Oral Contraceptive Preparations Research Articles

The Role of Oral Contraceptives in the Treatment of Hyperandrogenic Disorders

The clinical manifestations associated with hyperandrogenism, such as hirsutism and acne, are disturbing to most patients. In addition to correcting androgen-related problems, concerns such as contraception or other metabolic problems (for example, lipid/lipoprotein abnormalities, diabetes, hypertension) associated with these disorders and the effects of unopposed estrogen on the endometrium also need to be considered. Oral contraceptives are a therapeutic modality that may address these multiple problems. The potential mechanisms of action by which oral contraceptives correct excess androgen states include gonadotropin suppression, reduction of circulating androgens, increased androgen binding, suppression of adrenal androgen secretion and inhibition of 5 alpha-reductase, and androgen receptor binding. In normal women, there is good evidence that these actions occur with the use of oral contraceptives. Among women with anovulatory hyperandrogenic states, such as polycystic ovary syndrome, the response to oral contraceptives in each of these areas is somewhat more variable. However, oral contraceptive preparations that are more estrogen dominant appear to produce many of the desired effects. From a clinical standpoint, 60-100% of women with hirsutism improve on oral contraceptives; acne shows improvement in a high percentage of women as well. The use of oral contraceptives also reduces the risk of endometrial hyperplasia that may be associated with anovulatory states. Finally, current low-dose preparations containing the newer progestins (for example, norgestimate and desogestrel) appear to be either neutral, or perhaps beneficial, with respect to their metabolic impact.

Large increase in plasmatic 11-dehydro-TxB2 levels due to oral contraceptives

Coagulation factors, 11-dehydro-TxB 2 (metabolite of TxA 2) and 6-keto-PGF 1α (metabolite of PGI 2) levels in 87 women who were treated for 9 months with oral contraceptives (OC) containing low doses of oestrogens and progestogens (Triquilar R, Trinovum R or Cilest R) were investigated. In plasma, increases in F I, II, VII, VIII-c and 11-dehydro-TxB 2 levels, but no modification of 6-keto-PGF 1α were observed. In urine, FPA concentration rose, but no change occurred in 11-dehydro-TxB 2 and 6-keto-PGF 1α levels. No marked difference between the 3 OC preparations were noted. These data, and particularly the large increase of 11-dehydro-TxB 2 (p < 0.01), suggest that a hypercoagulable state persists in low dosage OC users.

Triphasic levonorgestrel

The triphasic levonorgestrel oral contraceptive preparation was introduced in the late 1970s and today it is available in more than 90 countries. The substantial volume of clinical experience now available has established that not only is this preparation clinically effective but that it also provides excellent cycle control. In this paper, results of efficacy, cycle control and patient acceptability/compliance are reviewed, drawing together the considerable clinical experience that now exists.All studies confirm the contraceptive reliability of triphasic levonorgestrel and report good patient compliance. Good patient compliance is, in part, due to the low incidence of breakthrough bleeding and spotting (intermenstrual bleeding) as well as the low incidence of failure of withdrawal menses (amenorrhea) that is achieved with this oral contraceptive, even in the first few cycles. The side-effect profile of triphasic levonorgestrel is also good and most studies report it to be well tolerated. When compared both with monophasic and other triphasic preparations, several studies show that triphasic levonorgestrel is associated with better cycle control. A further non-contraceptive benefit of triphasic levonorgestrel is reported in patients with acne vulgaris, which has been shown to improve in the majority of patients treated.

Contraception in women with intercurrent disease

Prescribing a contraceptive method for women with intercurrent disease poses a difficult clinical management problem for physicians. The contraceptive chosen may adversely affect the underlying disease of the patient. Conversely, failure of contraception could result in pregnancy, which could also adversely affect the patient's underlying disease. These factors must be taken into consideration in selecting appropriate and effective contraceptive agents to avoid complications and undesired pharmacologic interactions.

Hormone replacement therapy in perimenopausal women with a low dose oral contraceptive preparation: Effects on bone mineral density and metabolism

In a 2-year longitudinal, calcium-controlled study we evaluated bone density and metabolism in perimenopausal women with initial ovarian failure, and the effects of hormone replacement with a low dose oral contraceptive preparation (OC). In perimenopausal oligomenorrhoic women ( n = 16) a significant ( P < 0.01) increase in cycle length and plasma FSH levels as well as a parallel decrease in plasma estradiol levels ( P < 0.01) were evident. In this group, despite the calcium supplementation (500 mg/day), a significant ( P < 0.001) increase in the biochemical markers of bone remodelling paralleled a significant ( P < 0.001) decrease (-3.4% after 24 months) in bone density. Conversely, in premenopausal oligomenorrhoic women treated with a low dose oral contraceptive (OC) formulation (30 mcg ethinyl estradiol plus 75 mcg gestodene, n = 16), bone markers showed a significant ( P < 0.01) decrease, that paralleled a slight but significant ( P < 0.01) increase (+1.71%) in bone density. These data suggest that premenopausal administration of OC can prevent the acceleration of bone turn-over and reverse the decrease in bone density that follows the premenopausal impairment of ovarian function.

Clinical and metabolic features of desogestrel: A new oral contraceptive preparation

Desogestrel is a highly selective gonane progestin. A monophasic formulation containing 150 micrograms of desogestrel and 30 micrograms of ethinyl estradiol has recently been approved as an oral contraceptive (OC) in the United States. Although desogestrel-containing formulations are new to the United States, they have been the most widely prescribed OCs in Europe for almost 10 years. An extensive literature demonstrates that desogestrel-containing preparations are safe, effective, and well tolerated by most women. In light of desogestrel's high selectivity, low affinity for androgen receptors, and lack of interference with the increase in sex hormone-binding globulin, desogestrel-containing OCs may be particularly appropriate for women with androgen-induced skin disorders because of their high selectivity. Several European studies have found significant improvement or almost complete resolution of previously existing acne. Desogestrel provides excellent cycle control, no major impact on weight, minimal or no adverse effects on blood pressure, statistically significant increases in high-density lipoprotein cholesterol with low-density lipoprotein cholesterol usually unchanged or reduced, and little effect on glucose tolerance or insulin resistance.

Clinical and metabolic features of desogestrel: A new oral contraceptive preparation

Desogestrel is a highly selective gonane progestin. A monophasic formulation containing 150 of μg desogestrel and 30 μg of ethinyl estradiol has recently been approved as an oral contraceptive OC in the United States. Although desogestrel-containing formulations are new to the United States, they have been the most widely prescribed OCs in Europe for almost 10 years. An extensive literature demonstrates that desogestrel-containing preparations are safe effective and well tolerated by most women. In light of desogestrel's high selectivity, low affinity for androgen receptors, and lack of interference with the increase in sex hormone-binding globulin desogestrel-containing OCs may be particularly appropriate for women with androgen-induced skin disorders because of their high selectivity. Several European studies havefound significant improvement or almost complete resolution of previously existing acne. Deso estrel provides excellent cycle control no major impact on weight, minimal or no adverse effects on blood pressure, statistically significant increases in high-density lipoprotein cholesterol with low-density lipoprotein cholesterol usually unchanged or reduced and little effect on glucose tolerance or insulin resistance. Desogestrel is a highly selective gonane progestin. A monophasic formulation containing 150 of μg desogestrel and 30 μg of ethinyl estradiol has recently been approved as an oral contraceptive OC in the United States. Although desogestrel-containing formulations are new to the United States, they have been the most widely prescribed OCs in Europe for almost 10 years. An extensive literature demonstrates that desogestrel-containing preparations are safe effective and well tolerated by most women. In light of desogestrel's high selectivity, low affinity for androgen receptors, and lack of interference with the increase in sex hormone-binding globulin desogestrel-containing OCs may be particularly appropriate for women with androgen-induced skin disorders because of their high selectivity. Several European studies havefound significant improvement or almost complete resolution of previously existing acne. Deso estrel provides excellent cycle control no major impact on weight, minimal or no adverse effects on blood pressure, statistically significant increases in high-density lipoprotein cholesterol with low-density lipoprotein cholesterol usually unchanged or reduced and little effect on glucose tolerance or insulin resistance.

The Effect of the Phase of the Menstrual Cycle and the Birth Control Pill on Athletic Performance

Investigators are not in agreement on the effects of either the phase of the menstrual cycle, or the administration of OCAs on athletic performance. It appears, however, that apart from subtle changes in some variables, for most women there is no significant effect. Medals have been won and world records set in any phase of the menstrual cycle, and also by women taking OCAs. In terms of documentation of cycle phase, newer hormonal measurement techniques such as the levels of urinary luteinizing hormone (LH) to detect ovulation or salivary progesterone, should make it easier in the future to obviate the methodologic difficulties encountered in earlier studies. Further studies should also focus on the midcycle estradiol surge as well, in order to determine the relative contributions of estrogen and progesterone to any observed performance changes. Given the possibility that some cardiovascular, respiratory, and metabolic variables may change slightly during the course of a regular ovulatory menstrual cycle, it behooves researchers who are using women as subjects in other types of studies to standardize the menstrual cycle phase in which they are tested, in order to eliminate any possible confounding effects due to hormonal variation. Regarding the effects of oral contraceptives on performance, any conclusions from the studies to date are complicated by the proliferation of preparations currently on the market. Further studies are needed on monophasic, biphasic and triphasic formulations, including OCAs with the newer progestins (desogestrel, gestodene and norgestimate), as well as the progesterone-only agents (both oral and injectable). Prospective double blind randomized studies must be done, using a proper control group. The difficulty with this technique, however, is that women in the control group will inevitably be in various phases of the cycle, so accurate hormonal documentation is also essential in order to correctly interpret the findings. Just as the past few decades have seen a significant advancement in the participation of women in sports, future years should bring an enhanced scientific knowledge base about the interactions of the special hormonal considerations of the exercising woman throughout her reproductive life cycle.

Frequency of Pregnancy in Acne Patients Taking Oral Antibiotics and Oral Contraceptives

Dermatologists prescribe oral antibiotics to female acne patients on a regular basis. There have been reports of oral antibiotic interaction with oral contraceptive preparations,^1-3but no clinical study has precisely defined the risk for women taking these medications in combination with oral antibiotics. Amid the uncertainty, some dermatologists recommend that their female acne patients use additional birth control measures as a precaution. Our study examines the frequency of pregnancy in female acne patients taking oral antibiotics in conjunction with oral contraceptives compared with published failure rates for women taking birth control pills alone. <h3>Materials and Methods.</h3> Female acne patients were interviewed by mail questionnaire and by survey in an outpatient dermatology clinic. Patients were questioned about concurrent usage of their antibiotic and oral contraceptive preparations. Pregnancy occurrence and side effects were also investigated. Further inquiries were made concerning the use of additional medications while receiving the pill/antibiotic combination and

Safety and efficacy of a combined oral contraceptive: Gestodene 75 μg plus ethinyl estradiol 30 μg in Mexican women

An open prospective clinical trial designed to evaluate the efficacy and safety of the combined hormonal oral contraceptive (OC) containing 75 micrograms gestodene plus 30 micrograms ethinyl estradiol was undertaken in a Mexican population. Sixty-nine healthy women of reproductive age took part in the study for a total of 627 woman-months of observation. The combination of gestodene and ethinyl estradiol proved its effectiveness in preventing pregnancy during the study. Side-effects were minimal and regular endometrial bleeding patterns were observed during one year of continuous use of this OC preparation. The discontinuation rate for medical reasons was 11.6% at one year. Among a sample of 10 women, the gestodene/ethinyl estradiol combination did not induce significant changes in the serum concentration of total cholesterol and LDL cholesterol after 12 months of continuous administration. An increase in serum triglycerides and HDL cholesterol was observed; this effect could be attributed to a lack of androgenic and/or the intrinsic estrogenic behavior of gestodene. It can be concluded that this preparation is highly effective as a combined oral contraceptive; it is well tolerated and might offer some advantages with respect to other oral contraceptive combinations in its short- and medium-term impact on lipid metabolism.

Safety and efficacy of a triphasic oral contraceptive containing desogestrel: Results of three multicenter trials

This report combines the data obtained in three multicenter efficacy studies with a new triphasic oral contraceptive combination containing desogestrel (DSG) and ethinyl estradiol (EE). The studies were conducted at 40 investigational sites in the United States (38 centers) and Canada (2 centers) in support of the FDA approval of the product. In total, 1,095 subjects were exposed to the study medication for 11,231 cycles, corresponding to approximately 864 woman-years of use. Of these subjects, 414 completed at least 13 cycles of treatment. Contraceptive efficacy was high; six pregnancies occurred during the in-treatment period (two due to method failure and four due to user failure), corresponding to Pearl Indices of 0.23 and 0.46, respectively. The incidence of irregular bleeding was low, and the acceptability was excellent as evidenced by the low incidence of drug-related drop-outs. No drug-related serious adverse experiences were reported, and the incidence of other drug-related adverse experiences was generally low and decreased with continued use. No effects were seen on blood pressure, body mass index, laboratory parameters, cervical cytology and breast nodularity. These studies demonstrate that triphasic DSG/EE is an effective and acceptable triphasic oral contraceptive preparation with excellent cycle control and no significant physiologic effects.

Bone loss, contraception and lactation

Loss of bone mass with age, is a universal phenomenon and is more pronounced in women than in men. The condition where the bone loss has proceeded to the extent that fractures occur is termed osteoporosis. As the number of elderly persons in the population increases, its magnitude is likely to increase, both in the developing and the developed countries. Bone mass increases rapidly in childhood and the adolescent years, reaching a peak in the third decade of life, and begins to decline soon thereafter. Several factors are thought to influence bone loss: these include race, diet, smoking, and physical exercise. Although the rate of bone loss accelerates in the immediate postmenopausal period, the process actually begins in the premenopausal years. By the time osteoporosis is clinically apparent and manifested by fracture, it probably cannot be reversed. The peak adult bone mass achieved, and the subsequent rate of bone loss are the major factors that determine a woman's susceptibility to postmenopausal osteoporosis. A primary cause of bone loss after menopause is the associated decline in ovarian function. Scanty information is available on the factors that affect bone mineral density or initiate bone loss before menopause, although both estrogens and progestins have been shown to prevent bone loss in postmenopausal women. Available data on the relationship between steroid hormone contraceptive use and bone mass/density is limited to combined oral contraceptives and one report related to the use of depot medroxyprogesterone acetate.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral contraceptives and cycle control: a critical review of the literature.

Control of spotting and breakthrough bleeding and absence of withdrawal bleeding, collectively termed cycle control, is the single most important determinant of whether a new user of oral contraceptives (OCs) will continue this method. However, information about different OC preparations and how they affect such problems, including the effects of progestogen and estrogen phasing and the components of these hormones, is scant and confusing. Studies cited in this report reveal highly variable rates of bleeding problems in women taking OCs: after 6 months of OC use, the prevalence of spotting varied between 0% and 8.5%; of breakthrough bleeding, 0% and 12.2%; and of amenorrhea, 0% and 5.8%. At least some of this variation is attributable to differing study populations and cultures, study designs, and the manner in which data were collected and reported. However, methodologic weaknesses were common, often involving lack of randomization and blinding, and attrition rates were high. Despite these limitations, it is clear that the frequency of bleeding problems decreases with continuing use of OCs, emphasizing the need for patient reassurance about the transient nature of these problems. In addition, gestodene-containing preparations appear to offer better cycle control than do desogestrel-containing preparations and levonorgestrel-containing preparations better control than norethindrone-containing preparations. However, the strongest lesson to emerge is the need for more rigorous studies to adequately address questions of comparative bleeding problems, particularly with newer triphasic formulations. These conclusions underscore the importance of counseling new OC users about the possibility of bleeding problems, reassuring them that most such problems are temporary, and, that if compliance is maintained, these will not impair contraceptive efficacy.

The metabolic impact of oral contraceptives

The hormonal components of oral contraceptives exert major effects on plasma lipoprotein metabolism. Estrogens may increase production of plasma triglycerides, leading to increased levels of very low-density lipoproteins, but they may also reduce levels of cholesterol-enriched and potentially atherogenic intermediate- and low-density lipoproteins. Furthermore, estrogens increase levels of high-density lipoproteins (HDLs), particularly the HDL 2 subspecies, an effect linked to reduced mortality rates from cardiovascular disease in postmenopausal women receiving hormone replacement therapy. All combination oral contraceptives in use in the United States tend to raise levels of plasma triglycerides, low-density lipoprotein, and HDL 3 to varying degrees. In contrast, changes in HDL and HDL 2 reflect the combined effects of estrogen dose and relative androgenicity of the progestin component. Although in general, the lipoprotein changes are greater in magnitude with higher dose oral contraceptive preparations, they can be significant in lower dose preparations as well. Oral contraceptives also affect carbohydrate metabolism, primarily through the activity of progestin. Studies have demonstrated insulin resistance, rises in plasma insulin, and relative glucose intolerance by means of curve analysis of glucose tolerance tests. These effects are far less pronounced with lower dose preparations and with formulations using the newer progestins.

Risk Factors for Fatal Venous Thromboembolism in Young Women: A Case-Control Study

A case-control study of fatal venous thromboembolism in young women is described. Sixty women aged between 16 and 39 who died from thromboembolism in England and Wales between 1986 and 1988 were included in the study. Two living controls matched for age and marital status were sought from the records of the general practitioner with whom each case was registered. Some 115 controls were included in the study. The cases had a significantly higher prevalence of a history of major illness, particularly thrombotic episodes, than the controls. The odds ratio (OR) of a fatal thromboembolism in women who had a history of venous thrombosis was 4.0 (95% Cl: 1.4-11.5). There was also a significantly higher frequency of a recent operation or accident amongst the cases than the controls (OR = 11.1, 95% Cl: 1.3-92.5). There was no significant excess or oral contraceptive use amongst the cases. The overall OR associated with current use of oral contraceptives was 1.6 (95% Cl: 0.7-3.4), while the corresponding OR for 'idiopathic' diseases was 2.1 (95% Cl: 0.8-5.2). These risks are considerably smaller than those observed in previous studies. The observed risk may be low because the dosage of oestrogen in modern oral contraceptive preparations has been reduced, but it may also be because the cases of fatal venous thromboembolism included in this study represent only a small proportion of all cases of venous thrombeombolism; a disease which is rarely fatal in young women. These results cannot necessarily be extrapolated to nonfatal venous thromboembolism.

Etiologic and clinical characteristics of peripheral and hilar cholangiocarcinoma

A 20-year experience with 112 patients with cholangiocarcinoma was reviewed with reference to the demographic, etiologic, and clinical features and prognosis in the following two types: peripheral (originating from the intrahepatic small duct radicles) and hilar (originating from the major hepatic ducts at or near the junction of the right and left hepatic ducts). Seventy of the 112 patients were in the hilar group, and 42 were in the peripheral group. Prolonged high alcohol consumption was a prominent feature in both categories (45% and 37%, respectively). Among the women, 35% of those with the peripheral tumor had used oral contraceptive preparations. The major identifiable etiologic factor among the hilar tumors was ulcerative colitis, with or without sclerosing cholangitis, which was documented in 20 of 70 cases (28.6%), with an additional 4 patients having Crohn's disease. The hilar group mainly had obstructive jaundice initially, whereas abdominal pain and weight loss were the predominant symptoms in the peripheral type. Tumor recurrence was frequent in those undergoing resection or transplantation, and none of those undergoing chemotherapy or radiation therapy showed any objective evidence of response. Overall median survival time was poor in both groups at 12 months.

A multicentre study of coagulation and haemostatic variables during oral contraception: variations with four formulations

AbstractObjective— To explore the extent to which progestogen type and oestrogen and progestogen dose may modify the effects of combined oral contraceptives (OC) on coagulation and haemostasis.Design— Randomized double‐blind clinical trial.Setting— Gynaecological clinics in Salvador (Brazil), Santiago (Chile), Singapore, and Dublin (Ireland).Subjects— 622 women aged 18–35 years who had opted for oral contraception. A contrast group of 155 women who were not to receive OC was also studied. Both groups included approximately equal numbers from each of the four centres.Interventions— Treatment of approximately equal numbers of women at each centre with one of the following OC preparations for at least 12 months: Noreth isterone acetate (NEA) 1 mg + ethinyl oestradiol (EE) 50μg; levonorgestrel (LNG) 250 + EE 50 μg + EE 30 μg; LNG 150 μg + EE 30 μg.Main outcome measures— Changes over 12 months in 12 coagulation and haemostatic variables.Results— At 12‐month follow‐up, the women on each OC preparation showed acceleration of prothrombin time and increase in factor X and fibrinogen. With the OC containing NEA there was also a persistent rise in factor VIIC, and reduction of antithrombin 111 and arantiplasrnin. The formulation which contained low doses of both LNG and EE showed the least adverse coagulation changes. Large increases in fibrinolysis were found in all OC groups.Conclusions— The adverse effects of combined OC on clotting are affected by the type and dose of progestogen as well as the dose of oestrogen.

Cyclic fluctuations in human serum lipid and apolipoprotein levels during the normal menstrual cycle: Comparison with changes occurring during oral contraceptive therapy

The influence of menstrual cycle phases and hormonal contraception on serum lipid and apolipoprotein (apo) levels was investigated in a group of normally menstruating young women. The study period covered a normal menstrual cycle (pretherapy), the fourth cycle of treatment with a triphasic oral contraceptive (OC) preparation, and the cycle immediately following interruption of therapy (cycle 5, posttherapy). Cycle phases were defined on the basis of serum hormone levels and basal body temperature determinations. Significant differences in cholesterol (free and esterified) levels were observed during the menstrual phase of both the normal menstrual cycle (lower) and the OC cycle (higher), when compared with the other phases. Triglycerides, which were higher under OCs, fluctuated similarly throughout the two cycles, but phase differences did not reach statistical significance. Apo Al and apo B were both higher under OCs, and apo B followed a trend similar to cholesterol during the two cycles. During the first month after discontinuation of OCs, cholesterol levels returned progressively to baseline values, while triglycerides were only partially decreased. We conclude that cyclic fluctuations in lipid levels do occur under the influence of both endogenous and exogenous sex hormones.

Hirsutism: Metabolic effects of two commonly used oral contraceptives and spironolactone

Fifty-one hirsute women were randomly treated for nine months with ethinyl estradiol 35 ug plus norethindrone 0.4 mg or 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate if they needed contraception or spironolactone 200 mg daily if they did not. Metabolic evaluations in response to therapy demonstrated triglyceride elevations with the two oral contraceptives but not with spironolactone. While systolic blood pressure was lower with spironolactone, fasting insulin levels were higher as opposed to either low-dose oral contraceptive preparation. Ethinyl estradiol 30 ug plus 1.5 mg norethindrone acetate lowered 3-alpha-diol glucuronide levels, yet ethinyl estradiol 35 ug plus norethindrone 0.4 mg and spironolactone were more effective in lowering Ferriman-Gallwey Scores. Treatment strategies for hirsute women need to consider metabolic consequences as well as efficacy.

Carbohydrate metabolic studies in women using a levonorgestrel/ethinyl estradiol containing triphasic oral contraceptive for eighteen months

Carbohydrate metabolism was evaluated in 17 women before and after 18 months of triphasic oral contraceptive use. The triphasic oral contraceptive contained levonorgestrel and ethinyl estradiol. An oral glucose tolerance test was utilized and both plasma glucose and insulin levels were measured. There were no significant changes in the glucose levels. The fasting insulin level was raised at the 18-month test, whereas the other insulin values were similar. These results demonstrate that the new triphasic oral contraceptive preparations produce minimal carbohydrate metabolic changes.