Posted under Fertility Treatment by Dr. Suchetana Sengupta

Ovulation Induction with Oral medications vs Gonadotropins – How does it work?

What is ovulation Induction?

Ovulation Induction is a fertility treatment modality that uses Ovulation Inducing medications or fertility drugs to stimulate the ovaries to release eggs. Ovulation Induction is used for following purposes:

1. Help women who are not ovulating to ovulate and release an egg
2. Help women who do not ovulate regularly
3. By increasing the number of eggs available for fertilization, Help women who are ovulating but still not able to conceive to release more than one egg as a part of a treatment for unexplained infertility

What are the causes of ovulatory disorders?

• Selective failure of the pituitary gland to produce FSH and LH
• Physiological reduction in the hypothalamic production of gonadotropin releasing hormone. (experienced by women with low BMI, Obesity, and those who exercise excessively)
• Congentital disorders and Genetic disorders that affect the production of gonadotropins and GnRH.
• Trauma to hypothalamus and or pituitary that may affect the production of hormones
• Increased concentration of prolactin
• Premature Ovarian Insufficiency (premature menopause)
• PCOS

Is Ovulation Induction the right treatment for you?

Ovulation Induction is recommended for:

1. Women with unexplained infertility.
2. Women with long, irregular or infrequent cycles.
3. Women who are not spontaneously ovulating.
4. Couples with no male-factor infertility.
5. Women with Disorders that can directly inhibit normal ovulation such as PCOS
6. Women with disorders than can indirectly affect ovulation, such as thyroid disorders, eating disorders and obesity.

Ovulation Induction is not recommended for:

1. Women over 38 years of age.
2. Women with tubal blockage or severe tubal damage.
3. Women with severe endometriosis.
4. Couples with a low sperm count or poor sperm motility/morphology.
5. Women who have entered menopause
6. Women with Premature Ovarian insufficiency

What kind of ovulation inducing medications are used?

OI medications can be divided into two categories:

• Anti-Estrogenic Oral Medications for Ovulation Induction :
  • aromatase inhibitors (AIs) such as letrozole and anastrozole
  • Clomiphene citrate (CC)

• Injectable medications for Ovulation Induction
  • Gonadotropins
  • FSH injections

Let’s understand how these medications work briefly

The Rational behind ovulation Induction using oral medications:

The brain is the command center that controls the menstrual cycle. The Hypothalamus -the anterior pituitary ovarian axis(HPO) regulates the release of hormones related to the reproductive cycle.

The Gonadotropin releasing hormone (GnRH) secreted by the hypothalamus acts on the anterior pituitary to release Follicle stimulating hormone FSH and luteinizing LH that play an important role in the development of follicles and release of an egg every cycle.

Follicle stimulating Hormone plays an important role in the recruitment of follicles and releasing of an egg. FSH is secreted in the initial part of a menstrual cycle in response to low estrogen levels. So low levels of estrogen acts as a trigger for releasing FSH. As FSH levels rise, the follicles develop and secrete estrogen that will trigger the release of an egg later in the cycle.

The negative feedback loop: High levels of estrogen (released by the developing follicles during mid-cycle) on the other hand acts as a negative feedback loop telling the hypothalamus and Anterior pituitary to stop releasing FSH.

CC and and aromatase inhibitors (AIs) such as letrozole and anastrozole work by either lowering estrogen levels or by making the brain think they are low.

• CC works by helping cells resist estrogen. CC, a non-steroidal compound closely resembling an estrogen, acts by blocking hypothalamic estrogen receptors, signaling a lack of circulating estrogen to the hypothalamus and inducing a change in the pattern of pulsatile release of GnRH.

Clomiphene citrate is capable of inducing a discharge of FSH from the anterior pituitary and this is often enough to reset the cycle of events leading to ovulation into motion. The release of even small amounts of FSH into the system will often induce ovulation and pregnancy in a proportion of anovulatory women.

• AIs work by blocking certain kinds of hormones (androgens) from changing to estrogen. They inhibit release of estrogen from various sources, namely ovarian, adipose tissue and locally produced estrogen in the brain and thus release the HPO axis from the negative feedback effect of estrogen. Low estrogen levels tell the pituitary gland to produce FSH, which helps in follicular recruitment and growth and release an egg later in the cycle.

The Rational behind using Injectable medications for Ovulation Induction

Gonadotropins are fertility drugs that contain follicle stimulation hormone (FSH), luteinizing hormone (LH), or a combination of the two. These drugs are used to stimulate ovulation. Gonadotropins are informally known as injectables because they are only administered by injection.

The principle of gonadotrophin induction of ovulation is to mimic the normal physiological cycle of follicular selection, maturation and ovulation. FSH and LH are also known as gonadotropins. They are naturally occurring hormones in the body that play a pivotal role in ovulation. FSH as earlier discussed stimulates the development of follicles in the ovaries. LH typically peaks just before ovulation during a natural cycle and helps the dominant follicle to go through one last growth spurt and release the egg.

Exogenous gonadotrophins are used in the treatment of patients who have failed to conceive with antiestrogenic medications despite ovulation or have failed to ovulate with Clomiphene or Letrozole. Gonadotrophins are more effective than CC but are more expensive, require parental administration and have higher risk for ovarian stimulation and multiple pregnancy.

The different types of gonadotropin formulations used are:

• FSH injections: They are used to stimulate the ovary to produce egg-containing follicles and encourage those follicles to mature. Preparations of follicle-stimulating hormone (FSH) mainly include those derived from the urine of menopausal women, as well as recombinant preparations. The recombinant preparations are more pure and more easily administered, but they are more expensive.
• Human menopausal gonadotropin (hMG): It is a medication that is composed of follicle stimulating hormone (FSH) and luteinizing hormone (LH). Due to the variability in response from patient to patient, no fixed dosage regimen can be recommended.
• Human Chorionic Gonadotropin (hCG) : It is a natural hormone that helps with the final maturation of the eggs and triggers the ovaries to release the mature eggs (ovulation). It 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.

How effective are these medicines in helping a woman get pregnant?

The success of these medicines depends on many factors.

• In women not already ovulating, almost 80% of women who use CC or AIs over several months will ovulate.
• Numerous studies have highlighted the benefits of ovarian stimulation with IUI. Combined pregnancy rates of ovulation induction with IUI were better (8.3% -17.1%) than isolated ovulation induction without IUI

Why do some women need more dosage of medicines than others?

Some women will need increasing doses of the medicines. Pregnancy rates depend on your age, ovarian reserve, the length of infertility, and cause of infertility. These medicines are generally more effective in women who do not ovulate regularly. The medications and dosages to induce ovulation are tailored to suit you as an individual. While a standard dosage may work in majority of causes, there will always be some women who will need a higher dosage or combination medications to induce the desired results.

Tests before Ovarian Stimulation

A number of tests help in predicting the ovarian response to external stimulation and thus helps in determining the dosage of gonadotrophins. Out of these, basal FSH and ultrasound estimation of Antral follicle count (AFC) are the ones most commonly used.

What are the Side Effects of Ovulation Induction?

The main risks are:

OHSS (Ovarian Hyper-stimulation Syndrome) – This is a rare problem where a woman over-responds to the ovulation induction and can experience symptoms including pain, bloating, nausea and vomiting and, in worst cases, need urgent hospital treatment.

The risk of OHSS can be minimized by monitoring your treatment cycle with ultrasound scans, and sometimes blood tests. If we see potential for OHSS to develop, the medications can be either adjusted or discontinued.

Multiple Pregnancy – When the ovaries are stimulated, it is possible for more than one follicle to mature and release an egg at the same time. This could result in a multiple pregnancy. Our ultrasound monitoring checks for this and we adjust or stop medication and/or recommend abstinence from intercourse if we see too many follicles developing.

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About the author

The author, Dr. Suchetana Sengupta is a Fertility Consultant at Care IVF Kolkata. For an appointment with the doctor, call +91-33-66-398-600. You can also book a Skype Consultation here.