Joseph G. Schenker1
(1)
Department Obstetrics Gynecology, Hadassah Medical Centre, Hebrew University, Jerusalem, Israel
Joseph G. Schenker
Email: schenker@cc.huji.ac.il
Ovulation dysfunction is one of the most common causes of reproductive failure in infertile couples. The prevalence of this disorder in infertile women is about 30–40 %.
In order to appreciate the methods of inducing ovulation, a basic understanding of the endocrinology of the menstrual cycle is essential. Failure of synthesis or release of hypothalamic LHRH or the gonadotropins FSH and LH according to the normal pattern of the menstrual cycle will result in failure of ovulation with or without cessation of menses.
10.1 Principles of Ovulation
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10.2 Clomiphene Citrate
The first clinical trials of ovulation induction were carried out in 1961 with MER-25, a close structural analog of clomiphene, Greenblatt et al. [1] were the first to report the successful induction of ovulation and pregnancies following clomiphene therapy. Clomiphene is chemically related to chlorotrianisene (TACE), which is a weak estrogen. Structurally, it is related to the potent synthetic estrogen diethylstilbestrol. Clomiphene may exist in either the cis or the trans configuration, the former being significantly more potent. Structural similarity to estrogen allows Clomiphene citrate (CC) to bind to estrogen receptors (ER) throughout the reproductive system. However, in contrast to estrogen, CC binds nuclear ER for an extended period of time and ultimately depletes ER concentrations by interfering with the normal process of ER replenishment
Clomiphene citrate remains the first-line therapy for ovulation induction in anovulatory patients who are not estrogen deficient. It is a simple, cheap treatment, almost devoid of side effects, and yields ovulation in 70 %, pregnancy in 30 %.
Patients refractory to standard CC treatment may ovulate in response to combined treatment regimens: Clomiphene/hCG, Clomiphene/Estrogens, Clomiphene/Corticoids, Clomiphene/Hmg, and Clomiphene/Metformin.
10.2.1 Complications
Multiple Gestations
· Ovarian hyperstimulation syndrome (OHSS): Mild and moderate are common, severe is rare [2].
· Congenital Anomalies: There is no evidence that CC treatment increases the risk of birth defects.
· Cancer: Some reports demonstrated increase incidence of breast cancer and borderline ovary tumors [3, 4].
10.3 Letrozole: Aromatase Inhibitors [5]
Letrozole may be effective alternative to Clomiphene Citrate. It less inhibits estrogen synthesis, thereby causing enhanced GnRH pulsatility and consequent FSH and inhibin stimulation. This results in normal or enhanced follicular recruitment without the risk of multiple ovulation and OHSS. Letrozole has a very short half-life and, therefore, is quickly cleared from the body. For this reason, it is less likely to adversely affect the endometrium and cervical mucus. Combination of letrozole and FSH enhances follicular recruitment while reducing the amount of FSH needed for optimal stimulation.
10.3.1 Side Effects
Similar to Clomiphene, most of these are minor and temporary in nature. They include hot flashes, blurred vision, nausea, bloating sensation, and headache. Serious side effects are rarely seen. One of the side effects is the possibility of multiple pregnancy. Long-term use of letrozole is not recommended.
10.4 Hyperprolactinemia
Hyperprolactinemia of different etiology results in anovulatory cycles. In 1983, Ben-David and Schenker [6] suggested a possibility of a transient preovulatory rise in PRL levels.
That lasted for 2–3 days and coincided with estradiol (E) peak. In their study, 94 % of patients showed as this transient rise and 40 % conceived within 3 months of bromocriptine treatment.
10.5 Bromocriptine
Bromocriptine is an ergot medication that works by helping to restore the balance of a certain natural substance (dopamine) in the brain. It also prevents the release of certain hormones (growth hormone and prolactin). Bromocriptine can lower these hormone levels, but it does not cure the causes of the increased levels.
10.5.1 Side Effects
Nausea, constipation, dizziness, drowsiness, loss of appetite, vomiting, diarrhea, headache dizziness, syncope and symptomatic hypotension.
10.6 Other Dopamine Agonists
Several other compounds have been shown to decrease prolactin levels by binding with dopamine D2 receptors with greater affinity than bromocriptine.
The advantage of most of the newer dopamine agonists is the convenience of once a day dosage due to longer half-life.
10.6.1 Pergolide
Pergolide is a synthetic ergoline which lacks the peptide side chain of bromocriptine. It has been used in treatment of microadenomas for up to 5 years without any significant side effects or complications.
Many studies have shown the effectiveness and tolerance of pergolide over bromocriptine. It was found to be as efficacious as bromocriptine in decreasing prolactin levels, reducing galactorrhea and breast tenderness and resumption of normal menses.
10.6.2 Cabergoline
Cabergoline is a long acting dopamine receptor agonist with high affinity of D2 receptors and low affinity for D1, alpha adrenergic or 5HT and serotonin receptors. The estimated half-life is between 63 and 65 h, which is responsible for the prolonged prolactin lowering effect. It was found that cabergoline decreased prolactin levels more rapidly after a single dose as compared to bromocriptine.
10.7 Replacement Therapy using Gonadotropins
LH and FSH from animal sources were obtained in the 1930s. However, in clinical practice, it is only human gonadotropins, not available until the 1950s, which have proved clinically useful.
10.7.1 Heterologous Gonadotropins
The heterologous gonadotropin preparation, which has been most widely used, is equine serum-gonadotropin (pregnant mares’ serum, PMS) being placental in origin. Its activity is largely follicle stimulating with insignificant luteinizing activity. In large doses, it may produce ovarian hyperstimulation, but its biggest disadvantage is its ability to produce antihormones with cross-reaction to human gonadotropins [7].
10.7.2 Human Pituitary Gonadotropins
Human pituitary gonadotropin (HPG) consists essentially of a mixture of FSH and LH with a predominantly FSH action extracted from cadaveric pituitaries. The disadvantage of the biological preparation of HPG was its short supply [8].
10.7.3 Human Menopausal Gonadotropins [9]
The gonadotropins FSH and LH are excreted in urine in a bioactive form and this excretion rises rapidly after the menopause with the reduction of ovarian steroid negative feedback. Thus, menopausal urine has proved clinically the most useful source of gonadotropins [9]. Human menopausal gonadotropins (Hmg) has a predominantly FSH action with LH supporting effect and is commercially available as Pergonal (Serono and Searle) and Humegon (Organon).
Hmg is not usually successful alone as this therapy simply stimulates follicular development and an ovulatory surge of LH is required; this may be provided by Human chorionic gonadotropin (hCG).
The biological properties of hCG are very similar to LH, being capable of inducing ovulation after a follicle has been developed, converting it to a corpus luteum.
10.8 Recombinant Human FSH [10])
Recombinant DNA technologies were introduced in the early 1990s for the production of recombinant human FSH (r-hFSH) with the insertion of alpha and beta-FSH subunits into genetically engineered mammalian cells. The advantage of this technology is that the manufacture of r-hFSH is independent of urine collection, ensuring the consistent availability of biochemically very pure FSH preparation with minimal batch to batch variation.
There is some evidence that r-hFSH preparations have clinical advantages over Hmg or highly purified uhFSH. Several studies have demonstrated significant advantages for r-hFSH in terms of efficacy as assessed by the number of oocytes retrieved as well as efficiency judged by FSH consumption and the duration of treatment. Pregnancy rates were marginally higher after r-hFSH than after u-hFSH.
10.9 GnRH [11]
The main objectives of controlled ovarian stimulation (COH) for Assisted Reproductive Techniques (ART) are: hypophyseal activity suppression, multiple follicle growth stimulation, and ovulation induction. By suppressing hypophyseal activity, it is possible to prevent untimely LH surge and allow the appropriate development of the leading follicle.
10.9.1 GnRH-Agonist
GnRH-agonist (GnRH-a) administration is used for patients undergoing IVF. These properties of GnRH-a have been applied in clinical practice with two main regimens of administration.
10.9.2 The Long-Term GnRH-a Protocol
Both pituitary and ovarian desensitization are induced by GnRH-a administration in the early follicular or midluteal phase of the cycle preceding the planned IVF. Once desensitization is obtained, ovarian stimulation with gonadotropins is started and GnRH-a injection is continued until hCG is administered. In clinical practice, the long-term protocol is the most traditional and widely used regimen, probably because it is more convenient for programming.
10.9.3 The Short-Term GnRH-a Protocol
This regimen takes advantage of the initial rise (flare-up) of serum gonadotropins on follicular recruitment and of the subsequent pituitary desensitization induced by daily agonist administration. Gonadotropin administration is started in the early follicular phase. Several adjustments to this protocol have been suggested: a shorter period of GnRH-a administration, for 3 days (ultrashort protocol) or for 7 days, on the assumption that suppression of the endogenous LH surge may be obtained through a very short course of GnRH-a administration.
10.9.4 GnRH Antagonists
In initial clinical studies, GnRH antagonists were used to prevent a premature LH surge during the menstrual cycle and, subsequently, during ovarian stimulation for IVF. GnRH antagonists are synthetic analogs of GnRH that compete with endogenous GnRH for pituitary binding sites. Clinical advantages of GnRH antagonists over GnRH agonists are the absence of the initial stimulation of gonadotropin release (flare-up effect) and, as a consequence, a more direct, immediate and reversible suppression of gonadotropin secretion, which allows their use without the need for a desensitization period.
There are two regimens using GnRH antagonists.
Multiple-Dose GnRH Antagonist Administration
In this protocol, daily injections of low-dose antagonist are given from day 6 of ovarian stimulation using exogenous gonadotropins, which is when multifollicular development and estradiol secretion may trigger an endogenous LH surge.
The optimal daily dose is 0.25 mg. The short half-life of the antagonist with this dose requires a daily administration up to the time of hCG administration. Indeed, this dosage is able to adequately prevent the endogenous LH surge before hCG administration and simultaneously maintain a residual basal LH secretion compatible with a high rate of estradiol secretion, mature oocyte collection, and pregnancy.
Single-dose GnRH antagonist administration
The injection of a single and large dose of GnRH antagonist in the late follicular phase has proved to be effective in postponing the spontaneous LH surge.
10.9.5 Advantages of GnRH Antagonists Over GnRH-a in ART
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The main complications of ovarian stimulation are OHSS and Multiple Pregnancies.
10.10 Ovarian Hyperstimulation Syndrome [12]
OHSS is characterized by massive transudation of protein-rich fluid (mainly albumin) from the vascular space into the peritoneal pleural and to a lesser extent to the pericardial cavities. The intensity of the syndrome is related to the degree of the follicular response in the ovaries to the ovulation inducing agents. OHSS is still a threat to every patient undergoing ovulation induction.
The following are two types of severe OHSS:
(I)
(II)
10.10.1 Classification of OHSS
Schenker and Weinstein [2] divided OHSS into three main categories—mild, moderate, and severe syndrome.
10.10.1.1 Mild Hyperstimulation
Chemical hyperstimulation is a very common accompaniment of ovulation induction. The mild form of OHSS presents as a sensation of abdominal heaviness, tension, swelling, and pain. The physical findings are bilateral ovarian enlargement by multiple follicular and corpus luteum cysts; the ovaries may be up to 6 cm in diameter. In recent years, mild hyperstimulation has become more common with superovulation in ovulatory women participating in the various kinds of assisted reproduction programs. Occasionally, the cyst may rupture or undergo torsion. This often presents a difficult problem in the differential diagnosis between a ruptured cyst, torsion of adnexa, and an ectopic pregnancy.
10.10.1.2 Moderate Hyperstimulation
In cases of moderate hyperstimulation, the abdominal discomfort is more pronounced. Gastrointestinal symptoms, such as nausea, vomiting, and (less frequently) diarrhea, are present. There is some weight gain and an increase of abdominal circumference. The ovaries are enlarged to 12 cm in diameter, and some ascitic fluid is detected by ultrasonography. Most patients will have mode OHSS within 10 days of hCG administration—early OHSS. In nonconception cycles, the symptoms may appear later due to placental secretion of hCG, especially in multiple gestation—late OHSS. OHSS is a self-limiting process in nonconception cycles, the symptoms disappear by onset of menstruation, but regression of the ovarian can take 2–4 weeks and sometimes even longer.
10.10.1.3 Severe Hyperstimulation
Severe OHSS is a serious iatrogenic complication of ovulation induction in an otherwise healthy woman. The clinical manifestations may include pleural effusion, pericardial effusion, hypovolemia, impairment of renal function, electrolyte imbalance, disturbance in liver function, thromboembolic phenomena, shock, tension ascites, and adult respiratory distress syndrome (ARDS).
The condition of a patient with severe OHSS improves within several days when she is correctly treated, and when conception does not occur. The large ovarian cysts gradually subside after the abrupt appearance of clinical symptoms of hyperstimulation. The presence of ascites is a major sign of the capillary leak phenomenon present in OHSS. There is a direct connection between the intensity of capillary permeability and the severity of OHSS, as has been shown in our experimental model intraperitoneal pressure exceeds the normal intraluminal pressure of the abdominal vena cava, the inferior vena cava is compressed, and blood flow in the interior vena cava is reduced. During these pathological changes, there is reduced preload to the heart, leading to decreased cardiac output and impairment of renal and respiratory function.
The most serious complications of OHSS are thromboembolic phenomena, both arterial and venous. Thromboembolic events on arterial side were the common cause of death. The mechanism of thromboembolism in the course of OHSS mainly the arterial one were explained by us as result of increased permeability of blood vessels in response to excessive vasoactive substances of ovarian origin, and vasoconstrictive effects of some other agents of ovarian origin, which lead to hemoconcentration and hypovolemia with resultant arterial hypotension gonadotropin administration, increased supraphysiological concentrations of 17β-estradiol following ovulation induction, which may be a risk factor in patients with inherited thrombophilias. Arterial events are predominantly cerebrovascular accidents, usually occurring concurrently with the onset of OHSS. Venous thromboses occur several weeks later and are mostly reported in unusual yet specific sites such as large veins of the upper extremities and neck.
Hepatocellular and cholestatic changes have been noted with and without conception. Several factors may account for these changes including increased estrogen levels and increased vascular permeability.
Severe OHSS is characterized by an extraparenchymal restrictive type of pulmonary dysfunction, attributed to intra-abdominal or pleural fluid accumulation, which limits descent of the diaphragm and expansion of the thoracic cage. This may induce uncoordinated lung ventilation and atelectasis with subsequent ventilation–perfusion mismatch and hypoxemia. The clinical picture may deteriorate further because of pulmonary infection, pulmonary thromboembolism, or ARDS, all of which have distinct clinical, radiographic, and blood gas characteristics [13].
Hypoalbuminemia, a well-established feature of OHSS, is caused by leakage of albumin to the third space we determined globulin concentrations in the plasma and ascitic fluid of patients with severe OHSS from the time of admission until convalescence. Our studies demonstrated severe OHSS are at increased risk for infection due to leakage of gamma globulins from intravascular space [14].
10.10.2 Incidence
The incidence and severity of OHSS vary with the different clinical conditions in which ovulation is induced in anovulatory patients or ovulatory patients hyperstimulated and treated by assisted reproductive technology. In anovulatory women treated with different preparations for induction of ovulation, the incidence of mild hyperstimulation is 5–10 % of cycles. The incidence in women treated by assisted reproduction is 2–4 % of moderate OHSS and 0.1–0.5 % of severe OHSS.
10.10.3 Risk Factors
Several risk factors were reported to be associated with OHSS: young age (<35 years), polycystic ovary-like patients, asthenic habitus, pregnancy, and hCG luteal supplementation. Different protocols for ovarian stimulation in ART cycles affect the incidence and the severity of the syndrome. Ovarian stimulation results in high serum estradiol (E), multiple follicles (>35), and ultrasonic ovarian “necklace” sign. Data from sequential ultrasonographic measurements of follicles during induction of ovulation show a strong positive correlation between the total number of follicles (all sizes) and the occurrence of OHSS. Higher number of immature follicles (under 12 mm in diameter), small follicles (12–14 mm), and large follicles (>18 mm) were observed on the day of hCG administration in patients who developed OHSS.
Women with PCO disease are at increased risk of developing OHSS; therefore, it is of primary importance to diagnose PCO disease before induction of ovulation.
In spite of this data, there are no clear predictive risk factors for the development of OHSS. Stepwise logistic regression showed that early OHSS was predicted by the number of oocytes retrieved and the E2 concentration on the day of hCG administration. Late OHSS was predicted by the number of gestational sacs on ultrasound after embryo transfer but not by the number of oocytes or E2.
10.10.4 Pathogenesis of OHSS
There is a continuous effort to find the exact factors responsible for the increased vascular permeability, which was shown in our experimental model such as histamine, serotonin, prostaglandins, and prolactin, and variety of other substances were implicated in the past. However, only scant data support an important role for any of these factors.
The following factors were studied:
Histamine
It was found in animal model that OHSS could be blocked in rabbits by administration of antihistaminic preparations. In animals treated with antihistamine, a more rapid regression of the hyperstimulated ovaries was observed than in a control group. Although these animal studies had promising results, later studies demonstrated no difference in histamine levels between rabbits in whom OHSS was induced and controls [15].
Estrogens
Abnormally high levels of various steroids, estrogens in particular, are found in ascitic fluid and serum in cases of OHSS following Hmg-hCG ovulation induction. Thus, it is not a surprise that estrogens were implicated as a possible triggering factor that eventually increases capillary permeability. On the other hand, it is known that the administration of high doses of estrogens do not, by themselves, produce clinical hyperstimulation. Moreover, Meirow et al. [16] showed that induction of ovulation without elevation of estrogens may lead to OHSS.
Prostaglandins
Experiments in animal models set out to determine whether prostaglandins are the “active substances” playing a role in the development of this syndrome. It was demonstrated in early experiments on an animal model that Indomethacin, a blocker of prostaglandin synthesis, can prevent the fluid shift associated with the ascites, pleural effusion, and hypovolemia seen in this syndrome [17]. Moreover, other animal studies showed that in the presence of OHSS, ascites formation is not effectively suppressed by Indomethacin. In the clinical setting, Indomethacin was used as a therapeutic measure in cases of severe OHSS with variable results. Therefore, the role of prostaglandins in triggering the pathological processes of OHSS was not proved.
Renin–Angiotensin System
Increased vascularity as well as increased capillary permeability at the time of ovulation is an important part of the angiogenic response in the follicle. The angiogenic properties of human follicular fluid combined with high prorenin, high plasma renin-like activity, angiotensin II-like immunoreactivity, and angiotensin-converting enzyme (ACE) raised the hypothesis on the possible involvement of renin–angiotensin system in the pathogenesis of OHSS through new vessel formation and increased capillary permeability. The involvement of a locally activated renin–angiotensin–aldosterone cascade has been implicated as a possible cause of the severe form of the syndrome through neovascularization and increased capillary permeability rate through endothelial cells in vitro. Plasma renin activity and aldosterone in patients with ovarian hyperstimulation and demonstrated was studied by us. The results showed the pattern of plasma renin activity in Hmg hyperstimulated cycles is characterized by a mid-luteal peak which declines to normal in the late luteal phase in nonconceptual cycles, whereas a sustained elevation of plasma renin activity occurs in conceptual cycles. A direct correlation between the magnitude of plasma renin activity and the severity of OHSS was established [18].
According to this concept, the increased capillary permeability present in OHSS is due to the involvement of the renin–angiotensin system and the synthesis of prostaglandins in the ovaries. However, although the renin–angiotensin system may explain some of the characteristics in OHSS such as vasoconstriction as well as several other signs, it is not clear whether this system triggers the cascade leading to OHSS or merely is a secondary reactional feature.
Vascular Endothelial Growth Factor
It was found by us and others that VEGF is responsible for the significant increase in the capillary permeability in OHSS [19]. VEGF, also known as vascular permeability factor (VPF), can provoke extravascular fluid accumulation, hemoconcentration and elevated plasma concentration of von Willebrand factor all known complications of OHSS. VEGF is a potent vasoactive protein with a remarkable permeability enhancing capacity that is approximately 1,000 times that of histamine. Elevated levels of VEGF were found in the serum of patients who developed severe OHSS. Follicular fluid VEGF was found to be 100-fold greater than serum or peritoneal fluid 36 h after hCG administration. Abramov et al. [19] investigated the role of VEGF in OHSS. Samples of therapeutic paracentesis were collected from severe OHSS patients. They found that VEGF is the major capillary permeability factor in OHSS ascites since adding specific antibodies against VEGF (rhVEGF) was able to neutralize 70 % of capillary permeability activity. Several other evidence for the key role of VEGF in the pathogenesis of OHSS were also found. High concentration of this substance was found in ascites from OHSS patients. Lately, dynamic changes of VEGF levels in the ascitic fluid of patients with severe OHSS were reported. Moreover, it was found that VEGF is hCG trigger for OHHS.
Human Chorionic Gonadotropin
Severe OHSS is depended on either exogenous administration of hCG or endogenous pregnancy-derived hCG. It is administered during ovarian stimulation for both triggering ovulation and for luteal support. It is well known that hCG administration is critical for the development of OHSS. This iatrogenic syndrome cannot be totally prevented by GnRH substitution for hCG and inducing endogenous LH surge.
10.10.5 Treatment
Mild OHSS usually does not require any active form of therapy other than observation and maintenance of hydration by the oral route. Moderate grade OHSS requires close observation and, in most instances, hospitalization, since patients may rapidly undergo a change of status, particularly when conception occurs, and it may become severe with subsequent complications; thus, vigilant observation is required. Patients with severe OHSS require immediate hospitalization and treatment.
During hospitalization, meticulous monitoring of hemodynamic stability is required by restoration of the depleted intravascular volume. Large volume crystalloid infusion is recommended. However, these patients must be closely monitored, as this can result in sequestration of fluid in the third space. Since no treatable single causative mechanism has been found for this syndrome, therapy has remained conservative and supportive, aimed at refilling the arteriolar vasculature, mobilizing fluids from the third space back to the intravascular tree, maintaining circulatory hemodynamics, and preventing hemoconcentration.
We have previously shown that severe OHSS is characterized by leakage of albumin (with a molecular weight of 69 kD) as well as IgG and IgA (with molecular weights of 150 kD and 180 kD, respectively) to the abdominal cavity. Since IgM, which has a molecular weight of approximately 900 kD, did not leak at all, and since IgA leaked much less than IgG and albumin, we suggested that molecular human albumin, however, is considered the most “physiologic” solution for this purpose and is probably the most common one used. Its popularity may be attributed to publications that reported a benefit of prophylactic administration of human albumin before and immediately after oocyte retrieval in women at high risk for severe OHSS. However, some recent reports could not reproduce these results and found no significant benefit of human albumin therapy in prevention of severe OHSS.
We compared human albumin with 6 % hydroxyethyl starch, a powerful, high-molecular-weight colloid currently used to treat other states of intravascular volume depletion, such as burns and hemorrhagic or septic shock. It was proved that 6 % hydroxyethyl starch has advantage over albumin [20].
Tension ascites with oliguria calls for paracentesis. Impending renal failure and unrelenting hemoconcentration require intensive care and possibly dopamine drip. Heparin should be added for thromboembolic phenomena, whereas surgical intervention should be reserved for ovarian torsion, rupture of cysts, or ectopic (heterotopic) gestation. Therapeutic termination of an existing pregnancy may be lifesaving when all other measures have failed, making both patient and physician face extremely difficult decision with vast psychological consequences for the patient.
10.10.6 Prevention [21]
The key to the primary prevention of OHSS during ovarian stimulation is individual approach recognizing risk of the patient to develop OHHS. Several measures can be employed to prevent OHSS. There are, however, numerous reasons why even with the most careful and painstaking preventative measures, OHSS cannot be eliminated.
Monitoring of induction of ovulation is the most reliable method in the prevention of OHSS. Measurable parameters, which more or less accurately reflect follicular maturation, are used to monitor ovulation induction since direct observation is impossible.
Clinical evaluation is important, and such methods as cervical scoring may be used as adjuvant methods of evaluation. Determining the cervical score reflects indirectly the total estrogen activity. Serum estrogen values have established their effectiveness in monitoring induction of ovulation.
Estrogen monitoring has effectively reduced OHSS with clinical symptoms necessitating hospitalization. Higher levels of 17β-estradiol are reached in induced cycles to achieve the optimal pregnancy rate. However, we and others have observed OHSS with peak plasma estradiol levels of >2,000 pg/ml, hCG should be withheld.
An additional factor that may serve as a warning sign is the slope of rise of the plasma estradiol level. If values are more than doubling during 2 or 3 days (steep slope), then this should be regarded as a serious warning sign and hCG withheld in that cycle. In assisted reproductive programmers, hCG should be withheld when estradiol levels are >3,000 pg/ml.
We and others have demonstrated that there is a linear correlation between the follicular diameter and estradiol levels in plasma in normal ovulatory cycles. However in induced cycles, where there is more than one dominant follicle and several maturing follicles, there is a poor statistical correlation between the ultrasonographic ovarian morphology and the plasma oestradiol level.
In assisted reproductive of ovarian stimulation, the following manipulations and interventions during the treatment cycle have been used:
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
However, patients receiving a GnRHa trigger had poor clinical outcomes, with a reduced likelihood of pregnancy and an extremely high early pregnancy loss rate, which was attributed to luteal phase insufficiency, despite standard luteal phase support with progesterone.
10.10.7 Multiple Pregnancy
The frequency of multiple gestation has increased as a result of the relatively wide-spread use of induction of ovulation and ART. The overall multiple pregnancy rate for ART is 22–28 %, most of which are twins (20 %), triplets (4 %) and, occasionally, higher-order gestations.
The medical and social problems associated with multiple pregnancies have been recorded. There is an increased frequency of maternal complications together with higher perinatal morbidity and mortality [23]. It is now common for women who are carrying a pregnancy of high order, even of triplets, to have the number of fetuses reduced to two or one by selective abortion of the excess fetuses. In order to prevent the need for selective termination, the number of embryos transferred into the uterus should be limited to one or even two. Some countries have already regulations that limit the number of embryos transferred into the uterus.
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