Induction of Ovulation

Induction of ovulation is a term used to describe stimulation of part or the whole of the hypothalamo-pituitary-ovarian (HPO) axis by exogenous means to produce follicles and ultimately eggs. Normally the ultimate objective is to develop one follicle, and to shed one oocyte to reduce the risks of multiple pregnancies and hyperstimulation syndrome. Stimulation can be at the level of the hypothalamus, pituitary gland, or directly at the level of the ovaries. It is only indicated in women who are keen to conceive, but are not ovulating regularly, or frequently enough to give them a good chance of doing so. This is different from controlled ovarian hyperstimulation, when multiple follicles are stimulated during an in vitro fertilisation treatment cycle. The objective here is to produce multiple oocytes to be fertilised in vitro, to create embryos which can be replaced into the uterus. Certain conditions must be satisfied before induction of ovulation can be provided:

Different drugs are available to work at different levels of the HPO axis. They can be summarised as follows:

The type of drug selected depends on the category of the anovulation problem encountered. The WHO anovulation subgroupings will be used as examples in this case:

Polycystic ovary syndrome has been described as the most common endocrinopathy in women during their reproductive life (1). This view has been shared by many other authors, and the following percentages of endocrine dysfunctions have been reported in one series (2):

The exact percentages may be different in different populations, and care should be taken to establish the correct diagnosis before commencing patients on any specific medication.

Antioestrogens are the most commonly used drugs for induction of ovulation. They are only effective in patients with anatomically intact HPO axis, as in cases of PCOS and other types of WHO type 2 anovulatory problems. They occupy oestrogen receptors at the level of the hypothalamus; hence creating a false impression of central hypoestrogenic state. This will induce the hypothalamus to produce more GnRH pulses to stimulate gonadotrophins production by the pituitary gland. They are not effective in treating patients with hypogonadotropic hypogonadism (WHO type 1), or hypergonadotrophic hypogonadism (cases of ovarian failure) who already have high blood FSH levels.

Clomiphene citrate (clomid) is the most widely used drug in this group. It is a non-steroidal antioestrogen used for induction of ovulation since 1961 (3). It has a long ½ life, so it occupies cytoplasmic oestrogen receptors for a long period of time, rendering them unavailable after an initial stimulation phase. Such downregulation of oestrogen receptors ultimately creates a hypoestrogenic state, which the hypothalamus rectifies by producing more GnRH pulses to increase gonadotrophins production. The manufacturer’s product monograph reported that only 51% of an oral dose of clomiphene citrate was excreted after 5 days, mainly in the stools. The remaining part stayed in the body for a long period of time, mainly in the enterohepatic circulation. Less than 1% of the drug was still being excreted every day in faecal or urine samples collected 31 to 53 days after its administration (4). This explains the protracted antioestrogenic effects of the drug on the different systems of the body.

Since its discovery, various protocols have been tried before settling with the classical 5 days courses. Treatment is usually started after progestogen withdrawal bleeding. Extended therapy for 10 days has been reported to be effective in patients who failed to ovulate after 5-day courses. Fluker et al in 1996 (5) reported that 47% of initially resistant patients ovulated after daily 100 mg doses, used between days 3-12 after withdrawal bleeding episodes. They reported 65% of the treatment cycles to be ovulatory in this group, with no significant side effects.

Ovulation usually occurs 7-10 days after the last clomiphene citrate dose, but may occur a couple of days earlier. About 15-20% of patients, mainly with PCOS, may not respond or only have an inadequate response. Furthermore, only 30-40% of the patients who manage to ovulate usually conceive (6), and the pregnancy rate is generally inversely related to the dose used. Doses >100 mg/day are not usually indicated, and clomid should not be used for more than 6 cycles (4). The discrepancy between ovulation rate and pregnancy rate is related to its antioestrogenic effects, and reduced uterine receptivity. Different detrimental effects have been reported following clomiphene citrate therapy including:

More recent studies showed reduced endometrial thickness, and unfavourable endometrial pattern on ultrasound monitoring. This was coupled by reduced uterine arteries, subendometrial and endometrial blood flow in patients with PCOS using clomiphene citrate (7). Beside these specific antioestrogenic effects, clomid has been shown to increase the blood level of circulating androgens in patients with PCOS. This may have some bearing on the quality of the eggs produced, and the receptivity of the endometrium. Some women may also notice skin eruptions while on treatment. In fact all body systems can be affected by clomiphene citrate, though significant systemic complications are not common. The range of reported side effects included headaches, low mood, nausea and vomiting, fever, hot flushes, tinnitus, chest pain, shortness of breath, tachycardia, urticaria, arthralgia, back pain and myalgia, among many others. More serious side effects included visual symptoms including visual spots and blurred vision, due to intensification and prolongation of the after-images in brightly lit areas. Diplopia, scotoma, photosensitivity and reduced visual acuity have all been described. Treatment should be stopped immediately, and not repeated in these cases. Changes in liver enzymes and hepatitis have also been mentioned. It is important to reiterate that systemic side effects are not common, despite this long list of possible complications.

One of the more common side effects of clomiphene citrate therapy is multiple pregnancies. This follows multiple follicular recruitment and multiple ovulations in >30% of the patients. Ultrasound scan follow up should alert the treating doctor to this possibility. These patients should abstain from sexual intercourse during that cycle. Twin pregnancies have been reported in 5-10% of all pregnancies following clomiphene citrate therapy, but much lower figures were reported for twins (1 in 400 cases, 0.25%) and triplets (1 in 800 cases, 0.12%).

Figure 24 shows monofollicular ovulation in a patient with polycystic ovaries after induction of ovulation with clomiphene citrate. A corpus luteum is seen in the right ovary, while the left one shows polycystic changes. In contrast, Figure 25 shows a total of 11 recruited follicles of different sizes.

Clomiphene citrate should not be used by patients with liver disease and ovarian cysts, and by patients who had previous complications or hypersensitivity to the drug. Accordingly, before prescribing any further doses of clomiphene citrate, care should be taken to exclude the presence of undiagnosed pregnancy, and ovarian cysts which follow 14% of the induced cycles. Such cysts are functional and usually resolve spontaneously. It is also contraindicated in women with undiagnosed vaginal bleeding, and for the management of menstrual disorders in women who are not keen to get pregnant.

Other drugs have been combined with clomiphene citrate to improve its efficacy including corticosteroids, bromocripine, as well as oral and injectable oestrogens. Many studies have reported the efficacy of these medications in improving the response of patients who were initially resistant to clomiphene citrate. Pre-treatment with an oral contraceptive pill, and combined treatment with oestradiol benzoate injections (9), corticosteroids (10), bromocripine, and human chorionic gonadotrophin for the final triggering of ovulation have all been used with different claims of success, after an initial poor response. On the other hand, a Cochrane review published in 2009 showed no extra benefit of adding human chorionic gonadotrophin to clomiphene citrate (11). Nevertheless, the same review showed improved pregnancy rate when clomiphene citrate was combined with dexamethasone, or followed a course of oral contraceptives.

Other antioestrogenic drugs have also been used for induction of ovulation. The most commonly reported one is tamoxifen, which can be given in a dose of 10 – 20 mg every day for 5 days, starting on day 3 of a progestogen withdrawal bleeding. It is not very popular in comparison to clomiphene citrate. Recently, aromatase inhibitors have also been documented as effective drugs for induction of ovulation, either separately, or in combination with clomiphene citrate. By inhibiting the aromatase enzyme, they reduce the conversion of androgens to oestrogens, and hence create a hypoestrogenic effect. This can lead to increased production of GnRH pulses by the hypothalamus and gonadotrophins by the pituitary gland. The most commonly used drug in this group is letrozole which is a third generation aromatase inhibitor. It is given in a dose of 2.5 mg/day for 5 days, starting on day 3 of a progestogen withdrawal bleeding as well. A single dose of 10 – 30 mg was found to be equally effective as the 5-day course. Letrozole has been shown to be effective in clomiphene citrate resistant cases. It has another advantage of a short half life of 45 hours compared to the very long half life of clomiphene citrate which could occupy nuclear oestrogen receptors for 6-8 weeks. Accordingly, it is less likely to have significant detrimental effects on the cervical mucous and endometrium. Letrozole has also been used with gonadotrophins for induction of ovulation in poor responders with some good effect. It may also be used to augment the effect of gonadotrophins, hence reducing their total dose for cost saving. Other drugs within this group include anastrozole and exemestane. All aromatase inhibitors have similar antioestrogenic side effects as clomiphene citrate. They are not yet as popular as clomiphene citrate, but are potentially useful for patients who can not take clomiphene citrate, and in resistant cases (12).

There is some controversy regarding the value of ultrasound monitoring after using antioestrogens induction of ovulation, mainly clomiphene citrate. Unavailability of the service and the cost of repeated ultrasound scan examinations were the main factors responsible for the historical use of clomiphene citrate without monitoring. Many of the benefits in following patients with serial ultrasound scan examinations before and during clomiphene citrate medication have been discussed before, including:

One drug which gained great notoriety is metformin (glucophage), which is an insulin sensitising biguanide drug, used for the treatment of type II diabetes mellitus. It had an equal effect in improving anovulatory menstrual irregularities in both insulin resistant and insulin sensitive PCOS patients (13). A direct effect on the ovaries has been reported even in women who were not insulin resistant (14). A good account has been given about its mode of action, dose, and side effects in Chapter 6. It proved effective in the treatment of anovulatory PCOS patients by inducing regular menstrual cycle and fertility. It was also effective in converting clomiphene citrate resistant patients into responsive ones (15), and reduced early miscarriage rate (16, 17). The usual dose is 500 mg twice daily with food to reduce gastrointestinal side effects. It also has a favourable local effect at the level of the uterus, besides its other favourable endocrine effects on hyperinsulinaemia and hyperandrogenaemia. Such effects include improved endometrial thickness as well as uterine, subendometrial and endometrial blood flow to levels usually seen in a non PCOS control groups (18). It is inevitable that many patients on metformin, which is classified as category B drug for use during pregnancy, will fall pregnant while taking the drug. Recent work showed that it reduced the development of gestational diabetes in women with PCOS (19), and was safe to use during pregnancy (20).

Human pituitary gonadotrophins were isolated in 1958, and utilised successfully for induction of ovulation. They have been withdrawn from the market because of their limited supplies, and the association of Creutzfeldt-Jacob disease with human pituitary growth hormone. Products prepared from postmenopausal women urine have been used since the 1960s, and recombinant products were the latest to be produced. This incurred major changes in prices for patients, in return for more pure products and stable batch to batch consistency. Nonetheless, no significant differences in odds of pregnancy outcome or complications have been found between urinary and recombinant FSH during induction of ovulation in patients with PCOS in a Cochrane review conducted by Bayram et al in 2003 (21). The situation was rather different during assisted reproduction treatment cycles in a different Cochrane review conducted in the same year by Daya and Gunby (22). They reported significant increase in the odds of clinical pregnancy and live birth or ongoing pregnancy for recombinant FSH versus urinary FSH. This view has been challenged by a more recent randomised controlled multicentre study published by Abate et al in 2009 (23). They found no difference in oocyte or embryo quality produced by patients using either medication. Furthermore, there was no difference in the fertilisation, cleavage and implantation rates, or pregnancy and miscarriage rates between the two groups. Interestingly, less urinary FSH was needed for a shorter period of time than the recombinant FSH during the same study to give a similar clinical response. Combined drugs with equal proportions of FSH and LH, or only FSH medication are available in the market. Despite many claims and counter claims in the past, it is now evident that there is no significant superiority of one product over the others, in relation to induction of ovulation or pregnancy rate.

Gonadotrophins are currently used as primary medication in WHO group 1 and clomiphene citrate resistant patients. They act directly on the ovaries, with about 20% chance of multiple pregnancies. Hyperstimulation occurs despite strict monitoring, as follicles are produced in sequence rather than in parallel. It is usually advisable to start with the smallest dose, and to step it up as necessary. Doses and response may differ in different cycles, even in the same patient; hence the need for strict monitoring. Pre treatment counselling is necessary regarding the need for repeated visits to the clinic for monitoring, and to discuss the risks of hyperstimulation and multiple pregnancies. The need to cancel a cycle should be stressed clearly to the patient, in case of excessive response. Smaller doses should be used in the subsequent cycles.

One should always aim at monofollicular ovulation taking into account the endogenous FSH. Patient with WHO group 1 usually need higher doses, with lower risk of OHSS than women with PCOS or PCO. Treatment should be started with one ampoule of the preferred gonadotrophin for 5 – 7 days, and the dose should be increased by half or one ampoule every 5 - 7 days, if necessary. The minimum effective dose should be maintained till a mature follicle has developed. With excessive recruitment, the dose should be stepped down, or even abandon the cycle if multiple follicles have already developed. The minimum effective dosage should be used in subsequent cycles.

Regular monitoring with ultrasound scanning is adequate without the need for oestradiol estimations, in most if not all cases. If oestradiol is used, the ideal daily rise in serum level was shown to be a factor of 1.3 - 1.4, as seen during natural cycles. Exponential rise indicates increased risk of excessive response and hyperstimulation. Follicles may be recruited and grow in sequence, rather than in parallel in response to gonadotrophins medication during controlled ovarian hyperstimulation. Accordingly, new follicles may be seen each time a scan examination is preformed. A folliculogram is best suited to show this response as follicles would be spread along the whole column, rather than being grouped together as siblings of similar size. There is a higher chance of multiple follicles development with gonadotrophins (>60%), in comparison to clomiphene citrate (>30%). It is also noticeable that different patients hyperstimulate at different oestradiol levels. Accordingly, ultrasound scanning is a better parameter than E2 in predicting multiple pregnancies and OHSS. This depends on the total number of stimulated follicles, especially intermediate size ones, as will be discussed later on in this chapter.

It has been established that all these requirements can be fulfilled using ultrasound monitoring. This is because of the close relationship between follicular development and endometrial changes as documented by ultrasound on one hand, and oestradiol level on the other. Furthermore, ultrasound scanning can be used to time the hCG injection, whereas oestradiol is not useful in this respect. It can be useful for withholding the hCG injection, if the blood tests showed exponential rise in oestradiol levels. The reason why hyperstimulation occurs at different oestradiol levels depends most probably on the maturation index of the follicles at the time of the hCG injection. Monitoring ovulation should begin before starting medication to rule out the presence of ovarian cysts or any other pathology. The following scan should be performed 5-7 days after starting medication. The number of recruited follicles should be counted, and marked in a specially designated folliculogram. This should be filled serially, as it gives a visual picture regarding the number and the rate of follicular growth. The maximum endometrial thickness should be measured in the sagittal plane, during each examination. Its texture pattern should also be noted, being isoechoic to the myometrium, hypoechoic or echogenic. A trilaminar pattern with hypoechoic texture is considered to be the most receptive.

Figures 26 – 28 represent thin menstrual, midcycle trilaminar, and echogenic secretory endometrium respectively. Cervical mucous can also be seen as a dark line occupying the cervical canal in Figure 27.

Ovulation can be predicted biochemically by measuring the LH surge. This can be done by urine prediction kits or by serial measurements of LH blood levels, once a follicle has reached 16 mm in diameter. Neovascularisation of the dominant follicle, as detected by colour Doppler mapping, is a good predictor of imminent ovulation as well. All this might be academic, as an exogenous hCG injection is usually given to help with ovulation and timed intercourse. A recent study published by Farhi et al in 2010, showed that pregnancy rate was affected by follicular size when hCG was administered to trigger ovulation (24). The rate was highest (13.6 – 18.6%) when the follicles were 18-22 mm in diameter and lowest with 17 mm (8.8%), 23 mm (8.8%), and 24 mm (5.7%) follicles respectively. Most important, there was no difference in pregnancy rate between cycles with one or two follicles. In general, serum progesterone estimation one week following ovulation helps to indicate adequate ovulation or otherwise. Different levels have been used, but in general a blood level ≥30 nmol/l is considered to reflect adequate ovulation. On the other hand, ultrasound scanning can show the following signs of ovulation:

The corpus luteum has different looks depending on the amount of haemorrhage into the sac itself, and the time lag between ovulation and transvaginal ultrasound scan examination. Figure 29 shows a solid corpus luteum shortly after ovulation. A blood clot occupies the whole sac. Figure 30 shows a corpus luteum with a blood clot and irregular haemolysed areas in the middle, few days after ovulation. Figure 31 depicts a corpus luteum with a resolving blood clot showing reticular texture, may days after ovulation. In general, a corpus luteum behaves like any other haematoma as related to the texture, resolution and disappearance of the blood clot.

Occasionally a follicle may fail to ovulate despite increased oestradiol level, occurrence of an LH surge and rise in the level of luteal phase serum progesterone. This can occur in cases of luteinized unruptured follicle syndrome (LUF), which is seen more common in infertile women. In such cases, ultrasound scan examination may show a persistent follicle after the LH surge, with minimal vascular markings of the luteinized follicle during colour Doppler mapping. In the pre-ultrasound era, diagnostic laparoscopy was the main tool to diagnose LUF through failure to see ovulation ostium, and low serum progesterone in the peritoneal fluid during the luteal phase of the cycle. In cases of premature LH surge, ultrasound scanning can show ovulation of a small follicle with a thin endometrium. This can occur during both natural and clomiphene citrate induced cycles.

Figure 32 shows a new ovulation ostium, whereas figure 33 shows a corpus luteum with evident yellow discolouration, both in the left ovary in different women.

Doppler ultrasound has been studied extensively in relation to the uterine, endometrial and ovarian vasculature during spontaneous and induced ovulation. The uterine artery had more dominance in these studies, and basic findings can be summarized as follows:

Doppler studies at the middle of the cycle can show the following characteristics:

Certain sonographic parameters have been considered as favourable when documented during induction of ovulation:

Figure 34 shows a midcycle transvaginal ultrasound sagittal view of a uterus with thick endometrium and good endometrial and subendometrial blood flow, as shown by colour Doppler mapping. Figures 35 demonstrates a mature follicle with peripheral colour markings revealed during colour Doppler examination, and figure 36 shows favourable uterine artery Doppler pulse waveform, representing both the systolic and diastolic parts. The pulsatility index was 2.05 as shown in the lower right corner by the electronically generated data. Absence of the early part or the whole diastolic pulse had been associated with increased impedance, low tissue perfusion and infertility (26, 27).

It is usual to trigger ovulation with an exogenous dose of hCG, rather than wait for a spontaneous LH surge. This can be a necessity in the following conditions:

The usual hCG doses used for triggering the final act of ovulation are 5000 and 10000 IU, and ovulation usually occurs 36-40 hours later. The ovulation window can last for 3 or more days, as follicles of different sizes may take different times to ovulate. Secondary follicles continue to grow for a day or more with the production of more oestradiol, before ovulating. This group is the one more likely to cause OHSS, and multiple pregnancies. Smaller follicles usually luteinize immediately after hCG, and become atretic. The drug may stay in circulation for up to 10 days after a dose of 10000 IU. So it can trigger ovulation, and maintain luteal support. Such a high dose is more likely to have a wide ovulation window, so it is not ideal for patients with multiple follicles. Accordingly, a dose of 5000 IU should be used to trigger ovulation, and to reduce the risk of OHSS. Similarly, luteal hCG injections to support the corpus luteum can also increase the risk of OHSS. When necessary, progesterone supplements will be a better option, and should be used instead.

The triggering dose of hCG affects rupture of the dominant follicle through different mechanisms:

At the same time, the triggering hCG injection affects oocytes maturation. Normally oocytes meiosis is inhibited by the enzyme oocyte maturation inhibitor (OMI) produced by the granulosa cells. This OMI does not act directly on the oocytes, but through the cumulus cells. It is inhibited by the natural LH surge or hCG injection used to trigger ovulation of a mature follicle. They cause withdrawal of the cumulus cell mass, resulting in break down of the cumulus cells-oocytes communication.

A different role for hCG has been reported within the setup of controlled ovarian hyperstimulation protocol which is used during assisted reproduction treatment cycles. Small daily doses of 200 IU were found to support growth and maturation of follicles >12 mm in diameter, without any detrimental effects on the quality of the follicles. Such medication was associated with reduced number of small preovulatory follicles, resulted in more oestrogenic intrafollicular environment, and reduced FSH/HMG consumption (28)

GnRH is a decapeptide produced by the hypothalamus. It can be used in cases of hypothalamic failure or dysfunction. The best results should be expected in women with WHO type 1 anovulation [hypogonadotropic hypogonadism]. It is given through a pulsatile pump in a dose of 5-15 µg/pulse, every 90 minutes. Smaller doses are used when the intravenous route is used, rather than the subcutaneous one. It has the least risk of producing OHSS or multiple pregnancies, which should be taken into consideration when weighing its advantages and disadvantages.

Usually an exogenous hCG injection is not necessary to trigger the final act of ovulation, as a spontaneous LH surge usually occurs. Furthermore, luteal support can be maintained with the same pulse dose of GnRH. Alternatively, an exogenous progestogen can be used, to give the patient a break from continuous use of the pump.

Laparoscopic ovarian electrocautery is useful as a second line management for patients with PCOS not responsive to clomiphene citrate therapy. It is most effective in patients with blood LH levels > 12 IU/L, as reported by Abdel-Gadir et al in 1993 (29). Both LH and testosterone were reduced after the procedure, and it was equally effective as gonadotrophins for ovulation induction, as reported by the same authors. Almost 50% of the conceptions occurred within 6 months in patients with no other fertility problem. Nevertheless, about 25% of the patients did not respond, but got more sensitive to clomiphene citrate. A recent study reported by Amer et al in 2009 (30) found that patients with high AMH level ≥ 7.7 ng/ml had reduced chance of ovulation after the procedure. This can be used as another parameter, beside LH, to counsel patients regarding chances of response before surgery.

Ovarian drilling has many merits in comparison to other methods of induction of ovulation. It is a simple procedure which is easy to learn, and does not need strict ultrasound or oestradiol monitoring. There were also no increased risks of OHSS or multiple pregnancies, as documented in all the reports published so far. Many patients will continue to have regular periods for a long time, without the need for any further medication. Nonetheless, there is a danger of misusing the technique in patients who are not seeking to get pregnant. There is also the risk of ovarian adhesions if the technique used is not perfect. Using microsurgical principles can reduce this risk (31). The exact details have already been described in Chapter 6.

Figure 37 shows a polycystic ovary after ovarian drilling. Note that there was no slit cauterisation. Also note the characteristic dilated blood vessels usually seen on the surface of polycystic ovaries.

The risk of primary ovarian failure has been raised, but never materialised in any prospective study. Ovarian reserve markers were found to be lower after ovarian drilling, compared to women with PCOS who did not have the same procedure (32). The changes in FSH, inhibin B and antimullerian hormone blood levels, which were used as measures of ovarian reserve, should be considered as signs of normalisation of ovarian function rather than a reduction of ovarian reserve as suggested by Murat in 2009 (33). It is understandable that over cauterisation of the ovaries can lead to non-reversible damage. Accordingly, the number of drills should always be guided by the size of the ovary itself, and the duration of the current application should not exceed 4 seconds each time a drill is made.

Induction of ovulation in women with regular cycles raises many medical and ethical questions. This is especially so as drugs meant to stimulate the ovaries can unnecessarily lead to multiple pregnancies and OHSS. They may not improve the fertility potential in women <35 years, but can increase the multiple pregnancy rate. On the other hand, increasing the number of follicles in older women with gonadotrophins injections can increase cycle fecundity rate. This is usually done within a protocol of timed intercourse or intrauterine insemination (IUI). Nevertheless, the delivery rate in women over 40 years of age was less than 5%, following gonadotrophins injections and IUI as reported by Tsafrir et al in 2009 (34) Furthermore, induction of ovulation is not beneficial and should be avoided in patients with regular cycles and high FSH blood levels. There is always a risk that unnecessary use of clomiphene citrate in regularly cycling women may reduce cycle fecundity, due to its antioestrogenic effects on the cervical mucous, endometrium and fallopian tubes as mentioned before. Furthermore, there is increased risk of LUF (8).

Following adequate ovulation and a positive pregnancy test, early pregnancy ultrasound monitoring should concentrate on the following points:

Ovarian hyperstimulation syndrome is the most serious complication to follow induction of ovulation, and may lead to significant morbidity or even mortality. It is characterised by marked ovarian enlargement, high serum sex steroids, and extravascular exudation of fluid and protein due to increased vascular permeability. This can result in intravascular volume depletion, haemoconcentration, diminished organ perfusion and increased thrombotic tendency (35). It is usually more common with gonadotrophins than clomiphene citrate induced cycles (36). Paradoxically, it is more common with induction of ovulation than with superovulation utilised during IVF treatment cycles, as the risk is reduced by follicular aspiration during oocytes retrieval. Certain patients are more at risk than others, and the following factors increase the risk independently as reported by the Practice Committee of the American Society of Reproductive Medicine (36):

It is generally noticeable that a patient’s characteristics determine her individual response, more than the stimulation protocol. Of all these risk factors polycystic ovaries stand out as the most important entity. The risk is also higher during the first treatment cycle, and in patients with hypothyroidism and hyperprolactinaemia. It is also higher in downregulated cycles. GnRH analogues increase the risk by blocking the spontaneous LH surge and luteinisation which are the self protecting mechanisms against further follicular development (37). At the molecular level, it has been shown Mayorga et al (38) that ovarian response to FSH stimulation depends on the patient’s FSH receptor (FSHR) genotype. The same authors suggested that the number of FSH ampoules needed by each patient could be predicted from a linear combination of basal FSH level and the type of FSHR polymorphism.

The exact incidence of OHSS is usually difficult to ascertain, because of under reporting, and the different diagnostic criteria used. Furthermore, mild forms may even pass unnoticed or unreported by the patients themselves. A figure of 4% has been reported after standard ovulation induction with gonadotrophins with < 1.0% in its severe form. The overall incidence of moderate and severe OHSS during IVF cycles was reported by Brinsden et al in 1995 (39) as 1-10%, but only 0.5 – 2% of the cases were in the severe form. A figure of 38% was quoted by Asch et al in 1991 (40) when oestradiol level exceeded 10,000 pmol/l on the day of hCG administration. Furthermore, the higher the number of eggs collected, the higher was the risk. This risk exceeded 20% when 30 oocytes were collected, as reported by the same last authors. Different oestradiol cut off figures have been quoted when the risk of OHSS increased. In contrast, the rate of increase in oestradiol blood levels, rather than the absolute values, has been reported to be more important in this respect (37). This could reflect the hypersensitivity of the ovaries to stimulation. At the same time, the value of oestradiol levels in predicting OHSS has been questioned in different reports (41, 42). Accordingly, a combination of different parameters should be used during monitoring, including the following:

Patients with more secondary than tertiary follicles are more at risk to develop OHSS. This was demonstrated by a report published by Blankstein et al, as far back as 1987 (43). In mild OHSS, 68.7% of the follicles were 9 – 15 mm in diameter. On the other hand, 95% of the follicles were <16 mm in diameter, most of them (54.7%) <9 mm in cases of moderate to severe OHSS. This last point can explain the different oestradiol levels reported in the literature when the risk of OHSS increased, without taking note of the ratio of the number of secondary and tertiary follicles.

Figure 38 shows excessive ovarian response during IVF treatment cycle. More than 10 follicles were recruited in each ovary. The cycle was cancelled to prevent the development of OHSS.

It seems that certain women are more liable to develop OHSS than others. Figures 39 – 41 belong to a patient who developed moderate OHSS with ultrasonically diagnosed ascites during an IVF treatment cycle, in spite of normal ovarian response and normal oestradiol blood levels. Furthermore, despite the presence of significant ascites, her blood chemistry was not significantly affected. Figures 39 and 40 show transabdominal pictures of the right and left ovaries with only few residual corpus luteal cysts. Excessive amount of fluid is visible around the right ovary and uterus as shown in figure 40. The right and left ovaries were only mildly enlarged with diameters of 6.8 x 4.8 cm and 7.2 x 5.1 cm respectively. Figure 41 shows some fluid under the diaphragm and on top of the liver. This case shows that ovarian size, blood chemistry and the presence of significant ascites may not correlate in the same patient.

The exact cause of OHSS is not known, but certain factors were implicated in the development of OHSS, and have been summarised as follows (36):

Though only the ovarian protein-renin-angiotensin system is mentioned in this list, other ovarian vasoactive factors are also involved in mediating increased capillary permeability. The list includes the kinin kallikrein system, selectins, von Willebrand’s factors, prolactin, prostaglandins, but the most important one is vascular endothelial growth factor (VEGF) (37). This was shown by a major impact of recombinant VEGF antiserum in neutralising capillary permeability activity (44, 45). Further work showed significantly high free or unbound VEGF, and lower plasma and follicular fluid levels of the corresponding binding protein in patient with OHSS (46, 47). On the other hand it, is has been suggested that activation of the renin-angiotensin system in patients with OHSS may be a secondary response rather than a primary factor in the pathogenesis of OHSS (37).

The syndrome typically starts approximately one week after ovulation, but the affected patients may not show any specific symptoms to start with. The spectrum of abnormalities ranges from ovarian enlargement, to severe multiple systems failure. Patients may present with abdominal pain, feeling bloated and tired, diarrhoea and thirst, and abdominal distension in the early stages. In most cases the condition is self-limiting, and strict observation and reassurance will be adequate. The range of severe clinical and biochemical problems can be grouped into:

For such a self-limiting problem, unnecessary intervention can cause more harm than benefit. Accordingly, the management plan should focus on the following points:

These are easy objectives to set, but can be very taxing in cases with severe OHSS. Different methods have been used to classify its severity since 1967, when the first classification was introduced by Rabau et al (48). Various clinical, ultrasound and biochemical parameters have been combined into many subgrades which made them rather difficult to use. For clinical purposes, the following simplified classification has been used in many fertility units for many years, with good effect:

Not all patients with OHSS need daily hospital supervision, or admission to hospital. These will incur unnecessary inconvenience and expenses to the patients. In mild cases, outpatient management entails adequate oral fluid intake, at least 1 litre per day. The patient should also weigh herself daily, and any excessive weight gain of more than 2 pounds per day should be reported to the hospital for further investigations. She should also observe her own urine output. Any reduction in daily output or passage of concentrated urine should likewise be reported to the hospital. Furthermore, strenuous exercise should be avoided to prevent trauma or torsion of the enlarged ovaries. It is advisable to see the patient every few days to measure her abdominal circumference at a fixed point each time, and to ascertain her general condition. In cases of moderate to severe OHSS, the major cardinal monitoring parameters should include:

Strict initial clinical, ultrasound and biochemical assessment will give a clear picture of how much a patient’s systems are deranged. This helps regarding further management plans, and whether the patient should be referred to a unit with intensive care facilities. It is important to bear in mind that the general clinical appearance and the extent of ovarian enlargement are not good indicators of the patient’s biochemical derangement. The following guidelines should be followed:

It is important to remember that OHSS is a self-limiting condition, and resolves spontaneously in the majority of cases. Accordingly, treatment should fundamentally be supportive. More damage can be incurred through prescribed fluid overload. On the other hand, management of severe cases can be difficult, and should be conducted wand electrolytes imbalance.

Induction of ovulation is an art, as much as being a science. Even strict vigilance and attention to details will not prevent complications altogether. Accordingly, doctors involved with this discipline should have good experience in prescribing the drugs used for induction of ovulation. They should also be competent in monitoring patients to optimise response, and to prevent or detect early signs of any complication. It is always important not to prescribe gonadotrophins if there are no competent monitoring facilities in place, and there is no hospital backup support to deal with any complication which may result from such medication.

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