Human oocyte radiosensitivity.
In the past, radiographers could be confident, and their patients assured, that the benefits of examinations performed within the context of well-established radiation safety measures (ie, proper shielding, employment of the 10-day role and use of the as low as reasonably achievable [ALARA] concept) outweighed the risks. New research concerning the radiosensitivity of the human oocyte has provided another tool for radiologic technologists to reassure female patients. This article discusses studies of the long-term effects of therapeutic radiation doses, as well as current animal experimentation models, that support the following theories about cytogenic radiation damage:
* It is subject to a dose/response relationship.
* Doses received within the diagnostic radiology range are of minimal consequence with respect to a woman's ability to conceive.
* It is less likely to occur in the oocyte due to peculiarities in its life cycle.
It is the duty of radiologic technologists not only to understand this new evidence, but also to properly convey the information to their nongravid female patients.
Radiation has the potential to damage rapidly dividing cells. That is why it is a potent teratogen, why it is used to halt tumor growth and why it is implicated in the development of cancers such as leukemia and lymphoma. Bushong (2) states that observable human radiation injury results from molecular change. He notes that 3 major effects cause radiation damage to a macromolecule (such as DNA) in solution in vitro: main-chain scission, cross-linking and point lesions. Some of these effects may result in cell mutation.
If the radiation damage is sufficient to change or delete a purine or pyrimidine base, a point lesion may occur. Point lesions manifest themselves in 2 ways: substitutions and frame-shift mutations. Depending on whether the correct amino acid is still coded for, substitutions may or may not result in mutation. Frame-shift mutations, on the other hand, disrupt the genetic reading frame and result in extensive missense and nonsense mutations.
In simplest terms, radiation damage has 2 end results. Either the damage is repairable, or it is not. If the damage is irreparable, the cell dies or it mutates. "A mutation may disrupt either the normal replication of DNA or its role in synthesizing the messenger ribonucleic acid (mRNA) template that initiates protein synthesis." (See Fig. 1.) If the mutation affects the germ line (sex cells), it is termed a genetic mutation and may be passed on to progeny. A somatic mutation refers to a nongerm-cell mutation. This is a potentially neoplasm-inducing defect and is not passed on to offspring.
The Cell Life Cycle
Knowledge of the meiotic phase of the cell life cycle is important in understanding the radiosensitivity of the human oocyte. It is in this part of the cycle that female gametogenesis vastly differs from its male counterpart.
Germ cells undergo a special process known as meiosis. This is the means by which a human being produces haploid (containing only 23 chromosomes) sex cells, or gametes. It consists of 8 phases. (See Fig. 2.)
1. Prophase I--homologous chromosomes (each is composed of 2 chromatids) come together as pairs, a complex of 4 chromosomes known as a tetrad.
2. Metaphase I--tetrads line up along the equatorial plane.
3. Anaphase I--homologous pairs are pulled apart, yet sister chromatids remain attached (in contrast to mitosis).
4. Telophase I--each pole of the cell has a haploid set of chromosomes and cytokinesis occurs.
5. Prophase II--spindles form and chromosomes begin to move to equatorial plane.
6. Metaphase II--sister chromatids, joined by a centromere, align along the equatorial plane.
7. Anaphase II--sister chromatids are pulled apart to opposite poles of the cell.
8. Telophase II--nuclei form, membrane invaginates and cytokinesis occurs.
At 5 months gestation, a female fetus possesses approximately 6 to 7 million oogonia. Most of these primitive germ cells die by apoptosis. Those that survive begin meiosis toward the end of gestation. At this point, they are called primary oocytes. They are arrested at prophase I of their first meiotic division and are diploid. A newborn girl's ovaries contain about 2 million primary oocytes. By puberty, this number has been reduced to 400 000. Of these, only about 400 undergo ovulation.
Just before ovulation, a primary follicle containing a primary oocyte grows and eventually divides. This first meiotic division yields 2 cells, a secondary oocyte and a polar body. Because of an unequal division of cytoplasm, only the secondary oocyte is viable. It is arrested in development at metaphase II. If fertilized, the secondary oocyte undergoes a second division. This second division produces the haploid gamete that can join with the haploid sperm to form a diploid zygote. (3)
The oocyte life cycle has tremendous implications for both the radiologic technologist and patient. Because a woman's gametes are arrested for long periods of time at various points in their life cycle (in stark contrast to the male system in which replication is continuous), a woman's gametes are largely radioresistant for much of their life. To analyze why and at what point in the female cycle the oocytes are most vulnerable or resistant one must examine the function of the female reproductive system.
Female Reproductive Physiology
The female reproductive system is a dynamic, fascinating system that is regulated physiologically by a number of integrated hormones. (See Fig. 3.) The interplay of these hormones takes place during menstruation, a 28-day cycle that can be functionally divided into 2 distinct phases.
The Ovarian Phase
The first half of the menstrual cycle is the ovarian phase. During the first day of the cycle, a woman experiences the onset of the menses. This typically lasts 4 to 5 days. Stimulated by gonadotropin-releasing hormone (GnRH), concentrations of leuteninzing hormone (LH) and follicle-stimulating hormone (FSH) begin to increase somewhat. The increase in FSH accelerates the growth of 6 to 12 follicles. Usually only 1 follicle containing a primary, oocyte matures to release a secondary oocyte. The rest degenerate and become atretic.
At about day 12, there is a tenfold increase in the concentration of LH. On day 14, in response to the LH surge, the mature follicle (now termed a secondary oocyte) is released from the ovary and begins to descend down the fallopian tube. This is ovulation.
It is worth restating that up until the moments immediately preceding ovulation, all of a woman's oocytes are arrested at prophase I. At ovulation, usually only 1 primary oocyte divides to produce a secondary oocyte. This cell is arrested at metaphase II unless subsequently fertilized. In keeping with the theory that radiation damages rapidly dividing cells, the oocyte is only particularly vulnerable on the day of ovulation (usually day 14 of the cycle); it also is vulnerable if subsequently fertilized. Otherwise, it is dormant and largely radioresistant.
The Luteal Phase
After the ovary expels the secondary oocyte, a second phase of menstruation begins. This is termed the luteal phase because it is characterized by the presence of the corpus luteum. The corpus luteum develops in the spot vacated by the secondary oocyte. Lutein cells are formed by lipid inclusions and grow 2 to 3 times in diameter, taking on a yellowish appearance.
The corpus luteum peaks in size at about 1.5 cm in diameter, 7 to 8 days after ovulation. Its primary function is to secrete the ovarian hormones progesterone and estrogen. Progesterone negatively inhibits the hypothalamus and the estrogen negatively inhibits the anterior pituitary. Consequently, the levels of LH and FSH drop considerably. Estrogen plays a critical role in stimulating the buildup of the uterine wall while progesterone stops this buildup and readies the uterus for pregnancy. In the absence of fertilization, the corpus luteum degenerates, the uterine wall sloughs off in the menses and the whole cycle begins again. If fertilization does occur, the zygote implants and the developing embryo secretes human chorionic gonadotropin (hCG). This is the hormone detected in pregnancy tests.
Data concerning the harmful effects of radiation exposure are largely gleaned from nuclear disasters and animal model experiments. With respect to human oocyte radiosensitivity, much evidence also has been gathered from female patients who have received abdominal or pelvic radiation therapy. Radiation's cytogenic effects on women can manifest themselves in 2 ways: induction of premature menopause and the potential to pass on chromosomal damage to progeny.
With respect to premature menopause induction, radiation's effects appear to be dose dependent. At low doses (0.6 Gy delivered over the course of 2 weeks), ionizing radiation has been shown to actually increase fertility in women. Using this technique in 1958, Kaplan (4) induced 308 conceptions in 700 previously infertile women. However, according to Madsen, (5) doses in the range of 1.7 to 6.4 Gy are capable of causing temporary sterility; while permanent sterility, can occur following a single fraction of 3.2 to 10 Gy. In fact, Peck (6) showed doses between 5 and 10 Gy induce menopause in nearly all women older than 40. A controversy surrounding this issue is whether radiation induces the menopause or whether there are other causative factors. Patients who have received radiation therapy and who develop secondary amenorrhea often are assumed to have radiation-induced ovarian failure. However, Madsen (5) calls this into question and cites other possible causes of premature menopause including accelerated atresia of oocytes, abnormal gonadotropin function and circulating ovarian antibodies.
A definitive study by Wallace et al (7) sets the LD50 of the human oocyte at 4 Gy. This estimate is based on menopause induced in women receiving childhood radiation doses for intra-abdominal tumor. Because women have a fixed number of oocytes present at birth, any destruction to that pool (assuming subsequent normal follicular atresia) will accelerate the rate at which a woman approaches menopause. By combining a calculated radiation dosage with a mathematical model for oocyte decay, patients can be counseled and given information regarding their shortened reproductive window of opportunity. (8)
The second issue surrounding radiation damage to the human oocyte is the potential to pass on chromosomal damage to progeny. This appears to be less of a concern than the induction of premature menopause. The guinea pig has served as a useful model in studying the radiosensitivity of the human oocyte for 2 reasons. First, the guinea pig oocyte is diploid at birth. This means that, like humans, the guinea pig oocyte is arrested in development throughout much of its life. Second, it appears that human and guinea pig oocytes have approximately the same LD50, as estimated by Wallace (7) and Jacquet. (9)
In citing Caine and Lyon, Jacquet (9) states that the resting guinea pig oocyte is very radioresistant, with an LD50 of about 4 Gy. This estimate is based, in part, on the fact that guinea pig fertility was not greatly affected during a 2-year period following treatment with 4 Gy of radiation. In Jacquet's experiment, animals irradiated with 2 Gy actually produced more offspring than control animals; in addition, the offspring showed no significant difference in birth weight and no external malformations. (9)
Mature oocytes compose only a small fraction of the female germ cells in the ovary while immature oocytes (ie, those arrested at prophase I) represent 90% of total oocytes at any time. (10) In a subsequent experiment, Jacquet (11) tested guinea pig oocytes at the beginning of the estrous cycle (day 3 of a 17-day cycle) and in the middle (day 10) to analyze their radiosensitivity with respect to maturation. Effects were dose dependent. Those oocytes irradiated at the beginning of the cycle exhibited a low frequency of chromosomal aberration (3.8% of oocytes receiving a dose of 1 Gy were damaged, while 10.2% receiving a dose of 2 Gy were damaged). Oocytes irradiated in the middle of the cycle (1 week before ovulation) showed heavy chromosomal damage (40.9% of oocytes receiving a dose of 1 Gy were damaged, while 74.1% of those receiving a dose of 2 Gy were damaged). An interesting point, however, is that oocytes irradiated during the middle of the cycle were rapidly eliminated from the ovaries and did not ultimately undergo ovulation. (12)
Chromosomal radiation damage may not solely be a function of the dose to the oocyte, but it also may involve specific external factors (eg, repair enzymes) able to modify the level of chromosome damage. The success of the chromosomal repair mechanism is of primary importance when assessing the oocyte's likelihood to pass damage on to progeny. (12)
Current research has indicated that the human oocyte is radioresistant for a large portion of its life cycle. Although x-irradiation has the capacity to cause chromosomal damage to oocytes, it does not appear to subsequently affect a woman's ability to conceive. Chromosomal aberrations, if they do occur, do not appear likely to be passed on to progeny. The induction of premature menopause may be of concern, but this concern is associated more with radiation therapy than with diagnostic radiology. One must remember that doses used in the diagnostic radiology range do not approach those used in radiation therapy and animal experimental models. An average dose for an AP/lateral lumbar spine series, for example, is on the order of 0.001 Gy (assuming the 1 to 1 conversion of mrem to mrad and subsequent conversion to Gy). (13) This is well below the LD50 of 4 Gy established by experimentation.
Radiation protection is a science that has been studied for more than 100 years, yet it is continually developing. Recent evidence concerning x-ray-induced cytogenic effects in the human oocyte and studies of the long-term effects of intra-abdominal therapeutic radiation, have reassured radiation safety workers that doses administered within the diagnostic range are safe relative to risk. Because women are born with a finite number of oocytes, good radiation protection should always be employed. Exams should be ordered conscientiously and cumulative radiation doses should be considered.
More research is needed to assess the vulnerability of the oocyte at various stages of oogenesis. Although it is unethical to perform radiosensitivity experiments on humans, the guinea pig has served as a good model from which data may be extrapolated. In the meantime, new information on cellular resting phases and their impact on human oocyte radiosensitivity can add to the safety measures already employed by technologists. Such knowledge reinforces the fact that radiologic technology practice is founded on scientific principles. The confidence gained from that knowledge can be passed on to patients in the form of low-dose, high-quality examinations.
(1.) Sadler TW. Langman's Medical Embryology. 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000:124.
(2.) Bushong SC. Radiologic Science for Technologists. 7th ed. St. Louis, Mo: Mosby-Year Book Inc; 2001:470.
(3.) Fox SI. Human Physiology. 7th ed. New York, NY: McGraw-Hill Companies Inc; 2002:657-659.
(4.) Kaplan II. The treatment of female sterility with x-ray therapy directed to the pituitary and ovaries. Am J Obstet Gynecol. 1958;76:447-453.
(5.) Madsen BL, Guidice LG, Donaldson SS. Radiation-induced premature menopause: a misconception. Int J Radiat Oncol Biol Phys. 1995;32:1461-1464.
(6.) Peck WS, McGreer JT, Kretzschmar NR, et al. Castration of the female by irradiation. Radiology. 1940;34:176-183.
(7.) Wallace WH, Shalet SM, Hendry JH, et al. Ovarian failure following abdominal irradiation in childhood: the radiosensitivity of the human oocyte. Br J Radiol. 1989;62:995-998.
(8.) Wallace WH, Thomson AB, Kelsey TW. The radiosensitivity of the human oocyte. Hum Reprod. 2003;18:117-121.
(9.) Jacquet P, Vankerkom J, Lambiet-Collier M. The female guinea pig, a useful model for the genetic hazard of radiation in man: preliminary results on germ cell radiosensitivity in foetal, neonatal and adult animals. Int J Radiat Biol. 1994;65:357-367.
(10.) Jacquet P, de Saint-Georges L, Buset J, et al. Cytogenic effects of x-rays in the guinea pig female germ cells. I. The immature oocyte. Mutat Res. 1997;391:189-192.
(11.) Jacquet P, de Saint-Georges L, Buset J, et al. Cytogenic effects of x-rays in the guinea pig female germ cells. II. The maturing oocyte. Murat Res. 1997;391:193-199.
(12.) Jacquet P, Buset J, Vankerkom J, et al. Radiation-induced chromosome aberrations in guinea-pig growing oocytes and their relation to follicular atresia. Mutat Res. 2001;473:249-254.
(13.) Classic K. Medical and dental issues--diagnostic x-ray and CT. Available at: http://hps.org/publicinformation/ate/q1268.html. Accessed July 2, 2003.
Patrick J. Burke, B.A., R. T. (R), is a staff technologist at New England Baptist Hospital in Boston, Mass, where he has served as consultant radiographer to the Boston Celtics and the 2000 U.S. Olympic gymnastics team. He received his bachelor's degree at Boston College and his radiography training at Mount Auburn Hospital in Cambridge, Mass.
Reprint requests may be sent to the American Society of Radiologic Technologists, Communications Department, 15000 Central Ave. SE, Albuquerque, NM 87123-3917. [C] 2004 by the American Society of Radiologic Technologists.
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|Title Annotation:||Peer Review|
|Author:||Burke, Patrick J.|
|Date:||Jul 1, 2004|
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