Chapter 15 - Infertility (PDF)
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Central Mindanao University
2014
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This chapter discusses infertility, the difficulties some couples face conceiving or maintaining a pregnancy. It explores different approaches to diagnosing and treating infertility issues, including medical work-ups for both partners, and highlights common causes of male & female infertility. It also delves into assisted reproductive technologies like IVF and ethical considerations related to these procedures.
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C H A P T E R 15 Infertility INTRODUCTION be followed using the sympto-thermal method and/or...
C H A P T E R 15 Infertility INTRODUCTION be followed using the sympto-thermal method and/or hormone assay. If it is found that she is ovulating, pelvic Many couples routinely use contraception in an effort ultrasound, laparoscopy, or the administration of dyes to avoid unwanted pregnancies. In contrast, many other or gas can be used to check if her uterus or oviducts are couples want to have children but find it difficult to con- blocked. An endometrial biopsy can assess the condition ceive or to carry a pregnancy to term. According to the of her uterine lining, and her reproductive tract can be Centers for Disease Control and Prevention (CDC), more tested for infection. In the postcoital test (Huhner’s test), than 6 million women (1 in 10 women of childbearing a woman’s cervical mucus is checked for sperm num- age) in the United States suffer from infertility; other esti- ber and condition within 2 h of coitus. This test can be mates give figures of up to 15% of women. A couple is used to evaluate semen quality as well as the survival of considered infertile if they have participated in unpro- sperm in the woman’s mucus. There also are tests to see tected coitus for a year without becoming pregnant. if the woman is producing antibodies to her partner’s The problem is with the woman in approximately 35% sperm. of these couples, with the man in about 35%, and with For the man, semen can be collected and a sperm both partners in approximately 20%. In 10% of cases, the analysis performed. In 2009, the World Health Organi- cause is unknown. A couple can also be infertile because zation published reference guidelines of semen charac- of p regnancy wastage, or the inability to maintain a preg- teristics of fertile men. Information was gathered from nancy once established. 4500 men around the world whose partners had become Hope is present for infertile couples because the cause pregnant within 12 months of attempting to conceive. of infertility in 85–90% of cases can be diagnosed, and By comparing a man’s semen characteristics with these about 50–60% can be treated successfully. In those situ- guidelines, his probable fertility can be evaluated. If the ations in which treatment fails, a couple may want to man’s sperm count is in the fertile range (greater than consider adopting a child or seeking help in other ways. 15 million sperm/ml of semen, and at least 39 m illion We now look at some causes and treatments of infertility. sperm in a single ejaculation), the sperm will be exam- ined to determine whether motility and structure are normal. The semen will also be checked to see if it is ejac- SEEKING MEDICAL HELP FOR ulated in normal amounts (at least 1.5 ml). If the male’s INFERTILITY sperm count is low, levels of hormones (luteinizing hor- mone (LH); testosterone) will be assayed in his blood or When infertile couples seek medical help, the first urine, and the blood supply to his testes can be exam- step is to diagnose the cause of their problem by doing ined. Also, a sample of testicular tissue may be taken to an evaluation or “infertility work-up” on the woman, see if spermatogenesis is normal; this is called a testicular the man, or both partners. For both partners, a general biopsy. Finally, the condition of the sex accessory glands physical examination is performed, including medical and ducts can be assessed and immunological tests per- history of illnesses including sexually transmitted dis- formed to see if the man is producing antibodies to his eases, surgeries, medications, and sexual habits such as own sperm. frequency of intercourse. The woman is asked for a his- Infertile couples can suffer from psychological and tory of her menstrual cycle. Her cycle, if occurring, can emotional problems related to their condition. These Human Reproductive Biology, Fourth Edition. 283 Copyright © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/B978-0-12-382184-3.00015-5 284 15. INFERTILITY problems can be caused by feelings of inadequacy, loss, of 20 and 24 suffer from infertility; this increases to 5.5% and frustration over their situation. Therefore, it is often at ages 25–29, 9.4% at ages 30–34, and 19.7% at ages wise for infertile couples to seek counseling about their 35–39. Thus, the older a woman becomes, the more dif- problem. Organizations such as RESOLVE (the National ficult it is for her to become pregnant, even though she Infertility Association) and the American Fertility Asso- may become more equipped emotionally and finan- ciation can provide information and support to infertile cially to care for a child as she matures beyond her mid- couples. 20s. Usually, infertility is defined as inability to become pregnant after 1 year without the use of birth control (see Box 15.1), but many experts suggest that women FEMALE INFERTILITY over age 35 should consult a physician for infertility treatment if she has not conceived within 6 months. Age is an important factor in female infertility. Although men do not experience a dramatic decrease Women are most fertile in their early 20s. In the United in fertility similar to that experienced by women States, approximately 4.1% of women between the ages leading up to menopause (see Chapter 7), age-related BOX 15.1 SEASONAL CHANGES IN THE ABILITY TO CONCEIVE Most mammals have a limited season of fertility each born in the US from 1996 to 2002 demonstrated that chil- year. Even though humans are generally fertile through- dren conceived in late spring and summer had a signifi- out the year, there is a certain season when couples may cantly higher rate of birth defects than infants born at other have a harder time conceiving and carrying a pregnancy times of the year. These included genetic disorders such as to term. A seasonal cycle in fecundity (the ability to con- Down syndrome as well as developmental anomalies such ceive) exists in both hemispheres, and of course it is relat- as spina bifida and cleft lip. Being conceived during the ed to the seasonal cycles of birth mentioned in Chapter 11. low season of fecundity can lead to a slightly greater risk For example, births peak in the late summer and early fall of certain problems when the babies become adults. These in the United States. This means that the peak in fecundity include asthma, glaucoma, childhood diabetes, multiple is in late fall and early winter. However, the birth trough sclerosis, Parkinson’s disease, and alcoholism. In north- in the United States (spring) is preceded 9 months earlier ern Europe, one study found that people conceived in late by a time (summer) when it is less likely for a couple to summer could expect, at age 50, to live shorter lives (by conceive. The birth peaks and troughs in Europe are dif- almost half a year) than their counterparts conceived at ferent from those in the United States, but the same rules other times of the year. People conceived in the fecundity hold there as well as in the southern hemisphere, where trough and born in the spring also increase their chances the seasons are 180° out of phase with those in the north- as adults of developing schizophrenia, bipolar (manic- ern hemisphere. depressive) disorder, eating disorders, and seasonal affec- Research has shown that the low fecundity of a couple tive disorder. The extent to which these differences reflect around 9 months before the birth trough in the population seasonal differences in the quality of the gametes, in utero could be related to reduced ovum quality or poorer sperm conditions, neonatal experiences, or differences in the be- quality or quantity during the warm summer months, dif- haviors of reproducing adults, is yet to be understood. ferences in hypothalamic–pituitary–ovarian function and Thus, men and women in today’s industrialized world ovulation associated with changes in day length, lower re- may have subtle internal, biologically evolved mecha- ceptivity of the endometrium, or other seasonally fluctuat- nisms that say, “Don’t conceive now.” Although these ing factors. A moderate reduction in coitus frequency in the mechanisms probably evolved in our hunter-gatherer an- summer months, especially in warmer regions, contrib- cestors to prevent pregnancy or birth when food and water utes only partially to the lower conceptions at that time. It were not abundant, the ghost of their presence still haunts is as if there are inherent, subtle mechanisms that interfere us. However, births still occur, even though at a lower rate, with sperm or egg quantity or quality, embryo quality, or from pregnancies beginning in the season of low fecun- the ability of the embryo to implant in the uterine wall and dity. These effects of birth season are subtle. Children con- establish and maintain a pregnancy. ceived in the trough of the fecundity season (summer in The season of conception may have an influence on a the United States) have only a small increased risk of the child’s condition at birth as well as its long-term health aforementioned problems and the great majority of infants and longevity. A study evaluating all 30 million infants born in these months grow into healthy adults. (Continued) IV. FERTILITY AND ITS CONTROL Female Infertility 285 BOX 15.1 (cont’d) 10 9 Conceptions Percent per month Live births 8 Average 7 6 J F M A M J J A S O N D Month of occurrence Overall seasonal patterns for conceptions and live births in the United States 10 Live birth Induced abortion 9 Percent per month Spontaneous abortion 8 Nonspecified abortion 7 Ectopic pregnancy 6 Average J F M A M J J A S O N D Month of occurrence Overall seasonal patterns of pregnancy outcomes in the United States Total annual US conceptions and live births by month. (Top). Total annual US pregnancy outcomes by month. (Bottom). changes in sperm production and sperm delivery can ovulation. In this case, administration of GnRH stimula- also impair male fertility. tory agonists (Chapter 1) in small dosages has been effec- tive in inducing ovulation. A small pump can be placed under the skin, which slowly releases GnRH pulses into Failure to Ovulate the bloodstream. Failure to ovulate is the leading cause of infertility in Sometimes a woman’s pituitary gland is not capable females. Irregular or absent menstrual periods can be a of secreting enough LH and FSH even though adequate sign of ovulation problems. A woman may not ovulate levels of GnRH are present. In this case, one common because her hypothalamus or pituitary gland is not fully treatment is the drug clomiphene (Clomid), which can functional, such as resulting from the presence of a pitu- be administered orally. Clomiphene is an anti-estrogen itary tumor. Severe stress, excessive exercise, or extremes that inhibits the negative feedback action of estrogens of body fat can cause failure to ovulate (Chapter 3), or the on FSH and LH secretion. Thus, FSH and LH lev- hypothalamus may not be secreting enough gonadotro- els increase when clomiphene is given, and follicles pin-releasing hormone (GnRH) to stimulate an LH and develop sufficiently to be ovulated. Between 60% and follicle-stimulating hormone (FSH) surge that results in 80% of infertile women so treated will ovulate, and IV. FERTILITY AND ITS CONTROL 286 15. INFERTILITY about 50% will become pregnant. It is usually pre- In other women, failure to ovulate may not be caused scribed as a 5-day treatment during the follicular phase, by malfunction of the hypothalamus or pituitary, but starting a few days after the beginning of the menstrual instead the ovary may be incapable of responding to flow (if present). Because it is relatively inexpensive, an LH and FSH surge. This can be due to the pres- effective, and can be taken orally, clomiphene is often ence of endometriosis, ovarian cysts, tumors, or scars the first-order treatment for anovulation. One effect caused by ovarian infection. In these cases, ovarian sur- of clomiphene is that the chance of having twins is 5% gery may be needed to restore fertility. Some women, compared with 1% in untreated women. This is because however, have permanently malfunctioning ovaries. the increased gonadotropin levels can hyperstimulate The ovaries of women with Turner syndrome (XO), the ovary, causing ovulation of two eggs with resul- for example, lack follicles (see Chapter 5). Between 5% tant dizygotic (fraternal) twins. Other side effects can and 10% of adult women have symptoms of polycys- include hot flashes, mood swings, headaches, visual tic ovarian syndrome (PCOS); these symptoms include disturbances, and ovarian cysts. Although women with excess androgen secretion, menstrual disorders, a certain kinds of infertility may be at increased risk for tendency toward obesity and insulin resistance, and ovarian cancer, the use of clomiphene does not appear anovulation. Although not all women with PCOS have to affect this risk. difficulty in becoming pregnant, this syndrome is a Another treatment for a woman who is secret- leading cause of subfertility or infertility in women. For ing insufficient FSH and LH is the administration of some overweight women with PCOS, weight loss alone gonadotropins. FSH injections can be used to boost can restore fertility. Clomiphene or other fertility treat- the natural levels of this gonadotropin. More com- ments are also commonly prescribed. Finally, ovulation monly, human menopausal gonadotropin (hMG; e.g. can be suppressed in women who have extremely low Pergonal), which contains FSH and LH, followed by body weight, who are obese, or who exercise exces- human chorionic gonadotropin (hCG; Figure 15.1), is sively; fertility can also be impaired in women who prescribed. These gonadotropins are administered as intake excessive amounts of alcohol, nicotine, or illicit injections. This treatment causes ovulation in 50–70% drugs. In some cases, lifestyle changes to address these of cases, so it is highly effective. The incidence of twins, issues can restore fertility. however, is 15%; for triplets or more, the incidence is 5%. For these reasons, gonadotropin treatment is used Tubal Blockage only as a last resort unless, of course, twins or triplets are desired. Some women using hMG and other fertility In some infertile women, ovulation occurs but the drugs develop abdominal pain caused by enlargement sperm fail to reach the egg, or the fertilized egg cannot of the ovaries. This ovarian hyperstimulation syndrome reach the uterus because of a blockage in one or both can cause mild symptoms, but cases with severe pain, oviducts. Tubal blockage is the second leading cause of bloating, and shortness of breath require immediate infertility in females, occurring in 30–35% of infertile medical attention. women. Tubal blockage can be caused by a kink in the Another cause of infertility in relation to malfunction tube or by scarring as a result of past sexually transmit- of the pituitary gland is excess pituitary secretion of pro- ted disease infection (especially chlamydia) that caused lactin. Some infertile women have high prolactin levels pelvic inflammatory disease (see Chapter 17). Also, if a in their blood. The drug bromocriptine, which inhibits woman has suffered from endometriosis (see Chapter 2), prolactin secretion, restores fertility in many of these a piece of the uterine endometrium may have become women. displaced from the uterus and lodged in the oviduct. This can cause sterility because the uterine tissue grows and blocks the tubes. Endometriosis can also cause infertility hMG or GnRH stimulatory agonist Ovulation when the tissue does not block the tubes but is present outside the tubes or in the abdominal cavity, especially hCG around the ovaries. Tubal blockage sometimes can be repaired by intro- ducing a fluid or gas (CO2 or air) into the tubes. The tubes can be inspected by laparotomy or laparoscopy 1 3 5 7 9 11 13 15 and combined with the use of instruments to remove Day of menstrual cycle adhesions. Also, a small balloon can be inserted into the obstructed tube, and when it is expanded the tube is FIGURE 15.1 Treatment of an infertile woman with human meno- pausal gonadotropin (hMG) or a gonadotropin-releasing hormone unblocked. This is called transcervical balloon tuboplasty. (GnRH) stimulatory agonist followed by human chorionic gonadotro- If this fails to open the tubes, it may be possible to repair pin (hCG) to induce ovulation. The shaded area represents menses. them surgically. Women with fallopian tube blockages IV. FERTILITY AND ITS CONTROL Female Infertility 287 can use in vitro fertilization (IVF) to bypass the oviducts TABLE 15.1 Possible Causes and Treatments of Infertility in in an attempt to achieve pregnancy; IVF (see later) is Womena now more common than tubal surgery. Cause Possible treatment Maternal age Donor egg, own banked egg, or surrogate Absence of Implantation Excessive exercise Decrease exercise In some women, the preembryo may reach the uterus but implantation does not occur. Priming of the uterus Low body fat or obesity Gain or lose weight by estrogen and progesterone is needed for implanta- GnRH insufficiency GnRH stimulatory agonists tion to occur (see Chapter 10), and this priming may be Gonadotropin insufficiency Gonadotropins such as FSH, inadequate in some women. Some of these cases can be hMG, hCG; clomiphene treated by the administration of steroid hormones (estro- gens or progestins) to render the uterine endometrium Prolactin oversecretion Bromocriptine more receptive to the blastocyst. Other endocrine disorders Hormonal therapy; surgery Other cases of infertility may be due to damage to Ovarian disorders Microsurgery; donated egg; the endometrium. Perhaps fibroids or scars from pelvic (e.g. dysgenesis;b cysts; cancer) surrogate pregnancy infection are present (see Chapter 2) or a previous unsafe Tubal blockage IVF; GIFT; ZIFT; microsurgery; abortion (see Chapter 14) may have damaged the uterine (e.g. dysgenesis;b scarring) balloon tuboplasty lining. Uterine abnormalities Microsurgery; gestational carrier (e.g. dysgenesis;b abnormal endometrial growths) Reduced Sperm Transport or Antibodies to Sperm Endometriosis GnRH antagonist; danazol; microsurgery The female tract may not allow transport or sur- Cervical abnormalities Microsurgery; estrogen treatment; vival of the male’s sperm. The woman’s vagina, for (e.g. dysplasia; cancer; hostile gestational carrier example, may be overly acidic, which can be treated mucus) using alkaline douches. Alternatively, her cervical Pelvic inflammatory disease Antibiotics; safe sex mucus may be hostile to sperm movement, a condi- tion perhaps alleviated by estrogen administration. If Antisperm antibodies Immunosuppressant drugs; AID; the cervix has been damaged, as sometimes occurs as ICSI a result of infection, this damage may be corrected sur- Antibodies to own egg Immunosuppressant drugs; gically. In some cases, a woman produces antibodies surrogate pregnancy; donated egg to her husband’s sperm, and in this case the couple a See Figure 15.3 for other “high-tech” solutions. AID, artificial insemination using may choose to become pregnant using donor artificial donor sperm; FSH, follicle-stimulating hormone; GIFT, gamete intrafallopian transfer; insemination (see later). GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; hMG, human menopausal gonadotropin; ICSI, intracytoplasmic sperm injection; IVF, in vitro Table 15.1 summarizes the causes and possible treat- fertilization; ZIFT, zygote intrafallopian transfer. ments of female infertility. b Abnormal development. are lost after implantation but before the expected time Pregnancy Loss (Miscarriage) of the next menstrual flow (around days 8–14 postfer- About 10% of known pregnancies end in miscar- tilization). Prior to implantation (about days 1–7 after riage. However, these losses, which occur after a fertilization), loss of the conceptus is difficult to detect. woman recognizes that she is pregnant because of signs However, it is certain that some preembryos do not of pregnancy (see Chapter 10) or because of a positive successfully implant, and estimates of preimplantation pregnancy test or ultrasound, represent only a small loss are as high as 30%. Very early pregnancy losses are portion of pregnancy losses. It is estimated that 50–70% sometimes called “occult” because they occur before of all fertilized eggs do not complete development. Sev- a woman realizes that she is pregnant. Miscarriage eral studies of healthy young married women from a is the most common disorder of pregnancy. Unfortu- variety of study populations followed their attempts nately, some women are infertile because they experi- to conceive. Researchers were able to detect early preg- ence recurrent miscarriages (usually defined as three nancy losses using sensitive assays of hCG. This hor- or more miscarriages). Most early miscarriages occur mone, which is released by the conceptus a few days because of chromosomal abnormalities of the fetus, after implantation, can be measured in the urine or usually because of errors introduced during meiotic blood. The studies found that 20–30% of pregnancies disjunction in the oocyte or sperm. A woman who has IV. FERTILITY AND ITS CONTROL 288 15. INFERTILITY had repeated miscarriages may simply have the mis- MALE INFERTILITY fortune to have carried fetuses with unrelated chromo- somal anomalies. Women over age 35 have an increased Low Sperm Count risk of miscarriage, probably because mutations accu- mulate as the egg ages or the oocyte’s meiotic appara- A low sperm count is the leading cause of infertility tus becomes less accurate. However, some miscarriages in men. An infertile man may have a low sperm count do not have an apparent genetic cause. (oligospermia) or the absence of sperm (azoospermia) Recently, attention has focused on possible immu- in the semen because his hypothalamus or pituitary nological causes of miscarriage. Recall from Chapter gland is functioning below normal levels. Treatment 10 that the mother usually does not reject the fetus as with GnRH stimulatory agonists or gonadotropins foreign tissue because of several adaptations of the may restore fertility in these men. Also, giving the maternal immune system. It was suspected that cou- anti-estrogen clomiphene to infertile men can increase ples who shared certain major histocompatibility complex their GnRH secretion (by reducing the negative feed- (MHC) antigens were at higher risk for miscarriage, but back of estradiol on GnRH) and increase fertility. there is no clear evidence to support this idea. Current Some infertile men have high prolactin levels in their research is focused on one MHC gene (human leuko- blood, and treatment with bromocriptine can make cyte antigen [HLA]-G) that is expressed mostly in fetal them fertile. tissues of the placenta, the cytotrophoblast. Because it Sometimes the testes themselves are incapable of is found where maternal and fetal cells interact, this responding to gonadotropins. For example, there can antigen may play a role in the support of pregnancy. be structural abnormalities or permanent damage to the The presence of certain HLA-G variants in the man testes. When testes are damaged, the treatment may be and/or woman can increase a couple’s risk of having artificial insemination of the woman with donor sperm. a miscarriage. Some structural problems, however, can be corrected Other possible causes and treatments of pregnancy by testicular surgery. Permanent damage could occur loss are summarized in Table 15.2. because of exposure to radiation or chemotherapy from cancer treatment. Men at risk of infertility from these therapies might consider cryopreserving their sperm TABLE 15.2 Some Causes and Possible Treatments of Miscarriage before undergoing treatment. In the future, it may be possible to remove spermatogonial stem cells prior Cause Possible treatment to the cancer treatment; these can be kept alive in the Embryonic chromosomal Surrogate pregnancy; donated laboratory and reimplanted into the man at a later time, abnormalities (e.g. maternal egg; preimplantation genetic restoring his fertility. age; errors of fertilization) diagnosis A varicose vein in the scrotum (a condition called vari- Uterine developmental Microsurgery; gestational carrier cocele) can raise testis temperature and cause infertility. abnormalities (e.g. inherited; Men with retrograde ejaculation have low sperm counts diethylstilbestrol-induced) because semen flows into the bladder rather than into Uterine disorders (e.g. fibroids; Microsurgery; gestational carrier the urethra during ejaculation. This condition can arise polyps; hyperplasia; cancer) from previous surgery, diabetes, or certain medications. Uterine prolapse Surgery It can be treated surgically or reversed by stopping the medication. Orchitis, or inflammation of the testis, can Uterine infection or scarring Antibiotics; microsurgery; cause temporary or permanent infertility. It can result gestational carrier from infection associated with a sexually transmitted Cervical abnormalities Surgery; gestational carrier disease or other bacterial or viral (usually mumps) infec- (e.g. dysplasia; cancer) tion. Cryptorchid (undescended) testes often are unable Cervical incompetence Surgery, cerclage (stitch) to produce sperm. When only one testis is impaired, Low secretion of progesterone Administer progestins and/or however, usually the unaffected testis is sufficient to and/or estrogens estrogens maintain normal fertility. In about 8–13% of infertile men, the problem is caused Drugs (e.g. tobacco; alcohol; Stop using them some prescription drugs; some by the production of antibodies to their own sperm. This illegal drugs) occurs because some sperm inadvertently enter a man’s body outside the reproductive tract. Treatment with Teratogens (e.g. environmental Avoid pollutants) adrenal hormones has been shown to alleviate this prob- lem in some men. Finally, a small number of infertile Immunological rejection of Paternal leukocyte immunization; men have a low sperm count because they are missing embryo surrogate pregnancy part of the Y chromosome. IV. FERTILITY AND ITS CONTROL Assisted Reproductive Techniques 289 Sperm Transport TABLE 15.3 Possible Causes and Treatments of Infertility in Mena In some infertile men, the secondary accessory ducts Cause Possible treatment or glands are not functioning properly. The vasa defer- entia, for example, can be occluded by an enlarged tes- Recreational drugs (e.g. cocaine; Stop using them ticular vein pressing on it (varicocele). The vasa can also tobacco; marijuana; alcohol) be blocked by scar tissue caused by sexually transmit- Pollutants (e.g. endocrine Avoid ted infection (see Chapter 17). Many of these cases can disrupting contaminants; carbon be corrected with surgery. Finally, a sex accessory gland monoxide; lead) may be malfunctioning or inactive. If the glands are sim- Anabolic steroids Stop using them ply underdeveloped, this condition can be treated by the GnRH insufficiency GnRH stimulatory agonists; administration of an androgen. Infection of the prostate clomiphene can lead to sterility in some men. Erectile dysfunction, the Gonadotropin insufficiency Gonadotropins such as hMG, inability to gain or maintain an erection long enough to FSH ejaculate, can also result in infertility. Some types of erec- tile dysfunction can be treated (see Chapter 8). Prolactin oversecretion Bromocriptine Other endocrine disorders Hormonal therapy; surgery Environmental Factors Testicular disorders (e.g. Surgery; AID dysgenesis; varicocele; cancer) Some men can be temporarily infertile because of envi- Orchitis Antibiotics, anti-inflammatories ronmental factors. Smoking, for example, can decrease sperm motility and increase the number of structurally High testicular temperature Loose underwear abnormal sperm in the ejaculate. Testosterone levels in Low testosterone secretion Androgen administration the blood are also lower in men who smoke. Accumula- Sex accessory duct or gland Surgery; androgens; IVF; AIH; tion of some environmental pollutants including heavy disorders (e.g. dysgenesis; AID metals, industrial chemicals, and endocrine disrupters scarring) such as xenoestrogens can also reduce sperm count (see Prostate disorders Surgery; hormone therapy; Chapter 4). Chronic use of some drugs, such as alcohol, chemotherapy; radiation marijuana, and anabolic steroids, can also reduce fertil- ity. Certain medical conditions, including obesity, diabe- Sexually transmitted diseases or Antibiotics; safe sex other infections tes, and thyroid disease, can reduce a man’s fertility, and a gradual decline in fertility often occurs after age 35. Low zinc or magnesium Administer Heat, such as from frequent hot baths or saunas or from Antibodies to one’s own sperm AI with ICSI; AID wearing tight clothing, can temporarily lower sperm Missing part of Y chromosome AID count. Table 15.3 summarizes some of the causes and pos- a AI, artificial insemination; AIH, artificial insemination with husband’s or partner’s sible treatments of infertility in men. sperm; AID, artificial insemination using donor sperm; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization. ASSISTED REPRODUCTIVE TECHNIQUES insemination (AI). The sperm can come from a “donor” man who is not the woman’s husband or partner (arti- For couples whose infertility cannot be reversed by ficial insemination donor, AID) or from the husband treating one or both partners with medication, surgery, (artificial insemination husband, AIH). In both cases, the or other means, several advanced procedures or assisted man deposits semen into a vial by masturbating or into reproductive techniques (ARTs) are available to bring a specially designed condom during intercourse. Several together the egg and sperm. These include methods to ejaculations, which are collected and frozen, are usually retrieve and store gametes, control and monitor the pro- required to pool enough sperm to be effective. If a man’s cess of fertilization using the couple’s gametes or those sperm count is very low, sperm can be retrieved directly donated from others, and test an early embryo for the from the testes by testicular biopsy. A sperm sample can presence of genetic abnormalities. also be taken from the epididymis using a tiny syringe or by aspirating epididymal fluid using microsurgery under a microscope. Gamete Storage and Artificial Insemination If the quantity of motile sperm is sufficient, the pooled When sperm are introduced into a woman’s reproduc- sperm sample is “washed” (processed to concentrate tive tract by means other than coitus, it is called artificial motile sperm in a small amount of fluid) and then loaded IV. FERTILITY AND ITS CONTROL 290 15. INFERTILITY into a thin, flexible catheter and delivered into the in California using sperm donated by Nobel Prize win- woman’s uterus. This usually involves only slight dis- ners. What happens when sperm from a different donor, comfort. The timing is critical; sperm should be intro- including donors of a different race, are used by mis- duced into the uterus within a few hours of ovulation take? This situation has already occurred. (intrauterine insemination, IUI). Fertility drugs can In 1977, the first scientific report appeared showing be used to induce ovulation of several oocytes, thus that ovulated ova (oocytes) in the laboratory mouse improving the chances for fertilization. could be collected from the oviduct and stored at −196 °C If the male partner cannot produce sperm of suf- for 6 years. The eggs were then thawed, fertilized in a ficient quantity or quality or if a single woman wishes dish, implanted into the uterus of a female mouse, and to become pregnant without a partner, donor sperm developed into normal mouse pups. This is now possi- from a “sperm bank” can be used. Donors are classi- ble with human ova as well, and many babies have been fied, anonymously, by their physical and even personal- born using frozen eggs. “Ovum banks,” however, are not ity characteristics, and some sperm banks screen semen likely to become as common as sperm banks because egg for hereditary diseases and chromosomal abnormalities. retrieval is usually much more expensive and difficult Transmission of the human immunodeficiency virus than sperm collection. (HIV) from the use of donor artificial insemination is possible, and for this reason sperm banks are required In Vitro Fertilization to test semen samples for the presence of HIV antibod- ies. Sperm can be frozen at −196 °C (−321 °F) for up to On July 25, 1978, a 5 lb, 12 oz baby girl named Louise 10 years. Sperm banks across the United States, run by Joy Brown was born to Mr and Mrs Gilbert J. Brown hospitals or private businesses, store frozen sperm. Arti- of Bristol, England. Louise, a perfectly normal little ficial insemination can be useful for couples with certain girl, was the world’s first “test-tube baby.” That is, her causes of infertility, such as when the male partner has a father’s sperm fertilized her mother’s ovum in a dish, low sperm count or if the female has cervical irregulari- and the early embryo resulting from this in vitro fertiliza- ties that prevent movement of the sperm into the uterus. tion (IVF; in vitro is Latin for “in glass”) was then put Semen can be used from the husband or a donor male. back into Mrs Brown’s uterus to develop and be born. Sperm storage can also be useful for a man who is going Thus, Louise was conceived in a dish in the laboratory. to have a vasectomy, just in case he may later want to This remarkable achievement was the culmination of a father a child. Artificial insemination is a less costly fer- long history of research into mammalian reproduction. tility treatment than methods that rely on egg retrieval The first fertilization of a human egg in vitro was accom- (see later). However, the success rate of AI averages only plished by J. Rock and M. Menkin in 1944. Drs P. C. 10–20% per cycle, and some couples must repeat the Steptoe and R. G. Edwards of England then refined the procedure multiple times to achieve pregnancy. It is less technique and eventually determined how to implant successful in couples with a lengthy period of infertil- the embryo into the mother’s uterus. This procedure is ity, when the female partner is older or has a history of used as a treatment for infertile couples with conditions pelvic inflammatory disease or endometriosis, or when such as a fallopian tube blockage or very low sperm the male partner has very low sperm count or a high count. Following is a brief description of the steps of the percentage of abnormal sperm. IVF procedure. There are interesting ethical and legal considerations about the use of donor sperm. There are no US federal Ovarian Stimulation and Egg Retrieval regulations for AI, and individual states vary in their First, “fertility drugs” (usually FSH analogs) are legal attention to this matter. Questions can arise, such administered to cause several large follicles to mature as: Who is the legal father of a child born using semen in a woman’s ovary. GnRH agonists or antagonists may from a man other than the husband? If a couple having be used additionally to prevent premature ovulation. a child by this method is divorced, is the ex-husband Growth of the follicles over the next 8–14 days is moni- responsible for child support? If a child conceived in this tored using ultrasound. Circulating hormone levels are manner has a birth defect, can the physician be charged also checked. During follicular growth, estrogen levels with malpractice? What are the inheritance rights of a should rise but progesterone levels should remain low. child conceived by sperm from a man other than its legal When several large follicles have grown, an injection of father? When multiple women conceive using a single hCG is usually given. This mimics LH and causes the donor’s sperm, what are the implications if the result- eggs to mature and also triggers ovulation. Before ovu- ing half-siblings meet later in life? Should semen be lation occurs, however, oocytes (ova) are removed from used for selective breeding for certain inherited traits, the large follicles in the ovary. In most cases, several and what are the moral implications? An example of (up to 12) ova are removed to ensure a sufficient num- such an attempt at selective breeding is a sperm bank ber of embryos to transplant. The operation is done by IV. FERTILITY AND ITS CONTROL Assisted Reproductive Techniques 291 inserting a long needle through the vaginal wall toward prior to implantation. In an effort to rejuvenate aging the surface of the ovary. Guided by ultrasound, the eggs, cytoplasm from a young donor egg is injected into needle contacts each enlarged follicle and the ovum is the egg of an older ART patient, a process called cyto- removed by suction. It is also possible to monitor and plasmic transfer. This highly experimental treatment has retrieve oocytes that develop naturally without the use had some limited success, which may be explained by of fertility drugs, but this method is infrequently used. the introduction of healthy mitochondria into the oxi- datively weakened eggs. Embryos resulting from this Fertilization and Embryo Transfer treatment, however, would have mitochondria from Before the ova are retrieved, the male partner pro- two different females instead of inheriting mitochondria duces (by masturbation) fresh sperm, which are placed from the mother only, as in normal development. The in a petri dish. The dish contains a fluid that nourishes long-term consequences of this are unknown. and capacitates the sperm. The ova are then added to Sperm can be removed directly from a man’s testes the dish with the sperm, and fertilization, as evidenced and injected into an ovum in vitro and then transferred by the presence of two pronuclei, usually occurs within into the uterus. Even immature spermatogenic cells 12–14 h. Here it is possible to use a donor ovum instead (spermatids, spermatocytes) have been used for intra- of the ART patient’s own ovum, donor sperm, or even a cytoplasmic sperm transfer. A few births have occurred donor ovum and donor sperm. after removing an immature oocyte from a woman’s After fertilization, the embryos are transferred to a ovary, maturing it in a dish containing gonadotropins, new culture dish for incubation, and their development fertilizing the mature egg with sperm, and then implant- is monitored closely. It takes 2 days for an embryo to ing the embryo in the uterus. This method would allow a reach the two- to four-cell stage; in 3 days, the embryo has woman whose ovaries fail to grow large follicles to have about 32 cells. By the fifth day, the embryo has become a child. Additionally, frozen embryos have been used a blastocyst. Embryos that exhibit normal development successfully. In fact, there were over half a million frozen are transferred into the uterus usually between 3 and embryos in US fertility clinics in the year 2012. The suc- 5 days after fertilization. The preembryos are placed into cess rate with frozen embryos, however, is lower than a tiny tube, which is inserted into the woman’s uterus with fresh embryos. through her cervix. Finally, the embryos are released Currently, nearly 150,000 IVF cycles per year are per- into the uterus, and implantation can now occur. It takes formed in the United States. The CDC reported that the about 2 weeks to know if one or more embryos have woman’s own fresh eggs were used in 69% of cycles in implanted. Most ART clinics transfer only two or three 2010 and her frozen eggs were used in 19%. Donor eggs embryos in one in vitro fertilization cycle. The remaining (fresh or frozen) were used in 12% of ART cycles. eggs or embryos can be frozen for possible use in future IVF cycles. Risks of IVF Of 79 women first accepted for this procedure in One of the major risk factors associated with IVF is England in the late 1970s, 68 underwent laparoscopy, the the high risk of failure. In 2010, the most recent year method formerly used to retrieve eggs. Of the 68 women, for which data are available at the time of writing, the 44 produced ova in the correct state, and 32 of the ova success rate of cycles in which women used their own, were fertilized and developed into 8- to 16-cell embryos, non-frozen eggs was 30.2%. The success rate is better for which were then transplanted back into the mothers. women under age 35 (41%), and it decreases with every Only 4 of the 32 women became pregnant, meaning that additional year (32% from age 35–37 years, 22% from age only four women had successful embryonic implanta- 38–40 years, 12% from age 41–42 years, 5% from age 43– tion; only two of these pregnancies produced normal 44 years, and 1% for women older than 44 years). Using a infants at term. The other two fetuses were aborted early woman’s own previously frozen eggs, the success rate is in pregnancy because they were found to exhibit chro- 33% per cycle; using donor frozen eggs or embryos, it is mosomal abnormalities. 35%. Consider a 36-year-old woman (the average age for With recent refinements of the external fertilization an IVF patient) who undergoes an IVF cycle and freezes technique, IVF and other assisted reproduction meth- extra eggs or embryos from that cycle. If she does not ods (see later) have been more successful. One of these become pregnant on the first try, she is likely to use her improvements is intracytoplasmic sperm injection (ICSI), frozen eggs for a subsequent attempt. This is less expen- in which a single sperm is injected directly through the sive and invasive than a full IVF cycle because she does zona pellucida and into the ovum. Currently, 75% of not have to undergo the ovarian stimulation and egg the ART cycles in the United States use ICSI. Another retrieval steps. However, each succeeding IVF cycle has method is assisted hatching or zona drilling, in which part a lower probability of success because of the greater fail- of the zona pellucida is removed from the preembryo’s ure rate with frozen eggs and also because she is getting surface. This may facilitate hatching of the preembryo older. In 2010, 45% of women having an IVF procedure IV. FERTILITY AND ITS CONTROL 292 15. INFERTILITY 100% States, two embryos are transferred in over half of the 100 89.5% IVF cycles using a woman’s own non-frozen eggs, but 90 in 10% of cycles four or more embryos are transferred. 81.9% 80 There are no federal laws or agencies in the United States 70 that regulate ART procedures used in infertility clinics, Cycles started (%) although some states have regulations. The 1992 Fertil- 60 ity Clinic Success Rate and Certification Act requires all 50 US clinics performing ART to report annual data on IVF, 40 36.9% gamete intrafallopian transfer, and zygote intrafallopian 30.2% transfer procedures to the CDC. 30 23.5% Although there is no clear evidence overall of an 20 increase in congenital defects in babies conceived 10 through IVF, some studies have reported a higher risk. 0 For example, a recent review found a 67% increased risk of congenital anomalies in infants conceived through Cycles started Retrievals Transfers Pregnancies Live births Singletons IVF. This study also reported a higher incidence of pre- term birth, low birthweight, and perinatal mortality associated with IVF. There is a small increased rate of Stage reached genetic abnormalities in infants conceived using ICSI. This technique is often used when the male partner’s FIGURE 15.2 Outcome of in vitro fertilization (IVF) cycles in the sperm count is very low or the sperm lack normal motil- United States using fresh nondonor eggs. Numbers are percentages of cycles started that reached each stage. 2002 data from the Centers for ity, but it is also routinely used in most IVF procedures. Disease Control and Prevention. Defective sperm are often caused by genetic mistakes, and men using ICSI could pass these genetic errors and their fertility effects to their sons. Pregnancies using IVF had attempted one or more previous cycles, and 25% have an increased rate of miscarriage. Whether the high had undergone two or more previous attempts. Despite miscarriage rate is an effect of the IVF treatment itself modest gains in IVF success rates since the CDC began or a reflection of fertility problems or age of the women collecting data in 1995, failure can occur at each step of seeking IVF is not known. the IVF cycle (Figure 15.2). About 30% of women undergoing ovarian stimulation The inability of the preembryo to successfully implant with fertility drugs will develop some form of ovarian is the major reason that IVF cycles fail. In an effort to hyperstimulation. The ovaries swell, and fluid accumu- increase the chance of pregnancy, IVF clinics typically lates in the abdomen. Symptoms include abdominal transfer multiple embryos into the uterus. However, pain, bloating, intestinal disorders, and nausea. Most this practice increases the risk of multiple births. Cur- cases are mild and can be treated with rest and non- rently, 30% of births resulting from in vitro fertilization prescription painkillers; rarely, medical intervention is using a woman’s own, non-frozen eggs are multiples required. (twins or more). Using donor eggs, this rises to 39%. This compares with a multiple-infant birth rate of only Preimplantation Genetic Diagnosis about 3% in the general US population. Although a pre- viously infertile couple may be overjoyed by the pros- Remarkably, it is possible to remove a single cell from pect of twins, multiple births can pose greater potential an early (approximately 8-cell) embryo without jeopar- problems for mother and infants alike. Women carrying dizing the future development of the embryo. This deli- multiple fetuses have a greater probability of requiring a cate manipulation is called an embryo biopsy. The ability cesarean delivery. Infants born from multiple gestations of an embryo to regulate its development and compen- have a higher risk of prematurity, low birth rate, devel- sate for the loss of one cell makes it possible for scientists opmental delays, disabilities, and infant death. to remove a cell to examine the genetic make-up of an The medical, emotional, and societal costs of these embryo. Thus, embryos formed by IVF can be screened complications can be very high. Although the rate of for possible inherited disorders. For example, if a woman multiple births from ART has decreased slightly in and her partner each carry a recessive mutation for a recent years, complications resulting from multiple-fetus genetic disease, their child has a 25% chance of inherit- pregnancies remain a serious risk for families undergo- ing both mutations and having the disease. Couples can ing IVF. National guidelines in the United Kingdom now use IVF with preimplantation genetic diagnosis (PGD) stipulate that no more than two embryos be transferred to eliminate the risk of passing a serious or fatal famil- per cycle except in unusual circumstances. In the United ial disease to their child. Only those embryos found to IV. FERTILITY AND ITS CONTROL Assisted Reproductive Techniques 293 be free of genetic errors would be transferred into the produced from a donor egg will be genetically unrelated woman’s uterus. to the mother (unless the donor is a relative). There are now thousands of children who were geneti- Scientists are now refining techniques that allow a cally screened as embryos. The procedure may have pre- woman to be her own egg donor. Women undergoing vented devastating illness and suffering of children born chemotherapy and radiation for cancer treatment can with fatal genetic diseases. However, the potential to use suffer damage to their ovaries, resulting in infertility. In PGD to screen for other nonlife-threatening conditions 1997, when a Belgian woman faced chemotherapy for has raised considerable controversy. For example, PGD Hodgkin’s lymphoma, her doctor made a radical sug- has been used to select the sex of a baby, even by fertile gestion. Why not preserve a piece of her healthy ovary parents who used IVF for that purpose only. Several cou- before undergoing the destructive treatment? A section ples who already have a child with an inherited blood of her ovary was removed and frozen. Five years after disease have used this method to “design” a baby who the end of her chemotherapy, the piece of tissue was can be a stem cell donor for their sick child. Embryos implanted under her ovary; she conceived less than a obtained by IVF were tested genetically for the inherited year later and gave birth to a healthy baby girl in 2004. disease, as well as for immunological compatibility with Although there is a slight possibility that the egg grew their previous child. Immediately after birth, the new- from her damaged ovary, this transplant procedure may born’s umbilical cord blood cells were transplanted into provide hope for fertility renewal of patients with can- the affected sibling. Such preimplantation genetic test- cer and could also potentially prolong fertility in older ing that has no direct value to the newborn carries seri- women. Using ovarian stimulation and egg retrieval as ous ethical concerns. Should parents be able to select for in IVF, it is also possible for a young woman to “bank” other in heritable characteristics of their offspring, such eggs that will be cryopreserved (frozen) until she is as height and eye color? With a cost of over $20,000 for ready to become a biological mother later in life (see also each IVF/PGD cycle, will only the wealthy be able to Chapter 7). have “designer babies?” Gamete or Zygote Intrafallopian Transfer Egg Donation Gamete intrafallopian transfer (GIFT) is used for infer- If a woman’s ovaries are incapable of producing large, tile women who are ovulating but have blocked ovi- mature follicles or if she has a genetic disorder that she ducts (fallopian tubes) or for infertile couples who, for does not wish to pass on to her offspring, she could use religious reasons, wish to avoid fertilization outside the eggs produced by another woman (an egg donor). the human body. Mature ova are removed from large This could be a friend or family member or an anony- follicles in the infertile woman’s ovary, as in the IVF mous donor. Egg donation is more complicated and method. Then the ova are inserted by laparoscopy into expensive than sperm donation because the donor must one of the woman’s oviducts below the point of block- undergo ovarian stimulation with fertility drugs and age, and the sperm sample is also placed into the ovi- egg retrieval, as described previously. If fresh eggs are duct with the ova. Fertilization and implantation then to be used, the infertile woman must also be treated with can occur; steroid hormones (estradiol, progesterone) hormones so that her cycle is synchronized with that of may be administered to assist implantation and pre- the egg donor. This prepares her uterus to receive the vent miscarriage. donor egg after it is fertilized. Eggs can also be frozen, In a variation of this method, ova are removed and either before or after being fertilized, but the success fertilized with the male partner’s sperm in vitro. Then, rate is lower when using frozen eggs and embryos. zygotes (single diploid cells) are inserted into the ovi- Because the quality of a woman’s eggs diminishes with duct and allowed to travel down the oviduct before age, the likelihood of implantation decreases and the implantation. This is called zygote intrafallopian transfer chance of miscarriage increases. Thus, women in older (ZIFT). Success rates for ZIFT and GIFT are about the age groups (over age 39) are more likely to use donor same as for IVF. These techniques are not widely used eggs. In 2010 in the United States, one in eight IVF and account for a very small fraction of the ART cycles cycles used donor eggs or embryos. Many babies have performed in the United States. been born using this method, including some to post- menopausal grandmothers! The success rate using fresh Surrogate Mothers and Gestational Carriers donor eggs is around 50% regardless of the age of the infertile woman. Thus, using oocytes retrieved from A woman who is infertile because she cannot pro- an egg donor (who is usually in her 20s or 30s and not duce eggs or is unable to carry a pregnancy to term experiencing infertility issues) gives the greatest chance can ask another woman—a family member, friend, or of success among IVF procedures. Of course, an infant hired individual, usually through an agency—to carry IV. FERTILITY AND ITS CONTROL 294 15. INFERTILITY her child. A surrogate mother is artificially inseminated cases. Gay men who wish to father children can also with the sperm of the infertile woman’s partner or with use a surrogate mother. donor sperm. The surrogate then becomes pregnant, An infertile woman may be able to produce eggs but delivers the child, and gives the child to the original her uterus cannot carry a pregnancy, such as because couple. She is the biological mother of the child. Usu- of a hysterectomy. After ovarian stimulation, her ova ally, a contract is written between the couple and the can be retrieved and fertilized in vitro by her partner’s surrogate mother. Stipulations can include that the or donor sperm, and the resulting embryo(s) placed in surrogate be married with children of her own, have another woman’s uterus. The woman who “hires out” a physical and psychological examination, be willing her uterus is a gestational carrier. She is not related to the to surrender the child, and not use tobacco, alcohol, child genetically (unless she is a family member), but the and other drugs while she is pregnant. The cost varies legal, financial, and psychological issues are similar to widely but can total up to $100,000 or more. Legal ques- those surrounding surrogate pregnancies. tions about this procedure, including who is the mother Figure 15.3 summarizes some of the “high-tech” of the child and visiting rights of the surrogate mother, methods that can be used by infertile couples to have are complex and have resulted in several recent court children. In vitro fertilization Gamete intrafallopian transfer (GIFT) Wife’s Wife’s Wife’s uterus Wife’s uterus ovary ovary Husband’s AIH Ova Ova Sperm Preembryos External fertilization Zygote intrafallopian transfer Egg donation (ZIFT) Wife’s Wife’s Donor’s uterus Wife’s uterus ovary ovary Husband’s Husband’s Wife’s Sperm Ova ovary Sperm Ova Preembryos Zygotes External fertilization External fertilization Gestational carrier Surrogate pregnancy Ovulated Donor’s Donor’s Wife’s ovum uterus uterus Donor’s ovary ovary AIH Husband’s Ova Sperm Wife’s ovary Preembryos External fertilization FIGURE 15.3 Some of the advanced fertility treatments available for couples in which the woman has ovarian malfunctions, tubal blockage, or uterine problems. X, abnormal function; AIH, artificial insemination with the husband’s sperm. Donor sperm could be used for each procedure if the husband is infertile or if the woman is single. IV. FERTILITY AND ITS CONTROL Assisted Reproductive Techniques 295 Cloning and Ethical Issues in Assisted a patient suffering from a particular disease. These stem cells, which can potentially differentiate into any cell Reproduction type in the body, come from the inner cell mass of the The development of techniques used in assisted blastocyst (see Chapter. 10). Using techniques described reproductive technologies has made possible the manip- above, human cloned blastocysts can be produced and ulation of human eggs and embryos to achieve goals the stem cells extracted. The blastocyst is destroyed in scarcely imagined until recent years. This includes skills the process, raising moral concerns for some. The stem that enable scientists to use cloning techniques on human cells would then be grown in conditions that encourage cells. As discussed in Chapter 9, development of a differentiation into the desired cell type. In the future, human embryo begins after fertilization, when maternal therapeutic cloning may be used to produce replace- and paternal genes combine and begin to send instruc- ment cells to treat disorders such as cancer, Parkinson’s tions to activate the waiting egg cytoplasm. Thus, the disease, and heart disease, or even to grow replacement two components needed to initiate human development tissues or whole organs that would not pose a risk of are a diploid complement of chromosomes and the egg immunological rejection. cytoplasm equipped with specialized cellular machinery Ethical questions surround assisted reproductive to respond to developmental instructions from the DNA. technologies. Will they lead to selective breeding? Would Cytoplasm from an egg cell is essential to initiate embry- rich people pay poor people to carry their babies and, if onic development in animals, but the genetic comple- this happened, who would be the parents? Should the ment does not necessarily have to come from a sperm death of embryos in the laboratory be considered mur- and an egg. In the 1950s, Briggs and King developed a der? Recent cases have involved divorcing couples and method to remove the nucleus from (enucleate) a frog’s their battles over custody rights to their frozen embryos. egg and replace the egg nucleus with a diploid nucleus What is done with unwanted frozen embryos? Could harvested from one of the frog’s somatic cells (i.e. a non- some clinics sell or give away frozen embryos, without a germ cell). Subsequent experiments proved that nuclei couple’s permission? from highly differentiated cells such as those in the skin It is these kinds of questions that prompted the US of a frog’s foot can be “reprogrammed” by placing them government to ban research on external fertilization in in the egg cytoplasm, and that they can give rise to a 1975 while an Ethics Advisory Board of the Department wide variety of specialized cells. Tadpoles that develop of Health, Education and Welfare looked into the mat- from these recombined cells are genetically identical ter. In March 1979, this board sanctioned such research clones of the frog donating the nuclei. These nuclear in America with the ultimate goal of overcoming the transfer experiments first demonstrated the potential of problem of human infertility. In June 1979, the board animal cloning. approved research on external fertilization with cer- The first mammal to be cloned from adult DNA was a tain stipulations, some of which were as follows: (1) no sheep, Dolly, by Scottish scientists at the Roslin Institute. embryos fertilized in the laboratory can be maintained A single cell from the udder of a donor sheep was placed for over 14 days (the maximum time it takes for a normal adjacent to the enucleated egg cell from another sheep. embryo to implant fully in the uterus); (2) people donat- An electrical pulse caused the two cells to fuse, placing ing eggs or sperm must be notified about, and must the somatic cell nucleus inside the egg cell. After allowing approve of, the purposes and uses of their cells; (3) if the the resulting hybrid cell to divide and develop for a few embryo is to be implanted back into the uterus, the gam- days in vitro, the preembryo was placed into the uterus etes must be obtained from married couples; and (4) the of a third sheep who gave birth to the cloned lamb. Since public must be informed about incidences of abnormal the birth of Dolly in 1997, many other mammals, includ- offspring resulting from these procedures. ing goats, cows, mice, pigs, cats, and dogs, have been The US government then again banned federal sup- cloned through nuclear transfer technology. This process port of any research involving human preembryos or is expensive and inefficient (it took 276 tries to produce embryos in 1980. In 1993, however, the US Congress Dolly), and there are concerns about the overall health of lifted the 1980 ban on government funding for such cloned animals. Although techniques exist to potentially research. In 1994, two committees of the US National produce a human through cloning, the vast majority of Institutes of Health supported the funding of studies scientists and physicians express strong ethical opposi- of very early preembryos, including those developed tion to human reproductive cloning. However, many hope solely for research. Then, in late 1994, the US federal that therapeutic cloning will produce new tools to treat government banned the support of research on human some of the most common, serious human diseases. embryos created for such a purpose, but left open the Therapeutic cloning involves the synthesis of pre- possibility of supporting research on human embryos embryos for research and medicine. The objective is to discarded by fertility clinics. In 2001, President G. W. make embryonic stem cells that are a genetic match for Bush signed an executive order banning government IV. FERTILITY AND ITS CONTROL 296 15. INFERTILITY funding for research that would involve the destruc- ADOPTION tion of stored embryos. Federal funding for expanded research on embryonic stem cell lines was restored by Infertile couples, of course, have the option of adopt- President Barack Obama in 2009, but the ban on fund- ing a child. Adopted children usually are the product of ing used to destroy human embryos or create them for unwanted pregnancies or conditions in which the bio- research purposes was left in place. The recent produc- logical parents want their child but are unable to care for tion of induced pluripotent stem cells has opened the it. In traditional “closed” adoptions, the people who give possibility that nonembryonic stem cells may become up a child for adoption are not told who adopted their widely available for research. child. A person (single man or woman) or a couple who The achievement of Drs Steptoe and Edwards was desires to adopt should first contact an adoption agency. indeed a landmark of reproductive medicine, and their Then, the agency determines if the couple or person method has great promise in helping couples who oth- fits their standards. What are common standards? For erwise are infertile to have children. Millions of children many agencies, a couple must be infertile and not more around the world have been conceived by ART. However, than 40 years older than the child they adopt. Addition- the success rate remains low, the procedure is prohibi- ally, a home study is done to determine if the family tively expensive for many couples (see Box 15.2), and will provide adequate physical and emotional care for the risk of multiple births remains high. Improvements the adopted child. If the couple is approved, they may in the methods and technologies of ART are rapidly have to wait up to 5 years for a healthy American infant; bringing new hope for infertile couples. However, these this wait is often less for a foreign child or a “special- advances also bring with them additional medical and needs child” who may be older, non-Caucasian, or have ethical concerns from the public. physical, developmental, or psychological challenges. BOX 15.2 COSTS OF ASSISTED REPRODUCTIVE TECHNOLOGIES In 2010, the latest year for which data are available at to achieve pregnancy, adds considerably to the overall the time of writing, 147,260 women in the United States costs. What is the reason why fewer than half of preem- underwent assisted reproductive technology cycles (IVF, bryos transplanted into the uterus implant successfully? GIFT, ZIFT) and there were well over 200,000 cycles in A major factor is that many of the preembryos produced Europe. The numbers almost certainly are higher today. by IVF have chromosomal abnormalities such as aneu- A great majority of these procedures used IVF, about three ploidy. Even in natural fertilization, it is estimated that at quarters used ICSI, and many also used frozen sperm least 50% of embryos fail to implant or are lost to early and/or frozen preembryos. Nevertheless, despite manip- miscarriage, mostly because of chromosomal abnormali- ulating variables such as type of culture medium and age ties. Couples attempting to conceive naturally have only a of preembryos before implantation, whether frozen or not, 25% chance of becoming pregnant within a month of try- the overall success rate in the United States (having a live ing. Thus, the poor implantation results of IVF may simply birth from one attempt) was 30%. This means that a deter- be a reflection of the low natural reproductive capacity in mined couple will have to repeat the procedure an average humans. Tests for chromosomal abnormalities (preimplan- of 3–4 cycles until a successful pregnancy is established. tation genetic diagnosis) in 3-day-old preembryos may raise The cost of an IVF cycle averages $12,400 in the United the success rate of artificial implantation. Other reasons States, according to the American Society of Reproductive for loss of implanted embryos or fetuses (miscarriage) in- Medicine. (The fee is lower in Europe.) The average ex- clude uterine problems related to poor hormonal exposure penditure for IVF per live birth of a baby is about $60,000. and the basic difficulty of a human uterus to carry mul- Added to this is the cost of delivery and postnatal hospi- tiple pregnancies. tal care. Because pregnancy rates decline and miscarriage Another factor driving up the cost of IVF babies is the rates increase with age, IVF costs per live birth are three fact that 30% of IVF births in the United States are of mul- times higher for women older than 40 years than for those tiple infants. Until recently, three, four, or even more pre- 30 or younger. Insurance coverage of ART infertility treat- embryos were routinely implanted into the uterus in these ments varies in each state. procedures. Often, more than one will implant. This is the The high failure rate of each IVF cycle, as well as the reason that live births resulting from IVF and similar tech- consequent need to repeat the procedure in most cases niques are about 29% twin and 1.5% triplets or more. This IV. FERTILITY AND ITS CONTROL Adoption 297 BOX 15.2 (cont’d) can be compared to 1.4% for fraternal twins and 0.016% clinics to culture preembryos for 5–7 days and then im- for triplets born through natural means. The disturbingly plant blastocysts instead of earlier preembryos. However, large proportion of multiple gestations leads to more com- the rate of implantation of blastocysts is similar to that of plications during or after pregnancy. The average hospital earlier preembryos. Finally, there is a worldwide tendency cost for the birth of twins is four times higher than for a at present to reduce the number of embryos implanted to singleton birth; for triplets, it is 11 times higher. These ex- two. This is because using two preembryos has the same penses do not include the monetary and emotional costs success rate as using three or more, but has a decreased related to the long-term complications frequently associ- risk of multiple births. ated with multiple births. Each additional fetus shortens The monetary cost of having a baby through assisted a 40-week pregnancy by about 3.5 weeks, so many ba- reproductive technologies includes the costs of the IVF bies born by artificial reproductive technologies are born procedures, hospital delivery costs, and the possibility of prematurely and have low birth weight. Even singleton extensive additional expenditures for complications such newborns conceived through IVF have a greater chance of as multiple births, low birth weight, and prematurity. prematurity and low birth weight. Premature infants are Added to this can be significant emotional costs, psycho- more likely to suffer from mental retardation, learning dis- logical stress, and loss of work time during and after the abilities, lung disorders, and cerebral palsy. Furthermore, treatments. The psychological considerations can also be low-birthweight children are at greater risk for high blood significant for couples who attempt one or more IVF cycles pressure (hypertension), heart disease, and osteoporosis but ultimately fail to conceive. The high cost of ART inevi- when they become adults. tably leads to a disparity between those infertile couples Women carrying multiple fetuses can elect to selectively who can afford the treatments and those for whom it is an abort one or more of the fetuses to increase the likelihood economic impossibility. The inequality of access to these of a positive outcome of her pregnancy. Opting for multi- infertility treatments is an important ethical consideration fetal pregnancy reduction is certainly a difficult decision for regarding ART. Artificial reproductive technologies have, a woman highly motivated to become a mother. Further- since 1978, given infertile couples priceless happiness and more, the procedure carries the risk of miscarriage of all the ability to satisfy the powerful desire for procreation. of the fetuses. Sometimes the loss of a fetus in a multiple Nevertheless, anyone choosing these procedures should gestation occurs naturally. To minimize the possibility of be aware of the financial costs and potential risks to their multiple pregnancies, there is a recent tendency for IVF future babies. $14,000 40% $12,000 35% Cost of a single IVF cycle % live births/cycle 30% $10,000 % multiple births/delivery 25% $8,000 $12,513 20% $6,000 15% $8,500 $6,534 $4,000 $5,645 10% $5,549 37.7 $3,956 32.9 31.6 30.3 28.5 28.7 $2,000 26.3 24.2 5% 20.2 17.3