Chapter 7

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:

  • The exact cause of anovulation should be diagnosed, to allow proper selection of the appropriate medication to stimulate ovulation. The indiscriminate prescription of clomiphene citrate to all women with oligo-ovulatory cycles without reaching a diagnosis is not appropriate.
  • There should be no medical or social reasons to contraindicate pregnancy. Medical conditions should be addressed first, and social factors are better dealt with in collaboration with a counsellor.
  • At least one fallopian tube should be patent.
  • Specific endocrine problems including thyroid and adrenal glands dysfunction, and hyperprolactinaemia should be addressed first. Spontaneous ovulation may restart without the need for active stimulation of the HPO axis.
  • Obese and underweight patients should be encouraged to regain an appropriate body mass index between 18.5 – 24.9 kg/m2. This is more likely to kick-start the HPO axis to resume functioning spontaneously. More information about this subject can be found in Chapter 8.
  • There should be no contraindication to use the specific drug selected.
  • Monitoring facilities and experienced medical supervision should be available to maximise chances of patients’ safety. This will reduce, but does not abolish altogether excessive ovarian response, ovarian hyperstimulation syndrome or multiple pregnancies risks.
  • Hospital backup should be available to deal with any complications, especially ovarian hyperstimulation syndrome.

Treatment rationale

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

  1. Drugs acting at the level of the hypothalamus [anti oestrogens];
  2. Drugs acting at the level of the pituitary gland [pulsatile GnRH] ;
  3. Drugs acting directly on the ovaries [gonadotrophins].

Disease rationale

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:

  1. Hypogonadotropic hypogonadism [WHO type 1];
  2. WHO type 2 (non PCOS);
  3. Polycystic ovary syndrome which makes more than 50% of all the cases.

Aetiology of anovulation

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):

  • PCOS was diagnosed in 50.8% of all anovulatory women investigated.
  • Hypothalamic dysfunction was reported in 26.2% of the cases. Anovulation was linked to weight related problems, psychological problems, or excessive physical exercise. No specific association was noted in many patients.
  • Ovarian failure was reported in 8.7% of the patients as diagnosed by high FSH blood levels. Induction of ovulation is not a viable option in these patients.
  • Hypo-or-hyperthyroidism was diagnosed in 4.2% of all patients who presented with anovulation, or anovulatory menstrual dysfunction. As stated before, treating the underlying condition allows spontaneous resumption of ovulation in most cases. Adequate ovulation may take longer time to resume after the biochemical correction of the deranged thyroid indices.
  • Secondary amenorrhoea due to hypogonadotropic hypogonadism was diagnosed in 4.0% of the cases mainly due to empty sella syndrome. The diagnosis was made with the help of MRI.
  • Hyperprolactinaemia was reported in 3.1% of the cases.
  • Different other causes made the remaining 3.0%.

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.

Specific medications


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:

  • Thick and non-watery cervical mucous reduces colonisation of the cervical crypts with sperm, which is necessary for the continuous migration of sperm into the uterine cavity.
  • Patients on clomid were found to have advanced histological maturation of the endometrium relative to its chronological age.
  • Changes in fallopian tubes fluid chemistry and motility can affect the transport of the sperm and / or embryos.

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.

Other side effects include:

  • Clomiphene citrate has a thermogenic effect, which may give a false impression of thermal shift in non-responsive patients using temperature charts to document ovulation.
  • Premature LH surge with small follicles is not uncommon after clomiphene citrate induction of ovulation. Such occurrence can only be detected if ultrasound monitoring is used.
  • Increased incidence of luteinized unruptured follicles (LUF) syndrome has also been reported after using clomiphene citrate therapy. It can be diagnosed when a follicle fails to collapse or to shows internal changes reminiscent of a corpus luteum. Colour Doppler monitoring may show poor neovascularisation around the luteinized follicle, and serum progesterone may be low as well. The reported incidence of LUF ranged between 6-25% during the first cycle of clomiphene citrate use. Higher percentages were reported in women with unexplained infertility and regular cycles who received clomiphene citrate during intrauterine insemination treatment cycles. Figures of 78% and 90% were reported during the second and third cycles respectively in this group of women (8). This detrimental effect on follicular rupture was considered an indication for a possible role for clomiphene citrate in the aetiology of LUF, either by central or local means.

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:

  • To avoid taking the drug in cases with residual corpus luteal cysts. This is especially important during follow up cycles after previous use of the drug. Such cysts were reported in 14% of the cases as mentioned before;
  • Assurance of follicular growth as  ≈20% of the patients may not respond;
  • To detect multiple follicular development with increased risk of multiple ovulation (30 %) and multiple pregnancy (5 – 10%);
  • To detect ovulation of small follicles due to premature LH surge;
  • To confirm ovulation which is necessary for selecting the optimum time for intercourse or artificial insemination;
  • To detect cases with LUF syndrome (25 – 90%) as discussed to before.

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.

Gonadotrophins dosage

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.

The primary objectives for monitoring ovulation are:

  • To secure patients’ safety by detecting early signs of excessive response which precedes hyperstimulation;
  • To evaluate patients’ response to therapy in an attempt to secure monofollicular ovulation whenever possible;
  • To document changes in the endometrial thickness and echotexture;
  • To time hCG injection to trigger ovulation;
  • To document ovulation has taken place.

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:

  • Collapse of the monitored follicle;
  • The follicle becomes smaller with thicker wall;
  • The follicle outline becomes irregular with the appearance of intra-follicular echoes due to the presence of blood clots and serum;
  • There is increase in the amount of fluid in POD;
  • The endometrium shows an echogenic texture.

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.

The role of Doppler Ultrasound

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:

  • The uterine arteries can be identified just lateral to the cervix;
  • Typically they have moderate to high blood flow velocity;
  • Their resistance index depends on the phase of the cycle;
  • They have small end diastolic flow during the proliferative phase;
  • The resistance index declines before ovulation, and stays low till menstruation.

Basic Doppler studies of the ovarian arteries can be summarized as follows:

  • Ovarian vessels can be seen lateral to the upper pole of ovaries;
  • They are more difficult to visualize than the uterine arteries;
  • They do not show prominent colour flow on colour Doppler mapping;
  • They typically have low velocity;
  • Their resistance index depends on the phase of cycle.

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

  • Reduced resistance index of the uterine arteries and increased vascularisation of the dominant follicle in normal cycles;
  • Low or absent subendometrial and endometrial perfusion in infertile women;
  • Absent uterine arteries diastolic flow in some infertile women.

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

  • An endometrial thickness ≥8 mm;
  • A hypoechoic endometrium with trilaminar echotexture;
  • A dominant follicles 18-22 mm in diameter (24)
  • Uterine artery pulsatility index < 3;
  • High degree of endometrial blood perfusion as shown by colour Doppler or 3D power Doppler histograms reflect favourable endometrial receptivity (25).

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).


Triggering ovulation with hCG injection

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:

  1. For patients with hypogonadotropic hypogonadism;
  2. Following pituitary downregulation with a GnRH-analogue;
  3. For better timing of ovulation in cases of intrauterine insemination;
  4. When a follicle has reached 20-22 mm in diameter without evidence of an LH surge, or a good colour rim demonstrable by colour Doppler mapping.

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:

  • It increases follicular fluid volume;
  • It also increases collagenase and plasmin activity;
  • It increases the level of prostaglandins F2a;
  • It increases the contractility of myoepithelial cells in the ovary.

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)

Induction of ovulation with pulsatile GnRH

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.

The drawbacks of using pulsatile GnRH for induction of ovulation include:

  • Treatment can only be given within a dedicated infertility unit with staff available to respond to patients’ problems;
  • Patients must be motivated with good sense of hygiene to reduce the risk of infection;
  • The needle site should be changed regularly. This should be done weekly for subcutaneous sites, to avoid infection. More frequent changes will be needed with the intravenous route of administration, depending on dislodgment of the needle, or appearance of local signs of phlebitis;
  • The cost of the pump and the dedicated type of needles should be taken into consideration;
  • It may take longer to respond to pulsatile GnRH medication than to gonadotrophins depending on the dosage.

Ovarian electrocautery for induction of ovulation

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 periods

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).

Early pregnancy scanning

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

  • Confirm a diagnosis of intrauterine pregnancy;
  • Exclude the possibility of an empty uterus with positive ßhCG;
  • Exclude or ascertain a diagnosis of multiple pregnancy;
  • Ascertain chorionicity of multiple pregnancies. A thick septum between the two sacs during early pregnancy usually indicates binovular twining. The lambda sign is useful in this respect in the second trimester;
  • Help with monitoring of disturbed pregnancies;
  • Can be used for embryo reduction in cases of higher order multiple pregnancies.

Ovarian hyperstimulation syndrome

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):

  • Young age;
  • Polycystic ovaries;
  • Low body weight;
  • Higher doses of exogenous gonadotrophins;
  • High absolute or rapid rise in serum oestradiol;
  • Previous episodes of OHSS;
  • Exogenous hCG injections to trigger ovulation;
  • With hCG injections for luteal support;
  • During conception cycles because of endogenous hCG production.

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:

  • The number of follicles;
  • The rate of rise in oestradiol level;
  • The actual level of oestradiol;
  • The ratio of mature vs. intermediate follicles which denotes follicular maturation index on the day of hCG adminstration.

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):

  • High follicular fluid level of proteins and renin;
  • Angiotensin mediated increased capillary permeability;
  • Excessive exudation of protein-rich fluid from the peritoneal surface and enlarged ovaries.

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:

  • Volume depletion, hyponatraemia and ascites;
  • Haemoconcentration & thrombotic tendency;
  • Renal and hepatic dysfunction and respiratory distress.

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

  • Proper assessment of the severity of the condition, bearing in mind its dynamic nature which can change from one day to another;
  • Provision of symptomatic relief and reassurance to the patient;
  • Avoidance of haemoconcentration;
  • Prevention of thromboembolism;
  • Maintenance of cardiorespiratory and renal function.

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:

  • Mild OHSS when the ovaries are < 8 cm in diameter, and the patient complains of abdominal bloating, heaviness and mild pain;
  • Moderate OHSS entails ovaries 8-12 cm in diameter with increased abdominal discomfort, nausea and vomiting, and ultrasound evidence of ascites;
  • In severe cases of OHSS, the ovaries exceed 12 cm in diameter, with clinical evidence of ascites, hypovolaemia, haemoconcentration, electrolyte imbalance, decreased renal perfusion and liver dysfunction. All these systems dysfunctions need regular blood chemistry assessments to determine their severity and progression. The ascites can be tense, and there may be evidence of hydrothorax and generalised oedema.

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:

  • Signs of dehydration and fluid retention with deranged blood electrolytes;
  • Haematological signs of haemoconcentration including PCV > 50% and WBC >25 X 103;
  • Signs of decreased renal perfusion and renal failure, as shown by decreased urine output and changes in blood chemistry;
  • Signs of liver dysfunction with deranged liver function tests;
  • Signs of adult respiratory distress syndrome which may be difficult to diagnose initially. The patient may present with rapid pulse, shortness of breath with no abnormal signs on chest examination. The condition may deteriorate fast, and the patient could become hypoxic or even cyanotic, and in need of positive pressure ventilation. Arterial blood gas assessment is indicated in hypoxic patients at risk even in the absence of physical signs.

Management of moderate and severe OHSS 

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:

  • Aim at reassurance to reduce anxiety;
  • Keep a strict fluid chart and start crystalloid solutions 100-150 ml/ hour, if the urine output < 400 ml/day or the PCV > 45%;
  • Add low salt human albumin in a dose of 100 gm every 3-12 hours by intravenous infusion, if the PCV has not improved or the patient has developed oliguria;
  • To reduce the risk of deep venous thrombosis, patients should be encouraged to use full length thrombo-embolic deterrent (TED) stockings, and to mobilise as soon as possible;
  • Subcutaneous heparin in a dose of 5000 IU twice/day should be used to guard against thromboembolic problems;
  • A diuretic (furosemide) should be used only if PCV has improved, but there is no diuresis yet. Otherwise, it should be avoided as it can lead to further dehydration of the intravascular compartment and electrolyte derangement;
  • Dopamine infusion can be used in a dose of 5 µg / kg body weight / min, in patients with impending renal failure despite implementation of all the above measures;
  • Patients with tense ascites which is interfering with breathing should have ultrasonically guided paracentesis of the peritoneal fluid. This will reduce its splinting effect on the diaphragm, and can help with urine output as well in patients suffering from oliguria. This fluid is very rich in plasma proteins, and can lead to proteins deprivation if large amounts of the ascitic fluid are removed.

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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