Natural Cycle

If you and your doctor decide on the procedure in a natural cycle (or as it is called in medical terminology, a modified natural cycle – since one drug is given, i.e., hCG injection), the first follicle ultrasound exam should be performed between days 6 and 10 of the cycle. The day of the first ultrasound depends on the length of your cycle, your age, and the expected time of ovulation. Follicle growth should be monitored, and when the follicles reach 14-17 mm in diameter, you will be given hCG injection.

Sometimes, a doctor may require blood tests to determine your estradiol or LH level prior to injecting hCG to ensure ovulation has not yet begun. Ovulation should take place 36-38 hours after hCG injection. Insemination or follicular aspiration is planned 1-2 hours before that period has expired. If IVF/ICSI is planned, an ultrasound exam is usually carried out immediately prior to follicular aspiration in order to ensure a follicle has not ruptured. Since there is no ovulation in the case of amenorrhea, all of the above causes induce infertility, at least temporarily. Some are unfortunately hard or even impossible to treat.

Clomiphene citrate and letrozole

If a weight loss fails or in cases of non-obese patients, the drug of choice for ovulation induction in patients with no ovulation is clomiphene citrate (CC). It induces ovulation in 70-85% of patients, although only 40-50% of them manage to conceive. The total pregnancy rate after 12 cycles where clomiphene was used is up to 80%.

In the last several years, letrozole, an aromatase inhibitor (the medicine that lowers the level of estrogens in the body), was shown to be an excellent choice in ovulation induction, especially in women with idiopathic infertility, or PCOS. In addition, it appears that letrozole has a higher live birth rate than clomiphene, without the severe side effects. Also, letrozole does not have a negative effect on the endometrium, as does clomiphene. Ovulation induction with clomiphene starts with 50 mg daily over five days (the start is between the third and fifth days of the cycle) which in almost 50% of patients induces ovulation. As 50% of women fail to ovulate, it is more likely to start with a 100 mg daily dosage (two pills daily, both taken immediately). In exceptional cases, with very sensitive women, the initial dosage can be 25 mg daily. Ultrasound monitoring is obligatory for at least one cycle until the ovarian response is determined, i.e., if ovulation occurs and if uterine lining starts thinning.

Clomiphene is usually taken for five days, although more recent Japanese papers suggest clomiphene should be taken until ovulation. Clomiphene dosage can be elevated up to 150 mg daily, exceptionally to 250 mg daily, a top limit of clinical efficiency. Induction can be used throughout 3-6 cycles – three in cases of antiestrogenic effects (thin uterine lining) when pregnancy is unlikely, six if a woman ovulates. If conception is still failing after three months, further stimulation without intrauterine insemination (IUI) is futile. Furthermore, hCG injection-inducing ovulation is rarely required as ovulation occurs without applying it. Therefore, induction should not be continued after six months.

As clomiphene has been on the market for a long time, we are well aware of the advantages and disadvantages of this type of treatment. Clomiphene does induce ovulation in a significant number of patients; however, a large number of them fail to conceive. Reasons may be elevated LH, antiestrogenic effects (thin uterine lining, changes in cervical mucus), and poor influence on eggs. Furthermore, 10-30% of patients will be resistant (fail to ovulate) to clomiphene after six months of treatment. Clomiphene is also associated with a high rate of miscarriages. Problems also include multiple pregnancies as the incidence of quintuplets is several million times higher than in natural conception, which additionally emphasizes the need for ultrasound monitoring. If a woman reacts to the treatment with multiple follicles, it is better to refrain from timed intercourse for the period and lower the clomiphene dosage the following month. Treating clomiphene resistance is arguable as there are many other drugs and drug combinations available to induce ovulation.

Clomiphene + Glucocorticoid

It is believed that women suffering from hyperandrogenism and receiving clomiphene treatment should also be given glucocorticoid while attempting to induce ovulation. These drugs belong to corticoids, but they have been successfully used for quite some time in treating ovulation disorders in small dosages. Women suffering from hyperandrogenism usually also suffer from excessive hairiness and/or acne, but the main criteria for applying the above drugs are elevated levels of hormone didehydroepiandroandrosterone sulfate (DHEA-s).

If DHEA-s is higher than 2 mg/mL, clomiphene can be supplemented with Dexamethason 0.25-0.50 mg or prednisone 5-10 mg in ovulation induction. They are given in both stages of the cycle. Glucocorticoid increases synthesis and secretion of follicle-stimulating hormone (FSH) but predominantly decreases secretion of male sex hormones, so total androgens drop by 40%. This leads to more quality ovulation, and it is effective with hyper-androgenous women, even when DHEA-s level is normal.

Most papers whose authors used glucocorticoid in ovulation induction agree that ovulation occurs in 80-100%. The pregnancy rate is also satisfactory, between 40 and 80%. We should point out that this refers to women who had undergone three cycles of treatment with clomiphene only and failed to ovulate.

Clomiphene + Metformin

The other drug rather frequently used in ovulation induction is metformin. For a long time, this drug has been in use in treating the diabetic population with non-insulin-dependent diabetes. However, only after insulin importance was discovered in the development of polycystic ovarian syndrome has it been in use in ovarian induction treatments for women with PCOS.

The addition of metformin to clomiphene significantly increases chances for pregnancy in women who previously showed clomiphene resistance. Chances of pregnancy in women using the drug combination and women using clomiphene-only treatments are 4.41 and 3.65, respectively. Therefore, for women with clomiphene resistance, metformin should be introduced into their treatment after three months. A meta-analysis from 2003 showed that a combination of clomiphene and metformin results in 56% ovulation instead of 35% in a clomiphene/placebo group. Women with insulin resistance (IR) are otherwise more likely to be resistant to clomiphene, although there have not been sufficient studies to confirm that they react better to metformin than, for example, clomiphene-resistant hyperandrogenic women. Furthermore, it is not clear if thin women with PCOS with normal insulin resistance react to metformin since some recent studies have shown they seem to react.