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Clomiphene citrate ovulation induction in combination with a timed intrauterine insemination: the value of urinary luteinizing hormone versus human chorionic gonadotropin timing.

OBJECTIVE: To evaluate the clinical pregnancy rates (PRs) in anovulatory, male factor, and unexplained infertility using clomiphene citrate (CC) with an IUI and to evaluate the difference in PRs between urinary LH testing and hCG administration for timing of the IUI. DESIGN: Retrospective clinical study. SETTING: Academic, tertiary care fertility center. PATIENT(S): One hundred thirty-eight couples (432 cycles) undergoing IUI with CC ovulation induction as a treatment for unexplained, anovulatory, or male factor infertility were selected. INTERVENTION(S): All women with unexplained or male factor infertility received CC at a dose of 50 mg/d, and those with anovulation received CC at a dose ranging from 50 to 200 mg/d. All women in the study received a single IUI either the morning after a urinary LH surge or 36 to 38 hours after an evening hCG injection. MAIN OUTCOME MEASURE(S): Clinical PR. RESULT(S): There were no differences in the clinical PRs between LH testing or hCG administration in any of the three groups. Clinical PRs were extremely low in the male factor infertility group regardless of the timing used. CONCLUSION(S): These data suggest that the success of IUI with CC is not dependent on the method used to establish the timing for the IUI. In couples undergoing IUI with CC, the use of urinary LH testing may result in lower costs by reducing patient visits and the midcycle ultrasound.

Adult↗

Recombinant FSH in alternative doses or versus urinary gonadotrophins for ovulation induction in subfertility associated with polycystic ovary syndrome: a systematic review based on a Cochrane review.

This paper is based on a Cochrane review published in The Cochrane Library, issue 2, 2001 (see www.CochraneLibrary. net for information) with permission from The Cochrane Collaboration and Update Software. Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and The Cochrane Library should be consulted for the most recent version of the review. This systematic review was performed to study the efficacy and safety of recombinant FSH (rFSH) versus urinary FSH (uFSH) and to compare different dose regimens of rFSH for ovulation induction in women with clomiphene-resistant polycystic ovary syndrome (PCOS). Six randomized controlled trials were included in the review, according to the principles of the Cochrane Menstrual Disorders and Subfertility Group. Three trials compared rFSH with uFSH and three trials compared two different treatment regimens of rFSH. Participants were women with clomiphene citrate-resistant PCOS. Main outcome measures were ovulation, clinical pregnancy, miscarriage, multiple pregnancy, ovarian stimulation syndrome (OSS), total gonadotrophin dose used and total duration of stimulation. Summary statistics were expressed as odds ratios. Data from the trials comparing rFSH and uFSH could be pooled. There was no evidence of a difference between rFSH and uFSH in any of the outcomes. Data from the trials comparing different dose regimens of rFSH could not be combined, and for each comparison there was insufficient evidence of a difference. More randomized clinical trials with sufficient power are necessary to estimate the difference, if one exists, between rFSH and uFSH and between different dose regimens of rFSH.

Abortion, Spontaneous↗

[From pathological diagnosis to ovulation induction. The case of ovarian insufficiency].

The incidence of premature ovarian failure (POF) is around 1 to 3%. This pathology occurs in young women, who often wish to become pregnant. Theoretically, two mechanisms could be involved: initial follicle depletion and follicle dysfunction. However, in some cases, mixed mechanisms are involved. Initially, PFO was considered irreversible. In fact, signs of intermittent ovarian function in normal karyotypically women have been described, but predicting the probability of spontaneous remission in a specific woman is impossible. Therefore, various treatments for ovulation induction have been proposed to these patients. Most of the pregnancies occur after hormone replacement therapy. The action of this treatment is unclear and the cause-and-effect relation has not been proven by prospective, randomized studies. The benefit of suppressing endogen gonadotropins by GnRH agonists is not proven either. Estrogen supplementation and high-dose gonadotropin ovarian stimulation protocols have been proposed. Even so, this therapy cannot be recommended because of the lack of controlled studies. Finally, numerous case reports have described the return of ovarian function after using immunosuppressive therapies. The lack of particular criteria for the diagnosis of autoimmune mechanisms have lead to treat heterogeneous groups of patients. No randomized controlled studies with immunologic monitorage have been performed that could establish the success of this therapy. Therefore, in order to find effective treatments, basic pathophysiologic mechanisms must be better understood. For those women who want to become pregnant, the lack of prospective, randomized studies cannot lead to formal conclusions. Depending on the patients' age and history, it appears reasonable to attempt a corrective therapy based on defined etiology, before entering in a donor oocyte program.

Animals↗

[Ovulation induction using clomiphene and human gonadotropins in combined therapy].

Stimulation of ovulation combined with the clomiphene therapy and human gonadotropins is presented. Follicular maturation was followed by changes of the cervical score and ultrasonic folliculometry from the tenth day of the stimulating cycle. Ovulation was proved by the change of quality of the cervical mucus, the increase of the BBT, the increase of the progesterone concentration in serum, then by ultrasonically proved changes inside the follicle and in endometry, and finally by pregnancy. With the combined therapy the authors stimulated ovulation in a group of 14 females, altogether 21 cycles. In all the patients, before the application of the combined therapy, induction of ovulation with clomiphane alone through at least 6 cycles proved unsuccessful. Ovulation was proved in the 20 cycles of the combined stimulation. Altogether 11 pregnancies of all induced cycles were obtained: 6 pregnancies with term delivery, 2 extrauterine pregnancies, 1 spontaneous abortion in the 24th week, 1 missed abortion, and 1 blighted ovum. Two twin pregnancies were recorded. In one patient the syndrome of hyperstimulation of the first degree occurred, while in the others there were no complications at all.

Adult↗

Ovulation induction with GnRH agonist and human menopausal gonadotropins: response in patients with one versus two ovaries.

OBJECTIVE: To examine the effect of oophorectomy on response to gonadotropin releasing hormone-agonist/human menopausal gonadotropin (GnRH-a/hMG) for in vitro fertilization (IVF). DESIGN: Retrospective review. SETTING: Tertiary care academic institution. PATIENTS: Ninety-one infertile patients undergoing IVF. Eighty-four women had two ovaries and seven had only one ovary. RESULTS: There was no difference observed between women with one versus two ovaries with regard to response to medications, hormone production, number of oocytes retrieved and fertilized, or the number of embryos cleaved and transferred. CONCLUSION: Women with only one ovary are at no reproductive disadvantage when undergoing ovulation induction for IVF.

Adult↗

Ovulation induction with pulsatile luteinizing hormone-releasing hormone in women with clomiphene citrate-resistant polycystic ovary-like disease: endocrine results.

The pituitary and gonadal response to pulsatile luteinizing hormone-releasing hormone (LH-RH) administration during the first and consecutive second treatment unit (TU) was studied in nine women with clomiphene citrate-resistant polycystic ovary-like disease (PCOD). The control group consisted of eight eumenorrheic women. Luteinizing hormone levels, LH amplitudes, and total urinary excretion/24 hours did not differ between ovulatory and anovulatory TUs, but were significantly higher compared with the control group. Follicle-stimulating hormone (FSH) in PCOD did not differ from normal cycles. Androgen values in the anovulatory TUs were significantly higher compared with the ovulatory TUs (P = 0.001). We conclude that LH-RH therapy may result in ovulation; however, it does not redress the intrinsic abnormality in PCOD and FSH, and androgen levels do not seem to be critical in ovulation induction.

Adult↗

Successful induction ovulation and completed pregnancy using recombinant human luteinizing hormone and follicle stimulating hormone in a woman with Kallmann's syndrome.

The induction of ovulation in women with hypogonadotrophic hypogonadism requires follicle stimulating hormone (FSH) for follicular growth and both FSH and luteinizing hormone (LH) to induce optimal follicular steroidogenesis. The development of human recombinant FSH and LH means that individually tailored doses of both hormones can be used with the aim of inducing unifollicular ovulation. This report describes the use of recombinant human FSH and LH for the induction of ovulation and conception in the second cycle of treatment, and subsequently a successfully completed pregnancy in a woman with Kallmann's syndrome.

Adult↗

Low-dose ovulation induction with urinary gonadotropins or recombinant follicle stimulating hormone in patients with polycystic ovary syndrome.

Patients with polycystic ovary syndrome (PCOS) are highly sensitive to gonadotropins. In recent years a number of publications have shown that chronic low-dose protocols are effective in reducing complications, in particular ovarian hyperstimulation syndrome (OHSS), especially if recombinant human follicle stimulating hormone (rhFSH) is used. The aim of the present study was to compare the efficacy and safety of rhFSH (Gonal-F, Serono) versus urinary human FSH (uhFSH) (Metrodin, Serono) in a low-dose step-up protocol for ovulation induction in clomiphene-resistent infertile PCOS patients. Twenty PCOS patients were recruited in two centers for an open randomized comparative study. A starting dose of a 75-IU ampule of rhFSH or uhFSH was used for 14 days with an increment of 37.5 IU every 7 days. Human chorionic gonadotropin (hCG) (10,000 IU, Profasi, Serono) was administered if one to three follicles achieved a diameter of > or = 16 mm. Sonographic and hormonal (serum estradiol and progesterone) monitoring of the cycles was performed. All the six pregnancies induced were in the rhFSH group, but two of them ended with miscarriage. There were no differences between the two groups concerning the number of ampules used, the stimulation days, the estradiol levels on the day of hCG administration, and the progesterone levels 7 days after hCG administration. Three patients had grade II, and one patient grade III OHSS. In conclusion, our results support the literature data that rhFSH is superior to uhFSH regarding pregnancy rates, not only in in vitro fertilization cycles, but also with a low-dose protocol in patients with PCOS.

Drug Administration Schedule↗

Ovulation induction with pulsatile luteinizing releasing hormone in women with clomiphene citrate-resistant polycystic ovary-like disease: clinical results.

Eighty-four treatment units were given to 11 women with clomiphene citrate-resistant polycystic ovarian disease (PCOD). PCOD was defined as oligomenorrhea elevated luteinizing hormone (LH), normal follicle-stimulating hormone (FSH), and preference-elevated androgens. Luteinizing-releasing hormone (LRH) was administered intravenously via a portable infusion pump. Doses varied between 5 and 40 micrograms/pulse given at 60-, 90-, or 120-minute intervals. In 11 women, 85 treatment units (TUs) were completed, of which 74 were ovulatory, showing no specific advantage of any particular pulse dose or pulse interval. Five pregnancies occurred in three women. Two women did not ovulate during 52 and 284 consecutive days of therapy, respectively. Oligomenorrheic patients with PCOD can be made more regular by means of LRH, not necessarily leading to a regular menstrual cycle. In general, LRH is sufficient for luteal support. No signs of hyperstimulation were observed, although two patients incidently developed unilocular cysts with a maximum diameter of 8 cm. Ovulation induction with LRH in PCOD is possible, although the disease itself does not change during therapy. This may be further evidence that altered hypothalamic LRH secretion is more the result, rather than the cause, of the phenomenon of PCOD.

17-Ketosteroids↗

The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis.

A systematic review was conducted to evaluate the effectiveness of intrauterine insemination (IUI) with or without ovarian stimulation using gonadotrophin in the treatment of persistent infertility. Relevant randomized controlled trials were identified by a diverse strategy including a hand search of 43 core journals from 1966 to the present. Two approaches to meta-analysis were used to summarize data. First, using a standard Mantel-Haenszel approach, eight trials comparing FSH/IUI with FSH/timed intercourse for unexplained infertility were combined. The common odds ratio for pregnancy was 2.37 [95% confidence interval (CI), 1.43, 3.90], suggesting a significant improvement with IUI following ovulation induction in this patient group. Although the data were statistically homogeneous, clinically important heterogeneity was present. Second, across all diagnostic groups, the independent effects of treatment with follicle stimulating hormone (FSH), clomiphene citrate, IUI, as well as the diagnoses of male factor and endometriosis were assessed using stepwise logistic regression. Based on 5214 cycles reported in 22 trials, the odds ratio for pregnancy associated with FSH use was 2.35 (95% CI, 1.87, 2.94) for IUI, 2.82 (95% CI, 2.18, 3.66) for male factor, 0.48 (95% CI, 0.37, 0.61), and for endometriosis 0.45 (95% CI, 0.27, 0.76). This summary of the best available evidence may prove useful in counselling couples who are considering FSH and/or IUI therapy.

Clomiphene↗

Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles: effect of clomiphene citrate alone and with human menopausal gonadotropin.

OBJECTIVE: To determine if preovulation endometrial thickness or pattern are related to fecundity and to use of clomiphene citrate (CC) or hMG in IUI. DESIGN: Prospective ultrasound evaluation the day of hCG after CC alone (n = 197), hMG alone (n = 49), concurrent hMG or sequential CC and hMG (n = 205), and no medications (n = 23). SETTING: Private fertility clinic. PATIENTS: Two hundred seventy-one patients undergoing 474 cycles of IUI. MAIN OUTCOME MEASURES: Endometrial thickness, pattern, per cycle fecundity, and continuing pregnancy. RESULTS: Endometrial thickness was related to fecundity and continuing pregnancy. No pregnancies occurred when thickness was < 6 mm. The continuing pregnancy rate was 12.6% when thickness was > or = 9 mm, compared with 6.9% when thickness was 6 mm to 8 mm. Endometrial pattern was unrelated to pregnancy. Average endometrial thickness was decreased when hMG and CC were used in combination (7.9 mm) compared with hMG alone (9.4 mm). Endometrial thickness was negatively related to CC dose and positively related to the day of hCG administration by ANOVA. CONCLUSIONS: Endometrial thickness the day of hCG administration is prognostic of fecundity and continuing pregnancy in cycles of ovulation induction.

Adult↗

Changes in serum immunoreactive inhibin during ovulation induction in women with amenorrhea.

Changes in serum immunoreactive (IR)-inhibin were measured by RIA in two studies, in order to elucidate, firstly whether the pattern of IR-inhibin secretion is similar to that of estradiol (E2), and secondly, whether inhibin suppresses endogenous FSH release. Study 1: Purified urinary FSH (pFSH) or human menopausal gonadotropin (hMG) were daily injected intramuscularly into women with hypogonadotropic amenorrhea at 12 to 14 week intervals. PFSH and hMG stimulated IR-inhibin release in a similar fashion in the ovulatory cycles, but the increase in estradiol (E2) during pFSH administration was delayed and lower than that during the hMG cycles. This suggests that E2 and IR-inhibin are secreted independently from the granulosa cells. Study 2: Ovulation induction was performed in 18 cycles of 9 women with polycystic ovarian disease (PCOD) by the step-down administration of pFSH. The serum FSH concentration in cycles with premature LH release increased even after the dose of pFSH was reduced, and were significantly higher than those of cycles without premature LH release. It was also found that the serum IR-inhibin concentration in cycles with the premature LH release was 2 to 4 times as high as in cycles without premature LH release. This suggests that IR-inhibin does not suppress endogenous FSH release associated with premature LH release.

Adult↗

[The use of LHRH analogs in ovulation induction].

The use of LH-RH agonists is appropriate for the stimulation of ovulation. In contrast, in the case of induction of ovulation in a patient with deficient ovulation, suppression of influences of the hypothalamo-pituitary axis does not modify the pathological condition responsible for the ovulatory anomaly.

Clinical Protocols↗

Optimizing ovulation induction in women with polycystic ovary syndrome.

Recent developments in our understanding of the pathophysiology of polycystic ovary syndrome led to the introduction of new therapeutic approaches. It is apparent that a significant proportion of women with polycystic ovary syndrome have insulin resistance and compensatory hyperinsulinemia. Growing evidence indicates that elevated serum insulin induces hyperandrogenism, which in turn leads to anovulation and infertility. Hyperinsulinemia also contributes to the increased risk for cardiovascular disorders and type 2 diabetes mellitus. These concepts provide rationale for therapies focused on treatments of insulin resistance. In particular, weight loss and exercise have been shown to increase insulin sensitivity and improve ovulatory function. Metformin, an insulin-sensitizing agent, is particularly effective in women with polycystic ovary syndrome who have significant insulin resistance. Metformin use leads to a decrease in serum insulin and androgen levels as well as an improvement in ovulatory function. Moreover, it appears to ameliorate cardiovascular risk factors. Other approaches to ovulation induction in women with polycystic ovary syndrome include traditional therapies using clomiphene citrate or gonadotropins. In clomiphene-resistant subjects, one can consider laparoscopic ovarian drilling and other forms of partial ovarian resection or destruction.

Clinical Trials as Topic↗

Ovulation induction disrupts luteal phase function.

Abnormalities in the luteal phase have been detected in virtually all the stimulation protocols used in in vitro fertilization, on both the hormonal and endometrial levels. Supraphysiological follicular or luteal sex steroid serum concentrations, altered estradiol: progesterone (E2/P) ratio, and disturbed luteinizing hormone pituitary secretion leading to corpus luteum insufficiency or a direct drug effect have been postulated as the main etiologic factors. Luteinizing hormone supports corpus luteum function, and low LH levels have been described after human menopausal gonadotropin treatment, after gonadotropin-releasing hormone (GnRH)-agonist treatment, or after GnRH-antagonist treatment. These low luteal LH levels may lead to an insufficient corpus luteum function and consequently to a shortened luteal phase or to the low luteal progesterone concentrations frequently described after ovulation induction. A direct effect of the GnRH agonist or GnRH antagonist on human corpus luteum or on human endometrium and thus on endometrial receptivity cannot be excluded, as GnRH receptors have been described in both compartments. Endometrial histology has revealed a wide range of abnormalities during the various stimulation protocols. In GnRH-agonist cycles, mid-luteal biopsies have revealed increased glandulo-stromal dyssynchrony and delay in endometrial development, strong positivity of endometrial glands for progesterone receptors, decreased alphavbeta3-integrin subunit expression, and earlier appearance of surface epithelium pinopodes. These factors suggest a shift forwards of the implantation window. Progesterone supplementation improves endometrial histology, and its necessity has been well established, at least in cycles using GnRH agonists.

Endometrium↗

Peri-implantation phase endometrial estrogen and progesterone receptors: effect of ovulation induction with clomiphene citrate.

The effects of clomiphene citrate on endometrial nuclear estradiol receptors and progesterone receptors were examined in 10 normal women during an untreated cycle (control) and during treatment with 50 mg clomiphene citrate and 150 mg clomiphene citrate daily on days 5 through 9. Concentrations and binding constants of the receptors were determined in endometrium obtained 8 to 12 days after midcycle luteinizing hormone surge. Scatchard plots for both estrogen receptors and progesterone receptors were linear, indicating only one type of high-affinity binding sites. In control cycles, estrogen receptor levels (mean +/- SEM) were 199.6 +/- 23.1 fmol/mg deoxyribonucleic acid, (n = 8) and were not significantly different from either 50 mg clomiphene citrate (180.5 +/- 19.1 fmol/mg deoxyribonucleic acid, n = 6) or 150 mg clomiphene citrate (194.3 +/- 35.2 fmol/mg deoxyribonucleic acid, n = 4). Similarly, the dissociation constants were unaffected by clomiphene citrate treatment. The concentrations of progesterone receptors in the control cycles (613 +/- 31 fmol/mg deoxyribonucleic acid, n = 5) and treatment cycles (50 mg clomiphene citrate -652.8 +/- 121 fmol/mg deoxyribonucleic acid, n = 6; 150 mg clomiphene citrate -592.6 +/- 31 fmol/mg deoxyribonucleic acid, n = 7) were also not significantly different. Clomiphene citrate also did not affect dissociation constants for progesterone receptors. Therefore, ovulation induction with clomiphene citrate apparently did not affect peri-implantation phase endometrial estrogen receptors and progesterone receptors or their respective binding constants.

Adult↗

The role of growth hormone in ovulation induction.

During the last few years the potential importance of intraovarian regulators of follicular development has been recognized, and the effects of various growth factors on granulosa cell responses to gonadotrophins have been extensively investigated. Ovarian responses to exogenous gonadotrophins were improved by adjuvant growth hormone (GH) treatment of GH-deficient patients, and responses to hMG were apparently predicted by estimated GH reserve. However, the results of different studies of GH/hMG cotreatment were equivocal. Therefore, a randomized, prospective, cross-over study protocol between GH/hMG/hCG versus hMG/hCG was undertaken. Whereas 16 pregnancies were achieved in the 26 Clonidine-negative patients (61.5%) either in the GH/hMG cycle (11) or in the succeeding one (5), no benefit was detected in 8 Clonidine-positive patients from the GH/hMG combination. The recently described GH-binding protein (BP) may reflect the GH-receptor. GH-BP levels were evaluated in the sera and follicular fluids (FF) of patients undergoing ovulation induction with either hMG/hCG or GH/hMG/hCG. GH-BP increase in serum correlated with E2, and progesterone (P4) concentrations. The FF GH-BP correlated with serum GH-BP levels. Lower FF GH-BP levels were measured in older compared to younger women, while increased values were obtained both in patients with elevated E2 concentrations in serum and in FF, or when more than five oocytes were retrieved. Primary increased GH-BP in unexplained infertility may suggest a new mechanism whereby excessive GH-BP levels may deprive GH from its receptor and thus decrease the introavarian IGF-I production.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Development and influence of an endogenous serum luteinizing hormone surge after ovulation induction in stimulated cycles.

The aim of this study was to investigate whether the endogenous serum luteinizing hormone (LH) discharge in stimulated cycles--either simultaneously with or shortly after exogenous human chorionic gonadotropin (hCG) administration--is influenced by serum steroid hormones and follicle stimulating hormone (FSH). We also tested whether the LH discharge affects intrafollicular hormone metabolism and oocyte fertilization. In a group of 46 women with tubal pathology who were undergoing in vitro fertilization (IVF), follicular fluids were collected during oocyte retrieval. In addition blood samples were drawn daily, starting at cycle day 7 until the day of oocyte retrieval. LH, FSH, estradiol, progesterone, testosterone and prolactin were determined in all samples of serum and follicular fluid. Oocyte maturation was classified according to the morphology of the oocyte corona-cumulus complex. Of the 46 women studied, 15 showed no LH surge (group A) and 31 developed an endogenous LH surge (group B). Serum samples showed no significant differences between the two groups in follicular phase estradiol, progesterone, testosterone and prolactin. Only levels of serum FSH showed a significant difference between groups A and B (p < 0.0005). In follicular fluid samples LH (p < 0.05) and FSH levels (p < 0.005) were significantly different. Fertilization rate and cleavage rate, however, did not differ significantly. The late endogenous LH surge occurring simultaneously with or shortly after hCG application for ovulation induction did not affect intrafollicular steroid metabolism, oocyte maturation, fertilization rate or cleavage rate.

Adult↗