The release of an egg from the ovary is known as ovulation. It is estimated that problems with ovulation occur in 25% of infertile couples. This is an important problem to identify, as most of these patients can be treated successfully.
Normal ovulation The female reproductive cycle is controlled by hormones produced by the hypothalamus and pituitary glands at the base of the brain. These hormones promote the development of eggs and production of hormones from the ovary.
The ovaries lie either side of the uterus in the pelvic cavity. Every month the ovaries take it in turn to release a mature egg, which is picked up by the nearest fallopian tube where fertilisation takes place.
Gonadotrophin hormone releasing hormone (GnRH) produced by the hypothalamus stimulates the release of follicle stimulating hormone (FSH) and luteinising hormone (LH) from the pituitary. Ovulation is triggered by a steep rise in LH. Ovulation usually takes place 14 days before the start of the next menstrual period (i.e. Day 14 of a 28 day cycle, Day 20 of a 34 day cycle, where the first day of bleeding is known as Day 1). Normally ovulating women may notice pain or abdominal discomfort at the time of ovulation and occasionally have some slight vaginal bleeding. Regular periods, premenstrual tension and dysmenorrhoea (period pains) usually indicate ovulatory cycles.
After ovulation the follicle from which the egg has been released forms a cystic structure called the corpus luteum. This is responsible for progesterone production in the second half of the cycle.
How can you tell whether you are ovulating normally? Women who fail to ovulate or who have abnormal ovulation often have a disturbance of their menstrual pattern. This may take the form of complete lack of periods (amenorrhoea), irregular periods (oligomenorrhoea) or occasionally the cycle is short due to a defect in the second part (luteal phase) of the cycle. Detecting ovulation Tests for detecting progesterone can provide indirect evidence of ovulation. The basal body temperature chart is a traditional way of monitoring ovulation. Progesterone causes a slight temperature rise - an elevation of about onedegree Centegrade in the second half of the cycle suggests that ovulation has taken place. We do not advocate the use of temperature monitoring as it is unreliable and may cause additional stresses. A single blood test to measure progesterone performed a week after ovulation and a week before the next period can help confirm ovulation. This level should be at least 30nmol/L.
Patients may notice a change in their own cervical mucus. This should be thin, stretchy and colourless (like the white of a raw egg) just prior to ovulation.
Another way of monitoring ovulation utilises a home urine testing kit that measures luteinizing hormone (LH). This hormone rises sharply 24 - 28 hours prior to ovulation. Increased amounts of LH appear in the urine during this time and kits are 70% accurate in detecting this surge. However the exact timing of ovulation based on these kit results is still difficult and results may be confusing and unreliable in some cases.
Probably the single best way of confirming ovulation is with the use of ultrasound scans (either transabdominal or transvaginal). These can be used to track the growth of the fluid filled sac that contains the egg (follicle). Once this measures 18 - 22mm in diameter, ovulation is imminent. Following ovulation, the follicle usually collapses and this is the best evidence of ovulation. Defects detectable by ultrasound are follicles that do not grow at all, or not to a big enough size, or occasionally follicles that do not rupture at the appropriate time. These defects may be associated with a low progesterone level (usually less than 5nmol/l) in the second half of the cycles. There is often confusion when progesterone levels are at an intermediate value (5-30 nmoml/l) as this often means that ovulation has taken place but that the sample was taken on the wrong day, as progesterone is rarely produced unless there has been ovulation.
What are the causes of ovulatory problems? Failure of ovulation occurs either when there is a disorder of the ovary itself or when there is a failure of the pituitary gland to provide the correct signal to the ovary. About 85% of women with anovulaory infertility have a disorder called polycystic ovary syndrome (PCOS). Approximately 10% of women have problems in the hypothalamus or pituitary gland (often because of chronic illness or being underweight) and the remaining 5% have a premature menopause. In women with early menopause it is not possible to stimulate ovulation and egg donation IVF treatment is required. Polycystic ovary syndrome (see also separate fact sheet) In PCOS there are multiple tiny cystic areas in the ovaries which can be detected by ultrasound. Around one in five women have "polycystic" ovaries on ultrasound, but the full blown syndrome is much less common. It may be associated with a hormone imbalance, obesity, excess body hair and irregular menstrual cycles which may be anovulatory. Women with PCOS may have a raised LH level. This has been linked with a slightly increased chance of miscarriage compared with the general population and this is usually because of obesity. What treatments are available? It is important to diagnose the cause of the failure to ovulate before treatment begins. Hormonal disorders caused by serious dysfunction of the hypothalamus or pituitary need full investigation and often have specific therapies to correct the problem.
It is worth noting that one of the most common causes of poor pituitary signal to the ovary is weight loss. This loss of weight does not have to be severe, as in patients with anorexia nervosa. Even a small amount of weight loss may be enough to stop ovulation and it is important to have a normal body mass index (BMI) which should be between 20-25 kg/m2. For underweight women the correct treatment is to regain the weight that has been lost. Although it is possible to stimulate ovulation there is an increased risk of miscarriage and harm to the developing baby because of maternal under-nutrition.
Drug therapy The most commonly prescribed drugs are described below. Clomiphene citrate (Serophene/Clomid) or Tamoxifen (Nolvadex)
These drugs are most often used to stimulate ovulation in women who may have long irregular cycles or infrequent periods. These tablets have an antioestrogenic effect. They work by triggering the body's own pituitary hormones which in turn leads to the stimulation of the ovaries. The starting dose is usually one tablet a day for five days.
The first tablets should be started on day 2 of the cycle. The patient's response should be monitored, initially by ultrasound scans, as if ovulation fails to occur, the dose can be increased for
subsequent cycles. If ovulation does not occur, the patient becomes a candidate for FSH or LMG (see below).
Clomiphene and Tamoxifen increase a woman's risk of twin pregnancy from 1 in 100 to 1 in 10. However, the risk of having more than two babies is 1%. Occasionally ovarian cysts occur following Clomiphene/Tamoxifen administration. These usually resolve spontaneously when the drug is stopped.
Side effects can include hot flushes and mood swings early in the cycle, depression, nausea and breast tenderness later in the cycle. Severe headaches or visual problems, though rare, are indications to stop the medication immediately.
These drugs may have an adverse effect on the development of the lining of the womb (endometrium) and the cervical mucus making it thicker than usual. Clomiphene may cause an inappropriate rise in the LH level in the first half of the menstrual cycle. If this happens an alternative medication should be used. Clomiphene should not be taken for more than 6 months because of the possible increased risk of ovarian cancer associated with prolonged use.
Gonadotrophin therapy There are a number of injectable gonadotrophin drugs which contain combinations of the natural hormones FSH and LH that are derived either from the purified urine of post menopausal women or by recombinant-DNA technology (genetic engineering). These drugs may contain FSH (Fostimon, Gonal-F and Puregon) or FSH with LH (Menopur, Merional, Pergoveris). They are often prescribed for anovulatory women who have tried Clomiphene without success. The drugs are given daily until the ovary responds by producing follicles containing eggs. Intensive monitoring using ultrasound scans is required. There is a risk of multiple pregnancy associated with this treatment and that is why most clinicians prefer to start with a low dose and increase it gradually. If tests indicate that the response is poor the dose can be increased, the aim being to stimulate one or two follicles to grow.
Once the leading follicle has reached 18-20mm in diameter, a triggering dose of HCG can be administered to induce ovulation. If the woman responds more vigorously than expected, i.e. with more than three eggs developing, the doctor may decide to withhold the HCG injection so that the eggs are not released. However, as the woman could still have her own LH surge and ovulate, it is best to abstain from intercourse to avoid the risk of multiple pregnancy. Women with PCOS are at increased risk of hyperstimulation and the ovarian hyperstimulation syndrome (OHSS - see separate fact sheet).
Despite intensive monitoring, 10-20% of pregnancies achieved after FSH are multiple (usually twins) - the best centres should be able to keep multiple pregnancy rates down to 5%. Multiple pregnancies are known to be associated with increased risk of miscarriage and premature delivery.
Side effects from FSH include breast tenderness, abdominal bloating, mood swings and rashes at the injection site. The most serious side effect is the ovarian hyperstimulation syndrome which requires hospital admission in 1% of cases for rest and rehydration. The ovaries become swollen with cystic areas and cause pelvic discomfort, fluid retention, severe abdominal distension, difficulty tolerating oral fluids and difficulty with breathing may result. In almost all cases these symptoms settle spontaneously with conservative management.
Surgical treatment Ovarian diathermy or laser at the time of laparoscopy results in small burns to the surface of the ovary. This induces ovulation and lowers LH levels in some cases. The mechanism of this action is unknown. This treatment is an option for patients with PCOS not responding to Clomiphene .
Although correcting ovulatory dysfunction is one of the most rewarding infertility treatments, resulting in conception rates very similar to those of normal fertile women, not all infertile women are candidates for "fertility drugs". There is scant evidence that these substances increase the pregnancy potential of a normally ovulating woman.
Often ovulation induction requires an investment of time, money, energy and emotion before a satisfactory formula is achieved. However, for couples who ultimately succeed in producing a healthy baby all the effort is justified.
Updated June 2013
Professor Adam Balen MB, BS, MD, DSc, FRCOG Department of Reproductive Medicine Leeds Teaching Hospitals Infertility Network UK Charter House 43 St Leonards Road Bexhill on Sea East Sussex TN40 1JA Telephone: 0800 008 7464 / 01424 732361
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