Some women may have difficulty getting pregnant because their ovaries do not release (ovulate) eggs. Fertility specialists may use medications that work on ovulation to help these women get pregnant. There are two common ways these medicines are used:
1) to cause ovulation in a patient that does not ovulate regularly.
2) to cause multiple eggs to develop and be released at one time
About 25% of infertile women have problems with ovulation. These women may ovulate less often or not at all (anovulation). These medications can help a woman to ovulate more regularly, increasing her chance of getting pregnant. These medicines, sometimes called “fertility drugs”, may also improve the lining of the womb or uterus (endometrium). In some situations, these medicines may be used to cause multiple eggs to develop at once. This is usually desired when women undergo treatment known as superovulation with intrauterine insemination (IUI), in vitro fertilization (IVF), donate their eggs, or freeze their eggs (either as eggs or fertilized eggs [embryos]).
What are the common causes for failing to ovulate?
- Nearly 1 in 6 couples will require some form of sub-fertility assistance. The exact prevalence of various conditions can vary demographically. Ovulation disorders account for 10-15% of all sub-fertility patients and there are many causes some of which are listed below:
- Polycystic ovaries (PCO) or Polycystic ovary syndrome (PCOS)
- reduction in ovarian reserve
- hypo or hyper thyroidism
What happens in a natural ovulatory menstrual cycle?
Naturally the ovary continuously recruits and develops the eggs over 60-90 days but only the last 14 days are in the menstrual cycle. All of development occurs under the influence of the ‘pituitary gland’ which is located behind the eyes at the base of the brain. It produces the ‘Follicle Stimulating Hormone’ (FSH) under the influence of which one follicle is selected for ovulation. This follicle becomes visibly larger by the 4th-5th day of the menstrual cycle. Thereafter under the influence of FSH and other hormones it grows ahead of others and becomes the ‘dominant follicle’. This ‘dominant follicle’ exerts its dominance and prevents other follicles from growing that month. It ovulates releasing its egg in the middle of the month under the influence of the second hormone also released from the pituitary gland called the ‘Luteinising Hormone’ or the LH.
Eggs develop within the ovary in a fluid filled sac called the follicle. During this treatment, fertility drugs are expected to encourage eggs to develop to maturity within an appropriately growing follicle and then rupture to release its fluid which hopefully will also contain the egg (ovulation).
The growing follicle produces oestrogen which develops the lining of the womb for pregnancy and also affects the ‘pituitary gland’. It stops it from producing more FSH whilst the ‘dominant follicle’ is completing its development. After ovulation the follicle becomes ‘the corpus luteum’which produces mainly progesterone and also some oestrogen. This combination brings in a second phase of development in the lining of the womb for pregnancy. It also affects the ‘pituitary gland’ and allows it to produce only small amount of FSH and LH after ovulation so that new follicles do not grow in this period.
Naturally after the sperm are ejaculated in the vagina, they swim upwards, through the womb and into the fallopian tubes where they expect to meet the egg. Once the egg is released, it may be captured by the fallopian tube where it will meet the sperm which will enter into the egg (fertilisation). The sperm dissolve the cells surrounding the egg ‘cumulus’ to reach and fertilise the egg. Once the sperm reach the shell of the egg called the ‘zona pellucida’, it undergoes a series of changes before entering and fertilising the egg.
Immediately after this the egg undergoes a complex reaction that will stop any more sperm from entering.
Thereafter the fertilised egg will start to grow and form an embryo which will be gently propelled towards the uterus for implantation some 6-7 days after ovulation. Further growth of this embryo will release hormones from the embryo which will stop menstruation that normally occurs 14 days after ovulation and a pregnancy is then thought to have occurred.
After ovulation the ‘corpus luteum’ will carry on producing oestrogen and progesterone stimulated by another hormone produced this time by the embryo called the human chorionic gonadotrophin (HCG) and in this way further development of follicles does not happen and a pregnancy occurs. If the embryo does not implant or fails to grow, the ‘corpus luteum’disintegrates and menstruation occurs during which the lining of the womb is shed and new cycle begins.
In conditions such as polycystic ovaries there are many eggs but the interaction is deranged and this stops ovulation from occurring. When we induce ovulation we stimulate all glands involved in this process to work better. By giving you stimulating drugs however we can allow more than one egg to develop and this is how the risk of multiple pregnancy rises.
Thus in this very complex interaction between various glands and hormones, ovulation and pregnancy occurs. A derangement at many levels can lead to failure of ovulation and or pregnancy such as the pituitary gland, ovarian reserve of eggs, ovary’s ability to select and develop the dominant follicle, ovulate and release its egg, fallopian tube’s ability to capture the egg, sperm’s ability to fertilise the egg uterus receptiveness for embryo or embryos ability to develop. In older women or when ovaries have been affected by a past illness/treatment, the total number of eggs in the ovary goes down and hence the number it can allocate per month also reduces. There are therefore more cycle where ovulation fails to occur or the process is less than satisfactory for conception.
Essential Pre-requisites for this treatment
- Patent (open) and healthy fallopian tubes confirmed at least by hysterosalpingogram and in some at risk women by laparoscopy
- Absence of any disease in the pelvis such as moderate/severe endometriosis particularly that involving the ovaries and/or tubes and pelvic inflammatory disease
- A potentially fertile sperm test as defined by conventional methods and also the qualitative assessment with isolation of healthy normal sperm and the sperm antibody testing.
- Adequate ovarian reserve of eggs
Methods and Drugs commonly used for ovulation induction
Methods and drugs commonly used for ovulation induction include the following:
- Normalisation of weight and Body Mass Index
- Clomifene citrate
- Ovarian diathermy
- Hormone injections (gonadotrophins)
Weight & Exercise
Fertility and body weight are inter-related and both under weight as well as over weight women experience difficulties in conceiving. Furthermore, the risk of miscarriage, premature birth, restriction in baby’s growth, diabetes in pregnancy, hypertension and several other pregnancy complications are more likely.
The pattern of fat distribution also is important. When the fat distribution is mainly around the abdominal area (central obesity or apple shape), the risk of heart disease, diabetes, cancer of the womb, high blood pressure, diseases of the blood vessels, gall bladder, arthritis, cancer and respiratory problems increases.
Excessive aerobic exercise and especially long distance running can increase your metabolic requirements to the extent that the body’s preservation mechanisms see these as a famine state and will switch off the menstrual cycles.Marathonrunners can feel physically fit but often are in a hypogonadal state and their ovaries become inactive. In extreme circumstances they can stop having periods or develop irregular cyclicity with failing to ovulate. So extremes must be avoided but healthy exercise regime is encouraged.
Please ask if we have not already told you of your Body Mass Index. Ideally for fertility this should be between 20-25. When ever appropriate we will give you further detailed advice regarding this issue.
This is given in a tablet form from the 2nd to the 6th day of the menstrual cycle. Many women undergoing this treatment do not have a natural cycle and this has to be induced with progesterone tablets.
If you do not have a cycle or bleed extremely infrequently such as every 2 or 3 months, you are advised the following:
- Take a pregnancy test. If the test is negative, start Provera tablets for 5 days, as prescribed and await menstruation (likely to arrive in the next 3-14 days).
- On the 2nd day of the period take Clomifene tablets for 5 days (from day 2-6 of your menstrual cycle).
- Expect a period 4-5 weeks after taking the Clomifene tablets.
- If a period arrives as expected, it means that you have responded but have not become pregnant. You are advised to start the Clomifene tablets again on the 2ndday of the period for 5 days.
- If a period fails to arrive 4-5 weeks after taking Clomifene, it means that either you have not responded or you have become pregnant. You are advised to take a pregnancy test.
- If the pregnancy test is negative, repeat the course of Clomifene tablets for 5 days.
- If the pregnancy test is positive, contact your GP or us, so that a pregnancy scan can be arranged, when appropriate.
- Repeat this cycle until review or a pregnancy has been achieved.
- If you do not establish a cycle within 3 courses, please arrange a review, unless you already have one.
- It is important to have regular sexual intercourse during treatment. If you start cycling regularly, you may use an ovulation prediction kit in order to improve timing of sexual intercourse. Your fertile period (when having regular 28-30 day cycles) is day 10-14 of your cycle.
- Keep all of your dates for review, unless a conception occurs beforehand.
Risks of Clomifene
a. Multiple pregnancy: Sometimes the ovary will respond more than desired and will produce more than one follicle. This means that there would be an increase in the risk of a multiple pregnancy (5% as opposed to 1% risk in the normal population).
We like to monitor at least one of your cycles to ensure that you have controlled ovarian stimulation. Producing more than 3 follicles would mean that we would advise you to abstain in this treatment cycle, abandon that treatment in the future and suggest alternatives.
The number of implantations can be easily diagnosed with ultrasound scans in the first trimester. Amongst the multiple pregnancies twins are the commonest but triplets, and even higher order births have been reported. Fortunately these are quite rare.
b. Cyst formation: Sometimes the follicles fail to rupture and release the eggs. They can enlarge and form painful and tender fluid filled sacs that very uncommonly would rupture or bleed with in. This happens commonly in nature also but when occurring after treatment would be seen as a risk of treatment. There is some evidence that this is more likely to happen in women with polycystic ovaries because they have thicker and more firm ovarian capsule. This may also occur if the ovary is surrounded by scar tissue. In the vast majority of patients these cysts will spontaneously resolve and not require any further action.
c. Ovarian hyperstimulation: The risk of ovarian hyper-stimulation syndrome is theoretically increased although it is rarely seen with oral medication.
Side effects of Clomifene:
- Visual disturbance if it occurs would lead us to discontinue medication. This is very uncommon.
- Other side effects of lower importance are headaches and hot flushes. These are rarely severe enough to require discontinuation of therapy.
What is the association with ovarian cancer?
There may be an extremely small association between ovulation inducing agents and ovarian cancer. This association at the present time is completely theoretical and the results of appropriately conducted epidemiological studies have been very reassuring once family history and other important features have been taken into account. As in all clinical situations it is important to have a clear understanding of the benefits of treatment and known as well as potential risks. It is also important to establish clearly that the treatment has a reasonable chance of being effective.
Insulin-sensitising drugs – Metformin
PCOS can be associated with a resistance to insulin, leading to the body producing excessively high levels of insulin in an attempt to compensate. This higher level of insulin is known to cause abnormal cholesterol and lipid levels, obesity, irregular periods, higher levels of androgens, infertility due to disturbance of ovulation and an increased likelihood of diabetes.
Metformin belongs to the family of drugs that are known as ‘insulin-sensitising agents’. These lower the blood sugar level, in turn reducing the excessively high insulin.
The studies performed to date suggest that Metformin may be useful in helping weight reduction, improving irregular periods (70%), normalising blood cholesterol and leading to ovulation. One study found that when comparing to no treatment, 34% of women ovulated with Metformin as opposed to 4% who did not receive it. When Metformin was combined with Clomifene the ovulation rate rose to 90% as compared to 8% in those who only received Clomifene. These studies only contained overweight women with PCOS and the role of Metformin in treating women of normal weight has not been investigated.
The use of this drug in our centre is limited to obese women with PCOS who have not responded to weight reduction and Clomifene induction of ovulation. It is also important to realise that the investigation is still at a very early stage and long-term effects of Metformin are not known.
Side effects of metformin
The most common side effects are diarrhoea, nausea, vomiting and abdominal bloating. We usually introduce this medication gradually with a slow build up to the full adult dose. This way your body will adapt slowly and side effects will be limited.
This procedure is sometimes performed for induction of ovulation in those women where oral medication such as Clomifene citrate and Metformin has not been successful. It is done during a laparoscopy procedure under a general anaesthetic.
Its mechanism of action is poorly understood. Theoretically drainage of peripherally located old follicles drains the excess precursor hormones from the ovary which may have had a suppressive effect on the development of new follicles.
In the medical literature the likelihood of ovulation after such a procedure is approximately 60-70% especially when combined with the use of oral medication such as Clomifene and / or Metformin. Approximately 60-70% of responsive women may then conceive naturally.
Like other forms of induction of ovulation, it is useful to perform such a procedure only if tubal function is normal, male sub-fertility has been excluded and there is no other disease with in the pelvis.
Risks of ovarian diathermy
In addition to the standard risks of the laparoscopy (1% risk of bowel, bladder and vascular injury needing further surgery and repair) and the general anaesthetic (1 in 10,000 risk of complications), bleeding and adhesion formation can occur after ovarian diathermy. To minimise this risk precautions are taken routinely during surgery. One rare complication of this procedure is a reduction in ovarian reserve of eggs and in extremely rare situations even premature ovarian failure has been reported in the medical literature.
Gonadotrophin Induction of Ovulation
Gonadotrophins are pituitary hormones namely the FSH and the LH as described above in section 8. These hormones are administered by a subcutaneous injection and stimulate the ovary to develop follicles containing the egg in your ovary. It is given during the first half of the cycle and is usually given daily although it can also be given on alternate days. You will be instructed on the dose and timing of this hormone.
There are large variations between patients in the number of eggs recruited and developed in response to the same dose of the stimulating hormones (see below). This response is mainly dependent on the female partner’s age, the cause of her sub-fertility, her body weight and past treatments or ovarian surgery. There are other genetic determinants also. Having preformed the pre-treatment assessments, we judge the starting dose bearing in mind your clinical circumstances. When uncertain we may perform additional early scans to use the option of ‘stepping-up’ or ‘stepping down’ during the stimulation phase for a better response.
What does it involve?
The hormones (Puregon/ Gonal-F/ Menopur) will be started at the appropriate time of your cycle.
How to inject?
Gonal-F, Puregon and Menopur are usually given by a subcutaneous injection (very fine needle-injection in the fat layer under the skin).
How are they prepared?
Gonal-F and Puregon are synthetic compounds, very pure and with an identical structure to PURE FSH only. Menopur is extracted and purified from menopausal women’s urine and is therefore a combination of naturally produced hormones. This can contain protein impurities at a very low level which can rarely give a skin reaction. There are no other reported complications.
As stated above, to date the only additional side effect with urinary preparations has been that of an occasional rash on the injection site and rarely a more generalised allergy has been reported. Other risks with protein impurities are purely theoretical and there have been no cases reported to cause concern.
This can happen with any of the preparations available. Sometimes the ovaries will recruit a large number of eggs especially in young women and those with Polycystic ovaries. This can put you at risk of developing an illness called The Ovarian Hyper-stimulation Syndrome (see below for further details). We use ‘step-up and/or step-down’ method to adjust and protect you from this risk during the stimulation phase.
How effective are they?
We have used the Pure and Urinary preparations quite extensively and are happy with them all.
Who should give the injections?
The injections can be administered yourself or by your partner. We strongly advise you to consider learning self-administration.Independencewill save you time, effort and stress of professionals not being available when needed. However, if you are extremely anxious then you may seek the help of your doctor’s nurse.
When to take the injections?
The injection is taken once a day at approximately the same time but an absolute and accurate precision is not essential. We will be able to estimate the day of your ovulation/insemination once the growth rate of follicles is established. It will also help in deciding the time of abstinence in preparation for the semen sample to be given on the day of ovulation/insemination.
The hCG (Pregnyl) Injection
When your follicle/s have reached an appropriate size, as assessed by scan, you are ready to be prepared for ovulation. This hormone mimics a surge of a natural hormone that normally causes ovulation. It is given by subcutaneous or intramuscular injection, usually between the 9th and the 14th day of your menstrual cycle and late in the night after 10.00pm. This injection is usually given late in the night normally between 10.00 p.m. and 2.30 a.m. It is specifically timed to be between 35-37 hours before the time of your intra-uterine insemination.
It is also given after ovulation has occurred to strengthen and support the second half of the cycle after ovulation and insemination. We believe this gives the embryo (formed after fertilisation of the egg), a better chance to implant in the uterus. This support is at a lesser dose of 2,500 units, given twice, generally two days and five days after insemination. Dates and times of these injections will be given to you and occasionally they may differ between patients. Please ensure that you bring your schedule so that these injections can also be properly prescribed.
At the end of the treatment cycle: If you are not pregnant a period will start within 14 days of ovulation. If you miss your period, you need to have a pregnancy test. We will give you a date for the test at the time of your insemination.
Success rates of Induction of Ovulation with gonadotrophins
These are generally measured per cycle and also over a batch of 3 or 6 cycles. We normally run a success rate of 20% per cycle and find that nearly 60-65% of our patients conceive within 3 cycles of treatment. Please ask if you have not been shown our latest annual report detailing the latest results. A clinical pregnancy is defined as a pregnancy confirmed by ultrasound scans or by histology.
Common Questions regarding Ovulation Induction
What happens at the end of the treatment cycle?
If you are not pregnant a period will start within 14 days of ovulation. If you miss your period, you need to have a pregnancy test. We will give you a date for the test at the time of your insemination.
What happens if I do not respond?
If your ovaries show little or no response and your chance of conceiving is consequently reduced. You will be advised to return to the clinic for further advice and discussion.
What are the Success rates?
A clinical pregnancy is defined as a pregnancy confirmed by ultrasound scans or by histology. As an approximate guide with each step of treatment, you may expect that two thirds of the patients will respond to the above drugs alone or in combination with in 3 months. Approximately two thirds of the responders will conceive with in 6 months. We would usually assess suitability to continue drugs at 3 monthly intervals. Most patients will receive treatment for 6 months but sometimes we may continue until 12 months. During the 12 month period if a pregnancy does not occur, a change in management is needed.