Long-acting injectable hormonal dosage forms for contraception.

Although great efforts have been made to develop long-acting injectable hormonal contraceptives for more than four decades, few long-acting injectable contraceptives have reached the pharmaceutical market or even entered clinical trials. On the other hand, in clinical practice there is an urgent need for injectable long-acting reversible contraceptives which can provide contraceptive protection for more than 3 months after one single injection. Availability of such products will offer great flexibility to women and resolve certain continuation issues currently occurring in clinics. Herein, we reviewed the strategies exploited in the past to develop injectable hormonal contraceptive dosages including drug microcrystal suspensions, drug-loaded microsphere suspensions and in situ forming depot systems for long-term contraception and discussed the potential solutions for remaining issues met in the previous development.

Comparison of success rate of nifedipine, progesterone, and bed rest for inhibiting uterine contraction in threatened preterm labor.

AIM: To compare the success rates and gestational ages at delivery of nifedipine, proluton depot administration as a tocolytic agent and bed rest groups to pregnant women with threatened preterm labor. MATERIAL AND METHODS: A total of 150 pregnant women with threatened preterm labor between 28 and 35 weeks of gestation were enrolled in the study. All women underwent contraction inhibition randomly sorted into three groups. The first and second groups were inhibited with nifedipine and proluton depot, respectively. The third group was admitted for bed rest. RESULTS: Nifedipine, proluton depot and bed rest can be used to inhibit contraction in threatened preterm labor. However, when time-to-event test was used, nifedipine took the shortest time for contraction inhibition with statistical significance. CONCLUSION: Nifedipine, proluton depot and bed rest can be used successfully to inhibit contraction in threatened preterm labor. However, nifedipine took the shortest time to inhibit uterine contraction in threatened preterm labor.

Omega-3 fatty acid supplementation to prevent recurrent preterm birth: a randomized controlled trial.

OBJECTIVE: To assess whether the addition of an omega-3 long-chain polyunsaturated fatty acid supplement would reduce preterm birth in women with at least one prior spontaneous preterm birth receiving 17alpha-hydroxyprogesterone caproate. METHODS: We conducted a randomized, double-masked, placebo-controlled trial in 13 centers. Women with a history of prior spontaneous singleton preterm birth and a current singleton gestation were assigned to either a daily omega-3 supplement (1,200 mg eicosapentaenoic acid and 800 mg docosahexaenoic acid) or matching placebo from 16-22 through 36 weeks of gestation. All participants received weekly intramuscular 17alpha-hydroxyprogesterone caproate (250 mg). The primary study outcome was delivery before 37 weeks of gestation. A sample size of 800 was necessary to have 80% power to detect a 30% reduction in the primary outcome from 30%, assuming a type I error two-sided of 5%. RESULTS: A total of 852 women were included, and none was lost to follow up. Delivery before 37 weeks of gestation occurred in 37.8% (164/434) of women in the omega-3 group and 41.6% (174/418) in the placebo group (relative risk 0.91, 95% confidence interval 0.77-1.07). CONCLUSION: Omega-3 long-chain polyunsaturated fatty acid supplementation offered no benefit in reducing preterm birth among women receiving 17alpha-hydroxyprogesterone caproate who have a history of preterm delivery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00135902. LEVEL OF EVIDENCE: I.

Ovulation incidence with oral contraceptives: a literature review.

BACKGROUND AND METHODOLOGY: Combined oral contraceptives (COCs) provide reliable and convenient contraception, although contraindications and tolerability issues may limit their use in some women. Progestogen-only pills (POPs) may be more suitable for some women, however, traditional POPs do not have the same contraceptive efficacy as COCs. A literature search was performed in order to assess the incidence of ovulation with available COCs, traditional POPs and with a desogestrel POP [Cerazette, 75 microg desogestrel (DSG)]. The following databases were searched: MEDLINE, EMBASE, Biosis, Derwent Drug File, Current Contents and the in-house Organon database 'Docs' (which contains all published reports of Organon products). Searches used free-text terms [e.g. Contraceptive$ in combination with (Ovulat$ adj Rate$), (Ovar$ adj Activ$) or (Escap$ adj Ovulat$)] and were limited to the search criteria 'Human' and 'from 1979 onwards'. The searches included publications up to July 2008. RESULTS: Many of the studies were hampered by inadequate ovulation criteria; however, the overall incidence of ovulation determined by the reports uncovered in the literature search was 2.0% [95% confidence interval (CI) 1.1-3.3] with COCs containing 30-35 microg ethinylestradiol (EE), 1.1% (95% CI 0.60-2.0) with 15-20 microg EE COCs, 4.6% (95% CI 2.8-6.9) with phasic COCs, 1.25% (95% CI 0.03-6.8) with Cerazette and 42.6% (95% CI 33.4-52.2) with traditional POPs. CONCLUSIONS: The findings indicate that COCs and the desogestrel POP are equally effective in suppressing ovulation, whilst the traditional POP formulations are less effective.

Long-term effects of oral and transdermal hormone replacement therapy on plasma homocysteine levels.

OBJECTIVE: To compare the long-term effects of oral and transdermal hormone replacement therapy (HRT) on serum homocysteine levels in postmenopausal women. DESIGN: An open, prospective, controlled study. Seventy-five healthy postmenopausal women were recruited as eligible for the study. Fifty women seeking HRT were randomized to receive continuous 17beta-estradiol, either by oral (2 mg daily; n = 25) or transdermal (50 microg daily; n = 25) administration, plus 10 mg dydrogesterone daily for 14 days of each 28-day cycle. Twenty-five women unwilling to receive hormone treatment received only calcium supplementation, representing the control group. Fasting blood samples were analyzed at baseline and then after 6, 12, and 24 months to determine plasma homocysteine levels. RESULTS: Fifty-nine women completed the study. After 6 months of therapy, homocysteine concentrations showed a statistically significant reduction in the treated groups versus both baseline and controls, and no further significant variations were found thereafter. The mean reduction in the homocysteine levels throughout the study was 13.6% in the oral and 8.9% in the transdermal group, respectively, without significant difference between the two routes of estradiol administration. Women with the highest baseline levels of homocysteine experienced the greatest reduction. No significant variations in homocysteine concentrations were found in the control group. CONCLUSIONS: Oral and transdermal estradiol sequentially combined with dydrogesterone shows comparable effectiveness in reducing plasma homocysteine levels in postmenopausal women. Women with the highest pretreatment concentrations of homocysteine benefit the most by the lowering effect of HRT.

[After the early termination of the Women's Health Initiative study. New American recommendations for postmenopausal hormone therapy]. / Efter den i förtid avbrutna women's health initiative-studien. Nya amerikanska rekommendationer för hormonbehandling i klimakteriet.

One treatment-arm of the Women's Health Initiative (WHI) study was recently terminated because the overall risks of hormone treatment were considered to outweigh the benefits. The main findings were an increased risk of venous thromboembolism and a decreased risk of osteoporotic fractures with treatment. No beneficial effects on cardiovascular disease could be detected. The North American Menopause Society (NAMS) Advisory Panel has given the following recommendations concerning hormone therapy: The primary indications are vasomotor and urogenital symptoms. The only indication for progesterone treatment is for endometrial protection. Hormones should not be prescribed for primary or secondary prevention of coronary heart disease. Alternative therapies should also be considered for the prevention of osteoporosis. A short duration of therapy and lower-than-standard doses are preferable. Establishing an individual risk profile is essential. The author of this article also emphasizes a restrictive attitude for patients with increased risk of thromboembolic disease.

The effect of 2 combined oral Contraceptives containing either drospirenone or cyproterone acetate on acne and seborrhea.

A new oral contraceptive has been developed that contains a unique progestogen, drospirenone (DRSP), and that has both antiandrogenic and antimineralocorticoid activity. Our objective was to compare the effect of 30 microg ethinyl estradiol (EE)/3 mg DRSP (EE/DRSP; Yasmin, Schering AG, Berlin, Germany) with that of 35 microg EE/2 mg cyproterone acetate (EE/CPA; Diane-35, Schering AG, Berlin, Germany) on mild-to-moderate cases of acne. Diane-35 is used worldwide (it is not on the market in the United States and Japan) as a hormone treatment for acne, with additional contraceptive benefits. This multicenter, double-blind, randomized study was completed over 9 treatment cycles. A total of 128 women with mild-to-moderate facial acne, with or without seborrhea and/or hirsutism, were randomized. Treatment with either EE/DRSP or EE/CPA was assigned in a 2:1 ratio. Acne lesions, sebum production, and hair growth on the upper lip, chin, and chest were assessed, as well as levels of total and free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), and luteinizing hormone (LH). At study completion, dermatologists, gynecologists, and subjects gave their overall assessment of the effect of treatment on acne. After 9 treatment cycles, the median total acne lesion count was reduced markedly by 62.5% in the EE/DRSP group and 58.8% in the EE/CPA group. A comparison of the 2 groups revealed that EE/DRSP was at least as effective as EE/CPA. Both preparations also reduced sebum production and hair growth on the upper lip and chin. A 3-fold increase in the levels of SHBG was observed in both treatment groups, and levels of androgens and LH decreased. Treatment differences were not seen. Subjective evaluation of the effect of treatment on facial acne by dermatologists, gynecologists, and the subjects themselves indicated an excellent or good improvement for most subjects in both groups. EE/DRSP has been shown to be as effective for treating mild-to-moderate acne as a preparation containing EE/CPA. This new preparation may provide useful hormone therapy for women with androgen-dependent disorders who also require contraception.

Effects of long-term and reduced-dose hormone replacement therapy on endothelial function and intima-media thickness in postmenopausal women.

OBJECTIVE: Short-term estrogen therapy improves endothelial function in postmenopausal women. However, there are few reports on its long-term effects on endothelial function and carotid intima-media thickness. Further, we determined whether a reduced dosage of estrogen may maintain its beneficial effects. DESIGN: Eighteen postmenopausal women (53.7+/-1.1 years) who had been diagnosed as having osteoporosis were enrolled. Among them, 11 women were prescribed oral conjugated estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg per day, and 7 women were prescribed an oral calcium supplement as the control group. Each patient decided whether she would take hormone replacement therapy or a calcium supplement. We performed ultrasound measurement of endothelial function of the brachial artery and carotid intima-media thickness. Examinations were scheduled to be performed pre-therapy and after 3, 6, 12, 18, 24, and 36 months of therapy. RESULTS: After three years of therapy, 6 women in the hormone replacement therapy group agreed to take half the dose of oral conjugated estrogen. Improvement of flow-mediated dilatation was observed at 3 months and the improvement was preserved up to 36 months. A similar improvement was also observed while women were on hormone replacement therapy even at the reduced dosage. Intima-media thickness of the common carotid artery in the control group increased after 12 months, which was not observed in the hormone replacement therapy group. CONCLUSIONS: Our results indicate that even at half the dose of estrogen, hormone replacement therapy may improve endothelial function and prevent the progression of carotid intima-media thickening in postmenopausal women.

[Advanced breast cancer with multiple bone metastases successfully treated with combined chemoendocrine-therapy of CEF (cyclophosphamide, epirubicin, 5-fluorouracil) and 5'-DFUR (5'-deoxy-5-fluorouridine) + MPA (medroxyprogesterone acetate)--a case report].

We report the case of a 51-year-old female with stage IV advanced breast cancer accompanied by multiple bone metastases. A hard mass of about 3.0 cm in diameter was palpated just below the nipple. An excisional biopsy was performed and histological examination revealed infiltrated solid tubular adenocarcinoma. There were no estrogen or progesterone receptors in the tumor. Modified radical mastectomy was performed in October, 1998. Postoperative adjuvant therapy with 10 cycles of CEF therapy was undertaken for one year. Combined chemoendocrine therapy with 5'-DFUR and MPA was also conducted for 11 months. Bone scintigraphy showed that all bone metastatic lesions disappeared completely one year after the operation. Mild bone marrow suppression, alopecia and body weight gain were observed as side effects. It is suggested that this combination therapy may be useful for advanced breast cancer patients with multiple bone metastases.

Prevention of postmenopausal bone loss by low and conventional doses of calcitriol or conjugated equine estrogen.

OBJECTIVES: Estrogen deficiency is the most common cause of postmenopausal osteoporosis and estrogen replacement is well known to retard postmenopausal bone loss. Calcium supplement alone is generally considered to be insufficient for the prevention of bone loss associated with estrogen deficiency while the role of calcitriol is unclear. In the present study we examined the efficacy different doses of estrogen or calcitriol in the prevention of postmenopausal bone loss in Thais. METHODS: The subjects consisted of 146 Thai women no more than 6 years postmenopausal. The subjects were randomly allocated to receive 750 mg supplemental calcium alone, calcium and conjugated equine estrogen (CEE) at 0.3 or 0.625 mg, calcium and calcitriol at 0.25 or 0.5 microg daily. Those receiving CEE also took 5 mg medrogestone for 12 days each month. BMD at L2-4 and femoral neck were measured at baseline 1 year and 2 years after treatments. Data were expressed as mean +/- S.E. RESULTS: Subjects on supplemental calcium alone had approximately 2.5% decreases in L2-4 (P < 0.05) and femoral BMD (P < 0.01) at 2 years. CEE (0.3 mg) resulted in 3.20 +/- 1.2% increase in vertebral BMD (P < 0.05) while no significant change in BMD was demonstrated at the femoral neck. Likewise, 0.625 mg of CEE induced 5.4 +/- 1.4% increase in vertebral BMD at 2 years (P < 0.001) without change in the femoral BMD. In regard to calcitriol, no significant change in vertebral or femoral BMD was demonstrated with either 0.25 or 0.5 microg calcitriol. CONCLUSION: We concluded that calcitriol is effective in the prevention of early postmenopausal bone loss in Thais. It represents an option for the prevention of osteoporosis in postmenopausal women who are contraindicated for estrogen replacement.

Accidental, intravenous infusion of a peanut oil-based medication.

OBJECTIVES: To describe a case of fat embolus syndrome with lipoid pneumonia resulting from intravenous infusion of lipid and to illustrate the potential for accidental intravenous administration of vegetable oil-based progesterone preparations in the treatment of oncology patients. CASE REPORT: A patient with recurrent ovarian carcinoma accidentally received approximately 20 mL (0.29 mL/kg) of a peanut oil-based methylprogesterone product intravenously via infusion pump over 24 hours. The patient developed a lipoid pneumonia with dyspnea, cough, hypoxia, radiographic infiltrates, and a pleural effusion. She was hospitalized for 4 days, and signs and symptoms resolved over 2 weeks following steroids and supportive care. DISCUSSION: Experience with accidental or intentional intravenous lipid overdose in humans is limited. Typical findings of fat embolus syndrome are similar to lipid aspiration, with respiratory distress, hypoxia, and pulmonary infiltrates. In contrast to aspiration, however, fat embolus syndrome results in lipogranulomas surrounding blood vessels, rather than air passages, and potentially produces cerebrovascular, accident-like symptoms. Management of fat embolus syndrome is similar to that for lipid aspiration. However, as seen in this case, fat embolus syndrome typically resolves over several weeks as opposed to the 3-month to 1-year period seen with aspiration lipoid pneumonias. CONCLUSIONS: Accidental intravenous infusion of vegetable oil-based products is a potential complication of the increased use of intravenous progesterones.

Effect of nutritional management, trace mineral supplementation, and norgestomet implant on attainment of puberty in beef heifers.

We conducted a study to evaluate the influences of nutritional management, trace mineral supplementation, and exogenous progesterone on attainment of puberty in beef heifers. Heifers (n = 180) were assigned at weaning to blocks and treatments. Treatments included two dietary regimens (corn silage vs pasture + oatlage), trace mineral supplementation, and puberty induction strategy (with or without progestin implant). Heifers that received pasture + oatlage were managed on grass-legume pastures from October 14 until December 14 and were then placed in pens and fed an oatlage-based diet through May 1994. Heifers fed the corn silage-based diet were housed in pens throughout the study. Norgestomet was implanted in half of the heifers on April 11 for 10 d. Progestin implant increased (P < .05) the number of heifers that had attained puberty by the end of the study, compared with nonimplanted heifers (89% vs 71%). Trace mineral supplementation did not affect percentage of heifers that reached puberty before the implant period. Plasma copper levels were below recommended levels in heifers fed oatlage-based diets without trace minerals. We conclude that heifers can be placed on regrowth in irrigated pastures during the fall and still make acceptable gains for attainment of puberty the following spring and that progestin treatment can aid in inducing heifers to reach puberty.

Development of a progestin-based estrus synchronization program: I. Reproductive response of cows fed melengestrol acetate for 20 days with an injection of progesterone.

We designed two experiments to determine the efficacy of an estrus control system in cows that combined long-term progestin exposure (20 d) with an acute increase in progesterone concentration. In Exp. 1, cows (n = 30) were fed either melengestrol acetate (MGA; .5 mg x cow(-1) x d(-1)) or ground ear corn (MGA carrier) for 20 d. On d -15 (last day of MGA feeding = d 0), cows were administered 25 mg of PGF2alpha to regress the corpus luteum (CL) and establish an environment conducive to the development of persistent follicles. To synchronously regress persistent follicles, cows fed MGA (n = 15) were injected with 200 mg of progesterone on d -2 (MGA-P), and the cows fed the MGA carrier were not treated (CONT; n = 15). Cows in the CONT group were artificially inseminated 12 h after detection of spontaneous estrus from d -20 to d 8. Estrus was observed, and all cows in the MGA-P group were artificially inseminated during the period of estrus synchronization (SYNC; d 1 to 8). No difference in conception rate was observed between treatments. In Exp. 2, postpartum cows (n = 113) received either the MGA-P (n = 56) or CONT (n = 57) treatment. More (P < .05) cows were observed in estrus during SYNC in the MGA-P (50%) than in the CONT (28%) group. Of the cows in the MGA-P group that were not observed in estrus during SYNC, 50% were in estrus for the first time 23 to 29 d after MGA withdrawal (SYNC2), suggesting that these cows ovulated without observable estrus during SYNC. Estrus was observed for the first time during SYNC2 in more (P < .05) cows in the MGA-P (25%) than in the CONT (7%) group. Conception rate at the synchronized estrus, pregnancy rate, and interval to first service and pregnancy were similar between treatments. We conclude that administration of MGA-P results in the synchronization and(or) induction of a fertile estrus in cows.

Development of a progestin-based estrus synchronization program: II. Reproductive response of cows fed melengestrol acetate for 14 days with injections of progesterone and prostaglandin F2alpha.

We tested the efficacy of an estrus control system designed to provide optimal control of follicular development. In Exp. 1, postpartum cows (n = 133) and yearling heifers (n = 57) were fed either .5 mg x female(-1) x d(-1) of melengestrol acetate (MGA) or the carrier for MGA from d -13 to d 0 (d 0 = last day of MGA feeding). All females received 25 mg of PGF2alpha (i.m.) on d -13 and 0. On d -6, cows and heifers fed MGA were administered an i.m. injection of progesterone (200 mg; MGA/P4), and those fed the corn carrier (2XPGF2alpha) received no progesterone. Beginning on d 1, females were bred by AI from d 1 to at least d 5. During the estrus synchronization period (d 1 to d 5), more (P < .05) postpartum cows were observed in estrus (70.1 vs 42.4%), the timing of estrus was more (P < .05) precise, conception rate was similar, and pregnancy rate was higher (P < .05) in the MGA/P4 than in the 2XPGF2alpha treatment. More (P < .05) cows that were anestrous at the beginning of the breeding season were in estrus during the synchronization period in the MGA/P4 (55.8%) than in the 2XPGF2alpha (28.6%) treatment. In heifers, estrus was synchronized in over 90% of females, and neither conception nor pregnancy rate during the synchronization period differed between treatments. In Exp. 2, postpartum cows (n = 122) and heifers (n = 84) received treatments (MGA/P4 or 2XPGF2alpha) as described for Exp. 1 with one exception. In the MGA/ P4 treatment, progesterone was administered on d -7 rather than d -6. Females were bred by AI from d 1 to 5. The estrus response and conception rate during the synchronization period did not differ between treatments for either cows or heifers. We conclude that the progestin-based estrous synchronization system used in this study effectively synchronized an estrus of normal fertility in cyclic cows and induced a majority of anestrous cows to reinitiate estrous cycles.

Open randomised study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy.

OBJECTIVES: To assess whether the levonorgestrel intrauterine system could provide a conservative alternative to hysterectomy in the treatment of excessive uterine bleeding. DESIGN: Open randomised multicentre study with two parallel groups: a levonorgestrel intrauterine system group and a control group. SETTING: Gynaecology departments of three hospitals in Finland. SUBJECTS: Fifty six women aged 33-49 years scheduled to undergo hysterectomy for treatment of excessive uterine bleeding. INTERVENTIONS: Women were randomised either to continue with their current medical treatment or to have a levonorgestrel intrauterine system inserted. MAIN OUTCOME MEASURE: Proportion of women cancelling their decision to undergo hysterectomy. RESULTS: At 6 months, 64.3% (95% confidence interval 44.1 to 81.4%) of the women in the levonorgestrel intrauterine system group and 14.3% (4.0 to 32.7%) in the control group had cancelled their decision to undergo hysterectomy (P < 0.001). CONCLUSIONS: The use of the levonorgestrel intrauterine system is a good conservative alternative to hysterectomy in the treatment of menorrhagia and should be considered before hysterectomy or other invasive treatments.

Bone effects of transdermal hormone replacement therapy in postmenopausal women as evaluated by means of ultrasound: an open one-year prospective study.

OBJECTIVES: To evaluate the effectiveness of transdermal oestrogen replacement therapy plus medrogestone (HRT) in postmenopausal bone loss prevention by means of US. METHODS: We enrolled 112 healthy postmenopausal women in an open, prospective study. These women, after a gynaecological evaluation and an US assessment of the skeletal status, were advised to take cyclic sequential oestrogen/progestagen therapy: 50 microg/day of transdermal 17beta-oestradiol (Rotta Research Laboratorium) plus 5 mg/day of medrogestone, for 12 days per cycle (Wyeth-Ayerst). After 1 year we recalled these women: only 32 of them were taking HRT, while 49 had declined HRT without taking alternative therapies. The remaining women were excluded from the study as they were either unavailable for the check-up or they were taking prohibited therapies. We used DBM Sonic 1200 (Igea, Italy) to assess US parameter changes at phalanxes at enrollment and after 1 year. This device enabled us to evaluate US transmission velocity (AD-SoS) and US attenuation pattern (UBPS). In a previous study we had evaluated the intra- and inter-observer reproducibility of AD-SoS measurements (0.4 and 1.0% respectively). Using the same data we evaluated the intra- and inter-observer precision of UBPS. RESULTS: The UBPS intra-operator reproducibilities were 5.3% and 6.1% (for the 1st and the 2nd operator, respectively), while inter-observer precision was 8.8%. Both AD-SoS and UBPS significantly decreased in the non-user group(-0.7%, P < 0.001 and -14.3%, P < 0.001 respectively). In the user group AD-SoS showed a significant increase (+0.7%, P < 0.01), while a slight but significant decrease was observed for UBPS (-2.8%, P < 0.05). CONCLUSIONS: Our findings show that the effectiveness of transdermal HRT in slowing or even arresting postmenopausal bone loss can be monitored by quantitative US studies. The trend difference observed between AD-SoS and UBPS with and without therapy is at least partially explained by a different response to HRT with regard to bone density as well as structure.

Release characteristics, ovarian activity and menstrual bleeding pattern with a single contraceptive implant releasing 3-ketodesogestrel.

The properties of a single contraceptive subdermal implant releasing 3-ketodesogestrel were assessed in fifteen women over twelve months. Serum levels of 3-ketodesogestrel were monitored regularly following insertion and after removal. The mean serum level of 3-ketodesogestrel was 245 pg/ml after 72 h (steady state) and 176 pg/ml after twelve months. All volunteers demonstrated ovulation inhibition throughout the study. Transient oestradiol peaks occurred during the study. No luteal activity was noted. The cervical mucus was rapidly rendered hostile to sperm migration. Two women withdrew from the study during the first six months for medical reasons. Both volunteers cited bleeding irregularity as the main cause, one complaining of oligomenorrhoea, the other of prolonged bleeding/spotting episodes. A small but significant increase in weight was noted during the study period.

PIP: 15 sterilized women participated in a clinical trial of the implant Implanon (Organon), a single ethylene vinyl acetate rod containing 60 mg 3-ketodesogestrel (3-KDG), the metabolite of desogestrel. The rod is 40 mm long, 2 mm in diameter and is packaged in its inserter. In this trial the implants were treated to simulate the 2nd year of use. The study subjects underwent intensive hormone and ultrasound monitoring for 72 hours after insertion, twice weekly for 6 weeks and at 6-month intervals. 13 women completed 6 months, 7 completed 12 months, and 5 continued the trial 24 months. There were no complications related to insertion or removal. 3-KDG levels rose to a steady state of 245 pg/ml by 72 hours, then fell to a mean of 17 pg/ml at 12 months. 90 pg/ml of 3-KDG is the critical serum level for anovulation. After removal, 3-KDG declined to 54 pg/ml in 3 days. Follicle development tended toward small follicles or those larger than 10 mm. There was no luteal activity, and LH, FSH and progesterone remained in the follicular phase range. Estradiol levels were not low enough to risk osteoporosis. There was no significant change in serum sex hormone binding globulin. Systolic blood pressure decreased significantly at 12 months; mean weight gain was 3.7 kg (range from loss of 4 kg to gain of 22 kg); a variety of bleeding irregularities were recorded by individual women.

Effects of low-dose oral contraceptives on female whole saliva.

The composition and flow rate of paraffin-stimulated whole saliva were analysed in 22 women, of whom 11 used oral contraceptives and 11 did not. Ten men served as the controls. The salivary samples were collected during one month (oral contraceptive users and men), or during one menstrual cycle (non-users). The saliva analyses included flow rate, pH, buffer effect, sialic acid, thiocyanate, peroxidase, lysozyme, amylase, immunoglobulins A, G and M, total protein, mutans streptococci, lactobacilli, yeasts and total numbers of aerobic bacteria. The salivary buffer effect of oral contraceptive users was significantly (p less than 0.005) higher than that of non-users. All the other constituents showed intra- and interindividual variation in all groups, but with no apparent hormone-dependency.

PIP: The flow rate and composition of whole saliva were analyzed in 11 women using low dose oral contraceptives in comparison with 11 menstruating women and 10 men. Paraffin-stimulated whole saliva samples were collected Monday, Wednesday and Friday mornings for 1 cycle or 1 month in all subjects, checked for pH and buffer effect (Dentobuff method, Orion Diagnostics, Espoo, Finland, a measure of bicarbonate content) immediately, and frozen for later assay of salivary lysozyme, amylase, peroxidase, thiocyanate, sialic acid, total protein, IgA, IgG, IgM, Mutans streptococci, Lactobacilli, yeasts and aerobic bacteria. The oral contraceptives taken were Marvelon (Organon, Holland) by 4 subjects, Microgynon (Leiras, Finland) by 1, and Trikvilar (Leiras) by 6. The only significant differences between subject groups of cycle phases was a higher salivary buffer effect in oral contraceptive users than that seen in non-users, who resembled male controls. There was a wide individual variation in most values, but less variation in pH and buffer effect. Salivary buffer effect, which is correlated with HCO3-content and salivary flow, is also higher in late pregnancy.

Effect of oral high-dose progestins on the disposition of antipyrine, digitoxin, and warfarin in patients with advanced breast cancer.

The influence of two progestins, medroxyprogesterone acetate (MPA) and megestrol acetate (MA), given orally in high doses, on the pharmacokinetics of antipyrine, digitoxin, and warfarin were studied in patients with advanced breast cancer. Antipyrine and warfarin were given as a single test dose before and after 5 weeks of progestin treatment. The pharmacokinetics of digitoxin was investigated at steady state in patients receiving this drug therapeutically before and during treatment with progestins. Small changes in clearance rates for antipyrine, warfarin, and digitoxin were found. A minor decrease observed in warfarin clearance however may be of clinical importance. Half-lives decreased by 13% for antipyrine and increased by 71% for warfarin. High-dose progestins given orally do not seem to have a major influence on drug metabolism, probably reflecting a minor effect on drug and steroid-metabolizing microsomal mono-oxygenases in the liver.

Silastic implants releasing estrone in the treatment of climacteric complaints.

A study on continuous low-dose estrone treatment achieved with two different silastic implants is presented. In the study estrogen treatment was supplemented with the addition of progestin in three different modes of application. The measurements of plasma estrone and estradiol concentration showed a 3- to 6-fold and a 2- to 3-fold increase, and that of FSH a decrease of 25%. The measurements of plasma estrone gave concentrations of 200-400 pg/ml and plasma estradiol was 70-200 pg/ml with uncovered estrone-releasing implants after 4 wk of treatment. The ratio of plasma levels of estrone/estradiol was around 3. The initial high estrone concentration after implantation could be eliminated by covering the rods with a thin layer of neutral silastic material. Plasma FSH and LH concentration significantly depressed when the estrone treatment was combined with levonorgestrel-releasing implants. The insertion of estrone-releasing implants alone and in combination with the cyclic treatment with norethindrone perorally, or with a norgestrienone-releasing silastic vaginal ring suppressed only the plasma FSH concentration. The climacteric complaints disappeared in a few days in every patient treated with uncovered estrone-releasing implants. Because it is easy to remove when required, the treatment with estrone-releasing silastic implants can be regarded as being safe for the patients.