Clinical evaluation of a new oral contraceptive, 'Pregnon'.

'Pregnon', a new oral contraceptive containing 1 mg. lynestrenol and 0.05 mg. ethinyl oestradiol, was administered cyclically to 639 women of fertile age over a total of 9,159 cycles. There were no pregnancies. In most cases the withdrawal bleeding resembled normal menstruation. The incidence of metrorrhagia was relatively low and when it did occur it was usually confined to the early treatment cycles and was of very limited duration. The objective and subjective tolerance was excellent.

PIP: Pregnon is a new low-dosage ovulation-inhibiting agent containing 1 mg of lynestrenol and .05 mg of ethinyl estradiol in each tablet. It is also marketed under the name of Pregnon 28 or Ovostat 28 in which each package contains 22 active plus 6 placebo tablets. Data were collected from Belgian clinics and evaluated by the Medical Unit of Organon in Belgium and the Netherlands. During this study, 639 women of fertile age were monitored through 9159 cycles. The maximum period of treatment was 36 cycles. Clinical and gynecological examinations were made before treatment and then every 2 or 3 months. Treatment was begun by taking the 1st tablet on the 1st day of menstruation. After taking 22 tablets there was a 6-day tablet-free interval during which withdrawal bleeding usually occurred. The intensity of the withdrawal bleeding was normal in 57.3%, slight in 41.7%, and heavy in 1%. Spotting was noted in 3.1% of the cycles and breakthrough bleeding occurred in 2.9%. Usually they occurred in the first 3 cycles. Amenorrhea was observed in 2.9% of the cycles. Body weights were relatively unchanged. Blood pressures remained the same. Side effects were headache, nausea, vomiting, breast tenderness, heavy legs, leucorrhea, nervousness, depression, and decreased libido. Only 46 patients discontinued treatment because of these drug effects yielding an acceptability level of about 93%. Since no pregnancies occurred during this study, the Pearl index was 0.

A comparative randomized trial on the impact of two low-dose oral contraceptives on ovarian activity, cervical permeability, and endometrial receptivity.

In a double-blind randomized study, the suppression of ovarian activity and anti-conceptive effects on the cervix and endometrium were assessed during administration of two low-dose monophasic oral contraceptives (20 micrograms ethinyl estradiol [EE], 500 micrograms norethisterone--Eve 20 [Grünenthal, Aachen, Germany]; 20 micrograms EE, 150 micrograms desogestrel --Lovelle [Organon, Munich, Germany]). One hundred eighteen healthy women (ages: 18-35 years) were studied in 10 investigation centers during medication with either Eve 20 (n = 59) or Lovelle (n = 59). During three treatment cycles, ovarian activity was evaluated by sonographic determination of follicle-like structures (FLS) and by simultaneous assessment of serum endocrine profiles (gonadotropins LH and FSH, ovarian steroids estradiol [E2] and progesterone [P]). While on either treatment, no ovarian activity (as judged by no FLS and/or reduced sex steroid levels) was found in 90.8% (Eve 20) and 97.2% (Lovelle) of all investigated cycles. Follicular activity or cyst formation were detected in 18 of 173 cycles (Eve 20) and in 5 of 175 cycles (Lovelle), respectively. Gonadotropin levels were suppressed (LH < 6 IU/L, FSH < 8 IU/L) in most treatment cycles (Eve 20 76.6% vs. Lovelle: 84.8%). Serum E2 concentrations exceeding 0.1 nmol/L indicated residual follicular activity in 19.3% (Eve 20) versus 12.2% (Lovelle) of all cycles. An estimated by serum P levels over 5 nmol/L, ovulation had presumably occurred in 4.1% (Eve 20) versus 2.9% (Lovelle) of treatment cycles. However, when the sonographical and endocrinological data were combined, no ovulation was documented in any pill cycle. The quality and quantity of the cervical mucus was found to be minimal in the majority of women. Moreover, the endometrial layer was determined to be low by ultrasound during most pill cycles, indicating equally strong suppressive effects on endometrial receptivity by the two contraceptives. These observations suggest that ovarian activity is suppressed in the majority of cycles during use of low-dose contraceptives. This effect may mainly be medicated by pronounced suppression of serum gonadotropin levels. Strong anti-conceptive effects of these formulations on both cervical permeability and endometrial receptivity are additional factors ensuring the contraceptive efficacy of these formulations.

PIP: The impact of two low-dose monophasic oral contraceptives (OCs) on suppression of ovarian activity, cervical permeability, and endometrial receptivity was investigated in a randomized double-blind study involving 118 healthy women 18-35 years of age recruited from 10 study centers in Germany. 59 women received Eve (20 mcg of ethinyl estradiol and 500 mcg of norethisterone) and 59 were given Lovelle (20 mcg of ethinyl estradiol and 150 mcg of desogestrel) for a total of 3 cycles. No ovarian activity, as assessed by sonographic determinations of follicle-like structures and serum endocrine profiles, was detected in 90.8% of cycles of Eve users and 97.2% of cycles in the Lovelle group. Follicular activity or cyst formation was found in 18 of 173 cycles of Eve users and 5 of 175 cycles of Lovelle users. Gonadotropin levels were suppressed (luteinizing hormone under 6 IU/L and follicle-stimulating hormone less than 8 IU/L) in 76.6% of treatment cycles in the Eve group and 84.8% of cycles in the Lovelle group. Serum estradiol concentrations exceeding 0.1 nmol/L, indicative of follicular activity, were recorded in 19.3% of cycles of Eve users and 12.2% of cycles in the Lovelle group. Although serum progesterone levels were over 5 nmol/L in 4.1% of cycles in the Eve group and 2.9% of those in the Lovelle group, consolidation of sonographic and endocrinologic data failed to document ovulation in any treatment cycles. The quantity and quality of cervical mucus was minimal in most women in both groups. Finally, the endometrial layer was determined to be low by ultrasonography during most pill cycles, confirming the OCs' equally strong suppressive effects on endometrial receptivity.

Hemostatic and metabolic effects of lowering the ethinyl-estradiol dose from 30 mcg to 20 mcg in oral contraceptives containing desogestrel.

The metabolic and hemostatic effects of two oral contraceptives containing 150 mcg desogestrel and 20 mcg ethinyl-estradiol (EE) (MERCILON) or 30 mcg EE (MARVELON) were compared in order to examine the effect of reducing the EE dose in contraceptive pills. Forty-nine women participated in this randomized study during 6 cycles. In both groups, there was a significant increase in triglycerides, HDL-cholesterol and apoprotein A1; the same increase was observed for SBP and CBG. Slight and transient variations of fasting blood glucose levels were seen in the 30 mcg EE group and in the two groups for fasting insulin levels. The increase in renin substrate was significantly higher with the 30 mcg EE than with the 20 mcg EE pill. In both groups, plasminogen increased significantly, but antithrombin III, total and free protein S and fibrinogen decreased significantly only in women taking the 30 mcg EE pill, whereas there was no significant change in the 20 mcg EE group. Reducing the dose of EE in oral contraceptives from 30 mcg to 20 mcg minimizes their impact on renin substrate and hemostatic parameters.

[Changes in plasma levels of androgens and SHBG in patients with polycystic ovary syndrome (PCOs) treated with oral contraceptives containing desogestrel]. / Modificazione dei livelli plasmatici degli androgeni e della SHBG in pazienti con sindrome dell'ovaio policistico (PCOs) trattate con contraccettivi orali contenenti desogestrel.

PIP: 8 women, aged 17-25, with polycystic ovary syndrome (PCO) were treated with Practil 21 (Organon) containing 30 mcg of ethinyl estradiol and 150 mcg of desogestrel, or with Planum (Menarini). Checkups were conducted 3 and 6 months later to measure hormone levels. The average level of testosterone dropped significantly from 121.5 (+ or - 50.9) ng/dl to 23.1 (+ or - 10.6) ng/dl after 3 months. The level of androstenedione also decreased significantly from 265.2 (+ or - 101.4) ng.dl to 96.7 (+ or - 22.5) ng/dl. Similarly, the level of 17-hydroxyprogesterone declined from 120.5 (+ or - 69.8) ng/dl to 24.5 (+ or - 10.7) ng/dl . On the other hand, the level of sex hormone binding globulin rose from 1.3 (+ or - .6) mcg/100 ml to 3.9 (+ or - 1.8) mcg/100 ml. Cortisone level increased significantly from 15 (+ or - 3.2) mcg/100 ml to 30.6 (+ or - 10.4) mcg/100 ml after 3 months, but the normal range (5-20 mcg/100 ml) was attained at the end. Ecographic evaluation of the size of the ovaries indicated a 18.2-66.5% reduction after 3 months. In 3 cases, the number and dimension of follicles also diminished conspicuously. Acne, hirsutism, and other symptoms of hyperandrogenism also declined. Side effects were minor and included slight weight gain, spotting and headache; treatment was suspended in only 1 case because of a grand mal seizure. The administration of this new monophasic OC proved to be a valid alternative therapy for PCO.^ieng

Metabolism of a new synthetic progestagen, Org 2969, in female volunteers. The distribution and excretion of radioactivity after an oral dose of the labelled drug.

The metabolism of a new synthetic progestagen, Org 2969 was studied in 4 healthy female volunteers. During the first part of the study (Phase I), the volunteers ingested 50 microgram (about 0.1 mCi) of [16-3H5Org 2969 together with 50 microgram of ethinyloestradiol as a single dose. During the second part of the study (Phase II), a 10-day pre-treatment with the same dosage of non-radioactive compound preceded the administration of the radioactive steroid. A peak level of total radioactivity, representing 3.16-5.02% of the dose given/l of serum, was achieved within 2-3 h in Phase I. During Phase II, the corresponding figures were 4.54-5.13% after 1.5-3 h. The difference was mainly due to an increase of freely-extractable steroids during Phase II. The difference can at least partly be explained by assuming a change in the kinetics of the metabolism of Org 2969 by pre-treatment with Org 2969 and ethinyloestradiol. The mean recovery of radio activity in urine and faeces was 83.0%/48.1%/34.9% (total/urine/faeces) of the total dose in Phase I and 76.1%/45.2%/30.9% during Phase II. The differences in the total excretion and in the radioactivity excreted in the faeces were significant.

PIP: Org 2969, a newly synthesized progestin from the laboratory of Organon Int B.V., Oss, the Netherlands, was ingested by women volunteers in an oral, radioactive dose to learn more about the drug's metabolism in humans. 4 female volunteeers were studied. The study was conducted in 2 phases, the first had volunteers ingesting about .1 mCi (50 mcg) of tritiated Org 2969 along with 50 mg of ethinylestradiol (as a single dose), and the second phase was a 10-day treatment with the same (50 mcg) dose of Org 2969 without radiolabel followed by administration of tritiated Org 2969. In Phase 1, peak level of total radioactivity occurred within 2-3 hours; this peak represented 3.16-5.02% of the dose administered per liter of serum. The corresponding figures for Phase 2 were 1.5-3 hours and 4.54-5.13%. Phase 2 samples had increased levels of freely-extractable steroids compared with Phase 1, which explains the difference in measurements. Another aspect of the difference in metabolism of the 2 doses must result from a change in kinetics of the metabolism of Org 2969 by pretreatment with Org 2969 (Phase 2) or simultaneous administration with ethinylestradiol (Phase 1). 1 level was significantly different between Phase 1 and 2 and that was amount of drug excreted in feces. In Phase 1, mean recoveries of radioactivity in urine and feces were 83%/48.1%/34.9% (total/urine/feces) and for Phase 2 the same recoveries were 76.1%/45.2%/30.9%.