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- 1. What is ‘the biological clock’? “The biological clock” is the layman’s term for expressing the concept of the age-related decline in ovarian reserve that occurs in all women. Men remain able to father children even in the extremes of old age while women stop being able to reproduce at a comparatively much younger age. Men produce sperm from puberty until death, whereas women are born with their lifetime supply of eggs which begins to decline immediately after birth. Most women stop having periods in their late 40’s or early 50’s however, the changes that limit her changes of successfully reproducing have actually begun to occur many years before that. These changes have very few outward signs, if any at all. For most of human history, this was unimportant as the average life expectancy for women did not exceed 35 or 40. However, the life expectancy of today’s female is 70-80 year and for many reasons, it may be desirable or necessary for a woman to delay plans for childbearing. The end result is a significant number of women who are at risk for age-related infertility. The purpose of this article is to explain: 1) how age effects ovarian reserve 2) what testing is used to measure “egg supply” or ovarian reserve and 3) data source: Heffner L, N Engl J Med 351;19 Nov 2004 discuss how treatment options are affected by ovarian reserve. In addition to having difficulty becoming pregnant, a woman’s chance of miscarriage also increases with age. Between age 20 and 35, the risk of Age and Ovarian Reserve miscarriage roughly doubles. By the early 40’s the loss rate has doubled Since ancient times, it has been recognized that a woman’s chance of again with nearly a third of all recognized pregnancies ending in becoming pregnant declines with age. The actual decline in fertility starts miscarriage. The reason for this high miscarriage rate is that the older the in the early thirties and accelerates in the late thirties. It has been mother, the higher the chance that the embryo will be genetically estimated that nearly 1/3 of the couples with the woman over 35 will have abnormal. The majority of miscarriages are due to genetic or a problem conceiving. Studies also suggest that only 10-30% of the developmental abnormalities; conceptions that would not have resulted in women over 40 are able to become pregnant on their own. as well as normal births. When chromosomal analysis of the embryos resulting from from large numbers of infertility patients being treated simultaneously. IVF cycles has been performed, it has been shown that the older the The graph below shows the birth rate dropping rapidly as age mother, the higher the rate of genetically abnormal embryos produced. increases in populations that do not practice birth control. The identical trend is seen in data gathered from infertility patients undergoing treatment. Evaluation of Ovarian Reserve Women are born with roughly 1 million eggs. This number declines continuously, every day from the moment of birth onward. Out of every 1000 eggs (oocytes), only 1 will ever leave the ovary via ovulation. The other 999 may grow briefly then undergo “atresia” (basically dying) within
- 2. the ovary. No known therapy in humans can generate new oocytes. By with high FSH levels. Therefore elevated estrogen levels on day 3 may her 37th birthday, the average woman will have approximately 10% of her also suggest decreased ovarian reserve. original egg supply left. More importantly, because the “best” eggs are released first the fewer the number eggs remaining, the lower the overall Another test that can be incorporated into the evaluation of ovarian average “quality” of those eggs. reserve is the Clomiphene Citrate Challenge Test (CCCT) In this test, the day 3 FSH level is drawn and if normal, the patient is given the “Ovarian reserve” is the term that we use to describe how many of a ovulation induction agent clomiphene citrate 100 mg on cycle days 5-9. woman’s original egg supply remains. Age is one important determinant On cycle day 10, the FSH and estradiol are re-drawn. If the day 10 FSH of ovarian reserve. However, not all 37 year old women, for example level is high, this indicates abnormal ovarian reserve. The CCCT is have the same number of eggs. Other factors include genetics (how approximately 30% more sensitive in detecting ovarian reserve issues many eggs one is born with) factors that may damage the egg supply than the day 3 FSH level alone. (smoking, endometriosis, radiation, environmental toxins, ovarian surgery). There is no precise way to measure ovarian reserve (i.e. like a One additional simple test of ovarian reserve often used is the Basal sperm count) however an estimate of can be accomplished by some Antral Follicle Count (BAFC). Early in the cycle, the small follicles (2-10 relatively simple and easily available tests. mm) that can be seen with transvaginal ultrasound are counted. A low number of follicles (< 5 per ovary) predicts a higher chance of poor The standard screening test is the measurement of the DAY 3 FSH response to therapy and decreased chance of live birth. Very high LEVEL. FSH or “Follicle Stimulating Hormone” is the signal sent from numbers of small follicles (>20) suggests a tendency to over respond to the pituitary gland in the brain to the ovary, that tells the ovary to prepare hormonal stimulation. an egg for ovulation each month. Without FSH, there is no maturation of eggs and no ovulation. As the egg supply dwindles, the brain needs to High BAFC Low BAFC release larger and larger amounts of FSH (i.e. “louder signal”) in order to get an egg released each month. Finally, when there are no eggs left (i.e. menopause), the FSH levels remain elevated all the time. It is important to recognize that each lab can measure FSH levels slightly differently and each fertility program should analyze how FSH levels from their own lab predict pregnancies within their own program. In our program, we find that an FSH < 10 is normal, 10-14 is concerning and an FSH >14 is indicates a diminished egg supply. The day 3 FSH is only part of the larger picture. For example, a woman in her 40’s, despite having a “normal” (<10) FSH level still has a reduced chance of pregnancy based upon her age. FSH levels also vary from cycle to cycle. A previously elevated level which measures lower the next cycle obviously does not mean the egg supply has been HOW USEFUL ARE THE RESULTS OF OVARIAN RESERVE replenished, it is in fact expected as levels tend to be erratic in the TESTING? transition phase from normal to high levels. Some women with low egg supply tend to ovulate early and present with high estrogen levels on day These tests, while helpful, are not absolute in predicting a woman’s 3 due to early development of the dominant follicle. This will “mask” the reproductive potential. Unfortunately, FSH levels do not rise until the egg true FSH level, but their ovarian reserve may resemble that of women supply has declined markedly therefore a “normal result” does not rule out
- 3. a loss of reproductive potential. Also, it is still possible for women with which would be more effective for appropriately selected patients under elevated FSH levels to conceive, although their probability of pregnancy 40, will be much less effective in patients over 40 years old. Overall, in is greatly reduced and their chance of miscarriage is higher. vitro fertilization remains the most effective therapy for women using their own eggs at any age. NONE of these fertility treatments can create new eggs once the original supply is depleted and none of these therapies HOW DOES OVARIAN RESERVE AFFECT MY TREATMENT can reverse the age-related decline in egg quality. DECISIONS? WHAT OPTIONS ARE THERE FOR WOMEN WITH LOW OVARIAN Chance of Pregnancy per Month With RESERVE? Different Therapies Many studies have been done to examine the chances of a woman successfully having a baby after a documented elevated FSH level. In 50 general, most studies have found that regardless of treatment, pregnancy 40 rates remain very low (i.e. less than 2%). 30 CC/IUI Fortunately, women with diminished ovarian reserve still have good % P re g n a n t 20 options for becoming parents, which include oocyte donation and Gnd/IUI adoption. For example, the graph below shows the per cycle live birth rate 10 IVF for IVF cycle performed in the USA in 2004. Using egg donation, a young 0 <35 35-38 38-40 40-43 43+ woman with normal ovarian reserve donates her eggs another woman (typically older). In this scenario, live birth rates are excellent and this A g e (yrs ) method allows the patient the opportunity to become pregnant regardless of her ovarian function. Figure 3. The chance of pregnancy declines with age, regardless of choice of therapy. In vitro fertilization is the most effective therapy for women using their own eggs at any age. Key: CC/IUI=clomiphene citrate and intrauterine insemination; Gnd/IUI=Injectable gonadotropins and intrauterine insemination; IVF= in vitro fertilization (pregnancy per embryo transfer) There are a variety of treatments for infertility, but all of these options become less effective as age increases. This means that time is the most precious resource for an infertility patient. Surgical solutions can be appropriate for some patients, but we need to consider the recovery time as well as time allotted for attempts at conception afterward. Conservative hormonal therapies (such as clomiphene citrate or injectable gonadotropins combined with intrauterine insemination)
- 4. Graph data source: US Dept. Health and Human Services, Centers for Disease Control, 2004 Assisted Reproductive Technology Report (ART) http://www.cdc.gov/ART/ART2004/index.htm Summary • Aging, including reproductive aging is a normal part of life • Diminishing ovarian reserve is due to the irreplaceable loss of oocytes • The loss of eggs can be accelerated at any age by certain risk factors (smoking, endometriosis, radiation, etc) • For women, the decline in fertility starts in the early 30’s and accelerates after 35 • Day 3 FSH, CCCT and the BAFC are easy and simple ways estimate amount of “ovarian reserve” a patient may have left. • This data may be critical in deciding which treatment to pursue, and for how long. • Egg donation is a viable option for patients with poor ovarian reserve.