Answers to Commonly Asked Questions ( 1 - 9 )

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1. What is Premature Ovarian Failure?

Premature Ovarian Failure (POF) is a loss of ovarian function in women under 40. Periods stop, estrogen is low and the follicle-stimulating hormone (FSH) level is elevated. Generally, it is said that the diagnosis requires at least 4 months without a period and two FSH tests, taken at least one month apart that are greater than 40 (some doctors will use 30) mIU/ML

2. Failure seems like such an unfortunate word to use.

Yes, it certainly is one of those loaded terms especially if we use the word failure to mean complete stopping of ovarian function. When we use the term "Premature Ovarian Failure," failure means that ovarian function is not normal. The failure can be temporary or periodic and there can be residual ovarian function. Even with high FSH levels women may intermittently produce estrogen and even ovulate.

3. Why do I hear the term premature menopause used?

Yes, you will probably hear this term commonly used. However, it is incorrect. The most important thing to remember is that this is NOT menopause. This term originated from early studies when it was thought that, like menopause, there was a total lack of eggs. It was called "premature" to signify that it started at an earlier than normal age. However, unlike menopause, which appears to be a permanent loss of ovarian activity, POF may not be permanent. When the ovaries of women with Premature Ovarian Failure are looked at on pelvic ultrasound approximately 40 percent of the women have structures that appear to be ovarian follicles. Today, we know that women with Premature Ovarian Failure intermittently produce estrogen and ovulate. This is why the term Premature Ovarian Failure is preferred to premature menopause. Menopause means complete cessation of periods. In some cases, Premature Ovarian Failure may be reversible.

4. At what age do women normally enter menopause?

The average age of menopause is approximately 51 years. It generally ranges from 45 to 55 years.

5. Why do we say that Premature Ovarian Failure occurs in women under the age of 40?

In 1986 Carolyn Coulam (et al) published an article "Incidence of Premature Ovarian Failure." Since that time it has remained the standard by which researchers fix the incidence for Premature Ovarian Failure. She did the study in Minnesota at the Mayo Clinic. Medical records of women who lived in Rochester, Minnesota, who were seen for medical care at the Mayo Clinic in 1950, and who were born about 1930 were followed from 1950 through 1986 for the age at which natural menopause occurred. She discovered that natural menopause before age 40 is unusual because the incident rate in the 40 to 44 age group was more than ten times larger than in the 30 to 39 year age group.

6. How many women have POF?

In the study cited above by C. Coulam (et al), she discovered that it occurs naturally in 1 in 1000 women between the ages of 15 and 29 and 1 in 100 women between the ages of 30 and 39. In her study she excluded women who had had chemotherapy, radiation therapy or any type of a hysterectomy. We used her percentages and calculated that this affects a minimum of 250,000 women in the US!

Is this rare?

Actually, it isn't. The National Organization of Rare Disorders (NORD) states that "a rare disease is one which affects fewer than 200,000 people in the US." There are less than 5000 rare disorders. Among the rare disorders you may have heard of are: ulcerative colitis, carpal tunnel syndrome and multiple sclerosis.

7. Why is 39 used as the cut-off age for the diagnosis?

Many researchers will say that 39 is an arbitrary cut-off point. If we refer to C. Coulam's study again, she states that the incidence rate in the 40 to 44 year age group is more than 10 times larger than in the 30 to 39 age group. Since there is such a great increase in the 40 to 44 year old age group this seemed a natural cut-off point. Although this is the landmark study, you may hear some researchers say that Premature Ovarian Failure occurs before the age of 35. Or, in yet another study the age of 44 was used because when large populations of women are studied, 95 percent of all women will stop menstruation after age 44.

What is the average age at which this occurs?

The average age of onset is 27 years.

8. Is it true if you started your periods early you are more likely to have POF?

No, that isn't true. Nor is there a typical menstrual history for women with Premature Ovarian Failure. Some women state that they feel as if they went to bed one night feeling fine and woke up the next morning with this problem. Some women start to miss periods, know they are not pregnant but don't know the cause of the missed cycles. Some have normal periods but develop hot flashes and can't figure out what is going on. In some women the problem becomes apparent after they've had a baby but their periods never return. In others, it becomes apparent when they stop birth control pills (BCP) and, again, their period never returns. Use of the BCP may have hidden for years that a woman has POF but there is no evidence that BCP can cause POF.

9. Earlier you said that one of the indicators of Premature Ovarian Failure is an elevated FSH level but what does that mean?

This is a good time to talk about how the ideal menstrual cycle works. Yes, you've probably heard all this before. But since we're going to need to refer to some of this information throughout the discussion on Premature Ovarian Failure it will be convenient to have this information nearby so you can refer to it when needed.

Starting at the beginning, a female fetus has somewhere around 7 million follicles at about 4 - 5 months gestation of a pregnancy. A follicle is the small fluid-filled structure in the ovary that contains the egg (ovum). Through a process of "atresia" (a mechanism of programmed loss) by the time a girl is born there are about 2 million follicles left and by the time the girl reaches puberty and is ready to have her first menstrual period there are only about 300,000 - 400,000 left. These are the only follicles she will ever have. No new follicles are produced after birth. And generally there are enough follicles to last a woman until menopause. If you're looking at that number 300,000 you may be wondering why the eggs even run out at the average age of 51. If you've calculated that you ovulate one egg per month (or 12/year) and an average woman has 40 menstrual years this accounts for only 500 of the approximately 300,000 eggs. Although only one egg is selected for ovulation, 20 or more eggs may start to mature each cycle. As a cycle progresses there is basically a "race" for one follicle to become the largest. The follicle that becomes the largest is called the dominant follicle. The other follicles, which had started to ripen, disintegrate through the process of atresia. The one maturing follicle keeps growing until ovulation occurs. At ovulation the egg is released from the follicle and it begins its journey from the outer surface of the ovary into the fallopian tube.

Although the ovaries are in "resting" states from birth until the time of puberty both estrogen and progesterone are produced by the ovaries in small amounts from birth. At puberty, activation of the ovaries begins because the parts of the brain involved with reproduction, the hypothalamus and the pituitary gland begin releasing their hormones. Why this happens when it does is still somewhat of a mystery. This activation allows sexual maturation, ovulation and possible pregnancy over the next decades until the time of menopause.

Let's look at what happens during a menstrual cycle. We count Day 1 as the onset of menstruation. The first part of a cycle from Day 1 to ovulation is called the follicular or estrogenic phase. The second phase of the cycle is called the luteal or progestational phase. This phase lasts from ovulation to the day before the new period begins.

During menstruation, blood levels of estrogen are low. The hypothalamus responds to these low levels in the blood by sending a chemical message (it releases GnRH) to the pituitary gland (the master gland) and tells it to secrete follicle-stimulating hormone (FSH). The follicle-stimulating hormone (FSH) stimulates the development of a number of follicles. The follicle begins to produce estradiol, which is the major estrogen of the reproductive years. On about Day 5 (when menstruation is ending) the pituitary also begins to release small, but increasing amounts of LH (Luteinizing Hormone). As we said earlier about 20 follicles are going to start to develop but only one is going to become dominant and fully mature. The dominant follicle, which is now almost mature (and is called a Graafian follicle), signals that the egg wants to be released from the ovary. On approximately Day 12, the estrogen (estradiol) production in the cells of the ovarian follicle increases to its highest monthly level. In addition, the anterior pituitary releases a large amount of LH (called the "LH surge") and within 24 to 36 hours the follicle finishes maturing and the egg pops out into the abdominal cavity. This is called ovulation.

The egg is picked up by the fimbria, which are the petallike fingers at the end of the fallopian tubes. The fallopian tubes are the four and a half-inch long structures connecting the ovaries and the uterus. The walls of the tubes are lined with hairlike cilia. When the egg is released from the follicle the abandoned follicle fills with blood and turns into the corpus luteum. The corpus luteum remains on the ovarian wall and produces progesterone. It is the progesterone that thickens the lining of the uterus. In the days following ovulation, the combination of high progesterone and low estrogen signals the pituitary and the hypothalamus to slow the production of LH and FSH. These will stay very low from ovulation until near the end of the cycle. If the egg is not fertilized the corpus luteum disintegrates and there is a steep drop in progesterone and estrogen. The decrease in progesterone triggers the disintegration of the endometrial wall and the beginning of your next period.

10. Back to FSH. Is there a problem with the FSH stimulating the follicles?

The problem is a lack of follicles. In Premature Ovarian Failure there are either fewer than normal follicles or there is a dysfunction in the ovaries. Remember that the FSH stimulates the development of a follicle and that as the follicles ripen they release estrogen. The estrogen in turn sends a signal back to the brain that it can turn the FSH off. If a follicle isn't stimulated, there isn't enough estrogen to go back to the brain to say "turn off." So in a vicious cycle, instead of being able to turn off the FSH, the pituitary is driven to send out even more FSH to try to get a follicle to develop. And in turn the FSH level rises.

If there is a dysfunction of the ovaries, it is thought that women produce antibodies to their own FSH or to their own ovarian substances.

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