Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation

OBJECTIVE: This study was undertaken to report the outcome of pregnancies achieved after ovarian stimulation, including the use of the aromatase inhibitor, letrozole, for ovarian stimulation. STUDY DESIGN: A cohort study comparing the outcome of pregnancies achieved after letrozole and other ovarian stimulation treatments with a control group of pregnancies spontaneously conceived without ovarian stimulation. RESULTS: In 3 tertiary referral centers, there were 394 pregnancy cycles in 345 infertile couples (63 pregnancies with 2.5 mg of letrozole alone or with gonadotropins, 70 pregnancies with 5.0 mg of letrozole, 113 pregnancies with clomiphene alone or with gonadotropins, 110 pregnancies with gonadotropins alone, and 38 pregnancies achieved without ovarian stimulation). Pregnancies conceived after letrozole treatments were associated with similar miscarriage and ectopic pregnancy rates compared with all other groups. In addition, letrozole use was associated with a significantly lower rate of multiple gestation compared with clomiphene citrate. CONCLUSION: The favorable pregnancy outcome and low multiple gestation rate of aromatase inhibitors for ovarian stimulation is encouraging for the development of these agents as first-line ovulation induction agents.     

Gonadotropin dynamics in women receiving immediate or delayed transdermal estradiol after oophorectomy

A prospective study was performed in 24 premenopausal women to evaluate the gonadotropin dynamics of pharmacologic doses of transdermal estradiol-17 beta (E2) administered after bilateral oophorectomy. Patients were given 0.2-mg transdermal E2 patches for 2 weeks, followed by 0.1-mg patches for 4 weeks either immediately postoperatively (immediate estrogen replacement therapy [ERT]) or beginning 12-14 days after surgery (delayed ERT). Serum gonadotropins and E2 levels were measured serially, and postmenopausal symptoms were prospectively recorded. Administration of 0.2 mg transdermal E2 immediately after surgery suppressed the post-castration rise in gonadotropins for at least 4 days, but LH and FSH levels did increase to the menopausal range after 2 weeks despite continued therapy. Sustained circulating levels of E2 with transdermal E2 therapy were comparable to follicular phase values. Vasomotor symptoms were well controlled by 0.2 mg of transdermal E2 in the majority of patients during the clinical trial. There was no significant estrogen-related morbidity despite the large doses used. Two patients had skin irritation at the patch site causing discontinuation of therapy. These data suggest that large doses of transdermal E2 can suppress gonadotropin levels only for a brief interval. We were unable to demonstrate any long-term alteration in the hypothalamic-pituitary set point for sensitivity to exogenous E2.     

Revisiting the clomifene-gonadotropin protocol in IVF with the use of a GnRH antagonist

OBJECTIVE: To assess the ability of GnRH antagonists to prevent LH surges during superovulation for IVF in classical stimulation protocols with clomiphene and gonadotropins. PATIENTS AND METHODS: Fifty-eight patients were treated with clomiphene (100 mg daily for 5 days starting on cycle day 2) and gonadotropins (225 UI HMG on cycle days 5, 7 and 9), with monitoring starting on cycle day 10. Cetrorelix, 0.25 mg, was administered daily when dominant follicle diameter reached 18 mm and/or plasma estradiol levels 800 pg/ml. RESULTS: No premature LH surge was observed during the 48 stimulation cycles completed. The pregnancy rate was 20.8% per punction and 25.6% per transfer, and there was no clinical ovarian hyperstimulation syndrome in these series. CONCLUSIONS: Cetrorelix, 0.25 mg, optimizes the classical stimulation with clomiphene and gonadotropins by preventing LH surges; the so-completed protocol yields acceptable pregnancy rates with lower hormone quantities and reduced risks of ovarian hyperstimulation, and becomes a convenient choice when "softer" treatments for IVF are considered.     

Metformin administration in patients with polycystic ovary syndrome who receive gonadotropins for in vitro fertilization cycles: 10-year experience in a large infertile population

The study aim was to evaluate our personal experience regarding the use and the reproductive effect of metformin administration in a large population of infertile patients with polycystic ovary syndrome (PCOS) undergoing gonadotropins ovarian stimulation for in vitro fertilization (IVF). Infertile patients with PCOS undergoing gonadotropins ovarian stimulation with (metformin group, n?=?191) or without (control group, n?=?187) metformin and IVF were evaluated. Treatment characteristics, patients’ data and reproductive outcomes were evaluated. In all cases, metformin with an immediate-release formulation was administered, and in most of cases it was given as pre- and co-treatment (74.9%) and at a dosage of 1700?mg/day (59.7%). Stimulation length and gonadotropins doses were significantly (p?<?0.05) higher in metformin group than in control group. The number of dominant follicles on day of ovarian maturation triggering and peak oestradiol levels were significantly (p?<?0.05) lower in metformin group than in control group. Cycle cancellation rate under metformin resulted significantly influenced by interaction with body mass index (BMI), age and basal follicle-stimulating hormone (FSH) levels. Notwithstanding, metformin use in infertile PCOS patients who receive gonadotropins for IVF is not standardized, it seems to modulate the ovarian response to stimulation. This effect may benefit or harm on the basis of ovarian reserve and patients’ characteristics.     

A randomized controlled trial of laparoscopic ovarian diathermy versus gonadotropin therapy for women with clomiphene citrate-resistant polycystic ovary syndrome

OBJECTIVE: To compare the effectiveness of laparoscopic ovarian diathermy with gonadotropin ovulation induction for women with clomiphene citrate-resistant polycystic ovary syndrome. DESIGN: Randomized controlled trial. SETTING: A tertiary referral fertility clinic. PATIENT(S): Women with anovulatory infertility secondary to clomiphene-resistant polycystic ovary syndrome. Inclusion criteria were age of <39 years, body mass index of <35 kg/m(2), failure to ovulate with 150 mg of clomiphene citrate for 5 days in the early follicular phase, >12 months of infertility, and no other causes of infertility. INTERVENTION(S): Laparoscopic ovarian diathermy versus three cycles of urinary or recombinant gonadotropins. MAIN OUTCOME MEASURE(S): Cumulative pregnancy and miscarriage rates. RESULT(S): Cumulative pregnancy rates were 28% at 6 months for laparoscopic ovarian diathermy and 33% for three cycles of ovulation induction with gonadotropins. There were three miscarriages in each group. Women in the laparoscopic ovarian diathermy arm of the study had four additional spontaneous pregnancies 6 to 12 months after surgery. CONCLUSION(S): There was no statistically significant difference in pregnancy or miscarriage rates during the 6-month follow-up period or the three cycles. Laparoscopic ovarian diathermy is a safe and effective alternative to ovulation induction with gonadotropins.     

Characterizing pituitary response to a gonadotropin-releasing hormone (GnRH) antagonist in monkeys: tonic follicle-stimulating hormone/luteinizing hormone secretion versus acute GnRH challenge tests before, during, and after treatment

Pituitary sensitivity to a gonadotropin-releasing hormone (GnRH) challenge test before, during, and after GnRH antagonist administration was compared in four ovariectomized female monkeys receiving GnRH antagonist intramuscularly (IM) at increasing doses of 0.3, 1.0, and 3.0 mg/kg/day over 9 days. Three days before and 3 days after treatment, monkeys received vehicle alone. On experiment days 4, 7, 10, 13, and 16, 100 micrograms of GnRH was administered intravenously (IV) and blood drawn at 0 and 30 minutes. Before treatment, tonic follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were 248 +/- 105 and 178 +/- 31 ng/ml, respectively; after 0.3 mg/kg/day of GnRH antagonist, FSH and LH decreased to 30 +/- 6 and 41 +/- 4 ng/ml, respectively. After treatment with either 1 mg/kg/day or 3 mg/kg/day of GnRH antagonist, both gonadotropins were undetectable in serum. Monkeys with lower initial levels of gonadotropins were suppressed by 48 hours after GnRH antagonist, while those with higher tonic gonadotropins were suppressed 6 days later (FSH: r = 0.992; LH: r = 0.833). The data show that initial physiologic status is predictive of the rapidity of the suppression response induced by a GnRH antagonist and that, after achieving pituitary suppression, responsivity to an IV GnRH challenge test may be restored before normal tonic FSH/LH secretion is regained.     

A combination of gonadotropin-releasing hormone analog and human menopausal gonadotropins for ovulation induction in premature ovarian failure

A combination of gonadotropin-releasing hormone agonist and human menopausal gonadotropins was used for ovulation induction in a patient with premature ovarian failure. A paradoxical suppression of any ovarian response was noted despite increasing doses of human menopausal gonadotropins.     

Effect of tetrahydrocannabinol on the hypothalamic-pituitary axis in the ovariectomized rhesus monkey.

Single doses of delta9-tetrahydrocannabinol (THC) (5.0, 2.5, 1.25, or 0.625 mg/kg) can decrease the levels of both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the ovariectomized rhesus monkey. The inhibition of gonadotropins (50% to 88%) lasts for 6 to 24 hours depending upon the dose of THC. There are no great differences in the responses of the two gonadotropins to THC. The inhibition of gonadotropin levels by THC appears to be at the level of the hypothalamus, since both LH and FSH are released from the pituitary gland in response to LH- releasing factor in the presence of THC.     

Severe ovarian hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for in vitro fertilization: a European series and a proposal for prevention

Severe ovarian hyperstimulation syndrome (OHSS) was recorded in 8 of 413 patients after the use of gonadotropin-releasing hormone agonists (GnRH-a) associated with gonadotropins for in vitro fertilization. Seven of the 8 patients were pregnant. Common factors associated with the development of OHSS were high serum estradiol values on the day of ovulation induction and many follicles greater than or equal to 12 mm. Based on this experience, a new therapeutic schedule was used in a group of 10 patients who, after GnRH-a and gonadotropin stimulation, were judged to be at high risk of OHSS on the day of human chorionic gonadotropin (hCG). No hCG was administered and gonadotropins were stopped. The administration of GnRH-a was continued and, after a further period of pituitary desensitization, follicular stimulation was recommended with a lower dose of gonadotropins. No cases of OHSS occurred and 3 patients became pregnant.     

Clomiphene citrate in LH surge suppression for women undergoing ICSI

Objective

To evaluate the effect of adding clomiphene citrate (CC) in the mid-to-late follicular phase as an adjuvant to gonadotropins to suppress luteinizing hormone (LH) surge in women undergoing intracytoplasmic sperm injection (ICSI).

Microdose follicular phase gonadotropin-releasing hormone agonists (GnRH-a) compared with luteal phase GnRH-a for ovarian stimulation at in vitro fertilization

Objective: To compare an ovarian stimulation protocol using microdose follicular phase GnRH agonist (GnRH-a) and oral contraceptive (OC) pills to a luteal phase GnRH-a protocol.

Design: Retrospective analysis.

Setting: University affiliated IVF program.

Patient(s): One hundred seventy patients who underwent IVF and ET in 1996.

Intervention(s): Patients were assigned to either a midluteal start of leuprolide acetate (LA) 1 mg/d, reduced to 0.5 mg/d after addition of gonadotropins (LUT), or OC pills until cycle day 0 followed by 20 μg of LA every 12 hours on cycle day 3 with addition of gonadotropins on cycle day 5 (MICRO).

Main Outcome Measure(s): Number of FSH ampules, days of stimulation, peak E₂, and number of oocytes retrieved.

Result(s): There were no statistically significant differences in the main outcome measures between the two groups using an age-matched ANOVA. Clinical pregnancy rate per cycle start was not statistically different (LUT = 54%, and MICRO = 37%). The cancellation rate was significantly higher in the MICRO group (22.5% vs. 8.2%).

Conclusion(s): Given the higher cancellation rate in the microdose group, a randomized clinical trial is required to determine the possible benefit of a lower dose of GnRH-a in patients with normal ovarian function.     

Gonadotropins and glucocorticoid therapy for “low responders”—A controlled study

Purpose: A randomized, nonplacebo controlled study was conducted to determine the effect of dexamethasone supplementation to a protocol of gonadotropin therapy in 42 “low-responder patients” aged 32 to 43 years. Methods: All underwent at least two previous cycles treated by gonadotropins for unexplained infertility, or anovulation. Human menopausal gonadotropin was started on day 4 of the menstrual cycle combined with dexamethasone 0.5 mg administered nightly, as an adjuvant. A group of “low responders” who did not receive dexamethasone served as the controls. The number of follicles, total amount of gonadotropins used, time required for stimulation, fertilization, peak estradiol levels and pregnancy rate were evaluated. Results: The number of developing follicles, estradiol levels, fertilization rate and pregnancy rate did not differ significantly. Conclusions: Although certain beneficial effects were observed in the literature in some of the infertile patients treated with corticosteroids, the overall results did not support daily, low-dose dexamethasone (long-acting corticosteroid) as a clinically useful adjuvant therapy for “low responders” during gonadotropin therapy.     

Effects of gonadotropin on the growth of malignant ovarian neoplasms assessed by subrenal capsule assay

In the present study 18 cases of malignant ovarian neoplasm were studied to determine the possible role of sex steroid hormones and gonadotropins on tumor development. Twelve cases of serous cystadenocarcinoma, 2 of mucinous cystadenocarcinoma, 2 of endometrioid carcinoma, one malignant Brenner tumor, and one yolk sac tumor were examined with respect to their response to estradiol (E2), [D-Ser(But)6]-LHRH (1-9) nonapeptide-etylamide (Buserelin), human menopausal gonadotropin (HMG), RU 38486 (RU), and pure FSH by subrenal capsule assay (SRCA). Also 125I-FSH binding assay and the protein kinase C (CK) activity were studied in vitro. The results showed; 1) Seventy-three% cases showed a significant increase (p less than 0.05) in size due to SRCA. 2) In the FSH, HMG, and Buserelin treated groups, the size of xenografts increased (p less than 0.05) and the highest response was obtained with FSH. 3) Ninety-one% of cases demonstrated in vitro FSH specific binding which was significantly higher (p less than 0.05) in the cases which responded to gonadotropins in SRCA (42,288 +/- 25,454 vs 6,980 +/- 1,952, mean +/- SD, cpm/mg tissue). 4) CK activity was increased significantly (p less than 0.05) by gonadotropin (204.5 +/- 2.4 vs 363.9 +/- 7.2, mean +/- SD, cpm/mg tissue). These results suggest that gonadotropins possibly play a role in prompting the tumorigenesis of the malignant ovarian neoplasms through specific receptors and this mechanism may modify the CK system in malignant ovarian neoplasms.     

Mild/minimal stimulation for in vitro fertilization: an old idea that needs to be revisited

Mild ovarian stimulation for in vitro fertilization usually refers to the use of low-dose gonadotropins in conjunction with a gonadotropin-releasing hormone (GnRH) antagonist whereas minimal stimulation refers to the use of a sequential administration of clomiphene citrate followed by low-dose gonadotropins and a GnRH antagonist. These protocols offer important cost and tolerability advantages to all patients but specifically to high and low responders.     

Plasma estriol and its conjugates following oral and vaginal administration of estriol to postmenopausal women: correlations with gonadotropin levels

A study was designed to compared the metabolic fate and the biologic effects of 4 mg of estriol (E3) administered either orally or vaginally to six postmenopausal women. Blood samples were collected every hour for 6 hours and five different estriol fractions as well as gonadotropins were measured. Vaginal E3 administration resulted in a decline of 45% in luteinizing hormone (LH) levels and 17% in follicle-stimulating hormone (FSH) levels at 6 hours after treatment (p < 0.05). In contrast, the administration of 4 mg of E3 orally did not produce a decline of LH and FSH, despite the fact that the serum levels of E3-3-sulfate, E3-3-sulfate-16-glucosiduronate, estriol-3-glucosiduronate, and estriol-16-glucosiduronate were all fourfold to 24-fold higher after oral administration than after vaginal estriol administration. However, since the levels of unconjugated E3 were higher after the vaginal than after the oral administration of estriol, we conclude that only unconjugated E3 suppresses gonadotropins.     

Cotreatment with human growth hormone and gonadotropins for induction of ovulation: a controlled clinical trial

A randomized, double-blind, placebo-controlled trial of cotreatment with biosynthetic, human sequence, growth hormone (GH), and human menopausal gonadotropins (hMG) for induction of ovulation was performed in 16 women with amenorrhea and anovulatory infertility. Patients were randomly allocated to treatment with hMG + GH (24 IU on alternate days, total dose 144 IU) or hMG + placebo. Those who received placebo were given GH in a subsequent course of treatment. On cotreatment with GH compared with placebo, there was a significant reduction in the required dose of hMG, duration of treatment, and the daily effective dose of gonadotropins. Serum insulin-like growth factor-I (IGF-I) rose during treatment with GH but not with placebo. We conclude that growth hormone augments the response of the human ovary to stimulation by gonadotropins. These results suggest a role for the use of GH in induction of ovulation.     

Pituitary gonadotropins during long-term Enovid therapy

4 patients receiving the oral contraceptive Enovid, 5 mg tablets Day 5-24 of the treatment cycle, were studied for 7 cycles after therapy for a minimum of 12 and a maximum of 31 (mean duration of 25) consecutive months of therapy. In addition 1 patient was studied for a control cycle before receiving medication and a second cycle while on medication. Total gonadotropins and luteinizing hormone (LH) were determined on 24 hour specimens. There was a slight depression of total gonadotropins in the patients receiving long-term cyclic therapy. The results of the LH excretion studies showed no evidence of a midcycle peak in the patients on medication. It was suggested that the loss of the midcycle LH peak and generally diminished total gonadotropin levels might be adequate explanation for ovulation suppression by Enovid.     

A double-blind, randomized, placebo-controlled study to assess the efficacy of ketoconazole for reducing the risk of ovarian hyperstimulation syndrome

OBJECTIVE: To evaluate the role of ketoconazole in prevention of ovarian hyperstimulation syndrome (OHSS) in women with the polycystic ovary syndrome (PCOS) undergoing ovarian stimulation with gonadotropins. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: University hospitals.One hundred nine women with PCOS who were referred for treatment with gonadotropins. INTERVENTION(S): Fifty patients were randomly assigned to receive two ampoules of hMG beginning on day 2 or 3 of the cycle and ketoconazole (50 mg every 48 hours) starting on the first day of hMG treatment. Fifty-one patients received the same amount of hMG plus one tablet of placebo every 48 hours. MAIN OUTCOME MEASURE(S): Follicular development, E(2) level, and pregnancy rate. RESULT(S): The total number of hMG ampoules and duration of treatment to attain ovarian stimulation were higher among ketoconazole recipients. The serum E(2) level and number of patients with dominant follicles on day 9 of the cycle were greater in placebo recipients. Serum E(2) level and total number of follicles at the time of hCG administration did not differ between the two groups. The cancellation rate and OHSS rate were similar in the two groups. CONCLUSION(S): Ketoconazole does not prevent OHSS in patients with PCOS who are undergoing ovarian stimulation. It may reduce the rate of folliculogenesis and steroidogenesis.     

Dexamethasone as an adjuvant therapy for anovulatory,normoandrogenic patients during ovulation induction with exogenous gonadotropins

Objective: The objective of our study was to explore the effect of dexamethasone (DEX), a highly potent, long-acting glucocorticoid, on the treatment outcome of 74 anovulatory women aged 21 to 29 years, with normal gonadotropins, androgen, and prolactin (PRL) serum levels who failed to conceive on antiestrogen therapy. Methods: The patients received human menopausal gonadotropin/human chorionic gonadotropin (hMG/hCG) for ovulation induction. Starting on day 4 of the induced menstruation, hMG was administered in combination with DEX, 0.5 mg at night, or without DEX as an adjuvant treatment. The total amount of gonadotropins used, time required for stimulation, percentage of fertilization, serum estradiol levels, pregnancy rate, cumulative pregnancy rate, and abortions were recorded. Results: There were no differences in either the cumulative pregnancy rate (54.1% in the DEX group and 52.7% in the untreated group) or the abortion rates (21.7% in the DEX group compared to 20.8% in the untreated group). The other parameters investigated also did not differ significantly between the groups. Conclusions: The overall results did not support DEX as a clinically useful adjuvant therapy for anovulatory, normoandrogenic patients.     

Effect of a low dose combined oral contraceptive pill on the hormonal profile and cycle outcome following COS with a GnRH antagonist protocol in women over 35 years old

This prospective study examines if pre-treatment with two different doses of an oral contraceptive pill (OCP) modifies significantly the hormonal profile and/or the IVF/ICSI outcome following COS with a GnRH antagonist protocol. Infertile patients were allocated to receive either OCP containing 0.03?mg of ethinylestradiol and 3?mg of drospirenone, or OCP containing 0.02?mg of ethinylestradiol and 3?mg of drospirenone prior to initiation of controlled ovarian stimulation (COS) with recombinant gonadotropins on a variable multi-dose antagonist protocol (Ganirelix), while the control group underwent COS without OCP pretreatment. Lower dose OCP was associated with recovery of FSH on day 3 instead of day 5, but the synchronization of the follicular cohort, the number of retrieved oocytes and the clinical pregnancy rate were similar to higher dose OCP.