Gonadotrophin-releasing hormone agonist compared with human chorionic gonadotrophin for ovulation induction after clomiphene citrate treatment

The objective of this study was to compare hormonal response,luteal phase adequacy and pregnancy and abortion rates in patientsrandomized to receive human chorionic gonadotrophin (HCG) orgonadotrophinreleasing hormone agonist (GnRHa) during ovulationcycles stimulated by clomiphene citrate. Anovulatory patientsreceived either one s.c. dose of tryptorelin (0.1 mg; n = 104)or one i.m. dose of HCG (10 000 IU; n = 106) after clomiphenecitrate stimulation had induced enlarged ovarian follicles (>17mm in diameter). A short-lived, transitory increase in serumluteinizing hormone (98 ± 9 IU/1) and follicle-stimulatinghormone (30 ± 5 IU/1) concentrations was measured at12 h following the injection of GnRHa, and these concentrationsreturned to baseline levels by 36 h post-injection. Midlutealprogesterone concentrations were similar in both groups (>10ng/ml), and the mean luteal phase duration was also not significantlydifferent (13 days). There were no significant differences inthe mean number of pregnancies (12.0 versus 12.6% per cycle)and the abortion rate (18.2 versus 12.5%) between the GnRHa-and HCG-treated groups respectively. There were no complicationsrelated to treatment in either group. The results show thata relatively low dose of GnRHa can be used in place of HCG toinduce ovulation in clomiphene citrate-treated patients.     

Sequential clomiphene citrate and human menopausal gonadotrophin for ovulation induction: comparison to clomiphene citrate alone and human menopausal gonadotrophin alone

The need for frequent injections and monitoring, the possibilityof multiple gestations, and the higher cost compared to clomiphenecitrate, prevents many clinicians from using human menopausalgonadotrophin (HMG) for ovulation induction. A sequential medicationregimen, in which HMG is taken after clomiphene, overcomes theseproblems. We retrospectively compared per cycle fecundity andbirth rates in 119 cycles of clomiphene—HMG, 524 cyclesof clomiphene alone, 57 cycles of HMG alone, and 79 cycles ofconcurrent HMG and clomiphene in patients receiving intra-uterineinsemination (IUI), who were free of endometriosis or tubaldisease. Per cycle fecundity for clomiphene—HMG was 22%[95% confidence interval (CI) 12–34%], double that ofclomiphene alone (11%) (95% CI 8–14%) (P < 0.01), andequal to HMG alone (18%) (95% CI 7–29%) or HMG and clomiphenetogether (19%) (95% CI 10–28%). The multiple birth ratefor clomiphene—HMG (7/21) equalled that for HMG alone(3/12) and HMG and clomiphene together (3/8). The average numberof ampoules of HMG required [follicle stimulating hormone (FSH)75 mIU, luteinizing hormone (LH) 75 mIU] was decreased by 65%from 24.5 ± 1.0 for HMG or HMG and clomiphene togetherto 8.6 ± 0.3 for clomiphene—HMG (P < 0.001).Per cycle fecundity was identical when one, two or three ampoulesof HMG per day were administered after clomiphene. We concludethat ovulation induction with sequential clomiphene—HMGresults in fecundity double that of clomiphene alone and equalto HMG alone or concurrent with clomiphene, thereby reducingthe requirement for HMG.     

Response to clomiphene citrate in the polycystic ovarian syndrome according to different LH/FSH ratios

Twenty-nine clomiphene tests were carried out, 19 on subjectswith polycystic ovarian syndrome (PCO) who did not wish to conceiveand 10 on women with correct ovarian function (control women).The intention was to determine if the response of the hypothalamic—pituitary—ovaryaxis varies according to different LH/FSH ratios. The resultsindicate that with repeated LH/FSH ratios of <3, the positiveand negative feedback systems are preserved in most subjects,but when the ratio is higher than 3, both systems are significntlyaltered (P < 0.01). In the control group, both systems werepreserved in all subjects. In another group composed of 26 infertilepatients with PCO, the rate of ovulation and pregnancy afteradministration of clomiphene citrate (CC) was correlated accordingto different LH/FSH ratios. A significant (P < 0.0001) redudonin the rate of ovulation and a lesser reduction in pregnancywas found with increasing LH/FSH ratios. In conclusion we suggestthat the LH/FSH ratio is a good marker of this syndrome, andcan be used to give a prognosis on the severity of the syndrome,as well as the ovulatory capacity of the subject after administrationof CC.     

Pharmaco-dynamics of human menopausal gonadotrophin (HMG) and follicle-stimulating hormone (FSH). The importance of the FSH concentration in initiating follicular growth in polycystic ovary-like disease

Using a randomized double-blind cross-over design, the pharmaco-dynamicand pharmaco-kinetic properties of ‘pure’ follicle-stimulatinghormone (FSH) (Metrodin) and human menopausal gonadotrophin(HMG) (Pergonal) were studied in 24 women with polycystic ovary-likedisease (PCOD) during induction of ovulation. Fifty-six cycleswere stimulated with FSH and 60 cycles with HMG, according toa standard protocol. Gonadotrophins were administered i.v. ina pulsatile fashion using pulse frequencies of either 30 or120 min. The cycles stimulated with either 30 or 120 min pulseintervals showed no differences among themselves. During thestimulation phase, the FSH and HMG stimulated cycles showedequal and dose dependent FSH concentrations (mean ± SD).The luteinizing hormone (LH) concentrations (mean ± SD)were also equal but unchanged compared to the mean basal concentration.The LH, FSH, total urinary oestrogen excretion, and testosteroneprofiles (mean ± SD) obtained from cycle days –10to 0 as well as the pregnanediol profiles obtained from cycledays 0 to +14 showed no differences either. The occurrence ofan endogenous preovulatory LH surge was significantly more frequentin the cycles stimulated with a pulse interval of 30 min comparedto the cycles stimulated with a pulse interval of 120 min. Theaddition of LH as provided in HMG did not influence the FSHthreshold concentration above which initiation of folliculargrowth occurred, since no differences were found in the FSH‘stable’ concentrations between FSH and HMG stimulatedcycles. However, intra- and inter-individual variation in theFSH ‘stable’ concentration at which follicular growthwas initiated became obvious. It has been hypothesized thateither diminished circulating bioactive FSH or intrafollicularparacrine factors may influence the FSH threshold concentrationabove which the ovary responds with follicular growth.     

Pure FSH for ovulation induction in patients with polycystic ovary syndrome and resistant to clomiphene citrate therapy

Twenty-nine infertile women with polycystic ovary disease whichwas resistant to therapy with clomiphene citrate underwent acombined treatment for follicle recruitment consisting of pureFSH during the first days of the cycle and HMG during the lastdays of the follicular phase. Sixty cycles were stimulated ofwhich 83% were ovulatory. Eighteen pregnancies were achieved(36% of cycles, 62% of patients). The multiple pregnancy ratewas 39%. Twelve cycles (20%) showed the ovarian hyperstimulationsyndrome (OHS) although seven of these resulted in full termdeliveries. There were no miscarriages among the patients studied.     

Modern use of clomiphene citrate in induction of ovulation

Clomiphene citrate is the treatment of first choice in the managementof infertility in normally oestrogenized, anovulatory women(WH0 group II). The majority of women with 'pure' anovulatoryinfertility respond to treatment with clomiphene citrate. Therates of pregnancy and miscarriage are close to those expectedin a normal fertile population. Basal hormone concentrationsdo not predict outcome. An increased body mass index is theonly factor which is consistently associated with a decreasedresponse to clomiphene citrate; it follows therefore, that weightreduction should be an important part of therapy in anovulatorywomen. According to our data, only an increased luteinizinghormone value immediately post clomiphene citrate predictedan adverse pregnancy outcome in women who conceived. Clomiphenecitrate, along with other ovulation induction therapies, cancause multiple follicular development, with a risk of ovarianhyperstimulation and multiple pregnancy. Ultrasound monitoringof treatment is important in order to choose the appropriatedose of clomiphene citrate in subsequent cycles and to minimizethe risks of hyperstimulation and multiple pregnancy. When coupleswith other factors contributing to subfertility are excluded,the cumulative conception rate continues to rise after 6 monthsof treatment with clomiphene citrate, reaches a plateau by treatmentcycle 12 and approaches that of the normal population. It hasbeen reported that prolonged use of clomiphene citrate may beassociated with an increased risk of a borderline or invasiveovarian tumour. Taking into consideration these observations,we recommend that anovulatory women responsive to clomiphenecitrate should be treated for at least 6 cycles before consideringmore complex or invasive methods of ovulation induction, andthat treatment should probably be limited to a maximum of 12cycles.     

Comparison of tamoxifen and clomiphene citrate for ovulation induction: a meta-analysis

BACKGROUND: Both selective estrogen receptor modulators, tamoxifen and clomiphene have been used for ovulation induction for patients with anovulatory infertility. This meta-analysis sought to compare the effectiveness of tamoxifen to clomiphene for the induction of ovulation and achievement of pregnancy. METHODS: We searched MEDLINE, BIOSIS, PreMEDLINE, CINAHL, International Pharmaceutical Abstracts, DDSR, ACP Journal Club, DARE and CCTR, along with reference lists and national experts. Inclusion criteria were prospective clinical trials, which compared tamoxifen and clomiphene for ovulation induction in infertile couples with isolated anovulatory infertility. Main outcome measures were ovulation rate and clinical pregnancy rate. Pooled odds ratios were obtained using random effects meta-analysis. RESULTS: Four trials were included. After pooling all the trials, the use of tamoxifen or clomiphene citrate resulted in similar ovulation rates [odds ratio (OR) 0.755, 95% confidence interval (CI) 0.513-1.111]. There was no benefit of tamoxifen over clomiphene citrate in achievement of pregnancy per cycle (OR 1.056, 95% CI 0.583-1.912) or per ovulatory cycle (OR 1.162, 95% CI 0.632-2.134). CONCLUSIONS: Clomiphene citrate and tamoxifen are equally effective in inducing ovulation. Although data regarding pregnancy rates and outcome are limited, there does not appear to be a significant benefit of one medication over the other.     

Low multiple pregnancy rate in combined clomiphene citrate--human menopausal gonadotrophin treatment for ovulation induction or enhancement

Sixty-five infertile women, 37 with anovulation, eight with ovulatory disturbances and 20 with unexplained infertility were treated by a combination of clomiphene citrate (CC) from cycle day 5 (or 3) and human menopausal gonadotrophin (HMG) begun 3 days later for induction or enhancement of ovulation. Monitoring was carried out by measuring preovulatory 17-beta-oestradiol (E2) and progesterone (P) concentrations in blood samples and by follicle measurements using ultrasound. Forty-seven pregnancies resulted with a multiple pregnancy rate of 7.7% for those completed. This incidence is very low and within the range found for CC induction and might result from the later commencement of stimulation compared with many other protocols. These results were achieved with a low incidence of ovarian hyperstimulation syndrome (2.6% per cycle). The HMG doses given were low in comparison with those found in other forms of induction. The deleterious effects of this combined mode of induction on cervical mucus and the occurrence of premature spontaneous ovulation were much less than in the sequential mode of treatment. These results suggest that combined induction treatment by CC and HMG as described offers a means of achieving low rates of multiple pregnancies a known complication in the induction of ovulation.     

Randomized controlled trial comparing laparoscopic ovarian diathermy with clomiphene citrate as a first-line method of ovulation induction in women with polycystic ovary syndrome

BACKGROUND: Laparoscopic ovarian diathermy (LOD) is currently accepted asa successful second-line treatment for ovulation induction (OI)in clomiphene citrate (CC)-resistant women with polycystic ovarysyndrome (PCOS). The aim of this study was to test the hypothesisthat LOD may be superior to CC as a first-line treatment. METHODS: The study included 72 anovulatory women with PCOS who were randomizedto LOD (n = 36) or CC (n = 36). Women who remained anovulatoryafter LOD were offered CC. Similarly, women receiving CC whofailed to ovulate or conceive were offered LOD. Pregnancy rateswere compared between the two groups using ² and odds ratiowith 95% confidence interval (OR, 95% CI). RESULTS: After randomization, six women conceived before starting treatmentand another patient postponed treatment. The remaining 65 womenreceived the treatment (33 underwent LOD and 32 received CC).After the primary treatment, more pregnancies (44%) occurredin women receiving CC than in those undergoing LOD (27%), althoughthe difference did not reach statistical significance [P = 0.13,OR 2.1 (0.7 – 5.8)]. After adding the second treatment,the pregnancy rate was still higher, but to a less extent, inthe CC group [63% versus 52%, P = 0.2, OR 1.6 (0.6 – 4.2)]. CONCLUSIONS: LOD is not superior to CC as a first-line method of OI in womenwith PCOS. The trial is registered with ClinicalTrials.gov withan identifier number NCT00220545 [ClinicalTrials.gov] .     

Effect of opiate receptor blockade on the insulin response to oral glucose load in polycystic ovarian disease.

In order to test the hypothesis that endogenous opiates are at least partially responsible for hyperinsulinaemia in patients with polycystic ovarian disease (PCOD), the effect of naloxone (an opiate receptor blocker) on the insulin response to oral glucose load (OGTT) was studied in 20 women with PCOD and 17 control subjects at days 5-8 of their follicular phase. After fasting overnight for 10-12 h, each woman received an i.v. bolus injection (2 mg) of naloxone or an equal volume of saline infusion followed by a constant infusion of naloxone or saline solution at a rate of 8 ml/h (1 mg/h of naloxone) for 5 h. OGTT (75 g) was performed 1 h after the bolus injection. The naloxone study was performed 48 h after the saline study. Naloxone did not modify the insulin response to OGTT in either group. When the data were related to the insulin response, in PCOD hyperinsulinaemic patients, naloxone significantly reduced (P less than 0.02) the insulin response to OGTT without any change in glycaemic response curves. In control and PCOD normoinsulinaemic patients, naloxone did not change significantly either the glycaemia or the insulin levels after OGTT. No change of gonadotrophin and steroid secretion was found in any patient receiving naloxone. In conclusion, endogenous opiates may play a significant role in hyperinsulinaemia in PCOD.     

Predictors for treatment failure after laparoscopic electrocautery of the ovaries in women with clomiphene citrate resistant polycystic ovary syndrome

BACKGROUND: Laparoscopic electrocautery has been put forward as the treatment of choice in women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). In order to make an informed treatment decision it would be helpful if we could identify women with PCOS with a high probability of treatment failure following electrocautery of the ovaries. METHODS: Eighty-three women with CC-resistant PCOS were allocated to receive laparoscopic electrocautery followed by CC when anovulation persisted as part of a randomized controlled trial. Multivariable logistic regression analyses using clinical, ultrasonographic and endocrinological parameters were performed to predict (i) failure to ovulate within 8 weeks after electrocautery, and (ii) failure to reach an ongoing pregnancy after electrocautery with or without CC. RESULTS: Of the 83 women, 56 (67%) ovulated within 8 weeks after electrocautery. The model for predicting anovulation after electrocautery included LH/FSH rate, year of menarche and glucose level. Women who were younger at menarche, had a lower LH/FSH ratio and a lower glucose level were more likely to have persistent anovulation. The area under the curve was 0.74. After electrocautery and CC, 41 women reached an ongoing pregnancy. No prognostic parameters could be identified to predict failure to reach an ongoing pregnancy after electrocautery followed by CC. CONCLUSIONS: Persistence of anovulation after electrocautery could be predicted and women with a high risk of persisting anovulation could be distinguished. We were, however, not able to predict treatment failure after electrocautery followed by CC.     

Current and future status of ovulation induction in polycystic ovary syndrome

Great progress has been achieved during the last 20 years inthe field of ovulation induction in patients with polycysticovary syndrome (PCOS). Clomiphene citrate remains the firstline of treatment for all anovulatory women with PCOS, sincein properly selected patients the cumulative pregnancy rateapproaches that in normal women. Human urinary gonadotrophinshave been used extensively for ovulation induction but the developmentof low-dose regimens has opened a new era in the managementof anovulation related to PCOS. This article discusses the mainadvantages and disadvantages of the principal methods and regimenscurrently used for ovulation induction in patients with PCOSincluding clomiphene citrate, gonadotrophins, pulsatile gonadotrophin-releasinghormone (GnRH) and GnRH agonists. It also discusses new drugsdiscovered recently, particularly recombinant gonadotrophinsand GnRH antagonists, and provides some thoughts regarding theiruse in future protocols. Finally, based on the discovery ofnew ovarian substances which specifically control luteinizinghormone (LH) secretion, this article develops assumptions onpossible implications of these substances in the pathophysiologyof PCOS and their potential use in the management of the syndrome.     

An economic evaluation of laparoscopic ovarian diathermy versus gonadotrophin therapy for women with clomiphene citrate resistant polycystic ovary syndrome

BACKGROUND: Laparoscopic ovarian diathermy and gonadotrophin ovulation induction for women with clomiphene citrate resistant polycystic ovary syndrome have been shown to result in similar pregnancy rates, but their relative cost-effectiveness has not been evaluated. METHODS: A cost-minimization study was undertaken alongside a randomized controlled trial in women with anovulatory infertility secondary to clomiphene resistant polycystic ovary syndrome. Inclusion criteria were age less than 39 years, body mass index less than 35 kg/m(2), failure to ovulate with 150 mg of clomiphene citrate for 5 days in the early follicular phase, more than 12 months of infertility and no other causes of infertility. Laparoscopic ovarian diathermy was compared with three cycles of urinary or recombinant gonadotrophins. Direct and indirect costs were based on the results of a randomized trial. RESULTS: The cost of a live birth was one third lower in the group that underwent laparoscopic ovarian diathermy compared to those women who received gonadotrophins (19 640 New Zealand dollars and 29 836 New Zealand dollars, respectively). CONCLUSIONS: This economic evaluation shows that treating women with clomiphene-resistant polycystic ovarian syndrome with laparoscopic ovarian diathermy results in a significant reduction in both direct and indirect costs.     

Selective follicular reduction following ovulation induction by exogenous gonadotrophins in polycystic ovarian disease. A new approach to treatment

Seven patients with polycystic ovarian disease (PCO) and having polyfollicular development following ovulation induction by human menopausal gonadotrophin underwent selective follicular reduction by transvaginal ultrasound-guided aspiration of all follicles greater than or equal to 10 mm in diameter leaving two or three preovulatory mature follicles. Twenty-four and 48 h after injection of human chorionic gonadotrophin, the couples had intercourse. Five patients achieved pregnancy in 15 treatment cycles, four in their first cycle after 14 previous unsuccessful stimulation cycles. Four have delivered healthy children: three singletons and one set of twins. One patient spontaneously aborted twins in week 22 of pregnancy. No major complications were encountered. Selective follicular reduction seems to be a possible approach to the treatment of PCO patients having polyfollicular development following ovulation induction.     

The influence of body mass index, basal FSH and age on the response to gonadotrophin stimulation in non-polycystic ovarian syndrome patients

BACKGROUND: Adequate ovarian response to exogenous gonadotrophins is important for both ovulation induction (OI) and controlled ovarian stimulation (COS). The objective of this study was to analyse the effect of a number of clinical factors that influence ovarian response in non-polycystic ovarian syndrome (non-PCOS) patients. METHODS: A total of 140 OI cycles (52 subjects), where each subject had a single abnormality (elevated FSH, abnormal body mass index (BMI) or > or = 40 years of age), were compared with 54 cycles (15 subjects) where the patients displayed none of these abnormal features (the normal group). Similarly, 275 COS cycles (135 subjects), where each subject displayed a single abnormality, were compared with 79 cycles (40 subjects) in the normal group. RESULTS: For OI, subjects with a high basal FSH generally had an inadequate response with a poor chance of conception. Subjects with an abnormal BMI commonly required dosage adjustment so were more difficult to manage. Their potential for conception was normal. Older women seemed to respond normally with a normal expectation of conception. In the COS group, subjects with a moderately high basal FSH responded and conceived normally. Subjects with an abnormal BMI had an increased risk of an inadequate response leading to cancellation but if the response was adequate then the outlook was good. Older women required more gonadotrophin with a poor response and a low chance of conception. CONCLUSION: The results have better defined the anticipated responses of non-PCOS patients to gonadotrophin stimulation in both OI and COS.     

Endocrinology: The choice of treatment for anovulation associated with polycystic ovary syndrome following failure to conceive with clomiphene

The choice of treatment for clomiphene-resistant anovulationassociated with polycystic ovary syndrome (PCOS) is presentlyarbitrary and selection criteria are not available. A totalof 144 women with anovulatory infertility associated with PCOSwho failed to conceive on clomiphene were treated with eitherpure follicle stimulating hormone (FSH) (n = 29), or human menopausalgonadotrophin (HMG) (n = 60), or gonadotrophin-releasing hormoneanalogue (GnRHa) and HMG (n = 55). Analysis of 306 treatmentcycles and 53 pregnancies revealed a cumulative conception rateat 4 months of 23% with FSH, 47% with HMG and 69% with GnRHa+ HMG. The miscarriage rate was highest in the HMG group (44%)and consequently the cumulative live birth rate was superiorwhen GnRHa was used in combination with HMG. There were no significantdifferences in the basal clinical and endocrinological featuresof those who conceived compared with those who did not, eitherin the whole group, or in the individual treatment groups. Thus,the choice of treatment for clomiphene-resistant women withPCOS cannot be guided by the basal clinical or endocrinologicalfeatures of this heterogeneous syndrome with the present stateor knowledge.     

Laparoscopic electrocautery of the ovaries versus recombinant FSH in clomiphene citrate-resistant polycystic ovary syndrome. Impact on women's health-related quality of life

BACKGROUND: Ovulation induction with gonadotrophins is the standard treatment strategy for women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). Laparoscopic electrocautery of the ovaries is an alternative treatment modality, leading to a comparable cumulative pregnancy rate. In deciding which treatment to opt for, women's health-related quality of life (HRQoL) should be taken into account. METHODS: A total of 168 CC-resistant women with PCOS were randomly assigned to receive either the electrocautery strategy, entailing laparoscopic electrocautery of the ovaries followed by CC and recombinant FSH (rFSH) if anovulation persisted, or ovulation induction with rFSH. We assessed women's HRQoL with the standard questionnaires Short Form-36, Rotterdam Symptom Checklist and Center for Epidemiological Studies Depression Scale, administered before randomization and 2, 12 and 24 weeks thereafter. RESULTS: The intention to treat analysis revealed no significant differences between the treatment groups on any of the scales at any point during follow-up. In women without an ongoing pregnancy, those treated with rFSH showed significantly more depressive symptoms than women allocated to the electrocautery strategy, with or without CC, although differences were small. CONCLUSIONS: Overall, HRQoL was not affected in both groups. In women still under treatment, rFSH was slightly more burdensome for women's HRQoL than electrocautery with or without CC.     

Antral follicle count and FSH concentration after clomiphene citrate challenge test in the prediction of ovarian response during IVF treatment

BACKGROUND: We compared: (i) antral follicle count (AFC) in the early follicular phase, after the clomiphene citrate challenge test (CCCT) and before ovarian stimulation following pituitary down-regulation; and (ii) age of women, body mass index, basal and stimulated serum FSH concentrations and AFC in predicting the ovarian response of infertile women aged <40 years with basal FSH <10 IU/l on recruitment in their first IVF cycle. METHODS: Two months prior to the treatment cycle, AFC and basal FSH concentration were determined on day 2-3 of a spontaneous period and on day 10 after CCCT. All women received a standard stimulation regimen. Ovarian response was represented by the number of oocytes, serum estradiol, the duration and dosage of gonadotrophins. RESULTS: There was no significant difference between basal, stimulated and down-regulated AFC. AFC achieved the best predictive value in relation to the number of oocytes, followed by combined FSH concentration (sum of the two FSH concentrations) and age of women. Both basal AFC and combined FSH concentration were predictive factors of serum estradiol concentration, whereas stimulated FSH concentration was predictive of the total dosage of gonadotrophins. CONCLUSION: Combined FSH concentration after CCCT provides additional information in predicting ovarian response.     

Studies on the influence of gonadotrophin levels in the early follicular phase on the ovarian response to stimulation

The gonadotrophic regulation of folliculogenesis has been extensively investigated but little attention has been paid to the influence of early follicular phase levels of endogenous FSH and the FSH/LH ratio when planning ovulation stimulation therapy for IVF. The influence of these factors was investigated in the three studies reported in this paper. A fixed schedule of ovulation stimulation therapy which employed standard treatment regimens, irrespective of the ovarian response, was used to eliminate variation due to treatment factors. Cycles were pretreated with an oestrogen-progestogen contraceptive pill or a progestogen (norethisterone). It was found that both oestrogen-progestogen and progestogen alone decreased the plasma FSH level, although the FSH/LH ratio was significantly reduced only by oestrogen-progestogens. In clinical IVF studies, oestrogen-progestogen pretreatment was associated with a significant reduction in the preovulatory concentration of oestradiol in plasma and the number of aspirated follicles, compared to norethisterone. The administration of FSH for 2 days following oestrogen-progestogen pretreatment and prior to the fixed schedule of ovulation stimulation normalized ovarian steroidogenesis and follicular development. Early follicular phase supplementation with FSH had no influence on progestogen pretreated cycles. The final experiment investigated the influence of FSH/LH levels in the early follicular phase on the outcome of ovarian stimulation. The preovulatory oestradiol concentration was reduced when baseline FSH/LH levels were low compared with when these values were high. Administration of FSH for 2 days in the early follicular phase improved the preovulatory level of oestradiol when baseline FSH/LH was low but had no effect when baseline FSH/LH levels were high.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sequential hormonal supplementation with vaginal estradiol and progesterone gel corrects the effect of clomiphene on the endometrium in oligo-ovulatory women

BACKGROUND: We investigated the possibility of correcting the endometrial alterations induced with clomiphene citrate (CC) by vaginal hormonal supplementation (HS) with estradiol (E2) and progesterone gel. METHODS: Oligo-ovulatory women were prospectively randomized into four groups receiving either 50 mg (groups 1 and 2) or 100 mg (groups 3 and 4) of CC from cycle day 3-8. Groups 2 and 4 also received vaginal E2 cream 0.1 mg twice daily from day 8 until the LH surge and vaginal progesterone gel, starting 3 days after ovulation. All participants had an endometrial biopsy performed 10 +/- 1 days after ovulation. RESULTS: All biopsies in the HS groups (2 and 4) showed complete predecidual changes, and were 'in-phase' with findings normally made 10 days post-ovulation (+/- 2 days of clinical dating). However, without HS (groups 1 and 3), only 4/6 and 3/6 biopsies showed predecidual changes in women receiving 50 and 100 mg of CC. CONCLUSION: The addition of vaginal E2 and progesterone to CC ovulation induction regimens normalizes the alterations in endometrial morphology. Hormonal treatment combining vaginal E2 and progesterone may improve endometrial receptivity in CC cycles and ultimately yield higher pregnancy rates.