Controlled Ovarian Hyperstimulation for ART
Stimulation of the ovaries with gonadotropins, “superovulation,” with the aim of increasing the number of oocytes available for IVF, is currently a common procedure. This concept for the first time has widely demonstrated a dose-response relationship between the amount of FSH administered and the number of developing small antral follicles. FSH inhibits apoptosis in granulosa cells, preventing their atresia.
During Controlled Ovarian Hyperstimulation (COH) for ART, GnRH agonists are used to suppress pituitary release of both LH and FSH. Follicle growth and development can be achieved by the administration of pure FSH alone, in the absence of exogenous LH. However, in women with hypogonadotropic hypogonadism, who lack both LH and FSH, administration of FSH alone promotes follicular growth, but the oocytes apparently lack developmental competence. The difference between the two patient populations is explained by the fact that inhibition of GnRH by the agonist leaves sufficient residual LH secretion to support follicular development caused by FSH. The response to FSH in patients with negative regulation of ART does not depend on serum LH at the time of initiation of FSH administration. Granulosa cells synthesize estradiol in response to FSH and LH, and estradiol levels per retrieved oocyte appear to be correlated to developmental competence of the oocytes. Women who are at risk of hyper-response to FSH and subsequent OHSS should be given lower doses of FSH; this does not affect their chance of a live birth.
Follicular fluid contains high levels of steroids and enzymes, and aspiration of follicles during ART procedures removes this milieu from its natural environment after follicle rupture in vivo; in addition, follicle flushing removes the cells which would have been incorporated into the new corpus luteum. It is possible that this artifactual procedure leads to luteal insufficiency or other subtle consequences on ovarian physiology that are not presently obvious. Progesterone is usually administered to support the luteal phase in downregulated ART cycles.
GnRH analogs have been used in Controlled Ovarian Hyperstimulation (COH) protocols since the mid-1980s, when high tonic levels of LH during the follicular phase were found to be detrimental to oocyte competence, decreasing fertilization and pregnancy rates. GnRH agonists were used to suppress and control the LH surge, thus regulating the timing of ovulation. Their use then led to the development of programmed Controlled Ovarian Hyperstimulation (COH) protocols that provide convenient and effective means of planning and organizing a clinical IVF program: the search for oocytes can be scheduled on certain days of the week or in “batches.” GnRH analogs have substitutions in their peptide sequence that increase their bioavailability over that of native GnRH, and they bind to receptors on the anterior pituitary so that the receptors are fully occupied, blocking release of FSH and LH. Two types of analogs are currently used in ART protocols:
- GnRH agonists: Continuous administration initially causes LH and FSH hypersecretion (flare-up), and after a period of about 10 days, the pituitary store of gonadotropins is depleted. The pituitary is desensitized so that secretion of LH and FSH is suppressed, preventing ovarian steroidogenesis and follicular growth, creating an artificial but reversible menopausal state. Different GnRH agonist preparations can be administered by depot injection (Decapeptyl, Zoladex), daily subcutaneous injection (Buserelin) or daily intra-nasal sniff (Nafarelin, Synarel).
- GnRH antagonists bind to and immediately block receptors on the pituitary; there is no initial hypersecretion of gonadotropins, but their release is instead immediately and rapidly suppressed. A third generation of these compounds (Cetrorelix, Ganirelix) is now used to suppress LH secretion after follicular growth has been first stimulated by gonadotropin administration on Day 1 or 2 of a menstrual cycle (or withdrawal bleed after oral contraceptive pill administration). The antagonist is administered by daily subcutaneous injection from approximately Day 6 of stimulation, or when the largest follicle size reaches 14 mm, and continued until the day of hCG administration. Due to the fact that the suppression of LH is more complete than with the use of agonists, some protocols recommend compensation by simultaneously “adding back” recombinant LH (Luveris) during the period of treatment with antagonists.
Several protocols using GnRH analogs have been devised, and individual ART programs apply the same strategy with a variety of drugs and schedules. Downregulation with a GnRH agonist may begin either in the luteal or the follicular phase (“long protocol”) of the previous menstrual cycle and can be administered with any preparation of choice. It may also be administered from Day 1 of the treatment cycles and continued until ovulation induction with hCG (“short protocol,” sometimes also known as “flare-up protocol”). The “ultra-short protocol” uses only three doses of the agonist, on days 2, 3 and 4 of the treatment cycles. Treatment cycles can also be scheduled by programming menstruation using an oral contraceptive preparation, such as Norethisterone 5 mg three times a day, and inducing a withdrawal bleed. The “standard” protocols are not always suitable for every patient, and every treatment regimen should be tailored according to the patient’s medical history and response to any previous ovarian stimulation. Patients with suspected PCO and those with limited ovarian reserve (“poor responders”) require careful management and individualized treatment regimens.
The use of GnRH antagonists is thought to be more physiological (“natural”), since there is no initial suppression of pituitary FSH; however, antagonist cycles require more meticulous monitoring of the cycle in order to prevent a premature LH surge.
Original protocols for ovarian stimulation included oral administration of Clomifene citrate (Clomid), which acts as an agonist and antagonist, competing with receptors on the hypothalamus and pituitary gland. It displaces endogenous estrogen and eliminates feedback inhibition, which stimulates FSH release from the pituitary. Clomid is administered at a dose of 50–100 mg twice daily for 5 days from days 2 to 6 of the menstrual cycle, and FSH injections are commenced on Day 3. This protocol has the disadvantage that it does not block the release of LH, and therefore the cycle must be carefully monitored to detect and intervene before the release of LH causes ovulation. However, it may sometimes be useful for patients who have failed to respond to agonist or antagonist protocols.
With any of the Controlled Ovarian Hyperstimulation (COH) protocols, a baseline assessment may be normally conducted prior to starting gonadotropin stimulation, in order to ensure that the ovaries are quiescent and the endometrial lining has been shed, as well as to exclude any pathologies that might jeopardize the treatment cycle.
Oocyte extraction (OCR) procedures are performed by vacuum aspiration follicles under ultrasound control of the vagina using disposable OCR needles and collecting aspirates in heated 15 ml Falcon tubes. Oocyte retrieval can be safely carried out as an outpatient procedure, using para-cervical block for local anesthesia, intravenous sedation or light general anesthesia. An experienced operator can collect an average number of oocytes (i.e., 8–12) in a 5- to 10-minute period, and the patient can usually be discharged within 2–3 hours of a routine oocyte collection.
Luteal Phase Support
Hormonal support of the luteal phase is felt to be necessary following pituitary downregulation with GnRH agonist treatment and is usually also used in antagonist cycles. Progesterone supplementation may be administered in the evening after oocyte retrieval:
- Cyclogest pessaries per vagina, 200–400 mg twice a day,
- Utrogestan capsules per vagina, 100–200 mg three times a day,
- Crinone gel per vagina, once daily application,
- Gestone 50–100 mg daily by intramuscular injection,
- Oral Dydrogesterone 10 mg three times a day.
In-Vitro Maturation Protocols
“In-Vitro Maturation” techniques are now successfully used as an alternative to Controlled Ovarian Hyperstimulation (COH) in selected patient groups, particularly in those with PCOS who have large numbers of small antral follicles. Immature (GV) oocytes are recovered from antral follicles and cultured in vitro until they resume meiosis and reach metaphase II.
Protocols include initial priming of the ovaries with low doses of rFSH (100–150 IU) for 3–6 days with or without administration of hCG or a GnRH agonist. FSH priming generates GV stage oocytes that can undergo meiosis in vitro; in endocrinologically normal patients, small to mid-size antral follicles do not respond to the LH surge, and these will not respond to hCG in the same manner as larger pre-ovulatory follicles. Therefore, protocols that include hCG administration can produce some oocytes that may have been matured “in vivo,” as well as those that will mature in vitro. However, follicles from polycystic ovaries prematurely express functionally active LH receptors, and protocols, which includes hCG triggering, are in widespread use, especially for PCOS patients.
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