The sixth batch of Mansoura Manchester programme

The sixth batch of Mansoura Manchester programme
Professor: Alaa Mosbah , Mansoura Manchester programme

Monday, January 7, 2008

Ovulation induction

Introduction: Ovulation induction includes medical induction by ovulatory agents and surgical induction. Ovulatory agents were introduced in 1960, expanded considerably in the last years. Each drug has specific indication, mechanism of action & clinical monitoring. Surgical induction of ovualtion is resorted to when the medical methods of induction fail. It entails making a port through which the ovum is released in cases of polycystic ovarian disease ( PCOD). Pre-therapy work up: 1- Document anovulation (BBT, endometrial biopsy) 2- Rule out and treat reversible pathology (e.g. pituitary tumor). 3- Rule out ovarian failure ( FSH > 40mIU/ml). 4- Ensure that other elements of fertility are intact (good male and tubal factor). 5- Document the couple’s psychological readiness for - Prolonged therapy - Possible failure - Method risk Indication of ovulation induction: 1- Anovulatory infertility. 2- Timing of ovulation for artificial insemination-husband (AIH), artificial insemination- donor (AID). 3- Oocyte maturation for IVF, ICSI,……… Clomiphene Citrate Pharmacology: -Is an orally active non-steroidal compound which is structurally related to ( di-ethyl-stilbosterol (DES). -Exhibits both estrogenic and anti-estrogenic effects. Mode of action: 1- Central action ( hypothalamic): -It occupies estrogen receptors in the hypothalamus (because of its structural similarity to estrogen). -Its dissociation from chromatin is impaired and remains in the nucleus for a longer period blocking the interaction of receptors with estrogen. So, it causes a state of estrogen insensitivity of the target cells i.e. blinding them to the endogenous estrogen level ® inhibition of uptake of estrogen into the hypothalamus and pituitary. ® ¯ –ve feed back effect of estrogen ® ­ GnRH and gonadotropin release ® stimulate follicular activity. 2- Peripheral action ( ovarian): Clomiphene may also act by 2 mechanisms on the ovary; • Direct stimulating effect. • ­ ovarian sensitivity to gonadotropins. Selection of patients: 1- Should have intact hypothalamo – pituitary- ovarian axis. • Intact hypothalamus: capable of producing GnRH. • Intact pituitary gland: capable to respond to GnRH. • Ovary with certain degree of follicular activity (i.e endogenous estrogen present). 2- Should have normal prolactin value. 3- Should have good liver function. So, Clomiphene is used to treat patients with group II WHO which include; 1- Hypothalamic –pituitary dysfunction. 2- PCOD. Clomiphene citrate is ineffective in: 1- Severe hypothalamo-pituitary failure (Group I WHO) 2- Hypo-estrogenic patient. Success of Clomiphene depend on: 1- Sufficient stage of follicular maturation. 2- Body wt. not < 80% of the ideal body weight. Regimens of Clomiphene: [1]. Conventional regimen -Begin by 50mg/day (one tablet) beginning in the 5th day of a spontaneous or progesterone-induced bleeding for 5 days. -However, Clomiphene can be started in 2nd, 3rd, 4th or 5th day of onset of menses. The outcome in terms of ovulation rate, luteal phase defect or pregnancy rate is optimum for day 5. -The pre-ovulatory LH surge is expected to occur 5-10 days after the last tablet (average 7 days) and couples are advised to have intercourse on alternate days for 1w starting 5day after the last Clomiphene tablet. Monitoring of therapy: to document ovulation (a) FSH, LH on day 5 and 9 (b) Estradiol on day 14 (c) Progesterone on day 23 ( > 3ng/ml) However these assays are expensive and time consuming (d) Cervical mucus score and postcoital test (PCT) on day 14 (score 8 or more with ­BBT indicate ovulation). (e) Ultrasound folliculometry daily from day 9 until ovulation (18 – 22mm followed by collapse and fluid in cul-de-sac). (f) Timed endometrial biopsy (document ovulation if endometrial response appropriate). (g) Basal body temperature (BBT); thermogenic shift. -If ovulation is not documented and pregnancy does not occur ® continue another cycle after increasing the dose by 50mg (maximum 250mg/day) till ovulation. -If ovulation documented and pregnancy does not occur ® continue the same dose for other cycle(s). - If menstrual bleeding does not occur within 4 weeks after the last clomiphene tablet and the cycle was ovulatory, a pelvic examination or pregnancy test is done. - Another treatment is withheld if overstimulation is noted (ovarian cyst). - Once an ovulatory dose is reached, treatment should be continued on a regular basis until: 1- Conception occur 2- Other infertility factors are discovered which would prevent preg. 3- Serious side effects occurred 4- The couple wishes to discontinue therapy NB. However, because only 5% of all couples conceive after 6months of therapy, empiric use of other modalities should be considered at that time. - Another treatment cycle begins when: 1- Return of BBT to normal. 2- Intensity and duration of last menses is normal. 3- No signs and symptoms of ovarian enlargement. 4- Rule out preg. by HCG assay. Of all patients who conceive during therapy, 75% of them will do so within the first 3 ovulatory cycles. [2] Incremental or extended regimen: -For patients who did not respond to conventional C.C. therapy larger doses of Clomiphene are used; 50 mg for 5days then increase dose every 5 days by 50mg but maximum dose never exceed 250mg/day. -The treatment period of more than 3weeks does not improve the result. During therapy, monitoring of E2 and U/S until the largest diameter reaches 18-19mm when HCG is injected. [3] Combined Clomiphene therapy: - Used in cases of Clomiphene failure. - The combinations include the following: (A). Clomiphene + human chorionic gonadotropin (HCG): Patients who fail to ovulate with CC alone may ovulate after injection of HCG 5-7 days after CC. Idea: - 80% of anovulatory patients respond to cc by folliculogenesis, endogenous LH peak and ovulation. - 20% fail to ovulate by demonstration of persistent follicles by means of U/S but will do so after 35hr. after injection of HCG 10,000 I.U. -When 100mg Clomiphene fail to induce ovulation, inject 5000-10,000 IU 7 days after the last dose of cc this is followed by another injection 5 days later to stimulate the function of corpus luteum (CL). -Proper timing best with U/S folliculometry is important because HCG when given before follicular maturation favor atresia and inhibition of ovulation. A dose of 5000 I.U is usually sufficient and larger dose increase the risk of hyper-stimulation and multiple pregnancy. -The couple is advised to have intercourse in the same day of injection and in the following 2 days. (B) Clomiphene and HMG: (sequential fashion) -Clomiphene increase the reactivity of the ovary to HMG. This reduce the dose and duration of treatment. The dose of HMG is decreased by 50%. Begin by CC 50mg – 200mg/day for 5 days followed by HMG usually starting with 2 ampoules daily then the dose depend on urinary and serum E2. (C) Clomiphene + GnRH: 1- 100mg CC on days 5-9 plus, GnRH 0.6 – 1.2mg three times daily as nasal drops from day 11-14. 2- GnRH 25 mg 3 times daily on days 5-7 then 100mg CC on days 10-14. 3- GnRH 100 mg daily for 4weeks, followed by CC. (D) Clomiphene + Estrogen: -Estrogen increases the quantity and quality of cervical mucus. • Ethinyl estradiole 20-40 mg for 5 days after the last CC pill. • Estradiol benzoate 1mg for 7 days after 100mg cc • Sequential preparation: estrogen – progestogen; [2mg Estradiol valerate for 21 days & 50 mg Levonorgestrel for 10 days] gives some favorable results. (E) Clomiphene and Corticosteroids: -If there is androgen excess (androgen profile should be obtained), CC is effective if androgen excess is ovarian in origin, but if androgen excess is of adrenal or adrenal/ovarian origin, glucocorticoid should be given. 1- Continuos use: Dexamethzone 0.5mg started 2 weeks before inducing menses and continued while giving Clomiphene and until pregnancy test becomes positive. 2- Interval use: is better than continuos use CC on days 5-9 & dexamethazone on days 5-14 -The effect of glucocorticoid is attributed to its reduction of androgen of adrenal origin and consequently enhances the pituitary gonadotorpin release and ovarian follicle reactivity. (F) Clomiphene and Bromocriptine: -The suppression of prolactin increases the responsiveness of the hypothalamo-pituitary- ovarian axis to CC. -It may be due to direct effect on the ovary or ­ secretion of GnRH and gonadtropin. N.B.: Obese patients has high level of endogenous estrogen (E1) and ¯ SHBG so needs larger dose of Clomiphene to compete with estrogen for hypothalamic receptors. The anti-fecundity effect of Clomiphene: [= disparity between ovulation and pregnancy] There is discrepancy between ovulation rate and pregnancy rate & this is due to the anti-estrogenic effect of CC which interfere with conception by: 1- Impeding ascent of sperm through the cx mucus by altering its quantity. 2- Inhibition of implantation of the blastocyst by interfering with the proper development of the endometrium. 3- Impairing implantation by direct action on fertilized ovum 4- It causes luteal phase defect by • Inadequate stimulation of the endomet. during luteal phase • Direct negative effect of the ovary • Improper development of the ovary Also Clomiphene may cause luteinized unruptured follicle. Results of CC therapy: 1- Ovulation rate 70% 2- Pregnancy rate 40% 3- Multiple pregnancy 8% 4- Congenital malformations are not increased. 5- Abortion rate high 30-40% due to CL insufficiency & antiestrogenic effect on the endometrium. Clomiphene citrate treatment in ovulatory women: • IVF • GIFT • IUI Ovulation is initiated with CC then followed by HMG or FSH then HCG Side effects of Clomiphene: (not dose related and occur with 50mg dose) 1- Vasomotor flushes. 2- Abdominal pain or distention. 3- Breast discomfort. 4- Nausea and vomiting. 5- Visual spots or flashes. 6- Ovarian hyperstimulation syndrome (OHSS): -There is mild but significant ovarian enlargement (14%). - Moderate & severe OHSS is rare. *If the patient is symptomatic, pelvic examination, intercourse and undue exercise should be avoided because the enlarged ovaries are very fragile *Ovarian enlargement regresses rapidly and rarely delays subsequent treatment cycle. 7- Multiple pregnancy (4-9%). 8- Luteal phase defect (LPD): - Due to direct effect on the ovary & endometrium. Also it may be caused by non-physiologic circulation of gonadotropins & E2. - Treatment by: • increasing dose of CC (i.e. CC causes LPD & is used in its treatment). • HCG & progesterone. 9- Abortion (30-40%); due to LPD. 10- Dysmucorrhea: CC fails to produce pre-ovulatory cervical mucus peak despite increased estrogen, due to increased sensitivity of the endocervical glands to the anti-estrogenic effect of CC. N.B.: There is no evidence that the effect of clomid is long lasting & the response is limited to that cycle in which the drug is used. Cyclofenil (Ondogyn) - Chemically related to CC. and is similar to CC in biologic activity. - It is weak estrogenic activity (1/1000). Mode of action: as CC (i.e. acts on hypothalamo – pituitary axis & on ovary). Indications: as Clomiphene Regimen: • 200mg 3 times daily for 5 starting on day 3 or 5 • It may be combined with HMG. And may be combined with bromocriptine Results: ovulation and pregnancy rates are less than with CC: • Ovulation rate 50% • Less multiple pregnancy. • Pregnancy rate 20%. Tamoxifen (Nolvadex) Non steroidal anti-estrogen, structurally related to CC. Advantages over CC: 1- Lack of anti-estrogenic side effects on cervical mucus. 2- Lack of hyper-stimulation syndrome. 3- Lower cost. Dose: 10mg/day for 5 days may ­ up to 40mg/day Side effects: No toxicity but hot flushes are more with tamoxifen. Human Menopausal Gonadotropins -HMG are extracted from urine of postmenopausal women. -It has been in clinical use since 30 years. -It contains FSH and LH (75 or 150 IU of each) • HMG is available in 3 preparations FSH: LH with 1:1 ratio as in pregonal, Humegon FSH: LH with 3:1 ratio as in normegon Pure FSH as in metrodin This pure FSH contains negligible amount (< 1 IU) of LH and was initially developed as a product that might be used in conditions of LH excess such as polycystic ovaries. • A new preparation of genetically engineered recombinant FSH ( r FSH) is now available which has the advantage of being free from any extraneous proteins which are invariably present in most urinary extracted compounds Principles of gonadotropin therapy FSH LH Responsible for recruitment, selection growth and ripening of the dominant follicle • Final maturation of G. follicle • Ovulation • Formation of C.L Indications: (selection of patients): 1- Patients with hypothalamo-pituitary failure (WHO group I) 2- Patients with hypothalamo-pituitary dysfunction (WHO group II) who failed to conceive with C.C. Regimen -No fixed dose -HMG is given by I.M. injection and purified FSH by S.C injection . -The patient is started on day 2 of the cycle with 150 m daily and seen on cycle day 8 and every 1-3 days thereafter for monitoring. -Daily dose depend upon ovarian response. Monitoring of therapy Is done by: 1- Pelvic U/S for the size and no of follicles 2- Estrogen level: • Urinary and blood levels • Effect on cervical mucus The aim of monitoring 1- Assess the effective dose that causes ovarian response 2- Assess the length of time required for follicular maturation 3- Assess the appropriate time for induction with HCG 4- To ¯ the possibility of multiple pregnancy and ovarian hyperstimulation On the day of satisfactory follicular growth (Diameter 18-19mm) and acceptable E2 level ® HCG is given 5000 – 10,000 IU and the patient is instructed to have intercourse in the same day of injection and in the following 2 days The cycle is cancelled and the HCG is withheld and the couple advised to abstain from intercourse if: 1- More than 3 dominant follicles are present 2- E2 level exceeded 2000ng/ml In order to avoid multiple pregnancy and hyperstimulation syndrome. N.B.: Group II: more sensitive to HMG than group I ® more cancelled cycles. Less response to HMG than group I. Results: • Ovulation rate 90% • Preg. rate 50-70% preg. is less in group II due to age factor (advanced age) premature luteinization) • Multiple preg 10-30% • Abortion rate 20% Side effects 1- Hyperstimulation syndrome 2- Multiple preg. 3- Local reaction at the injection site perhaps due to prot. content (patients are switched to purified preparation FSH). Combination HMG therapy [1] Clomiphene citrate + HMG CC 100mg from day 2-6 for follicular recruitment then followed by HMG daily or on alternate days. This ¯ the amount of HMG need However, this regimen is only of use for anovulatory patients of group II who have endogenous gonadotropins and hence endogenous E2 [2] GnRH agonist and HMG combination Principle • Group I patients (hypogonadotropic) have better response and outcome than group II patients (normogonadotropic) • Patients with elevated levels of LH as in PCO are particularly prone to lower success rate after HMG and higher abortion rate this led to the suggestion that converting group II patients into a hypogonadotropic state may improve the results. This is done by giving Gn-Rh agonist before starting HMG, the so called medical menopause, induced by down regulation caused by the agonist. Regimen Complete down regulation (serum estradiol < 50 pgm/ml) takes about 3w if started in the follicular phase and 10-14 days if started in midluteal phase as flare up is accentuated by the natural rise in FSH if the agonist is given in the follicular phase, where the action of the agonist is prolonged. Following downregulation, HMG is started in the usual way but patients may need higher doses with higher costs N.B.: Down regulation may persist for some time after stoppage of the agonist. So, luteal phase support should be given to replace the ¯ed endogenous LH we can give: • HCG 2000 u twice in the 3rd and 6th day following ovulating dose • Progesterone I.M. (50-100mg daily) • Progesterone supp. (100-200mg daily) for 14 days HCG has the Advantage of less frequent administration but it has the disadvantage of - ­ risk of hyperstimulation - Give false +ve preg. test [3] HMG co-treatment with growth hormone This co-treatment with GH ­ serum and follicular fluid IGF, level when compared with standard HMG. Regimen without GH. Although this regimen ¯ amount of HMG needed, it does not appear to improve the clinical response in normal women the ultimate role for cotreatment may be in women who have previously responded very poorly to standard HMG regimen Gonadotropin – Releasing hormone GnRH is a 10 aa protein synthesized and released from the arcuate nucleus of the hypothalamus and released in discrete secretory bursts into the portal circulation and acts to release both LH and FSH . When delivered in pulses, exogenous GnRH acts in physiologic manner to stimulate gonadotropin release. In contrast, when delivered in a continuous fashion, GnRH ttt results in downregulation of pit. Gonadotropin release and suppression of gonadal function Indications: Used in patients lacking endogenous GTH but having intact pit. gland . 1- Hypothalamic amenorrhea 2- Hypothalamic infertility 3- Also used in cases of resistant PCOD Regimen Pulsatile GnRH is delivered by means of small infusion pump that can be programmed to deliver small bolus (1-20 mg) every 60-90 minutes . It can be delivered either subcutaneously or I.V. however the I.V. route of administration appears to be more effective Ovulation usually occurs after 14 days of ttt (10-21 days) when the leading follicle is 14mm or over, the women is instructed to use the urinary LH kit and when the surge is detected, the couple is advised to have intercourse on the following 3 days. Luteal support is needed and done either by: • Continuing GnRH • or using HCG • or Progesterone Advantages 1- More physiologic and safer then GTH 2- Used alone or with cc or HMG 3- Less OHSS. 4- Less multiple preg. Results • Group I : 30% conception rate/cycle and 5% multiple preg. • Group II: lower preg. rate Side effect 1- Formation of anti GnRH antibodies 2- Allergic reaction 3- Infection at catheter site 4- Pump failure Bromocriptine 2 bromo a ergocriptine is a semisynthetic product derived from the family of ergot alkaloids . Indications 1) Anovulation in cases of : • Pit. microadenoma • Hypothyroidism ( ­TSH ) • Following steroid contraceptives • Following drugs • Following electroconvulsive therapy 2) Inhibition of postpartum lactation 3) Acromegaly 4) Parkinsonism Action : ¯ RRL (dopaminergic on hypoth – direct on pit) Dose : 2.5mg twice daily for 21 days with building of the dose Side effects 1- Nausea and dyspepsia 2- Constipation 3- Postural hypotension 4- Nasal congestion 5- Muscle cramps Superovulation: Induction of multiple ovulation in patients who are ovulatory Used in: - Long unexplained infertility with IUI - Assisted reproductive technology ART (IVF – GIFT) * Unexplained infertility Induction of ovulation is used as an empirical therapy either alone or with IUI CC ® 3-5% preg. rate/ cycle And higher with IUI combination HMG ® 18-15% preg. rate/cycle * IVF – GIFT Superovulation is used as preg. rate is related to the no. of embryos replaced Surgical induction of ovulation [1] Multiple ovarian puncture: ovarian drilling: Laparoscopic multiple ovarian puncture (15-20 sites) using cautery diathermy or laser vaporization lead to a response similar to that with HMG in CC resistant PCO patient Also, patients who don’t ovulate spontaneously following the procedure become more responsive to medical therapy and up to 60% of them will ovulate when cc is recommended The advantage of ovarian puncture over HMG are 1- One step ttt 2- No monitoring is required 3- The risk of iatrogenic multiple preg. is eliminated Disadvantages 1- Operative procedure with general anaethesia 2- Postoperative adhesions: however it is less than ov. wedge resection which is now obsolete Mechanism: removing part of hormone producing ovarian tissue ® ¯ androgen and inhibin levels ® ¯ FSH, LH ¯ and resumption of spont. ovulation The choice between ovarian puncture and HMG in cc – resistant patients will depend on: 1- Local availability of facilities 2- Experience 3- Patent wishes [2] Ovarian wedge resection: Removing part of the ovary now obsolete as it ® post op. Adhesions

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