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Induction of Ovulation
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Approximately 25% of infertile women have problems with ovulation.
These include the inability to produce fully matured eggs, or failure to release an egg.
The inability to produce and/or release eggs is called anovulation. Anovulation is diagnosed
based on the menstrual history, documentation of failure of the development of dominant
follicle on ultrasound examination, and also by hormonal assessment.
Ovulatory problems can be temporarily corrected by using a group of medications called
‘fertility drugs’, which increase a woman’s chances of pregnancy. Fertility drugs also improve
the ovarian hormone production to favorably affect the lining of the uterus (endometrium) in
addition to inducing ovulation. |
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Moreover, these medications are also used to stimulate the ovaries
for development of more eggs (superovulation or controlled ovarian hyperstimulation) as in an
invitro fertilization (IVF) cycle. |
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For the management of infertility, based on the associated infertility factors, a timed intercourse
is advised or an intrauterine insemination (IUI) may be planned with ovulation induction.
A controlled ovarian hyperstimulation protocol is usually associated with IVF/ICSI–ET procedures. |
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Who require Ovulation Induction? |
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Induction of ovulation as a treatment of infertility is planned in women
 Who ovulate irregularly
Who do not ovulate (anovulation, detected by various diagnostic methods)
Following factors can lead to anovulation:
PCOS
Hormonal disturbances like in Thyroid disorders (Hypothyroidism), Prolactin excess (Hyperproalactinemia), obesity, extreme weight loss and eating disorders
Pituitary dysfunction like insufficient production of LH and FSH |
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Commonly Used Medications for Induction of Ovulation |
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The commonly used medications for ovulation induction are Clomiphene Citrate,
aromatase inhibitors like Letrizole, insulin sensitizing agents like Metformin,
gonadotropins like Human Menopausal Gonadotropin (hMG), Follicle Stimulating
Hormone (FSH), Human Chorionic Gonadotropin(hCG), and GnRH analogs and antagonists.
Bromocriptine, Cabergoline, LH are used in specific conditions when needed according
to patient’s hormonal profile and type of ovulatory dysfunction. In cases of Hypothyroidism,
Thyroxine supplementation is recommended.
The medications used, their mechanism
of action, dosage prescribed, probable side effects and complications are explained in detail
individually below. |
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Clomiphene Citrate (CC) |
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It is the most commonly prescribed drug for induction of ovulation.
Clomiphene Citrate works by causing the pituitary gland to secrete more FSH.
The higher level of FSH spurs the development of ovarian follicles that contain eggs.
As the follicles grow, they secrete estrogen into the bloodstream.
About 5 days after the last tablet of CC is taken, LH surge occurs and the mature follicle
ruptures to release the egg in a process called ovulation.
Dosage
It is usually prescribed for a duration of 5 days.
Starting on any day between the 2nd to 5th day, an ultrasound monitoring of the dominant follicle
is done to document the ovarian response and ovulation for that particular dose.
A dosage of 50 mg per day is prescribed to start with. Later on, based on the individual ovarian response,
the dosage may be increased in subsequent cycles by 50mg increments, with a maximum of 200mg per day.
Once the dominant follicle reaches 18-20mm in diameter, further ovulation may be triggered with an
intramuscular human chorionic gonadotropin (hCG) injection. A timed intercourse or intrauterine insemination
(IUI) may be planned along with ovulation induction with clomiphene citrate
Success rate
About 80% of patients ovulate and 40-45% conceive at the end of 4-6 cycles of
induction of ovulation by clomiphene citrate. However, the chances of success become less after
6 cycles of clomiphene. Alternatives may be considered after six CC cycles.
Women who have irregular or absent ovulation due to hypothalamic disorders, or who have very low estrogen levels,
generally do not respond well to clomiphene. Women who are obese may have better success if they lose weight.
Side effects
Clomiphene is generally well-tolerated. Side effects like breast heaviness, nausea, and mood swings are relatively common, but mild. A few may complain of hot flashes, which typically disappear once treatment is stopped. Side effects like severe headache, visual problems like blurring of vision or double vision are relatively uncommon, usually associated with higher dosage, and are reversible. If these side effects occur, the patient needs to stop the medication and immediately inform her doctor.
Complications
Women who conceive with clomiphene have approximately a 10% chance of having twins. Triplet and higher order pregnancies are rare (<1%), but may occur.
Ovarian cysts, which can cause pelvic discomfort, may form as a result of the drug’s overstimulation of the ovaries. A pelvic exam or ultrasound may be performed to look for ovarian cysts before beginning another clomiphene treatment cycle. |
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Aromatase Inhibitors |
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Letrizole is the most commonly used drug for ovulation induction from this group of medications,
which are FDA approved for management of post menopausal breast cancer. It acts by reducing estrogen levels.
Dosage
The drug is prescribed for 5 days duration, starting on any day between the 2nd day to 5th day. The dose prescribed is 2.5mg per day for 5 days and may be increased up to two tablets per day as per the ovarian response documented on ultrasound follicular monitoring.
Success rate
About 80% of patients ovulate and 40-45% conceive at the end of 4-6 cycles of induction of ovulation by clomiphene citrate. However, the chances of success become less after 6 cycles of clomiphene. Alternatives may be considered after six CC cycles. Women who have irregular or absent ovulation due to hypothalamic disorders, or who have very low estrogen levels, generally do not respond well to clomiphene. Women who are obese may have better success if they lose weight.
Complications
Recent data available on Letrizole that it may be associated with increased risk of congenital abnormalities is controversial. |
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Insulin Sensitizing Agents |
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Insulin resistance is most commonly seen in women with PCOS and they may be resistant to Clomiphene. They respond well when treated with insulin sensitizing agents like Metformin. These drugs act by improving body’s sensitivity to insulin.
Dosage
The dosage varies from 250 mg per day to 1500 mg per day based on the individual BMI and insulin resistance.
Success rate
When used alone for four to six months, Metformin can restore cyclic ovulation and menses in many women with PCOS. Many PCOS patients who fail to ovulate in response to either CC or Metformin alone will respond when the two medications are used in combination. Response is more when associated with weight loss.
Side effects
Gastrointestinal side effects are common and include nausea, vomiting, and diarrhea. Since Metformin therapy is associated with liver dysfunction, and rarely, a severe condition called Lactic Acidosis, liver and kidney function tests are performed periodically, especially when Metformin is used for a longer period of time. |
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Gonadotropins |
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Gonadotropins are injectable fertility medications used for ovulation induction and also for controlled ovarian hyperstimulation in IVF/ICSI cycles. Ovulation induction with gonadotropins is planned in women who fail to ovulate (CC resistance) or conceive (CC failure) with clomiphene. Usually, intrauterine insemination (IUI) is planned following induction of ovulation with gonadotropins.
Gonadotropins, when injected, act by bypassing hypothalamus and pituitary and directly stimulating the ovaries to develop and ovulate more than one follicle.
Gonadotropins prescribed may contain FSH (Follicle Stimulating Hormone) alone or a combination of both FSH and LH (Luteinizing Hormone). Sometimes LH alone is used, but Human Chorionic Gonadotropin (hCG) is also used. hCG is commonly used to trigger ovulation. It is structurally similar to LH and mimics natural LH surge. |
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Human Menopausal Gonadotropin (hMG) |
| | It contains approximately equal amounts of FSH and LH. The FSH and LH in hMG are extracted and purified from the urine of postmenopausal women, who have high levels of these hormones. For ovulation induction, hMG is prescribed at 75-150 units per day dosage for about 8 days duration. Increase in the dosage and number of days depends on the individual ovarian response. For controlled ovarian hyperstimulation in IVF cycles, hMG is prescribed at a higher dosage for about 8-12 days. hMG is injected via intramuscular route. |
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Follicle Stimulating Hormone (FSH) |
| | It contains only FSH without the LH component. It is prepared by two methods – purified from urinary extraction or by recombinant DNA technology. FSH is administered via the subcutaneous route. Presently, pen injectors are available which are more safe and easy for patients use. |
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Luteinizing Hormone (LH) |
| | It contains only the LH component. Recently, recombinant LH product has been made available to be used along with recombinant FSH in anovulatory women with low levels of FSH and LH. |
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Human Chorionic Gonadotropin (hCG) |
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It has a chemical structure similar to LH. hCG acts on the dominant follicle, produces an LH surge similar to the natural LH surge and triggers ovulation (release of egg). Ovulation usually occurs 36 to 48 hours after injection hCG is administered. hCG is usually administered to trigger ovulation in ovulation induction cycles when the dominant follicle reaches 18-20mm in diameter. This enables appropriate planning of the IUI or a timed intercourse, which improves chances of fertilization and pregnancy rates.
Dosage
In gonadotropin cycles, stimulation is planned from day 2 or 3 of the menstrual cycle. It involves daily injections for about 8 days along with serial ultrasound follicular monitoring. When the dominant follicle reaches 18-20mm in diameter, ovulation is triggered with an injection of hCG and followed by intrauterine insemination. Usually in gonadotropin/IUI cycles, hMG is prescribed. To start with, 75 units or 150 units of hMG is preferred. Later on, the dosage is increased according to requirements, based on the individual ovarian response documented in follicular monitoring.
Success rate
The chances of pregnancy are up to 15% per cycle in gonadotropin/IUI cycles.
Side effects
Breast tenderness, pain, swelling, and (occasionally) rash at the injection site. Some women may experience mood swings.
Complications
The most potential complication is the Ovarian Hyperstimulation Syndrome (OHSS). It usually occurs when more number of follicles develop, wherein ovaries get more enlarged and painful. In severe cases, fluid may accumulate in the abdominal cavity and chest, necessitating hospitalization. By careful follicular monitoring during gonadotropin stimulation, OHSS can be prevented. In cases where multiple follicles develop, sometimes injection hCG is withheld to prevent OHSS.
Another complication of gonadotropin stimulated cycles is occurrence of multiple pregnancies in up to 30% of the cases. About two-thirds are twins and one-third are of higher order gestation, such as triplets. In a few instances, fetal reduction may be required to reduce risks such as miscarriage, premature delivery, and associated neonatal complications associated with higher order gestation. |
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GnRH analogs and Antagonists |
| | Gonadotropin releasing hormone (GnRH) is released from the hypothalamus in a pulsatile manner into the blood stream, which stimulates the pituitary to secrete the gonadotropins FSH and LH.
GnRH Analogs
GnRH analogs are synthetic hormones similar to natural GnRH, but are chemically modified. When a woman takes a GnRH agonist, her pituitary gland is exposed to a constant (as opposed to a pulsatile pattern of) synthetic GnRH. There is an initial acceleration in LH and FSH production. Thereafter, the pituitary stops releasing these two hormones, halting the production of ovarian hormones. Thus estrogen levels are reduced and ovulation is prevented.
GnRH Antagonists
The GnRH antagonists act by suppressing the production of FSH and LH without the initial stimulation.
Both GnRH analogs and antagonists prevent unwanted spontaneous ovulation during gonadotropin stimulation cycles, which may occur due to an undesired rise in LH levels and causes the follicles to release the eggs before they are harvested. The use of GnRH analogs/anatgonists during IVF cycles helps to yield more number of mature eggs for fertilization and, therefore, more embryos for transfer.
Dosage
GnRH analogs/antagonists are administered via subcutaneous injection daily for the required number of days during ovarian stimulation. The long acting GnRH analogue depot preparation is given once during the luteal phase in the long protocol planned IVF cycles.
Side effects
The side effects caused by GnRH analogs/antagonists are temporary, and the effect on the pituitary is completely reversible after GnRH agonists and GnRH antagonists are discontinued. The side effects usually occur in women who are taking a GnRH antagonist or agonist on a long term basis. The symptoms are similar to those of menopause - hot flashes, mood swings, and vaginal dryness. A few women may experience headaches, insomnia, decreased breast size, pain during intercourse, and bone loss, but these symptoms are rare when the medication is used during stimulation cycles. |
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Bromocryptine and Cabergoline |
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These medications are prescribed in women who either ovulate irregularly or do not ovulate due to elevated serum prolactin levels (hyperprolactinemia). Increased blood levels of prolactin inhibit the release of FSH and LH and, therefore, stop ovulation.
The prolactin level is elevated due to the increased secretion of prolactin by the prolactin producing cells in the pituitary (hyperactivity) or due to a pituitary adenoma. High prolactin levels can also result from the use of certain drugs such as tranquilizers, hallucinogens, pain killers, alcohol, and, in rare cases, oral contraceptives. Disease of the kidney or thyroid may also raise prolactin levels. Before treating the condition of anovulation, the cause of hyperprolactinemia must be looked into, especially in cases of very high values of prolactin.
The medications Bromocriptine or Cabergoline, used to treat hyperprolactinemia, suppress the prolactin production by the pituitary, thereby reducing the blood prolactin levels. In about 90% of women, serum prolactin levels return to the normal range.
Dosage
Bromocriptine is taken orally as a tablet or capsule one to four times a day until the prolactin level is normal. Cabergoline is usually prescribed orally; one tablet once a week, sometimes one or two tablets twice a week.
Bromocriptine and cabergoline treatment should be discontinued during pregnancy.
Success Rate
Approximately 85% ovulate and become pregnant with bromocriptine/cabergoline, if no other cause of infertility is present. There is no risk of multiple pregnancies with bromocriptine/cabergoline. Women who fail to ovulate even after their prolactin levels are normal may be given clomiphene or gonadotropins along with bromocriptine and cabergoline.
Side effects
Possible side effects of bromocriptine and cabergoline include nasal congestion, fatigue, drowsiness, headaches, nausea, vomiting, fainting, and dizziness. For most patients, adjusting the dosage can eliminate these side effects. Some physicians start their patients on a very low dose and increase it gradually in an effort to prevent side effects. |
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