A question of fertility
PCOS is the most common cause of anovulatory infertility (where ovulation does not occur). A high blood insulin level as a consequence of insulin resistance is a major reason for ovulation failure.
As alluded to earlier, reduction in insulin resistance through our treatment increases the frequency of ovulation and regulates menstrual cycles. This improvement in reproductive function allows couples to predict the timing of ovulation and plan sex accordingly. Ovulation can be ascertained by over-the-counter kits and testing for the LH surge which precedes ovulation by 30 to 36 hours. We prefer, as evidence of ovulation, a rise in progesterone levels in the mid-luteal phase of a period or days 20-22 of a 28-day cycle. Measuring basal body temperature is a long-standing means of predicting ovulation but is not as reliable as the hormonal tests.
Referral to a fertility specialist, often a gynecologist, is advisable if ovulation fails to occur or if the woman has not fallen pregnant after six months of regular ovulation.
Prior to initiating ovulation induction, it is recommended that other factors which determine fertility should be evaluated. There is a need to establish that the uterus (womb) and fallopian tubes are normal. The fallopian tubes must be confirmed to be patent (open) to enable egg entry from the outer end as well as sperm transport from the uterine end. The male partner must be assessed for semen and sperm function.
Induction of ovulation
Clomiphene
Clomiphene citrate (Clomid) is usually the first line treatment for stimulation of ovulation. Clomid is taken for five days starting on day two of the cycle. The starting dose is 50 mg, rising to 100mg if ovulation does not occur with the lower dose. Successful ovulation occurs in 80% of women without PCOS but in only 42% of those with PCOS. Although four out of five women given Clomiphene ovulate, only about one in three become pregnant. In women with PCOS, the rate of ovulation is only 42% and the rate of subsequent pregnancy proportionately lower compared to women without PCOS.
If, after six months of treatment with Clomiphene, pregnancy does not occur, alternative therapies should be considered.
Treatment is usually for six months only although the recent guidelines from the National Institute of Clinical Excellence (NICE) in the UK suggest that the duration of treatment can be extended to 12 months.
Clomiphene has several side-effects which include stomach and bowel upset, bloatedness, head-aches, sensitivity to bright light, dizziness, hot flashes, depression, and breast discomfort. Mild to moderate cystic enlargement of the ovary may necessitate discontinuation of the drug and close monitoring. Multiple pregnancy related to multiple follicular development may be as high as 15. Clomiphene does not cause birth defects.
Clomiphene and Metformin
Metformin enhances the effect of Clomiphene on ovarian stimulation. On its own, Metformin has been shown to promote ovulation but taken in conjunction with Clomiphene its effect has been found to be superior to either drug taken alone. Aggregate information from 13 clinical trials show that Metformin alone achieved a 46% ovulation rate, Clomid alone achieved 42% and Metformin and Clomid achieved 76%. It is important to note that the women in these programs did follow measures to reduce insulin resistance as emphasized in our management program.
Gonadotrophins
If Clomiphene either alone or in combination with Metformin fails to induce ovulation, treatment using a group of injectable hormonal preparations, known as Gonadotrophins, may be employed. In specialized fertility centers, success in ovulation induction has been achieved by using these compounds resembling normal pituitary gonadotrophins. These substances stimulate the ovaries directly to produce eggs.
There are two types of Gonadotrophin preparations: one contains a combination of both FSH and LH (hMG; Human Menopausal Gonadotrophin), while the other contains FSH alone. Although the combined FSH/LH preparation works well in women with PCOS many clinicians prefer to use the products which contain primarily FSH. Women with PCOS are likely to be hyperstimulated so that an initial low dose regime is employed. This starts with a daily administration of a small amount of the drug progressing to an increase in dose until ovulation is achieved. Follicular development and growth is carefully monitored by hormone measurements and serial ultrasound scan examinations. Treatment is started at the start of a cycle while a woman is still menstruating. Insulin resistance sensitizes the ovary to gonadotrophin stimulation and these PCOS have a tendency to over respond to gonadotrophin therapy resulting in the production of multiple follicles.
If monitoring by ultrasound scans indicates that too many follicles have developed, increasing the risk of multiple pregnancies, treatment will usually be suspended and ovulation induction in that cycle cancelled. When development and growth of the follicle reaches optimum maturity, human chorionic gonadotrophin (hCG) is administered by injection to stimulate the final maturation and release of the egg from the follicle.
Women with PCOS treated with gonadotrophins are at an increased risk of a rare but potentially serious condition known as Ovarian Hyperstimulation Syndrome. This condition arises if an excessive number of follicles are produced. The diagnosis is suspected when unusually large number of follicles and ovarian cysts together with free fluid in the abdominal cavity is seen on the ovaries on ultrasound. This is a potentially fatal condition and better understanding of the condition has led to reduction in its incidence.
Women with PCOS who conceive have a higher rate of early fetal loss than women without PCOS. As such, these pregnancies should be considered as "valuable pregnancies" and require the early care of a gynecologist. The prospective mother is at greater risk of gestational diabetes. It is important, therefore, to maintain low glycemic index eating throughout the pregnancy, although calories will need to be increased. Glucose monitoring at the time of regular blood testing must continue in pregnancy. Where measures at ovulation induction are not effective or if effective, fail to result in pregnancy, IVF is to be contemplated.
Other Fertility and Ovulation Induction Treatments
Ovarian Capsule Puncture
It is well recognised that in women with PCOS, penetration of the ovarian capsule by multiple punctures results in resumption of regular ovulatory function. This is usually performed at the time of laparoscopy (telescopic examination of abdomen and pelvis), and puncture may be achieved by either laser or electrical energy. Successful ovulation has been demonstrated in up to 60% of cases. In some cases, regular ovulation persists for some time after the procedure creating a "fertility window". For others ovulation may not occur spontaneously but will respond better to hormonal stimulation. This option creates a fertility window of limited duration after which time the ovaries resort to their pre treatment patterns.
You should resort to ovarian puncture or "drilling" after failure of medical treatment. The procedure is not without consequences and has been reported to result in ovarian failure in a small percentage of women.
In Vitro Fertilization (IVF)
The technique of IVF refers to the fertilization of a woman’s egg with her partner’s sperm outside her body. Eggs are retrieved from the ovaries under ultrasound control and then mixed with prepared sperm and monitored for at least 72 hours by which time fertilization and the production of embryos will have occurred. Following fertilization, the embryo is then transferred into the woman’s uterus in anticipation of implantation and pregnancy. This procedure is recommended to women who have blocked or absent fallopian tubes, or men with poor quality sperm. Where measures in ovulation induction are not effective or, if effective, do not result in pregnancy, IVF may need to be contemplated. IVF is also offered to women with PCOS who wish to conceive after other treatment strategies have failed. Since a part of the protocol for IVF includes gonadotrophin induction of ovulation, these patients must be carefully monitored in an effort to avoid Ovarian Hyperstimulation Syndrome.
Contributed by Prof Nadir Farid and Mr Yunus Tayob