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Here we report the findings of a two-centre, open-label, randomised, Phase IIa study designed to investigate whether an ethinyl estradiol (EE)/gestodene (GSD) patch that has been developed (referred to herein as the ‘EE/GSD patch’) reliably inhibits ovulation in comparison with patches delivering lower doses of these hormones. The study rationale was to provide justification of the doses of EE and GSD selected for the EE/GSD patch. Healthy women, aged 18–35 years, were randomised to receive treatment with either the EE/GSD patch, a ‘reduced-GSD patch’ (delivering similar amounts of EE and approximately half the amount of GSD) or a ‘reduced-EE/GSD patch’ (delivering half the amount of EE and GSD). Treatment was administered for three 28-day cycles (three × 7 patch-wearing days, plus a 7-day patch-free interval). The primary pharmacodynamic variable was the percentage of women with ovulation in at least one of Cycles 2 and/or 3, as indicated by Hoogland score. Pharmacokinetic parameters for EE and GSD were also measured. Results indicated that the EE/GSD patch effectively suppressed ovulation, while patches delivering lower doses of EE and GSD were less effective for this purpose. All three patches showed comparable tolerability. [ABSTRACT FROM PUBLISHER]

Study Question: Is there a pharmacodynamic interaction between ulipristal acetate (UPA) 30 mg for emergency contraception and a daily progestin-only contraceptive pill, desogestrel (DSG) 0.75 mg, when initiated the next day?Summary Answer: In this study, DSG impaired the ability of UPA to delay ovulation, but UPA had little impact on the onset of contraceptive effects due to DSG.What Is Known Already: UPA is a progesterone receptor modulator used for emergency contraceptive (EC) at the dose of 30 mg. UPA delays ovulation by at least 5 days when administered in the mid to late follicular phase. In theory, potent progestins could reactivate progesterone signaling that leads to follicle rupture, thereby impacting the effectiveness of UPA as EC. In addition, UPA could alter the onset of the contraceptive effect of progestin-containing contraceptives started immediately after UPA.Study Design, Size, Duration: A single-blind (for observer), placebo-controlled, partial crossover study was conducted in two sites [Dominican Republic (DR) and the Netherlands (NDL)] over 11 months from October 2012 to September 2013. Healthy female volunteers participated in two of the three treatment cycles separated by a washout cycle. Treatment combinations studied were as follows: (i) a single 30 mg dose of UPA followed by 75 µg per day DSG for 20 days, (ii) a single 30 mg dose of UPA followed by 20 days of placebo matching that of DSG (PLB2) or (iii) one tablet of placebo-matching UPA (PLB1) followed by 75 µg per day DSG for 20 days. Participants were randomized to one of the three treatment sequences (UPA + DSG/UPA + PLB2, PLB1 + DSG/UPA + DSG and UPA + PLB2/PLB1 + DSG) when a lead follicle was ≥ 14 to <16 mm diameter on transvaginal ultrasound imaging (TVU).Participants/material, Setting, Methods: A total of 71 women were included, and 49 were randomized to a first treatment combination of the three period sequences (20 in the DR and 29 in the NDL); 41 of the 49 continued and completed two treatment combinations (20 in the DR and 21 in the NDL).Main Results and the Role Of Chance: Initiating DSG treatment the day after UPA significantly reduced the ovulation delaying effect of UPA (P = 0.0054). While ovulation occurred in only one of the 29 UPA-only cycles (3%) in the first 5 days, it occurred in 13 of the 29 (45%) UPA + DSG cycles.Limitations, Reasons For Caution: This was a small, descriptive, pharmacodynamic study in which some findings differed by study site. Distinguishing between a cystic corpus luteum and a luteinized unruptured follicle (LUF) by TVU was difficult in some cases; however, the investigators reached consensus, when the study was still blinded, regarding ovulation based on hormone levels and careful review of daily TVU images.Wider Implications Of the Findings: Initiating the use of a DSG progestin-only pill (POP) immediately after UPA reduces the ability of UPA to delay ovulation and thus may decrease its efficacy as EC. If starting a DSG POP after using UPA for EC, and possibly any progestin-only method, consideration should be given to delaying for at least 5 days after UPA intake in order to preserve the ovulation delaying effects of UPA. [ABSTRACT FROM AUTHOR]

Objectives: To compare carbohydrate metabolism, adrenal and thyroid function during use of a combined contraceptive vaginal ring (NuvaRing, NV Organon, Oss, The Netherlands) with those of a combined oral contraceptive.Methods: Healthy women aged 18-40 years used either the vaginal ring, delivering 15 microg ethinylestradiol and 120 microg of etonogestrel per day, or a combined oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel, for six cycles. Each cycle comprised 3 weeks of use of the ring or the pill followed by 1 ring- or pill-free week. The following parameters were measured at baseline and at the end of cycles 3 and 6: carbohydrate metabolism (glucose, insulin, glycosylated hemoglobin); adrenal function (total cortisol, cortisol binding globulin, dehydroepiandrosterone sulfate); thyroid function (thyroid stimulating hormone, free thyroxine).Results: Small and similar increases in insulin were seen in both groups. Concentrations of cortisol binding globulin and total cortisol rose significantly less during ring use than during combined oral contraceptive use (cycle 3, p= 0.0002; cycle 6, p < 0.0001). Levels of dehydroepiandrosterone sulfate did not change in either group. Thyroid stimulating hormone levels increased significantly more in the ring group at cycle 3 (p = 0.0016) but free thyroxine levels were unchanged in both groups.Conclusions: Both the vaginal ring and the oral contraceptive have no clinically relevant effects on carbohydrate metabolism, adrenal or thyroid function. [ABSTRACT FROM AUTHOR]

Recently, several new urinary gonadotrophin preparations have been developed, containing less luteinizing hormone (LH) activity than human menopausal gonadotrophin. Normegon is a gonadotrophin preparation with a follicle stimulating hormone (FSH)/LH ratio of 3:1; Follegon and Metrodin-HP are purified FSH preparations. The aim of the present randomized study was to compare pharmacodynamics, -kinetics and local tolerance of these preparations after repeated s.c. administration. Thirty-six healthy female subjects were treated with Lyndiol contraceptive pills for 5 weeks to suppress endogenous gonadotrophin concentrations. After 3 weeks of Lyndiol treatment, 150 IU of Normegon, Follegon or Metrodin HP were administered once daily, s.c. for 7 days. Blood samples were collected once daily during the fourth and fifth weeks of the study and assayed for FSH and oestradiol. After the last gonadotrophin injection, blood samples were collected more frequently to determine pharmacokinetic parameters of FSH. During the fourth and fifth study weeks, daily ultrasound measurements of follicular growth were performed. Endogenous FSH and LH values were extremely suppressed during Lyndiol treatment. Serum FSH values showed similar patterns in the three groups. The maximum FSH concentration was reached 9–11 h post-injection, the terminal half-life was 43–47 h. The preparations were bioequivalent with respect to FSH immunoreactivity. The number of follicles tended to be larger after Normegon than after Follegon and Metrodin HP treatment, though this was not statistically significant. Serum oestradiol concentrations were significantly higher after Normegon treatment. In general, s.c injections were well tolerated. In conclusion, the three preparations were bioequivalent with respect to FSH immunoreactivity. Nevertheless, the biological activity of Normegon tended to be higher than that of Follegon and Metrodin HP in Lyndiol-suppressed women. [ABSTRACT FROM PUBLISHER]

A randomized study was performed in nine healthy women, to investigate pharmacokinetic parameters and bioequivalence of two human menopausal gonadotrophin preparations after i.v. administration. Endogenous gonadotrophin activity was suppressed by triptorelin administration. Humegon and Pergonal (225 IU of each) were injected i.v. in a cross-over way with an interval of 1 week. Blood samples were collected frequently and serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH), specific LH, and human chorionic gonadotrophin (HCG) were determined by fluoroimmunoassays assays. Serum LH bioactivity was measured by an in-vitro bioassay. The area under curve (AUC) and half-life of FSH were respectively 431.5 IU h/l and 22.20 h for Humegon, and 402.6 IU h/l and 21.33 h for Pergonal. For both preparations, the (total) LH immunoactivity and in-vitro bioactivity of serum LH were very similar, and appeared to be a composite of specific LH and HCG activity. The AUC data of specific LH were 17.50 IU h/l for Humegon and 21.79 IU h/l for Pergonal respectively. The AUC and half-life of HCG were 153.7 IU h/l and 14.80 h for Humegon, and 134.1 IU h/l and 12.11 h for Pergonal. The two preparations were bioequivalent with respect to FSH and HCG immunoreactivity. Bioequivalence could not be proven for LH activity because of the small number of subjects. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate whether reducing the amount of luteinizing hormone (LH) in gonadotrophic preparations impairs follicular growth in in-vitro fertilization (IVF) cycles during suppression of endogenous LH levels. A selected group of 20 IVF patients was randomly divided into two groups. One group was treated with Org 31338 [follicle stimulating hormone (FSH)/LH 3:1], the other group with Metrodin (purified FSH), both during pituitary down-regulation with buserelin. A fixed daily dose of 150 IU FSH i.m. was given. Serum concentrations of FSH, LH, oestradiol and progesterone were determined frequently and serial ultrasound examinations were performed. Multiple follicular growth with concomitant rise of oestradiol levels was observed in all cycles. The duration of the stimulation phase was shorter in the group treated with Org 31338 than in the group treated with Metrodin. The number of follicles and oocytes and the fertilization rate was larger and the mean embryo quality was higher in the Org 31338 group, but the differences did not reach statistical significance. No significant differences were found in hormonal values. In women with normal endocrine profiles, lowering of the LH activity in gonadotrophic preparations during gonadotrophin-releasing hormone agonist treatment results in adequate ovarian stimulation. However, a preparation with some LH needed a shorter stimulation than a purified FSH preparation. Whether the other beneficial effects of Org 31338 also occur in a larger population needs further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Combined oral hormone contraceptive use is associated with decreased circulating androgens (Burrows LJ, et al. J Sex Med. 2012) and increased hormone binding globulins (Mawet M, et al. Eu J Cont Rep Hlth Care. 2015). Estetrol (E4) is a human-specific estrogen produced by the fetal liver, and has selective action in different tissues. The combination of E4 and Drospirenone (DRSP) was evaluated in a Phase-2 study to determine the potential effects on endocrine parameters. Objectives: To evaluate the change from baseline in serum concentration of various endocrine and liver protein markers at cycle 3 and 6 in subjects receiving E4/DRSP and two comparison combined oral contraceptive (COC) formulations. Methods: In this randomized, open-label, three-arm parallel study, participants received E4 15 mg /DRSP 3mg (n = 38), or ethinyl-estradiol (EE) 30 g/Levonorgestrel (LNG) 150 g (n = 29) or EE 20 g/DRSP 3 mg (n = 31) in a 24/4-day regimen of 6 consecutive, 28-day treatment cycles. Changes from baseline in serum total testosterone (TT), free testosterone (FT), androstenedione, dehydroepiandrosterone sulfate (DHEA-S), cortisol binding globulin (CBG), sex hormone binding globulin (SHBG), and thyroxine binding globulin (TBG) were determined at cycle 3 and 6. Potential differences between baseline and cycle 3 and 6 for all treatments, as well as pairwise comparisons of E4/DRSP and each of the other two formulations are considered statistically significant with an exploratory P-value < 0.05. Results: TBG was significantly increased with EE/LNG (47% and 37%) and EE/DRSP (80% and 70%) at cycle 3 and 6. TBG was also increased significantly but to a lesser extent with E4/DRSP (27% and 17%). CBG increased at cycle 6 in all treatments. The increase in CBG was significantly greater with EE/LNG (152%) and EE/DRSP (140%) than that noted for E4/DRSP (40%). A significant increase in SHBG was observed at cycle 3 (240%) and 6 (251%) with EE/DRSP as compared to baseline or E4/DRSP (52% and 55%). At cycle 3, a significant decrease in TT was observed for E4/DRSP (35%), EE/LNG (40.5%), and EE/DRSP (41%). FT was significantly reduced at cycle 3 for E4/DRSP, EE/LNG, and EE/DRSP at 50%, 60%, and 75%, respectively. At cycle 6, a similar pattern of significant reductions in both TT and FT was observed with each treatment. Pairwise comparison, revealed no significant differences in TT and FT among groups. There were significant decreases in androstenedione at cycle 3 and 6, with E4/DRSP (32% and 31%), EE/LNG (44% and 49%), and EE/DRSP (40% and 40%). DHEA-S was significantly reduced from baseline at cycle 3 and 6 in all treatments. There was a significant difference in DHEA-S at cycle 6 with EE/DRSP (27%) compared to E4/DRSP (11%). Conclusions: E4/DRSP had lower increases in hormone binding globulins compared to EE/LNG or EE/DRSP. Increases in SHBG were significantly higher for EE/DRSP than E4/DRSP. A decrease in TT and FT with E4/DRSP was not significantly different from EE/LNG or EE/DRSP. E4/DRSP had a significantly lower impact on DHEA-S levels than EE/DRSP. Disclosure: Yes - Mithra Women's Health. Industry initiated, executed and funded study – Yes. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of estetrol 15 mg/drospirenone 3 mg on ovarian function., Study Design: Single-center, randomized, open-label, parallel study in healthy young women with proven ovulatory cycles. Participants received either estetrol 15 mg/drospirenone 3 mg (E4/DRSP) (n = 41) or ethinylestradiol 20 µg/drospirenone 3 mg (EE/DRSP) (n = 41) in a 24/4-day regimen for 3 consecutive cycles. Follicular size and endometrial thickness were measured by transvaginal ultrasound every 3 days in cycles 1 and 3. Blood was sampled for hormone analysis. Ovarian function expressed as Hoogland score was based on follicular size, serum estradiol (E2) and progesterone (P) concentrations. Ovulation was defined as a ruptured follicle-like structure >13 mm with serum E2 concentrations >100 pmol/L and serum P concentrations >5 nmol/L. We assessed return of ovulation after treatment cessation, and safety throughout the study., Results: None of the participants ovulated with E4/DRSP use, while one participant ovulated once and one participant ovulated twice during EE/DRSP treatment. Most participants had a Hoogland score of 1 (no ovarian activity) in cycle 1 (85.0% and 82.9% of participants on E4/DRSP and EE/DRSP, respectively) and in cycle 3 (65.8% and 83.8%, respectively). E4/DRSP suppressed follicle-stimulating hormone and luteinizing hormone to a lesser extent than EE/DRSP, whereas both treatments comparably suppressed E2 and P and endometrial thickness. Return of ovulation occurred, on average, 15.5 days after E4/DRSP treatment discontinuation. E4/DRSP was safe and well-tolerated., Conclusions: E4 15 mg/DRSP 3 mg results in adequate ovulation inhibition and ovarian function suppression, comparable to a marketed combined oral contraceptive containing EE/DRSP., Implications Statement: Treatment with E4 15 mg/DRSP 3 mg showed complete ovulation inhibition, despite less suppression of follicle-stimulating hormone and luteinizing hormone compared to EE/DRSP. If it becomes commercially available, E4/DRSP, containing a naturally occurring estrogen, should be as effective as EE/DRSP., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP)., Study Design: Randomized, open-label, controlled, 3-arm, parallel study. Healthy subjects received either E4 15 mg/DRSP 3 mg (E4/DRSP) (n = 38), or ethinylestradiol (EE) 30 µg/levonorgestrel (LNG) 150 µg (n = 29), or EE 20 µg/DRSP 3 mg (n = 31) for 6 treatment cycles. Median percentage change from baseline to cycle 3 and to cycle 6 were evaluated for endocrine parameters, liver proteins, lipid profile, and carbohydrate metabolism., Results: At cycle 6, E4/DRSP treatment had less effect on gonadotropins (follicle stimulating hormone [FSH] +30.5%, luteinizing hormone [LH] -7.5%) compared to EE/LNG (FSH -84.0%, LH -92.0%) and EE/DRSP (FSH -64.0%, LH -90.0%). With E4/DRSP increases in total cortisol (+26.0%) and cortisol binding globulin ([CBG] (+40.0%) were less compared to EE/LNG (cortisol +109.0%, CBG +152.0%) and EE/DRSP (cortisol +107.0%, CBG +140.0%). Liver proteins, except CRP, increased, but the effect was less pronounced with E4/DRSP for angiotensinogen (+75.0%) compared to EE/LNG (+170.0%) and EE/DRSP (+206.5%) and for sex hormone binding globulin ([SHBG] +55.0%), compared to EE/LNG (+74.0%) and EE/DRSP (+251.0%). E4/DRSP had minimal impact on lipid parameters; the largest effect was observed for triglycerides (+24.0%), which was less compared to EE/LNG (+28.0%) and EE/DRSP (+65.5%). E4/DRSP had no effect on carbohydrate metabolism., Conclusions: E4/DRSP treatment has limited effects on endocrine and metabolic parameters. The effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG and triglycerides were less pronounced compared to EE-containing products., Implications Statement: Combining E4 15 mg with DRSP 3 mg resulted in a COC with a different metabolic profile in comparison to EE-containing products. The clinical relevance of these findings needs to be further assessed, using clinical endpoints to establish the safety profile of this new COC., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To assess the effect on hemostasis parameters of a new combined oral contraceptive (COC)., Study Design: In this randomized, single centre, open-label, exploratory study, healthy women received either 15 mg estetrol/3 mg drospirenone (E4/DRSP) (n = 39), 30 mcg ethinylestradiol/150 mcg levonorgestrel (EE/LNG) (n = 30), or 20 mcg ethinylestradiol/3 mg drospirenone (EE/DRSP) (n = 32) for six 28-day cycles. Blood was collected at baseline, cycle 3, and cycle 6. Median change from baseline was evaluated for procoagulant, anticoagulant, and fibrinolytic parameters, and for sex hormone-binding globulin (SHBG)., Results: Median change of endogenous thrombin potential (ETP) based activated protein C sensitivity resistance (APCr) at cycle 6 was +30% for E4/DRSP, +165% for EE/LNG (p-value <0.05 vs E4/DRSP), and +219% for EE/DRSP (p-value <0.05 vs E4/DRSP). Changes to prothrombin fragment 1 + 2 and SHBG for E4/DRSP, EE/LNG, and EE/DRSP were +23%, +71%, and +64% (p-value <0.05 vs E4/DRSP); and +55%, +74% and +251% (p-value <0.05 vs E4/DRSP), respectively. At cycle 6, changes to other hemostasis parameters for E4/DRSP were similar or smaller than for EE/LNG or EE/DRSP., Conclusions: In this study, changes in hemostasis parameters after treatment with 6 cycles of E4/DRSP were smaller or similar to those observed for EE/LNG. Similar, but more pronounced changes were also observed versus EE/DRSP, which supports the hypothesis that the effect of COCs on hemostasis parameters is mainly mediated by the estrogenic component. Further studies are needed to provide more insight into the venous thromboembolic risk of E4/DRSP., Implications Statement: This study reports that the effects on hemostasis parameters of a COC containing 15 mg E4/3 mg DRSP are less or similar to those for EE/LNG or EE/DRSP. It also demonstrates that the choice of estrogen modulates the effects of COCs on hemostasis parameters., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Among combined oral contraception (COC) users, to determine the effect on ovarian activity and ovulation of waiting five days before restarting COC, versus restarting immediately, having taken ulipristal acetate 30 mg (UPA, the dose used for emergency contraception) after missing three consecutive COC pills., Study Design: Women already using COC were enrolled for two cycles of COC use (21/7 regimen). In cycle 2, all women omitted COC pills for three consecutive days (days 5,6,7), and on day 8 took UPA 30 mg. They were randomized either to restart their COC pills that same day (immediate restart) or to wait five days (delayed restart). Transvaginal ultrasound, and blood sampling for estradiol and progesterone were undertaken on days 4,8,11,13,15,18,22 and 26. A modified Hoogland score was used to quantify ovarian activity/ovulation and to assess whether luteal phase progesterone concentrations were sufficiently 'adequate' to have conferred a theoretical risk of pregnancy., Results: No one ovulated with risk of pregnancy during the five days following UPA. Among 26 women with immediate restart, none ovulated with a theoretical risk of pregnancy at any time in the cycle. Four of 23 women (17.4% CI [5.0; 38.8]) with delayed restart ovulated with theoretical risk of pregnancy before the end of the cycle. This difference was statistically significant (p = 0.042)., Conclusion: Women who delay restarting COC for five days after taking UPA 30 mg are at much greater risk of ovulation, and therefore theoretically of pregnancy, than if they restart their COC on the same day as taking UPA. Current recommendations should be revisited., Implications: Women who take UPA-EC after having missed combined oral contraceptive pills are advised to wait five days before restarting the COC. This delay puts them at risk of ovulation and, if intercourse occurs, theoretically therefore of pregnancy. Women who restart their COC pills immediately are much less likely to ovulate. The label for UPA-EC and clinical guidelines on using EC after missed pills should be revisited., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To identify at least one contraceptive vaginal ring that effectively inhibits ovulation and demonstrates cycle control that is non-inferior to NuvaRing ® (Merck Sharp & Dohme B.V., The Netherlands) in terms of an unscheduled bleeding incidence, with a non-inferiority margin of 10%., Methods: This was a randomised, active controlled, parallel group, multicentre, partially blinded trial in healthy women 18-35 years of age. Subjects received one of six contraceptive vaginal rings with an average daily release rate of 300 µg 17β-estradiol (E2) and various rates of either etonogestrel (ENG; 75, 100, or 125 µg/day) or nomegestrol acetate (NOMAC; 500, 700, or 900 µg/day), or the active control NuvaRing ® (ENG/ethinylestradiol 120/15 µg), for three 28-day cycles., Results: Ovulation inhibition was observed in all groups as confirmed by absence of progesterone concentrations compatible with ovulation (>16 nmol/L) and absence of ultrasound evidence of ovulation. All investigational rings provided good cycle control, with the ENG-E2 125/300 µg/day group being associated with the best cycle control based on the numerically lowest incidence of unscheduled bleeding and absence of scheduled bleeding. Non-inferiority to NuvaRing ® with respect to the incidence of unscheduled bleeding could not be concluded for any of the investigational ring groups. The safety profile was consistent with the known safety profile of combined estrogen/progestin contraceptives and similar across all groups., Conclusions: Contraceptive rings releasing 300 µg E2 and 75-125 µg/day of ENG or 500-900 µg/day of NOMAC provided adequate ovulation inhibition and cycle control and are generally well-tolerated. While non-inferiority to NuvaRing ® was not met, among the investigational rings, the ENG-E2 125/300 ring provided the best cycle control.

Study Question: What are the differences and similarities of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the novel recombinant human FSH follitropin epsilon expressed in the human cell line GlycoExpress compared with a Chinese hamster ovary (CHO) derived compound and a urinary derived product?, Summary Answer: Overall follitropin epsilon, with a fully human glycosylation, shows a comparable PK profile at single-dose as well as multiple-dose administration compared to recombinant CHO-derived FSH as well as urinary derived FSH, whereas the PD properties differ from product to product with follitropin epsilon being most active in PD parameters., What Is Known Already: Recombinant FSH produced in CHO and FSH obtained from the urine of postmenopausal women show comparable PK and PD properties. However, more recently a comparative study of a recombinant FSH produced in the human cell line PerC6 and a CHO-derived FSH preparation revealed differences in PK and PD properties of the molecule., Study Design, Size, Duration: Both studies were randomized, placebo- and comparator-controlled, single-blind phase I studies in healthy pituitary-suppressed female volunteers aged 18 and 40 years. The single-dose, dose escalation study included 19 women (April 2011 to September 2011) with three ascending dose levels per subject or placebo/comparators with a 14-day washout phase between dosings. The multiple-dose study included 57 women (October 2011 to April 2012) in five cohorts with three dose levels versus placebo and two comparators. Randomization to the respective treatment was performed after successful downregulation of the pituitary gland prior to Investigational Medicinal Product dosing., Participants/materials, Setting, Methods: In the single-dose study, 12 subjects received follitropin epsilon (25, 75, 150 and 300 IU) in three of four possible ascending doses and seven subjects received one dose of two comparators (150 IU Bravelle and 150 IU Gonal-f) and placebo in random order in each treatment period. In the multiple-dose study, 30 subjects received follitropin epsilon (75 IU or 150 IU once daily [QD], or 150 IU every other day [QAD], 10 subjects each) and 27 subjects received 150 IU Gonal-f, 150 IU Bravelle, or placebo for 7 days (11/10/6 subjects). Blood samples for measuring PK as well as PD parameters were collected systematically before, during and after dosing. Adverse events (AEs) and other relevant safety parameters were recorded. Data were summarized using descriptive statistics., Main Results and the Role of Chance: The single- and multiple-dose PK parameters maximum concentration (Cmax) and area under the concentration-time curve (AUC0-last) increased in a linear fashion with increasing dose levels of follitropin epsilon. Follitropin epsilon showed PK characteristics comparable to the comparators indicating that well established treatment schemes could be applied. There was a dose-response effect of single and multiple doses of follitropin epsilon on follicular growth, which was shown for the biomarker inhibin B as well as for the mean number and size of follicles. Multiple doses of 75 IU follitropin epsilon given daily, as well as 150 IU follitropin epsilon every second day, showed a follicle growth comparable with 150 IU Gonal-f given daily, while in case of daily administration of 150 IU Bravelle only weak follicle stimulation was observed. Multiple doses of 150 IU follitropin epsilon induced a much higher follicle growth compared to the same dose of Gonal-f. All single and multiple follitropin epsilon doses tested were safe and well tolerated, and overall there were no relevant differences between follitropin epsilon and the comparators in terms of safety. The average number of AEs increased with increasing dose levels. No clinically relevant abnormalities were reported for any of the other safety parameters assessed. No follitropin epsilon anti-drug antibodies were observed., Limitations, Reasons for Caution: The studies were conducted as a single-blind design. Hormone levels or other parameters assessed in serum are generally not considered as being subject to bias. Other assessments directly performed by the investigators, such as transvaginal ultrasound assessments, may have been subject to personal bias. No prospective calculations of statistical power had been made, as is common practice for first in human and early phase I studies in healthy volunteers., Wider Implications of the Findings: These early development studies showed that follitropin epsilon exhibits comparable PK characteristics, as well as inducing stronger PD effects in terms of follicle growth and serum inhibin B, than the comparators. Follitropin epsilon induced a dose-dependent increase in follicular growth. The results warrant further studies with this new fully human recombinant FSH., Study Funding/competing Interest(s): The studies were sponsored by GLYCOTOPE GmbH, Berlin, Germany. K.A-E. is an employee of QPS-Netherlands, B.V., which received funding for the studies from Glycotope GmbH; I.D. and C.K. are employees of Dinox B.V., which received funding for the studies from Glycotope GmbH; L.S. and S.G. are employees and shareholders of Glycotope GmbH; B.D. and K.E. are employees of Glycotope GmbH., Trial Registration Number: www.clinicaltrials.gov: NCT01354886 (single-dose); NCT01477073 (multiple-dose)., Trial Registration Date: The single-dose trial was registered on 11 May 2011 while the multiple-dose trial was registered on 09 November 2011., Date of First Subject's Enrolment: First subject was enroled in the single-dose trial in 27 April 2011 and in the multiple-dose trial in 02 October 2011., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Objective: To assess the safety, pharmacokinetics, and pharmacodynamics of MK-8389., Design: Double-blind, placebo-controlled, parallel-group, ascending dose study., Setting: Two clinical research organizations., Patient(s): Healthy young women., Intervention(s): Once-daily oral doses of MK-8389 or placebo for 14 days., Main Outcome Measure(s): Safety, including thyroid function tests (TFTs), pharmacokinetics, and follicular development (follicle size and number and serum E2 and inhibin B levels)., Result(s): Treatment with MK-8389 was generally safe and well tolerated. An effect on TFTs was observed, which was transient and did not lead to clinical signs or symptoms but prevented dose escalation above 40 mg. MK-8389 was rapidly absorbed, slowly eliminated, and showed a large peak-to-trough ratio. No clinically meaningful effect was seen on follicle size and numbers, which was consistent with the low E2 levels. At doses >20 mg, inhibin B levels were increased, suggesting early follicular development at higher doses., Conclusion(s): Oral administration of MK-8389 demonstrated acceptable systemic exposure and was generally well tolerated. This study failed to demonstrate a clinically meaningful effect of MK-8389 on follicular development, whereas MK-8389 unexpectedly affected thyroid function. This study did not explore doses above 40 mg given the changes observed in TFTs, which may relate to high MK-8389 peak concentrations., Clinical Trial Registration Number: EudraCT Number 2010-022396-57., (Copyright © 2016 American Society for Reproductive Medicine. All rights reserved.)

Background: The estrogen step-down/progestogen step-up 28-day estradiol valerate/dienogest (E(2)V/DNG) oral contraceptive effectively inhibits ovulation; however, limited data are available regarding its effects on estradiol (E2), progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) or its additional extraovarian contraceptive effects., Study Design: In this secondary analysis, 100 women received E(2)V 3 mg on days 1-2, E(2)V 2 mg/DNG 2 mg on days 3-7, E(2)V 2 mg/DNG 3 mg on days 8-24, E(2)V 1 mg on days 25-26 and placebo on days 27-28 for one treatment cycle. Measures included the presence/absence of cervical mucus; endometrial thickness; and serum E2, progesterone, and gonadotropin levels., Results: E2, progesterone, LH and FSH levels did not exhibit the typical ovulatory increase and remained relatively stable during the cycle. E(2)V/DNG reduced mean maximal endometrial thickness and proportion of women with visible cervical mucus. All parameters returned to pretreatment levels during the posttreatment cycle., Conclusion: E(2)V/DNG provides extraovarian contraceptive effects (reducing endometrial thickness and cervical mucus production) in addition to inhibiting ovulation, assuring contraceptive efficacy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Dienogest offers pharmacological advantages for the effective treatment of endometriosis and for use in contraception and hormone replacement therapy. This pharmacodynamic study investigated the ovulation-inhibiting effects of dienogest monotherapy in healthy women. Dienogest was administered at 0.5, 1, 2, or 3 mg daily for up to 72 days to women aged 18 to 35 years (n = 102). Ovarian activity was assessed pretreatment and during 2 treatment periods (days 0-36 and days 37-72) by the Hoogland score, based on follicle size and serum estradiol and progesterone levels. Additional hormonal parameters and endometrial thickness were assessed. Hoogland scoring indicated ovulation in all women pretreatment, decreasing to 3 of 21, 1 of 23, 0 of 20, and 0 of 23 women in the 0.5-, 1-, 2-, and 3-mg groups, respectively (per-protocol set). Maximum serum estradiol concentrations were similar to pretreatment levels in the 0.5- or 1-mg group and decreased moderately (within physiologic levels) in the 2- or 3-mg group. Endometrial thickness was reduced by all dienogest doses. Hormonal changes during follow-up indicated resumption of ovulation in most women, shortly after treatment cessation. Dienogest ≥2 mg daily provides moderate suppression of estradiol production and reliable ovulation inhibition, which reverses rapidly after treatment cessation.

Background: The etonogestrel (ENG)-releasing implant is a subdermal progestogen-only contraceptive that provides coverage for up to 3 years. This long-acting hormonal contraceptive has been available in Europe since 1998 and in the US since 2006. To date, localization of non-palpable implants at insertion and before removal has been dependent on ultrasound or magnetic resonance imaging by an experienced clinician. To facilitate localization in rare cases of non-palpable implants using widely available equipment without the need for a specialist, a radiopaque ENG implant has been developed that is detectable by two-dimensional x-ray imaging., Objective: This study aimed to establish whether the radiopaque ENG implant is bioequivalent in situ compared with the original non-radiopaque ENG implant, and to assess x-ray visibility of the radiopaque ENG implant., Methods: This was a 3-year, randomized, double-blind, parallel-group study carried out in nine international clinical trial centres. Women aged 18-40 years at the time of screening, with menstrual cycles of a usual length of 24-35 days and a body mass index of between ≥18 and ≤29 kg/m(2) were included. Women were assigned to either the radiopaque or non-radiopaque ENG implant in a 1 : 1 ratio via a block randomization by centre. Bioequivalence testing was performed based on the peak ENG concentration (C(max)), and the area under the curve (AUC) for ENG at 6, 24 and 36 months (AUC(6 mo), AUC(24 mo) and AUC(36 mo)) after insertion. For this purpose, blood sampling for pharmacokinetic determination was performed prior to insertion and for up to 3 years afterwards. Bioequivalence was defined as the 90% confidence interval (CI) of the ratio radiopaque implant/non-radiopaque implant of the geometric means (GMR) within the acceptance range of 0.80-1.25. x-Ray visibility was assessed by two-dimensional x-ray imaging after insertion and before removal of the implant., Results: The pharmacokinetic profiles of ENG indicated that the radiopaque and non-radiopaque implants were bioequivalent with respect to the geometric mean of C(max) (GMR 1.06; 90% CI 0.91, 1.23), AUC(6 mo) (GMR 1.00; 90% CI 0.91, 1.10), AUC(24 mo) (GMR 0.98; 90% CI 0.88, 1.10) and AUC(36 mo) (GMR 1.00; 90% CI 0.89, 1.11). The radiopaque ENG implant was clearly visible in 50 out of 52 women after insertion and in all 52 women before removal, whereas none of the non-radiopaque implants were visible., Conclusion: The radiopaque ENG implant is bioequivalent in situ compared with the original non-radiopaque ENG implant and is clearly visible using x-ray imaging., Clinical Trials Registration: Registered as ClinicalTrials.gov identifier NCT00620464.

Background: This study was designed to assess the long-term safety and tolerability of a new flexible extended regimen of ethinylestradiol (EE) 20 μg/drospirenone (DRSP) 3 mg, which allows management of intracyclic (breakthrough) bleeding [flexible management of intracyclic (breakthrough) bleeding (MIB)], in comparison to conventional 28-day and fixed extended regimens., Study Design: In this Phase III, multicentre, open-label study, women (aged 18-35 years) were randomised to EE/DRSP in the following regimens: flexible(MIB) (24-120 days' active hormonal intake followed by a 4-day tablet-free interval), conventional 28-day (24 days' active hormonal intake followed by a 4-day hormone-free interval) or fixed extended (120 days' uninterrupted active hormonal intake followed by a 4-day tablet-free interval) during a 1-year comparative phase. Thereafter, women entered a 1-year safety extension phase in which the majority received the flexible(MIB) regimen. Safety/tolerability outcomes were measured over 2 years. A separate analysis of certain safety parameters (endometrial, hormonal, lipid, haemostatic and metabolic variables) was conducted at two of the study centres., Results: Results were analysed in 1067 and 783 women in the comparative and safety extension phases. Overall, 56.3% of women experienced ≥1 adverse event (AE) in the safety extension phase. Serious AEs occurred in 3.0%, 1.4% and 3.3% of women receiving the flexible(MIB), conventional and fixed extended regimens, respectively. No unexpected endometrial, hormonal, lipid, haemostatic or metabolic findings occurred with any of the three regimens., Conclusions: EE/DRSP in a flexible extended regimen with management of intracyclic (breakthrough) bleeding is well-tolerated and, when administered for up to 2 years, has a good safety profile comparable to other estrogen/progestogen oral contraceptives.

Background: The contraceptive efficacy and tolerability of a new flexible extended regimen of ethinylestradiol (EE) 20 μg/drospirenone (DRSP) 3 mg to extend the menstrual cycle and enable management of intracyclic (breakthrough) bleeding (flexible(MIB)) was investigated and the bleeding pattern compared with a conventional 28-day regimen and a fixed extended 124-day regimen., Study Design: This Phase III, 2-year, multicentre, open-label study randomly (4:1:1) allocated women (aged 18-35 years) to the following regimens: flexible(MIB) (24-120 days' active hormonal intake with 4-day tablet-free intervals); conventional (24 days' active hormonal intake followed by a 4-day hormone-free interval); or fixed extended (120 days' uninterrupted active hormonal intake followed by a 4-day tablet-free interval). Primary outcomes included the number of bleeding/spotting days during Year 1 (all regimens) and the number of observed unintended pregnancies over 2 years (flexible(MIB) only)., Results: Results were analysed in 1067 women (full analysis set). The mean number of bleeding/spotting days was lower with the flexible(MIB) vs the conventional regimen [41.0±29.1 (95% CI 38.8-43.3) vs 65.8±27.0 (95% CI 62.2-69.4) days, p<0.0001; treatment difference -24.8 (95% CI -29.2 to -20.3) days]. The corresponding value for the fixed extended regimen was 60.9±51.1 (95% CI 53.9-67.9) days. The Pearl Index for the flexible(MIB) regimen was 0.64 (95% CI 0.28-1.26). All regimens had comparable tolerability profiles., Conclusions: EE 20 μg/DRSP 3 mg administered as a flexible extended regimen with MIB is effective, well tolerated and is associated with statistically significantly fewer bleeding/spotting days and fewer withdrawal bleeding episodes vs EE/DRSP in a conventional 28-day regimen. The flexible(MIB) also provided statistically significantly fewer spotting days vs EE/DRSP in a fixed extended 124-day regimen (post hoc evaluation). The flexible(MIB) regimen allows women to extend their menstrual cycle and manage their intracyclic (breakthrough) bleeding.

Background: A novel estradiol-based combined oral contraceptive (COC) is currently available in many countries worldwide, including Europe and the US. Based on previous studies, it is expected that this estradiol-based COC will have a reduced hepatic effect compared with COCs containing ethinylestradiol with regard to proteins controlling the hemostatic balance., Objective: The aim of this study was to compare the hemostatic effects of the estradiol valerate/dienogest COC with a monophasic low-estrogen dose COC containing ethinylestradiol/levonorgestrel., Study Design: Healthy women aged 18-50 years were randomized to receive a COC containing estradiol valerate/dienogest (2 days estradiol valerate 3 mg, 5 days estradiol valerate 2 mg/dienogest 2 mg, 17 days estradiol valerate 2 mg/dienogest 3 mg, 2 days estradiol valerate 1 mg, 2 days placebo) or ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg in a crossover study design. Women received each treatment for three cycles, with two washout cycles between treatments. The primary efficacy variables were the intra-individual absolute changes in prothrombin fragment 1 + 2 and D-dimer from baseline to cycle three., Results: Data from 29 women were assessed. Intra-individual absolute changes in prothrombin fragment 1 + 2 and D-dimer from baseline to cycle three were less pronounced with estradiol valerate/dienogest than with ethinylestradiol/levonorgestrel., Conclusion: The novel COC containing estradiol valerate/dienogest had similar or less pronounced effects on hemostatic parameters than ethinylestradiol/levonorgestrel.

Background: Attempts to improve the tolerability of combined oral contraceptives (COCs) have included the substitution of ethinylestradiol (EE) with 17beta-estradiol (E2). However, this has proved unsatisfactory, specifically in terms of cycle control. To improve upon the poor cycle control seen previously, E2 [in the form of estradiol valerate (E2V); 1 mg of E2V contains 0.76 mg of E2] was combined with dienogest (DNG) in a novel four-phasic regimen. In the current studies, the ovulation-inhibition potency of four variations of this regimen was assessed., Study Design: Two randomized, open-label, Phase II studies were performed. The first study compared two regimens (Regimens 1A and 2A) with similar dosages of DNG but different lengths of application. Having established in Study 1 that the length of application of Regimen 2A was most suitable, but that the dosages of DNG were too low for effective ovulation inhibition, a second study, which compared two regimens (Regimens 2B and 2C) with similar lengths of application but with increased dosages of DNG, was undertaken. The primary efficacy variable in both studies was the proportion of women with a Hoogland score of 5 or 6 during Cycle 2., Results: The full analysis set comprised 192 and 203 women in Studies 1 and 2, respectively. In Study 1, 10 women (10.9%) in Regimen 1A and 6 women (6.4%) in Regimen 2A had a Hoogland score of 5 or 6. In Study 2, three women (3.1%) in Regimen 2B and one woman (1.0%) in Regimen 2C had a Hoogland score of 5 or 6. There were no safety concerns with any of the regimens., Conclusion: The results of these studies identified a four-phasic COC preparation comprising E2V/DNG that provides efficient ovulation inhibition. It is expected that this regimen will lead to an innovative COC containing E2 instead of EE.

Objective: To investigate whether the first cycle after stopping oral contraceptive (OC) intake had a normal duration., Methods: A retrospective study was performed in 680 women, 300 non-OC users and 380 women discontinuing OC intake. The length of one or two menstrual cycles was recorded., Results: In the non-user group, the median duration of both the first and second cycle was 29 days (range 18-97 and 20-56 days, respectively). In the OC user group the median duration from withdrawal bleeding until next menstruation was 30 (15-82) days. The second cycle lasted 29 (17-122) days. The duration of the first post-treatment cycle was not significantly different from the next cycle or the cycle length in non-users. When the subjects were divided into different age categories, a significantly longer first post-treatment cycle was observed in the group aged 18-24 years, but a shorter first post-treatment cycle in the group aged 25-29 years. No differences were seen in the higher age groups. The ethinyl estradiol dose of the OC preparation did not influence the results., Conclusions: The first cycle after OC discontinuation had a normal duration.

Background: In contrast to traditional progestagen-only pills (POPs), the desogestrel-only pill Cerazette consistently inhibits ovulation. This study was performed to test the hypothesis that desogestrel alone will keep inhibiting ovulation even when pills are taken 12 h late, indicating that delays in tablet intake of up to 12 h do not jeopardize contraceptive efficacy., Methods: Women aged between 19 and 40 years with confirmed ovulation were admitted to this open-label pharmacodynamic study. They were treated with Cerazette for 56 days with three tablets to be taken 12 h late, having been randomized to a regimen with scheduled late tablets on Days 39, 42 and 49 (Group A) or on Days 11, 14 and 21 (Group B). The occurrence of ovulation during treatment was determined by measuring progesterone serum levels every 2 days., Results: One of the 103 treated subjects ovulated during treatment. The ovulation incidence thus amounts to 1.0% (two-sided 95% confidence interval 0.02-5.29%). There was no apparent relationship between these ovulations and scheduled late tablets. The minimum time to first posttreatment ovulation was 7 days, whereas it took 17.2 days on average from last tablet intake until ovulation., Conclusions: Ovulation inhibition with Cerazette is maintained after 12-h delays in tablet intake and return of ovulation takes at least 7 days. These properties distinguish Cerazette from all other POPs.

Objective: In addition to the routinely used methods to evaluate the menstrual cycle, a new method will be described, assessing the aspect of the endocervix and the presence of cervical mucus by transvaginal ultrasonography., Study Design: 36 healthy female volunteers with regular menstrual cycles participated in the study. Transvaginal ultrasonography was performed every other day until ovulation was observed, assessing the diameter of the largest ovarian follicle, endometrial thickness, the aspect of the endocervix, and the presence of cervical mucus. On the same days serum hormone concentrations were determined., Results: Changes in the echodensity of the endocervix were observed in 35 volunteers, from 7 (1-19) (median and range) days before ovulation onwards. The presence of cervical mucus could clearly be observed in the preovulatory phase in 25 volunteers, from 3 (1-7) days before ovulation onwards., Conclusion: Preovulatory changes in the aspect of the endocervix and cervical mucus can be observed by transvaginal ultrasonography. Ultrasonography of the cervix may offer an additive diagnostic tool in fertility disorders and will, in many cases, make visual inspection of the cervix unnecessary.

Objective: A small amount of LH is necessary for 17 beta-estradiol production in the ovarian follicle. Human menopausal gonadotropin (hMG) contains equal amounts of FSH and LH activity, whereas recombinant FSH is a gonadotropin preparation without LH. The aim of the present randomized study was to investigate whether ovarian stimulation treatment with recombinant FSH or hMG resulted in different steroidal composition of follicular fluid., Methods: Antral fluid from mature follicles was collected in in vitro fertilization cycles and concentrations of testosterone, androstenedione, estrone, estradiol, progesterone, FSH, and LH were determined. Seven patients (27 samples) were treated with hMG, 6 patients (22 samples) with recombinant FSH., Results: Androgen, estrogen, progesterone, and FSH concentrations in follicular fluid tended to be lower in the group treated with recombinant FSH, but the variation was large and differences were statistically not significant., Conclusion: Treatment with a gonadotropin preparation containing no LH resulted in adequate androgen and estrogen levels in antral fluid of the ovarian follicle in women with normal endocrine profiles, even during pituitary suppression by a GnRH agonist. Apparently, the amount of endogenous LH was sufficient for steroid production within the follicle.

Objective: The aim of the present randomized study was to investigate whether ovarian stimulation treatment with gonadotropin preparations containing different amounts of LH activity resulted in variations of steroidal composition of follicular fluid. A different endocrine milieu within the follicle might influence oocyte quality., Methods: Antral fluid from mature follicles was collected in in vitro fertilization cycles and concentrations of testosterone, androstenedione, estrone, estradiol, progesterone, FSH, and LH were determined. A comparison was made between treatment with a purified FSH preparation (nine patients, 35 follicular fluid samples) and a FSH-dominant human menopausal gonadotropin (hMG) preparation (nine patients, 34 samples)., Results: No differences in any of the hormone levels could be detected between the two groups., Conclusion: Treatment with gonadotropin preparations containing different FSH/LH ratios did not result in different androgen, estrogen and progesterone levels in follicular fluid.

Objective: A small amount of LH is necessary for 17beta-estradiol production in the ovarian follicle. Human menopausal gonadotropin (hMG) contains equal amounts of FSH and LH activity, whereas recombinant FSH is a gonadotropin preparation without LH. The aim of the present randomized study was to investigate whether ovarian stimulation treatment with recombinant FSH or hMG resulted in different steroidal composition of follicular fluid., Methods: Antral fluid from mature follicles was collected in in vitro fertilization cycles and concentrations of testosterone, androstenedione, estrone, estradiol, progesterone, FSH, and LH were determined. Seven patients (27 samples) were treated with hMG, 6 patients (22 samples) with recombinant FSH., Results: Androgen, estrogen, progesterone, and FSH concentrations in follicular fluid tended to be lower in the group treated with recombinant FSH, but the variation was large and differences were statistically not significant., Conclusion: Treatment with a gonadotropin preparation containing no LH resulted in adequate androgen and estrogen levels in antral fluid of the ovarian follicle in women with normal endocrine profiles, even during pituitary suppression by a GnRH agonist. Apparently, the amount of endogenous LH was sufficient for steroid production within the follicle.

Objective: To investigate the possible benefits of in vitro fertilization (IVF) of oocytes retrieved during selective follicular reduction of supernumerary follicles in non-IVF cycles., Methods: Selective follicular reduction of supernumerary follicles was used to prevent ovarian hyperstimulation syndrome and multiple pregnancies in gonadotropin-stimulated cycles. We analyzed the data of 13 cycles (13 women) retrospectively., Results: Three pregnancies occurred in these 13 cycles (23%), one after intra-uterine insemination and two after timed coitus. In all cycles, oocytes were retrieved, and in 10 cycles fertilization was achieved (77%); in 6 cycles cryo-preservation was successful (46%) and in 3 cycles embryo transfer (ET) was performed (23%). All embryos were of poor quality and no pregnancies occurred after ET of frozen-thawed embryos. The diagnostic value of fertilization failure seems to be low, since one of the patients who failed to show fertilization became spontaneously pregnant afterward., Conclusion: Based on our observations, the beneficial effect of IVF/cryopreservation during selective follicular reduction appears questionable.

Objective: The present study investigated the pharmacokinetics of a single subcutaneous dose of human menopausal gonadotropin (hMG) on serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations., Subjects and Methods: Six healthy female volunteers, aged 20-40 years, with regular menstrual cycles and normal endocrine profiles, who were not receiving any hormonal medication, were treated with the gonadotropin-releasing-hormone agonist buserelin to suppress endogenous gonadotropin release. One volunteer dropped out during treatment. When the serum estradiol concentration had fallen to below 500 pmol/L, an injection of 150 IU hMG (HumegonR) was given subcutaneously. Immediately before injection and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 15, 20, 24, 48 and 96 hours after, blood samples were drawn for determination of FSH and LH concentrations., Results: The baseline FSH level was 2.8 IU/L, and peak concentration (6.8 IU/L) was reached 12 hours after hMG injection (median values). Exogenous LH could not be measured because of the presence of endogenous LH., Discussion: The pattern of serum FSH concentrations after a single injection of hMG was found to resemble that seen after intramuscular hMG administration, although the peak FSH value was reached somewhat later.

A study was performed to compare, in a randomized way, the effect of pulsatile intravenous (i.v.) and intramuscular (im) human menopausal gonadotrophin (hMG) administration on hormonal serum profiles and follicular development in in vitro fertilization (IVF). Fourteen IVF patients participated in the study, aged between 20 and 40 years, with a normal endocrine profile, no hormonal medication used for at least 3 months previously, no endometriosis, both ovaries present and a normal male factor. Seven patients were treated with im hMG at a daily dose of 150 IU and seven patients with pulsatile i.v. hMG at a daily dose of 112.5 IU, in both cases in combination with buserelin. Ultrasonography was performed every other day during the stimulation phase and blood samples were collected once daily up to five times a day during the entire IVF cycle. Serum concentrations of follicle-stimulating hormone, luteinizing hormone, 17 beta-oestradiol, progesterone and human chorionic gonadotrophin were determined. There were no differences in hormonal profiles between the two groups. The numbers of retrieved oocytes, fertilization rates and mean embryo quality were identical in this study, as was follicular growth. In conclusion, in the present randomized study no differences were observed in hormonal levels or follicular development after im and pulsatile i.v. hMG treatment.

OBJECTIVE -- The study was undertaken to investigate the effects of a commonly used ovarian stimulation regimen on gonadotropin levels. METHODS -- The behavior of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and human chorionic gonadotropin (hCG) was studied after intramuscular (i.m.) and intravenous (i.v.) human menopausal gonadotropin (hMG) administration. Six female volunteers participated in the study. During pituitary suppression with a gonadotropin-releasing hormone (GnRH) agonist (Buserelin), a single dose of hMG (150 IU) was injected i.m. or i.v., in a cross-over design with an interval of 2 weeks. Blood samples were collected frequently after the injection. Serum concentrations of FSH, specific LH and hCG were determined. RESULTS -- After i.m. administration of hMG, a peak FSH concentration of 7.4 +/- 1.3 U/L was reached after 8 (6-24) hours, with a subsequent decrease. At 0.5 hour after i.v. administration, peak FSH values of 30.5 +/- 5.6 U/L were obtained, followed by a decrease to baseline levels within 48 hours. Exogenous LH and hCG were hardly detectable after i.m. administration of hMG. One-half hour after i.v. injection of hMG, a small increase in specific LH levels to 6.7 +/- 2.6 U/L was shown, followed by a decline. hCG concentrations increased after i.v. hMG administration to 7.6 +/- 1.6 U/L.