Ovulation induction

Methods to induce ovulation in anovulatory women have blossomed over the last three decades. The introduction of clomiphene citrate in 1960 allowed us for the first time to provoke follicle development in patients with normo or hyperestrogenic forms of anovulation. The development of human menopausal gonadotropins in the early 1960s gave us a much more powerful tool with which to influence ovulation in all forms of ovulatory disturbances. Elucidation of the pulsatile secretion of gonadotropin-releasing hormone together with its isolation and synthesis has allowed us to streamline our methods of inducing ovulation in hypothalamic amenorrheic patients by using endogenous control mechanisms to maximize both safety and effectiveness. However, there are problems yet to solve. Polycystic ovarian disease has long eluded our efforts to resolve its pathophysiology as well as to devise a consistently effective and safe means of treatment. Methods to restore ovulation in patients with polycystic ovarian disease refractory to clomiphene citrate is the quest of future investigations.     

Ovulation induction

The different methods of inducing ovulation and the results which one can hope to obtain relative to the indications for each of them are discussed. It is interesting to note that the cumulative total of pregnancies over 12 months shows that the prognosis in terms of fertility is similar to that of a normal population, provided that it has been treated under optimal conditions.     

Ovulation induction in IVF

This review examined current controlled ovarian hyperstimulation (COH) protocols used in ART. Controversies still exist regarding selection of gonadotropin preparation (i.e., recombinant versus urinary forms, pure FSH versus FSH-LH containing preparations), choice of adjuvant therapy with GnRH analogues (agonists versus antagonists), and pretreatment with oral contraceptive pills. Patients prospectively identified as intermediate responders have excellent outcomes with adjuvant therapy with either a GnRH agonist (long protocol) or a GnRH antagonist, but tailoring of gonadotropin dose and type must be performed to achieve optimized results. High responders perform satisfactorily with gentler gonadotropin stimulation regimens that minimize the occurrence of ovarian hyperstimulation syndrome. On the other hand, results in low/poor responders remain sub optimal both in terms of ovarian response and oocyte/embryo quality in spite of a variety of stimulation approaches and adjuvant therapies implemented. It is concluded that ovarian stimulation is a critical step in IVF therapy. There are a variety of available and efficacious novel COH regimens but individualization of management is essential and dependent upon proper and prospective assessment of the ovarian reserve. The identification of the pathogeneses underlying poor ovarian response constitutes a formidable challenge facing reproductive endocrinologists.     

Ovulation induction and cancer risk

OBJECTIVE: To review and critique the literature regarding ovulation induction and cancer risk. DESIGN: Identification of relevant clinical and epidemiological literature through PubMed and other sources. CONCLUSION(S): Ovulation and associated hormonal changes have been linked with selected cancers, raising concerns regarding ovulation-inducing agents. Clinical studies have suggested potential links, but more definitive analytic investigations have been difficult to interpret given the small numbers, short follow-up, and imprecise information on drugs or indications for usage. Prospective studies have been limited by inabilities to control for other cancer predictors (including parity), while selective recall has been a concern for retrospective studies. Reports of large increases in ovarian cancer risk associated with fertility medications have not been replicated by more recent investigations. Some findings, based on small numbers, suggest slight increases in risk associated with fertility drugs among nulligravid women or after extended follow-up or for certain tumor subtypes, but further replication is needed. Fewer studies have assessed relationships with other hormonally related cancers, but limited findings support the need for further monitoring of long-term effects for breast and endometrial cancers. Findings regarding other cancers are extremely limited but should be pursued for cancers showing evidence of hormonal influences, including colon cancers and melanomas.     

Ovulation induction in anovulatory women

Ovulation induction therapy is administered to stimulate follicular growth and induce ovulation in anovulatory infertile women. In anovulatory women with polycystic ovary syndrome, the treatment of choice is clomiphene citrate, whereas in clomiphene nonresponders, gonadotrophins are given as secondary therapy. Currently, insulin-sensitizing agents are used in the treatment of polycystic ovary syndrome to restore menstrual cyclicity. In selected patients, laparoscopic drilling has also been suggested. In anovulatory patients affected with hypogonadotropic hypogonadism, treatment is based on gonadotrophin replacement therapy or pulsatile gonadotrophin-releasing hormone infusion. In ovulation induction therapy the clinician's attention should be directed at restoring normal ovary function. When pharmacotherapy is required, monofollicular growth should be induced to reduce the risk of multiple pregnancy.     

Ovulation induction in amenorrheic women

Seventy-six patients with primary or secondary amenorrhea who wished to conceive were treated with clomiphene citrate, 2-Br-alpha-ergocryptine, and/or human menopausal gonadotropins (hMG). Of these 71 patients who received clomiphene citrate, 39 (55%) ovulated. Of these 71 patients, 52 had withdrawal uterine bleeding following IM progesterone, and 38 (73%) ovulated; only 1 of the 19 who did not bleed ovulated (P less than 0.001). Ovulation occurred in the former group of patients whether or not they had galactorrhea. Of the 32 patients who failed to ovulate despite treatment with the maximal dose of clomiphene, 250 mg/day for 5 days, 26 received hMG-hCG. All 26 ovulated and 15 conceived. All 8 patients with amenorrhea-galactorrhea who were treated either primarily or secondarily with bromergocryptine ovulated, and 4 conceived. Therefore, the drug of choice for ovulation induction in amenorrheic patients depends on 1) the presence of withdrawal bleeding after progesterone and 2) the presence of galactorrhea. In all patients with progesterone withdrawal bleeding with or without galactorrhea, the initial treatment of choice is clomiphene citrate. In the absence of withdrawal bleeding, hMG should be administered if galactorrhea is absent, and bromergocryptine should be administered if galactorrhea is present.     

Ovulation induction using clomiphene conversion

20 anovulatory and clomiphene resistant patients had been treated by the so called clomiphene conversion. Pregnancies could be achieved in 6 women. 7 further patients reacted by ovulation. In selected cases the clomiphene conversion may be an alternative of therapy with gonadotrophins and GnRH pulsatile.     

Ovulation induction management of PCOS

Ovulation induction is the principal infertility treatment for women with polycystic ovarian syndrome (PCOS). Among PCOS patients who are overweight or obese, weight loss is the most physiologic method of inducing ovulation. For women in whom weight loss is not possible, or for lean women with PCOS, clomiphene citrate is an effective first-line method of ovulation induction. In clomiphene-resistant women, alternative treatments include adjunctive metformin or dexamethasone, aromatase inhibitors, or ovarian drilling. If there is no pregnancy despite several cycles of successful ovulation induction, gonadotropin treatment should be considered, in which case in vitro fertilization is recommended as the safest and most effective strategy.     

Ovulation induction with pulsatile intravenous GnRH

Human menopausal gonadotropin has been the treatment of choice for hypogonadotropic hypogonadism patients who fail ovulation induction with clomiphene citrate. Several authors have reported successful ovulation induction with the use of gonadotropin releasing hormone (GnRH). We used commercially available GnRH (Factrel, Ayerst Laboratories) and the Auto Syringe AS6H Infusion Pump for ovulation induction in such patients. Eight patients completed 15 cycles of pulsatile intravenous GnRH therapy. A mean of 12.2 days of therapy was required per cycle. Basal body temperatures and ultrasound documented ovulation of a single, dominant follicle in 12 cycles (80%). There were four singleton pregnancies. The overall corrected pregnancy rate was four pregnancies for ten cycles (40%) in six patients (67%). No complications were observed, and the cost of care was one-third that of human menopausal gonadotropin at our institution.     

Ovulation induction by an LH-RH pump

The induction of ovulation by pulsatile administration of LH-RH is an extremely attractive method because it appears to be entirely physiological. It only remains for the practical details to be precisely defined, when it is probable that it can ultimately replace induction by administration of HMG and hCG.     

Ovulation induction with intravenous gonadotropin-releasing hormone

The efficacy of ovulation induction with the use of pulsatile gonadotropin-releasing hormone (GnRH) therapy was examined in 21 infertile women. Seventeen had hypothalamic amenorrhea (HA) and 4 polycystic ovary syndrome (PCO). All patients were treated as outpatients. GnRH was infused in a pulsatile mode by means of portable auto-infusion pumps connected to an indwelling intravenous catheter inserted into a forearm vein. The doses varied from 1.8 to 5 micrograms/pulse with a frequency of 90 minutes. Ovulation occurred in 52 out of 64 cycles (81.2%). Ten (47.6%) of the 21 patients became pregnant. Seven patients had normal term deliveries and 3 aborted spontaneously. With regard to the 17 patients with HA, ovulation occurred in 93.7% of treatment cycles and 6 women became pregnant. In the case of the PCO patients, ovulation was achieved in 6 out of 15 cycles (40%) and 2 women became pregnant. There was no overstimulation or any other serious complication. In conclusion, therapy with GnRH provides an elevated probability of therapeutic success, especially in HA.     

Ovulation induction for polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the commonest cause of anovulatory infertility. Various factors influence ovarian function, and fertility is adversely affected by an individual being overweight or having high serum concentrations of LH. Strategies to induce ovulation include weight loss, oral anti-oestrogens (principally clomiphene citrate), parenteral gonadotrophin therapy and laparoscopic ovarian surgery. There have been no adequately powered randomized studies to determine which of these therapies provides the best overall chance of an ongoing pregnancy. Women with PCOS are at risk of ovarian hyperstimulation syndrome (OHSS) and so ovulation induction has to be monitored carefully with serial ultrasound scans. The recognition of an association between hyperinsulinaemia and PCOS has resulted in the use of insulin sensitizing agents, such as metformin, which appear to ameliorate the biochemical profile and improve reproductive function.     

Ovulation induction with human menopausal gonadotropins

This review has summarized the evolution of hMG stimulation of ovulation in amenorrheic individuals, its monitoring, and its complications. Based on the principles learned from these individuals, use of hMG has now extended to women with cervical mucus deficiencies or luteal phase defects, as well as in vitro fertilization. Recommendations regarding the use of hMG at the current time when assessment by both serum E2 and ultrasound are available have been made. Briefly, it is suggested that an "E2 window" of at least 1000 pg/ml be achieved over the course of a 9- to 12-day follicular phase. Furthermore, assessment of these monitoring modalities should be made in combination in order that findings from one modality alone not be allowed to initiate premature hCG administration.     

Ovulation induction in in vitro fertilization

The main goal of an in vitro fertilization (IVF) program is to maximize the number of women who become pregnant in any treatment cycle. In order to achieve pregnancy, many steps should be successfully accomplished. The number of mature oocytes that are retrieved and fertilized in a treatment cycle has the major impact on the success rate of the IVF program. The chances of achieving conception increases dramatically when the number of embryos replaced into the uterus increases^1-3. Hence, most IVF treatment programs currently use some combination of ovulation induction agents in order to stimulate and aspirate as many follicles as possible.     

Ovulation induction for polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the commonest cause of anovulatory infertility. Various factors influence ovarian function, and fertility is adversely affected by an individual being overweight or having high serum concentrations of LH. Strategies to induce ovulation include weight loss, oral anti-oestrogens (principally clomiphene citrate), parenteral gonadotrophin therapy and laparoscopic ovarian surgery. There have been no adequately powered randomized studies to determine which of these therapies provides the best overall chance of an ongoing pregnancy. Women with PCOS are at risk of ovarian hyperstimulation syndrome (OHSS) and so ovulation induction has to be monitored carefully with serial ultrasound scans. The recognition of an association between hyperinsulinaemia and PCOS has resulted in the use of insulin sensitizing agents, such as metformin, which appear to ameliorate the biochemical profile and improve reproductive function.