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Ovulation Induction. Dr Elsamawal El Hakim Head Department of Obstetrics & Gynaecology Subspecialist in Reproductive Medicine Sulaiman Al Habib Hospital- Al Qassim MSc, MRCOG, MD, DRH. Development in Reproductive Medicine. Move toward all biosynthetic gonadotrophins
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Ovulation Induction Dr Elsamawal El Hakim Head Department of Obstetrics & Gynaecology Subspecialist in Reproductive Medicine Sulaiman Al Habib Hospital- Al Qassim MSc, MRCOG, MD, DRH
Development in Reproductive Medicine • Move toward all biosynthetic gonadotrophins • Increase treatment success rates • Enhance safety of stimulation regimens • Simplify treatment regimens
Background • Ovulation induction is mainly to patients with anovulatory infertility • Hypogonadotrophic hypogonadism • Polycystic ovary syndrome (PCOS) • Hyperprolactinaemia
Hypogonadotrophic hypogonadism • Amenorrhoea BUT no withdrawal bleeding after treatment with progesterone • Limited production of FSH and LH from the pituitary gland
Gonadotrophins • Gonadotrophins used for ovulation induction in women are either urinary or recombinant products. • Urinary derivatives (HMG) contain 75 IU FSH and 75 IU LH per ampoule • Recombinant preparations contain either FSH or LH activity • Treatment of such women with recombinant FSH (rFSH) alone stimulates follicular growth, but results in inadequate estrogen production
Hypo- Hypo • Ovulation induction aims at the selection of a single follicle that will be able to reach the pre-ovulatory size and rupture. At the same time, estradiol (E2) levels and endometrial thickness should be appropriate. • The lowest effective dose should be used • Treatment is individualized and monitored by serum E2 measurements and ultrasound scans of the ovaries. The starting dose of HMG is usually 150 IU/day given for ≥5 days
Hypo- Hypo • The criteria for the administration of HCG include serum E2 concentrations ≤2000 pmol/l • with one to two follicles >16 mm in diameter by ultrasound. The ovulatory dose of HCG is 5000–10 000 IU i.m. for the urinary and 250–500 µg s.c. for the recombinant preparation. • Extra HCG is administered during the luteal, which decreases the incidence of luteal phase defects and increases the pregnancy rate significantly
Hypo-Hypo: Pregnancy Rate • A collection of published results in 14 studies from 1966 to 1984 showed considerable variation in the percentage of patients who conceived (16–78%) • Cumulative pregnancy rates of 89% after six treatment cycles and 72% after seven ovulatory cycles have been reported in two small series of hypogonadotrophic women • Incidence of severe ovarian hyperstimulation syndrome (OHSS) is very low (∼1%), Multiple pregnancy rate is high (up to 30%)
Pulsatile GnRH • Idiopathic hypogonadotrophic hypogonadism and weight loss-related amenorrhoea • The infusion of GnRH is performed by way of a computerized minipump at pulse intervals of between 60 and 180 min • Monitoring of treatment, serum progesterone measurements could verify normal luteal phase, while ultrasound scans of the ovaries can predict the risk of multiple pregnancy
Pulsatile GnRH • Low rate of multiple pregnancy • No evidence that HCG is required • Disadvantages include the need for the pump to be connected to the body all day for a considerable number of days, the necessity to refill the pump at frequent intervals and the possible reactions of the skin
PCOS • In patients with PCOS, ovulation is induced either with the use of pharmaceutical compounds, or the application of other methods, such as weight loss and exercise, or laparoscopic ovarian drilling.
Antiestrogens • The two main antiestrogens used for ovulation induction are clomiphene citrate and tamoxifen • Clomiphene, by blocking the negative feedback effect of E2, stimulates the secretion of gonadotrophins from the pituitary gland • Clomiphene is given for 5 days (D2-D6) • The recommended starting dose is 50 mg/day, up to a maximum dose of 150 mg/day
Clomophine Citrate • induces ovulation at a high rate (70–90%) and, although the pregnancy rate is lower (30–40%) • Multiple pregnancy rate is ∼6–8%, mainly twins • OHSS is a rare event • About 10–30% of the patients will be ‘clomiphene resistant’
Gonadotrophins • Second line treatment for ovulation induction in PCOS • ‘low-dose step-up’ protocol, which involves a starting FSH dose of 75 IU/day given for 7–14 days • Unless a follicle ≥12 mm is seen in the ovaries, the dose is increased by 37.5 IU/day at weekly intervals up to a maximum dose of 225 IU/day • HCG is injected when the leading follicle is ≥18 mm in diameter with no more than one other follicle >14 mm
Gonadotrophins- Other Protocols • ‘step-down’ protocol, starting dose of 150 IU/day until a follicle ≥10 mm is seen by ultrasound. The dose is then decreased by 37.5 IU/day and further to 75 IU/day 3 days later and is kept constant until the day of HCG administration • Very low incidence of OHSS (1.4%) and a multiple pregnancy rate of only 5.7% with step up • Modified step down, and modified step- up protocols
GnRH agonists • Ovulation and pregnancy rates using the GnRH agonists in FSH-treated cycles in PCOS were encouraging, subsequent studies demonstrated an increased risk of OHSS • GnRH agonists are not recommended as a treatment of choice for ovulation induction in PCOS
GnRH antagonists • The use of GnRH antagonists in combination with gonadotrophins for ovulation induction in PCOS has until now been very successful • Less incidence of OHSS
Gonadotropin-releasing hormone agonists versus antagonists • GnRH antagonists are more effective, safe and a well tolerated alternative to agonists for assisted reproduction cycles in PCOS patients • GnRH antagonists are associated with a reduction in the incidence of OHSS in PCOS patients • J Obstet Gynaecol Res. 2010 Jun;36(3):605-10
Complications of Ovulation Induction • OHSS • Multiple Pregnancy
OHSS: Prevention • Withholding hCG administration • Reduced dose of hCG • Administration of native GnRH or GnRH-a • Administration of rec-LH • Freeze the embryos
Human Albumin Administration of 50 g Half-life 14 days Luteal Phase Increase blood volume within 15 min > 800 mL
Ovulation Induction: Multiple Birth Unacceptable high. Triplet and higher order is a major medical problem. Twins are also a medical problem. Can only be overcome by carefull management of O.I. and reducing number of embryos transferred.
Multiple Pregnancy: Complications Maternal Fetal IUGR Congenital Anamolies Birth asphyxia Neonatal Death • Miscarriages • High Blood Pressure • Operative delivery • Haemorrage
Weight loss and exercise • Loss of weight in obese patients with PCOS improves substantially hyperandrogenaemia and insulin sensitivity, decreases LH concentrations and restores normal fertility • Weight loss and exercise are inexpensive, they should be recommended as the first choice for the management of obese women with PCOS
Insulin sensitizers • In the UK, the guidelines support the use of metformin in association with clomiphene in anovulatory infertility • Reduce the risk of miscarriages, and gestational diabetes
Aromatase inhibitors • Aromatase inhibitors suppress the biosynthesis of estrogen • Reduce the negative feedback effect on the hypothalamic–pituitary system • increased secretion of FSH that can lead to follicle selection and maturation • Letrozole daily dose of 2.5 mg from days 3 to 7 of the menstrual cycle
Laparoscopic ovarian drilling • Ovarian drilling is performed by using a pointed monopolar or bipolar electrode or with laser energy • Restored ovulation in 92% of patients with a pregnancy rate of 69% • Risks of laparoscopy and general anaesthesia, may be related to periadnexal adhesion formation in 19–43% of patients and theoretically to premature ovarian failure
Conclusions • Many women with PCOS are anovulatory but not infertile • Most PCOS patients will conceive with minimal help if given enough time • Ovulation induction Treatment is effective • Age, duration of infertility are important factors to consider when offering treatment to anovulatory patients