Infertility Treatment - Clomiphene - Metformin - FSH - IVF - In Vitro Fertilisation - ICSI

How can we assess ovulation (egg release)?

If you are seeing your periods on a reasonably regular monthly cycle, without hormone treatment, there is a very good chance that you are ovulating; a regular cycle does not, however, guarantee this. No test, other than a positive pregnancy test, can provide absolute evidence that you have ovulated.

Anovulatory (eggs are not being released) infertility is suggested by amenorrhoea (absent periods - amenorrhoea), oligomenorrhoea (infrequent periods - Q6.2) or irregular menstruation.

Many women experience a change in their vaginal discharge just before ovulation, the mucus becoming more watery and stretchy. Mid-cycle pelvic pain usually indicates ovulation.

A basal temperature chart provides a simple and inexpensive early indication of ovulation. The temperature can be taken by mouth with a regular thermometer that should be easy to read. The clinic nurse can teach you how to use this instrument. The temperature should be taken before the day's activity begins. Typically, the temperature falls and then rises by 0.5 degrees centigrade around the time of ovulation. Sexual intercourse should be recorded on the chart as this may show that timing of intercourse may be inappropriate in relation to ovulation. The temperature remains elevated through the luteal phase (second half of the cycle) as a marker of progesterone activity (Fig.2.3). The rise of the temperature in association with ovulation is apparent only retrospectively and couples should appreciate that it is not a useful predictor of imminent ovulation. A sustained elevation of the temperature in association with failure to menstruate is usually diagnostic for pregnancy. The popularity of the temperature chart has fallen as other tests seem more accurate.

Home testing for the LH surge (menstrual cycles) provides a valuable method for determining the timing of ovulation, potentially reducing stress and costs of fertility treatments. These ovulation predictor tests are available from your local chemist.

A blood test for progesterone level is a useful guide to ovulation. The test should be taken between four and ten days before a period (day 21 is perfect for a 28 day cycle). A result in excess of 30 nmol/l is generally accepted as evidence of ovulation. There is a suggestion that slightly higher levels of progesterone should occur in patients taking clomiphene or tamoxifen.

Ultrasound (pelvic ultrasound) has found an important role in the investigation and treatment of infertility. An initial single ultrasound evaluation of the pelvis on the twelfth day of your cycle provides a useful assessment of your ovaries and uterus. At this time there should be a dominant follicle of at least 12 mm in a twenty eight day cycle and the endometrium should be well developed with adequate oestrogenic activity. A series of ultrasound examinations (follicle tracking scans) from about the sixth day of your cycle will chart egg (follicular) development and release.

Mullerian inhibiting substance has been studied extensively in the context of in-vitro fertilization and has been correlated with several outcome parameters.⁰⁸⁰¹

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Related Medical Abstracts - Click on the paper title:-

What can cause anovulation - failure to release eggs)?

Failure of ovulation (anovulation) is the cause of infertility in 20 - 25% of couples referred to an infertility clinic. Anovulation may be associated with:

diagnosed when the prolactin level is inappropriately elevated (hyperprolactinaemia).

Prolactin (hyperprolactinaemia) is the hormone responsible for milk production after childbirth. Breast feeding mothers tend not to see their periods quite as quickly as non-breast feeding mothers as a result of the increased prolactin levels. This is probably nature's way of providing some spacing between pregnancies.

In mild hyperprolactinaemia there may be reduced frequency of periods whereas in severe cases there may be amenorrhoea (Q6.4).

Galactorrhoea (inappropriate lactation) is a symptom indicative of hyperprolactinaemia. 

Ovulatory disorders may be a manifestation of hyperprolactinaemia. Prolactin levels may be slightly elevated in patients with polycystic ovary syndrome and hypothyroidism. Higher levels may be found with pituitary adenomas (tumours) and radiological examination of the pituitary fossa is indicated. Routine prolactin measurement in women with normal menstrual cycles is probably of no value.

Ovulation Induction

With the exception of primary ovarian failure (the menopause), ovulatory disorders (failure to release the egg) can usually be successfully treated. Ovulation induction regimens depend on the underlying cause (infertility cause).

Sometimes appropriate advice may be all that is required. When weight loss is responsible for secondary amenorrhoea (amenorrhoea causes), improved diet leading to correction of your weight may prove to be successful.

The main drugs used to overcome anovulation are clomiphene (clomiphene)(clomiphene citrate), tamoxifen (tamoxifen infertility), bromocriptine (bromocriptene), metformin (Q10.12), and gonadotrophins (gonadotrophins).

There are three concerns associated with drugs used to induce ovulation:

They are associated with a greater chance of multiple pregnancy. The general rate of twins in the population is one in every eighty deliveries but with clomiphene, it is one in twenty or a four-fold increase. Higher order multiple pregnancies (e.g. triplets and quads) can occur with clomiphene but this is rare. Injections of gonadotrophins are more likely than clomiphene to result in multiple pregnancy.

Occasionally ovulation induction can lead to ovarian hypersensitivity syndrome (OHSS).

Finally, there has been concern that ovulation induction treatments may increase the chance of ovarian cancer. A comparison was made of the risk of cancer among women who received clomiphene with the risk among infertile women who did not receive it. There were 11 invasive or borderline malignant ovarian tumors, as compared with an expected number of 4.4^1994-01. A confounding factor is that infertility is itself associated with an increased risk. Furthermore, the risk is reduced with secondary infertility and is dependent on the causation of the infertility.^2004-01Several infertility units have reported their data. Some seemed to confirm the link between clomiphene and ovarian cancer but the majority have produced reassuring results.^{1999-02,2004-02 2006-01}

Monitoring may be required to confirm that ovulation is occurring and to ensure that too many follicles are not developing. Blood tests for progesterone levels around the twenty-first day of the cycle provide an indication of ovulation (Q9.17). Ultrasound monitoring of follicular development is helpful with tablet treatment (clomiphene and tamoxifen) and is really essential with gonadotrophins (injections). When controlled ovarian hyperstimulation is undertaken in IVF protocols, oestradiol levels are used. The need for monitoring hormone levels in IVF protocols has been questioned.^{1998-01, 2006-01}

How important is endometrial thickness

Implantation of the embryo into the endometrium is unlikely if the endometrium is thin.

There is a lot of debate on the administration of low-dose aspirin, estrogen, vaginal sildenafil citrate, pentoxifylline, vitamin E, and gonadotropin-releasing hormone agonist for the management of thin endometrium with an aim to increase the pregnancy and implantation rates in assisted reproductive technology cycles. These seem to be useless and inefficient from an evidence-based medicine point of view. At the moment, evaluation of endometrium using different ultrasonographic markers seems to be superior to all those therapies.⁰⁸⁰¹

Thin endometrium in assisted reproductive technology.(2008-01)

Clomiphene Citrate

Clomiphene citrate, although not a steroid (Q 2.9), has a biochemical configuration similar to that of oestrogens. It modifies hypothalamic and pituitary activity by binding to oestrogen receptor sites (hormones). The negative feedback effect of oestrogens from the ovaries (Figure 10.1) is blocked and the hypothalamus and pituitary gland assume a falsely low reading of oestrogen levels. As a result, GnRH activity and also FSH and LH output from the pituitary are increased and this increases the drive stimulating the ovarian follicles and egg release. Ovulation rates can be in the region of ninety per cent but pregnancy rates do not exceed sixty per cent. Clomiphene therapy is traditionally started with 50mg daily for five days. We generally commence on the second day of the cycle although there is probably no clinical advantage arising from the exact start day. Some commence the clomiphene on the fifth day.

Figure 10.1 Clomiphene - Mode of Action

There is a slightly increased chance of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS). Other side effects of clomiphene therapy include hot flushes and headaches but these are not usually severe enough to discontinue treatment and may be less troublesome with time.

The majority of pregnancies occur in the first few treatment cycles. Some find that simple monitoring with basal temperature alone is as good as urinary LH monitoring and ultrasound for the first few clomiphene cycles but we prefer checking progesterone levels on the twenty-first day of the cycle. If there is no success with 50mg, the dose can slowly be increased in 50mg increments up to 200mg daily for five days.

Although attention has been drawn to the anti-oestrogenic activity of clomiphene , there is probably no substance in the suggestion that the cervical mucus is adversely affected. There would appear to be no increased risk of congenital abnormality (Q3.3) in pregnancy after clomiphene ovulation induction. Early pregnancy loss and ectopic pregnancy rates are not significantly increased in association with clomiphene induced ovulation.

There continues to be debate on the question of a relationship between the use of clomiphene and later development of ovarian cancer. The debate arose in 1994 when an analysis of 3,837 women previously investigated for infertility in Seattle between 1974 and 1985 was reported. Invasive or borderline malignant tumours of the ovaries had subsequently developed in 11 women whereas statistically four or five would have been expected. Nine of the women developing ovarian malignancy had taken clomiphene and five of these nine had taken the drug for twelve months or more. Treatment with clomiphene for less than a year was not associated with increased risk. The consensus is that the risk has probably been overstated. If it is clinically felt to be in your interests for you to continue with clomiphene this is medically acceptable provided that you have been given the current information.

Treatment of chronic anovulation resistant to clomifene citrate (CC) by using oral contraceptive ovarian suppression followed by repeat CC treatment. (1999)

HCG

Human gonadotrophic hormone (HCG), which is produced by the early pregnancy tissues, keeps the corpus luteum functioning (Q 2.13). HCG is almost identical chemically to LH. It is a surge of LH that normally results in ovulation (Figure 2.3). When there is evidence of follicular development with clomiphene but ovulation or pregnancy do not occur, HCG administration can increase the chance of conception. The HCG should be given when the leading follicle reaches approximately 18mm diameter as visualised by ultrasound.

Tamoxifen

Tamoxifen is an anti-oestrogen and it is generally considered to increase fertility rates in a similar way to clomiphene. In contrast to clomiphene, however, tamoxifen does not increase follicular phase FSH and LH levels, although there is an increase in oestradiol levels and luteal phase progesterone. It has, therefore, been postulated that tamoxifen improves follicular development by direct action on the ovary rather than through the hypothalamic-pituitary axis (menstrual cycles). We usually start with 20mg daily from the second to the sixth day and build up to a maximum of 80mg. When used for short periods, tamoxifen does not appear to be associated with any increased risk of either ovarian or endometrial malignancy.

Early studies indicated similar success rates between tamoxifen and clomiphene. In one series of 66 anovulatory patients, both drugs achieved pregnancy rates of 80% within nine months. When clomiphene fails to achieve ovulation or pregnancy, tamoxifen may prove to be effective and vice versa.

Some authorities have recommended tamoxifen as their first choice for women with polycystic ovary syndrome (PCOS). The argument has been that PCOS is associated with relatively high levels of LH and this seems to reduce the chance of conception and increase the chance of miscarriage. Unlike clomiphene , tamoxifen does not further increase LH levels. Metformin may supersede tamoxifen and clomiphene as the first choice agent in PCOS (Q10.12).

Hyperprolactinaemia - Bromocriptene

Since 1976, bromocriptine, which inhibits prolactin secretion by the pituitary, has been the drug of choice (Q6.21) and ovulation rates of 90 per cent and pregnancy rates of 75 per cent have been reported. There would not appear to be any adverse effects on pregnancy outcome following cessation of bromocriptine or even if bromocriptine is continued throughout pregnancy; we advise that treatment be stopped as soon as pregnancy is confirmed.

The standard dose of bromocriptine is 2.5mg twice daily although much higher doses are sometimes required to achieve normal prolactin levels. Side effects frequently occur and include headache, nausea and diarrhoea. These problems can be reduced by prescribing a gradually escalating regime starting with half a tablet at night and increasing at four day intervals. Occasionally the vaginal route of administration proves to be better tolerated.

Recently there have been some new agents that may prove to be better tolerated than bromocriptine. Cabergoline may become the drug of choice although it is currently relatively expensive.

PCOS Metformin

Sadly, although for a few years following the introduction of metformin for PCOS in 1998, many of us believed that it was beneficial. Recent evidence, however, has been disappointing.

Metformin use in PCOS should be restricted to women with glucose intolerance. Based on recent data available in the literature, the routine use of this drug in ovulation induction is not recommended.0803

 

The Metformin - PCOS Infertility - the original  story: Metformin has recently become recognised as potentially beneficial for women with infertility and PCOS (Q7.14). This syndrome appears to be related to insulin resistance, which is reversed by the metformin. Early reports are encouraging. As metformin works by reversing the underlying disease process rather than specifically inducing ovulation, it seems likely that it will not be associated with the risks of ovulation induction (Q10.8).

There is evidence that metformin is effective for restoring normal menstrual cycles in anovulatory PCOS patients, and that it is more effective and cheaper than laparoscopic ovarian drilling as the second therapeutic step in PCOS patients previously defined as resistant to clomiphene citrate. Co-administration of metformin in PCOS patients treated with gonadotrophin improves the mono-ovulation rate and can prevent ovarian hyperstimulation syndrome in patients treated with gonadotrophins for IVF cycles.⁰⁸⁰¹ Others have concluded that metformin is better for ovulation induction than CC alone and equivalent for pregnancy achievement and suggest that metformin can be used first for ovulation induction in patients with PCOS regardless of their weight and insulin levels.⁰⁷⁰¹  There is evidence that metformin is effective for restoring normal menstrual cycles in anovulatory PCOS patients, and that it is more effective and cheaper than laparoscopic ovarian drilling as the second therapeutic step in PCOS patients previously defined as resistant to clomiphene citrate.⁰⁸⁰¹ Using all available evidence, one meta-analysis suggests that metformin increases the likelihood of ovulation and, in combination with clomiphene, increases the odds of both ovulation and pregnancy in women with polycystic ovary syndrome.⁰⁸⁰² Another meta-analysis demonstrated that CC is still first choice therapy for women with therapy naïve PCOS. In CC-resistant women, the combination of CC plus metformin is the preferred treatment option before starting with LOD or FSH.⁰⁷⁰²

Letrozole

Letrozole is being used as an infertility treatment. It is the most recent addition to the drugs being used for fertility treatment. Fertility drugs are used often in infertility treatments. There are two situations in which fertility drugs may be useful. First, these drugs can be used to induce an egg to develop and be released in women who are not ovulating on their own. Fertility drugs can also be used to increase the chances of pregnancy in women who are already ovulating.

Aromatase is an enzyme that is responsible for the production of oestrogen in the body. Letrozole is in a class of medications known as aromatase inhibitors. Letrozole works by inhibiting aromatase thereby suppressing estrogen production. Clomiphene citrate, on the other hand, blocks oestrogen receptors. In both cases, the result is that the pituitary gland produces more of the hormones needed to stimulate the ovaries. These hormones, FSH and LH, can cause the development of ovulation in women who are anovulatory or increase the number of eggs developing in the ovaries of women who already ovulate. As a result, several studies have now been published using letrozole as a fertility drug. By reducing oestrogen production the hypothalamus and pituitary increase their hormone production and this increases the stimulation to the ovaries.

Clomiphene citrate lasts for a long time in the body and may therefore have an adverse effect on the cervical mucus and uterine lining.

Letrozole is a medication that has been widely used in women with breast cancer.

Recently, the manufacturer of Letrozole sent a notice to doctors warning that there are reported cases of birth defects that arose in the children of women who received Letrozole while pregnant. Novartis, the manufacturer of letrozole, reviewed their safety database and found 13 reports of pregnant women receiving the drug worldwide. Of those 13 women, two had children with birth defects. In the United States, the labeling of letrozole already warns that it has been associated with birth defects. Novartis has never sought FDA approval to market letrozole as a fertility medication and is clearly concerned about their liability if given in pregnancy.

There are no reports of letrozole being associated with birth defects when given prior to pregnancy. It is important to make the distinction that when used as a fertility medication, letrozole is given before the establishment of pregnancy. Letrozole is a medication that is metabolized rapidly in the body. It is not thought to have significant levels in the blood or tissues for a prolonged period of time.

At least one major pharmaceutical company, Serono, is conducting studies with a similar medication called anastrozole in the hopes of obtaining FDA approval to market it specifically as a fertility medication.

One of the earliest studies using letrozole as a fertility drug looked at 12 women with inadequate response to clomiphene citrate. Ovulation on letrozole occurred in 9 of 12 cycles and 3 patients conceived. A later study by the same investigators compared the effects of letrozole to those of clomiphene citrate. This time 19 women were studied. Ten women received clomiphene citrate and nine women received letrozole. This study was unable to demonstrate any difference in the number of women who ovulated, the number of eggs that developed in each woman, or the thickness of the uterine lining during treatment. However, a more recent study by a different group of investigators found that compared with clomiphene citrate, letrozole is associated with a thicker uterine lining and a lower miscarriage rate.

Nobody has yet identified the optimal dose for letrozole. Three dose regimens have been tested: 2.5 mg, 5 mg and 7.5 mg. Different studies comparing these dose regimens have occasionally found favor with one dose or another but there is no conclusive data that one dose is better than another. The usual length of treatment is for five days.

Some early studies suggested that the pregnancy rates with letrozole far exceeded those with clomiphene citrate and were possibly even higher than gonadotropins. Further data has determined that this is not the case. Pregnancy rates with letrozole are similar to those seen with clomiphene citrate and are lower than the pregnancy rates seen with gonadotropins. Older patients have a lower chance of success than younger patients.

Treatment with letrozole may still be successful even if other treatments have failed. For example, some data shows that in women who did not ovulate with clomiphene citrate, they still may ovulate with letrozole.

Letrozole side effects

Letrozole works based on its ability reduce estrogen levels. Low estrogen levels of any cause can cause a woman to have symptoms. The data on side effects comes from women who have been using letrozole for an extended period of time in order to treat breast cancer. The treatment duration for letrozole is only five days. Side effects are similar to those seen with clomiphene citrate:

Hot flushes

Headaches

Breast tenderness

Studies conducted so far have shown either no increased risk of miscarriage or a decrease in miscarriage risk. Letrozole should not be given to women who are already pregnant. Studies in rats and mice have shown that letrozole increases the risk of fetal death and malformations. Since there are no studies in human beings, it should be assumed that a similar effect is possible.

The aromatase inhibitors such as Letrozole would seem to hold promise for ovulation induction and superovulation. For the moment they should be considered for research in carefully controlled clinical trials.

Gonadotrophins - FSH and LH

The gonadotrophins (FSH and LH) are released from the pituitary and they stimulate the ovaries (Figure 10.1). Gonadotrophins have become commercially available using extraction techniques on urine from menopausal women (HMG) who have high levels of gonadotrophins. The objective of gonadotrophin therapy is to produce mature follicles, which can be released by injection of HCG.

For low-tech treatment the objective is to stimulate maturation preferably of one follicle but with a maximum of three follicles. Patients who fail to ovulate or conceive with clomiphene or tamoxifen are candidates for gonadotrophin therapy. Tubal patency, normal prolactin levels and satisfactory semen analysis are essential pre-requisites. Patients with hypergonadotrophic hypogonadism (menopausal gonadotrophin levels) do not respond to gonadotrophin therapy. There have been a variety of regimens for the administration of gonadotrophins. The fixed regimen involves a predetermined dose administered in a single intra-muscular injection on three alternate days e.g. Days 1, 3 and 5 of the menstrual cycle and HCG is given three days later if the oestrogen response is in the accepted range.

In the variable regimen, gonadotrophins tended to be administered daily, the dose being adjusted according to plasma or urinary oestradiol results. In the early days of gonadotrophin therapy, the only investigation for monitoring ovarian response was oestrogen assay of urine or blood. Ultrasound tracking of follicular development (pelvic ultrasound), initially transabdominally and more recently by the transvaginal route, has provided a valuable addition for the monitoring of gonadotrophin therapy. 

The risks of gonadotrophin therapy are:

multiple pregnancy (twins, triplets etc.): rates are higher with gonadotrophins than clomiphene.

ovarian hyperstimulation syndrome (OHSS) is more commonly associated with polycystic ovary syndrome and accordingly for these women, the quantity of gonadotrophin administered should be reduced. Some units continue to monitor oestrogen levels in addition to ultrasound but it has been shown that ultrasound alone can be used safely and efficiently.

As with clomiphene (Q10.8), there is concern that gonadotrophin therapy may be associated with an increased risk of ovarian cancer although the latest data does not support the earlier anxieties.

Recombinant FSH

The most recent advance in gonadotrophin production involves recombinant DNA technology. The DNA code (Q32.1) for FSH has been defined and can be inserted into mammalian cells, which then produce the FSH. The resultant recombinant human FSH has become commercially available (Gonal-F - Serono; Puregon - Organon).

Ovarian Hyperstimulation Syndrome - OHSS

This is a possible complication of ovulation induction. In its mild form it is of little significance but in its severe form it is potentially dangerous.

Mild OHSS is characterised by some abdominal distension and discomfort and there may be sickness and diarrhoea. The ovaries may enlarge up to 12 cms. In moderate OHSS there may be some excess of fluid in the abdomen. Severe OHSS is characterised by free fluid in the abdomen that can be detected clinically, even without ultrasound. Occasionally there may be changes in the blood. It is believed that there are about 100,000 cycles of assisted conception annually around the world and about 100 cases of severe OHSS. The risk of severe OHSS is therefore one in a thousand IVF treatments.

The first objective is to prevent OHSS from developing. During treatment cycles, if there is evidence that there is a significant risk that OHSS could occur, the cycle may be abandoned or treatment dosage reduced. When severe OHSS develops, admission to hospital and correction of changes in the blood are required.

Ovarian Drilling For PCOS and Infertility

For more than sixty years, we have known that women with PCOS are prone to infrequent periods and infertility. When a section of the ovaries was removed for microscopic examination, many women with PCOS became pregnant. The exact mode of action has not yet been fully determined. Those with expertise in minimally invasive surgery have shown that small holes can be drilled into polycystic ovaries at the time of laparoscopy with clinical benefit. Only time will determine whether metformin (Q10.12) or ovarian drilling will prove to be more effective but it would seem prudent to try a medical treatment first.

Failed Infertility Treatment

Although there have been tremendous advances in the treatment of infertility, it is a matter of frustration for all concerned that a successful outcome cannot be guaranteed. Sometimes with IVF, fertilisation failure may occur and this could explain for the couple concerned why other treatments have been unsuccessful. The majority of human embryos are lost as a result of implantation failure and any treatment that may reduce this problem would be a major advance in infertility treatment. Low dose aspirin (75 mg daily) improves pregnancy rates in patients with increased antiphospholipid antibody (Q12.17).

It may be difficult to know how long to continue with your infertility treatment. Sometimes a counsellor may provide assistance. It can be particularly difficult if one partner is keen to continue and the other is not. There are times in life when it is helpful to have a plan. You may, for example, decide that you will continue for another six months or a year and then stop. One of the difficulties for you will be that inevitably, with current rates of progress, you may live in hope that a new treatment will prove effective. The medical profession never gives up and is always seeking to improve. Rest assured that however busy your carers may be, they will always have your best interests at heart and they will share with you in any success as well as failures.

Comparing Infertility Treatments

When comparing outcomes of various infertility treatments, we must make allowance for a variety of confounding factors. Couples seeking infertility treatment are likely to be slightly older and this confers a negative bias. Those who follow all possible treatment options including IVF tend to be educated and of higher socio-economic status and these confer a more positive influence. Treatment regimens using ovulation induction drugs and particularly gonadotrophins, are more likely to result in multiple pregnancy resulting in a higher birth rate but greater obstetric (childbirth) risks.

Results reported from individual departments are more likely to be from pioneers or those achieving the best results. National statistics and meta-analyses (Q33.23) indicate a more appropriate reflection of the situation. Treatment advances are occurring so frequently that trends are difficult to interpret. Intracytoplasmic sperm injection (ICSI - Q10.25), for example, has resulted in a fall in donor insemination treatment cycles.

Recommended Book:

 Practical Guide to Ovulation Induction

This is an excellent guide. The author of this website contributed a chapter on the role of computers in an ovulation induction program.

If we have infertility treatment, will our baby be healthy?

In spontaneous conception, the one follicle that has become dominant that cycle is fertilised by the sperm that has beaten all the others in a race. There have been millions of sperm released during the ejaculation. The concept of natural selection is dependent on the idea that the fittest survive. Infertility treatment, particularly IVF, ICSI and cryopreservation circumvent natural selection. There has been understandable concern that these infertility treatments may be associated with an increased risk of congenital abnormality. Reassuringly, however, results reported from around the world indicate that there is no major increase in the rate of babies being born with abnormality.

A negative effect of assisted conception on the developing human brain has not been identified; however, further research of high methodological quality in children beyond pre-school age is needed.⁰⁸⁰¹

  Recommended Book:

Step by Step Ovulation Induction

Neuromotor, cognitive, language and behavioural outcome in children born following IVF or ICSI-a systematic review.(2008-01)