Approximately 25% of women attending infertility clinics suffer from disorders of ovulation. Female egg production and maturation is a complex process involving coordination between brain and ovaries. Also, several other factors like hormones and medical conditions can affect release of eggs. As a result, any disturbances in these pathways can lead to ovulatory dysregulation. Subsequently the couple face problems of infertility and need treatment. OI medications are simple treatments for female infertility. This treatment helps you to conceive naturally with the help of your gynecologists. However if this treatment fails for 3- 4 cycles, you should see a fertility specialist. Further infertility evaluation and higher treatment may be needed thereafter. Ovulation induction offers a solution for the large percentage of women with disorders of anovulation and irregular cycle.

Ovaries and eggs

      The production of the eggs in a woman is much earlier when she is still in mothers womb. At birth a female newborn ovary contains immature eggs known as primary oocytes. These primary eggs are in the sleeping stage within small follicles called primordial follicles. Although ovaries contain one million oocytes at birth, only 400-500 eggs ovulate during the childbearing age of a female. 

Menstrual cycle and growth of egg

           Growth of the human egg starts from the primordial follicle. It progressively develops into the primary follicle, then the secondary follicle. These phases of development are not dependent on hormones. The majority of secondary follicles undergo atresia at this stage. Slowly the follicle grows and fluid fills and accumulates to form a cavity known as antrum. At this stage it is called antral follicle which is seen immediately after the onset of menstruation. Antral follicles now are dependent on the gonadotropin hormones for their growth.

Hormones regulate the growth of eggs                    

      In the follicular phase,  the antral follicles grow and mature into graafian follicles, or preovulatory follicles. Although multiple follicles are recruited in a cycle only few grow and mature. These growing follicles gradually become sensitive to FSH hormone and start secreting estrogen hormone. At one point, the follicle with maximum estrogen activity thrives whereas others stop growing and regress.  

Basics of infertility treatment

                As you attend the infertility clinic, your doctor will advise you to undergo certain tests. She will suggest a complete workup including any endocrine or hormone disorders. Your menstrual calendar along with the hormone tests help in assessing the cause of infertility. Laboratory tests include thyroid and prolactin levels, day 3 FSH, LH and estradiol. Progesterone levels on day 21 or 1 week prior to onset of menses can indicate any deficiency in ovulation.       Among all other tests are infection screening, anti-Mullerian hormone for ovarian reserve. tubal patency test via hysterosalpingogram or saline infusion sonohysterogram. Also your partner will be evaluated for any problem in male factor. 

 When does your doctor suggest ovulation induction?

     After the investigations your doctor will reveal the cause of infertility. In cases of unexplained infertility no cause is found. If the cause is ovulatory dysfunction then your doctor will suggest ovulation induction. Ovulation induction is the first line of treatment in cases of unexplained infertility as well.

What are ovulatory disorders?

Ovulation dysfunction can be due to –

  • Failure of pituitary gland
  • Increased prolactin hormone
  • PCOS and metabolic syndrome
  • POF
  • Genetic abnormality

Can we correct ovulatory dysfunction?

Some of the factors leading to failure of the pituitary gland can be modified. They are

  • Excessive exercise leading to amenorrhoea
  • Extreme underweight
  • Overweight or rapid gain in weight
  • Women with PCOS

Who will benefit from ovulation induction?

Women with PCOS are most commonly treated with ovulation induction. Underweight women should undergo a weight gain program before medications. Athletes trying to conceive also should refrain from heavy exercises. Women with POF or genetic abnormality causing ovarian dysfunction will not benefit.

Before ovulation induction

Monitoring and correcting weight – Overweight women have problems of ovulation . They need to lose weight before fertility treatment. Proper diet and exercise help them shed the extra weight.

Should treat underlying diseases – Hypothyroid, High prolactin level are some of the modifiable factors of ovulatory disorders. Your doctor will advise correction of these abnormalities before the treatment process. 

Bromocriptine is a safe and commonly used treatment for hyperprolactinemia. Cabergoline is a newer alternative  with fewer side effects. These medications are given twice weekly for 4 weeks. Once prolactin levels have returned to normal, women start ovulating. Hypothyroid levels are connected to high prolactin levels in blood. Correction of hypothyroidism allows normal ovulation.

Where ovulation induction doesn’t help?

Premature ovarian failure (premature menopause)

These women don’t have any reserve in their ovaries. This condition cannot be reversed. Donated eggs with in vitro fertilization is the only choice for these women. 

Genetic abnormalities

Women with genetic abnormalities like Turner’s syndrome (45,X0), don’t have eggs in their ovaries. Their ovaries are underdeveloped (streak) which results in premature menopause. These women can conceive using donated eggs with in vitro fertilization. 

Androgen insensitivity syndrome (formerly testicular feminization)- These women have a 46,XY chromosome and have testes inside but with external looks of a  female. They are unsuitable for ovulation induction as there are no ovaries.

How ovulation induction is done?

Ovulation induction starts with lifestyle modifications. Your doctor will advise you on a healthy diet plan to follow. Quitting smoking and reducing alcohol intake will help a lot. Treatment of medical disorders like diabetes, hypothyroid and high blood pressure is mandatory before treatment. She may put you on oral contraceptive pills for one or two cycles before induction. The medications commonly used for ovulation induction are –

  • Clomiphene – Women with PCOS benefit most from clomiphene citrate. It remains its most frequent and most successfully treated indication of CC
  • Letrozole – It is a promising new drug for the induction of ovulation and superovulation with less side effects.
  • Metformin –
  • Gonadotropin injections

What is Clomiphene citrate?

Clomiphene citrate is the most efficient drug for ovulation induction. It gives a success rate of around 25 % in young women worldwide. It acts by inhibiting the estrogen action on the brain. Women with menstrual problems like highly irregular or no menstrual cycles also benefit from this. The action of clomiphene is long standing and more effective. Hence more commonly gives rise to multiple follicles and twin pregnancy. Your doctor will administer the medicine from the second day of your cycle for 5  to 7 days. After stoppage of this medicine ovulation may follow within 10days.  The dosage and duration of this drug may differ in clinics and depends on patient profile as well. CC is an oral drug, and relatively a cheap preparation. Hence. your doctor prefers this over costly gonadotropin injections.

Side effects of clomiphene

Clomiphene citrate can cause  ovarian hyperstimulation due to  elevated FSH levels. It also carries a risk of inducing multiple gestations, most often twins with rare triplets. However these side effects are more common with use of Gonadotropins. Antiestrogenic mechanisms like thin endometrium can negate its fertility efficiency.  It also causes symptoms such as mood changes, vaginal dryness/atrophy, hot flashes, and irregular menses. It may slightly increase the risk for future ovarian malignancy by inducing multiple ovulations if used for a long period. 

Where does Clomiphene fail to act?

Although clomiphene restores ovulation in patients, it can only give successful pregnancy in half of these women. Some women who do not respond at all to and are clomiphene resistant. You are more likely to be resistant to clomiphene, if you are obese, insulin resistant or have high androgen levels. Response to Clomiphene is best predicted by the androgen index in infertile women. Overweight women respond less well and may need a higher dose to induce ovulation.

What other medications can be used to induce ovulation?

Letrozole 

This is a relatively newer drug used for fertility treatment, also called an aromatase inhibitor. It is an oral medicine and easy to use. Letrozole is relatively inexpensive, with minor side effects.  It doesn’t cause thin endometrium unlike clomiphene. Letrozole can even give higher pregnancy rates than CC due to superovulation. It reduces the use of gonadotropin when used for IVF treatment making it more cost effective. The dose of letrozole is 5mg daily for five days and is the most effective.

Metformin

In PCOS women insulin resistance and high androgen levels make them more resistant to ovulation induction therapy. Metformin works in these women as an insulin sensitizer. It can lower insulin resistance and might reduce ovarian dysfunction.  This in turn improves ovarian responsiveness to FSH. This may be more effective in overweight and insulin-resistant PCOS patients. It is given along with CC or gonadotropins as a pretreatment or co-treatment in FSH ovulation induction. 

Gonadotropins

Ovarian drilling or Laparoscopic electrocoagulation of the ovaries (LEO)

Some of the women with PCOS are resistant to any kind of medications to induce ovulation. These women have high androgen levels as their ovaries contain more theca cells. These cells can produce more androgen and make them unresponsive to ovulation induction. Laparoscopic ovarian drilling can destroy some of these cells so that these women respond to clomiphene or letrozole therapy. After ovarian drilling overall testosterone levels in ovaries decrease to give a favorable outcome. It enables women to regularize their cycles, ovulate on their own or become more sensitive to OI medication. However this is not the first line therapy due to risks of surgery. It may destroy normal ovarian tissue as well.

How do you monitor ovulation induction?

During ovulation induction your doctor will monitor your cycle by ultrasonography to see the growth of follicles. By USG she will directly visualize the number and size of follicles. This helps her to time the ovulation trigger and intercourse. Few other methods which you can use at home to know ovulation are: use of LH kits and measurement of body temperature. Serum progesterone levels on day 21 can indicate whether ovulation has happened or not.

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