Herjan J.T. Coelingh Bennink

Ovarian function during the use of a single contraceptive implant: Implanon compared with Norplant.

OBJECTIVE To study the mechanism of action of Implanon, a single-rod contraceptive implant containing etonogestrel, in healthy women during 3 years. DESIGN Prospective, randomized comparison with Norplant. The study was conducted for 2 years in Sweden but was extended to 3 years in Finland. SETTING Two outpatient clinics. PATIENT(S) Thirty-two healthy women who were between 18 and 40 years of age with normal ovulatory cycles. Seven women receiving Implanon and three receiving Norplant participated in the third year. INTERVENTION(S) On or between days 1 and 5 of a spontaneous menstrual cycle, the subjects received either the etonogestrel-containing implant (Implanon) or the levonorgestrel-containing implant (Norplant). MAIN OUTCOME MEASURE(S) Ultrasonography was performed and/or progesterone concentrations were determined to confirm ovulation in a control cycle. Follicular development, endometrial thickness, and serum concentrations of 17beta-estradiol and progesterone were assessed twice per week during 4-week periods at regular intervals and after implant removal for 6 weeks to monitor return of ovulation. Times required to remove the respective implants were evaluated, as were possible complications. RESULT(S) Seven women who received Implanon and three who received Norplant completed 3 years of study. There were no pregnancies. Ovulation was observed for the first time with Norplant after 18 months. The first ovulation with Implanon was observed after 30 months. Mean endometrial thickness was <4 mm during treatment with Implanon from month 12 onward. The mean (+/-SD) time to remove Implanon was 5.9 +/- 3.4 minutes. The mean (+/-SD) time to remove Norplant was 17.9 +/- 9.9 minutes. Ovulation resumed promptly after the use of either implant. CONCLUSION(S) Results from this study provide convincing evidence of 3-year contraceptive efficacy with Implanon, mainly by ovulation inhibition.

Recombinant follicle-stimulating hormone (FSH; puregon) is more efficient than urinary FSH (Metrodin) in women with clomiphene citrate- resistant, normogonadotropic, chronic anovulation: A prospective, multicenter, assessor-blind, randomized, clinical trial

OBJECTIVE To compare the safety and efficacy of recombinant FSH (follitropin beta, Puregon; NV Organon, Oss, the Netherlands) and urinary FSH (urofollitropin, Metrodin; Ares-Serono, Geneva, Switzerland). DESIGN A prospective, multicenter, assessor-blind, randomized, clinical trial. SETTING Twelve European infertility clinics. PATIENT(S) One hundred seventy-two women (recombinant FSH: n = 105; urinary FSH: n = 67) with clomiphene citrate-resistant normogonadotropic chronic anovulation (World Health Organization group II). INTERVENTION(S) Eligible subjects were randomized (ratio of recombinant to urinary FSH, 3:2) and treated for a maximum of three cycles. A low-dose step-up regimen was used, with 75 IU of FSH given IM daily for a maximum of 14 days and, if needed, weekly increments of half an ampule given thereafter until the threshold dose for follicular development was achieved. MAIN OUTCOME MEASURE(S) Cumulative ovulation rate after three cycles, total FSH dose, and treatment period needed to achieve ovulation. RESULT(S) The cumulative ovulation rates after three treatment cycles were 95% and 96% for the recombinant and urinary FSH groups, respectively. Overall, ovulation was seen in 155 of 223 treatment cycles (69.5%) in the recombinant FSH group, compared with 92 of 138 treatment cycles (66.7%) in the urinary FSH group. In the first cycle, a statistically significantly lower total dose (750 versus 1,035 IU) and a shorter treatment period (10 versus 13 days) were needed in the recombinant FSH group to reach ovulation. Only one case of ovarian hyperstimulation syndrome led to hospitalization. Two sets of twins (one in each treatment group) and one set of triplets (in the recombinant FSH group) were born. CONCLUSION(S) Recombinant FSH (Puregon) is more efficient than urinary FSH (Metrodin) in inducing follicular development.

Effects of tibolone and continuous combined hormone replacement therapy on parameters in the clotting cascade: a multicenter, double-blind, randomized study☆

OBJECTIVE To determine the effects of tibolone and continuous combined HRT (ccHRT) on parameters in the clotting cascade. DESIGN Randomized, double-blind study. SETTING Hemostasis unit of a university hospital clinic in Germany. PATIENT(S) Sixty healthy postmenopausal women. INTERVENTION(S) Twenty-nine subjects were treated with tibolone (2.5 mg/d) and 31 with oral ccHRT containing estradiol (2 mg/d) + estriol (1 mg/d) + norethindrone acetate (1 mg/d). MAIN OUTCOME MEASURE(S) Effects on parameters in the clotting cascade at baseline and after 12 and 24 weeks of treatment. RESULT(S) Tibolone increased fibrinolysis parameters without significantly altering coagulation parameters. Treatment with ccHRT resulted in a stimulating effect on parameters of both fibrinolysis and coagulation. Tibolone showed a stronger reduction of factor VII activity; less reduction of AT-III, protein C activity, and protein S activity; stronger increase of the activated partial thromboplastin time, plasminogen and plasminogen-antiplasminogen complexes; and less increase of D-Dimer than ccHRT. Both preparations similarly reduced climacteric complaints, whereas tibolone showed less breast complaints than ccHRT. CONCLUSION(S) This study confirms that tibolone, and to a lesser extent also ccHRT, changes hemostasis parameters toward a more fibrinolytic profile, which may diminish the risk of venous thrombosis.

Single-Dose Pharmacokinetics and Pharmacodynamics of Recombinant Human Follicle-Stimulating Hormone (Org 32489) in Gonadotropin-Deficient Volunteers

OBJECTIVE To assess safety, pharmacokinetic, and pharmacodynamic properties of recombinant human follicle-stimulating hormone (FSH; Org 32489, Organon International, Oss, The Netherlands) after a single intramuscular injection in the buttock. DESIGN In a prospective study, safety variables, serum FSH, luteinizing hormone, inhibin, estradiol (females only), and testosterone (males only) were evaluated up to a maximum of 11 days after injection of 300 IU recombinant FSH. SETTING Four specialist Reproductive Endocrinology and Infertility units. VOLUNTEERS Fifteen men and women exhibiting all pituitary gonadotropin deficiency. RESULTS A single bolus of 300 IU recombinant FSH was well tolerated, and no drug-related adverse effects were noted. Comparison of before and after treatment safety variables, including serum antirecombinant FSH antibodies, showed no changes of clinical relevance. Analysis of serum FSH levels revealed comparable elimination half-lives of 44 +/- 14 (mean +/- SD) and 32 +/- 12 hours in women and men volunteers, respectively. In contrast, peak FSH concentrations were significantly lower in women than in men volunteers (4.3 +/- 1.7 versus 7.4 +/- 2.8 IU/L), and the time required to reach peak levels of FSH was significantly longer in women than in men (27 +/- 5 versus 14 +/- 8 hours). The area under the serum level versus time curve tended to be smaller in women than in men volunteers (339 +/- 105 versus 452 +/- 183 IU/L x hours), but the difference did not reach statistical significance. Together these data suggest that recombinant FSH is absorbed from its intramuscular depot to a lower rate and extent in women than in men. In both sexes a relationship between serum FSH levels and body weight was apparent. During the experimental period, other hormones remained low at baseline levels or were only slightly increased. CONCLUSION Our findings indicate that recombinant FSH is well tolerated and that it is absorbed from its intramuscular depot to a higher rate and extent in men than in women. After intramuscular administration, its half-life is in good agreement with that previously reported for natural FSH.

Dynamics of the development of multiple follicles during ovarian stimulation for in vitro fertilization using recombinant follicle-stimulating hormone (Puregon) and various doses of the gonadotropin-releasing hormone antagonist ganirelix (Orgalutran/Antagon)

OBJECTIVE To investigate relations between dose of GnRH antagonist and follicular phase characteristics. DESIGN Randomized controlled multicenter trial. SETTING Tertiary referral fertility centers. PATIENT(S) Three hundred and twenty-nine IVF patients. INTERVENTION(S) Ovarian stimulation for IVF with recombinant FSH starting on cycle day 2. From cycle day 7 onwards, cotreatment was provided with 0.0625, 0.125, 0.25, 0.5, 1.0, or 2.0 mg/d GnRH antagonist. MAIN OUTCOME MEASURE(S) Number of follicles, total follicular surface area, gonadotropin, and serum steroid concentrations. RESULT(S) In 311 patients, similar follicular growth was observed in all treatment groups. FSH levels increased during the follicular phase. Late follicular phase LH, androstenedione (AD), and E(2) levels showed a GnRH antagonist dose-related decrease (P<0.05). Late follicular phase E(2) levels correlated with total follicular surface area, AD, LH, and FSH (all P<0.001). Increasing GnRH antagonist doses exhibited additional suppressive action on E(2) levels. CONCLUSION(S) Follicular growth was unaffected by the dose of GnRH antagonist. A rise in follicular phase FSH serum concentrations during the follicular phase, largely related to exogenous FSH, enabled ongoing follicular growth in all treatment groups. The effect of GnRH antagonist on late follicular phase E(2) levels could not be exclusively attributed to suppression of LH.

Ovulation inhibition with a combined oral contraceptive containing 1 mg micronized 17β-estradiol

OBJECTIVE To evaluate ovarian function by ultrasonography and endocrine measurements. DESIGN Prospective, open study. SETTING Outpatient clinic of the First Department of Gynaecology and Obstetrics, University of Vienna, Austria. PARTICIPANTS Twenty healthy women with regular cycles and established ovulation by ultrasonography. INTERVENTION Treatment with a combination of 1 mg micronized E2 with 150 micrograms desogestrel daily for 21 days, followed by 7 pill-free days. MAIN OUTCOME MEASURES Transvaginal ultrasonography and estimation of E2 and P at least twice a week for two consecutive cycles, followed by one after treatment cycle. RESULTS Ovulation inhibition was apparent in all cases and no functional ovarian cysts were observed during treatment. On a few occasions a persistent follicle was noted, but in the majority of cases there was total absence of follicular activity. The bleeding pattern showed a tendency toward prolonged and more heavy bleeding when compared with the before treatment situation. Return of ovulation was prompt in all women but one. CONCLUSIONS Ultrasonographic observations, accompanied by P and E2 measurements, allow us to conclude that the combination of 1 mg E2 with 150 micrograms desogestrel provides complete ovulation inhibition. However, the bleeding pattern does not show an acceptable profile.

Hormone replacement therapy in perimenopausal women and 2-year change of carotid intima-media thickness

OBJECTIVES To assess the 2-year effects of a combined regimen of oral 17beta-estradiol and desogestrel (17betaE-D) and a sequential combination of conjugated equine estrogens and norgestrel (CEE-N) on common carotid intima-media thickness and end-diastolic lumen diameter in comparison to placebo in perimenopausal women. METHODS The study was a single center, randomized, group-comparative, double-blind study with respect to the 17betaE-D and placebo groups and open with respect to CEE-N. After cycle 6, the blind was broken and the trial was continued as an open trial for another 18 months for the active study arms. The study included 121 perimenopausal women recruited from the general population. Common carotid intima-media thickness and end-diastolic lumen diameter were measured at baseline and cycle 24 with B-mode ultrasonography. RESULTS At cycle 24 small changes in intima-media thickness and lumen diameter were observed. Relative to placebo, changes in intima-media thickness were -0.009 mm [95% CI -0.045; 0.027] for 17betaE-D and -0.016 mm [95% CI -0.055; 0.024] for CEE-N. For end-diastolic lumen diameter the changes were -0.091 mm [95% CI -0.236; 0.055] and -0.125 mm [95% CI -0.820; 0.032] for 17betaE-D and CEE-N, respectively. CONCLUSIONS In this study among perimenopausal women a significant effect of 17betaE-D and CEE-N on common carotid intima-media thickness and lumen diameter could not be demonstrated. Although the sample size of the present trial is too limited to provide definite conclusions, the direction of the effect is in agreement with evidence from earlier studies on the effects of hormone replacement therapy in postmenopausal women.

Estetrol: A unique steroid in human pregnancy

Estetrol (E(4)) is an estrogenic steroid molecule synthesized exclusively by the fetal liver during human pregnancy and reaching the maternal circulation through the placenta. Its function is presently unknown. After its discovery in the mid-1960s, E(4) research revealed rather unique properties of this steroid and spawned a large body of state-of-the art publications. Nevertheless, 20 years later experimental work was virtually abandoned. In recent years based on new data, E(4) has experienced a vita nova, a revival of preclinical and clinical research activities with the goal to elucidate its physiological function and explore its potential for therapeutic use in humans. This review is intended to offer an historical account of the discovery of E(4) and the preclinical studies conducted during the heyday of E(4) research that ended in the mid-1980s.

Ovulation inhibition by estetrol in an in vivo model

BACKGROUND Currently, the synthetic steroid ethinylestradiol (EE) is the preferred estrogen in combined oral contraceptives. The aim of the present study was to evaluate the effectiveness of the natural steroid estetrol (E(4)) as an ovulation inhibitor in rats when compared to EE. STUDY DESIGN Regularly cycling female rats were treated orally twice daily for four consecutive days, starting on the day of estrus, with E(4) (0.03, 0.1, 0.3, 1.0 or 3.0 mg/kg), EE (0.0003, 0.001, 0.003, 0.01 or 0.03 mg/kg) or vehicle control (eight animals per group). In a second experiment conducted under the same experimental protocol, 2.0 mg/kg of E(4) was administered as a single daily dose or as a dose of 1.0 mg/kg twice daily. In both studies, the primary end point was the number of ovulated oocytes in the genital tract. RESULTS Estetrol at the twice daily dose of 0.3 mg/kg and above inhibited ovulation. This effect was statistically significant (p<.05). The comparator, EE, significantly inhibited ovulation (p<.05) at the highest dose (0.03 mg/kg) administered twice daily. An E4 dose of 2.0 mg/kg administered once daily for four consecutive days inhibited ovulation in four of eight rats. In contrast, when the same dose was administered in two separate doses, that is, 1.0 mg/kg twice daily, ovulation was inhibited in eight of eight rats. The ED(50) for the EE and the E(4) dose response curves shows that EE is 18 times more potent than E(4). CONCLUSION Twice daily administration of E(4) effectively inhibits ovulation in cycling rats. The effect is dose-dependent. The relative potency of E(4) is about 18 times less compared to that of EE. We conclude that based on these data, combined with available pharmacological and clinical data on the safety and efficacy of E(4), the human fetal estrogenic steroid estetrol is a potential candidate to replace EE in combined oral contraceptives.

The use of progesterone antagonists and progesterone receptor modulators in contraception.

Progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) have contraceptive potential by suppressing follicular development, delaying the surge of luteinizing hormone (LH), retarding endometrial maturation, and promoting endometrial bleeding. Mifepristone, in daily doses of 2-10 mg, blocks the LH surge and ovulation. Many of the studies were conducted in women not at risk of pregnancy, and thus the contraceptive efficacy is not yet known. Nevertheless, there is evidence that daily doses of 2 or 5 mg of mifepristone have contraceptive potential. Because of anovulation, there may be an unopposed estrogen effect on the endometrium, although this risk may be mitigated by the noncompetitive anti-estrogenic activity exhibited by both PAs and PRMs. Low doses of PAs and PRMs, which do not affect ovulation, retard endometrial maturation, indicating that the endometrium is exquisitely sensitive to these compounds. This raises the prospect of endometrial contraception, i.e. prevention of endometrial maturation without disturbing ovulation or producing alterations in bleeding patterns. This approach works well in monkeys but was not found to be very promising when given to women not using contraception. On the other hand, 200 mg mifepristone administered 48 h after the LH surge, which has minimal or no effect on ovulation and bleeding patterns, is an effective contraceptive; yet, it is not a practical approach to contraception. Late luteal phase administration of mifepristone produces menstrual bleeding. However, when mifepristone was administered every month at the end of the cycle either alone or together with prostaglandins, it was not very effective in preventing pregnancy. In contrast, a mifepristone-prostaglandin combination has been shown to be a very effective treatment for occasional menstrual regulation, with vaginal bleeding induced in 98% of pregnant women, with menses delay of 11 days or less. Mifepristone is an excellent agent for emergency contraception when used within 120 h of unprotected intercourse. It is also possible that PAs and PRMs may be used to reduce the occurrence of bleeding irregularities induced by progestin-only contraceptive methods. Both classes of progesterone receptor ligands may also have contraceptive efficacy by having a pharmacological effect on the embryo or altering tubal transport or other aspects of tubal physiology.