The Normal Physiology

For a couple to have a child it is essential that the female gamete called the oocyte/ovum (egg) and the male gamete called the sperm unite. The result is a zygote, which develops into the embryo and then into the fetus or unborn child.

Both the oocyte and the sperm must meet in the fallopian tube, which is a hollow-tube like structure between the uterus and ovary. At the time of sexual intercourse sperms deposited in the vagina make their way into the uterus, to the fallopian tube. At the time of ovulation, which is around the 12^th day  (+ 2 days) of a 28-day menstrual cycle, the mature oocyte is released from the follicle (sac-like structure) in the ovary. The oocyte gets into the fallopian tube, where it meets the sperm. This play of events in the reproductive cycle is controlled by hormones released from several organs in the body.  At the base of the brain, the hypothalamus gland produces a hormone called gonadotrophin-releasing hormone (GnRH).  This hormone stimulates another gland known as the pituitary, which is situated just below the hypothalamus.  The pituitary releases two important hormones, which are involved in reproduction – follicle stimulating hormone (FSH) and luteinising hormone (LH).  Both these hormones have a direct effect on the ovaries during the menstrual cycle.  The ovary in turn releases hormones called estrogens and later progesterone, which also influences the reproductive cycle.

Although commonly referred to as ovulation induction, in essence it is a stimulation of the ovaries to develop more number of mature follicles. The final event is inducing ovulation i.e. release of the ripe egg from the mature follicle by causing the follicle to rupture. It has been proven that having more number of follicles can increase the chances of conception.

Indications for Ovarian induction

• Various types of disorders in the ovary wherein the development of the follicle is either improper or absent. The problem may lie in the ovary or in organs influencing the functions of the ovaries.
• In assisted reproductive techniques (ART) as a fundamental adjunct to treatment.
• Empiric treatment with or without intrauterine insemination, to maximize changes of conception in cases of male infertility and unexplained infertility

Methods of ovulation induction

Medications used for ovulation induction are generally referred to as fertility drugs.  Ovulation Induction can be carried out by using either tablets or injections or a combination of both. Regimens for ovulation induction vary depending on the results of the infertility evaluation. It must be emphasized that these medications are to be used only under supervision of an experienced doctor.

Types of medications available are

1. Oral medications - Clomiphene Citrate (CC) and letrozole.

These are available in the form of tablets to be taken orally. Treatment is started in the early days of the menstrual cycle (D2/D3), at a low dose and then stepped-up in subsequent cycles depending on the initial response. These drugs cause an increase in the production of FSH and LH, hormones produced by the pituitary gland to promote follicular development.

Common side effects of CC are hot flushes, headaches, mood swings, insomnia, transient hair loss and blurred vision.  

2. Injectables:

Gonadotrophins and Gonadotropin releasing hormone agonists (GnRHA). Gonadotrophins

– These medications provide FSH and LH in varying doses. The dose of the gonadotrophins varies from patient to patient.  The drug is given in the form of injections either daily or on alternate days, and is administered into the muscle or into subcutaneous tissue. The initiation of gonadotrophin injections may be early in the menstrual cycle.  Injections can be painful.  Some patients may experience some discomfort, redness or bruising at the injection sites. Side effects of the drugs may include hot flashes, breast tenderness, fluid retention, a bloated feeling, moodiness, depression and/or tenderness in the ovaries.

GnRH agonists - This drug stimulates the release of gonadotrohins from the pituitary. Continued administration for more than a week will suppress the secretion of LH and FSH; therefore, it is used in preparation for cycles of treatment with ovulation induction drugs. It improves the recruitment of follicles. It will also prevent premature ovulation (release of eggs) by preventing LH release. The injections are started either early in the menstrual cycle or in the later part.Side effects may include hot flushes, vaginal dryness, and skin rash.

Side effects of long-term treatment (greater than six weeks) include bone loss in addition to the above. These side effects are extremely rare after short-term use associated with standard IVF. No long-term side effects after treatment occur.

A treatment cycle

Based on the results of infertility evaluation a treatment regime for ovulation induction is planned for each patient. Either oral drugs or injections or combinations of both may be used.

• A baseline ultrasound scan of the pelvis, usually transvaginal is performed on D2 or D3 to note the uterus and ovaries.  Day 1 of a cycle is the first day of full menstrual flow prior to midnight.
• Treatment is then commenced and written instructions regarding dosage and timing is given to the patient.
• The response of the ovaries to the medications is monitored by an ultrasound scan a few days later, between D7-D10. The follicles in the ovary are noted in terms of number and size. The ultrasound also notes the uterine lining or endometrium, which shows certain changes at different times of the menstrual cycle. The endometrium is assessed for its receptivity to implantation of the fertilized egg.

Further medications are then administered based on the ovarian response, and subsequent response also assessed by scans. Sometimes it may be necessary to monitor the response by hormonal measures in the blood. Estrogen levels are the most important, because they indicate how well the follicles are growing. However, only ultrasound can reveal their number. Monitoring the response to treatment is a vital part of the programme, to maximize the chances of a successful pregnancy and minimize any risks.

Once the follicle is deemed to be mature (as noted by size) another injection called human chorionic gonadotrophin (HCG) or GnRH is administered to bring about rupture of the follicle and thereby release of the mature ovum. One must note that there is no way to determine the presence or size or maturity of the egg by any tests. Maturity of the follicle is an indicator of the maturity of the egg. Ovulation usually occurs between 24-36 hours after administration of HCG or GnRH. Once this step of ovulation is undertaken, the couple is advised either on timing sexual intercourse or going through an intrauterine insemination (link). For these two options it is important that the fallopian tubes must be patent. If the line of treatment is IVF (link) then the woman is advised regarding timing of egg or oocyte collection (see  IVF)