Ovulation induction

Stimulation of ovulation by medication

Ovulation induction is the stimulation of ovulation by medication. It is usually used in the sense of stimulation of the development of ovarian follicles to reverse anovulation or oligoovulation.

Clomifene citrate (or clomid) is the medication which is most commonly used to treat anovulation. It is a selective estrogen receptor modulator, affecting the hypothalamic–pituitary–gonadal axis to respond as if there was an estrogen deficit in the body, in effect increasing the production of follicle stimulating hormone. It is relatively easy and convenient to use. Clomifene appears to inhibit estrogen receptors in hypothalamus, thereby inhibiting negative feedback of estrogen on production of follicle stimulating hormone. It may also result in direct stimulation of the hypothalamic–pituitary axis.

Letrozole has been used for ovarian stimulation by fertility doctors since 2001 because it has fewer side effects than clomiphene and less chance of multiple gestation. A study of 150 babies following treatment with letrozole or letrozole and follicle stimulating hormone presented at the American Society of Reproductive Medicine 2005 Conference found no difference in overall abnormalities but did find a significantly higher rate of locomotor and cardiac abnormalities among the group having taken letrozole compared to natural conception. A larger, follow up study with 911 babies compared those born following treatment with letrozole to those born following treatment with clomiphene. That study also found no significant difference in the rate of overall abnormalities, but found that congenital cardiac anomalies was significantly higher in the clomiphene group compared to the letrozole group. Dosage is generally 2.5 to 7.5 mg daily over 5 days. A higher dose of up to 12.5 mg per day results in increased follicular growth and a higher number of predicted ovulations, without a detrimental effect on endometrial thickness, and is considered in those who do not respond adequately to a lower dose.

Tamoxifen affects estrogen receptors in a similar fashion as clomifene citrate. It is often used in the prevention and treatment of breast cancer. It can therefore also be used to treat patients that have a reaction to clomifene citrate.

The gonadotropin releasing hormone pump is used to release doses in a pulsatile fashion. This hormone is synthesised by the hypothalamus and induces the secretion of follicle stimulating hormone by the pituitary gland. Gonadotropin releasing hormone must be delivered in a pulsatile fashion to imitate the random secretion of the hypothalamus in order to stimulate the pituitary into secreting luteinizing hormone and follicle stimulating hormone. The gonadotropin releasing hormone pump is the size of a cigarette box and has a small catheter. Unlike other treatments, using the gonadotropin releasing hormone pump usually does not result in multiple pregnancies. Filicori from the University of Bologna suggests that this might be because gonadotrophins are absent when the treatment is initiated, and therefore the hormones released by the pituitary (luteinizing hormone and follicle stimulating hormone) can still take part in the retro control of gonadotrophin secretion, mimicking the natural cycle. This treatment can also be used for underweight and/or anorexic patients; it has also been used in certain cases of hyperprolactimenia.

In the Nordic countries, letrozole is practically the standard initial regimen used for ovulation induction, since no formulation of clomifene is registered for use there. India banned the usage of letrozole in 2011, citing potential risks to infants. In 2012, an Indian parliamentary committee said that the drug controller office colluded with letrozole's makers to approve the drug for infertility in India.

During ovulation induction, it is recommended to start at a low dose and monitor the ovarian response with transvaginal ultrasound, including discernment of the number of developing follicles. Initial exam is most commonly started 4–6 days after last pill. Serial transvaginal ultrasound can reveal the size and number of developing follicles. It can also provide presumptive evidence of ovulation such as sudden collapse of the preovulatory follicle, and an increase in fluid volume in the rectouterine pouch. After ovulation, it may reveal signs of luteinization such as loss of clearly defined follicular margins and appearance of internal echoes.

Ovulation induction can be repeated every menstrual cycle. For clomifene, the dosage may be increased by 50 mg increments in subsequent cycles until ovulation is achieved. However, at a dosage of 200 mg, further increments are unlikely to increase pregnancy chances. In women with anovulation, 7–12 attempted cycles of pituitary feedback regimens (as evidenced by clomifene citrate) are recommended before switching to gonadotrophins, since the latter ones are more expensive and less easy to control. Symptoms depend on whether the case is mild, moderate, or severe, and can range from bloating and nausea, through to shortness of breathe, pleural effusion, and excessive weight gain (more than 2 pounds per day).

There is also the risk that more than one egg is produced, leading to twins or triplets. Women with polycystic ovary syndrome may be particularly at risk. Multiple pregnancy occurs in approximately 15–20% of cases following cycles induced with gonadotrophins such as human menopausal gonadotropin and follicle stimulating hormone. The risks associated with multiple pregnancy are much higher than singleton pregnancy; incidence of perinatal death is seven times higher in triplet births and five times higher in twin births than the risks associated with a singleton pregnancy. It is therefore important to adapt the treatment to each individual patient. If more than one or two ovulatory follicles are detected on ultrasonography, sexual abstinence is recommended. However, there still isn't enough evidence to prove the effectiveness and security of the technique.