The target of ovulation induction in anovulatory patients ...



Concepts and Regimens of Ovarian Stimulation

J.G. Schenker

Department Obstetrics and Gynecology, Hebrew University Hadassah Medical Center, Jerusalem, Israel

Follicular development is thought to commence only when the level of circulating FSH exceeds a certain threshold. In addition, the number of follicles to ovulate is determined by the length of time that the level of FSH remains above this threshold value. The threshold is subject to considerable inter subject variation and this leads to difficulty in determining optimum dosage and dosing regimens when FSH preparations are used therapeutically. Additionally, various autocrine and paracrine factors of ovarian origin modulate gonadotrophin action at the level of the target cell1 and ensure optimum steroidogenesis and granulosa cell differentiation throughout the menstrual cycle.

The target of ovulation induction in anovulatory patients and those of ovarian stimulation for IVF are totally different, although the same stimulatory drugs can be given. Anovulation in patients is due to decrease or inappropriate gonadotrophin secretion and the aim of the treatment is to restore the imbalance very precisely to induce the growth and maturation of a single follicle. ART patients mostly have an ovulatory cycle and the purpose of the stimulation is to get a reasonable number of follicles and oocytes by extra ovarian stimulation.

The first successful human pregnancies and births after in vitro fertilization (IVF) by Steptoe and Edwards was produced with oocytes from unstimulated natural cycles (1). The disadvantages of this approach were the need for frequent measuring of blood or urine luteinizing hormone (LH) level, the need for a 24-hour commitment of staff and facilities, a low (0 to 60%) chance of aspirating at least one oocyte, and a low mean number of oocytes aspirated per patient

The availability of natural-cycle IVF and the many treatment protocols that follow allow individualization of treatment for patients who do not not respond to one method.

Clomiphene Citrate

Clomiphene citrate is the first drug of choice used in management of anovulatory cycles. It structurally similar to estrogen and hence binds competitively with estrogen receptor resulting in its pharmacological action. Clomiphene citrate was first synthesized in 1956. It is clear that since the main mechanism of action of (CC) is to increase gonadotrophin section, it can only be effective in inducing ovulation in the presence of an intact hypothalamic-pituitary-ovarian axis, particularly with respect to the positive feedback effects of estradiol. Therefore, (CC) is useful in women with normogonadotropic amenorrhoea or with amenorrhoea or oligomenorrhoea associated with an elevated LH: FSH ratio as in polycystic ovarian syndrome (PCOS). Women with hypogonadotrophic hypogonadism do not generally respond to (CC) and those with hyperprolactinaemia are better treated with Bromocriptine.

In practice, the use of clomiphene citrate is not limited to women with anovulatory infertility. It is fairly widely used empirically to treat women with unexplained infertility. The disadvantages of (CC) is it adverse effects on cervical mucus and the endometrium which in some cases probably outweigh its benefits.

Clomiphene citrate has also been used to treat women with proven or suspected luteal phase defects. Results of treatment are variable. Many clinicians prefer to use other methods of treatment such as exogenous luteal phase progesterone administration. When given to normoprolactinaemic women who bleed either spontaneously or in response to gestagens withdrawal, an ovulation rate of around 70% can be achieved. Of the women who do ovulate, 50% will do so on a dose of 50mg, and few will require more than 150mg. Women who have oligomenorrhoea in general respond better than those with amenorrhoea; whether infertility is primary or secondary. Reported pregnancy rates vary greatly 25-35% (2). It is almost universally agreed, however, that there is a significant discrepancy between the ovulation rate and the pregnancy rate achieved by Clomiphene citrate. The reasons for this discrepancy are multiple. The selection of patients, the regimen used and the monitoring of treatment vary widely between centres.

Clomiphene citrate has also been widely used, in early days of ART practice, alone or in combination with gonadotrophins, for the induction of superovulation for simple IVF and gamete intrafallopian transfer (GIFT).. This approach was abounded, when it was shown that ovulation induction with Clomiphene citrate (CC) coupled with either a naturally occurring LH surge or administration of human chorionic gonadotropin (hCG) resulted in an 8% rate of viable pregnancies (3). The combination of clomiphene citrate with HMG leads to a higher incidence of premature LH surges. The overall pregnancy rate for the use of CC-HMG was in the range of 15% to 17% per aspiration (4). CC -hMG protocol demonstrated: a faster growth rate, so that at time of aspiration, follicles are larger and easier to aspirate; a higher estradiol response; a large preovulatory progesterone rise; a high rate of early LH surge.

With the introduction of ICSI for male infertility when modest forms of ovarian stimulation is sufficient, only one or two oocytes are required to be retrieved, the use of Clomiphene citrate was tried.

A total of 15 nulliparous women were treated in their first ICSI trial with 100 mg of Clomiphene citrate per day from days 3-7 of the spontaneous menstrual cycle. HCG (10.000 IU) was administered when a follicular diameter of at least 18 mm was achieved in a minimum of two follicles. Five cycles had to be cancelled, four due to insufficient response and one due to a premature LH surge. Only in 8 patients, 17 oocytes were retrieved. Sixteen embryos were obtained and transferred. Only one pregnancy was achieved (5).

Ovarian stimulation by oral administration of clomiphene citrate is extremely simple but the number of retrieved oocytes per oocyte retrieval (1.7), may be too low and the cancellation rate of cycles too high for the procedure to be considered efficient (5). A regime of Clomiphene citrate alone or in combination with HMG with addition GnRH antagonists over a short period in the mid-cycle avoids any premature LH surges.

Gonadotropins -hMG

Treatment with exogenous gonadotrophic hormones to overcome certain cases of female infertility has been used for more than 40 years. Children born after such treatment have not shown any increased incidence of abnormalities (genetic or otherwise) and their reproductive ability seems normal. Two categories of patients are treated today. Firstly, hypothalamic- hypophyseal insufficiencies (WHO group I), where treatment is compulsory for attaining fertility, and secondly (including anovulation WHO group II), more or less regularly cycling women, where gonadotrophic treatment is used to augment fertility. Especially in the latter group, caution must be taken not to induce adverse effects, ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies.

The first gonadotrophin preparations utilized for ovarian stimulation in the human were of pituitary origin (Gemzell et al, 1958) (6). The commercial preparations contained both follicle-stimulating hormone (FSH) and luteinizing hormone (LH).Research into extraction and concentration of the minute amounts of FSH which occur in the urine of postrnenopausal women began in the late 1940s. By the early 1960s, a purified extract of human menopausal gonadotrophin (hMG) was made available and the first pregnancy was obtained with this product in 1962. As the name of the early material suggests, in addition to FSH it contained significant amounts of LH activity as well as other contaminant proteins. The use of hMG of ovulation in anovulatory women shows an average pregnancy rate of 12 percent per cycle and 34 percent per patient (7). In patients of group I WHO classification, the use of HMG therapy results in almost 82 percent conception rate over 6 treatment cycles.

A variable dosage method is used to achieve follicular growth and maturation. Follicle stimulation is achieved by 7-14 days of continuous gonadotropin administration, beginning with one ampoule daily. Ovarian response is evaluated by the degree of estrogen produced by the growing follicles. The patient is monitored periodically by level of the circulating estradiol and vaginal ultrasound assessment of the number and size of follicles. On the 7th day of treatment, and a decision is made to continue or increase the dose of gonadotropin. The approach of increasing the dose is defined, step-up method. Another approach the step down method, starts with a higher dose (2-3 ampoules) and reduces the dose to one ampoule after the initial response. At the peak of response, 10,000 units of HCG are given as a single dose intramuscularly. The woman is advised to have intercourse the day after the HCG injection and for the next 2 days. Pregnancy is usually achieved with the administration of gonadotropins for 7-12 days. The conventional protocol used in all patients is the step-up protocol. Conventional therapy has shown high rate of ovulation (76-95%) and pregnancy (28%), however, it has equally high rates of OHSS (11%) and multiple pregnancy (33%), (8). Most authors agree that in order to decrease the rate of OHSS and multiple pregnancies, the conventional regime should be replaced by the low dose step-up or the step-down protocols especially in cases of PCO (9). The mechanism of single dominant follicle selection is explained as follow. During normal ovarian cycle the concentration of FSH rises to a level high enough to "activate" a single small antral follicle (2-4 mm diameter) so that it can produce large amounts of estradiol. As the follicle develops, the concentration of FSH is suppressed below this threshold level by the secretion of estradiol and inhibin. The dominant follicle becomes increasingly sensitive to FSH so that it continues to develop in an environment which inhibits development of other follicles. Multiple ovulation can be achieved by extending the period during which the level of FSH remains above this threshold level (e.g. during treatment with (CC) or gonadotrophins). Although multiple ovulation occurs when the gate is widened in this way, the follicles are never completely synchronous as they continue to grow at approximately the same rate. Current evidence suggests that ovulation occurs at random between the two ovaries in successive cycles and that the corpus luteum exerts an inhibitory effect on folliculogenesis by suppressing the secretion of FSH and LH. These observations are compatible with the hypothesis that while small antral follicles are recruited continuously, at all stages of reproductive life, selection of the dominant follicle requires the unique gonadotrophic environment which is only present in the early follicular phase. The follicle of the month is, therefore, selected by chance because it is at the right place at the right time. In women with PCOS the aim of treatment is to try to induce monifollicular development. Knowledge of the mechanisms of single dominant follicle selection has led to the development of an ovulation induction regimen for anovulatory women;(WHO II), the step down protocol. This commences with a fixed high gonadotropin dose followed by several decremental steps. For some patients the initial dose is too high, risking ovarian hyperstimulation syndrome.

Low dose protocol is particularly useful in patients with PCOS where a large follicular recruitment and its subsequent complications are common the incidence of multiple pregnancies is about 35%and OHSS 23% (10). It allows for safe, and successful induction in these PCOS patients. The gonadotropins are administered in slowly increasing amounts until that threshold level of gonadotropins required for mono-follicular development is reached. Several studies reported a lower pregnancy rate compare to the conventional regime. It was deemed safe respect to the of risk of OHSS and the number cycles recruited as well as incidence of multiple pregnancy. The incidence of missed abortions to be lower with the low dose protocol and may be beneficial in PCOS (23% with conventional vs. 9% with low dose) (11).

Recruitment of Multiple Oocytes for ART

Edwards and Steptoe had used stimulated cycles for many years without success. In1979 they reported that they had achieved two normal births following in vitro fertilization and embryo transfer of oocytes recovered during natural cycles. They believed that this change to the spontaneous cycle was the important breakthrough and was responsible for their success (12). The Australian group in 1980 initiated a preliminary step to attempt in vitro fertilization following stimulation with clomiphene citrate (CC), (13). The clinical results showed the advantages of stimulated cycles.

a. The stimulation of follicular growth results in the development of multiple preovulatory follicles. This improves the chances of obtaining more than a single mature oocyte for fertilization and embryo transfer, thus improving the chance of pregnancy.

b. Exogenous stimulation controls the time of follicular maturation more precisely.

c. When using HCG, the need for the protracted monitoring of the endogenous LH surge becomes less important.

The majority of the IVF programs today use only stimulated cycles, applying different regimens

It was elected to use gonadotrophins in preference to clomiphene citrate (CC) for multiple follicular development because it was anticipated that in a normal cycle the ovarian response would be more dependable with gonadotrophins than with CC.

The goal of recruitment and development of multiple follicles was readily accomplished with the use of hMG alone, hMG-CC, hMG in combination with pure FSH alone. Gonadotrophin stimulation was begun early on in the follicular phase to allow for recruitment of multiple follicles before the selection of the dominant follicle. The retrieval of multiple mature oocytes was considered desirable as initial results showed that increasing the number of embryos was transferred resulted in an improved pregnancy rate. In all gonadotrophin protocols used the dose of gonadotrophin has been highest on days 3 and 4 of the menstrual cycle and then tapered down for the remainder of the follicular phase. This approach mimics the physiological conditions during the natural ovarian/menstrual cycle when in the early follicular phase relatively high levels of FSH recruit follicles from the 'gonadotrophin-sensitive' pool.

The administration of a high dosage of hMG or FSH may induce the development of many follicles, but if stimulation is excessive or too short or prolonged, immature and/or post-mature eggs may be obtained with subsequent failed or abnormal fertilization and cleavage and possibly reduced embryo quality. Using this regimen, it was possible to obtain

An average of six mature oocytes with 18% clinical pregnancy per transfer and a 15% abortion rate (14).

Pure u-FSH is used either in combination regimens with hMG or alone followed hCG. The highest pregnancy rate (25%) was achieved in combination of (2 ampoules hMG + 2 ampoules u-FSH on day 3 or 4 and 2 ampoules hMG there after, in which u-FSH was used to augment the recruitment phase. The success rate was lower for fixed protocol of 2 ampoules of hMG /day (21.5%) and lowest- (17%) for 2 ampoules of u-FSH. Similarly, the viable pregnancy rate was low (12.2%) for 2 ampoules of u-FSH and high 18%) for combination of HMG/FSH. It was suggested that the addition of FSH to hMG at the beginig of the treatment cycle mimics the normal menstrual cycle improving, the FSH/LH ratio and by providing a healthier follicular environment for oocyte development because of a decrease in the androgen-to-estrogen ratio and a lower testosterone level. A significantly lower rate of cancellation cycles for the u- FSH was observed.

It is concluded that hMG and u-FSH regimens seem to offer the same clinical conception rate per transfer (20%) as CC- hMG cycles but are associated with a lower clinical abortion rate (18% versus 25%) and consequently a slightly higher number of live births (15).

Stimulation must be adjusted individually according to the patient's characteristics and response.

GnRH Agonists

The use of gonadotropin-releasing hormone (GnRH) agonists together with gonadotropins for ovarian stimulation in assisted conception was first reported in 1984.

It was suggested that the introduction of GnRH agonists into ovarian stimulation regimens might improve follicular response, fertilization and implantation rates leading to a net increase in pregnancy rate. In the meta-analysis studies was found significantly lower cancellation rate, increased number of oocytes obtained and increase pregnancy rates in cycles where GnRH agonists had been added to the standard regimen (16). There are several possible explanations for the better results in GnRH agonist cycles. Primarily, the administration of GnRH agonists prevents premature LH surges and ovulation and therefore reduces cancellation rates. Additionally, in cases of asynchronous follicular growth in standard gonadotropin cycles oocyte recovery has to be scheduled when the largest follicle reaches 18 mm in diameter. In GnRH agonist cycles, growth of follicles is safe to continue with gonadotropin stimulation until a sufficient number of follicles reach an adequate size. From all the data, it is clear that GnRH agonist regimens have an advantage over standard gonadotropin or gonadotropin / clomiphen citrate ovarian stimulation regiments.

There are three protocols of GnRH agonist administration: a. Long protocol,b. Short protocol. c. Ultrashort protocol.

Long Protocol

GnRH- is usually started in mid luteal phase of previous cycle or early follicular phase of treatment cycle itself, as a daily subcutaneous injection or nasal spray. The most widely used GnRH-agonists are buserelin, triptorelin and leuprolide, but it is still not known what the minimal effective dose is for ART use. Gonadotropin stimulation is started after pituitary suppression is achieved and GnRH along with gonadotropins is continued until the day prior to hCG injection. Pituitary suppression is confirmed either by standard ultrasonic parameters, i.e. the endometrium measures less than 5 mm in the largest cross section with absence of ovarian cysts, or the plasma estradiol level is below 150 mmo/l, then gonadotropin therapy is commenced. This protocol described is the most widely used protocol and considered as "gold standard" (17).

In the long protocol administration of GnRH agonist may be in the

folicullar or mid-luteal phase. The advantages of initiation of GnRH agonist in the follicular rather than mid-luteal phase are not so clear. It has also been reported that when the long protocol is used, initiation of GnRH agonists in the early follicular phase results in less profound pituitary suppression, a larger number of oocytes are collected and possibly higher pregnancy rates are achieved compared with initiation of GnRH agonists in the mid-luteal phase. Additional studies has not showed a significant difference in clinical pregnancy rates between two regimens. The only disadvantage of follicular over mid-luteal initiation of GnRH agonists is the possibly increased incidence of ovarian cyst formation, if GnRH agonists are started in the early follicular phase.

Short Protocol

In this protocol, agonist is started with the beginning of menstrual cycle and the flare provides the surge of gonadotropin secretion. A few days latter gonadotropins are administered to supplement the flare. In the short protocol the GnRH agonist is continued until the day of HCG administration. In this protocol the LH suppression is not absolute, and in some 5-10% of cases the cycle may be complicated by premature LH surge.

Ultrashort Protocol

The 'ultrashort and 'short' protocols utilize the initial stimulatory effect (also called 'flare' effect) of the GnRH agonist on pituitary gonadotropin release and the consequent stimulation of follicular growth. To achieve the 'flare' effect the GnRH agonist is administered concomitantly with human menopausal gonadotropin (hMG) at the start of the treatment cycle. In the short protocol the GnRH agonist is continued until the day of human chorionic gonadotropin (hCG) administration, while in the ultrashort protocol the GnRH agonist is administered only for 3 days(18).

The advantages of long protocol are: it prevents unwanted LH surge and hence cancellation of cycles, it allows synchronization in growth of follicles, minimizes monitoring of the cycle and reduces the stress on the patients, laboratory and the clinician, it makes planning and timing of ovum pick easier, it improves the overall pregnancy rates and take home baby rates. The long protocol has the following disadvantages: the treatment cycle is quite long, higher gonadotropin dose is required, overall expense increases.

The ultrashort protocol was originally used in poor responders, whereby the enhanced gonadotropin secretion caused by the administration of GnRH agonists would recruit more follicles. The main difference between the ultrashort and the other protocols such as short and long ones is the time of the patient's exposure to the GnRH agonist. The administration of a short-acting GnRH agonist in the early follicular phase for only 3 days was sufficient to achieve periovulatory desensitization. The low LH in the late follicular phase leads to more mature oocytes, better embryos, well developed secretory changes in the endometrium and, thus, better implantation conditions. Therefore it was expected higher pregnancy rates with the ultrashort protocol than with the other protocols. However, most studies showed worse results compared to the long protocol and even worse to the short one (19).

A possible explanation is, that enhanced gonadotropin surge in the beginning of the cycle of treatment promotes follicle recruitment but the presence of elevated levels of LH and of progesterone during the cycle days 2 to 7 has a deleterious effect on the developing oocytes.

Dose of Gonadotrophins

The dose of gonadotrophins should be adapted to the characteristics of the patient (previous response, age, number of antral follIcles in basal condition) and the protocol that is used.As a rule and for evident reasons, the dose of gonadotrophins in the long protocol is about 50% higher than in the short protocol.

Normal responders: Treatment is started with three ampoules of hMG- long protocol or two ampoules of hMG –short protocol and continued at the same dose unless follicular growth (monitored by ultrasound and determination of estradiol concentrations after even and ten days of stimulation appears to come to a standstill prematurely. In that case, the dose should be doubled.

High responders: Treatment is started with two ampoules both in the short and long protocol, and adapted according to the results of the monitoring.

Poor responders: Short protocol should be applied. There is the need for higher doses of hMG, 4 to 6 ampoules a day.

In the last decade superovulation is almost always performed with the use of adjuvant GnRH- agonist therapy. The superiority of combined GnRH therapy over gonadotrophins alone, or in combination with clomiphene citrate, has been confirmed in a meta-analysis of results achieved with different regimens (20).

Adjuvant therapy has been shown to allow the sustained growth of a large cohort of follicles, whilst preventing the spontaneous LH surge which previously caused up to 20% of stimulatory cycles to be abandoned.

Highly -Purified Urofollitropin (u-FSH HP)

Highly -purified urofollitropin is obtained using hMG as a starting material. It contains only FSH activity, all of the contaminant proteins having been removed. It was introduced by Serono in 1993. In recent years there has been a trend amongst clinicians to administer available FSH preparation for ART. Some studies demonstrated higher pregnancy rates per oocyte retrieval, despite lower estradiol levels on the day of hCG, following FSH alone vs. HMG combined with a long agonist protocol. A meta-analysis of clinical trials, in which FSH was compared with hMG for in vitro fertilisation cycles, has demonstrated that the use of FSH in IVF cycles is associated with a 50% significantly higher clinical pregnancy rate than with HMG (21).

Recombinant FSH (r-FSH)

Recombinant FSH is produced by first inserting the alpha and beta subunits of FSH into a mammalian vector that is then introduced into the genome of the Chinese hamster ovary.

r-FSH has been shown to be identical to pituitary and urinary FSH in amino acid sequence, glycosylation sites, receptor-binding activity, and in vitro biologic activity and differs only in the carbohydrate side chains.

r-FSH has several advantages over urinary gonadotropins in that its production is independent of urinary collection, and it is a pure product free of LH activity.

Several randomized clinical trials have compared r-FSH with urinary gonadotropins in women undergoing IVF. All of the patients were pretreated with a GnRH agonist to achieve pituitary desensitization, followed by stimulation with FSH. In a randomized study; no significant difference was observed in the dose of FSH required; the duration of treatment; or the number of follicles, retrieved eggs, or fertilized embryos. Clinical pregnancy rates per cycle initiated were not significantly different. A recent meta-analysis randomized studies has concluded that r-FSH is superior to urinary FSH, leading to significant improvements in clinical pregnancy rates in IVF. The total gonadotropin dose required was lower, fewer units of rFSH than uFSH achieved the same E2 level and oocyte yield. No differences were found between treatments in rates of spontaneous abortion, OHSS, and multiple gestation (22).

A number of studies assessing the role of a GnRH-agonist pre-treatment on the endocrine response and IVF outcome stimulated with r-gonadotropins. In these studies, various GnRH-agonist protocols and agents have been employed (23). Different degrees of LH suppression were achieved, but this did not appear to significantly influence. It was also suggested that the dosing regimen of GnRH agonist administration may be an important variable of the dose of FSH required to reach their criteria for hCG administration. It may be affected by the type of pituitary down-regulation the patients were given. In patients down-regulated by means of a GnRH agonist in a long protocol (0.1 mg triptorelin daily), the total dose of r-hFSH required was 24.3 x 75 IU ampoules, whereas in patients given the same starting dose of GnRH agonist (with a subsequent reduction to a quarter of the standard dose), only 21.4 ampoules were used and the cycle outcome was not compromised (24).

GnRH Antagonists

GnRH antagonists are competitive inhibitors of GnRH. They bind to the GnRH receptor, blocking the release of bioreactive and immunoreactive LH, as well as the release of FSH. This suppression is observed within hours of administration and may last between 10 and 100 hours depending on the dose of the antagonist administered. The suppression activity of the antagonist may be overridden by exogenous administration of GnRH or a GnRH agonist.

Advantages of the use of GnRH antagonist include initiating gonad- otropin stimulation at the beginning of the menstrual cycle, contributing to patient conveniece, potentially reducing the dose and duration of gonadotropin treatment, the ability to postpone or interrupt the LH surge, and the ability to induce ovulation with native GnRH or a GnRH agonist.

The minimal effective dose for preventing a midcycle LH surge is 0.25 mg of either cetrorelix, (Cetrotide; Asta Medica, Frankfort, Germany) or ganirelix (Antagon; Organon, Oss, Netherlands) daily,from day 5 or day 6 of the cycle or after the follicle reach size of 14mm., until the day prior to ovulation (25). Another regimen is a single 3-mg dose of the GnRH antagonist administered when the leading follicular diameter is greater than 14 mm will prevent an endogenous LH surge without the profound depletion of gonadotropins seen with the daily dose regimen (26).The results of clinical trial comparing antagonist v/s agonist showed that antagonist are effective in terms of clinical pregnancies, a lower incidence of severe OHSS was observed. The treatment regimen is simple, the dose of gonadotropins is reduced, therefore the cost of treatment is lower.

Recent study in our institution compare the efficacy of GnRH antagonists to GnRH-agonists in ovarian stimulation of poor responders undergoing IVF (28). Results demonstrated that there was no statistically significant difference between the two studied protocols for cancellation rate, number of ampoules of gonadotropins used, number of total and mature oocytes retrieved, estradiol concentrations on the day of injection of human chorionic gonadotropin and fertilization rate. Only the number of embryos transferred was significantly higher (P=O.046) in the GnRH- antagonist than in the GnRH-agonist stimulation protocol (2.5:t1.6 vs. 2.0:t1.4, respectively). The clinical pregnancy and implantation rates per transfer in the GnRH-antagonist group appeared higher than in the GnRH-agonist, but did not differ statististically (26.1% and 10.7% compared with 12.2% and 5.9%, respectjvely).

Studies have shown that there is a reduction in cases of ovarian hyperstimulation syndrome (OHSS), using treatment regimens with antagonist compare to long protocol of GnRH agonist making these protocols safer than the long protocol (29). On the other hand, there is a significant reduction in pregnancy rates when GnRH antagonists are used. A recent meta-analysis showed that the overall rate of (OHSS)

was not reduced, reduce number of oocytes was retrieved,a reduction in pregnancy rate might be expected. Different results were obtained when the two drugs, cetrorelix and ganirelix were compared (30).

Ovarian Hyperstimulation Syndrome (OHSS)

Ovarian hyperstimulation syndrome is a serious complication affecting ovulation induction. (31,32,) Its most severe manifestation takes the form of massive ovarian enlargement and multiple cysts, haemoconcentration and accumulation of fluid in the third-space. Renal failure and oliguria, hypovolaemic shock, thromboembolic episodes, adult respiratory distress syndrome (ARDS), and death may complicate the full-blown clinical syndrome. The underlying mechanism responsible for the clinical manifestations of OHSS appears to be an increase in capillary permeability of the ovarian vessels and other mesothelial surfaces (33). It is the third space fluid sequestration and the associated systemic vascular effects that contribute most to the morbidity and mortality associated with OHSS. The anatomical changes of the enlargement of the ovaries and the increased capillary permeability, which lead to acute fluid shift, may explain the different clinical features observed in this syndrome. Rapid body fluid shift in cases of ovarian hyperstimulation may lead to hypovolemia and hemoconcentration, as evidenced by increased hematocrit values and serum osmolarity. When not corrected immediately, hypovolemia may lead to decreased renal perfusion, subsequently stimulating the proximal renal tubules to reabsorb salt and water, resulting in clinical manifestations of oliguria, electrolyte imbalance and azotemia. The loss of fluid and protein into the peritoneal cavity and occasionally to the pleural cavity accounts for the hypovolemia and hemoconcentration. This in turn results in low blood pressure and decreased central venous pressure. The dynamic fluid changes due to the vascular leak may lead to ascites, ARDS and to hemoconcentration and thromboembolic phenomena (34). The enlarged ovaries composed of follicular and luteal cysts may cause the intra-peritoneal bleeding or torsion that require immediate surgical

intervention.

Based on the clinical presentation and laboratory findings OHSS is divided into three categories: mild, moderate and severe and to six grades of severity.

Ideally, ovulation induction should stimulate the ovaries only to a desired level of ovulation. However, the narrow therapeutic range of human menopausal gonadotropin (HMG) as well as other ovulation induction agents and the occasional unpredictable patient response makes total prevention of OHSS virtually impossible in cases of infertility due to anovulation.

Successful induction of ovulation in ART should ideally attain as many follicles and oocytes as possible to obtain the maximal number of embryos in a single treatment cycle. This goal is achieved by using different regimens employing of ovarian hyperstimulation Unfortunately, these regimens are associated with a serious and potentially life-threatening medical complication, i.e. ovarian hyperstimulation syndrome (OHSS) and high rate of multiple pregnancies of high order. The exact incidence of severe OHSS in the world has not yet been determined, since most of the data on this subject derive from relatively small series. Available data, however, suggest an incidence up to range up to 14% of stimulated cycles,but the prevalence of the severe OHSS is probably around 1-2% (35). A national study in Israel showed that the number of severe OHSS cases following conventional ovulation induction treatments remained unchanged, the number of cases following IVF increased dramatically from 2 (0.06% of all IVF cycles) in 1987 to 41 (0.24% of all IVF cycles) in 1996 (36). No doubt the over-utilization of high-dose gonadotrophin protocols by assisted reproductive units today carries some responsibility for this phenomenon. These units seem to have become more competitive during the last few years, with oocyte and embryo numbers being considered as main criteria for their success. With recent refinements in embryo and oocyte cryopreservation, facilitating repeat embryo transfers, these numbers have become even more important in terms of overall pregnancy rates. Expansion of oocyte donation programs where high-dose gonadotrophin regimens play a key-role in achieving maximal numbers of oocytes for donation may have also contributed their part to this trend. Since the incidence of severe OHSS in Israel as presented in our study was lower than that reported worldwide, this phenomenon may be even more serious in other parts of the world. In fact, over-utilization of ovulation induction medication by IVF units worldwide has been suggested previously with respect not only to OHSS but also to other undesired consequences, such as multiple pregnancies and increased costs. Hence, we should ask ourselves how far we are willing to go in treating infertility, and where we should draw the line so that life is not endangered. Different methods for prevention of ovarian hyperstimulation syndrome may be attempted (37): (i) all embryo cryopreservation with luteal phase (ii) avoidance of ovulatory human chorionic gonadotrophin (HCG) and continuation of agonist; (iii) cancellation of ovulatory HCG, prolongation of agonist and later recommencement of menotrophin; (iv) pre-ovulatory LH surge triggering by agonist instead of the conventional HCG. Gonadotrophin-releasing hormone agonist may affect the steroidogenic ovarian stroma directly and such interaction may aggravate the development of ovarian hyperstimulation syndrome;(V) administration of i.v. albumin. Various prophylactic methods not appear to reliably prevent OHSS in all cases.

Multiple Pregnancy

In recent years there has been a dramatic increase in multiple pregnancies throughout the world. For example, some countries have reported a doubling of twin pregnancies and the quadrupling of triplets over the last twenty years (38). Undoubtedly, the main factor to this findings has been the use of ovulation inducing drugs and of multiple embryo transfer in the treatment of infertility. Multiple pregnancy has very serious implications for the mother and her offspring, for the family and the community, and for health service resources. International and national professional bodies have a responsibility to issue recommendations for good practice with a view to reducing the incidence of iatrogenic multiple pregnancy. Using assisted reproductive technologies, whether by the induction of ovulation or the transfer of pre-embryos (in all stages of development including blastocysts), should aim to achieve singleton pregnancies. Under optimal conditions, not more than two pre-embryos should be transferred although circumstances of age and other clinical considerations may warrant three embryos transfer (39).

Conclusions

In the anovulatory patient there is a pathological condition which prevents the patient from ovulating spontaneously, and drugs are used to try to correct this condition to provoke follicular maturation and rupture. The aim is to obtain maturation of one follicle which will release one oocyte ready to be fertilized. In ART program the goal is of recruitment and development of multiple follicles. The retrieval of multiple mature oocytes was considered desirable as initial results showed that increasing the number of embryos transferred resulted in an improved pregnancy rate. Furthermore, the recovery of multiple fertilizable oocytes allows for cryopreservation of extra or surplus or embryos, with the consequent reduction in the risk of multiple pregnancies and the improvement of the cumulative pregnancy rate following ART cycles. Thus, revision of the eligibility criteria for extracorporeal fertilization treatments as well as serious reconsideration of the currently used ovulation induction regimens, are strongly recommended. Ideally, as has already been suggested, the best option would be to collect a single oocyte from a natural cycle, develop it into a blastocyst and maximize pregnancy potential (40). Whilst this is currently not feasible with a sufficient degree of success, less vigorous stimulation of ovaries may contribute to prevent the complication of ART practice. There is no advantage in over-stimulating patients to obtain 20 or 30 oocytes. Mild ovarian stimulation may lead to the improvement in efficiency and safety of infertility treatment applying different ART procedures. The ovarian stimulation protocol should be tailored individually and even differently to the same group of patient requiring ART in the different parts of the World. This suggested approach should be based on the cost of the different procedures involved in ART in different countries.

References

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