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.

High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up.

Human papillomavirus (HPV) causes cervical, vulvar, and vaginal cancers, precancerous dysplasia, and genital warts. We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine. In total, 552 women (16-23 years) were enrolled in a randomised, placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0, 2, and 6. At regular intervals through 3 years, subjects underwent gynaecologic examination, cervicovaginal sampling for HPV DNA, serum anti-HPV testing, and Pap testing, with follow-up biopsy as indicated. A subset of 241 subjects underwent two further years of follow-up. At 5 years post enrollment, the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96% (two cases vaccine versus 46 placebo). There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients, and six cases in placebo recipients (efficacy = 100%; 95% CI:12-100%). Through 5 years, vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection. In conclusion, a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18. This duration supports vaccination of adolescents and young adults, which is expected to greatly reduce the burden of cervical and genital cancers, precancerous dysplasia, and genital warts.

Five-year longitudinal study on limited food consumption and development of osteoarthritis in coxofemoral joints of dogs.

OBJECTIVE: To examine the effects of limited food intake on frequency and severity of osteoarthritis in coxofemoral joints of labrador Retrievers. DESIGN: Dogs were paired according to gender and body weight, within each litter at 8 weeks of age. One dog of each pair was fed ad libitum. The limit-fed pairmate was fed 75% of the amount eaten the previous day by the ad libitum-fed counterpart. ANIMALS: 48 Labrador Retrievers. PROCEDURE: All dogs received the same diet. Radiographic evaluation of coxofemoral joints for frequency and severity of osteoarthritis were made when dogs were 4 and 6 months and 1, 2, 3, and 5 years old. RESULTS: Radiographic evaluation for osteoarthritis indicated greater frequency and more severity of osteoarthritis in the ad libitum-fed group of dogs. CLINICAL IMPLICATIONS: Analysis of data suggested that limit feeding of dogs over a 5-year period minimizes development of osteoarthritis in the coxofemoral joints.

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.

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.

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 after seven years' use of a levonorgestrel IUD.

Fifteen women with regular menstrual periods and seven amenorrheic women who had been using a levonorgestrel-releasing (LNg) IUD for more than seven years were studied. For controls, eight women using TCu380Ag IUDs for more than seven years were studied during two complete menstrual cycles. Ovarian function was assessed with hormonal determination and ultrasound examinations. The regularly menstruating women were studied for two complete menstrual cycles and the amenorrheic women for eight weeks. In the regularly menstruating LNg-IUD users, according to progesterone levels, 93% of the cycles were ovulatory but just 58% of these 'ovulatory' cycles showed normal follicular growth and rupture. Follicular cysts and luteinization of regressing follicles were observed in 42% of the 26 'ovulatory' cycles studied. SHBG capacity was decreased in the LNg-IUD users compared with the TCu380Ag users. Progesterone levels were lower in the LNg-IUD users compared with the TCu380Ag users but this difference was not statistically significant. Preovulatory estradiol and LH levels were lower in the LNg-IUD users than in the TCu380Ag users. These differences were not statistically significant. For the amenorrheic women, five had follicular cysts that disappeared spontaneously within 45 days. Two women showed follicular development and rupture. The presence of good cervical mucus was observed in 69% of the ovulatory cycles studied in the LNg-IUD users. This indicates that effects on cervical mucus cannot be the main mechanism of action of the LNg-IUDs. It is concluded that LNg-IUDs may exert a contraceptive effect in many different ways, such as inhibition of ovulation, endometrial changes preventing implantation, alteration of physical and chemical properties of cervical mucus affecting sperm transport and subtle disturbances in hypothalamic pituitary ovarian function, resulting in alterations of follicular development and rupture.

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.

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.

Effects of dietary electrolyte balance on subluxation of the femoral head in growing dogs.

Effects of increased dietary chloride and reduced sodium and potassium ion concentrations on coxofemoral joint conformation, as assessed by radiography, were examined in growing dogs. Dietary electrolyte balance was quantified by dietary anion gap (DAG), defined as Na+ + K+ - Cl- in milli-equivalents per 100 g of food. Diets had anion gap ranging from 8 to 41 mEq/100 g of food. One hundred sixty-seven pups from 27 litters representing 5 breeds were studied during the period of rapid growth. The extent of subluxation of the femoral head was measured on radiographs, using the method of Norberg. On average, less subluxation of the femoral head (P < 0.05) was observed when diets with lower DAG were fed. Differences in DAG balance did not result in different rates of weight gain; therefore, the reduction in coxofemoral joint subluxation attributable to low DAG was unrelated to weight gain. Norberg angles measured at 30 weeks of age were highly correlated with coxofemoral joint status at 2 years of age, as measured by the Swedish diagnostic system and the scoring system of the Orthopedic Foundation for Animals (lrl > or = 0.70, P < 0.0002, n = 24). This diet-related improvement in coxofemoral joint subluxation would be expected, on average, to delay or mitigate the characteristic clinical and radiographic signs of hip dysplasia in growing dogs.

Effects of limited food consumption on the incidence of hip dysplasia in growing dogs.

Forty-eight 8-week-old Labrador Retrievers were allotted to 2 groups of 24 dogs each; 1 group was fed ad libitum and the other group was given 25% less of the same feed until the dogs were 2 years old. Radiography of the hip joints was done when the dogs were 30, 42, 54, 78, and 104 weeks old. Subluxation was measured by the Norberg angle on radiographs made with the dog in the standard (extended limb) position. Independent of age at which the radiography was done, there was less subluxation of the femoral heads in the limit-fed dogs. Using the Swedish method of hip joint evaluation on the same radiographs, it was found that fewer dogs on limited food intake had signs of hip dysplasia. Radiographs done when dogs were 2 years old, for all the methods used (Norberg angle in standard and frog-limb position, the Orthopedic Foundation for Animals [OFA] score, and the Swedish score), revealed less hip dysplasia (less joint subluxation and less degenerative joint disease) in the limit-fed dogs. Using the OFA method, 7 of the 24 limit-fed dogs and 16 of the 24 ad libitum-fed dogs were diagnosed as having hip dysplasia. Similarly, using the Swedish method, 5 of the 24 limit-fed dogs and 18 of the 24 ad libitum-fed dogs were diagnosed as having hip dysplasia. The food-intake-related differences were significant both for the OFA score and for the Swedish score.(ABSTRACT TRUNCATED AT 250 WORDS)

Vaginal rings for contraception: endocrine parameters.

PIP: Most of this review of the development of steroid-containing vaginal rings for contraception consists of a table listing drug dose, effect of the ring on bleeding and ovulation, and citation. The advantage of formulating a medicated vaginal ring is that the first-pass effect of an oral route of administration is avoided. Blood levels of the steroid are constant throughout the day. Low-dose progestin rings generally result in menstrual bleeding anomalies. Bleeding patterns improve when the progestin dose is raised and estradiol is added. A levonorgestrel ring developed by WHO has been fairly acceptable, with normal bleeding patterns in 50% of users, 365 ovulatory cycles, and pregnancy rates of 9.8% in women weighing 80 kg, and 1.7% in women 40 kg. Another approach is to combine progestin and estrogen. A ring releasing 120 or 150 mcg 3 keto-desogestrel and 15 mcg ethinyl estradiol daily has prevented ovulation and left bleeding patterns intact. The rings are used for 21 days, and removed for 7, and last 3 months. Generally about 70% of women find vaginal rings acceptable.^ieng

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.

Detection of Chlamydia trachomatis in urinary samples from women.

With a mean age of 21 years 197 women at risk for an infection with Chlamydia trachomatis (CT) had a urinary sample (20 ml first-void urine, minimum 4 hours from prior mictuation) analysed with an enzyme immunoassay (IDEIA-III) for the detection of CT. They also had samples taken from both cervix and urethra for cultivation on McCoy's cells and testing with an enzyme immunoassay (Chlamydiazyme), plus verification of positive samples in the enzyme immunoassay (EIA) with monoclonal antibodies against CT. The urethral samples were compared against the urinary samples with regard to sensitivity and specificity in detecting CT. Women with a positive culture for CT and/or a positive verified EIA from either the cervix or the urethra, were regarded as "true" infections with CT. The prevalence of CT was 12.2%. The urinary EIA sample had a sensitivity of 84% whereas the urethral EIA sample had a sensitivity of 57%. The specificity was 98% and 100% for the urinary samples, and the urethral samples respectively. It is concluded that the urinary sample is superior to the urethral sample, and that the urinary sample could be used for screening programs, to detect CT among women.

Screening for Chlamydia trachomatis infection in women and aspects of the laboratory diagnostics.

Nine hundred and thirty-three women who attended consecutively a gynecological clinic for various symptoms, for abortion, or for contraceptives, were screened for genital Chlamydia trachomatis infection. A total of 95 (10.2%) women were found infected. Of women below 25 years of age, 13.4% were infected, as compared with 4.9% over 25. Women with symptoms of genital infection were not over-represented in the infected population. Enzyme immunoassays (EIA) verified with a direct fluorescence antigen test were evaluated and compared with culture controls. Reactive samples detected using EIA were regarded as true positive if they were also positive according to the verification test. The sensitivity of the verified EIA test was 91%, the specificity 100%, the positive predictive value 100% and the negative predictive value was 99%. The sensitivity of the culture was 90%. Low age is the most predictable risk factor for genital Chlamydia trachomatis infection. Compared with cultures, EIA verified with a direct fluorescence antigen test is a rapid and effective method for clinical use.

PIP: 933 women who attended a gynecologic clinic for the treatment of various symptoms, to receive contraceptives, or to undergo abortion were screened for genital Chlamydia trachomatis infection. A total of 95 *10.2%) women were found to be infected. Of the women under age 25, 13.4% were infected, as compared with 4.9% over the age of 25. Women with genital infection symptoms were not overrepresented in the infected population. Enzyme immunoassays (EIA) verified with a direct fluorescence antigen test were evaluated and compared with culture controls. Reactive samples detected using EIA were regarded as being true positive if they were also positive according to the verification test. The sensitivity of the verified EIA test was 91%, the specificity 100%., the positive predictive valued 100%, and the negative predictive value 99%. The sensitivity of the culture was 90%. Low age is the most predictable risk factor for genital Chlamydia trachomatis infection. Compared with cultures. EIA verified with a direct fluorescence antigen test is a rapid and effective method for clinical use.

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.

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.

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.

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.

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.