Producing Mature Eggs from the Ovaries

The most crucial clinical step in IVF, ovarian stimulation, is the simplest. It involves approximately ten days of subcutaneous fertility shots and nothing more. The response to hormonal stimulation is an important factor that affects the number and quality of eggs. The goal is to produce enough high-quality eggs to have a high pregnancy rate and a low miscarriage rate.

The precise regimen used for ovarian stimulation must be tailored to the individual woman. If the response to hormonal stimulation is inadequate, the cycle will be canceled. This occurs in 6–10% of cycles. In all cases, we want to avoid unnecessarily high doses of drugs, which could lead to a severe adverse reaction called ovarian hyperstimulation syndrome (OHSS).

What Are Ovarian Follicles?

Each egg is contained in a small, fluid-filled structure called a ‘follicle.’ The egg is attached to the inner wall of the follicle. The follicle is also the structure that produces estrogen in a woman’s body. In a natural cycle, several of these follicles are visible on ultrasound, ranging from 2–9 mm. These are called antral follicles. Smaller follicles, called preantral follicles, cannot be visualized by ultrasound. During the natural cycle, one of the follicles enlarges to a size of 18–22 mm. When it reaches this size, typically on Day 14, the follicle ruptures, and the mature egg is released.

In a stimulated IVF cycle, the growth of follicles is similar but essentially magnified. Instead of one follicle growing, hormonal stimulation leads to the recruitment of many follicles. The follicles increase in number and size. At the same time, there is a corresponding increase in estrogen secretion. As the follicles enlarge, the eggs are simultaneously maturing. This is a synchronized process. The development of the follicles and the rising estrogen levels are indirect indicators of the maturity of the eggs.

How Do Hormones Stimulate the Ovaries?

The first part of the IVF cycle uses powerful hormones called ‘gonadotropins’ to stimulate the ovaries to produce mature follicles and mature eggs. It is important to understand that gonadotropin hormones are not foreign chemicals. In fact, they are the hormones found in a woman’s body, albeit in higher concentrations. In other words, we are using the natural hormones, FSH and LH, not contrived drugs. The second component of the ovarian stimulation cycle involves the use of a pharmaceutical that prevents premature ovulation. It blocks any surge of LH that the pituitary could unexpectedly secrete. Such LH surges would result in the premature secretion of progesterone and interfere with the maturity of the eggs. These are the two hormones that can be used to block the LH surge. These two hormones are called GnRH agonists or GnRH antagonists. The third component of ovarian stimulation involves the administration of hCG to trigger the final step of egg maturity before retrieval. Here is the paradox. We have been using the GnRH agonist or GnRH antagonist for a significant part of the stimulation to prevent an LH surge.

Now, we want to give an LH surge. This is called the ‘trigger.’ The egg retrieval is timed so that it is performed before ovulation and before significant progesterone secretion. The hormones used during the IVF stimulation cycle are related to natural hormones that are present in the human body:

1. Gonadotropins, FSH and LH, are the same hormones as those seen in a natural cycle. These are the primary hormones that stimulate the ovary.
2. LH surge blockers, either a ‘GnRH agonist’ or ‘GnRH antagonist,’ are minor modifications of the natural brain hormone GnRH (gonadotropin-releasing hormone).
3. hCG is the hormone of pregnancy, Human Chorionic Gonadotropin. At the end of the stimulation process, only one dose is given, referred to as the hCG trigger.

What Are Gonadotropins?

Gonadotropins are used to stimulate the ovaries to increase the number and size of follicles and promote the process of egg maturation. Gonads refer to the reproductive organs, the ovary, and the testes. These organs produce the gametes, egg cells, and sperm cells. The suffix ‘tropin’ refers to something that stimulates. Hence, gonadotropin is a substance that stimulates the ovary or testes. There are two such categories. One is pure FSH, and one is a combination of FSH and LH, referred to as human menopausal gonadotropin. Pure LH has been recently developed.

FSH is the abbreviation for follicle-stimulating hormone. As its name implies, it directly stimulates the growth and expansion of the follicles during an IVF cycle. It also stimulates the production of estrogen from the follicles. LH is the abbreviation for luteinizing hormone. LH is responsible for the production of steroids within the ovary. It is called LH because it converts cells within the follicle into ‘luteal cells.’ These cells are responsible for the production of progesterone. FSH and LH are pituitary hormones. They control hormone secretion during a natural cycle and trigger ovulation. During IVF, we use these exact hormones to stimulate the ovaries. To mature several eggs, we use amounts of FSH and LH, which are much higher than what the body produces in a natural cycle.

What is ‘Recombinant FSH?’

Recombinant follicle-stimulating hormone, or rFSH, is a purified form of FSH. It is derived from recombinant DNA technology and not from a direct human source. A cloned gene coding for FSH is put into a mammalian cell, the Chinese Hamster Ovary Cell, which then produces FSH. The two products commonly used are Follistim and Gonal-F. These compounds are identical to the FSH produced by the pituitary, which functions during the natural ovulation cycle. They are given by subcutaneous injection using an insulin syringe and needle.

What Are Human Menopausal Gonadotropins?

Products containing LH and FSH hormones are called human menopausal gonadotropins, or hMG. It has equal amounts of LH and FSH because it comes from a human source. The most common product used is called Menopur. It is not derived from DNA technology; it is purified from urine.

Here is a strange fact. It does not come from the urine of just any woman. Instead, it only comes from the urine of menopausal women. Why is this? Menopausal women have high levels of circulating LH and FSH. This is because the ovaries have now reached a diminished or absent function, and the pituitary gland tries to compensate by producing excess amounts of FSH and LH. Gonadotropins are injected by the subcutaneous route, similar to pure FSH.

What Dosages of LH And FSH Are Used?

The most basic amount of FSH is contained in an ampoule of the hormone, consisting of 75 international units (IU). In a carefully synchronized way, I use pure FSH throughout the 9–11 days of stimulation until the day of the trigger. I choose either Gonal-F or Follistim. After two or three days, I add a second drug-containing LH and FSH.

Most typically, 2 to 4 ampoules of FSH are given daily. Multiplying each by 75 gives you 150 to 300IU doses. This is just an approximation since the stimulation of each patient is individualized. Frequently, I drop the dosage by one or two ampoules (75–150IU) and replace it with one ampoule of Menopur, i.e., 75IU, which has both LH and FSH. LH supports follicular development. LH is required to produce normal steroids, including the estrogens and androgens produced by the ovary. Receptors are the chemical molecules to which hormones are attached. Only 1% of the receptors must be occupied in the case of LH. Pure LH, created by DNA technology, is available but lasts in the system for too short a time.

How is the stimulation process individualized?

Every step of the process is individualized. Primarily, this is based on the antral follicle count, age, and hormone levels of AMH and FSH. For example, women with very few follicles in their ovaries, i.e., less than 6–8, may require 4–6 ampoules daily, i.e., 300–450IU daily. Higher doses than this are almost always ineffective. Women with 10–14 follicles from both ovaries can receive a lower dose, such as 2–3 ampoules daily.

Finally, if a woman has more than 14 follicles, I am very wary of her overreacting. Consequently, I only use one to two ampoules, and sometimes only one ampoule, daily. If my patient has polycystic ovaries, there is always a risk of developing ovarian hyperstimulation syndrome. Two primary basic protocols are used to achieve adequate responsiveness from the ovaries. Many other variants of these protocols, as well as entirely different methodologies, have been utilized.