Effect of obesity on the effectiveness of hormonal contraceptives: an individual participant data meta-analysis.

OBJECTIVE: The objective of this investigation was to assess the potential effect of obesity on the effectiveness of hormonal contraceptives (HCs). STUDY DESIGN: A meta-analysis was conducted using individual participant data directly from the Phase 3 clinical trials of combination oral contraceptives (COCs) rather than extracting summary data from literature. Trials selected were reviewed by the US Food and Drug Administration (FDA) between 2000 and 2012, conducted in North America, had more than six 28-day cycle equivalents of exposure, and had readily retrievable participant-level data. Contraceptive effectiveness was measured by the Pearl Index (PI: the number of pregnancies per 100 woman-years) in women aged 18-35 at risk of unintended pregnancy. The incidence rate ratio (IRR), a ratio of PIs for obese women (defined as body mass index [BMI] ≥30 kg/m(2)) compared to non-obese women (BMI <30 kg/m(2)) was calculated. A Cox proportional-hazard regression model with fixed and random-effects were used to estimate hazard ratios (HRs) for unintended pregnancy in obese women compared to non-obese women. RESULTS: Seven clinical trials with COCs (N=14,024: 2707 obese and 11,317 non-obese women) met the inclusion criteria for the meta-analysis. The PI for each trial varied: 2.05-5.08 for obese and 1.84-3.80 for non-obese women. The pooled PI estimated using direct weighted average method was 3.14 (95% CI: 2.33-4.22) for obese and 2.53 (95% CI: 1.88-3.41) for non-obese women. The pooled IRRs estimated using direct weighted average and Mantel-Haenszel adjustment methods were comparable: 1.37 (95% CI: 1.02-1.84) and 1.43 (95% CI: 1.07-1.92), respectively. The overall HR of 1.44 (95% CI: 1.06-1.95; p=.018) in the meta-analysis suggested a 44% higher pregnancy rate during COC use for obese women after adjusting for age and race. IMPLICATIONS STATEMENT: Obesity may increase the risk of unintended pregnancy in women using COCs; more data on obese women from ongoing and future Phase 3 clinical trials are necessary to allow further evaluation of this topic. CONCLUSIONS: Results of this meta-analysis suggest that obese women may have a higher pregnancy rate during COC use compared to non-obese women. Future analysis should assess differences in pharmacodynamics or compliance that could potentially account for the observed difference in unintended pregnancy rates.

The effect of oral contraceptives on orthodontic tooth movement in rat.

INTRODUCTION: The purpose of this study was to investigate the effect of ethinyl estradiol/norgestrel - used in some oral contraceptives- on orthodontic tooth movement in Wistar rats. MATERIAL AND METHODS: Forty eight female three-month old Wistar rats with an average weight of 250 ± 25 gr were divided into two experimental and control groups. One week prior to appliance insertion and during the appliance therapy period, 100 mcg/kg/day of ethinyl estradiol and 1 mg/kg/days of norgestrel were administered to the experimental group by gavage; meanwhile the control group received an equivalent volume of Sodium Chloride 0.9 % (Saline). Maxillary central incisors were tipped distally by insertion of springs exerting 30 g force. Two, seven and fourteen days after spring insertion animals were sacrificed. The mesioincisal distance between maxillary incisors were measured. Subsequently, histological sections were prepared for histomorphometric studies. RESULTS: 14 days after force application the orthodontic tooth movement was significantly lower in the experimental group (p<0.05). The number of osteoclasts were significantly lower in the experimental group 2, 7 and 14 days after spring insertion (p<0.05). CONCLUSION: Ethinyl estradiol/norgestrel (oral contraceptives) can significantly decrease the amount of tooth movement in the linear phase.

Comparative biochemical studies on steroidogenic compounds in chickens.

Comparative studies of the effects of Nordette and Lutofolone on 15 days old chicken were carried out to determine their effects on growth performance, biochemical parameters and an analysis of hormonal residues in the liver and muscle. Sixty chickens were equally divided into three groups. Group 1 was served as a control. Groups 2 and 3 were treated daily with Nordette (1 mg/kg B.W.) mixed in the ration and Lutofolone (0.5 mg/kg B.W.) orally via a bent stainless steel feeding tube, respectively, for 30 days (from the 15th till the 45th day old). Then these treated groups were left for another 15 days without any treatment. Blood samples were collected at 45 and 60 days old and used for biochemical studies, while liver and muscles were excised from each chicken and used to prepare tissue homogenate for estimation of hormonal residues (estrogen and progesterone). Both drugs caused a gain in body weight. They also increased several serum variables, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, creatine kinase (CK), creatinine and uric acid, and reduced total proteins, albumin and globulin levels at 30 days post-administration. Moreover, this study exhibited a significant increase in the levels of estrogen residues in the liver and muscle. Estrogen level was much higher in the liver than muscles. However, some of these findings were insignificant changed at 15 days post-stopping of the hormones. Data on the biochemical parameters and residue levels obtained from these results clearly indicate that anabolic agents may entail a special risk to the chickens and probably to the consumer.

Mechanisms of action of hormonal emergency contraceptives.

Hormonal emergency contraceptives have been used to prevent unwanted pregnancy for more than 3 decades. The mechanisms of action of the regimen containing a combination of estrogen and progestin, known as the Yuzpe regimen, and those of the levonorgestrel regimen continue to be controversial, especially over the possibility that these regimens might act by interfering with implantation of the fertilized ovum. We performed a search of the PubMed (1949-July 2009) and EMBASE (1980-July 2009) databases to identify literature on the mechanisms of action of these contraceptive regimens, and data were extracted from pertinent English-language studies. We classified studies according to the approach taken by the investigators to study the actions of emergency contraceptives on pregnancy: an indirect method that uses statistical models to determine whether emergency contraceptives would be as effective as reported if they act only by disrupting ovulation; direct observation of the effects of emergency contraceptives on surrogate outcomes, including ovulation, sperm activity, hormonal levels, and endometrial receptivity to implantation; and analysis of directly observed pregnancy outcomes against statistical data. Acceptability of emergency contraceptives by women and clinicians may depend on personal opinions about when life or pregnancy begins. The evidence strongly supports disruption of ovulation as a mechanism of action. The data suggest that emergency contraceptives are unlikely to act by interfering with implantation, although the possibility has not been completely excluded. The data also suggest that emergency contraceptives are ineffective after ovulation. Women and clinicians who consider implantation or later events to be the beginning of pregnancy should be aware that emergency contraceptives are likely nonabortive by this definition of pregnancy.

Light and electron microscopic studies on the effect of a contraceptive drug on the stomach of mouse.

The present study was an investigation of the effect of the contraceptive drug, Nordette, on the stomach of the mouse when administered daily at a recommended therapeutic dose rate of 0.0026 mg kg(-1) for 30 days. Extensive light and electron microscopic changes were noticed. The drug caused enlargement in the all types of cells. The oxyntic cells appeared hypertrophied with irregular cell boundaries, enlarged nuclei and faintly stained cytoplasm. Their cytoplasm contained irregularly distributed mitochondria with dense matrix, decreased rER, obviously increased sER, disorganized intracellular canaliculi and some lysosomes. The peptic cells appeared enlarged and contained hypertrophied rough endoplasmic reticulum and an increase amount of ribosomes and secretory granules. There was an increase in the amount of the secretory granules in the lumen of the gastric gland. The mucus cells at the upper region of the gastric gland were greatly decreased. Smooth muscle fibers showed enlargement and degeneration. The submucosa and lamina propria showed vacuolation. The most pathological effects were restricted to the obvious decrease of the lymphoid cells in the submucosa and lamina propria. Dilatation and congestion of the blood vessels and blood capillaries were noticed. Blood capillaries lined by enlarged endothelial cells containing enlarged heterochromatic nuclei.

A continuous regimen of levonorgestrel/ethinyl estradiol for contraception and elimination of menstruation.

Clinicians and patients desiring amenorrhea for therapeutic or social reasons will find continuous-use 90 microg levonorgestrel/20 microg ethinyl estradiol to be an attractive oral contraceptive dosing option. Although other formulations of oral contraceptives can be dosed in a continuous manner off-label, the convenience of a 28-day dose pack represents a major advance that will likely increase acceptability of the strategy. The availability of FDA-approved continuous-use 90 microg levonorgestrel/20 microg ethinyl estradiol will help mainstream continuous oral contraception in the same way that Preven and Plan B helped legitimize and mainstream emergency contraception. Patients wishing to use continuous 90 microg levonorgestrel/20 microg ethinyl estradiol must recognize and accept that unscheduled breakthrough bleeding is typical during the first four to six cycles of use. Control of cycle-related symptoms may emerge as an off-label indication for use.

Different effects of oral contraceptives containing different progestogens on protein S and tissue factor pathway inhibitor.

BACKGROUND: Oral contraceptives (OC) containing different types of progestogens induce different sensitivities to activated protein C (APC) measured with the thrombin generation-based APC-resistance test. These differences in APC resistance may be the biological explanation for the differences in thrombotic risk of the various pills. The mechanistic basis of APC resistance observed in OC users is unknown. Our objective was to study the effect of OC on the two main determinants of the APC-resistance test, free protein S and free tissue factor pathway inhibitor (TFPI). PATIENTS/METHODS: We measured free protein S and free TFPI in 156 users of various types of OC. RESULTS: Users of desogestrel-containing OC, known to double the risk of thrombosis compared with levonorgestrel-containing OC, had lower free protein S (24 vs. 33 U dL(-1)) and TFPI free antigen (2.9 vs. 3.6 ng mL(-1)) levels than users of OC containing levonorgestrel. Women using cyproterone acetate-containing OC, known to confer a high thrombotic risk, had the lowest free protein S (19 U dL(-1)) and free TPFI antigen (2.5 ng mL(-1)) levels. Users of OC containing drospirenone had lower free protein S (23 U dL(-1)) and TFPI antigen levels (3.2 ng mL(-1)) than users of levonorgestrel-containing OC. Low free protein S and low free TFPI antigen levels were associated with an increased resistance to APC, an established risk factor for thrombosis. CONCLUSIONS: This study observed that the differences in APC resistance induced by OC containing different progestogens can at least in part be explained by different effects of OC on free protein S and TFPI.

[State of the hypothalamo-hypophyseal-ovarian system in young nullipara women with ectopia of the cervix of uterus during taking the hormonal contraceptives].

Background diseases of the cervix of the uterus play one of the leading roles in the structure of gynecological pathology and present the risk of the development precancerous changes. Ectopia is observed in the structure of precancerous processes of the cervix of the uterus in 38, 8% of women and in 42, 2% cases of gynecological diseases. Our aim is to investigate the content of gonadotropic and steroid hormones in the blood plasma of young nullipara women with different types of ectopia during taking hormonal contraceptives. Cohort study has been carried out by using simple blind method. The quantitative data analyses were performed using the Statistical Package for the Social Sciences (SPSS) in order to reveal the correlation between taking of oral hormonal contraceptives and the hormone content in the blood plasma among young nullipara women with different types of ectopia. Descriptive statistics were calculated for all the study variables. The results displayed correlation between taking the oral hormonal contraceptives and changes of hormonal background in young women with ectopia of the cervix of the uterus during taking hormonal contraceptives. The study show that the secretions of gonadotropic hormone and ovary hormone peculiarities depend on the type of ectopia of the cervix of the uterus. The effect of hormonal contraception on cervix of the uterus of young nullipara women with ectopia was investigated. The oral contraceptive, Exluton is recommended in young nullipara women with ectopia.

Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in adolescent females with anorexia nervosa: a double-blind, placebo-controlled study.

PURPOSE: To evaluate the effect of an oral contraceptive (OC) on bone mineral density (BMD) in adolescent females with anorexia nervosa (AN) or eating disorder not otherwise specified (EDNOS). METHODS: Females 11-17 years of age with AN or EDNOS entered the study. Subjects were randomized equally to treatment with a triphasic OC containing norgestimate (NGM) 180-250 microg and ethinyl estradiol (EE) 35 microg or placebo for 13 28-day cycles. Dual energy x-ray absorptiometry scans (DXA) of the lumbosacral spine (LS) and hip were obtained at baseline and after 6 and 13 cycles. RESULTS: Demographic characteristics of the 112 subjects (NGM/EE 53; Placebo 59) who received study drug and had at least one on-treatment DXA were similar between groups for age (mean: 15 years in each group) and body mass index (mean: NGM/EE 17.9 kg/m2; Placebo 17.6 kg/m2). At the end of Cycle 6, there was a significant increase in the mean LS BMD in the NGM/EE group compared with placebo (.020 g/cm2 vs. .008 g/cm2; p = .021); however, at the end of Cycle 13 the mean increase in LS BMD in the NGM/EE group compared with placebo was no longer significant (.026 g/cm2 vs. .019 g/cm2, p = .244). There was no significant difference in change in hip BMD between groups. The incidence of adverse events was similar between groups. CONCLUSIONS: In a group of adolescent females with AN or EDNOS, treatment with a triphasic OC for 13 cycles did not have a statistically significant effect on LS or hip BMD.

Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol.

OBJECTIVE: To assess the efficacy and safety of Seasonique, a 91-day extended-regimen oral contraceptive (OC) utilizing continuous low-dose ethinyl estradiol (EE) during the typical hormone-free interval. METHODS: A multicenter, open-label, 1-year study of Seasonique [30 microg EE/150 microg levonorgestrel (LNG)] for 84 days followed by EE 10 microg for 7 days was conducted in sexually active, adult women of childbearing potential. All patients completed daily electronic diaries to monitor compliance and bleeding. RESULTS: Method failure rate was 0.78 (Pearl index) and 0.64% (life table analysis). Cycle control and safety of the regimen were similar to that reported for other OCs. CONCLUSION: This study demonstrates that Seasonique is effective, safe and well tolerated for the prevention of pregnancy.

Triphasic oral contraceptive treatment alters the behavior and neurobiology of female cynomolgus monkeys.

Oral contraceptives (OCs) are the most widely prescribed and effective of the reversible contraceptive methods. In addition to inhibiting ovulation, OCs alter central nervous system function in women; however, methodological problems have prevented clear human studies. Thus, in this experiment we investigated the effects of OC treatment on behavior, hypothalamic- pituitary-adrenal axis function and the central nervous system in 75 adult female cynomolgus monkeys (Macaca fascicularis) housed in social groups of four to five monkeys per pen. Monkey social groups were randomly divided into either a control or an OC treatment group which was administered a clinically prescribed OC (Triphasil(R), levonorgestrel and ethinyl estradiol tablets) for 2 years. OC treatment increased the frequency of contact aggression received, time spent in locomotion, and sitting close to another animal, and decreased time spent fearfully scanning. OC treatment decreased heart rate, increased activity levels, and increased baseline cortisol concentrations and the cortisol response to adrenocorticotropin compared to control animals. OC treatment decreased the prolactin response to fenfluramine suggesting decreased serotonergic activity. These results suggest that this triphasic OC disrupts social behavior, hypothalamic-pituitary-adrenal axis regulation and the underlying central nervous system function.

A multicenter, randomized study of an extended cycle oral contraceptive.

OBJECTIVE: To assess the efficacy and safety of Seasonale, 91-day extended cycle oral contraceptive (OC). METHODS: A parallel, randomized, multicenter open-label, 1-year study of the OC Seasonale [30 microg ethinyl estradiol (EE)/150 microg levonorgestrel (LNG), and Nordette-28 (30 microg EE/150 microg LNG)] in sexually active, adult women (18-40 years) of childbearing potential. Patients received either four 91-day cycles of extended cycle regimen OC, or 13 cycles of the conventional 28-day OC with daily monitoring of compliance and bleeding via electronic diaries. RESULTS: When taken daily for 84 days followed by 7 days of placebo, the extended cycle regimen was effective in preventing pregnancy and had a safety profile that was comparable to that observed with the 28-day OC regimen that served as the control. While unscheduled (breakthrough) bleeding was reported among patients treated with the extended cycle regimen, it decreased with each successive cycle of therapy and was comparable to that reported by patients who received the conventional OC regimen by the fourth extended cycle. CONCLUSION: This study demonstrated that Seasonale, 91-day extended cycle OC containing 84 days of 30 microg EE/150 microg LNG followed by 7 days of placebo, was effective, safe and well tolerated.

[Experimental study on estrogenic function of triphasic contraceptive tablets].

OBJECTIVE: To assess the estrogenic effect and activity of oral triphasic contraceptive tablets and provide the theoretical foundation for the use of homemade Kalirui in the treatment of metrorrhagic, menometrorrhagic, oligomenorrheic, and polymenorrheic dysfunctional uterine bleeding. METHODS: The vaginal smears of mice treated by triphasic contraceptive tablets (Kalirui and Trinordiol) were examined using light microscope. Radiational receptor analysis was made to measure the estrogenic effect of Kalirui and Trinordiol on Compared with the control group, the three dosage groups of homemade (Kalirui) rabbit uterus. RESULTS: triphasic contraceptive tablets and the import tablets (Trinordiol) group all showed obviously accelerate vagina kera-epithelium forming (P < 0.01), especially in the first phase and second phase. Both Kalirui and Trinordiol were found to have higher affinity to estrogenic receptor, and there were no significant differences between them Kalirui and Trinordiol triphasic oral contraceptive and the estrogenic standard sample (P > 0.05). CONCLUSION: tablets have apparently estrogenic effect and activity.

Influence of low-dose oral contraception on peripheral blood lymphocyte subsets at particular phases of the hormonal cycle.

OBJECTIVE: To investigate the effects of low-dose oral hormonal contraception on the immune system during certain phases of the hormonal cycle. DESIGN: Prospective, nonrandomized, controlled study. SETTING: Academic research setting. PATIENT(S): Women with regular menstrual cycle using hormonal oral contraception (OC; Cileste, 250 microg of norgestimat and 35 microg of ethinylestradiol, or Marvelon, 150 microg of desogestrel and 30 microg of ethinylestradiol) and women not using hormonal or other forms of contraception. INTERVENTION(S): Peripheral blood lymphocyte subsets were determined by flow cytometry on the first day of menstruation (day 1), in the follicular phase (day 8), midcycle (day 15), and in the luteal phase (day 22). MAIN OUTCOME MEASURE(S): Levels of lymphocyte subpopulations. RESULT(S): Women using OC had significantly higher levels of CD3+ CD8+ cells throughout their pill cycle compared to controls. Furthermore, women taking Cileste had lower levels of natural killer (NK) cells during their cycle and also women taking Marvelon but only from days 8-15. Within the pill cycle of Cileste we observed an increase in CD20+ and CD20+ CD5+ cells from days 1-8. CONCLUSION(S): Cytotoxic lymphocytes, which are responsible for first-line immune defense, and B cells, which are involved in autoimmune disorders, are affected by OC.

The effects of an oral contraceptive containing ethinyloestradiol and norgestrel on CYP3A activity.

AIMS: To examine the effects of an oral contraceptive containing ethinyloestradiol and norgestrel on intestinal and hepatic CYP3A activity using midazolam as a probe substrate. METHODS: In a nonblinded sequential study, nine healthy women received simultaneous doses of intravenous midazolam (0.05 mg kg(-1)) and oral 15N3-midazolam (3 mg) on days 0, 4, 6, 8, and 14. On study day 5, Ovral(50 microg ethinyloestradiol/500 microg norgestrel) was administered for 10 days. Serum and urine samples were assayed for midazolam, 15N3-midazolam and metabolites by liquid chromatography-mass spectrometry. A Digit Symbol Substitution Test (DSST) was used to assess changes in the pharmacodynamic activity of midazolam. RESULTS: Moderate (% CV 26-46) interindividual variability in the pharmacokinetics of midazolam were observed. Compared with baseline, AUC(0,infinity)iv ratios (95% CIs) after 2, 4, and 10 days treatment with OC were 89% (79, 101), 96% (85, 109), and 88% (77, 99), respectively. The AUC(0,infinity)oral ratios (95% CIs) were 101% (82, 125), 105% (85, 130), and 114% (92, 141), respectively, after 2, 4, and 10 days OC treatment compared with baseline. Concomitant administration of the oral contraceptive, Ovral for 2, 4 or 10 days did not significantly alter the area under the curve, clearance, or half-life of midazolam after either oral or intravenous administration. No alterations in pharmacodynamic effects of midazolam were observed between treatment days. Mean DSST scores strongly correlated with mean total midazolam blood concentrations (r = -0.936). CONCLUSIONS: Administration of Ovral for 10 days had no impact on intestinal or hepatic CYP3A activity as determined by midazolam metabolism.

Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by phenotyping with dextromethorphan.

Gender-based differences in cytochrome P450 (CYP) activity may occur due to endogenous hormonal fluctuations with the menstrual cycle, which are altered by oral contraceptives. This study assessed the average activity and within-subject variability in CYP3A4 and CYP2D6 in men, women taking Triphasil, and regularly menstruating women not receiving oral contraceptives. Thirty-three healthy volunteers participated in this 28-day pilot study (12 women receiving Triphasil) (OCs), 11 regularly menstruating women not on exogenous progesterone or estrogen (no OCs), and 10 men. CYP3A4 and CYP2D6 activities were phenotyped with dextromethorphan (DM) on study days 7, 14, 21, and 28 using urinary ratios of DM:3-methoxymorphinan (3MM) and DM:dextrorphan (DX), respectively. Serial blood concentrations of estrogen and progesterone and menstrual diaries were used to determine menstrual phase in both groups of women. Average urinary DM:3MM and DM:DX in the 28 extensive metabolizers of CYP2D6 did not differ between the three study populations (p = 0.86 and 0.93, respectively). Post hoc power analysis indicated that more than 1000 subjects would be needed for 80% power (alpha = 0.05) to detect a +/- 15% difference from the population mean in the urinary ratios of dextromethorphan and its metabolites 3MM and DX. Variability in CYP3A4 and CYP2D6 activity, characterized by intrasubject standard deviation, also did not differ. The varying doses of levonorgesterol and ethinyl estradiol in Triphasil, fluctuations in estrogen and progesterone, and menstrual phase did not influence CYP3A4 or CYP2D6 activity. It was concluded that CYP3A4 and CYP2D6 activity and intrasubject variability were not different in the three study populations, and thus a clinically important difference between men, women on Triphasil, and women not receiving oral contraceptives is unlikely. High inter- and intrasubject variability in DM:3MM and DM:DX were clearly demonstrated and limit the use of dextromethorphan to phenotype endogenous CYP3A4 and CYP2D6 activity.

Effect of two oral contraceptives with different ethinyl estradiol and levonorgestrel concentrations on the urinary excretion of biochemical vasoactive markers.

In the present study the effect on the urinary excretion of vasoactive markers of two oral contraceptives (OCs), i.e., Leios, containing 0.02 mg ethinyl estradiol and 0.1 mg levonorgestrel, and Stediril 30, containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel, was investigated. cGMP, prostacyclin and its antagonist thromboxane, serotonin, and urodilatin, a natriuretic and diuretic peptide formed in the kidney, were measured as markers. In a comparative, double-blind, randomized, parallel group study, 34 women received Leios and 33 women Stediril 30. Nocturnal urine was collected before treatment and during cyclic treatment after 3 and 12 cycles. Both contraceptives significantly enhanced cGMP excretion after 12 cycles. The prostacyclin metabolite remained unchanged for both formulations, but the excretion of the thromboxane metabolite was significantly decreased after 12 cycles. Thus, the ratio of prostacyclin to thromboxane, crucial for the resulting effect on vascular tone, increased significantly. For the serotonin metabolite, no changes were observed for both contraceptives. The excretion of urodilatin significantly increased for both preparations after 12 cycles compared to the pretreatment values. These results indicate that the low-dose OCs Leios and Stediril 30 may stimulate the production of some vasoactive markers, at least after 12 cycles of treatment. The positive influence of these contraceptives on the various markers investigated may improve vascular tone, impede development of atherosclerosis and arterial thrombosis, and improve water and electrolyte homeostasis. These effects most likely can be attributed to the estrogenic component. Levonorgestrel may elicit no impact on these estrogen-induced changes that, however, seem only to be manifested after a longer treatment period.

Effect of progestin on the ovarian epithelium of macaques: cancer prevention through apoptosis?

OBJECTIVE: The apoptosis pathway is a vital mechanism in vivo that functions to eradicate genetically damaged cells prone to malignancy. The purpose of this study was to determine whether oral contraceptives, which confer significant protection against subsequent epithelial ovarian cancer, induce apoptosis in the ovarian epithelium. METHODS: Female cynomolgus macaques (N = 75) were randomized to receive a diet for 35 months containing either no hormones, the oral contraceptive Triphasil (Wyeth-Ayerst Laboratories, Philadelphia, PA), the estrogenic component of Triphasil (ethinyl estradiol) alone, or the progestin component of Triphasil (levonorgestrel) alone, each administered in a cyclic fashion. At study termination, the animals underwent ovariectomy and the ovarian epithelium was examined morphologically and immunohistochemically for apoptosis. The percentage of ovarian epithelial cells undergoing apoptosis was measured in each animal and compared between the treatment groups. RESULTS: The median percentage of ovarian epithelial cells undergoing apoptosis by treatment was control (3.8%), ethinyl estradiol (1.8%), Triphasil (14.5%), and levonorgestrel (24.9%). Compared with control and ethinyl estradiol-treated monkeys, a statistically significant increase in the proportion of apoptotic cells was noted in the ovarian epithelium of monkeys treated with the oral contraceptive Triphasil (P < or = .01) or levonorgestrel (P < .001), with a maximal effect (six-fold) seen in the group treated with levonorgestrel alone. CONCLUSION: Oral contraceptive progestin induces apoptosis in the ovarian epithelium. Given the importance of the apoptosis pathway for cancer prevention, an effective chemopreventive strategy may be possible using progestins or other agents that selectively induce apoptosis in the ovarian epithelium to prevent the development of ovarian cancer.

The effects of monophasic and triphasic oral contraceptives on ovarian function and endometrial thickness.

OBJECTIVE: To analyze and compare the effects of seven low-dose oral contraceptives (OCs) on ovarian function and endometrial thickness. METHODS: Cross-sectional study of users of one of five monophasic OCs, one of two triphasic OCs and a control group of non-users. Ovarian function, endometrial thickness and serum hormone levels were monitored during days 10-12 and 16-18 of the cycle. RESULTS: Serum estradiol was suppressed in OC users to a greater degree during days 16-18 than during days 10-12, whereas serum progesterone during 16-18 was in the anovulatory range with each preparation. Ovarian activity as measured by follicular size was lowest with desogestrel-containing OCs, whereas greater activity was seen with triphasic levonorgestrel/ethinylestradiol and triphasic norgestimate/ethinylestradiol. Endometrial thickness in OC users was significantly smaller than in controls. CONCLUSIONS: All preparations demonstrated profound suppression of ovarian activity and effectively prevented ovulation. Ovarian suppression with desogestrel/ethinylestradiol 150/20 did not differ from that of other OCs despite its lower ethinylestradiol content. The use of both triphasic OCs, having a relatively low progestogenic activity, was associated with a higher ovarian activity than that of the monophasic OCs.