Testosterone levels after treatment with urofollitropin in infertile patients with idiopathic mild reduction of testicular volume.

INTRODUCTION: A reduction of testicular volume (TV) represents an important clinical sign, which may hide sperm abnormalities and predispose to hypogonadism. AIM: The primary purpose of this study was to evaluate the serum levels of total testosterone after treatment with urofollitropin in selected patients with male infertility and idiopathic mild reduction of testicular volume. METHODS: In this 1-year-long prospective design, patients with abnormal sperm parameters, mild reduction in TV (8-12 mL) and normal gonadotropin, and total testosterone (TT) serum levels were recruited in this study. Patients treated for 4 months with urofollitropin were included in group A, those treated with intracytoplasmatic sperm injection due to a female-factor infertility were included in group B. Hormone values, sperm parameters, and TV were detected at baseline (T0), after 4 (T1) and 12 months (T2) in group A and at T0 and T2 in group B. RESULTS: Group A (n = 80) showed increased follicle-stimulating hormone (FSH) at T1 and sperm morphology at T1 and T2 compared to T0 (all p < 0.05). Group B (n = 50) had lower TT and higher FSH levels at T2 compared to T0 (all p < 0.05). At T2, TT, VT, total sperm count, progressive motility, total motility, and sperm morphology were higher in group A compared to group B (all p < 0.05). CONCLUSION: Reduced TV may predispose to infertility and hypogonadism. FSH treatment may improve Sertoli and Leydig cell function and prevent the development of hypogonadism.

Pharmacokinetics and Pharmacodynamics of Follicle-Stimulating Hormone in Healthy Women Receiving Single and Multiple Doses of Highly Purified Human Menotrophin and Urofollitrophin.

BACKGROUND AND OBJECTIVE: Highly purified human menotrophin and urofollitrophin preparations obtained from human urine via a novel patented purification method have been tested over a timeframe of 14 years in the studies presented in this article. The objective of the studies was to investigate the pharmacokinetics and the pharmacodynamics of follicle-stimulating hormone (FSH) after single subcutaneous and intramuscular doses and multiple subcutaneous doses of the tested preparations in healthy fertile pituitary-suppressed women. DESIGNS: We performed five open, randomised, crossover, single-dose bioequivalence and/or bioavailability studies and one open, multiple-dose, pharmacokinetics and pharmacodynamics study. STUDY SUBJECTS AND TREATMENTS: The six studies included 121 healthy fertile women taking their usual combined oral contraceptives for 3 months before the study: Study 1: 300 international units (IU) of highly purified menotrophin as single subcutaneous and intramuscular doses. Study 2: 300 IU of highly purified menotrophin (test formulation vs. comparator) as single subcutaneous doses. Study 3: 300 IU of highly purified urofollitrophin (hp-FSH) (test formulation vs. comparator) as single subcutaneous doses. Study 4: 300 IU (2 × 150 IU vs. 4 × 75 IU) of hp-FSH as single subcutaneous doses. Study 5: 225 and 445 IU of hp-FSH as single subcutaneous doses. Study 6: daily 225 IU of hp-FSH as subcutaneous doses for 5 consecutive days. MAIN OUTCOME MEASURES: The main outcome measures were the FSH pharmacokinetic parameters, estradiol concentrations, and the number and size of the follicles. RESULTS: FSH after single subcutaneous and intramuscular injections of menotrophin or urofollitrophin attained a systemic peak (maximum) concentration (C max) that was on average consistent throughout the first four studies and ranged from 4.98 to 7.50 IU/L. The area under the plasma concentration-time curve (AUC) from administration to the last observed concentration time t (AUCt) ranged from 409.71 to 486.16 IU/L·h and the elimination half-life (t ½) ranged from 39.02 to 53.63 h. After multiple doses of urofollitrophin (225 IU) for 5 days, FSH attained a mean C max of 14.93 ± 2.92 IU/L and had an AUC during the time interval τ between two consecutive doses at steady state (AUCτ) of 322.59 ± 57.92 IU/L·h, which was similar to the mean AUCt after a single subcutaneous dose of 225 IU of urofollitrophin in study 5 (306.82 ± 68.37 IU/L·h). CONCLUSIONS: In our studies, the intramuscular and subcutaneous routes of menotrophin were equivalent; both menotrophin and urofollitrophin were bioequivalent to their marketed reference; FSH kinetic parameters following injection of urofollitrophin were dose proportional and independent from the administered concentration; and multiple doses of FSH increased estradiol levels and enhanced growth of follicles with a good dose-response correlation. Local tolerability was excellent throughout the six studies.

450 IU versus 600 IU gonadotropin for controlled ovarian stimulation in poor responders: a randomized controlled trial.

OBJECTIVE: To compare the outcomes of controlled ovarian stimulation/in vitro fertilization cycles using 450 IU and 600 IU gonadotropin per day in women at risk of poor ovarian response. DESIGN: Prospective randomized controlled nonblinded study. SETTING: University-affiliated private IVF center. PATIENT(S): Women considered to be at risk of poor ovarian response: aged <41 years with basal FSH >10 IU/L, antimüllerian hormone <1 ng/mL, antral follicle count ≤ 8, or a previous IVF cycle with ≥ 300 IU/d gonadotropin that resulted in a cancellation, <8 follicles, or <5 oocytes. INTERVENTION(S): A total of 356 patients underwent a microdose GnRH agonist flare-up IVF/intracytoplasmic sperm injection protocol with a fixed daily dose of either 450 IU FSH (n = 176) or 600 IU FSH (n = 180) equally divided between Menopur and Bravelle. MAIN OUTCOME MEASURE(S): Number of mature oocytes retrieved. RESULT(S): The two groups were similar in terms of age, ovarian reserve, cause of infertility, duration of stimulation, and cycle cancellation rate. There were no significant differences in the number of metaphase II oocytes retrieved (4 [range 0-6] vs. 4 [range 2-7]), fertilization rate (62.4% vs. 57.0%), biochemical pregnancy rate (20.5% vs. 22.9%), clinical pregnancy rate (16.4% vs. 18.3%), and implantation rate (29.8% vs. 30.4%) between the 450 IU and 600 IU groups, respectively. CONCLUSION(S): Gonadotropin of 600 IU/d does not improve outcome of IVF cycles compared with 450 IU/d in women at risk of poor ovarian response. CLINICAL TRIAL REGISTRATION NUMBER: NCT00971152.

Sequential Versus Continual Purified Urinary FSH/hCG in Men With Idiopathic Hypogonadotropic Hypogonadism.

CONTEXT: Gonadotropin therapy using a human chorionic gonadotropin (hCG) and FSH preparation is an effective regimen in inducing masculinization and spermatogenesis in men with idiopathic hypogonadotropic hypogonadism (IHH). However, the high cost of medication and frequent injections affect compliance. OBJECTIVE: The aim of this study was to determine the efficacy of sequential use of highly purified urinary FSH (uFSH)/hCG in men with IHH. DESIGN AND SETTING: A randomized, open-label, prospective, controlled noninferiority trial with an 18-month follow-up was conducted in 9 tertiary hospitals. PATIENTS AND INTERVENTION: A total of 67 Chinese men with IHH were randomly allocated into group A receiving continual uFSH (75 U, 3 times a week) and hCG (2000 U, twice a week) injection and group B receiving sequential uFSH (75 U, 3 times a week every other 3 months) and hCG (2000 U, twice a week) injection. MAIN OUTCOME MEASURE: The primary outcome was the proportion of subjects with a sperm concentration of ≥ 1.0 × 10(6)/mL during the 18 months. The efficacy between groups A and B was compared for noninferiority. RESULTS: Of the patients, 17/33 (51.5%) receiving continual uFSH/hCG and 19/34 (55.9%) receiving sequential uFSH/hCG achieved sperm concentrations of ≥ 1.0 × 10(6)/mL. The efficacy in the sequential uFSH/hCG group was not inferior to that in the continual uFSH/hCG group (noninferiority, P = .008) by intention-to-treat analysis. CONCLUSIONS: The efficacy of the sequential uFSH/hCG regimen is not inferior to that of the continual uFSH/hCG regimen in inducing spermatogenesis and masculinization of patients with IHH.

Initiation of ovarian stimulation independent of the menstrual cycle: a case-control study.

PURPOSE: In the GnRH-antagonist protocol, ovarian stimulation with gonadotropins typically commences on cycle day 2 or 3. Initiation of ovarian stimulation with a spontaneously occurring menstruation, however, poses significant organizational challenges for treatment centres and patients alike. It has previously been demonstrated in the context of fertility preservation that initiation of stimulation in the luteal phase is feasible in terms of retrieval of mature oocytes for cryopreservation. Herein, we report the extension of this concept to a routine IVF setting with the aim of establishing an ovarian stimulation protocol, which can be utilized independent of menstruation. Because of asynchrony of endometrium and embryo in such a setting, all fertilized oocytes have to be cryopreserved for a later transfer. METHODS: This was a prospective, case-control study (trial registration: NCT00795041) on the feasibility of starting ovarian stimulation in a GnRH-antagonist protocol in the luteal phase. Inclusion criteria were: IVF or ICSI; 18-36 years; ≤3 previous IVF/ICSI attempts; BMI 20-30 kg/m(2); regular cycle (28-35 days); luteal phase progesterone >7 ng/ml at initiation of stimulation. Exclusion criteria were: PCOS, endometriosis ≥AFS III°, unilateral ovary, expected poor response. Stimulation was performed with highly purified uFSH (Bravelle®) 300 IU/day and 0.25 mg/day GnRH-antagonist starting on cycle day 19-21 of a spontaneous menstrual cycle and commencing until hCG administration when three follicles ≥17 mm were present. All 2PN stage oocytes were vitrified for later transfers in programmed cycles. Feasibility was defined as the achievement of ongoing pregnancies progressing beyond the 12th gestational week in at least 2/10 study subjects (primary outcome). Secondary outcomes were gonadotropin consumption per oocyte obtained, stimulation duration, and fertilization rates. Study subjects were matched in a 1:3 ratio with concomitantly treated control cases of similar age, BMI, and duration of infertility who were treated in a conventional GnRH-antagonist protocol with 150-225 rFSH or HP-HMG/day. RESULTS: The study group consisted of ten subjects, mean age 31.4 years, BMI 25.4 kg/m(2), of which one had fertilization failure. Mean stimulation duration was 11.7 (SD 1.6) vs. 9.1 (SD 1.3) days, mean cumulative FSH dose was 3,495.0 (SD 447.5) vs. 2,040.5 (SD 576.2) IU, and mean number of oocytes was 8.8 (SD 5.0) vs. 10.0 (SD 5.4) in study vs. control group, respectively. Per follicle ≥10 mm, the cumulative FSH dose was 274.5 (SD 130.8) IU vs. 245.2 (SD 232.3) IU in study and control groups, respectively. Cumulative ongoing pregnancy rates were 1/10 (10 %) and 6/30 (20.0 %) in study and control group, respectively (difference: 10 %, 95 % confidence interval of the difference: -29.2-22.2 %, p = 0.47). Fertilization rate was similar between groups, with 63.5 % (SD 32.9) in the study and 61.3 % (SD 26.7) in the control group, respectively. Serum estradiol levels were significantly lower on the day of triggering final oocyte maturation with 1,005.3 (SD 336.2) vs. 1,977.4 pg/ml (SD 1,106.5) in study and control group, respectively. Similarly, peak estradiol biosynthesis per growing follicle ≥10 mm was lower in the study group (134 pg/ml, SD 158.4 vs. 186.7 pg/ml, SD 84.7). CONCLUSIONS: Per retrieved oocyte, a nearly threefold higher dose of FSH had to be administered when ovarian stimulation had been initiated in the luteal phase. Furthermore, the present study casts doubt on the efficacy of initiating ovarian stimulation in the luteal phase in terms of pregnancy achievement. Thus, this concept is currently not feasible for routine use, and it should also be explored further before using it at larger scale in the context of emergency stimulation for fertility preservation.

Recombinant human LH supplementation versus supplementation with urinary hCG-based LH activity during controlled ovarian stimulation in the long GnRH-agonist protocol: a matched case-control study.

An observational, matched, case-control study was carried out to compare the efficacy of recombinant human luteinizing hormone (r-hLH) supplementation with that of urinary human menopausal gonadotrophin (u-hMG)-based LH activity during controlled ovarian stimulation (COS) for assisted reproductive technology (ART) using a long gonadotrophin-releasing hormone (GnRH)-agonist protocol. A total of 4719 women, 1573 per group, matched by age, body mass index, indication and number of previous ART cycles, were treated with either recombinant human follicle-stimulating hormone (r-hFSH) and r-hLH in a fixed 2:1 ratio or u-hMG, either alone or in combination with r-hFSH, after down-regulation in a long GnRH-agonist protocol. Compared with the two u-hMG groups (u-hMG alone or in combination with r-hFSH, respectively), r-hFSH consumption was significantly lower (p < 0.001; p < 0.001), and pregnancy rates per cycle (p = 0.006; p = 0.022) and per embryo transfer (p = 0.025; p = 0.008), and implantation rate per embryo transferred (p < 0.001; p < 0.001) were significantly higher in the group treated with the fixed combination of r-hFSH and r-hLH. In COS protocols with r-hFSH, supplementation with r-hLH appears to be more effective than supplementation with u-hMG using the long GnRH-agonist protocol for ART.

Endometrin for luteal phase support in a randomized, controlled, open-label, prospective in-vitro fertilization trial using a combination of Menopur and Bravelle for controlled ovarian hyperstimulation.

OBJECTIVE: To assess the efficacy and safety of a vaginal progesterone (P(4)) insert (Endometrin) for luteal support for assisted reproductive technology (ART). DESIGN: Multicenter, randomized, open-label (assessor-blinded) phase III clinical trial. SETTING: Twenty-five U.S. ART centers. PATIENT(S): A total of 1,211 ART patients randomized to three groups: Endometrin 100 mg twice daily (n = 404), Endometrin 100 mg three times daily (n = 404), and P(4) 90 mg 8% gel daily (n = 403). INTERVENTION(S): In vitro fertilization and ET were performed according to site-specific protocols. The day after oocyte retrieval, Endometrin or vaginal P(4) gel was begun for luteal support and continued for up to 10 weeks of pregnancy. MAIN OUTCOME MEASURE(S): Biochemical, clinical, and ongoing pregnancy and live birth rates. RESULT(S): Pregnancy rates were high and similar in all treatment groups, with biochemical rates exceeding 50%, clinical and ongoing rates >or=40%, and live birth rates at 35%-38%. The adverse event profiles were similar across groups. CONCLUSION(S): Pregnancy rates and live birth rates for Endometrin (twice daily and three times daily) were high and similar to those for P(4) gel. The adverse event profiles for both were similar to that for P(4) gel and primarily due to IVF stimulation and oocyte retrieval. Endometrin was safe and well tolerated.

Gonadotrophin products: empowering patients to choose the product that meets their needs.

Gonadotrophins are injected daily over several days in follicular stimulation protocols. To facilitate self-injection, various injection or reconstitution devices are available. It was investigated whether injection training enabled patients to choose their preferred device. Patients and their partners received nurse-led training about: powdered urofollitropin (Bravelle) with needle-free reconstitution (Q-Cap)and conventional needles and syringes for administration; follitropin beta (Follistim AQ) in a premixed, prefilled cartridge (Follistim AQ Cartridge) with a reusable injection device (Follistim Pen); or follitropin alfa (GONAL-f) in a disposable, premixed, prefilled injection device (GONAL-f RFF Pen). A total of 123 participants (81 women) attended the training and were asked to complete a questionnaire after training. More participants expressed a preference for a pen injection device than the needle-free reconstitution and conventional syringe (84.6% versus 5.7%; P < 0.0001). Of the 94 participants who preferred a particular device, more preferred the follitropin alfa prefilled pen (68.1%) than the follitropin beta cartridge and pen (24.5%; P < 0.0001) or urofollitropin with needle-free reconstitution device and conventional syringe (7.4%; P < 0.0001). It was concluded that nurse-led training classes empowered participants to choose a device that they considered most suitable to their needs.

Urinary follicle-stimulating hormone (FSH) is more effective than recombinant FSH in older women in a controlled randomized study.

OBJECTIVE: The following study was conducted to determine which FSH, recombinant or urinary, works better in older women. DESIGN: We conducted a controlled randomized study in a single university IVF center. SETTING: University IVF center. PATIENT(S): Women (N = 257) over 39 years old undergoing IVF. INTERVENTION(S): The patients were randomized into two study groups at their first IVF cycle: 121 patients were treated with recombinant FSH, and 120 patients were treated with urinary FSH. Both groups were suppressed with a long GnRH analog protocol. MAIN OUTCOME MEASURE(S): Days of stimulation, E2 at the day of hCG, total amount of FSH administered, number of oocytes collected, amount of FSH per oocyte, and number of embryos obtained. RESULT(S): Patients treated with urinary FSH required a significantly lower total amount of FSH, and a lower amount of FSH per oocyte than women treated with recombinant FSH. The other measures evaluated did not show any statistically significant differences. CONCLUSION(S): Our study showed that urinary FSH performed better in older women than recombinant FSH when associated with the long protocol.

Beneficial effects of a higher starting dose of gonadotrophins in some poor responders.

We performed a prospective study to examine the benefits of higher starting dose in poor responders to gonadotrophins. One hundred eighty-seven normal responders (group 1), 40 poor responders (group 2), and 25 poor responders from group 2 (group 3) were included in the study. Groups 1 and 2 received 300 IU of metrodin HP for 5 days followed by 150 IU of recombinant human follicle-stimulating hormone (rhFSH) until the day before hCG. Group 3 received 450 IU of metrodin followed by rhFSH as in groups 1 and 2. Number of oocytes retrieved, rates of fertilization, implantation, pregnancy, and miscarriage rates were compared between the groups. There were no differences between the three groups in the fertilization rate. The higher dose of metrodin (450 IU) for 5 days increased the number of oocytes retrieved in some patients belonging to group 3 and significantly increased (P < 0.01) the implantation and pregnancy rates compared with group 2 patients. However, the higher dose of metrodin also increased miscarriage rates significantly in group 3 compared with groups 1 and 2 (P < 0.04). In some poor responders, a higher starting dose of gonadotrophin resulted in more oocytes retrieved and led to higher implantation and pregnancy rates and a higher miscarriage rate.

Mixed protocols: multiple ratios of FSH and LH bioactivity using highly purified, human-derived FSH (BRAVELLE) and highly purified hMG (MENOPUR) are unaltered by mixing together in the same syringe.

BACKGROUND: The use of mixed or blended protocols, that utilize both FSH and hMG, for controlled ovarian hyperstimulation is increasing in use. To reduce the number of injections a patient must administer, many physicians instruct their patients to mix their FSH and hMG together to be given as a single injection. Therefore, the goal of this study was to definitively determine if the FSH and LH bioactivities of highly purified, human-derived FSH (Bravelle) and highly purified hMG (Menopur) were altered by reconstituting in 0.9% saline and mixing in the same syringe. METHODS: Bravelle and Menopur were reconstituted in 0.9% saline and mixed in a Becton Dickinson plastic syringe. The FSH and LH bioactivities of the products were determined after injecting female and male rats, respectively, with Bravelle, Menopur, or a mixture of Bravelle and Menopur. Ratios of FSH:LH activity tested were 150:75 IU (1 vial Bravelle: 1 vial Menopur), 300:75 IU (3 vials Bravelle: 1 vial Menopur) or 300:225 IU (1 vial Bravelle: 3 vials of Menopur). RESULTS: There were no statistically significant changes in either FSH or LH bioactivity that occurred after mixing Bravelle with Menopur in the same syringe. The theoretical vs. actual FSH bioactivity for Bravelle and Menopur were 75 vs. 76.58 IU/mL and 75 vs. 76.0 IU/mL, respectively. For the 3 ratios of FSH:LH activity tested, 150:75 IU (1 vial Bravelle: 1 vial Menopur), 300:75 IU (3 vials Bravelle: 1 vial Menopur) or 300:225 IU (1 vial Bravelle: 3 vials of Menopur) tested, the theoretical vs. actual FSH bioactivities were 150 vs. 156.86 IU/mL, 300 vs. 308.69 IU/mL and 300 vs. 306.58 IU/mL, respectively. The theoretical vs. actual LH bioactivity for Menopur in the above mentioned ratios tested were 75 vs. 77.50 IU/mL. For the 3 ratios of FSH:LH activity tested, 150:75 IU (1 vial Bravelle: 1 vial Menopur), 300:75 IU (3 vials Bravelle: 1 vial Menopur) or 300:225 IU (1 vial Bravelle: 3 vials of Menopur), the theoretical vs. actual LH bioactivities were 75 vs. 78.38 IU/mL, 75 vs. 78.63 IU/mL and 225 vs. 233.48 IU/mL, respectively. CONCLUSION: Mixing human-derived FSH (Bravelle) with highly purified hMG (Menopur) in the same diluent, 0.9% NaCL, does not alter the FSH or LH bioactivity of either gonadotropin preparation.