Impact of various progestins with or without transdermal testosterone on gonadotropin levels for non-invasive hormonal male contraception: a randomized clinical trial.

Although several progestins have been tested for hormonal male contraception, the effects of dosage and nature of various progestins on gonadotropin suppression combined with and without additional testosterone has not been performed in a comparative trial. The aim of this study was to evaluate the differential impact of four oral or transdermal progestins on the suppression of gonadotropins in healthy men: oral: cyproterone acetate (CPA), levonorgestrel (LNG), norethisterone acetate (NETA), and transdermal: Nestorone® (NES), all in combination with transdermal testosterone (T). Randomized clinical trial testing was performed with four progestins at two doses each. After a 2-week progestin-only treatment, transdermal T was added for further 4 weeks and was followed by a 3-week recovery period. Progestin-dose per day: CPA 10 mg/20 mg, NES 2 mg/3 mg/dose e.g. 200/300 µg/day absorbed, NETA 5 mg/10 mg, LNG 120 µg/240 µg. From an andrology outpatient clinic, 56 healthy men aged 18-50 years, with body mass index ≤33 kg × m-2 were included in the study. Serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied. Secondary outcome measure included were serum testosterone concentrations, sperm concentrations, and safety parameters. Intergroup comparisons demonstrated that CPA and LNG had the strongest effect on LH/FSH suppression. Nevertheless, every substance showed significant inhibitory effects on gonadotropin secretion, especially in combination with transdermal T. A decrease in hematocrit and insulin sensitivity as well as cholesterol subfractions and triglycerides was uniformly seen for every group. The combination of oral or transdermal progestins with a transdermal testosterone preparation is able to suppress gonadotropins. Further dose titration studies with sperm suppression as an end-point should be conducted to determine the lowest effective dose for hormonal male contraception.

Progesterone and related progestins: potential new health benefits.

Progesterone is a steroid hormone that is essential for the regulation of reproductive function. The main physiological roles of this hormone have been widely described. Progesterone and progestins have been approved for a number of indications including the treatment of irregular and anovulatory menstrual cycles and, when combined with estrogen, for contraception, and the prevention of endometrial hyperplasia in postmenopausal hormonal replacement therapy (HRT) regimens. Lack of understanding between the differences in categories of the progestins as well as with the physiological hormone has resulted in considerable controversy surrounding the use of progestins for HRT regimens. Newer evidence suggests that there are distinct differences between the molecules and there is no progestin class effect, with regard to benefits or side-effects. In addition to its role in reproduction, progesterone regulates a number of biologically distinct processes in other tissues, particularly in the nervous system and the vessels. Recently, it has been shown in animal experiments that progesterone and the progestin Nestorone(®) have positive effects on neuroregeneration and repair of brain damage, as well as myelin repair. The potential benefits of natural progesterone and its related derivatives warrant further investigation. It is hoped that a better understanding of the mechanism of action of progesterone and selected progestins will help in defining better therapies for men and women.

Increased impact of a contraceptive vaginal ring with ethinyl estradiol and nestorone on C-reactive protein.

UNLABELLED: OBJECTIVE & STUDY DESIGN: In a parallel design, 23 and 22 healthy pre-menopausal women were randomly administered a contraceptive vaginal ring (CVR) delivering 150/15 µg Nestorone®/ethinyl estradiol (EE) daily or an oral contraceptive (OC) containing levonorgestrel and EE (150/30 µg) for three cycles, to compare the effects on C-reactive protein and other markers of inflammation. ANCOVA was performed with baseline values as covariate. RESULTS: The CVR caused [estimate of difference (95% CI), 109% (16-275%)] higher levels of CRP than the OC, while no difference was observed for leukocyte 1% (-13/+17%) and monocyte counts 6% (-9/+23%). The greater increase in CRP was confined to CVR recipients exhibiting low pre-treatment CRP-levels, whereas no difference was observed in the increases for recipients in the highest tertile of pre-treatment CRP levels. CONCLUSION: The difference in CRP rise in CVR and OC users does not correspond with the effects on other markers of inflammation and is most likely due to a specific difference in the effect of ethinyl-estradiol combined with nestorone in cases with low CRP.

A new combination of testosterone and nestorone transdermal gels for male hormonal contraception.

CONTEXT: Combinations of testosterone (T) and nestorone (NES; a nonandrogenic progestin) transdermal gels may suppress spermatogenesis and prove appealing to men for contraception. OBJECTIVE: The objective of the study was to determine the effectiveness of T gel alone or combined with NES gel in suppressing spermatogenesis. DESIGN AND SETTING: This was a randomized, double-blind, comparator clinical trial conducted at two academic medical centers. PARTICIPANTS: Ninety-nine healthy male volunteers participated in the study. INTERVENTIONS: Volunteers were randomized to one of three treatment groups applying daily transdermal gels (group 1: T gel 10 g+NES 0 mg/placebo gel; group 2: T gel 10 g+NES gel 8 mg; group 3: T gel 10 g+NES gel 12 mg). MAIN OUTCOME VARIABLE: The main outcome variable of the study was the percentage of men whose sperm concentration was suppressed to 1 million/ml or less by 20-24 wk of treatment. RESULTS: Efficacy data analyses were performed on 56 subjects who adhered to the protocol and completed at least 20 wk of treatment. The percentage of men whose sperm concentration was 1 million/ml or less was significantly higher for T+NES 8 mg (89%, P<0.0001) and T+NES 12 mg (88%, P=0.0002) compared with T+NES 0 mg group (23%). The median serum total and free T concentrations in all groups were maintained within the adult male range throughout the treatment period. Adverse effects were minimal in all groups. CONCLUSION: A combination of daily NES+T gels suppressed sperm concentration to 1 million/ml or less in 88.5% of men, with minimal adverse effects, and may be further studied as a male transdermal hormonal contraceptive.

Combined transdermal testosterone gel and the progestin nestorone suppresses serum gonadotropins in men.

CONTEXT: Testosterone (T) plus progestin combinations are the most promising hormonal male contraceptives. Nestorone (NES), a progestin without estrogenic or androgenic activity, when combined with T may be an excellent candidate for male contraception. OBJECTIVE: Our objective was to determine the effect of transdermal NES gel alone or with T gel on gonadotropin suppression. DESIGN AND SETTING: The randomized, unblinded clinical trial was conducted at two academic medical centers. PARTICIPANTS: A total of 140 healthy male volunteers participated. INTERVENTIONS: One hundred subjects were randomized initially (20 per group) to apply NES gel 2 or 4 mg, T gel 10 g, or T gel 10 g plus NES gel 2 or 4 mg daily for 20 d. Because only about half of the subjects in T plus NES 4 mg group suppressed serum gonadotropins to 0.5 IU/liter or less (suboptimal suppression), two additional groups of 20 men were randomized to apply daily T gel 10 g plus NES gel 6 or 8 mg. MAIN OUTCOME VARIABLE: Suppression of serum LH and FSH concentrations to 0.5 IU/liter or less after treatment was the main outcome variable. RESULTS: A total of 119 subjects were compliant with gel applications with few study-related adverse events. NES alone reduced gonadotropins significantly but less than T gel alone. Combined T gel 10g plus NES gel 6 or 8 mg suppressed both serum gonadotropins to 0.5 IU/liter or less in significantly more men than either gel alone. CONCLUSION: Transdermal NES gel alone had gonadotropin suppression activity. Combined transdermal NES (6 or 8 mg) plus T gel demonstrated safe and effective suppression of gonadotropins, justifying a longer-term study of this combination for suppression of spermatogenesis.

Endometrial histology, microvascular density and caliber, and matrix metalloproteinase-3 in users of the Nestorone-releasing contraceptive implant with and without endometrial breakthrough bleeding.

OBJECTIVE: This descriptive study evaluated endometrial histology, microvascular density and caliber, and quantification of matrix metalloproteinase (MMP-3) expression in long-term users of the Nestorone (NES)-releasing implant who presented or not endometrial breakthrough bleeding (BTB). METHODS: Endometrial biopsies were obtained from 32 healthy women with unpredictable BTB. The quantitative analysis was performed only in 20 samples. RESULTS: The mean duration of use of the implant among the 14 women with BTB was 19.6+/-1.0 months, and the other six women had used the implant for 17.7+/-2.3 months (mean+/-S.E.M.). Histological analysis of the endometrial tissue showed a predominance of progestogenic pattern followed by atrophic and proliferative endometrium in both groups. Mucosal breakdown and glandular pseudostratification were observed in half of the cases. Endometrial vascular density was 73.1+/-10.0 and 57.5+/-24.1 vessels/mm(2), and maximum vessel diameter was 923.3+/-86.0 and 1038.0+/-404 microm (mean+/-S.E.M.) in the group with and without BTB, respectively, without significance, and the rate of cells expressing MMP-3x1000 counted stromal cells was 155.8+/-24.8 and 127.0+/-19.0 (mean+/-S.E.M.) in both groups, respectively, without significance. CONCLUSIONS: This study provides information about some endometrial aspects of women using NES in contraceptive implants. In addition, the endometrium was similar during long-term use of NES-releasing contraceptive implants in women with and without endometrial bleeding.

Feasibility study of Nestorone-ethinylestradiol vaginal contraceptive ring for emergency contraception.

OBJECTIVE: The Nestorone/ethinylestradiol (NES/EE) vaginal ring is being developed as a regular contraceptive method by the Population Council. This ring is designed to release NES 150 microg/day and EE 15 microg/day during 1 year. Here, we report a Phase I clinical trial to determine the usefulness of this ring for emergency contraception. To that end, we tested the ability of this ring to interfere with ovulation when it is inserted during the follicular phase. METHOD: Forty-eight women protected from the risk of pregnancy by nonhormonal methods were divided into three groups, which differed by the size of the dominant follicle at the time of ring insertion: 12-14 mm (n = 16), 15-17 mm (n = 18) and >or=18 mm (n = 14) diameter. The NES/EE ring was left in the vagina for 7 consecutive days, after which it was removed. The growth of the leading follicle and plasma levels of estradiol, progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) in the ensuing 5 days after ring insertion were determined. Afterwards, steroid hormones were measured twice a week, until menses took place. All women had a control cycle before the ring cycle, and the range of maximum follicular diameter assigned to each volunteer was the same for the control and the ring cycle at the time when placebo was ingested or the ring inserted. RESULTS: During the 5-day period after ring insertion with follicles 12-17 mm, ovulation was absent in 25 of 34 cycles (p < .01 vs. control), and ovulatory dysfunction (absent, blunted or mistimed LH peak) occurred in 8 of the 9 remaining cycles (33/34 ovulatory processes altered; p < .005 vs. control). After ring insertion with follicles >or=18 mm in diameter, ovulation did not occur in 2 of 14 cycles or was dysfunctional in 7 of the 12 remaining cycles (9/14 ovulatory processes altered; p<.025 vs. control). Altogether, 87.5% of ring cycles (42/48) had either no ovulation or ovulatory dysfunction in the 5-day study period, in contrast to 39.6% (19/48 cycles) in control cycles (p < .001). Among follicles that failed to rupture within the 5-day study period, none ruptured later on in the ring-treated cycles, while 9 of 16 did so in control cycles. Sixty-two percent of ring-treated cycles were shorter than 24 days. Nausea, vaginal discharge and abdominal pain were the most frequently reported adverse events during ring use. CONCLUSION: Interference with 87.5% of ovulatory processes, without ovulation occurring later in the cycle and shortening of cycle length, suggests the NES/EE ring may be used as an emergency contraceptive method, with the potential advantage of providing continuing contraception after it has performed its emergency function.

Clinical performance and menstrual bleeding patterns with three dosage combinations of a Nestorone progestogen/ethinyl estradiol contraceptive vaginal ring used on a bleeding-signaled regimen.

OBJECTIVE: We examined the clinical performance of contraceptive vaginal rings (rings) delivering Nestorone (NES) progestin and ethinyl estradiol (EE). Ring removal times were signaled by menstrual events. Bleeding patterns, adverse events, patterns of use and continuation rates were the principal parameters evaluated. METHODS: In a two-stage 6-month trial, subjects were randomized to use rings releasing 50 microg/day of NES and either 10 (50/10) or 20 (50/20) microg/day of EE. Subjects were to keep rings continuously in situ until menstrual bleeding or prolonged spotting-signaled removal. Reinsertion was to occur 96 h later. After the randomized stage, an open-label 6-month trial of rings releasing 150 microg/day of NES and 15 microg/day of EE (150/15) began with the same menstrually signaled regimen. RESULTS: Two-hundred forty-six subjects participated in the trial. Six-month pregnancy rates ranged by ring dose from 1.3 to 3.9 per 100. For each ring dose combination, 6-month continuation rates were above 80 per 100. Bleeding and spotting (B+S) days in women with the 50 microg/day NES rings were similar in number to those experienced by cycling women not using contraception. Nevertheless, in the initial 90 days, fewer B+S days were reported by subjects with the 50/20 ring than by subjects with the 50/10 ring (p < .05). Throughout the trial, subjects using the 150/15 ring reported significantly fewer B+S episodes than did subjects with either 50 microg/day NES ring. CONCLUSION: Combined contraceptive rings used with a bleeding-signaled regimen led to few terminations attributed to bleeding problems and to acceptable continuation rates. The 150/15 ring appeared to induce fewer bleeding problems than did the lower-dose NES combination rings, but no important difference in 6-month continuation rates among the three doses was noted.

Two-year performance of a Nestorone-releasing contraceptive implant: a three-center study of 300 women.

A 2-year trial of a single Nestorone (NES) rod implant was conducted at three Latin American centers, each enrolling 100 women. We studied the safety, effectiveness and acceptability of this progestin-releasing contraceptive implant. Three pregnancies occurred, the last at 18 months of use. Because no pregnancies were expected in the first 18 months, the trial was halted. At that time, 224 women had completed at least 18 months of use, and 99 women had used the implant for more than 24 months. Few participants used adjunctive contraception between the time the study was halted and the time they had their implant removed. No additional pregnancies occurred before the removal of the last implant. The 2-year cumulative pregnancy rate was 1.7 per 100 with a Pearl index of 0.6 per 100 for the 2-year period. The 1-year and 2-year continuation rates were 80.5 and 66.7 per 100, respectively. Menstrual and medical disturbances were the principal reasons for discontinuation, followed by planned pregnancy. Headache and weight gain frequently led to discontinuation. The NES implant had little important effect on most clinical chemistry and lipid parameters. Over the study course, the mean change in hemoglobin was <1%. Slight modification of the design of this single 2-year implant, restoring features previously examined in clinical trials, is likely to improve its effectiveness. A single NES implant appears to provide acceptable contraception for women.

Enlarged ovarian follicles in users of a levonorgestrel-releasing intrauterine system and contraceptive implant.

OBJECTIVE: To evaluate the prevalence of enlarged ovarian follicles among users of a 20 micrograms/d levonorgestrel-releasing intrauterine system (Mirena, Leiras Oy, Turku, Finland), of subdermal contraceptive implants releasing Nestorone (Population Council, New York, New York) and of the TCu 380A intrauterine device. STUDY DESIGN: A cohort study was conducted at the Universidade Estadual de Campinas, Brazil. Three hundred women were enrolled, with 100 participants in each group. Bimanual pelvic examination and vaginal ultrasound were performed during routine gynecologic examinations in women without complaints. In women with enlarged ovarian follicles (> or = 25 mm), estradiol and progesterone levels were assessed weekly until disappearance or reduction of the ovarian image. RESULTS: Enlarged ovarian follicles were detected in 19%, 10% and 5% of users of the levonorgestrel system, implants and intrauterine device, respectively. Most of the enlarged ovarian images disappeared after 2 weeks of follow-up. Progesterone levels showed that the intrauterine system and TCu 380A IUD (FEI, North Tonawanda, New York) users had presumably ovulated before the first ultrasound examination in contrast to the implant users. CONCLUSION: Physicians and users should be aware that findings of enlarged ovarian follicles during the use of progestin-only contraceptives are transient and that no medical interventions are necessary.

Contraceptive efficacy and clinical performance of Nestorone implants in postpartum women.

The objective of this study was to evaluate the contraceptive efficacy and clinical performance of a Nestorone subdermal implant (NES) in the postpartum period. NES (n = 100) and Copper T intrauterine device (T-Cu; n = 100) acceptors initiated contraception at 8 weeks postpartum and were followed at monthly intervals during the first year and at 3-month intervals thereafter. Pregnancy rates, breastfeeding performance, infant growth, bleeding pattern, and side effects were assessed. Blood and milk NES concentration were measured. No pregnancy occurred in 2195 and 2145 woman-months of NES implant and T-Cu use, respectively. No effect of NES on lactation and infant growth and no serious adverse events were observed. Lactational amenorrhea was significantly longer in NES users (353 +/- 20 days) than in T-Cu users (201 +/- 11 days). More NES users (55.8%) experienced prolonged bleedings than did T-Cu users (36.2%). Concentrations of NES in breast milk ranged between 54-135 pmol/liter. The Nestorone implant is a highly effective contraceptive, safe for breastfed infants because the steroid is inactive by the oral route.

Vaginal rings for contraception in lactating women.

Contraceptive methods for breastfeeding women should be safe for the mother and infant and should not interfere with lactation. Progestin-only methods meet these conditions and can be used from the sixth week postpartum. Because all progestins are excreted in milk, those that are insufficiently active by the oral route are preferable to avoid any possible effect on the baby. These steroids, however, must be administered to the mother by a non-oral route. Initially, progesterone was administered subdermally to test this concept. Subsequently, a progesterone vaginal ring was developed to be used continuously for 3 to 4 months and replaced with a new device, as needed, until weaning. Clinical trials have shown a high contraceptive efficacy (over 98.5%) and safety. The gross continuation rate of this method is approximately 40% at 12 months of use, with use-related problems being the main reason for discontinuation (26.8%). Currently, a Nestorone vaginal ring is under development, delivering 50 microg of Nestorone per day. It may be used continuously for up to one year, even if weaning occurs earlier. Both of these progestin-only rings prolong lactational amenorrhea to 10 to 12 months, which represents a health benefit and convenience for many women. The registration of the progesterone vaginal ring, developed as a contraceptive method to be used exclusively during lactation, has been approved in Chile and Perú. The fact that it is a user-controlled long-term contraceptive that delivers a natural hormone makes it an attractive option for many women.

Vaginal epithelial surface appearances in women using vaginal rings for contraception.

Vaginal inspections using colposcopy before insertion of contraceptive vaginal rings and at 2-month intervals during ring use were conducted on 169 users of four different formulations. The rings studied released Nestorone alone (50, 75, 100 g daily over 6 months); ethinyl estradiol: Nestorone (30:100 and 15:150 g daily over 6 months); ethinylestradiol:norethindrone acetate (20:1000 and 15:1000 g daily over 4 months); and ethinyl estradiol:norethindrone acetate (20:1000 g daily over 12 months). A total of 88 altered or atypical conditions of the vaginal surface appearance were recorded in 507 inspections (17.4% of inspections). Many of these atypical appearances were quite subtle. The incidence was significantly higher (p <0.01) than in the single pretreatment examinations (11 in 158 inspections; 7.0%), but closely matched that of a "control group" of sexually active women who were the subject of an earlier study by the same investigators. In that study, the incidence was 18% (57 atypical conditions in 317 inspections). In all, 83% of atypical conditions identified in the vagina during ring use had disappeared by the next scheduled colposcopy despite continued ring use. Findings of potential significance were conservatively defined as all ulcerations, those abrasions and ecchymoses that were >0.5 cm in any direction, and fields of five or more petechiae. Findings fitting those criteria comprised 30% of atypical conditions in ring users, 33% in the control group, and 27% pretreatment. The corresponding incidence as a percentage of inspections were 5.3%, 6. 0%, and 2.5% in the ring users, control groups, and pretreatment groups, respectively. These differences were not statistically significant. The findings suggest that the vaginal rings included in the studies contributed little, if at all, to clinically significant lesions or to total lesion incidence. Further definition would require a larger and longer-term study with matched controls.

Parenteral administration of progestin Nestorone to lactating cynomolgus monkeys: an ideal hormonal contraceptive at lactation?

Nestorone (NES) progestin is highly effective for contraception following parenteral administration, but ineffective after oral ingestion due to rapid first-pass metabolism. Thus, NES might be ideal for lactational contraception; possible NES in milk should be metabolized by the nursing infant. We evaluated the distribution of NES, its endocrine effects and infant weight gain in five cynomolgus monkeys and their nursing infants. Nestorone implants, releasing approximately 40 microg NES/day in vitro, were placed s.c. in the mothers 3-4 months following delivery, where they remained in situ for 4 weeks. Sampling (blood daily from the mother; milk and blood from the infant at 3 day intervals) was initiated at 2 weeks prior to insertion, and continued for 2 weeks following removal of the implant. NES, oestradiol, progesterone and prolactin were measured by radioimmunoassays and the infants were weighed weekly. The (mean +/- SD) maternal serum and milk concentrations of NES were 337 +/- 90 and 586 +/- 301 pmol/l during the use of the implants. The ratio of milk/serum NES was 1.68 +/- 0.12 (mean +/- SE), and the serum and milk concentrations were significantly correlated (r = 0. 75, P < 0.001). NES was not detectable (<13 pmol/l) in any infant serum samples. Concentrations of prolactin (mean +/- SD) were 41.1 +/- 32, 26.7 +/- 7.6 and 26.3 +/- 9.5 ng/ml before, during and after the use of the implants respectively. The (mean +/- SE) infant weight increased from 643 +/- 54 g 1 week prior to insertion to 713 +/- 54 g 1 week following removal. These data confirm that NES in milk is rapidly metabolized by the suckling infant. Therefore, NES appears to be an ideal hormonal contraceptive for use during lactation.

A contraceptive subdermal implant releasing the progestin ST-1435: ovarian function, bleeding patterns, and side effects.

OBJECTIVE: To study ovarian function, bleeding patterns, and side effects during the 1-year use of a new modified contraceptive subdermal implant releasing the progestin ST-1435 with a lifetime of 2 years. DESIGN, PATIENTS: The effect on ovarian function and bleeding patterns of one contraceptive implant releasing the progestin ST-1435 was studied in 26 healthy women who volunteered. Side effects were recorded. SETTING: The outpatient clinic of the City Maternity Hospital, Helsinki, Finland. INTERVENTION: One ST-1435 contraceptive implant was inserted subcutaneously into the ventral aspect of left upper arm. MAIN OUTCOME MEASURES: The women attended the clinic at half-year intervals. Records of bleeding were kept. Blood samples were collected from 5 women before insertion of an implant, from 12 women during the first 5 to 6 weeks of use, and from 10 women during the 6th and 12th month of use. Serum concentrations of ST-1435, progesterone, and estradiol were determined. Side effects were reported. RESULTS: The study covered 302 woman-months. The implant gave serum concentrations of ST-1435 high enough to inhibit ovulation in all of the 37 analyzed cycles. No pregnancies occurred. Irregular bleeding or spotting was the main event observed, especially during the 1st year of use. One half of the users had irregular cycles. None of the women's implants was removed during 1 year of use because of irregular bleeding. The implant was well accepted and tolerated by the women; no hormonal side effects were reported. CONCLUSIONS: One single 4-cm subdermal ST-1435 implant with a lifetime of 2 years showed good contraceptive efficacy and led to suppression of ovulation. No hormonal side effects were reported. Irregular bleeding patterns were common but well-tolerated, and the implant had a high continuation rate.

PIP: Physicians inserted a new 4-cm subdermal implant releasing the progestin ST-1435 (78 mg) into the ventral area of the left upper arm in 26 healthy 20-36 year old women at the outpatient clinic at the City Maternity Hospital in Helsinki, Finland, and followed them for 12 months (total of 302 woman months) to examine its side effects, ovarian function, and bleeding patterns. (This implant has a lifetime of 2 years.) The implant released ST-1435 at serum levels high enough to suppress ovulation in all 37 analyzed menstrual cycles. None of the women became pregnant. Irregular bleeding occurred in 11 women. Even though a high proportion of women experienced irregular bleeding, it did not lead any women to request removal of the implant. The total spotting days decreased significantly between the first 6 months and the last 6 months (24-16 days; p .05). None of the women experience hormonally induced side effects, other than irregular bleeding. After 1 year of use, the continuation rate stood at 89%. 2 women wanted the implant removed so they could become pregnant. 1 woman wanted it removed for personal reasons. In conclusion, the women tolerated this implant well. Moreover, it was effective in preventing pregnancy.

Suppression of ovarian function with the transdermally given synthetic progestin ST 1435.

OBJECTIVE: To study transdermal administration of the synthetic progestin ST 1435 and effectiveness of the steroid in suppression of ovarian function. DESIGN, PATIENTS: The effect of transdermal administration of the synthetic progestin ST 1435 in suppression of ovarian function was studied in a short term (17 to 93 days) study in healthy regularly menstruating women. SETTING: The outpatient clinic of the City Maternity Hospital, Helsinki, Finland. INTERVENTION: Nine women used the progestin ST 1435 transdermally during a total of 21 menstrual cycles. Treatment was started on the 5th day of the menstrual cycle and continued for 17 to 93 days. Three different daily doses (0.5, 0.8, and 1.0 mg) were tested. The steroid was applied to the periumbical area once a day in a gel. MAIN OUTCOME MEASURES: Serum concentrations of ST 1435, progesterone, and estradiol (E2) were determined during the luteal phase of control cycles and in a total of 16 treatment cycles. Bleeding records were kept and side effects registered. RESULTS: Transdermal absorption of the progestin ST 1435 resulted in relatively constant serum concentrations in each subject, depending on the dose used. All doses caused changes in ovarian function. With the 0.5-mg/d dose, inhibition of ovulation was observed in three of five treatment periods. The 0.8-mg/d dose was high enough to inhibit ovulation in 7 of 10 cycles analyzed. With the 1.0-mg/d dose, the serum concentrations of the progestin were high, and anovulation was seen. Serum E2 concentrations were variable in all cases; occasional high peak values were seen, typical of progestin treatment. Bleeding control was variable; irregular bleeding was seen, especially in anovulatory cases. CONCLUSIONS: A 0.8-mg dose of the progestin ST 1435 administered transdermally once a day appeared to suppress ovulation, if properly applied, and excessive suppression of ovarian function was not seen. The steroid was well accepted. The synthetic progestin ST 1435 given transdermally represents an effective alternative for inhibition of ovulation and for progestin therapy.

PIP: Physicians monitored serum concentrations of the synthetic progestin ST 1435, progesterone, and ethinyl estradiol in 9 healthy 28-42 year old women attending the outpatient clinic at City Maternity Hospital in Helsinki, Finland who agreed to apply ST 1435 gel to the periumbilical area daily for 21 menstrual cycles. They 1st applied it on day 5 of the menstrual cycle and continued treatment for 17-93 days. The physicians wanted to examine the daily dose of ST 1435 needed to suppress ovarian function and ovulation. A daily dose of 0.8 mg ST 1435 achieved the optimal serum concentration of ST 1435 (112-278 pmol/L) to inhibit ovulation. Each woman tended to have constant serum concentrations and those concentrations depended on the dose. All 3 different doses (0.5, 0.8, and 1 mg) affected ovarian function. The 0.5 mg/day dose prevented ovulation in 3 of 5 treatment periods while the 0.8 mg/day dose did in 7 of 10 cycles. Anovulation occurred in the only women who used the 1 mg/day dose. ST 1435 levels (mean 691 pmol/L) were high at this dose. Serum ethinyl estradiol levels differed among the women in each dose group and between dose groups. A few women even had very high levels which typifies progestin treatment. Irregular bleeding occurred in some women especially during the anovulatory cycles. Bleeding control was the only side effect. 0.8 mg/day of ST 1435 applied transdermally appeared to be an effective and acceptable contraceptive. Researchers should conduct more studies on transdermal ST 1435 to account for the interindividual differences in ST 1435 serum levels and to determine ST 1435's efficacy.

Contraception with subdermal ST-1435 capsules: side-effects, endocrine profiles and liver function related to different lengths of capsules.

One Silastic capsule of 15 mm, 20 mm or 30 mm length was inserted subcutaneously into the ventral aspect of the left forearm or upper arm of 28 healthy women during menstrual bleeding or not later than on the seventh day of the menstrual cycle. A new capsule of the same length was inserted after six months and both capsules were removed twelve months after the first insertion. Side-effects, including changes in body weight, blood pressure, menstrual bleeding and liver function test results, were registered. Blood samples were taken from selected subjects twice a week during the 1st, 2nd, 3rd, 6th, 7th and 12th month of use. Plasma concentrations of ST-1435 were measured by radioimmunoassay and the effects of treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone. There were no differences in hormonal side-effects between subjects who had a 30 mm capsule or subjects who had 20 mm or 15 mm capsules, but subjects who had 20 or 15 mm capsules had significantly longer bleeding or spotting periods in comparison with subjects who had a 30 mm capsule. There were no changes in blood pressure, body weight or liver function test results in comparison with pre-insertion values. The plasma level of ST-1435 was not significantly higher during the use of 30 mm capsules than during the use of 20 or 15 mm capsules. During the use of the shorter ST-1435 capsules, plasma estradiol elevation and slightly suppressed FSH were seen, while the use of longer capsules resulted in a slight suppression of LH. Progesterone concentrations during monitored cycles indicated anovulation. No pregnancies occurred during the study period of one year. The continuation rate at one year was 71% in the 30 mm capsule group and 57% in the 20 and 15 mm capsule groups taken together.

Long-term contraception with a single implant of the progestin ST-1435.

Silastic capsules containing the synthetic progestin ST-1435 was inserted in 282 women of reproductive age who desired long-term contraception. Each woman received a single implant for 6 months' use. After evaluating the experience of the first 45 subjects, replacement capsules were offered to women desirous of continuing the method after the initial 6 months of use. In the first 6-month segment one pregnancy and 1720 woman-months of use were recorded. The total experience, through as many as six segments of use was 3373 woman-months of use and one pregnancy. The Pearl Index is 0.36 per 100 woman-years. The single pregnancy, recorded in the 1st month of the first segment, may represent a conception prior to implant placement. Amenorrhea was the most common side effect reported, with 83% of the women having at least one nonbleeding interval longer than 60 days during the first segment of use.