Case Study 4 (Reproductive)

My doctor explained that Clomid works by "tricking the brain into thinking that estrogen levels in the body are low". She explained that this is what leads to the extra stimulation of the ovaries to encourage eggs to be released. One of the references for Clomid said this happens because there is less negative feedback. Can you explain to me how this "trick" and the decreased negative feedback are related? Why would these factors lead to the stimulation of the ovaries?

Clomid interferes with the ability of the hypothalamus and pituitary gland to measure the rising estrogen levels that occur during the menstrual cycle. During the normal cycle the rising estrogen levels produce negative feedback, which leads to a drop in LH and FSH levels. Clomid prevents this from happening, so LH and FSH levels remain high. The elevated levels of gonadotropins stimulate the ovaries and promote follicle development.

My doctor also explained that birth control pills "trick the body into thinking it is pregnant". She explained that women do not normally ovulate when they are pregnant. Can you explain to me why a pregnant woman does not ovulate? How is this related to how the birth control pill works?

During a pregnancy, the placenta produces estrogen and progesterone. The levels of these hormones rise throughout the pregnancy and help to maintain the uterus and prepare the mammary glands for lactation. These hormones produce negative feedback which leads to the inhibition of the release of gonadotropins from the pituitary. The low levels of LH and FSH mean that no new follicles can develop during the pregnancy. Birth control pills produce levels of estrogen and progesterone in the body that mimic this effect.

My doctor told me that if I take Clomid, I would be taking it on days five through nine of my normal menstrual cycle. She explained that this is when it will have the greatest chance of stimulating the ovaries. What is going on during this part of the menstrual cycle that makes it the best time to take this drug?

During days five through nine of the menstrual cycle, the rising estrogen levels are exerting negative feedback on the hypothalamus and anterior pituitary. This would normally lead to a drop in LH and FSH levels. By taking Clomid during this time, this negative feedback can be reduced and LH and FSH levels can remain high to stimulate the ovaries. This stimulation leads to the development of mature follicles.

In the information about Ortho Tri-Cyclen, it mentions that the hormones in the pill make cervical mucus thicker and stickier. Does this happen during my natural cycle? How are estrogen and progesterone involved in this process?

During the normal menstrual cycle, the viscosity of the cervical mucus changes under the influence of estrogens and progesterone. During the first 14 days of the cycle, the rising estrogen levels cause the mucus to become thin and watery. This change helps to facilitate the passage of sperm through the cervical canal. The rising progesterone levels during the second 14 days cause the mucus to thicken again.

Some of the references talk about how "negative feedback" is involved in understanding how these drugs work. Can you explain what is meant by negative feedback?

Feedback makes reference to the idea that the output of a system "feeds back" to influence the input of that same system. A frequently used example is the thermostatic control of the temperature of a house. As the temperature falls inside the house, the thermostat measures the drop and sends a signal to the furnace to turn on. The result is that the temperature of the house begins to rise. In negative feedback, the effect on the input is that it will reverse the direction in which the variable is changing. In the house example, the dropping temperature begins to rise.

My doctor told me that birth control pills contain small amounts of estrogen and progesterone, and these hormones prevent me from ovulating. I don't understand how giving me these hormones in a pill would prevent me from ovulating. I assume that it has something to do with the levels of the gonadotropins that I asked about earlier. Can you explain this to me?

In female reproductive physiology, estrogen and progesterone levels have an effect on the output of the gonadotropins—this is an example of a negative feedback system. When estrogen and progesterone levels rise, they inhibit the release of the two gonadotropins from the pituitary. The birth control pill takes advantage of this effect by causing blood levels of estrogen and progesterone to rise so that they inhibit gonadotropin release. Without sufficient gonadotropin release, the gonads are not stimulated. In the case of female reproductive physiology, this means that follicles will not develop and release an egg.

In my research, I found that the levels of "gonadotropins" in the body are critical to understanding how the drugs Clomid and Ortho Tri-Cyclen work. What are gonadotropins? What role do they play in fertility?

The two gonadotropins are luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones are released from the pituitary gland under the influence of gonadotropin-releasing hormone (GnRH) that is produced by the hypothalamus. LH and FSH are called gonadotropins because they stimulate the gonads.

I read an article that mentioned that women on Clomid may be more likely to get pregnant with twins, triplets, or more! The article said that normally there is a dominant follicle that releases a single egg, but Clomid can potentially make lots of follicles release an egg in a given month. How does Clomid do that?

Under the influence of rising LH and FSH levels, several follicles are allowed to develop further at the start of the normal menstrual cycle. Not all of these follicles are in the same stage of development. The more mature follicles begin producing estrogen. As estrogen levels rise, negative feedback leads to a reduction in LH and FSH levels. Follicles rely on a steady supply of FSH in order to continue their development. As FSH levels begin to fall, only the most mature follicles can continue to develop because of their increased sensitivity to this hormone. The less mature follicles will begin to degenerate. Eventually, a single "dominant" follicle is all that remains and it will continue to develop. Clomid reduces the negative feedback that normally leads to a drop in LH and FSH levels, so even the less mature follicles can continue their development. This leads to the possibility of multiple eggs being released and increases the risk of multiple births.