Counteracting side effects of combined oral contraceptives through the administration of specific micronutrients.

OBJECTIVE: The occurrence of side effects related to the use of combined oral contraceptives (COCs) - or even the fear of them - often affects patients' compliance and their quality of life. Such adverse effects include both physical and psychological alterations. Therapies based on COCs are related to lower levels of vitamins and minerals, including vitamins B, C and E, zinc, magnesium, and selenium. This review gathers scientific evidence about the effectiveness of the administration of specific micronutrients to address nutritional needs and recover adverse conditions. MATERIALS AND METHODS: We reviewed literature searching through different databases (MEDLINE, Scopus, Google Scholar). We used different keywords, including micronutrients, COCs, side effects, B vitamins, vitamin C, vitamin E, vitamin D, zinc, magnesium, selenium and Centella Asiatica. We narrowed the search down to English literature, including both preclinical and clinical studies. The outcome of database search was to highlight beneficial effects of specific micronutrients on the evaluated side reactions. RESULTS: Based on the collected evidence, dietary supplementations of specific micronutrients, whose depletion occurs during COC treatments, have significant beneficial effects. By acting on different aspects and pathways, such supplementation prevents and counteracts discomforts and side effects related to COC treatments. CONCLUSIONS: Considering the wide use of OCs, taking appropriate dietary supplements could be an effective approach in clinical practice, tailoring therapies and improving both safety and tolerability.

Comparative evaluation of low-level light therapy and ethinyl estradiol and desogestrel combined oral contraceptive for clinical efficacy and regulation of serum biochemical parameters in primary dysmenorrhoea: a prospective randomised multicentre trial.

We aimed to compare low-level light therapy with oral contraceptive pills for pain relief and serum levels of nitric oxide and prostaglandin E2 in patients with primary dysmenorrhoea. This was a randomised, active comparator-controlled, multicentre study. In total, 156 patients were randomised to receive either low-level light therapy with light-emitting diodes (LED) applying on two acupoints, namely, conception vessel 4 (CV4) and CV6 or conventional treatment with oral Marvelon, 30 µg of ethinyl estradiol and 150 µg of desogestrel (DSG/EE), for three consecutive menstrual cycles. The main outcome was the proportion of patients who achieved 33% or more decrease in pain scores measured using the visual analogue scale, which was deemed as efficient rate. Absolute changes in visual analogue scale scores, serum levels of nitric oxide (assessed by nitrites and nitrates reflecting nitric oxide metabolism) and prostaglandin E2 (measured by enzyme-linked immunosorbent assay) were the secondary outcomes. A total of 135 patients completed the study (73 in the light therapy group and 62 in the DSG/EE group). The efficient rate at the end of treatment was comparable between the groups (73.6% vs. 85.7%, χ2 = 2.994, p = 0.084). A more significant reduction in pain scores was observed in the DSG/EE group (39.25% vs. 59.52%, p < 0.001). Serum levels of prostaglandin E2 significantly decreased from baseline but did not differ between groups (- 109.57 ± 3.99 pg/mL vs. - 118.11 ± 12.93 pg/mL, p = 0.51). Nitric oxide concentration remained stable in both groups. Low-level light therapy with LED-based device applied on acupuncture points CV4 and CV6 demonstrated a similar level of dysmenorrhoea pain reduction to DSG/EE combined contraceptive. Both treatment modalities achieved clinically meaningful levels of pain reduction. Registration on ClinicalTrials.gov: TRN: NCT03953716, Date: April 04, 2019.

Co-administration of St. John's wort and hormonal contraceptives: a systematic review.

OBJECTIVES: St. John's wort (SJW) is a known strong inducer of the cytochrome P450 (CYP) 3 A4 enzyme, and both the ethinyl estradiol and progestin components of hormonal contraceptives are substrates of CYP3A4. This systematic review examined whether the co-administration of SJW and hormonal contraceptives leads to significant safety or efficacy concerns. STUDY DESIGN: Systematic review. METHODS: PubMed and Cochrane Library databases were searched for articles of any comparative study design (clinical or pharmacokinetic) that examined potential interactions between SJW and hormonal contraceptives in women of reproductive age. RESULTS: Of the 48 identified articles, four studies met inclusion criteria and compared use of combined oral contraceptives (COCs) alone to the use of COCs co-administered with SJW. Two studies demonstrated no change in markers of ovulation, but one study demonstrated increased follicular growth and probable ovulation when COCs were co-administered with SJW. Three studies demonstrated an increased risk of breakthrough bleeding with COCs and SJW. Three studies showed changes in at least one pharmacokinetic parameter that suggested a significantly decreased exposure to hormone concentrations when COCs were co-administered with SJW. The only study that did not demonstrate any significant pharmacokinetic differences examined a SJW product containing a low amount of hypericin. CONCLUSION: Limited evidence showing increased risk of ovulation and breakthrough bleeding raises concern for decreased contraceptive efficacy when COCs are co-administered with SJW. The pharmacokinetic evidence is mixed but suggests that SJW administration may be associated with weak to moderate induction of the metabolism of COCs.

The effect of multivitamin supplements on continuation rate and side effects of combined oral contraceptives: A randomised controlled trial.

OBJECTIVES: This study aimed to assess the effect of multivitamin use during the pill-free interval on the continuation rate and side effects of combined oral contraceptives (COCs) within the first few cycles of use. METHODS: In this trial, 332 women presenting to public health centres in an Iranian city each received a COC pack containing 21 pills and were randomised to one of three groups: two of the groups also received 42 multivitamin pills or 42 placebo pills to be taken once a day for 7 days before starting COCs and again during the 7-day pill-free interval for five cycles, while the third group received no multivitamin or placebo pills with their COCs. The groups were compared using Cox regression and χ(2) tests. RESULTS: There were no losses to follow-up. Continuation rates at the sixth cycle were 88% for the multivitamin group, 75% for the placebo group and 67% for the no intervention group. Compared with the multivitamin group, the six-cycle discontinuation rate was significantly higher in the placebo group (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.15-4.45; p = 0.019) and no intervention group (HR 3.15, 95% CI 1.66-5.99; p < 0.001). Nausea, mood changes, weight gain and breast tenderness were significantly less common in the multivitamin group than in the other groups in all cycles, and spotting/irregular bleeding and dizziness were significantly less common in most of the second, third and sixth cycle follow-up. CONCLUSIONS: Multivitamin supplements could significantly reduce the side effects of COCs in the initial cycles and improve continuation rates. However, the study limitations do not allow for any definite conclusion for their use in clinical practice, especially in communities rich in nutrients.

No interacting influence of lavender oil preparation silexan on oral contraception using an ethinyl estradiol/levonorgestrel combination.

PURPOSE: Silexan is an oral Lavender oil preparation with proven anxiolytic efficacy. Given the high prevalence of anxiety and restlessness in younger women, oral contraceptives and Silexan will likely be co-administered. METHODS: A double-blind, randomised, 2-period crossover study was performed to investigate the effects of Silexan on the pharmacokinetics and pharmacodynamics of Microgynon(®), a combination oral contraceptive containing ethinyl estradiol 0.03 mg (EE) and levonorgestrel 0.15 mg (LNG) in healthy, fertile, adult females. During 2 consecutive cycles of 28 days, oral contraception was given for 21 days combined with 1 × 160 mg/day Silexan or placebo. Plasma concentration-time profiles of EE and LNG were obtained on day 18 ± 1 up to 24 h after dosing. The primary outcome measure was the area under the concentration-time curve over a dosing interval of τ = 24 h (AUCτ) for EE and LNG plasma levels. An interaction with Silexan was formally excluded if the 90 % confidence interval for the AUCτ ratio during co-administration with Silexan or placebo was included within the range of 0.80-1.25. Secondary outcomes included EE and LNG peak concentration (C max) and time to C max (t max), follicle size, endometrial thickness, the Hoogland score, and serum levels of estradiol, progesterone, and sex hormone-binding globulin. RESULTS: A total of 24 women (mean age 27.3 years; mean body mass index 22.2 kg/m(2)) participated. The confidence intervals for the EE and LNG AUCτ and C max ratios fell within the pre-specified limits, indicating no interaction (point estimates [Silexan/placebo] AUCτ EE 0.97, LNG 0.94; C max EE 0.99, LNG 0.96). For LNG, t max was slightly delayed. No secondary outcome indicated any impairment of contraceptive efficacy. CONCLUSIONS: Co-administration of Silexan did not affect the efficacy of a combination oral contraceptive containing EE and LNG and was well tolerated.

The effect of therapeutic and supratherapeutic oral doses of nomegestrol acetate (NOMAC)/17ß-estradiol (E2) on QTcF intervals in healthy women: results from a randomized, double-blind, placebo- and positive-controlled trial.

BACKGROUND AND OBJECTIVE: Nomegestrol acetate (NOMAC)/17ß-estradiol (E2) is a monophasic oral contraceptive that contains a progesterone-derived progestogen (NOMAC), and E2, a bio-identical estrogen. The primary objective of this thorough QT/QTc study was to investigate whether once-daily administration of therapeutic (2.5/1.5 mg) and supratherapeutic (12.5/7.5 mg) doses of NOMAC/E2 were associated with prolongation of the mean Fridericia-corrected QT (QTcF) interval in electrocardiograms at steady-state concentrations of NOMAC/E2 versus placebo. The co-primary objective was to establish assay sensitivity after a single dose of moxifloxacin (positive control). METHODS: This was a randomized, double-blind, parallel-group trial comparing 2.5/1.5 mg of NOMAC/E2 (therapeutic dose), 12.5/7.5 mg of NOMAC/E2 (supratherapeutic dose), placebo, and moxifloxacin 400 mg. Double-blind study medication was administered from day -1 to 14. Healthy women aged 18-50 years were randomized. RESULTS: The largest time-matched mean QTcF difference compared with placebo for the therapeutic dose of NOMAC/E2 was 1.6 ms, with an upper limit (UL) of a one-sided 95% confidence interval (CI) of 5.2 ms, and 3.1 ms with an UL 95% CI of 7.0 ms for the supratherapeutic dose. The UL for the time-matched QTcF differences compared with placebo were below the 10 ms threshold defined in the ICH E14 guideline for all time points, both for the therapeutic and the supratherapeutic dose. For moxifloxacin, assay sensitivity was demonstrated. CONCLUSIONS: This thorough QT/QTc study showed that therapeutic and supratherapeutic doses of NOMAC/E2 were not associated with clinically relevant QTc interval prolongation in healthy women after a 2-week period of dosing.

Evaluation of oxidative stress after treatment with low estrogen contraceptive either alone or associated with specific antioxidant therapy.

BACKGROUND: The aim of the study is to analyze the effect of low estrogen contraceptives (OC) on oxidative stress (OS) and concomitantly also the changes produced by different treatments using physiological modulators (PMs) with antioxidant action. STUDY DESIGN: Sixty-four female volunteers using a low estrogen OC regimen were analyzed for their OS status through the reactive oxygen metabolites-derived compounds (d-ROMs) test, during 5 different cycles (Cycle I to V). Three experiments were performed. RESULTS: In the first experiment (Cycle I), OS showed almost a constant 50% increase in all the determinations. In the second experiment (Cycles II and III), the participants were divided into two groups and treated double-blind with a placebo or with a PM (MF Templar®) that significantly reduced OS, on average by 69%, while the placebo had no effect. In the third experiment (Cycles IV and V), the placebo group was divided into three subgroups, A, B, C and treated, respectively, with MF Templar®, green tea containing the same amount of catechins present in MF Templar® or with MF Templar® devoid of catechins. Only the complete product, MF Templar®, was able to reduce OS levels, on average by 70%. CONCLUSION: We conclude that to control the OS generated by OC, specific types of PMs are needed. In particular MF Templar® was able to induce a significant reduction of OS levels.

Nonspecific side effects of oral contraceptives: nocebo or noise?

Side effects of combined oral contraceptives are the most common reason why women discontinue them. Over the past half century, an elaborate mythology about these ill effects has evolved, fueled by rumor, gossip and poor-quality research. In contrast, placebo-controlled randomized trials document that nonspecific side effects are not significantly more common with combined oral contraceptives than with inert pills. These reported nonspecific side effects may reflect the nocebo phenomenon (the inverse of a placebo): if women are told to expect noxious side effects, these complaints occur because of the power of suggestion. Alternatively, nonspecific complaints may simply reflect their background prevalence in the population. Because Level I evidence documents no important increase in nonspecific side effects with oral contraceptives, counseling about these side effects or including them in package labeling is unwarranted and probably unethical. When in doubt, clinicians should err on the side of optimism.

Contraceptive use among solid organ transplant patients: a systematic review.

BACKGROUND: Women undergoing solid organ transplantation are advised to avoid pregnancy for up to 24 months following transplant surgery. STUDY DESIGN: We conducted a systematic review of the literature, from database (PubMed) inception through February 2009, to evaluate evidence on the safety and effectiveness of contraceptive use among women having undergone solid organ transplantation. RESULTS: From 643 articles, eight articles from seven studies satisfied review inclusion criteria; six articles pertained to kidney transplant patients, and two reported on liver transplant patients. Two reports of one prospective cohort of 36 kidney transplant recipients taking combined oral contraceptives (COCs) or using the transdermal contraceptive patch reported no significant changes in biochemical measures after 18 months of use for either group, although 13 women modified antihypertensive medication, and two women discontinued the study because of serious medical complications. Four case reports of five kidney recipients using intrauterine devices reported inconsistent findings, including both beneficial health effects and contraceptive failures. One retrospective, noncomparative study of 15 liver transplant recipients using COCs or the transdermal contraceptive patch found no significant changes in any biochemical measures obtained, no discontinuations or severe complications and no pregnancies after a 12-month follow up. One case report of a liver transplant recipient on cyclosporine and prednisone documented the development of cholestasis associated with high-dose (50 mcg ethinyl estradiol) COC use as treatment for heavy uterine bleeding. CONCLUSIONS: Very limited evidence on COC and transdermal contraceptive patch use among kidney and liver transplant recipients indicated no pregnancies and no overall changes in biochemical measures. Excluding case reports, evidence on other contraceptive methods or contraception among other types of solid organ transplants was not identified.

Low-dose oral contraceptives in adolescents: how low can you go?

CONTEXT: The use of combined oral contraception (COC) before the accrual of peak bone mass in adolescents is common. Despite the tendency to prescribe lower ethinyl estradiol concentrations so as to reduce thromboembolic complications, concerns have developed as to whether low-dose COC provides sufficient estrogen supplementation for adequate adolescent bone development. OBJECTIVE: This paper reviews the available literature on bone mineral density (BMD) and low-dose COC in adolescents in an effort to determine whether adult-oriented recommendations for the lowest tolerated estrogen dose should apply to adolescent populations. DESIGN: A MEDLINE search of all English-language literature (1966 to January 2008) was performed using the terms "adolescent," "oral contraception," and "BMD." Bibliographies were reviewed to extract additional relevant sources. Articles were selected based on pertinence to BMD changes in association with low-dose (20 microg ethinyl estradiol) hormonal contraception with emphasis on adolescent study groups. RESULTS: A limited number of studies examining 20-microg preparations in adolescents have demonstrated a significantly smaller mean percentage BMD acquisition in COC groups vs untreated controls. Bone mineral density decreases appeared to positively correlate with early gynecological age of first COC use and treatment duration. CONCLUSIONS: Loss of bone mass as a result of hormonal contraceptive use may have serious long-term implications in the adolescent population, who have yet to achieve peak bone density. Both age at first COC use and cumulative estrogen dose appear to be important factors in determining skeletal development in adolescents. Further studies are warranted to inform specific prescribing practices for this population.

Patients with adverse mood effects from combined oral contraceptives have lower levels of prepulse inhibition than healthy controls.

BACKGROUND: Negative mood symptoms remain one of the major reasons for discontinuation of oral contraceptive pills. The aim of this study was to compare acoustic startle response and prepulse inhibition (PPI) in women with different experience of oral contraceptive pills. METHODS: Thirty women currently on combined oral contraceptives (COCs) with no reports of adverse mood symptoms, 28 women currently on COCs and experiencing mood-related side effects from treatment, 27 women who had discontinued COC use for reasons other than adverse mood symptoms and 32 women who had discontinued COC use due to adverse mood effects were included. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of musculus Orbicularis Oculi. Twenty pulse-alone trials (115dB 40ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115dB 40ms noise burst preceded at a 100ms interval by 20ms prepulses that were 72, 74, 78, or 86dB. RESULTS: Patients with adverse mood effects of COCs exhibited lower levels of PPI with 86dB prepulse compared to COC users with no adverse effects of COCs (p<0.05). There was no difference in PPI between the two groups of prior COC users. No significant difference was found between the groups regarding acoustic startle response. CONCLUSION: Relative to COC users with no reports of adverse mood symptoms, subjects suffering from COC-induced negative mood displayed deficits in PPI of acoustic startle. The fact that there was no difference in PPI between the two groups of prior COC users indicates that deficient PPI is related to adverse mood effects caused by COCs.

[St. John's wort: a pharmaceutical with potentially dangerous interactions]. / Johanniskraut: Ein Phytopharmakon mit potentiell gefährlichen Interaktionen.

Over-the-counter preparations of St. John's wort are widely used as 'natural' herbal medicine alternative to traditional antidepressants. The antidepressant effect has been shown in numerous placebo controlled studies. The mechanism of action is assumed to be at least in part, similar to conventional antidepressants, due to presynaptic serotonin reuptake inhibition as well as GABA-modulation and inhibition of monoaminoxidases. Because of its favorable safety profile compared to conventional antidepressants, the use of St. John's wort preparations has gained high acceptance with doctors and patients. However, any biologically active compound contains a certain risk of untoward effects and/or interactions which often are neither known nor recognised with the use of herbal remedies. Thus, doctors, pharmacists, and patients might feel themselves in false safety. Recently, a variety of case reports of potentially hazardous interactions due to drug combinations with St. John's wort have been published (e.g. cellular rejection of pancreas-, kidney- as well as heart transplants with ciclosporin therapy, rise of INR with oral anticoagulants, bleeding with oral contraceptives, reduction of plasma concentration of digoxin, indinavir, amitriptyline, and theophylline). We report a case of irregular bleeding with oral contraception and discuss these drug interactions and the mechanisms.

Oral contraceptives: a cause of hyperbilirubinemia in stem cell transplant patients.

Conjugated hyperbilirubinemia in the clinical setting of hematopoietic stem cell transplantation can have multiple etiologies that may prompt various therapeutic interventions. Two patients who received short courses of a high-dose estrogen-progesterone combination to treat breakthrough menstrual bleeding during transplant are reported. Conjugated hyperbilirubinemia developed in both patients within days of beginning therapy and resolved after the ethinyl estradiol and norgestrel (Ovral; Pharmacia and Upjohn, Kalamazoo, MI, U.S.A.) was discontinued. In one of the patients, this occurred on three separate occasions during the course of transplantation. Recognizing the cholestatic effect of estrogens during transplantation may prevent unnecessary alterations in therapy beyond the simple discontinuation of these medications.

[Recurrent bleeding of thalamic cavernous angioma under hormonal treatment. A case report]. / Saignements itératifs d'un angiome caverneux sous traitement hormonal.

A case of recurrent bleeding from a probable left thalamic cavernoma in a 26 year old woman taking hormonal treatment is reported. Four episodes of bleeding were clinically and radiologically documented, prior to her referral to our institution. Interestingly, each episode occurred three weeks after starting hormonal treatment, dydrogesterone, desogestrel ethinylestradiol, chlormadin, nomegestrel acetate). The patient was not operated because of the deep situation of the cavernoma which was remote from the thalamic surface within the third ventricle. There was no recurrent bleeding after the onset hormonal treatment was discontinued. Although no similar case has been found in the literature, we believe that this case gives further argumentation in favor of a role of hormonal factors influencing the biological behavior of cavernous angiomas which has been previously suggested in pregnant females with bleeding cavernous angiomas.

Calcium and phosphorus in milk of Brazilian mothers using oral contraceptives.

OBJECTIVE: Oral contraceptives (OC) are the most efficient method of contraception and it is the most prescribed by doctors in developing countries. Therefore we studied the effects of combination pill and mini-pill on calcium and phosphorus in milk of breast-feeding mothers at different stages of lactation. METHODS: Fifty-four breast-feeding mothers made up three study groups: 33 mothers who had been advised by their doctors to use either combination pill (12), or mini-pill (21), as well as a control group of 21 mothers that used no hormonal contraceptives. All mothers completed a questionnaire and provided samples of milk before and after a measured period of observation. Mean duration of study was 76, 120, and 101 days, respectively for users of mini-pill, combination pill, and controls. Determination of calcium and phosphorus was done by inductively coupled plasma-atomic absorption spectrometry. RESULTS: Overall the decrease in milk concentrations of phosphorus (6%) and calcium (26.3%) during the study period was not influenced by OC treatment. Regression analyses which took into consideration length of treatment, socioeconomic status, number of children, duration of previous lactation, type of contraceptive, and age of mothers and repeated measurements (before and after OC) showed that milk calcium was significantly affected by stage of lactation (p=0.0013). CONCLUSION: The use of hormonal contraceptive such as the combination pill (levonorgestrel 0.15 mg+ethynilestradiol 0.03 mg) and mini-pill (norethindone 0.35 mg) does not seem to affect the secretion of calcium and phosphorus in milk of mothers.

PIP: This article is based on a study of the effects of oral contraceptives (OCs) on the concentration of calcium and phosphorus in breast milk among 54 lactating Brazilian women. Confounding constitutional variables were considered which include maternal age, previous lactation, length of breast-feeding, and variables associated with contraception, such as type and length of use. The subjects were divided into 3 groups: 12 using combination pills, 21 using mini-pills, and a control group of 21 mothers that used no hormonal contraceptives. Milk was sampled before and after a measured period of observation. The mean durations of study were 76, 120, and 101 days, respectively, for users of mini-pills, combination pills, and controls. The determination of calcium and phosphorous was done by inductively coupled plasma-atomic absorption spectrometry. The results indicate that a mean stage of lactation at start of treatment for the 3 groups ranged from 2.5 to 4 months. Both calcium and phosphorous declined in concentration with time, confounded with OC treatment. There was no significant difference for calcium concentration due to OC treatment, only stage of lactation, per se, was a significant source of variation for calcium concentration. As lactation progressed, the calcium and phosphorous concentration decreased for all mothers. Therefore, short-term use of OCs containing estrogen do not affect calcium and phosphorous concentrations in breast milk.

Changes in androgens during treatment with four low-dose contraceptives.

The aim of the present study was to compare changes in the endogenous androgen environment in healthy women while on low-dose oral contraceptives (OCs). One-hundred healthy women were randomized to receive one of four OCs during six months: 21 tablets of Cilest, Femodeen, Marvelon, or Mercilon. During the luteal phase of the pretreatment cycle, body weight and blood pressure were recorded and the following parameters were measured: sex hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), testosterone (T), free testosterone (FT), 5 alpha-dihydrotestosterone (DHT), androstenedione (A), dehydroepiandrosterone-sulphate (DHEA-S) and 17 alpha-hydroxyprogesterone (170HP) while also the free androgen index (FAI) was calculated. Measurements were repeated during the 3rd week of pill intake in the 4th and the 6th pill month. There were no differences on body mass and blood pressure with the use of the four OCs. The mean serum DHEA-S decreased significantly in all groups though less in the Mercilon group when compared to Cilest and Marvelon (approximately 20% vs 45%). Mean serum SHBG and CBG increased significantly in all four groups approximately 250% and 100%, respectively. In each group CBG also increased significantly but less in women taking Mercilon (-75%) as compared to the others (-100%). Current low-dose OCs were found to have similar impact on the endogenous androgen metabolism with significant decreases of serum testosterone, DHT, A, and DHEA-S. They may be equally beneficial in women with androgen related syndromes such as acne and hirsutism.

PIP: Health researchers randomly assigned 100 healthy women aged 18-38 from the Netherlands and Saudi Arabia to one of four various oral contraceptive (OC) groups to undergo six cycles of OC therapy so they could evaluate changes in plasma concentrations of sex hormone binding globulin (SHBG), corticosteroid-binding globulin (CBG), albumin (Alb), testosterone (T), free testosterone (FT), dihydrotestosterone (DHT), androstenedione (A), dehydro-epiandrosterone-sulphate (DHEA-S), and 17 alpha-hydroxyprogesterone (17OHP). The four monophasic OCs were Cilest (35 mcg ethinyl estradiol [E2] and 250 mcg norgestimate), Femodeen (30 mcg E2 and 75 mcg gestodene), Marvelon (30 mcg E2 and 150 mcg desogestrel), and Mercilon (20 mcg E2 and 150 mcg desogestrel). There were 12 dropouts. Neither body weight nor blood pressure changed significantly during the study. All steroidal serum parameters (T, FT, DHT, A, DHEA-S, 17OHP, Alb) fell significantly during the six cycles of OC treatment (ratio of decrease, 1.3-3), regardless of OC type. These changes had appeared after cycle 4. The only significant difference between the OC groups was that the mean decrease of DHEA-S for Mercilon was lower than that for the other OC groups (21% vs. 43% for Cilest, 44% for Marvelon, and 34% for Femodeen; p 0.05). SHBG and CBG rose greatly during OC use in all four OC groups (mean increase = 263% and 94%, respectively; p 0.05). The increase in CBG was significantly less in the Mercilon group than in the other OC groups (74% vs. 96% for Cilest, 101% for Femodeen, and 102% for Marvelon; p 0.05). These findings show that OC use changed the endogenous androgen environment in the direction of hypoandrogenism. Thus, all four OCs can equally treat androgen-related syndromes (e.g., acne and hirsutism).

Clinical comparison of two low-dose oral contraceptives, Minulet and Mercilon, in women over 30 years of age.

A comparative study of two low-dose oral contraceptives, gestodene (GES) 75 mcg/ethinyl oestradiol (EE) 30 mcg and desogestrel (DES) 150 mcg/EE 20 mcg, was conducted in women over 30 years of age. This randomised, open-label study was organised in Denmark, Italy, New Zealand and United Kingdom. A total of 505 women received GES/EE and 501 received DES/EE for 6 consecutive menstrual cycles. The two groups were comparable in terms of demographic and gynaecologic characteristics at baseline. However, the menstrual flow length was slightly longer in the GES/EE group before the start of the treatment. The mean age (+/- SD) was 35 +/- 4 years in the GES/EE group and 35 +/- 5 years in the DES/EE group. The subjects in the GES/EE group contributed data for a total of 2800 cycles and those in the DES/EE group, data for 2796 cycles. There were no pregnancies on medication with either preparation. The results showed that there were significantly more normal cycles in the GES/EE group for cycles 1 to 6. Irregular bleeding between withdrawal bleeds occurred in 10% of GES/EE and 18.5% of DES/EE cycles. Absence of all bleeding was reported in 29 (1%) and 63 (2%) cycles, respectively. The incidence of missed pills was low in both groups (11% of cycles). No significant differences were observed in cycle length or withdrawal bleeding episode length. Withdrawal bleeding mean intensity was statistically significantly greater with GES/EE. However, for both preparations, the mean intensity was close to light bleeding. No clinically significant differences were noted in weight, blood pressure, Papanicolaou smears or laboratory data. Sixty-eight (13.5%) subjects in the GES/EE group and 64 (12.8%) in the DES/EE group discontinued before the end of the study. Among them, 37 (7%) and 40 (8%) in the respective groups withdrew because of adverse reactions. There was no difference between groups in terms of primary reasons for withdrawal. The most frequently reported complaints that led to discontinuation in both groups were headache, nausea and metrorrhagia. Breast tenderness led to the discontinuation of 1 subject in the GES/EE group and 3 in the DES/EE group. These results show excellent cycle control, efficacy and very low rate of side effects with both GES/EE and DES/EE. These low-dose oral contraceptives could be well suited to healthy nonsmoking women requiring contraception up to the age of menopause.

PIP: At 66 sites in Denmark, Italy, New Zealand, and the UK, clinicians randomly allocated 1006 women 30 years old, some of whom were in their early 50s, into 1 of 2 groups receiving a low-dose oral contraceptive (OC): Minulet containing 75 mcg gestodene (GES)/30 mcg ethinyl estradiol (EE) and Mercilon containing 150 mcg desogestrel (DES)/20 mcg EE. The study aimed to compare these 2 low-dose OCs to help physicians prescribe an OC that could be continued into later years. Before treatment, the 2 groups had similar demographic and gynecologic characteristics. The mean menstrual flow length in the GES/EE group was longer than that of the DES/EE group (4.7 days vs. 4.5 days; p = .035) though. None of the women during 2800 cycles of GES/EE use and 2796 cycles of DES/EE use conceived, even though women forgot to take at least 1 pill in 11% of cycles. The GES/EE OC had significantly better cycle control than did the DES/EE OC. For example, the GES/EE group was more likely to have normal cycles than the DES/EE group (84-93% vs. 73-83%; p .001). The DES/EE group experienced a significantly lower withdrawal bleeding mean intensity than the GES/EE group in all 6 cycles, but the bleeding for both groups was close to light bleeding. The 2 groups were similar in weight, blood pressure, Papanicolaou smears, and laboratory data. Discontinuation rates for the GES/EE and DES/EE groups were 13.5% and 12.8%, respectively. Adverse reactions accounted for discontinuation in 7% of the GES/EE group and 8% of the DES/EE group. The major complaints leading to discontinuation were headache, nausea, and breakthrough bleeding. Both GES/EE and DES/EE had very good cycle control and efficacy and a very low rate of side effects. These results suggest that both these low-dose OCs would be acceptable for healthy nonsmoking women needing contraception up to menopause.

Comparative profiles of reliability, cycle control and side effects of two oral contraceptive formulations containing 150 micrograms desogestrel and either 30 micrograms or 20 micrograms ethinyl oestradiol.

OBJECTIVE: To compare two oral contraceptive pills, both containing 150 micrograms desogestrel, but with either 20 micrograms (Mercilon) or 30 micrograms (Marvelon/Desolett) ethinyl oestradiol (EE), regarding reliability, cycle control and side effect profile. DESIGN: A double blind, randomised, multicentre study over one year with follow up after three, six and 12 months. The women noted tablet intake and all bleedings on specifically designed diary cards. SETTING: University clinics, central hospitals and private gynaecological practices in Norway, Sweden and Denmark. SUBJECTS: One thousand women aged 18 to 40 years requesting oral contraceptive pills. MAIN OUTCOME MEASURES: Reliability, cycle control, side effects, blood pressure, body weight and haemoglobin. RESULTS: In a total of 4543 cycles with the 20 micrograms EE dose pill and 4688 cycles with the 30 micrograms EE dose pill, the number of pregnancies ascribed to method failure were 0 and 2, respectively. Irregular bleeding (break-through bleeding or spotting) was significantly more frequent with the 150/20 combination in about two-thirds of the cycles randomly distributed over the one year of the study. Mean blood pressure decreased slightly, particularly in the group on the 150/20 combination (about 1 mmHg), whereas mean body weight increased approximately 0.5 kg in the group with the 150/30 combination after 12 months. Haemoglobin did not change. Side effects other than bleeding problems were rare, but dizziness and mood changes were more frequent in the group on the 150/20 combination. Due to side effects, more women on the 150/20 combination discontinued the study during the one to three and four to six month periods, and women on this pill were also less positive about continuing the study drug at the end of the trial. CONCLUSIONS: Both pills have high contraceptive reliability and are well tolerated, but with the 150/20 combination the cycle control is less effective. However, in view of the potentially increased safety profile of the 150/20 combination, many women can be expected to accept some additional discomfort due to irregular bleeding.

PIP: A double-blind, randomized, multicenter study compared 2 combined oral contraceptives containing 150 mcg desogestrel and either 30 mcg (Marvelon/Desolett) or 20 mcg (Mercilon) of ethinyl estradiol, focusing on reliable pregnancy prevention and cycle control. The women were 300 Norwegians, 500 Swedes, and 200 Danes, 52% of whom switched from a prior brand of pill. Women completed bleeding diaries: all bleeding that did not start in the 7-day tablet-free interval and last for 7 or fewer days was considered irregular bleeding, either breakthrough bleeding or spotting. The 2 groups were similar except that those taking the 150/20 combination were slightly older. There were 2 pregnancies with the 20 mcg combination and 3 with the 30 mcg pill, 2 of which were considered method failures. In 8573 cycles analyzed there were more instances of irregular bleeding and amenorrhea with the 20 mcg pill than with the 30 mcg pill. Duration of breakthrough bleeding was not significantly different. Irregular bleeding was also more common n women switching from another brand of pill to a lower estrogen dose pill. Blood pressure decreased slightly on the 20 mcg ill and body weight rose slightly on the 30 mcg pill, but hemoglobin did not change. More women dropped out or chose not to continue taking the 150/20 mcg pill because of side effects, usually irregular bleeding, mood changes, dizziness, or weight gain. Despite these differences, there were enough women who tolerated the lower dose combination pill to merit continuing to take it.