Ovulation Induction (OI)
Ovulation induction/stimulation (OI) medications can help a woman ovulate more regularly, increasing her chances of getting pregnant.
Some Women May Struggle to Get Pregnant Simply Because They Don’t Ovulate
To help these women conceive, medications that stimulate ovulation are often necessary.
Ovulation problems are present in about 25% of women who experience infertility. Some of these women may ovulate less frequently than normal, while others may not ovulate at all (a condition known as anovulation).
Ovulation induction (OI) medications can help a woman ovulate more regularly, thereby increasing the chances of pregnancy.
A woman who has regular menstrual periods is likely ovulating each month. Ovulation typically occurs 14 days before the first day of the next period (in a 28-day cycle, this means ovulation occurs around day 14 from the start of menstruation).
However, it’s important to note that even women who don’t ovulate at all may still experience some bleeding, albeit irregularly.
There are several ways to detect ovulation. The most effective methods include measuring progesterone levels during the luteal phase (the period after ovulation) and monitoring ovarian follicles using ultrasound.
At-home ovulation predictor kits that measure the LH (luteinizing hormone) surge before ovulation can also be used. Although less commonly used, basal body temperature (BBT) charting can track the slight temperature rise that follows ovulation.
Women with irregular periods (oligo-ovulation) or no periods at all (amenorrhea or anovulation) are more likely to have ovulation dysfunction. Medications may be used to help these women ovulate regularly. Before prescribing medications, your fertility specialist should determine the cause of the ovulation issue.
Common causes of ovulation problems include:
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Polycystic Ovary Syndrome (PCOS)
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Low LH and FSH production from the pituitary gland
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Ovaries that don’t respond to normal LH and FSH levels
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Thyroid disorders
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Elevated prolactin hormone levels (hyperprolactinemia)
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Obesity
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Eating disorders or extreme weight loss
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Excessive exercise
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Sometimes, the exact cause cannot be determined.
Women with ovulation dysfunction often benefit from fertility medications used in ovulation induction. Even in cases of unexplained infertility (where ovulation dysfunction is not present), ovulation induction with fertility medications may be used. The goal is to stimulate the ovaries to produce more than one follicle per cycle and release multiple eggs in the hope that at least one will be fertilized and result in pregnancy. This is known as controlled ovarian stimulation (COS) or superovulation, and it can be done using oral medications or injections.
COS combined with timed intercourse or intrauterine insemination (IUI) is often the first treatment option for various types of infertility when the woman’s fallopian tubes are open.
Before starting ovulation induction, the male partner should undergo a semen analysis to determine whether the treatment should be combined with timed intercourse, IUI, or IVF.
Medication
Medications Used in Ovulation Induction (OI)
The most commonly prescribed ovulation medications are clomiphene citrate (CC), aromatase inhibitors (letrozole), and gonadotropins (FSH, LH, human menopausal gonadotropin (hMG), chorionic gonadotropin (hCG)).
Other medications that may assist in ovulation induction include bromocriptine, cabergoline, insulin-sensitizing agents, GnRH, and GnRH analogs.
Clomiphene Citrate (CC)
Clomiphene is an ovulation induction drug used to stimulate ovulation in women with ovulation problems who have infrequent or absent menstrual cycles. It is also used in cases of unexplained infertility and for individuals who cannot or do not wish to proceed with more aggressive treatments. It is often combined with IUI to promote the development of multiple follicles.
Clomiphene works by stimulating the pituitary gland to produce more FSH. Higher FSH levels promote the development of one or more follicles (each containing a single egg). As follicles grow, they release estradiol into the bloodstream. About a week after the last dose of CC, the elevated estradiol levels trigger the pituitary gland to release an LH surge, which leads to the release of the egg(s) from the dominant follicle.
The standard CC dosage is taken for five consecutive days. Treatment typically begins on the second to fifth day of menstruation, but if a woman is anovulatory, it can start without a menstrual period. If a woman is not menstruating, oral progestin may be administered for 5–12 days to induce a period.
Your doctor will determine the appropriate dose. Sometimes, if the medication does not trigger ovulation, other drugs may be added to the CC regimen.
CC is generally well tolerated. Side effects are relatively common but usually mild. Hot flashes occur in about 10% of women using clomiphene and usually resolve shortly after the last pill. Mood swings, breast tenderness, and nausea are also common. Severe headaches and visual disturbances such as blurred or double vision are rare and almost always reversible, but treatment should be stopped immediately and a doctor notified if these occur.
The chance of twins in women who conceive with CC is about 5–8%. Triplets or higher-order multiples are rare (<1%). Ovarian cysts, which can be uncomfortable, may develop but usually resolve over time. A pelvic exam or ultrasound may be performed before starting another cycle of CC to evaluate for ovarian cysts.
Side effects are more common with higher doses.
Aromatase Inhibitors
Aromatase inhibitors are drugs that temporarily reduce estrogen/estradiol levels in the blood, prompting the pituitary gland to produce more FSH.
Treatment usually begins in the early phase of the cycle, on day 2–5 of menstruation, but may also start without a period if the woman is anovulatory. The dose prescribed by your doctor is taken for five days.
Studies show that pregnancy rates with aromatase inhibitors are similar to those with CC and may be more effective for certain ovulation disorders such as polycystic ovary syndrome (PCOS).
Like CC, aromatase inhibitors can be used in combination with IUI to promote the development of multiple follicles and have similar success rates to CC + IUI combinations. Recent research has shown no increased risk of birth defects in children of mothers treated with aromatase inhibitors for fertility treatment.
Insulin-Sensitizing Agents
Insulin resistance and elevated insulin levels in the blood (hyperinsulinemia) are common in women with polycystic ovary syndrome (PCOS). Although most women with PCOS ovulate with clomiphene, some do not ("clomiphene-resistant") and may need alternative or additional treatments.
When used alone for 4–6 months, insulin-sensitizing agents such as metformin can lead to regular menstrual cycles and ovulation in some women with PCOS. However, when combined with other medications, the response is much better.
Metformin often causes gastrointestinal side effects such as nausea, vomiting, and diarrhea. Rarely, it can lead to liver dysfunction and, in very rare cases, a serious condition called lactic acidosis. Periodic blood tests may be conducted to monitor liver and kidney function.
Gonadotropins
Gonadotropins are fertility drugs that contain either FSH alone or a combination of FSH and LH. Unlike oral agents like CC, aromatase inhibitors, and insulin-sensitizing agents, gonadotropins are administered via injection.
Gonadotropins may be prescribed to anovulatory women who have not conceived after trying CC. They are also used in women whose pituitary gland does not produce sufficient FSH and LH. Gonadotropins stimulate the development of multiple follicles simultaneously for ovulation induction (OI) in IUI and IVF treatments.
It’s important to note that gonadotropins do not "use up" more eggs than a natural cycle would. Rather, they rescue eggs that would otherwise undergo atresia (degeneration), allowing them to mature and be collected.
For non-IVF ovulation induction/OI cycles, gonadotropin treatment typically begins on day 2 or 3 of the menstrual cycle and starts with a lower daily dose than used in IVF.
Usually, 7–12 days of treatment is sufficient, but the duration may be extended if the ovaries respond slowly. Follicle growth is monitored by ultrasound, and estradiol levels in the blood are also often checked. If estradiol levels do not rise and the ovaries show no response to gonadotropins, the dose may be increased or, in rare cases, treatment may be canceled.
The goal is to develop one or more mature follicles and reach an appropriate estradiol level so that ovulation can be triggered with hCG, mimicking the natural LH surge. If too many follicles develop or estradiol levels are too high, the hCG injection may be withheld to avoid the risk of ovarian hyperstimulation syndrome (OHSS) or multiple pregnancies.
Bromocriptine and Cabergoline
Some women may ovulate irregularly or not at all due to excessive prolactin secretion by the pituitary gland. Elevated blood prolactin levels (hyperprolactinemia) inhibit the release of FSH and LH, impairing dominant follicle development and ovulation.
In some women, high prolactin levels are caused by a benign tumor of prolactin-secreting cells called a pituitary adenoma. Other causes include the use of medications such as sedatives, hallucinogens, painkillers, alcohol, and, in rare cases, oral contraceptives. Kidney or thyroid disorders may also elevate prolactin levels.
Hyperprolactinemia is typically treated with bromocriptine or cabergoline, which reduce prolactin secretion by the pituitary. In about 90% of patients taking these medications, blood prolactin levels return to normal. Around 85% of treated women ovulate and can conceive if there are no other causes of infertility. Treatment is usually stopped once pregnancy is achieved.
After prolactin levels normalize, women who still do not ovulate may start CC or gonadotropins.
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