The term assisted reproductive technology (ART) covers a variety of medical approaches to infertility. These include in vitro fertilization (IVF), cryopreservation of gametes and embryos, embryo transfer (ET), gamete intrafallopian tube transfer (GIFT), zygote intrafallopian tube transfer (ZIFT), and intracytoplasmic sperm injection (ICSI). In this section attention will focus on the combination of in vitro fertilization and embryo transfer, IVF-ET, which allows thousands of births each year to otherwise infertile couples. The first successful IVF-ET started with the transfer of an 8-cell embryo produced by in vitro fertilization into the uterus of the mother and resulted in the birth of a healthy child in 1978. In the ensuing years, as every aspect of this process has been studied and refined, a greater understanding of the cellular processes involved in it has been achieved. Today in the United States approximately 1% of live births result from assisted reproductive technology.

The Center for Disease Control (CDC) has kept detailed statistics on many aspects of ART, examples of which are shown in Table 1 and Figure 1. Table 1 shows the outcome in 2010 of ART cycles started using fresh nondonor eggs or embryos. Many women undergo more than one cycle, so the 100% number does not reflect the number of patients undergoing the procedure. Many factors influence the prognosis for a success fuloutcome of IVF-ET. Foremost among these is ovum vitality, which declines with the age of the ovum donor. As shown in Figure 1, maternal age has little effect on outcome until early in the fourth decade. At age 33 both the number of pregnancies and the number of live births begin to fall and by age 40, the chances for IVF-ET success are reduced to 53% and 40%, respectively, of what they were at age 24 for pregnancy and live birth.

Table1. Outcomes of IVF Cycles, 2010^a

Fig1. Effect of age on IVF success rates. The percentages of IVF cycles resulting in pregnancy (blue), a live delivery (purple) which may be a multiple birth and a singleton live birth (green) are shown. The vertical lines show that the age-related decline in success begins at about 33 years of age (vertical line) and at age 40 the success rate by all three measures is 40–54% of what it was at age 30. From the 2010 CDC Assisted Reproductive Technology (ART) Report, http://www.cdc.gov/art/ART2010/ sect2_fig6-15.htm#14.

About half of the patients using IVF-ET have one of the following widely accepted indications for the procedure, for which the procedure has the most successful outcomes: poor Fallopian tube function, endometriosis, mild to moderate problem of the male partner, and unexplained infertility. Other reasons, for which the success of the treatment is more variable, include polycystic ovary syndrome (PCOS, serious problem of the male partner, and uterine dysfunction. Overall, however, in the absence of multiple causes, the single most important determinant of success is ovum age and ovarian reserve.

The many IVF-ET protocols used in the approximately 450 fertility clinics in the United States differ from one another in major ways and in more minor details. However, all protocols share common major steps. In the first phase of hormonal manipulation, controlled ovarian hyperstimulation, the aims are to suppress the natural hormonal cycle, overstimulate the ovary to induce the development of multiple mature follicles, and synchronize the final maturation of the follicles. In the second phase of hormonal treatment, the uterus is prepared for implantation and maintenance of the pregnancy for the first 8–10 weeks of gestation. Following retrieval of the ova prior to ovulation, in vitro fertilization of the ova, and cell division of the zygote, the embryo is transferred to the uterus and maintenance of the pregnancy for the first 8–10 weeks of gestation is provided.

The hormonal treatments given to meet these objectives are depicted in Figure2. Three typical protocols are shown and in practice there are many variations on these. To interrupt the natural hormonal cycle either a gonadotrophin agonist (Figure 2A and B) or antagonist (Figure 2C) is given. High continuous levels of GnRH inactivate the normal hypo thalamic-pituitary axis, which depends on the pulsatile secretion of the releasing hormone. The “long” version of this protocol, in which GnRH is given during the preceding cycle, also empties the pituitary of endogenous gonadotrophins so that the levels of these hormones can be controlled completely by their exogenous administration. Blocking GnRH secretion or action prevents premature ovulation, which would lead to the cancellation of the current cycle. In the “short” protocol (Figure 2B), the GnRH agonist is given on day 3 of the treatment cycle, so that endogenous gonadotroph ins are added to those being given exogenously. GnRH antagonists (Figure 2C) are given somewhat later in the follicular phase of the cycle to block the LH surge at the level of the GnRH receptor in the gonadotrophs and therefore prevent premature ovulation. Each approach has advantages and drawbacks and the choice among them depends on many factors such as the rea sons behind the infertility, co-existing conditions in the patient, cost, and individual clinic practices.

Fig2. Typical IVF protocols. Three typical IVF protocols are shown. Although all have the same goals, there are variations in how the hormonal milieu is manipulated. Across the bottom of each protocol is shown the cycle day. Hormonal treatments are indicated by the bars and the red arrow. Ova retrieval and embryo transfer are depicted by the downward and upward black arrows, respectively. (A) In this protocol (termed a GnRH agonist long protocol) a GnRH agonist (pink bar) is begun during the cycle prior to treatment and continued during the follicular phase of the treatment cycle to suppress the natural hormonal cycle. Gonadotrophins (blue bar) are added at the beginning of the treatment cycle to stimulate the growth of several follicles to maturity. Release of the ova is stimulated by a single large dose of hCG (red arrow) and eggs are retrieved 36 hours later (↓). Embryo transfer takes place three (8 cells) to six (blastocyst) days later (↑). Luteal support (green bar) refers to the administration of progesterone to support the growth and maintenance of the endometrium. (B) This protocol (termed the GnRH agonist short protocol) differs from (A) in that the GnRH agonist is started 3 days into the treatment cycle. (C). In this protocol, a GnRH antagonist (tan bar), rather than an agonist, is used to block the natural hormonal cycling. The structures of GnRH agonists and antagonists are shown in Figure3. Gonadotrophins used are recombinant human FSH (rhFSH) or FSH purified from urine or human pituitary glands and/or hMG (human menopausal gonadotrophin), a combination of LH and FSH isolated from the urine of postmenopausal women.

The structures of agonists and antagonists of GnRH are shown in Figure 3. For the agonists, substitution of a D-amino acid at position 6 increases the half life of the peptide and derivatization at the C-terminal increases biological activity by one or two orders of magnitude. GnRH antagonists have at least five amino acid substitutions including three at the N-terminus where the GnRH receptor activation function lies. As with the length of treatment, the choice between GnRH analogs depends on a number of considerations including speed of reversibility, cost, and possible side effects.

Fig3. GnRH Agonists and antagonists. The amino acid sequence of the decapeptide GnRH is shown along with two agonists and two antagonists which are used in IVF treatment cycles. D, dextro; DCit, D-citrulline; DhArg, D-homoarginine; D-Nal, D-naphthylalanine; DPal, D-pyridylalanine; hArg-homoarginine; pGlu, pyroglutamate.

Supraphysiological levels of gonadotrophins are given during the follicular phase of the treatment cycle to override the normal hormonal interactions limiting ovulation to a single ovum. Ultrasound monitoring, measurement of blood hormone levels, and individualized dosing help minimize untimely harvesting of pre- or postmature ova. Levels of both LH and FSH rise in postmenopausal women as estrogen levels fall and cease to inhibit the pituitary output of these hormones. Human menopause gonadotrophins (hMG) refers to the mixture of the two gonadotrophins purified from the urine of postmenopausal women and is a common source of the hormones for IVF treatment. Each preparation is standardized to an equal amount (biological activity) of each gonadotrophin, with addition of hCG to raise LH activity if necessary. Thus, the actual amount of gonadotrophin given is standardized across protocols and patients. In other protocols, FSH alone is used. It is either highly purified from urine (uFSH) or produced by recombinant technology (rFSH). Patient history and dosing convenience are among the considerations used to determine the gonadotrophin regimen to be used.

Towards the end of the follicular phase of the treatment cycle, when tests have shown a desirable number and maturity of ova, a bolus of hCG is given to synchronize the follicles and mimic the LH surge prior to harvest. The ova are collected by aspiration from the ovary, incubated with sperm and the fertilized eggs allowed to undergo division to either the 8-cell stage or to the blastocyst stage. If necessary, the embryos undergo cryopreservation until the time (normally 3–5 days following retrieval) for transfer to the uterus. Beginning at the time of egg retrieval through the next 8 to 10 weeks, progesterone is given, at first to prepare the uterus for implantation, and then to maintain the pregnancy as the corpus luteum stimulated by hCG would have done in an unassisted pregnancy.

This discussion has been based on procedures when nondonor ova are being used for ART. In those cases in which a woman is unable to produce her own eggs and must rely on those of a donor, hormonal preparation of both the donor and recipient is required so that there are sufficient eggs from the donor and a prepared uterus in the recipient. Other variations include cryopreservation of unused embryos for later use; embryos produced from both donor eggs and donor sperm and therefore genetically unrelated to either of the prospective parents; and implantation of an in vitro generated embryo into the uterus of a surrogate for gestation in cases where the woman is unable to carry a pregnancy to term.

اخر الاخبار

اخبار العتبة العباسية المقدسة

مجموعة العميد التربوية تعقد اجتماعًا لمناقشة الاستعدادات الخاصة بالموسم التدريبي الصيفي

قسم الإعلام ينظم ورشة تدريبية حول تطبيق (إعلامي) لعدد من منتسبي قسم حفظ النظام

قسم الشؤون الخدمية ينفذ حملة لتنظيف الشوارع المحيطة بصحن مرقد أبي الفضل العباس (عليه السلام)

وفد العتبة العباسية المقدسة يزور شعبة الإعداد البدني للاطّلاع على برنامج تأهيل المنتسبين الجدد

المزيد

الآخبار الصحية

ماذا يحدث إذا تناولنا الطعام مرة واحدة فقط في اليوم

اكتشاف عوامل خطر غير متوقعة لمرض الكبد الدهني

فيروس هانتا والسفينة الموبوءة.. تحديث من الصحة العالمية

طبيب يحسم الجدل السجائر الإلكترونية وعلاقتها بالسرطان

المزيد

الآخبار التكنلوجية

لأول مرة في الولايات المتحدة.. تشغيل مفاعل مصغر نووي يغذي الذكاء الاصطناعي بالطاقة

الكشف عن تفاصيل أول عملية ناجحة لاستعادة انتاج الحيوانات المنوية

أطلس يكشف خفايا الجسم البشري بدقة أرفع بـ50 مرة من شعر الإنسان

المتحف المصري الكبير يتحول إلى "أيقونة خضراء" بدعم ياباني

المزيد

مواضيع ذات صلة

Cultivation of Microorganisms : Sources of Metabolic Energy

Cultivation of Microorganisms : Requirements for Growth

Renewal of Epithelial Cells

Transport Across Epithelia

Covering or Lining Epithelia

Anticoagulants for Clinical use

The Rationale and Methodology for Hepcidin-Lowering Agents

Therapy of Iron Deficiency

Intestinal Iron Absorption

Liver Regulation of Systemic Iron Homeostasis and Iron Storage

Recycling of Erythrocyte Iron by Macrophages

Use of Iron For Erythropoiesis