Evaluation of consumer self-selection of a proposed over-the-counter, progestin-only daily oral contraceptive.

OBJECTIVES: In an effort to switch a norgestrel 0.075 mg progestin-only pill (Opill) from prescription to over-the-counter, we conducted this study to assess whether consumers can use the drug facts label alone to guide appropriate self-selection. STUDY DESIGN: Two studies assessed self-selection: (1) an all-comers, actual-use study evaluating self-selection before purchasing and using norgestrel 0.075 mg and (2) the Targeted Breast Cancer Self-Selection Study evaluating theoretical self-selection among participants with a history of breast cancer. RESULTS: In the actual-use study, based on the label, 1670/1772 participants (94%) were appropriate for use of norgestrel 0.075 mg; 102 (6%) were not appropriate. Of the 102, 66 (65%) correctly did not select and 36 (35%) responded it was okay for them to use norgestrel 0.075 mg. Of the 36 participants who incorrectly self-selected, one had a history of breast cancer and thus might have been adversely affected had they taken norgestrel 0.075 mg. In the Targeted Breast Cancer Self-Selection Study (N = 206), 97% of participants correctly stated norgestrel 0.075 mg was not appropriate for them. CONCLUSIONS: The proposed over-the-counter label enables 98% of potential users to self-select norgestrel 0.075 mg appropriately. Only 2% of potential purchasers may have bought and started to use norgestrel 0.075 mg inappropriately. For two-thirds of these, the potential benefits of their use of the method outweighed any theoretical risks. Adverse clinical consequences of norgestrel 0.075 mg use are unlikely even in those rare cases when the drug facts label was not followed. IMPLICATIONS: The balance of the risk of inappropriate selection to the benefit of taking an over-the-counter progestin-only pill appears to be very much in favor of an overall benefit in terms of unintended pregnancy prevention.

The role of combined oral contraceptives containing norgestimate for acne vulgaris treatment: a review.

INTRODUCTION: Both Food and Drugs Administration and European Medicine Agency (EMA) approve the use of a triphasic combined oral contraceptive (COC) containing ethinyl-oestradiol (EE) and norgestimate (NGM) for acne vulgaris treatment in women requiring an effective contraception. COCs can target sebum production and may also play a role in decreasing follicular hyperkeratinisation. RESULTS: Specific advantages of the use of an anti-androgenic progestin such as NGM in this condition are presented in this review, including the lowest venous thrombosis risk in the COCs scenario, as established by the EMA, associated with a very satisfactory cycle control. The results of aggregate analysis of published data (n = 163 vs. n = 161 treated subjects) demonstrate a significant effect in comparison with the placebo of a greater than 50% reduction, in terms of inflammatory lesions (from 19.0 to 8.2), comedones (from 35.2 to 17.7) and total lesions (from 54.3 to 25.9) count. CONCLUSIONS: The choice of a triphasic combination of EE/NGM seems a referenced, highly effective, easy-to-use and safe therapeutic approach for acne vulgaris, alone or in combination with different targeted drugs.

Triphasic ethinyl-oestradiol and norgestimate is on label for mild to moderate acne vulgaris treatment worldwide, in women requiring an effective contraception. This combination demonstrated a significant effect in comparison with the placebo of a greater than 50% reduction, in terms of inflammatory lesions, comedones and total lesions count.

Adhesion Evaluation of AG200-15: An Investigational Transdermal Contraceptive Delivery System.

INTRODUCTION: AG200-15, an investigational transdermal contraceptive delivery system or patch, is designed to be a low-dose, non-daily, combined hormonal contraceptive option for women. In this phase 1 study, the in vivo adhesion of the AG200-15 patch was compared to Xulane®, the only contraceptive patch available in the USA. METHODS: This phase 1, randomized, open-label, single-dose, two-treatment, two-period crossover adhesion study compared the 7-day adhesion of the AG200-15 and Xulane contraceptive patches. Eighty-three women, ages 18 to 35 years old, with body mass index (BMI) ≥ 19 kg/m2 and < 35 kg/m2, and weight ≥ 48 kg and < 90 kg were enrolled. Trained study site personnel used a five-point scale to assess patch adhesion daily. A score of 0 reflected at least 90% adhesion; while a score of 4 represented complete detachment of the patch. The primary objective was to compare the adhesion properties of the two patches; AG200-15 would be considered statistically non-inferior to Xulane if the upper 95% confidence limit (CL) of the mean difference in adhesion scores was below + 0.15. RESULTS: The overall mean (standard deviation) scores for AG200-15 (N = 78) and Xulane (N = 77) were 0.14 (0.28) and 0.39 (0.40), respectively (lower scores on the adhesion scale indicate better adhesion). The study demonstrated a difference in mean adhesion scores of - 0.24, meeting the prespecified non-inferiority criterion by demonstrating a one-sided upper CL of - 0.16. Thus, the in vivo adhesion of AG200-15 was shown to be non-inferior to that of Xulane. Most subjects experienced no skin irritation at the application site for either patch and no serious adverse event was reported in the study. CONCLUSION: The in vivo adhesion of AG200-15 is non-inferior to that of Xulane on the basis of the prespecified criterion of the upper bound of the one-sided 95% CL for the mean adhesion score difference being below + 0.15. Both patches were generally well tolerated. FUNDING: Agile Therapeutics, Inc.

Microglial-induced Müller cell gliosis is attenuated by progesterone in a mouse model of retinitis pigmentosa.

Norgestrel, a progesterone analogue, has demonstrated neuroprotective effects in a mouse model of retinitis pigmentosa. Neuroprotection is achieved in part through Norgestrels anti-inflammatory properties, alleviating detrimental microglial activity. Gliosis is a feature of many neurodegenerative diseases of the retina, including retinitis pigmentosa. Müller glia, a type of macroglia found in the retina, are major contributors of gliosis, characterized by the upregulation of glial fibrillary acidic protein (GFAP). Microglia-Müller glia crosstalk has been implicated in the initiation of gliosis. In the rd10 retina, increased microglial activity and gliotic events are observed prior to the onset of photoreceptor loss. We hypothesized that Norgestrels dampening effects on harmful microglial activity would consequently impact on gliosis. In the current study, we explore the role of microglia-Müller glia crosstalk in degeneration and Norgestrel-mediated neuroprotection in the rd10 retina. Norgestrels neuroprotective effects in the rd10 retina coincide with significant decreases in both microglial activity and Müller cell gliosis. Using a Müller glial cell line, rMC-1, and isolated microglia, we show that rd10 microglia stimulate GFAP production in rMC-1 cells. Norgestrel attenuates gliosis through direct actions on both microglia and Müller glia. Norgestrel reduces the release of harmful stimuli from microglia, such as interferon-γ, which might otherwise signal to Müller glia and stimulate gliosis. We propose that Norgestrel also targets Müller cell gliosis directly, by limiting the availability of pSTAT3, a known transcription factor for GFAP. These findings highlight an important aspect to Norgestrels neuroprotective effects in the diseased retina, in combating Müller cell gliosis.

Role of the combination spironolactone-norgestimate-estrogen in Hirsute women with polycystic ovary syndrome.

OBJECTIVE: To compare the combination spironolactone-norgestimate-ethinyl estradiol in hirsutism with other protocols including the same dose of estrogen. STUDY DESIGN: In this open prospective study, 167 women with hirsutism due to polycystic ovary syndrome (PCOS) were randomly assigned to the following treatment protocols: Group A (n = 72): spironolactone 100 mg-norgestimate 250 mcg-ethinyl estradiol 35 microg; Group B (n = 70): cyproterone acetate 12 mg-ethinyl estradiol 35 microg; Group C (n = 25): norgestimate 250 microg-ethinyl estradiol 35 microg. RESULTS: The decrease in the hirsutism score was higher in group A than in the other groups (p < 0.001) and comparable in groups B and C. The decrease in acne score, androgen and estradiol levels, and ovary volume was similar in groups A and B. C-reactive protein increase was similar in all groups, but the augmentation of fibrinogen (p = 0.04), triglycerides (p < 0.01), monocyte count (p = 0.04), platelet number (p < 0.001) and mean volume (p = 0.01) was more pronounced in group B than in group A. Low-density lipoprotein/high-density lipoprotein cholesterol ratio decreased in groups A and C. CONCLUSION: Spironolactone-norgestimate-ethinyl estradiol is an effective and well-tolerated combination for the treatment of hirsutism in PCOS, with a favorable influence on lipids and indices of low-grade inflammation.

A comparison of multiphasic oral contraceptives containing norgestimate or desogestrel in acne treatment: a randomized trial.

OBJECTIVE: This study aimed to compare the effectiveness and safety of triphasic combined oral contraceptives (OCs) containing ethinyl estradiol (EE) and norgestimate (NGM) and biphasic combined OCs containing EE and desogestrel (DSG) in the treatment of mild to moderate acne. STUDY DESIGN: This was an investigator-blinded, randomized, parallel group trial conducted at 3 centers in Thailand. Female subjects 18-45 years old were assigned to one or the other OCs and evaluated for efficacy and safety parameters at the baseline visit and after 1, 3 and 6 months of treatment. RESULTS: Among 201 randomized subjects, data from 93 subjects in the EE/NGM group and 95 subjects in the EE/DSG group were analyzed. After 6 months of treatment with EE/NGM and EE/DSG, no differences between formulations were found for the decrease in total acne lesion counts (74.4% vs. 65.1%, respectively, p=.070) or facial improvement score. More women using EE/NGM showed a decrease in severity of facial seborrhea than those using EE/DSG (p=.005). No changes in weight were noted in either group as compared to baseline. CONCLUSION: Multiphasic OCs containing EE/NGM and EE/DSG provided comparable efficacy and tolerability in the treatment of acne. However, EE/NGM had a more beneficial effect on facial seborrhea reduction than EE/DSG. IMPLICATIONS: EE/NGM and EE/DSG are multiphasic OCs, which were shown to be clinically equally effective for mild to moderate facial acne, and the multiphasic combined OC with NGM was more effective for women with facial seborrhea. Clinicians may apply the results of this study when considering treatment options for facial acne and seborrhea.

Mood and physical symptoms improve in women with severe cyclical changes by taking an oral contraceptive containing 250-mcg norgestimate and 35-mcg ethinyl estradiol.

BACKGROUND: The purpose of this study was to investigate how women without and with different severity of premenstrual symptoms react to treatment with a combined oral contraceptive containing 250-mcg norgestimate/35-mcg ethinyl estradiol (EE). Focus was placed on mood and physical symptoms. STUDY DESIGN: This open, prospective study evaluated 24 women using norgestimate/EE for three cycles in a 21/7 regimen. Symptoms and bleeding pattern were captured by daily ratings on the Cyclicity Diagnoser scale. RESULTS: Women with severe premenstrual mood symptoms improved in summarized negative mood (p<.001) and summarized positive mood (p<.05), as well as in swelling (p<.05) and effect on daily life (p<.05). Women with no or mild or moderate symptoms did not show any significant improvement or deterioration in any symptom after 3 months of treatment. CONCLUSIONS: Norgestimate 250 mcg/EE 35 mcg significantly improved premenstrual summarized negative mood symptoms during 3 treatment months compared to pretreatment in women with severe premenstrual symptoms, together with improvement in positive symptoms, swelling and effect on daily life.

Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10.

OBJECTIVE: To assess the risk of venous thrombosis in current users of non-oral hormonal contraception. DESIGN: Historical national registry based cohort study. SETTING: Four national registries in Denmark. PARTICIPANTS: All Danish non-pregnant women aged 15-49 (n=1,626,158), free of previous thrombotic disease or cancer, were followed from 2001 to 2010. MAIN OUTCOME MEASURES: Incidence rate of venous thrombosis in users of transdermal, vaginal, intrauterine, or subcutaneous hormonal contraception, relative risk of venous thrombosis compared with non-users, and rate ratios of venous thrombosis in current users of non-oral products compared with the standard reference oral contraceptive with levonorgestrel and 30-40 µg oestrogen. Diagnoses were confirmed by at least four weeks of anticoagulation therapy after the diagnosis. RESULTS: Within 9,429,128 woman years of observation, 5287 first ever venous thrombosis events were recorded, of which 3434 were confirmed. In non-users of hormonal contraception the incidence rate of confirmed events was 2.1 per 10,000 woman years. Compared with non-users of hormonal contraception, and after adjustment for age, calendar year, and education, the relative risk of confirmed venous thrombosis in users of transdermal combined contraceptive patches was 7.9 (95% confidence interval 3.5 to 17.7) and of the vaginal ring was 6.5 (4.7 to 8.9). The corresponding incidences per 10,000 exposure years were 9.7 and 7.8 events. The relative risk was increased in women who used subcutaneous implants (1.4, 0.6 to 3.4) but not in those who used the levonorgestrel intrauterine system (0.6, 0.4 to 0.8). Compared with users of combined oral contraceptives containing levonorgestrel, the adjusted relative risk of venous thrombosis in users of transdermal patches was 2.3 (1.0 to 5.2) and of the vaginal ring was 1.9 (1.3 to 2.7). CONCLUSION: Women who use transdermal patches or vaginal rings for contraception have a 7.9 and 6.5 times increased risk of confirmed venous thrombosis compared with non-users of hormonal contraception of the same age, corresponding to 9.7 and 7.8 events per 10,000 exposure years. The risk was slightly increased in women using subcutaneous implants but not in those using the levonorgestrel intrauterine system.

Norgestrel may be a potential therapy for retinal degenerations.

Retinal degenerations cover a broad spectrum of diseases, retinitis pigmentosa being the most common inherited retinal degeneration. It remains an untreatable disorder, partly owing to its genetic complexity and variability. Gene therapies, stem cell transplantation and administration of slow release growth factors are some of the treatments currently under development for the treatment of this disease. More recently, steroid hormones, now known to have functions within the CNS aside from their traditional targets, have been suggested as potential therapeutic agents. Progestogenic hormones are thought to modulate pro-survival pathways in the retina and since these hormones are produced naturally in the body their value as potential therapeutic agents is clear. Current data detailing the pro-survival effects of progestogens in the brain and particularly in the eye will be discussed.

Unusual regression of severe recurrent lymphatic malformation of a face after contraception and pregnancy.

We report the case of a female who had suffered from progressive lymphatic malformation in the orbito-temporal region since childhood. Many surgical interventions were performed, including radical excision and shunt drainage. Despite aggressive surgical treatment, recurrence was observed after every intervention. Eventually, the condition regressed after the patient began taking a contraceptive. Moreover, it virtually disappeared after pregnancy.

Acupuncture might have contributed to improving amenorrhoea in a top athlete.

A 26-year-old top female athlete (height 157 cm), who took part in competitive sport similar to middle- and long-distance running, became amenorrhoeic in February 2009. In late May 2009, athletic amenorrhoea was diagnosed and a norgestrel-ethinyl estradiol combination (norgestrel 0.5 mg and ethinyl estradiol 0.05 mg three times daily) was prescribed for 2 weeks. She experienced menstrual bleeding on one occasion for 4 days in mid-June before becoming amenorrhoeic again. The athlete visited our centre to try acupuncture treatment. Forty-six acupuncture sessions were given between 1 October 2009 and 2 November 2010. Acupuncture point selection was based on classical acupuncture medicine and included points long used for gynaecological disorders in Japan--namely, CV6, CV12, LR3, LR14, BL17, BL18, BL23, SP6 and SP10. On 7 May 2010, owing to lack of regular normal vaginal bleeding, she again consulted her gynaecologist and was prescribed the same hormone preparation as used previously. She took it for 2 weeks in conjunction with acupuncture treatment. From July, the amount and duration of menstrual flow increased at regular intervals. Throughout July, a biphasic pattern in basal body temperature (BBT) was gradually established. In conclusion, the single hormone replacement therapy in May 2009 without acupuncture treatment was not effective for the amenorrhoea, nor was the single acupuncture treatment between October 2009 and May 2010. However, after hormone replacement therapy was started in May 2010 in conjunction with regular acupuncture treatment, menstrual blood flow restarted and BBT moved close to the biphasic pattern.

Enhancing survival of photoreceptor cells in vivo using the synthetic progestin Norgestrel.

Retinal degenerations such as Retinitis Pigmentosa remain difficult to treat given the diverse array of genes responsible for their aetiology. Rather than concentrate on specific genes, our focus is on identifying therapeutic avenues for the treatment of retinal disease that target general survival mechanisms or pathways. Norgestrel is a synthetic progestin commonly used in hormonal contraception. Here, we report a novel anti-apoptotic role for Norgestrel in diseased mouse retinas in vivo. Dosing with Norgestrel protects photoreceptor cells from undergoing apoptosis in two distinct models of retinal degeneration; the light damage model and the Pde6b(rd10) model. Photoreceptor rescue was assessed by analysis of cell number, structural integrity and function. Improvements in cell survival of up to 70% were achieved in both disease models, indicating that apoptosis had been halted or at least delayed. A speculative mechanism of action for Norgestrel involves activation of survival pathways in the retina. Indeed, Norgestrel increases the expression of basic fibroblast growth factor which is known to both promote cell survival and inhibit apoptosis. In summary, our results demonstrate significant protection of photoreceptor cells which may be attributed to Norgestrel mediated activation of endogenous survival pathways within the retina.

Familial glucocorticoid resistance caused by a novel frameshift glucocorticoid receptor mutation.

CONTEXT: Familial glucocorticoid resistance is a rare condition with a typical presentation of women with hirsutism and hypertension, with or without hypokalemia. OBJECTIVE: The aim was to determine the cause of apparent glucocorticoid resistance in a young woman. PATIENTS AND METHODS: We studied a family with a novel glucocorticoid receptor (GR) mutation and a surprisingly mild phenotype. Their discovery resulted from serendipitous measurement of serum cortisol with little biochemical or clinical evidence for either hyperandrogenism or mineralocorticoid excess. RESULTS: The causative mutation was identified as a frameshift mutation in exon 6. Transformed peripheral blood lymphocytes were generated to analyze GR expression in vitro. Carriers of the mutation had less full-length GR, but the predicted mutant GR protein was not detected. However, this does not exclude expression in vivo, and so the mutant GR (Δ612GR) was expressed in vitro. Simple reporter gene assays suggested that Δ612GR has dominant negative activity. Δ612GR was not subject to ligand-dependent Ser211 phosphorylation or to ligand-dependent degradation. A fluorophore-tagged construct showed that Δ612GR did not translocate to the nucleus in response to ligand and retarded translocation of the wild-type GR. These data suggest that Δ612GR is not capable of binding ligand and exerts dominant negative activity through heterodimerization with wild-type GR. CONCLUSION: Therefore, we describe a novel, naturally occurring GR mutation that results in familial glucocorticoid resistance. The mutant GR protein, if expressed in vivo, is predicted to exert dominant negative activity by impairing wild-type GR nuclear translocation.

Contraceptive options for women in selected circumstances.

Young women under the age of 16 years require special consideration when requesting contraception. Such young women can give voluntary consent, which enables prescription and supply providing that the practitioner has determined that the minor is sufficiently mature to understand the details of the method and its use. All reversible methods may be appropriate but it is necessary to provide information in a form that is fully understood. For women with pre-existing medical conditions including obesity, the benefits and risks of the use of individual methods needs to be weighed against the risks of pregnancy for that woman.

Intrauterine device or estrogen treatment after hysteroscopic uterine septum resection.

OBJECTIVE: To investigate the effects on adhesion formation and pregnancy maintenance of an intrauterine device (IUD) and/or estrogen treatment after hysteroscopic septum resection. METHODS: After septum resection 100 women received either no treatment, or estrogens, or an IUD, or an IUD plus estrogens (n=25 per group). Most were later checked hysteroscopically for uterine cavity adhesions. All pregnancies occurring during the study period were recorded. RESULTS: Adhesions developed in 1 of 19 (5.3%) of the untreated women, 3 of 25 (12%) of the women treated with an IUD plus estrogens, 2 of 19 (10.5%) of the women treated with an IUD only, and none of the women treated with estrogens only. None of the differences, however, were significant. Regarding pregnancy, the differences between groups were also not significant. CONCLUSION: Neither IUD placement, nor estrogen treatment, nor both were found to prevent intrauterine adhesions or facilitate pregnancy after hysteroscopic uterine septum resection.

Comparison of contraceptive ring and patch for the treatment of symptomatic endometriosis.

OBJECTIVE: To evaluate the efficacy and tolerability of a contraceptive vaginal ring and transdermal patch in the treatment of endometriosis-associated pain. DESIGN: Patient preference cohort study. SETTING: Academic center. PATIENT(S): Two-hundred and seven women with recurrent moderate or severe pelvic pain after conservative surgery for symptomatic endometriosis. INTERVENTION(S): Continuous, 12-month treatment with a vaginal ring supplying 15 mcg of ethinyl E and 120 mcg of etonogestrel per day or a transdermal system delivering 20 mcg of ethinyl E and 150 mcg norelgestromin per day. MAIN OUTCOME MEASURE(S): Satisfaction with treatment. RESULT(S): One-hundred and twenty-three women preferred the ring, and 84 preferred the patch. Forty-four ring users (36%) and 51 patch users (61%) withdrew. Thirty-six of 79 subjects (46%) in the ring group and 14 of 33 (42%) in the patch group shifted from continuous to cyclic use because of irregular bleeding. Pain symptoms were reduced by both treatments, with the ring being more effective than the patch in patients with rectovaginal lesions. According to an intention-to-treat analysis, 88 of 123 ring users (72%) and 40 of 84 patch users (48%) were satisfied with the treatment received. CONCLUSION(S): Patients who preferred the ring were significantly more likely to be satisfied and to comply with treatment than those who chose the patch. Both systems were associated with poor bleeding control when used continuously.

New developments in hormonal therapy for acne.

Oral contraceptives (OCs) are a valuable option for the treatment of women with acne. The use of OCs can be considered across the spectrum of acne disease severity in women. In Canada, three preparations are approved for mild-to-moderate acne, and a fourth is indicated for severe acne. These formulations contain estrogen in the form of ethinyl estradiol and a progestin. In Canada, the most recently approved OC is ethinyl estradiol 0.03 mg and drospirenone 3mg (Yasmin, Bayer). With the accumulating evidence on the efficacy and safety of drospirenone-containing hormonal preparations, this formulation provides dermatologists with a new treatment option for acne and other hyperandrogenic disorders.

Advances in hormonal contraception.

This article presents a review of advances made in hormonal contraception over the past 15 years. It looks at the different routes of administration that have been developed, at newer formulations of conventional methods, and at novel contraceptive agents that are in the process of approval. The article provides a short description of each of these contraceptive methods, information about compliance, side effects, and efficacy, and an update on that particular method.