogenic, anovulatory oligoamenorrheheic women
• PCOS
• Group III: Ovarian Failure
• Hypergonadotropic hypogonadism
Drugs used in ovulation induction/ovarian stimulation
• Clomiphene citrate
• meformin
• HMG (Human Menopausal Gonadotropins)
• Purified FSH
• recombinant FSH
• GnRH-agonist:
• GnRH-antagonist
• GH (growth hormone)
Assessment of ovarian reserve:
the key of choosing the right stimulation protocol
• The day3 FSH level
• The FSH:LH ratio
• The GnRH stimulation test
• The basal antral follicle count
• The clomiphene citrate challenge test(CCCT)
• Age ,indication
Clomiphene Citrate
• Hypothalamic effects
• The concentration of intracellular estrogen receptors decreased
• Normal cycling women: GnRH pulse frequency increase
• FSH, LH pulse increase
• Anovulated women: GnRH pulse amplitude increase
• FSH, LH amplitude increase
• Pituitary effects
• Influence pituitary response to GnRH
• Promoting the production of FSH
• Ovarian effects
• Enhancing the FSH stimulation of LH receptor formation on granulosa cell
• Uterus, cervix and vaginal effect
• Antiestrogenic effects
• The effect of estrogen on endometrium and cervical mucus is antagonized, potentially important actions on implantation, sperm transport and early embryo development
• Selection of patients
• Exclude the pituitary, adrenal and thyroid dysfunction
• Exclude the prominent male factor: semen analysis
• Clomiphene trial
• 75% accumulative pregnancy rate for the first 3 months
• Infertility detail work up delayed till after clomiphene trial for 3 months
• How to use clomiphene
• Starting day: 5th day of a cycle
• Timing of follicle selection
• Administration too late in the cycle, beyond 9th day may have no effect
• Intercourse days
• Ovulatory surge: anywhere from 5 to 10 days after the last day of clomiphene administration
• Intercourse every other day for 1 week beginning 5 days after the last day medication
• Initial dose: 50 mg/day for 5 days
• The same pregnancy rate of initial dose of 50 mg/day or 100 mg/day
• More severe side effects of the initial dose of 100 mg/day
• Miximal dose: 250 mg/day for 5 days
• Combined with estrogen to overcome the antiestrogenic effect is not recommended
• Clomiphene success
• Biphasic BBT with temperature elevation period more than or equal to 11 days
• Biphasic BBT with temperature elevation period less than 11 days:
• To increase the clomiphene dosage
• Complications
• Side effects do not appear to be dose-related, occuring more frequently at the 50 mg/day dose
• Side effects
• Vasomotor flushes: 10%
• Abdominal distension, bloaqting, aoin: 5.5%
• Brease discomfort: 2%
• Nause, vomitting: 2.2%
• Visural disturbance: 1.5%
• Headache: 1.3%
• Loss of hair: 0.3%
• Results
• Ovulation rate: 80%
• Pregnancy rate:
• Accumulative 6-month pregnancy rate: 65-70%
• Per cycle pregnancy rate: 20-25%
• Multiple pregnancy rate 5%
• Abortation rate: not increased
• Abnormality: not increased
• Clomiphene failure
• If all factors are corrected, and conception has not occurred in 6 months, prognosis is poor
• Mechanisms
• Excessive LH in the follicular phase
• The dysfunctional effects of an untimely LH surge
• Excessive local concentration of androgen
• Strategies to overcome clomiphene failure
• The supplemental use of dexamethasone to reduce androgen burden
• GnRH agonists to eliminate endogenous LH surge
• Pulsatile GnRH therapy to preserve physiologic interactive feedback mechanisms
• Purified FSH to diminish excessive LH in the follicular phase
• The use of HMG
HMG
• 1 Amp contains 75 IU FSH and 75 IU LH
• Selection of patients
• Exclude ovarian failure to demonstrate ovarian competence
• Progesterone challenge test + baseline FSH level
• Other infertility work up to exclude tubal factor, uterine factor and male factors
• How to use HMG
• Starting day: 3th day of a cycle
• Initial dose: 75-150 IU/day for 7-12 days
• Monitoring
• Serum E2 level
• On 7th day of treatment, then every day to every 3rd day
• Optimal level: 1000- 1500 pg/ml
• Risk level: > 2500 pg/ml
• 400 pg principle: 400 pg per mature follicle ( > 16 mm)
• Folliculometry
• On 7th day of treatment, then every day to every 3rd day
• Largest preovulatory follicle: 15-18 mm
• Optimal growth rate: during the 5 days preceeding ovum expulsion, the dominant follicle exhibit a linear growth pattern of approximately 2 to 3 mm per day
• Risk of OHSS
• Many (> 15)small (< 9 mm) to intermediate (10-14) follicles on the day of HCG injection
• Pregnancy rate:
• Accumulative 6-month pregnancy rate
• WHO Gr I: 90%
• WHO Gr II: 40%
• Multiple pregnancy rate 30%
• Abortation rate:
• WHO Gr I: 23%
• WHO Gr II: 24-40%
• Abnormality rate: not increased
• Premature LH surge
• The dominant follicle: ovulation
• The other follicles: atresia
• Prevention: HMG combined with GnRH-a
• Hyperstimulation syndrome
• OHSS: ovarian hyperstimulation syndrome
OHSS
• Pathophysiology
• A shift of fluid from intravascular space to extravascular space, due to increased local capillary permeability
• Syndromes
• Mild
• Ovarian enlargement, abdominal distension and weight gain
• Moderate
• Severe
• Ascites, pleural effusion, electrolyte imbalance, hypovolemia with hypotension and oligouria
• Complications
• Acute abdomen due to torsion
• Internal bleeding dur to rupture
• Hypovolemic shock
• Hyperkalemic acidosis
• Arterial and venous thrombosis
• ARDS
• Management
• The key point is that the hyperstimulation syndrome will undergo gradual resolution
• Not pregnant: 7 days
• Pregnant: 10-20 days
• Treatments
• Bed rest
• Monitoring
• Albumin: controversial
• Diuretics: contraindicated
• Mild: very common
• Moderate severe: 1-2%
• Risk factors
• E2 level at HCG injection day: > 2500 pg/mL
• Follicular number > 15
• Luteal phase supported with HCG injection
• PCOS
• Younger age
• Prevention
• Withheld the ovulatory HCG injection
• E2 > 2500 pg/mL
• Total small to intermediate follicles > 15
• Aspiration the residual follicles as possible
• Cryopreservation of embryos
• Luteal phase supported with progesterone but not HCG
HMG
• HMG failure
• If all factors are corrected, and conception has not occurred in 6 HMG cycles, prognosis is poor
• Prediction of failure
• D3 baseline FSH level > 15 IU/L
• Decreased level of inhibin
IUI protocols with combination of clomiphene-gonadotropin
•
• Protocol I
• Clomiphene (100 mg/day): D3-D7
• gonadotropin ( 2 amps/day): D3 … ..
• Protocol II
• Climiphene (100 mg/day): D3-D7
• gonadotropin ( 2 amps/day): D8 …… .
• Protocol III
• Clomiphene (100 mg/day): D3-D7
• gonadotropin (2 amps every other day): since D5(7,9 … ) or D6 (8,10 … )
(highly)Purified FSH
• 1 Amp contains 75 IU FSH and less than 1 IU LH
• Selection of patients
• Exclude ovarian failure to demonstrate ovarian competence
• Progesterone challenge test + baseline FSH level
• Other infertility work up to exclude tubal factor, uterine factor and male factors
• PCO patient
• Pregnancy rate: not surperior to HMG
• The risks of multiple pregnancy and hyperstimulation appear to be less than HMG(?)
Recombinant FSH
• sc use
• Bioactivity
• High availability and batch-to-consistency
• No nonspecific urinary proteins
|