Treatment of patients with ovulation problems that are causing menstrual problems will depend on whether the patient wishes to become pregnant or not.
Prior to beginning treatment, it is important that the patient is adequately investigated to define the exact cause of the ovulation problem and menstrual disturbance.
In the great majority of cases it should be possible to tell patients why their ovaries are not working properly and why they have some menstrual disturbance.
PCOS treatment options
If the patient does not wish to become pregnant
If the patient has been thoroughly investigated and understands the cause of her ovulation problem and her absent or deficient periods then no treatment is one option. This means if the patient can continue to have no periods or infrequent periods. There are however two problems with this option.
If no treatment is given the patient will not have any contraception. Patients who do not wish to become pregnant but are sexually active can therefore become pregnant even though their periods may be infrequent or absent. Patients in this situation often have times of great anxiety when they have been sexually active but are not having any periods. They may be constantly concerned about whether they are pregnant or not.
In patients with no periods, it must be remembered that the ovary is not working properly and is not providing the full quota of the female hormone, oestrogen. Therefore many patients with ovulation disorders and infrequent or absent periods are hormonally deficient for much of the time. This hormonal deficiency is like that of a menopausal lady.
This means that patients may be prone to increasing de-mineralisation and weakening of their bones as well as exposing themselves to an increased risk of heart attack and stroke. There is therefore an argument for hormone replacement therapy in women where their ovaries are working poorly. If hormone replacement is given the hormone deficiency status is reversed. They may feel and function better, have better intercourse and avoid the risks of pregnancy as discussed.
For patients who are overweight with PCOS, weight loss by 5-10% is a proven treatment that might reverse the condition. Weight management is very important for patients with PCOS and will improve ovulation, periods and will reduce long-term diabetes risk.
Oral contraceptive pill
Patients who are not having any or many periods and who have been adequately investigated but do not wish to become pregnant may be put on the oral contraceptive pill.
The advantages of this treatment are:
- Contraception is provided
- Regular bleeds occur (although these are not true periods but hormone withdrawal bleeds)
- Hormone replacement therapy is achieved
- Anxiety about unwanted pregnancies is reduced
- The pill provides a cheap and convenient form hormone therapy
- The lining of the uterus is controlled and the development of serious abnormalities in the lining of the uterus are often avoided
Almost any of the commercially available oral contraceptive agents can be used. The usual side effects and risks of the oral contraceptives may occur.
For patients with PCOS the oral contraceptive of choice is called Diane-35. It contains 35 micrograms oestrogen (ethinyloestradiol) which is the most common oestrogen used in nearly all the oral contraceptive pills. This is slightly more than some of the ultra low-dose pills on the market which may contain only 30 micrograms of oestrogen. However it is still a lower dose pill than many other commercially available oral contraceptives which may contain up to 50 micrograms of oestrogen. What makes Diane-35 special is the progesterone agent.
Nearly all oral contraceptive pills contain two components. These combined oral contraceptives contain oestrogen and a progesterone agent. The progesterone agent used in Diane-35 is cyproterone acetate. This has rather special properties in that it is an anti-male hormone. Cyproterone acetate reduces the conversion of testosterone to its more active forms in areas of the body such as the skin. Diane-35 therefore has the ability to reverse the action of excessive or too active male hormone and reduce problems such as acne and abnormal hair growth.
Diane-35 is therefore the oral contraceptive pill of choice for patients with PCOS or patients who have evidence of excessive male hormone activity such as acne or excessive hair growth. It comes in a packet with 21 active pills and 7 sugar pills. It has the usual risks and side effects of any oral contraceptive pill. In Australia it is not available on Medicare and is therefore slightly more expensive than the ordinary pill. Patients with PCOS can sometimes claim the costs from their health funds in view of their medical condition.
Other hormonal treatments for PCOS or ovulation problems.
It is not necessary to only use the oral contraceptive pill. Patients can have hormone therapy protocols made for them using either oestrogen and progesterone or progesterone alone. Various commercially available progesterones can be used such as Norethisterone (Primolut-N), Medroxyprogesterone (Provera) and the mini-pill preparations. These can be used to regulate cycles and produce more regular and controlled periods. Their place however is quite limited and they are not often used.
A special sort of ovulation disturbance caused by pituitary tumour called a prolactinoma has been previously discussed. The treatment of choice for this condition is a drug called Bromocriptine or a newer one called Dostinex.
If the patient does wish to become pregnant
Patients with disordered ovulation who wish to become pregnant can have treatment with a number of hormones which will induce ovulation. The success rates with these treatments are very high. Ovulation defects are the most successfully treated area of infertility.
Agents used to induce ovulation:
As previously explained GnRH is the messenger hormone, which travels from the higher centres of the brain to the pituitary gland. It is possible to administer GnRH in small continuous doses via a syringe pump. This pump is normally attached to the patient’s arm, leg or abdomen and connected to a needle which is permanently left in place. In this way small continuous doses of GnRH are pumped into the blood stream. These can then go to the pituitary gland and encourage it in turn to send messenger hormone (FSH and LH) to the ovary.
In practice GnRH is very rarely or never used, because:
- It is expensive
- The doses are complex
- The patient needs a permanently inserted needle attached to a syringe pump for 7 to 14 days
- It is often easier to use other agents such as clomiphene or give injections of FSH and LH which will go directly to the ovary than indirectly attempt to influence the ovary through the pituitary.
Clomiphene Citrate (Serophene or Clomid)
This is one of the oldest ovulation induction agents available. It is a steroid-like substance that binds to oestrogen receptors. Oestrogen receptors are protein sites in the body, which bind the female hormone oestrogen and then trigger the response to oestrogen in the individual cells and tissues of the body. It is only through these receptor sites that the hormones can exert their influences throughout the body.
When clomiphene binds to oestrogen receptor sites in the pituitary gland in the brain it prevents the pituitary gland receiving any oestrogen messages from the ovary. The pituitary gland is then dummied into believing that the ovary is not working and therefore proceeds to pump out more FSH to tell the ovary to work harder. This FSH travels to the ovary and induces egg growth and development.
Serophene/Clomid comes as 50 mg tablets. The normal dose is a half to one tablet per day for five days but up to three tablets per day for five days can be given. If a patient is having disturbed ovulation with roughly 28-day cycles it would normally be given from Day 4 to Day 8 or Day 5 to Day 9 of the cycle. In patients who do not have periods (or only have them infrequently) it can be given for five days. Ovulation usually occurs five to eight days after the last tablet.
It is best to combine treatment with some monitoring of the cycle to assess how well the Clomid has worked and to define the time of egg release. Patients can have daily blood tests which begin usually about five days after the last tablet. These blood tests can predict the time of egg release to optimally time intercourse or artificial insemination. Monitoring will double pregnancy rates per treatment cycle to about 8% per cycle. Clomid tablets and “best given” intercourse has a 4% pregnancy rate per month.
Side effects of Serophene/Clomid relate mainly to the fact that it blocks the action of the female hormone oestrogen. The patient may get a dry vagina, mood changes, hot flushes, headaches and breast discomfort. These side effects are often minor and will disappear near ovulation. The multiple pregnancy risk has been quoted at 4 to 8% of all pregnancies. Clomid is a relatively weak fertility agent and is rarely associated with high-order multiple pregnancies. Quadruplets and triplets have been reported after treatment but the majority of multiple pregnancies are twins.
Serophene/Clomid works best in patients who have minor disorders of ovulation. In these patients it will induce ovulation 60 to 70% of cases with total pregnancy rates of up to 50%. In patients who have more severe ovulatory disturbance, such as absent or very infrequent periods, the response will be much less. Ovulation will only be induced in 30 to 40% of patients and pregnancy rates are usually in the order of 25 to 30%. Many of these patients will need more sophisticated treatment than Serophene/Clomid provides.
The advantages of Serophene/Clomid therapy are:
- It is cheap
- It is simple to take 5 or 10 tablets over 5 days
- It is convenient
- It has a low incidence of side effects
- It has a low incidence of multiple pregnancies
- It does not require complex or sophisticated monitoring
FSH is the hormone which travels from the pituitary gland to the ovary, telling the ovary to grow and mature eggs each month. FSH is available in ampoules. Each ampoule has a dose of 75 or 150 units.
Treatment with FSH is the most powerful and reliable treatment for patients with ovulation disorders. Pregnancy rates of up to 15% per treatment cycle can be expected. The overall pregnancy rate for patients who need and use this treatment is in the order of 60% per patient. Unlike Clomid, the more serious the ovulation disturbance, the more likely FSH is to work.
The aim of giving FSH treatment is to mimic the normal egg development during the menstrual cycle. FSH injections are therefore given each morning as an intramuscular injection. It is best to start with the lowest dose of FSH per day (using 75 units per day). These doses are used for 4 to 6 days at a time. The ovarian response is determined by measuring oestrogen levels in the blood.
When the oestrogen begins to rise, the FSH is successfully growing an egg or eggs. If there is no response to a dose of FSH in 5-6 days of injections the dose will be increased. The normal dose increments are 75 units, 112 units, 150 units and 225 units per day. Most patients respond with 75 to 150 units per day. However it is very important that increments are only made cautiously. The ovary is very sensitive to FSH dosage and too much FSH rapidly grows multiple eggs. It is important that patients receiving FSH therapy start with the lowest possible dose and the increments in the dose are only made gradually after a trial of a particular dose for at least five to seven days.
When the blood levels of oestrogen rise to a point consistent with the mature egg an ultrasound scan will be done. The size and number of follicles (egg containing cysts) growing on the ovary can be measured. Follicle sizes of 14 to 20 mm usually indicate a mature egg. It is important to know the number of follicles present to minimise the risk of a multiple pregnancy.
If conditions are favourable, release of the egg is then initiated. The egg is released by giving an injection of hormone called Human Chorionic Gonadotrophin (HCG). HCG is a natural pregnancy hormone. It has a structure almost identical to LH and can therefore be used to trigger egg maturation and release. A dose of 2,000-5,000 units of HCG is given as an intramuscular injection. Egg release will occur 36 to 44 hours later. The HCG injection is therefore given 1½ to 2 days prior to intercourse or insemination.
HCG is also used to provide support to the ovary in the second half of the cycle after ovulation has occurred. As the first half of the cycle has been artificially created with FSH injections it is important to support the second half of the cycle. If this is not done there will be insufficient progesterone production and the pregnancy will find it very hard to implant as the corpus luteum undergoes premature degeneration. HCG injections 3 days and 7 days after ovulation will prevent this and provide appropriate early pregnancy support.
Side effects of FSH treatment are few. FSH is a natural hormone and apart from the inconvenience of a daily injection has little side effects. The major risks of FSH therapy are those of multiple pregnancy and overstimulation. Multiple pregnancy rates are up to 20% of all pregnancies produced by this treatment. If FSH treatment is not strictly controlled it is treatment with this ovulation drug which causes high order multiple pregnancies such as quins and sextuplets. The combination of oestrogen levels and ultrasound scan should be used to assess the likely number of eggs being released by the HCG injection. If more than two or three eggs are likely to be released, cancellation should be discussed with the patient.
It is very difficult in some patients, especially those with PCOS to choose the correct dose of FSH. If too little FSH dosage is used then no eggs grow. If the dose is increased only a very small amount sometimes many eggs grow on the ovary, often as many as 15 or 20. In some patients with PCOS there is no correct dose. Some patients with PCOS therefore have a very high risk of multiple pregnancy when FSH is used. Conversion to an IVF cycle is often used to control multiple pregnancy risk by only replacing one or two embryos. IVF pregnancy rates can be up to 40-50% per cycle depending on age.
If too much FSH is given the patient may develop over-stimulation syndrome. This is characterised by sore ovaries and a very swollen abdomen. It occurs about 7 to 10 days after ovulation and mostly in patients who are pregnant. It is actually very rare in patients who are having ovulation induction with FSH and then intercourse. Usually these patients do not have enough eggs growing to make overstimulation syndrome common. It is however much more common in patients who grow large numbers of eggs with FSH, usually on the IVF program.
The advantages of FSH treatment therefore include:
- High pregnancy rates
- Powerful management of serious ovulation disorders
- Conversion to versions of the IVF program can occur with high pregnancy rates.
The disadvantages of FSH treatment are:
New forms of FSH have the advantage of being able to be given by a smaller less painful subcutaneous injection. This is a small injection using a fine needle, which just goes under the surface of the skin into the fat rather than the deeper bigger injection into the muscle.
Letrazole and Anastrazole
These drugs are ovulation stimulators in a class called “aromatse inhibitors”. They can be used, like Clomid, to grow eggs. However the side effects can be more severe and safety in pregnancy is uncertain. Australian guidelines recommend caution in their use and only as second line therapy after Clomid.