The impact of a quadrivalent human papillomavirus (types 6, 11, 16, 18) virus-like particle vaccine in European women aged 16 to 24.

BACKGROUND: Quadrivalent human papillomavirus (HPV types 6/11/16/18) L1 VLP vaccine is highly effective in preventing HPV 6/11/16/18-related cervical and external genital disease. Herein, we evaluated the impact of the quadrivalent HPV 6/11/16/18 L1 VLP vaccine on prevention of HPV-associated cervico-genital lesions in a broad population of sexually active European women. METHODS: Female subjects (N = 9265) aged 16-24 with four or fewer lifetime sexual partners were enrolled and randomized to quadrivalent HPV vaccine or placebo. Subjects underwent cervicovaginal sampling for HPV DNA detection. Papanicolaou testing and anti-HPV 6/11/16/18 serology testing was also performed. RESULTS: Vaccine efficacy against lesions representing immediate cervical cancer precursors (cervical intraepithelial neoplasia grade 2/3 or adenocarcinoma in situ) related to HPV 6/11/16/18 in the per-protocol population was 100.0%[95% confidence interval (95% CI), 89.8-100.0]. Efficacy against external genital lesions (vulvar or vaginal intraepithelial neoplasia, condyloma, vulvar or vaginal cancer) related to vaccine HPV types in the per-protocol European population was 99.0% (95% CI, 94.4-100.0). CONCLUSION: These data demonstrate that quadrivalent HPV 6/11/16/18 vaccination programs in 16- to 24-year-old European women can be beneficial. NCT0009252, NCT00092534, NCT00092495.

Effects of a single contraceptive Silastic implant containing nomegestrol acetate on ovarian function and cervical mucus production during 2 years.

OBJECTIVE: To study the mechanism of action of Uniplant (South to South Corporation in Reproductive Health, Salvador, Brazil), a single Silastic capsule containing nomegestrol acetate (Lutenyl, Theramex, France) in women during 2 years. DESIGN: Comparison between the hormonal levels, follicular development, cervical mucus (CM) production, and endometrial thickness in the menstrual cycle before implant insertion and at 1, 6, 12, 18, and 24 months after implant insertion. PARTICIPANTS: A total of 15 women of reproductive age were enrolled for the 1st year of use. Twelve of these women continued for a 2nd year of Uniplant use. MAIN OUTCOME MEASURES: Hormonal plasma levels were measured in control cycles and at 1, 6, 12, 18, and 24 months of Uniplant use. Cervical mucus, follicular development, and endometrial thickness also were evaluated. RESULTS: In this study, Uniplant blocks ovulation in 86 percent of cycles studied. Disturbances in follicular growth were observed also. Cervical mucus was scanty and viscous in all women during this study. Endometrial thickness was <8 mm in all cycles studied. CONCLUSION: This study shows that Uniplant is a long-acting contraceptive that probably acts at the hypothalamic-pituitary levels, on the ovary, on CM production, and on the endometrium. These properties suggest the use of Uniplant as a contraceptive agent, especially if one considers the lack of androgenic and metabolic effects and the maintenance of periodic bleeding similar to menstruation.

PIP: A total of 15 healthy women volunteers were enrolled in this study. Their mean age was 23 +or- 1.2 years (range, 18-33 years), mean weight was 55.7 +or- 2.6 kg (range, 40-72 kg), and mean parity was 1.1 (range, 0-4). Venous blood samples were drawn every other day from day eight of the cycle until sonographic evidence of a 12-mm follicle, and then every day until sonographic evidence of follicular rupture and thereafter every other day until the next menstrual bleeding. The capsules were removed at the end of one year of Uniplant use, and a new capsule was inserted in 12 subjects. The blood samples for hormonal analyses were taken after 18 and 24 months of Uniplant use in the 12 women who continued in the study. Levels of luteinizing hormone (LH) were significantly lower than in the control cycles during the observation period (p .01, p .05). According to transvaginal sonography, four different patterns of follicular development were found: normal follicular growth and rupture, persistent follicle, follicular cysts, and no follicular growth. Follicular growth and rupture were observed in 20% of the treated cycles. Persistent follicles were present in approximately 15% of the treated cycles. Follicular cysts were observed in 29% of the cycles studied during 24 months of Uniplant use. All subjects had normal cervical cytology before starting treatment, after 12 months, and after 24 months of Uniplant use. The maximum cervical mucus score for pretreatment cycles was 12.8 +or- 0.4. Endometrial thickness was 8 mm in all cycles studied. 58% (7 of 12) of the women showed a normal menstrual cycle (26 to 32 days). 33% (4 of 12) of the women experienced one or two episodes of amenorrhea (90-134 days), whereas 8.3% of women (1 of 12) experienced episodes of spotting, six times in a period of 24 months of Uniplant use (10-30 days). Before Uniplant insertion, plasma concentration of sex hormone binding globulin was 72.3 nmol/L. After 24 months of Uniplant use, the concentration was 78.0 nmol/L.

Proteoglycan alterations during developing experimental osteoarthritis in a novel hip joint model.

Degenerative hip joint disease was induced in dogs by extra-articular surgery that created a condition that mimics hip dysplasia. Decreased acetabular coverage of the femoral head gave altered mechanical load, with ensuing cartilage degeneration. For comparison, degenerative knee joint disease was induced in other dogs by transection of the anterior cruciate ligament of the knee. The femoral head articular cartilage showed macroscopic signs of degeneration within a month. No macroscopical changes of synovitis were present. Chemical analysis of cartilage samples showed loss of proteoglycans. Guanidine hydrochloride extracts of the cartilage contained proteoglycan fragments that could be separated by equilibrium density gradient centrifugation in cesium chloride. The data indicate that proteoglycans are fragmented by proteolytic cleavage and lost from the cartilage. The proteoglycans remaining in the tissue are smaller and have lost the ability to aggregate with hyaluronic acid. Similarly, in experimental knee joint osteoarthritis, the proteoglycan content of the cartilage decreased. The structural changes of those proteoglycans remaining were of a different nature, with no changes in proteoglycan size or aggregation properties, possibly indicating that both degradation and repair took place in the knee articular cartilage and/or that fragments were rapidly lost from the tissue. This may follow from different surgical procedures, only the one used for the hip joint being extra-articular, or from the different anatomy and physiology of the hip joint and the knee joint.

Proteoglycans and calcification of cartilage in the femoral head epiphysis of the immature rat.

The femoral heads of young rats have been used to monitor changes in proteoglycan structure during growth and endochondral ossification. Proteoglycans were extracted in good yield. The tissue content of proteoglycans increased until the time of calcification and then decreased. In contrast, the collagen content increased over the period studied. On Day 20, just preceding the onset of calcification, the proteoglycans had a lower glycosaminoglycan content, were somewhat smaller, and contained a larger proportion of molecules that were not capable of interacting with hyaluronic acid. On Day 25, during ongoing calcification, the proportion of proteoglycans that were not capable of interacting with hyaluronic acid was low, while it again was high on Day 40, just preceding ossification. The relative glycosaminoglycan content of the proteoglycans was somewhat lower on Day 20 and Day 40. The results indicate that both at the time of calcification and at the time of ossification the proteoglycan structure changes, perhaps indicating a functional role for the proteoglycans in the calcification process.

Plasma concentrations of medroxyprogesterone acetate, estradiol and estrone following oral administration of Klimaxil, Trisequence/Provera and Divina. A randomized, single-blind, triple cross-over bioavailability study in menopausal women.

The absorption of estradiol and medroxyprogesterone acetate was investigated in a randomized single-blind, triple cross-over study, in 12 menopausal women, for four different HRT drugs (Klimaxil, a combination tablet containing 17 beta-estradiol 2 mg and medroxy-progesterone acetate 5 mg; Divina, a combination tablet containing 17 beta-estradiol valerate 2 mg and medroxyprogesterone acetate 10 mg; Trisequence, a triphasic preparation containing 17 beta-estradiol 2 mg in the first phase; Provera, a tablet containing medroxyprogesterone acetate 5 mg). Trisequence and Provera were ingested simultaneously. In conclusion, there was no statistically significant difference between the drugs with respect to the estradiol levels. The estrone concentration, however, differed between the different drugs. The serum concentration was higher after intake of tablets containing estradiol than after intake of tablets containing the valerate ester. There was a significant increase in the MPA levels between periods 1 and 3. Finally, Divina produced higher MPA concentrations than Klimaxil and the combination of Trisequence and Provera, although the mean AUC was not twice as high, as might have been expected.

Enhanced metabolism of levonorgestrel during phenytoin treatment in a woman with Norplant implants.

A 26-year-old woman, treated with phenytoin for 10 years because of epilepsy, had Norplant subdermal implants inserted after a legal abortion. She became pregnant again after nine months of Norplant use. Her plasma levonorgestrel (LNG) levels were followed during one month during phenytoin treatment and then later during one month after discontinuation of phenytoin. During phenytoin treatment, plasma LNG levels were markedly below the levels found in healthy women with Norplant. There was a pronounced, statistically significant increase in plasma LNG levels after discontinuation of phenytoin. The plasma levels of sex hormone binding globulin were markedly above those found in normal healthy women during treatment with phenytoin and decreased significantly after cessation of phenytoin. The effects on the pharmacokinetics of LNG were reflected by effects on the menstrual cycle. During phenytoin treatment, the woman had regular ovulatory menstrual cycles. After cessation of phenytoin, her cycles became irregular and during the study period of one month, no signs of ovulation were found. It is concluded that treatment with phenytoin during use of Norplant subdermal implants enhances the metabolism of LNG to an extent where the contraceptive efficacy is endangered.

Contraception with a vaginal ring releasing 3-keto desogestrel and ethinylestradiol.

Eleven healthy women used a contraceptive vaginal ring for three cycles. The rings released 15 micrograms of ethinylestradiol and 150 micrograms of 3-keto desogestrel per 24 hours. The rings were used for 21 days and then removed, rinsed in clean water and stored. After a 7-day ring-free period, the rings were reinserted. Totally, each ring was used for 3 cycles. The rings were well tolerated. The bleeding pattern was excellent. No woman showed any signs of ovulation when using the ring. Estradiol levels were suppressed, but showed an increase during the ring-free period as can be found during the pill-free period of an oral contraceptive regimen. When the ring was reinserted, the estradiol levels were rapidly suppressed again. SHBG capacity increased during use of the ring.

Differential effects on bone density of progestogen-only methods for contraception in premenopausal women.

The question of differential effects on bone density by two different types of progestogen-only methods for contraception in premenopausal women was addressed. Data from a prospective randomized clinical trial among 22 premenopausal women, age 32.6 (range 20-45 years), who were randomly assigned to either of two treatments with continuous progestogens for contraception were analyzed; depot-medroxyprogesterone acetate (DMPA) or continuous levonorgestrel treatment with subdermal implants (Norplant), respectively. Forearm bone density (BMDprox) increased with 2.94% (p = 0.006) in women who were prescribed levonorgestrel, which was in contrast to stable values in those prescribed depot-medroxy-progesterone acetate; group difference at 6 months for BMDprox 3.4% (95% CI 1.3, 5.5; p = 0.025) and BMDdist 4.1% (95% CI - 1.3, 9.6; p = 0.077). The changes in bone density were consistent with the changes in biochemical indices for bone metabolism; DMPA users showed signs of increased bone turnover and users of levonorgestrel showed increased bone formation with increased levels of both alkaline phosphatase (p = 0.004) and osteocalcin (p = 0.007). The findings suggest an increase in bone density during treatment with levonorgestrel and stable values during short-term administration of DMPA, in standard clinical doses for contraception.

PIP: Researchers randomly allocated 22 premenopausal women aged 20-45 to treatment with either Depo-Provera (150 mg depot-medroxyprogesterone acetate [DMPA] injected intramuscularly every 3 months) or Norplant (30-60 g levonorgestrel/day during 1st year of use) to determine the differences in the short-term effects (at 6 months) on bone mass and bone metabolism. The women, clients of the Family Planning Unit of the University Hospital in Uppsala, Sweden, gave their informed consent to try either of the types of continuous progestogen contraception. The researchers examined biochemical indices for bone metabolism. Alkaline phosphatase and osteocalcin increased significantly in the levonorgestrel group (1.88-2.26 mckat/l [p = 0.004] and 1.22-3.05 mcg/l [p = 0.007], respectively). DMPA increased bone turnover (serum calcium: 2.33-2.38 [p = 0.038]; urine hydroxyproline/creatinine ratio: 12.1-24) and bone formation (serum osteocalcin: 1.2-1.61). Women treated with levonorgestrel experienced a 2.94% increase in forearm bone mineral density (BMDprox) (p = 0.006), while women treated with DMPA experienced an insignificant 0.41% decrease in BMDprox. These changes in BMDprox corresponded with the changes in the biochemical indices for bone metabolism. These findings reveal that treatment with levonorgestrel at standard clinical doses for contraception increases bone density, while treatment with DMPA at standard clinical doses for contraception does not affect bone density.

Aspects of thyroid function during use of Norplant implants.

Plasma thyroxin (T4), triiodothyronine (T3), T3-uptake and thyroid stimulating hormone (TSH) were measured in 18 women using Norplant implants or Norplant-2 implants for six months. Free T4-index and free T3-index were also calculated. All women had used non-hormonal contraceptives before insertion of the implants. T4 decreased and T3-uptake increased, indicating a lower level of thyroid binding proteins during treatment. Free T4-index remained unchanged, indicating that the free concentration of thyroxin was unaltered. All women were euthyroid and TSH was unchanged. It is concluded that treatment with Norplant implants does not result in a change in thyroid function.

PIP: Plasma thyroxin (T4), triiodothyronine (T3), T3-uptake and thyroid stimulating hormone (TSH) were measured in 18 women using Norplant implants or Norplant-2 implants for 6 months, in Uppsala, Swenden. Free T4-index and free T3-index were also calculated. All women had used non-hormonal contraceptives before insertion of the implants. T4 decreased and T3-uptake increased, indicating a lower levlel of thyroid binding proteins during treatment. Free T4-index remained unchanged, indicating that the free concentration of thyroxin was unaltered. All women were euthyroid and TSH was unchaned. It is concluded that treatment with Norplant implants does not result in a change in thyroid function.

Androgen levels in women using Norplant implants.

Plasma concentrations of sex hormone binding globulin (SHBG), testosterone, free testosterone, androstenedione (A4) and levonorgestrel were studied in 17 women before and during use of two levonorgestrel covered rods resulting in identical plasma concentrations of levonorgestrel as Norplant implants. There was a highly significant decrease in SHBG during treatment. Total testosterone and A4 also decreased significantly. Free testosterone remained unchanged. Diurnal variations were found to occur for A4, total and free testosterone, but not for SHBG or levonorgestrel. Moreover, plasma concentrations of testosterone, free testosterone, levonorgestrel and SHBG were measured in a second group of 88 women participating in a clinical study on Norplant implants, who at the one year follow-up visit either denied or claimed to have developed increased facial acne during treatment. There was no difference regarding SHBG, total testosterone, free testosterone or levonorgestrel between the groups of women with and without facial acne. However, the women in the group noticing increased acne during treatment, reported significantly more often to have had acne before treatment compared to the women who did not notice increased acne during treatment. It is concluded that treatment with Norplant implants does not result in increasing plasma levels of androgens.

PIP: Plasma concentrations of sex hormone binding globulin (SHBG), testosterone, free testosterone, androstenedione (A4) and levonorgestrel were studied in 17 women before and during use of 2 levonorgestrel covered rods resulting in identical plasma concentrations of levonorgestrel as Norplant implants. There was a highly significant decrease in SHBG during treatment. Total testosterone and A4 also decreased significantly. Free testosterone remained unchanged. Diurnal variations were found to occur for A4, total and free testosterone, but not for SHBG or levonorgestrel. Moreover, plasma concentrations of testosterone, free testosterone, levonorgestrel and SHBG were measured in a 2nd group of 88 women participating in a clinical study on Norplant implants, who at the 1 year follow-up visit either denied or claimed to have developed increased facial acne during treatment. There was no difference regarding SHBG, total testosterone, free testosterone or levonorgestrel between the groups of women with and without facial acne. However, the women in the group noticing increased acne during treatment, reported significantly more often to have had acne before treatment compared to the women who did not notice increased acne during treatment. It is concluded that treatment with Norplant implants does not result in increasing plasma levels of androgens.

Plasma levels of cortisol and corticosteroid binding globulin during use of Norplant-2 implants.

Plasma levels of cortisol and corticosteroid binding globulin (CBG) were studied during one year in eleven healthy women using NORPLANT-2 implants. NORPLANT-2 implants release approximately 50 ug of levonorgestrel/day. A significant diurnal variation of cortisol levels was found during the study. No significant change in cortisol levels compared to pretreatment levels was found. Levels of CBG showed no diurnal variation, but decreased significantly during use of the implants. This was most probably due to a direct effect of the levonorgestrel, as the levels of estradiol did not change compared to pretreatment levels, except for the values after 6 months that were significantly lower than pretreatment levels. A "free cortisol index" calculated as: level of cortisol/level of CBG, was unchanged during treatment compared to pretreatment levels. It is concluded that although CBG levels were reduced, no significant change in cortisol patterns was seen during use of the implants.

Clinical results with subcutaneous implants containing 3-keto desogestrel.

Eight healthy women using one Silastic implant of 30 mm length filled with 3-keto desogestrel, the active metabolite of desogestrel, were studied for 36-664 days. The release rate of 3-keto desogestrel was quite constant and around 30 micrograms/day. No ovulations occurred. One woman was amenorrheic, while the others had different bleeding patterns, often with periods of spotting. No other side effects were recorded. The mean plasma levels of 3-keto desogestrel were 0.9 nmol/l after 1 month and 0.5 nmol/l after 12 months. 3-Keto desogestrel was less effective than testosterone, estradiol or levonorgestrel in displacing 3H-dihydrotestosterone from SHBG. It is concluded that contraception with 3-keto desogestrel delivered through an implant is a promising method for further investigation. With a single implant we found a duration of at least one year.

Plasma levels of levonorgestrel and free levonorgestrel index in women using NORPLANT implants or two covered rods (NORPLANT-2).

Plasma levels of levonorgestrel, sex hormone binding globulin (SHBG) and estradiol were studied during four years in 283 healthy women using either NORPLANT implants or two covered rods (NORPLANT-2). The women were randomized to use either type of implant. Both implant systems have previously been shown to have similar release rates of levonorgestrel. In both groups plasma levels of levonorgestrel decreased throughout the study, and there were no statistically significant differences between the two groups in mean plasma levels of levonorgestrel. During the study 8 women became pregnant. All pregnancies but one occurred after 35 months of implant use and only in women using the covered rods. No significant differences were seen between the women who became pregnant and the rest of the group using two covered rods with respect to plasma levels of levonorgestrel. SHBG capacity tended to be somewhat higher in women using the two covered rods. As levonorgestrel is to a great extent bound to SHBG, and in that form not biologically active, a "free levonorgestrel index" was calculated as a ratio between levonorgestrel and SHBG. This index was significantly lower in users of two covered rods than in users of NORPLANT implants at 1, 12 and 48 months of use. Women who became pregnant had significantly lower "free levonorgestrel index" than had the rest of the group. It is postulated that the difference in "free levonorgestrel index" between users of the two implant systems reflect differences in release rate, the covered rods having a lower release rate of levonorgestrel than NORPLANT throughout the observation period. It is concluded that "free levonorgestrel index" is a better parameter than levonorgestrel plasma levels to describe implant function, and to discriminate women who are at risk of pregnancy.

PIP: The plasma levels of levonorgestrel, sex hormone binding globulin (SHBG), and estradiol were compared over a 4-year period in 283 users of 2 types of Norplant systems--implants and covered rods. Plasma levels of norgestrel decreased throughout the study period in both groups, and there were no significant differences in mean plasma levels of levonorgestrel. 7 of the 8 pregnancies recorded during the study occurred after 35 months of implant use, and all involved women in the covered rods group. No significant differences were found between the women who became pregnant and the rest of the study subjects in terms of plasma levels of levonorgestrel. SHBG capacity was slightly higher in women using the 2 covered rods. The free levonorgestrel index, calculated as a ratio between levonorgestrel and SHBG, was significantly lower in users of 2 covered rods than in users of implant capsules at 1, 12, and 48 months of use. In addition, women who became pregnant had a significantly lower free levonorgestrel index. These findings suggest that the 2 covered rods had a lower release rate of levonorgestrel than Norplant implants, despite almost identical plasma levels. Thus, the free levonorgestrel index is considered a better parameter than levonorgestrel plasma concentrations to describe implant function and to predict the risk of pregnancy.

Contraception with NORPLANT implants and NORPLANT-2 implants (two covered rods). Results from a comparative clinical study in Sweden.

Two-hundred-and-forty healthy women, ages 18 to 40 years, were randomized in a ratio of 2:5 to use NORPLANT implants or NORPLANT-2 implants. Through three years of use, no pregnancies were recorded among women using NORPLANT implants and two pregnancies were noted among women using NORPLANT-2 implants resulting in a cumulative net pregnancy rate of 1.3 +/- 0.9 per 100 acceptors (mean +/- SE) by the end of year three. This difference was not statistically significant. During the fourth year, no pregnancies were observed in the NORPLANT group, but 4 pregnancies occurred in the NORPLANT-2 group. The most common reason for terminating the study was bleeding disturbances. During the first year there were significantly more terminations due to bleeding problems in the NORPLANT group than in the NORPLANT-2 group. However, during the second year of use the proportion of women discontinuing for bleeding problems dropped considerably among NORPLANT users and during the third year very few women in either group discontinued because of bleeding problems. The continuation rates after one year were for NORPLANT users 59.4% and for NORPLANT-2 users 77.2%. Corresponding figures after three years of use were 46.1% and 51.7%, respectively. The second most common reason for discontinuation was depression and other mood changes. In both groups we noted a slight increase in weight during the study and a slight decrease in blood pressure and hemoglobin levels with time. In conclusion, both NORPLANT and NORPLANT-2 implants are very effective methods for contraception. The efficacy of NORPLANT-2 implants, however, was not acceptable during the fourth year of use in this study. The latter system could, however, become a suitable three-year contraceptive method, possibly with less bleeding disturbances than NORPLANT in the first year.

The effects of nomegestrol acetate subdermal implant (Uniplant) on carbohydrate metabolism, serum lipoproteins and on hepatic function in women.

This study was undertaken to assess possible variations in body weight, blood pressure, fasting glucose, HbA1C, insulin, total cholesterol, HDL-C, LDL-C, triglycerides, SGPT, SGOT, GGT and bilirubin in women bearing a single subdermal Silastic implant containing 55 mg (10%) of nomegestrol acetate during two years. A total of eighteen volunteers of reproductive age who desired to avoid conception were enrolled in this study. Subjects were healthy women with no contraindications to hormonal contraception. All women were investigated before starting treatment and were followed up for one year. At the end of one year the capsules were removed and a new capsule was inserted. Fasting blood samples were drawn at 8:00 to 8:30 am twice prior to implant insertion and then at the first, third, sixth and twelfth months and every six months thereafter. Body weight increased from 54.9 +/- 1.5 kg at admission to 55.3 +/- 2.0 kg at 12 months of use (p < 0.05) and to 56.0 +/- 2.7 kg at 24 months of use. A slight increase in both systolic and diastolic blood pressure was recorded at month 12 (p < 0.01). At month 24, blood pressure was not significantly different from admission values. All levels were within the normal range. Insulin, HbA1C, LDL-C and GGT remained unchanged during twenty-four months of Uniplant use. A significant decrease in total cholesterol (p < 0.05) was observed in the third month while a significant decrease in HDL-C (p < 0.01) was observed only in the sixth month of Uniplant use.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: Possible variations in body weight, blood pressure, fasting glucose, HbA1C (glycosylated hemoglobin), insulin, total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides, serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), GGT, and bilirubin were assessed for 2 years. 18 healthy female volunteers with a mean age of 23.0 years and mean parity of 0.9 used a single subdermal Silastic implant (Uniplant) containing 55 mg (10%) of nomegestrol acetate. Fasting blood samples were drawn twice prior to implant insertion and then at the 1st, 3rd, 6th, and 12th months and every 6 months thereafter. Body weight increased from 54.9 kg at admission to 55.3 kg at 12 months of use (p 0.05) and to 56.0 kg at 24 months of use. Both systolic and diastolic blood pressure increased slightly at month 12 (p 0.01). Insulin, HbA1C, LDL-C, and GGT remained unchanged during 24 months of Uniplant use. A significant decrease in total cholesterol (p 0.05) was observed in the 3rd month, while a significant decrease in HDL-C (p 0.01) was observed only in the 6th month of Uniplant use. A significant increase in triglycerides (p 0.05) was observed only in the 12th month. Significant increases in fasting blood glucose levels (p 0.05 and p 0.01) were observed in the 3rd and 6th month, respectively, for 24 months of Uniplant use. Significant decreases in SGOT (p 0.05, p 0.01 and p 0.05) were observed in the 6th, 18th, and 24th months, respectively. A significant decrease in SGPT (p 0.05) was observed in the 18th month of Uniplant use. A significant increase in bilirubin (p 0.05) was observed only in the 3rd month of Uniplant use. Within the normal range, variation of fasting glucose was not correlated with changes in insulin levels and no clinical effects on lipoproteins, carbohydrate metabolism, insulin levels, and on hepatic function were observed in these women.

Antichlamydial activity of cervical secretion in different phases of the menstrual cycle and influence of hormonal contraceptives.

Cervical secretion from three groups of asymptomatic women, either being oral contraceptive (OC) non-users or users (ethinylestradiol plus desogestrel or levonorgestrel), was tested for its capacity to prevent Chlamydia trachomatis, serotype I, from forming inclusions in cycloheximide-treated McCoy cells. The non-user groups were comprised of 12 women from whom cervical secretion was collected twice weekly during the menstrual cycle and 15 women from whom cervical secretion was collected once or twice weekly. The OC users included 66 women from whom cervical secretion was collected once or twice during their menstrual cycle. Cervical secretion from the non-users produced a decrease in the chlamydial inclusion count by 70%-90% during the first 3 weeks of the menstrual cycle, as compared with the fourth and fifth week when the reduction was 56%-68% (p < 0.001). Secretion from the OC users showed a more effective decrease in the inclusion count during the first 3 weeks of the menstrual cycle, as compared with samples obtained at the fourth and fifth weeks, i.e. 15%-35% vs. 20%-25% (p < 0.001). Cervical secretion of the non-users as compared to the users produced a significant decrease in the inclusion count, viz. 70%-90% vs. 15%-35% (p < 0.001) during the first 3 weeks as compared with 56%-68% vs. 20%-25% (p < 0.001) in the fourth or fifth week. The study suggests that natural resistance to genital chlamydial infection can differ during the menstrual cycle and it may be influenced by oral contraceptive use.

Temporal relationship between Uniplant insertion and changes in cervical mucus.

This study was undertaken to determine the time required by a single implant containing nomegestrol acetate to affect cervical mucus production and sperm penetration in women. All subjects were investigated and, if necessary, treated for any kind of cervicitis or vaginitis prior to starting cervical mucus study. The subjects had not used hormonal contraception for at least three months prior to investigation. They were counseled to use condoms during this study and also to refrain from intercourse during the period of cervical mucus sampling. Follicular development and endometrial thickness were analyzed by transvaginal sonography. Cervical mucus examination, sperm penetration test, and transvaginal sonography were performed during the control cycle and during the first cycle of Uniplant use. Blood samples were taken for the measurement of estradiol, LH, and progesterone. Cervical mucus and sperm penetration tests were evaluated according to the World Health Organization (WHO) criteria. In the treated cycle, when cervical mucus reached a score of 8-10, Uniplant was inserted, independent of the day of the cycle. Cervical mucus was then collected at 0, 4, 8, 12, 24, 48, and 96 h later until a marked change in volume, consistency, ferning spinnbarkheit, and cellularity was observed. All samples were also used for sperm penetration test. Preovulatory estradiol and LH peak decreased significantly compared to pre-implant insertion. Progesterone levels were within the normal limit. Cervical mucus and sperm penetration tests were not affected by Uniplant in the first 12 h. Twenty-four hours after Uniplant insertion, cervical mucus and sperm penetration tests were affected in 70.6% of the women. Forty-eight hours after implant insertion, the women were affected. Follicular rupture occurred in the majority of the women 48 h after implant insertion. Based on these results, it is possible to conclude that Uniplant can affect estradiol and LH preovulatory peaks and disrupt the process of cervical mucus production and sperm penetration, but it was unable to prevent ovulation when inserted in the preovulatory phase.

PIP: In Brazil, physicians inserted one single capsule of the nomegestrol acetate contraceptive implant (Uniplant) subcutaneously in the gluteal region of 17 healthy female volunteers (mean age = 24.62 years) when their cervical mucus score was 8-10. They performed cervical mucus examination, sperm penetration test, and transvaginal sonography during the control cycle and during the first cycle of Uniplant use. They took blood samples to measure estradiol, luteinizing hormone (LH), and progesterone. Uniplant contained 55 mg of nomegestrol acetate. The researchers aimed to determine the time between Uniplant insertion and changes in cervical mucus and in the ability of sperm to exhibit forward motility in the cervical mucus. When Uniplant was inserted in the early follicular phase, the preovulatory peaks of estradiol and LH were significantly lower than preinsertion peaks (539.4 vs. 1087.1 pmol/l and 12 vs. 40.4 IU/l, respectively; p 0.01). The lower progesterone levels in the treatment cycle were not significantly different than preinsertion progesterone levels (46.6 vs. 53.8 nmol/l; p = 0.055). Ultrasonography and progesterone levels indicated that 16 of the 17 treatment cycles were ovulatory. Neither cervical mucus nor sperm penetration was affected in the first 12 hours postinsertion. By 24 hours postinsertion, 70.6% of the women exhibited significant changes in both cervical mucus and sperm penetration. At the end of 48 hours, all 17 women had these changes. These findings suggest that Uniplant inserted in the periovulatory phase affects cervical mucus production, sperm penetration, and preovulatory peaks of LH and estradiol but does not affect ovulation.

Androgen levels in women using a single implant of nomegestrol acetate.

This study was undertaken to evaluate the effects of a single implant containing nomegestrol acetate (Uniplant) on plasma levels of sex hormone-binding globulin (SHBG), testosterone, free testosterone, androstenedione and on blood pressure, body weight, and the development of acne vulgaris. Plasma levels of sex hormone-binding globulin, testosterone, free testosterone and androstenedione were measured. Blood pressure and body weight were determined. The development of acne vulgaris was evaluated. Total testosterone and androstenedione decreased significantly during two years of Uniplant use but all levels were within the normal range. There were no significant differences in sex hormone-binding globulin and free testosterone during 24 months of Uniplant use. All changes observed in this study were within normal range. SHBG was not affected by Uniplant use. No significant increase in androgen levels and in the development of acne vulgaris was observed in these women using nomegestrol acetate implant during two years. Based on these results, it is possible to conclude that Uniplant had no androgenic effect in women during this study.

PIP: In Bahia, Brazil, clinical researchers enrolled 18 women of reproductive age into a clinical study examining the effects of a single contraceptive implant (Uniplant) on plasma levels of sex hormone-binding globulin (SHBG), testosterone, free testosterone, androstenedione, and on blood pressure, body weight, and the development of common acne. They followed the women for 24 months. The implant consisted of silastic tubing filled with 55 mg crystalline, finely ground nomegestrol acetate. The implant did not significantly change the plasma level of SHBG (69.2 nmol/l at baseline and 59.8 nmol/l at 24 months). The plasma level of total testosterone fell from 1.9 to 1.2 nmol/l at 12 months (p 0.01) and to 0.8 nmol/l at 24 months (p 0.01) (p = 0.019 for entire study period). Yet all these levels fell within the normal range. The free testosterone plasma level did not change significantly (2.6 pmol/l at baseline and at 24 months). The plasma level of androstenedione fell steadily throughout the study period (8.7 nmol/l at baseline, 6.2 at 6 months, 4.8 at 12 months, 3.3 at 18 months, and 3.2 at 24 months; p = 0.029), probably a result of ovulation inhibition. Body weight increased from 54.7 kg at baseline to 55.3 kg at 12 months (p 0.01) and to 56 kg at 24 months. Between baseline and 12 months of Uniplant use, both systolic and diastolic blood pressure increased (p 0.01) but did not change significantly thereafter. No woman developed acne. These findings indicate that Uniplant does not induce an androgenic effect in women during two years of use.

Ovarian function during use of a levonorgestrel-releasing IUD.

Ovarian function was studied for two complete menstrual cycles in 9 regularly menstruating women and for 8 weeks in three amenorrhoeic women who had used levonorgestrel-releasing IUDs (LNG-IUD) for more than four years. Nine patients using copper IUDs (Nova-T) were studied for two complete menstrual cycles as controls. According to progesterone levels, 15/17 cycles in women using LNG-IUDs were ovulatory, whereas only 8/17 cycles showed normal follicular growth and rupture as judged by ultrasound. In ovulatory cycles, the peak progesterone levels were lower than in the controls. The preovulatory estradiol and LH peak levels were also lower than in control subjects. SHBG levels were lower in LNG-IUD users than in copper IUD users. It is concluded that, although the dose of levonorgestrel released from the IUD is very low, it probably exerts an effect on the gonadotrophin secretion, which disturbs follicular development in many of the women studied, which in addition to the local effect on the endometrium, contributes to its high contraceptive efficacy.

Long-interval treatment regimen with a desogestrel-containing oral contraceptive.

A randomized multicenter study was performed in order to investigate the acceptance of a low-dose OC (30 micrograms of ethinyloestradiol and 150 micrograms of desogestrel), using a 9 weeks on and 1 week off schedule (prolonged regimen, n = 198), compared to a traditional 3 weeks on, 1 week off schedule (standard regimen, n = 96). Haemoglobin and blood pressure remained the same in both groups during the study. No significant differences were found in body weight changes between the two groups. There was significantly more breakthrough bleeding and spotting in the group with prolonged regimen than in the group with standard regimen, but both breakthrough bleeding and spotting decreased during the trial. Irregular bleeding was significantly less in women who were already using OC, compared to "new starters." No serious side effects occurred. Significantly more women stopped the trial because of bleeding problems in the group with prolonged regimen, while there were significantly more women who stopped the trial because of headache in the group with standard regimen. After completing 12 months, or after premature withdrawal from the study, each women completed a questionnaire. Sixty-three per cent of the women preferred the studied alternative and twenty-six per cent preferred the traditional OC.