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Ovulation induction has developed as a valuable noninvasive therapy for the infertile couple. The nurse's role focuses on assisting the couple, as a unit, to understand and cope with the necessary regimen, tests, examinations, and therapies necessary to reach the goal of conception. The physiologic regulation of the menstrual cycle, current pharmacologic therapy, treatment protocols, and the unique role of the infertility nurse are reviewed.
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Ovulation induction protocols for oocyte retrieval have evolved from clomiphene citrate/human menopausal gonadotropins (menotropins) to human menopausal gonadotropins alone and, finally, to a combination of human menopausal gonadotropins and an agonist of gonadotropin-releasing hormone (GnRH-a). The almost abandonment of clomiphene use is due to findings from studies that showed reduced implantation due to the antiestrogen effect of clomiphene. The use of GnRH-a was introduced to maintain low levels of luteinizing hormone late in follicular development to prevent premature ovulation or premature senescence of the oocyte. The GnRH-a increases oocyte yield in poor responders, decreases cycle cancellations, improves the rate of pregnancy, and allows some control over the timing of retrieval. Attempts to use the GnRH-a to stimulate follicle maturation in a "short protocol" have resulted in variable and sometimes poor results. Therefore, the long GnRH-a/human menopausal gonadotropin protocol is currently used for most patients to prepare for oocyte retrieval.
This randomised study was carried out on 77 patients who underwent 269 cycles of donor insemination (AID). The randomization was carried out to decide whether HCG should be used or not to provoke ovulation. The results in AID show, in our study, that using HCG in estimating oestradiol makes very little difference. On the other hand, measuring LH and the quality of the sperm that is used for the insemination seem to us to be important, whereas the quality of the cervical mucus is absolutely fundamental. Ultrasound makes it possible to determine the date when the AID should be carried out in difficult cases. The use of HCG to release the oocytes can be discussed when the cervical score is less than 7 when the other parameters are favourable, and in particular when the diameter of the dominant follicle is 18 mm or more. A higher pregnancy rate should be able to be obtained in AID if all parameters are looked at.
The use of exogenous gonadotropins for treatment of clomiphene-resistant chronic anovulation in women with the polycystic ovary syndrome (PCO) is hazardous and often ineffective, possibly because of the abnormal endogenous gonadotropin secretion characteristic of PCO. We evaluated the effect of leuprolide acetate, a long-acting GnRH agonist, on serum gonadotropin and sex steroid concentrations before and during human menopausal gonadotropin (hMG) induction of ovulation in women with PCO. In this controlled prospective randomized study, leuprolide was administered daily for 4 weeks, followed by concomitant hMG administration. Gonadotropin and steroid hormone concentrations were compared with those during ovulation induction cycles in women with PCO receiving hMG only. Daily administration of leuprolide for 4 weeks resulted in significantly decreased serum LH, estradiol, and testosterone concentrations, but no change in serum progesterone, FSH, and dehydroepiandrosterone sulfate. Compared to ovulation induction using hMG alone, leuprolide administration before and during hMG treatment prevented preovulatory rises in serum LH and P concentrations, while having no effect on serum FSH, testosterone, estradiol, and dehydroepiandrosterone sulfate. We conclude that leuprolide administered to women with PCO decreases gonadal steroid production and is capable of preventing premature luteinization during hMG induction of ovulation.
Ovulation under bromocriptine was studied in 14 women with normoprolactinemic amenorrhea (5 primary, 9 secondary), unresponsive to clomiphene citrate (CC). On bromocriptine alone, ovulation occurred in 4 (28.6%). In the same subjects, bromocriptine was subsequently associated with CC. Seven patients ovulated (50.0%), including 3 that had responded to bromocriptine alone. Ovulation occurred once or twice in 6 of the 9 cases of secondary amenorrhea (66.6%). In several occasions, when ovulation induction failed, luteinized unruptured follicles were found under ultrasonographic monitoring. Four patients who had a negative response to progestin challenge did not ovulate with the treatment. Women with plasma prolactin in the upper normal range had a greater probability of achieving ovulation induction.
The results of ovulation induction in patients with ovulatory dysfunction were reviewed for a one year period. Eighty-six women were assigned to four groups: secondary amenorrhea, anovulation, oligo-ovulation, and luteal phase defect/short luteal phase (LPD). All patients were monitored with basal body temperature (BBT) graph, postcoital testing, and ultrasonic scanning of ovarian follicles. All patients received therapy with clomiphene citrate (CC) for a minimum of four cycles and 13 patients conceived. Fifty patients were offered additional therapy with human menopausal gonadotropins (HMG-HCG). Seventeen completed a minimum of four cycles, and 13 conceived. The number of CC-treated patients with poor mucus quality in the face of adequate follicular development was 24, or 48%. The overwhelming problem with ovulation induction when CC failed was the large number of patients who dropped out of therapy, 48%. In summary, close monitoring during ovulation induction to confirm ovulation, and assess mucus quality and luteal function allow detection and correction of inadequate response. Induction of ovulation can be highly successful if patients can follow through and complete protocols of therapy.
The patient with PCOD remains a challenge to the reproductive endocrinologist. Although successful induction of ovulation can often be achieved using standard therapeutic regimens of CC or hMG, too often this group of anovulatory patients fails to respond as expected. Over the past 10 to 15 years, alternate approaches to ovulation induction have been investigated with encouraging results. Whereas no one method is productive in all patients, these varied regimens offer us a number of options in dealing with this difficult clinical problem.
The effectiveness of ovulation induction with clomiphene citrate or human menopausal gonadotropins was evaluated in 52 infertile women with stage I or stage II endometriosis and ovulatory dysfunction: anovulation or luteinized unruptured follicle (LUF) syndrome before (group I) and after (group II) danazol treatment. The incidence of anovulation and LUF in the endometriosis population was 9% and 34%, respectively. In group I, 10 of 36 patients (27.8%) conceived, with an average of 17.6 induction cycles per pregnancy. In group II, 21 of 30 patients (70%) conceived, with an average of 4.5 cycles per pregnancy (difference significant at P less than 0.001). There was no difference in the average number of ovulation induction cycles per patient between groups I and II (4.9 and 3.1, respectively). Of 14 patients who did not conceive in group I and crossed over to group II, 9 (64.3%) conceived (not different from group II). Spontaneous abortion rates were 20% in group I and 14% in group II. These results indicate that mild endometriosis may interfere with conception through mechanisms other than ovulatory dysfunction and that treatment with danazol appears to more than double the fertility rate.
Induction of ovulation was performed in 148 cycles using human menopausal gonadotropins (HMG) in 52 patients, seven with hypothalamic-pituitary failure and 45 suffering dysfunction at this level. Several induction schemes were used beginning on the second day of the cycle, until one or more follicles larger than 14 mm were found, to administrate 10,000 UI of human chorionic gonadotropin (HCG). Clinical valuation of cervical mucus and ultrasound of the ovaries to assess follicular development were done, from day eight of the cycle. Twenty five pregnancies resulted in 23 patients (44%), three in patients with failure and 22 in the dysfunction group. A total of 19 healthy babies were taken home, however three neonatal deaths, four miscarriages and one ectopic pregnancy occurred. Multiple gestation was present in three patients (12%), one was quadruplet, one triplet and one twin. The ovarian hyperstimulation syndrome (OHS) was detected in seven patients (13.4%), three were mild, two moderate and two severe; two cases of OHS had multiple pregnancies. Although induction of ovulation with HMG in patients with anovulation is a complex procedure requiring strict clinical vigilance and advanced technological resources, in this clinical study it was possible to obtain similar results to other series, using high resolution ultrasound only, without daily measurements of hormones.
The plasma levels of proteins bound to steroids come under the influence of the levels of estrogens. This is why we have studied the changes in plasma SHBG in sterile women who were being treated by gonadotropins (HMG-HCG). The plasma level of SHBG was worked out using Laurell's electroimmunoassay technique with an autoradiographic display using estradiol labeled with I.125. It only takes 48 hours contact with radio films. Out of 12 patients 9 responded to the treatment as demonstrated by the plasma levels of estradiol (E2) and progesterone (P). We have found that in these women there was a rise in plasma SHBG which was significant from the 7th day of the treatment onwards (3.7 +/- 1.7 mg/l as against 5.9 +/- 2.6 mg/l, p less than 0.01) and this reached nearly twice the base level when E2 reached its maximum level (6.4 +/- 2.7 mg/l). When treatment was stopped the plasma level of SHBG dropped to that of the follicular phase, but it was out of step with the plasma E2 levels. The index of free E2 as compared with E2/TEBG showed a close superimposition when compared with the levels of E2 obtained using a radioimmunological method. This fact reinforces the value of plasma E2 as the way of monitoring the effect of induction of ovulation. Our overall conclusion is that a marked and rapid change in the level of plasma E2 directly influences the level of plasma SHBG. The consequences for treatment are that it is important to respect as far as possible the physiological conditions that are present when induction of ovulation is undertaken.
Clinical hyperstimulation is the most serious complication of ovulation induction, occurring in approximately 3% of cases (0.8% in the severe form). Paradoxically, it seems to be rare following in vitro fertilization, probably because all the follicles are aspirated. High-risk patients are those with polycystic ovarian disease, hyperprolactinaemia and hypothyroidism. All forms of ovulation induction have been implicated. Use of LHRH agonists have not reduced the incidence of hyperstimulation and they may even have increased it. An ongoing pregnancy seems to predispose to the occurrence of hyperstimulation, due to the secretion of hCG. Clinically, three stages of hyperstimulation have been described by the WHO (mild, moderate and severe). The pathophysiology is not completely understood, although prostaglandins, histamines and, especially, the ovarian renin-angiotensin system may be involved. Local ovarian complications and thromboembolic complications have also occurred. The treatment of severe hyperstimulation is both symptomatic (fluid replacement, aspiration of effusions, moderate sodium and water restriction, small doses of diuretics) and specific (corticosteroids, aspiration of ovarian cysts, even voluntary interruption of pregnancy in the most serious forms). If the hyperstimulation occurs in the absence of pregnancy, antihistamines or antiprostaglandins can be given. Prevention is exceedingly important. This can be helped by recognition of polycystic ovarian disease and stimulation of these cases by clomiphene citrate or pure FSH associated, for use in in vitro fertilization, with prolonged desensitization using LHRH agonists. Daily ultrasound and hormonal monitoring of ovulation induction is required. When there is excessive response to stimulation, it is prudent not to induce ovulation with hCG or, alternatively, to aspirate all the follicles and freeze the embryos obtained without giving further injections of hCG in the luteal phase. Clinical ovarian hyperstimulation is the classic form of iatrogenic disorder and is the most important complication of ovulation induction treatments, since it can be life-threatening in its most severe form. In this chapter we review current knowledge concerning the frequency, factors associated with its occurrence, clinical aspects, physiopathological mechanisms and, finally, the possibilities for treatment and prevention.
The effects of ovulation induction on pre-implantation embryos (day 4 of gestation) were studied in mature cycling mice (the Jcl:ICR strain) using relatively small doses of pregnant mare's serum (PMS)/human chorionic gonadotropin (HCG) (2.5 or 5 IU each) given at two different stages (in-phase or out-of-phase to the estrous cycle). The proportion of degenerated embryos was increased and the development of the embryos was retarded in the treated groups, especially in the out-of-phase subgroups. Therefore, we propose that the use of PMS/HCG for ovulation induction should be more restricted in mouse reproductive experiments when mature females are used, and that, even when ovulation induction is used, a treatment synchronized to the spontaneous estrous cycle should be elected.
With the induction of ovulation, clomiphene citrate and human menopausal gonadotropin have the potential to stimulate the endocervical glands. We have found that the degree of mucus production can occasionally be quite large and hence is detectable by sonographic evaluation as an anechoic cervical mass. The incidence of this specific ultrasonic finding was found to be approximately 5%. This physiologic process should be differentiated from disease states affecting the cervix.
OBJECTIVE: To assess the deleterious effect of clomiphene citrate (CC) on the development of the endometrium and its improvement by the addition of ethinyl estradiol (E2). PARTICIPATING PATIENTS: Infertility-treated patients, monitored for induction of ovulation or timing of insemination (control group). DESIGN: We studied four groups of women during an ovulatory cycle with various treatment schedules. Group 1: untreated patients; group 2: patients treated by CC; group 3: patients treated by CC + ethinyl E2; group 4: patients treated by human menopausal gonadotropin. Follow-up of the patients was done by vaginal ultrasonography and measurements of blood E2. RESULTS: In the group treated by CC, both endometrial thickness and uterine volume growth during the follicular phase were lower as compared with untreated controls and menotropin-treated patients. The addition of ethinyl E2 to these patients reversed this deleterious effect of CC without interfering with ovulation. CONCLUSION: Ethinyl E2 may reverse the deleterious effect of CC on endometrial development during the follicular phase.
Multiple births after artificial induction of ovulation (AIO) are usually considered to be due to fertilisation of multiple ova. In the East Flanders Prospective Twin Study between 1978 and 1985 the frequency of zygotic splitting after AIO (1.2%) was significantly higher than the expected frequency (0.45%) among spontaneous twins and triplets. Moreover, after AIO the frequency of zygotic division was significantly higher in triplets than in twins. AIO seems to be the first identified biological mechanism influencing the monozygotic twinning rate.
An ovulatory cycle was induced by oral administration of a specific opiate antagonist: naltrexone, at a dose of 50 mg/day for 26 days in a woman suffering from secondary hypothalamic amenorrhea. The follicular growth was monitored by ultrasound and serial blood measurement of LH, FSH, E2 and progesterone. The hormonal and ultrasound profiles showed an ovulatory cycle with a single dominant follicle. After discontinuation of the treatment, the patient became amenorrheic again. The gonadotropin as well as estradiol plasma levels declined, to that observed before treatment. Naltrexone may be a useful agent for induction of ovulation in women suffering from hypothalamic amenorrhea.
Several authors have reported a possible association between IVF or induction of ovulation on the one hand and the occurrence of neural tube defects on the other hand. Here a review is given of recent literature on this subject, including data available from The Netherlands. Collaborative epidemiologic studies are needed to evaluate the potential risks. In individual pregnancies prenatal examination is advised. In spontaneous abortions fetal pathological evaluation is desirable.