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Ovulation induction

Before discussing ovulation induction, it is important to understand everything about ovulation and fertility as well as about ovulation and infertility.

Ovulation and Fertility

Women fertility is programmed prior to their birth – all females receive their lifetime allotment of eggs very early in their development with an average of seven million eggs being formed. These eggs are in a very immature state, incapable of being ovulated or fertilized as they rest deep in the tissue of the ovaries until puberty is started. It is important to highlight that most of above mentioned initial eggs will be reabsorbed by the body before ever maturing. Usually the number of initial eggs is already reduced to a million eggs at the time of birth and down to about three hundred thousand by the time puberty is reached.

Usually healthy woman will ovulate approximately 400 times in her life. Every menstrual cycle (every month) several dozen to several hundred of immature eggs leave their resting state and resume growth, with usually only a single egg fully maturing and able to ovulate. The remaining eggs that had resumed growth are reabsorbed by the body never to be heard from again.

The whole complicated process of maturation and release of one egg from several hundred is controlled by hormones produced in the pituitary gland – mainly by FSH (Follicle Stimulating Hormone) and LH (Luteinizing Hormone).

FSH stimulates the initial growth of the many egg-filled structures known as follicles. Follicles are a combination of an egg and surrounding cells that provide for the egg’s development. As follicles begin to grow in response to FSH, they begin producing their own hormone called estrogen which stimulates LH levels to surge at around day 14 of the menstrual cycle triggering one of the follicles to burst, and the largest egg is released into one of the fallopian tubes.

Ovulation and Infertility

Ovulation induction

One of the most common causes of female infertility can be anovulation – absence of normal ovulation. Ovulation induction uses hormonal therapy to stimulate egg development and release.

Ovulation induction can be used in following cases:

First, when women did not ovulate themselves (typically women with abnormal and/or irregular menstrual cycles);

The second use of ovulation induction was to increase the number of eggs reaching maturity in a single cycle to increase chances for conception;

Third, ovulation induction can be used for infertile women with ovulation. These women with “unexplained infertility” may have subtle defects in ovulation and the use of medications may induce the maturity of 2-3 eggs versus only one. This treatment therefore improves the quality and quantity of the ovulation, thus enhancing pregnancy rates.

Fourth, modern infertility treatment with assisted reproductive technologies (ART) including in-vitro fertilization (IVF) need special ovulation induction for multiple dominant follicles development and for collection of multiple mature eggs for future artificial fertilizations. In these cases women should be informed about increased risks of multiple gestation and ovarian hyperstimulation.

Ovulation induction should be used only after complete and thorough evaluation. All underlying hormonal disorders (such as thyroid dysfunction and some others) should be treated prior to resorting to ovulation induction with fertility drugs.

Ovulation induction drugs

Ovulation induction is the process of stimulating the ovary to produce one or more eggs, which can be desirable in a number of clinical situations. Because the process of maturing a single egg requires such a delicate hormonal balance between the ovary and the pituitary gland, it only makes sense that some of the most common causes of infertility are a direct result of an imbalance in the hormones critical to egg development and ovulation. Various medications can be effectively used to restore hormonal balance to the ovulatory cycle and/or increase the number of mature eggs available.

Common fertility drugs used for ovulation induction include:

  • Clomiphene Citrate (Seraphene, Clomid)
  • Tamoxifen
  • HMG: LH/FSH (Letrozole, Repronex, Menopur) Human Menopausal Gonadotropin (hMG)
  • FSH (Follistim/Gonal F, Bravelle)
  • HCG (Profasi or Pregnyl, Ovidrel) Human Chorionic Gonadotropin (hMG)
  • Leuprolide (Lupron), Synthetic Gonadotropin (FSH/LH) Inhibitor

Clomiphene Citrate (Seraphene, Clomid)
Clomiphene citrate is the simplest and most common starting point for treating women with ovulatory disorders. Clomiphene citrate is an oral medication that induces ovulation by blocking estrogen receptors. This artificial anti-estrogen effect causes female body to believe estrogen is low and therefore cause the production of more FSH. The ultimate goal of clomiphene citrate is to indirectly cause the body to produce more of its own natural FSH in order to improve ovulatory function. Clomiphene citrate acts as a fertility agent in women by inducing superovulation, i.e. the release of multiple eggs in a given menstrual cycle.

The normal starting dose in women suffering from anovulation or oligoovulation is 50 mg (one pill taken orally) per day for 5 days. If ovulation fails to occur at this dosage, the level may be increased sequentially by one pill per day until the desired effect is achieved. The dosage can be increased to as many as 5 pills per day. Generally, the medication is taken on days 5 through 9 of a menstrual cycle but the best timing can vary from patient to patient and will be precisely determined by doctor. If successful, ovulation typically occurs about 5 to 9 days after completion of the medication.

Monitoring is necessary while taking clomiphene citrate. This monitoring may include ultrasounds, blood estrogen levels, and/or urinary LH testing. Clomiphene citrate, for unexplained infertility is prescribed with intrauterine insemination (IUI). When used for ovulation induction in women who do not ovulate, IUI is not necessary.

Tamoxifen is an alternative to clomifene that may be offered to women with ovulation problems.

HMG: LH/FSH (Letrozole, Repronex, Menopur)
Human Menopausal Gonadotropin (hMG)
HMG is a medication that is composed of FSH, with LH, and is used for stimulation of egg development in women who do not ovulate spontaneously, who ovulate extremely irregularly, or to increase the number of eggs developed in a single cycle in women who already ovulate. Due to the variability in response from patient to patient no fixed dosage regimen can be recommended. Each patient and cycle must be individualized. This medication is generally thought to be a stronger superovulation agent than oral medications.

Monitoring of the ovarian response is necessary including blood test for estrogens and ultrasound. HMG can be used with both intrauterine insemination (IUI) and in vitro fertilization (IVF). hMG is available only in an injectable form.

FSH (Follistim/Gonal F, Bravelle)
FSH medications are used to stimulate the recruitment and development of multiple eggs in women during an ovulation induction cycle. FSH products may be used alone or in combination with hMG to induce superovulation. Due to the variability in response from patient to patient, no fixed dosage regimen can be recommended. Each menstrual cycle and each client could need different doses of FSH.

Monitoring of the ovarian response is necessary including blood test for estrogens and ultrasound. FSH is available only in an injectable form.

HCG (Profasi or Pregnyl or Ovidrel) Human Chorionic Gonadotropin
HCG is a “surrogate” LH that has the same stimulatory effects on the ovary that LH does and can be provided by injection to trigger ovulation at the optimal time in the cycle. Usually HCG is given around the time of ovulation in order to reinforce or replace a naturally weak or poorly timed LH surge. This is particularly important for women undergoing stimulated cycles, as most women doing so will not have a spontaneous LH surge. Since spontaneous LH surges can be unpredictable in terms of timing, it is actually desirable to eliminate the possibility of such a surge and optimize the timing of ovulation with HCG injections based on follicle size and estradiol levels.

HCG also stimulates the corpus luteum to secrete progesterone to prepare the lining of the uterus for implantation of the fertilized egg. Ovulation usually occurs about 36 hours after the HCG is given. It is self-administered as an injection.

Leuprolide (Lupron)
Synthetic Gonadotropin (FSH/LH) Inhibitor
Lupron suppresses the brain’s secretion of LH and FSH; therefore, it is used in preparation for cycles of treatment with ovulation induction drugs (exogenous hMG-LH/FSH and or FSH). It improves the recruitment of follicles by preventing the recruitment of a dominant follicle for the next menstrual cycle. Lupron enables the ovaries to respond with the recruitment of multiple follicles since in most cases it is possible to override the selection of a single dominant follicle. It also prevents premature ovulation (release of eggs) by preventing LH release.

Lupron may also be utilized to stimulate FSH if it is used early in the menstrual cycle. This property of the drug is helpful in patients expected to respond poorly.

Monitoring of the ovarian response is necessary including blood test for estrogens and ultrasound. Lupron is available in an injectable form.

Ovulation induction success rates

Many infertile women (large percentage) stimulated with above mentioned medications will ovulate, but will not all conceive. Typically, most pregnancies occur in the first 3 to 6 treatment cycles. This is highly dependent on a number of factors including women age, pelvic factors, uterine factors, tubal factors, male factors, other hormonal dysfunctions, genetic factors, etc.

Ovulation induction in combination with assisted reproductive technology (ART) methods including IVF can dramatically increase the pregnancy rate.

Ovulation induction risks and side effects

The risk of multiple pregnancy is increased in women undergoing ovulation induction. Side effects could include bloated feelings and/or ovaries enlargements, nausea, fluid retention, and headaches.

One side effect that deserves special attention is OHSS, or ovarian hyperstimulation syndrome, and is almost unique to ovulation induction cycles, particularly in women who develop a large number of follicles (usually 20 or more) in response to injectable gonadotropins. This fairly rare condition is characterized by significant enlargement of the ovaries, possible fluid retention in the abdomen, and general swelling throughout the body.

In most cases OHSS begins about a week after ovulation and is not unusual to occur in cycles where the woman winds up pregnant, as there may be some unidentified characteristic of pregnancy that helps to trigger the onset of OHSS. The syndrome usually resolves on its own and/or could take a few days to a few weeks before the discomfort is gone. In severe cases of OHSS where there is nausea and substantial discomfort due to fluid retention, the client could need hospitalization. Careful monitoring and proper dose adjustments during the ovulation induction treatment can dramatically reduce the possibility of OHSS.

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