Bust without boom.

PIP: Just like injectables, oral contraceptives (OCs), including progestin-only ¿minipill¿ and ¿morning-after¿ pill regimens, have experienced a bust without a boom. Fear of political and religious backlash over emergency contraceptives containing estrogen and progestin prompted large companies not to market these regimens. Another major factor in the bust phase of OC use and acceptance has been a small coterie of English and American epidemiologists focused on the adverse effects of Ocs, including risks of thrombotic events, heart attacks, and strokes. The media played a crucial role in the bust phase of these OCs. In the UK, the alleged increase of cancer risk with pill use, which leaked before publication in London newspapers, resulted in 50,000 additional unintended pregnancies. Nevertheless, there is no doubt that boom-and-bust cycles will continue simply because many of the actors in this drama have too great a vested interest to desist. Groups involved in this field must recognize the hazards that come with the territory and be proactive, anticipatory, and well armed with facts--and get good with media access. Drug companies should think on a long-term basis the potential effects of leaving the field, as they have done, or shooting down competitive innovations.^ieng

Providing combined OCs: examine special issues.

PIP: This article focuses on issues concerning the prescription and restriction of oral contraceptive (OC) use among smokers and new moms based on the findings from Contraceptive Technology's Update 2000 Contraception Survey involving family planning providers and clinicians. Overall, a majority (72%) of the providers restrict the pills to smokers aged 35-39 years, and 88.6% withhold the pills from smokers aged 40 and above. Providers believed that smoking increases the risk for developing cardiovascular disease; thus, all smokers are warned of that risk and are encouraged and advised to stop smoking. In addition, 42.5% of providers recommend new mothers to begin using the pills 4-6 weeks postpartum; and 45.1% say they start nursing mothers on progestin-only pills 4-6 weeks postpartum. Finally, half of survey participants chose Alesse, a 20 mcg pill, as their top choice for women who have experienced nausea on previous OC formulations.^ieng

The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices.

Modern hormonal contraceptives and intrauterine contraceptive devices have multiple biologic effects. Some of them may be the primary mechanism of contraceptive action, whereas others are secondary. For combined oral contraceptives and progestin-only methods, the main mechanisms are ovulation inhibition and changes in the cervical mucus that inhibit sperm penetration. The hormonal methods, particularly the low-dose progestin-only products and emergency contraceptive pills, have effects on the endometrium that, theoretically, could affect implantation. However, no scientific evidence indicates that prevention of implantation actually results from the use of these methods. Once pregnancy begins, none of these methods has an abortifacient action. The precise mechanism of intrauterine contraceptive devices is unclear. Current evidence indicates they exert their primary effect before fertilization, reducing the opportunity of sperm to fertilize an ovum.

PIP: The mechanism of action of contraceptive method is essential for the development of new methods. It also influences cultural and individual acceptability of a contraceptive method. Modern hormonal contraceptives and intrauterine contraceptive devices have multiple biologic effects. Some of them may be the primary mechanism of contraceptive action, whereas others are secondary. For the combined oral contraceptives and progestin-only methods, the main mechanism of action are the inhibition of follicular development, ovulation, and as consequence, corpus luteum formation. Further, it is also involved in the alteration of the cervical mucus that inhibit sperm penetration. For hormonal methods, particularly the low-dose progestin-only products and emergency contraceptive pills have effects on the endometrium that, theoretically, could affect implantation. However, no scientific evidence will indicate that prevention of implantation actually results from the use of these methods. Once implantation has taken place, none of these methods are effective and pregnancy proceeds normally. The precise mechanism of IUDs remains unclear because of difficulties in carrying out relevant investigations in humans and the limitations of extrapolating findings from animal studies. However, several studies evidenced that IUDs exert their primary effect before fertilization, by impeding the ascent of sperm to the fallopian tubes or by reducing the ability of sperm to fertilize an ovum.

Maximizing the use of the progestin minipill.

PIP: Although the progestin-only oral contraceptive (OC) is a safe, effective method for women who cannot use agents that include estrogen because they are breast-feeding or for another reason, it accounts for only 1-26% of the OC market in the US. The progestin-only OC is less effective than combined OCs, and about 5% of women who use rely on the progestin-only formulation and use it correctly will become pregnant in the first year. However, the added contraceptive effect of breast-feeding makes the method nearly 100% effective in lactating women. The progestin-only OC does not interfere with the quality or quantity of breast milk and causes fewer and milder side effects or adverse effects than combined OCs, with irregular bleeding being the most troublesome. The doses of progestin are even lower in the progestin-only OCs than in combined OCs, and the progestin is metabolized within 24 hours, so a back-up method of contraception must be used until the regular schedule has been reinstated for 48 hours if a woman misses a dose by more than 3 hours unless she is fully breast-feeding. The pills are taken daily, and the regimen can be started at any time in the menstrual cycle. Shorter and simpler labeling for the progestin-only OCs was accepted in 1995. The OCs can be given to women immediately postpartum and are a good choice for women who smoke or are over age 35 but should be avoided by women taking hepatic enzyme-inducing medications or by women with a history of gestational diabetes.^ieng

The trimonthly combination oral contraceptive regimen: is it cost effective?

The extended use of combination oral contraceptive pills (COCPs) to decrease the frequency of withdrawal bleeding can be convenient and beneficial to women. We conducted a cost-effective analysis comparing the standard regimen (21 days of estrogen/progestin) to a trimonthly regimen (84 days of estrogen/progestin) followed by a pill-free week for 1-year. The economic savings for patient out-of-pocket expenses from decreased sanitary product usage as a result of nine fewer withdrawal bleeding episodes is offset by the cost of three extra packages of COCPs from the trimonthly regimen. On the basis of an average use of 18 tampons per month, the trimonthly regimen is cost effective when the patient cost per package of pills is less than $9.45. The trimonthly regimen is also cost effective when the sanitary product usage is in the higher range; an above average use of 48 tampons per month is cost effective when the patient cost per package of pills is less than $25.20. Therefore, the trimonthly regimen may be useful for women with menorrhagia, but for the average women, the qualitative benefits of less frequent withdrawal bleeding need to be weighed against an increase in cost.

PIP: The extended use of combination oral contraceptives (COCs) to decrease the frequency of withdrawal bleeding can be convenient and beneficial to women. The authors conducted a cost-effective analysis comparing the standard regimen (21 days of estrogen/progestin) to a trimonthly regimen (84 days of estrogen/progestin) followed by a pill-free week for 1-year. The economic savings for patient out-of-pocket expenses from decreased sanitary product usage as a result of 9 fewer withdrawal bleeding episodes is offset by the cost of three extra packages of COCs from the trimonthly regimen. On the basis of an average use of 18 tampons per month, the trimonthly regimen is cost-effective when the patient cost per package of pills is less than $9.45. The trimonthly regimen is also cost-effective when the sanitary product usage is in the higher range; an above average use of 48 tampons per month is cost-effective when the patient cost per package of pills is less than $25.20. Therefore, the trimonthly regimen may be useful for women with menorrhagia, but for the average women, the qualitative benefits of less frequent withdrawal bleeding need to be weighed against an increase in cost.

Contraception-associated menstrual problems: etiology and management.

PIP: Menstrual cycle irregularities are common during the first few months of use of hormonal contraception and the IUD. Although most contraception-related menstrual problems are not clinically significant, they can lead to erratic method use or even discontinuation. This article presents guidelines for the assessment and management of bleeding problems related to use of combined oral contraceptives (OCs), progestin-only pills, subdermal progestin implants, injections, and IUDs. Much of the patient dissatisfaction that results from these menstrual changes can be averted by careful counseling prior to method selection. Candid dialogue regarding the potential for bleeding disturbances is critical before a method is prescribed in order to avert the interrupted contraceptive practices that place women at risk of unintended pregnancy.^ieng

Premature introduction of progestin-only contraceptive methods during lactation.

Experts on contraceptive technology concur that progestin-only methods can be used safely during lactation. However, very few studies exist of the effects on lactation of the introduction of progestin-only methods prior to the sixth postpartum week. Since progesterone withdrawal is the likely stimulus that initiates lactogenesis, it appears necessary for natural progesterone levels to decline to baseline before a progestin-only contraceptive is initiated. Therefore, the use of such contraceptive methods should be delayed for at least 3 days after the birth. Non-hormonal methods remain the first choice category of contraceptive methods for breastfeeding women, since there is no possibility that they will interfere with lactation. Progestin-only methods comprise a viable and often desirable next choice category, although the timing of their commencement must be determined with care in order to support lactation.

PIP: All major international family planning organizations have endorsed the use of progestin-only contraceptive methods once lactation has been established. Prospective, multicenter studies of infants of acceptors of progestin-only pills, injections, and implants have found no deleterious effects of the drug on infant growth and development; however, women enrolled in these trials did not initiate method use until at least the sixth postpartum week. Of concern is a recent trend toward administration of progestin subdermal implants and injectables to women prior to their discharge from the hospital (i.e., 0-72 hours after delivery). Since progesterone withdrawal is the likely stimulus that initiates lactogenesis, natural progesterone levels need a chance to decline to baseline before progestin contraceptive use is initiated. Moreover, the immature neonatal liver may have difficulties metabolizing exogenous steroids, the binding capacity of plasma is low, and the immature kidney may be inefficient in steroid excretion. Use of progestin-only contraceptive methods should be delayed for at least 3 days (optimally, until 6 weeks) after birth so lactation can become established. Nonhormonal methods remain the first choice for breast-feeding women, given the lack of potential to interfere with lactation, while progestin-only agents are a viable second choice.

Ovarian activity during regular oral contraceptive use.

The aim of this study was to assess whether during regular OC use ovarian activity might lead to ovulation, as assessed by ultrasound (US) evaluation of follicular growth and blood levels of 17-beta-estradiol and progesterone. A total of 51 healthy women with normal menstrual cycles (28 +/- 3 days) and no gynecological symptoms were recruited. A total of 22 patients were given a triphasic OC pill containing 35 mg ethinyl estradiol (EE) and 50 mg desogestrel (DSG) in the first seven tablets; 30 mg EE and 100 mg DSG in tablets 8 to 14, and 30 mg EE and 150 mg DSG in tablets 15 to 21; 29 patients received one of two OC pills, both containing 20 mg EE plus 150 mg DSG (15 patients) or 75 mg of gestodene (14 patients). A total of 86 cycles were monitored: 51 during the 3rd-4th cycle and 35 during the 6th-8th cycle of OC treatment. Follicular-like structures were observed in nine patients. The frequency of follicular-like structures was similar during the 3rd-4th cycle (9%) and during the 6th-8th cycle (11%). There was no relationship between follicular growth and blood levels of E2 and progesterone, which always appeared suppressed. In conclusion, the results of this study suggest that during OC use (even with low dose of ethinyl estradiol), a little ovarian activity may be present without ovulation.

PIP: Several studies have described a 10-20% incidence of folliculogenesis during low-dose oral contraceptive (OC) use. This study used ultrasound evaluation of follicular growth and blood levels of 17-beta-estradiol and progesterone to determine whether OC-induced ovarian activity led to ovulation in 51 healthy women with regular menstrual cycles. Subjects were given a new triphasic OC containing 35 mg ethinyl estradiol (EE) and 50 mg desogestrel (DSG) in the first 7 tablets, 30 mg EE and 100 mg DSG in tablets 8-14, and 30 mg EE and 150 mg DSG in tablets 15-21 (22 women); an OC containing 20 mg EE and 150 mg DSG (15 women); or an OC comprised of 20 mg EE and 75 mg gestodene (14 women). A total of 86 cycles were monitored: 51 during the third and fourth cycles and 35 during the sixth through eighth cycles of treatment. Follicular-like structures were observed in 9 patients. Follicular growth occurred in 4 cycles (11%) in the triphasic group, 3 (13%) in the EE-DSG group, and 2 (7%) in the EE-gestodene group. The frequency of follicular-like structures was similar during the third-fourth cycle (9%) and the sixth-eighth cycle (11%). There was no association between follicular growth and blood levels of estradiol and progesterone. These results are compromised by the fact that only 35 of the 51 subjects completed 2 cycles. Nonetheless, they tend to confirm the observation that even a low dose of ethinyl estradiol can produce some ovarian activity without ovulation.

Progestogen-only pills and bleeding disturbances.

The progestogen-only pill (POP), minipill, is quite an effective second line contraceptive. Despite this, it is used relatively infrequently except during lactation. The main reason for this is that women on POP often have abnormal bleeding patterns, with an increased frequency of bleeding, lengthened cycles, breakthrough bleeding, spotting and prolonged bleeding. These menstrual disturbances are the most common quoted reason for discontinuation in up to 25% of users.

PIP: Although the progestogen-only minipill decreases side effects such as dizziness, nausea, headaches, and breast tenderness associated with combined oral contraceptives, this advantage is outweighed by disturbances of menstrual flow. 1/3 - 1/2 of minipill users experience prolonged menstruation, and up to 70% report breakthrough bleeding or spotting in 1 or more cycles. These menstruation disorders are the most frequently cited reason for method discontinuation. In some studies, under 50% of mini-pill users continued method use for 12 months. Morphometric studies of endometrial biopsies from progestogen-only pill users suggest that the endometrial response is variable and unpredictable, including irregular secretory endometrium and a lack of or suppressed proliferation. Other studies have found increases in the total and dilated veins at the endometrial-myometrial junction in minipill users. New strategies to improve cycle control would enhance acceptance of this excellent second line contraceptive method.

Increased risk from third-generation progestogens: fuzzy logic or fuzzy science?

PIP: The British Committee on Safety of Medicines' warning about the risk of increased incidence of venous thromboembolic disease with the use of oral contraceptives (OCs) containing the "third-generation" progestogens desogestrel or gestodene sparked international debate and controversy. This warning was based on unpublished results of studies which showed that the risk of venous thromboembolism doubled from about 16/100,000 in users of "second-generation" combinations to 28-29/100,000 in users of the newer agents (the background rate is a very similar 10-30/100,000 non-OC users). These studies failed to control for age, weight, and tobacco use, and the sampling error was further affected because the study patients were hospitalized. There may also be a prescribing bias whereby women who had initial problems with second-generation OCs switched to another method of contraception, and women who seemed predisposed to vascular disease and first-time users were given the newer preparations. Users of third-generation formulations also have a reduced risk of myocardial infarction (reflecting the fact that the newer formulations were developed to create a more favorable cardiovascular profile in users). No reliable studies to date have demonstrated an increased risk of thromboembolism in users of the new progestogens, and, if such a risk does exist, it is likely much less than has been reported. This question can only be properly addressed through further studies with proper controls.^ieng

Effects of a sequential regimen of mifepristone-medroxyprogesterone acetate on ovarian function, endometrial development and hormonal parameters.

The efficacy of a low dose of mifepristone, 5 mg/day for the first 15 days of the menstrual cycle, followed by medroxy-progesterone acetate (MPA), 10 mg/day for the next 13 days, for inhibiting ovulation was assessed in ten volunteers who were treated for three successive cycles. Hormonal determinations in blood and urine samples, ovarian ultrasonography and an endometrial biopsy taken on day 21-24 of the third treatment cycle were used to monitor the cycles. Ovulation was confirmed in 11 of the 30 treated cycles and, in these 11, the LH peak and follicular rupture occurred during MPA treatment periods. Out of 19 anovulatory cycles, 16 had no increase in progesterone levels and another 3 developed a luteinized unruptured follicle. Progestin administration induced secretory changes in the endometrium, but irregular or delayed development was found. Regular withdrawal bleeding occurred in all subjects. These data indicate that the sequential regimen can suppress ovulation while maintaining regular bleeding but increased efficacy is needed for phase II clinical trials.

PIP: The efficacy of a low dose of mifepristone, 5 mg/day for the first 15 days of the menstrual cycle, followed by medroxyprogesterone acetate (MPA), 10 mg/day for the next 13 days, for inhibiting ovulation was assessed in 10 Chilean volunteers who were treated for 3 successive cycles. They were healthy, surgically sterilized women with a mean age of 36.6 years and mean weight of 58.6 kg. Hormonal determinations in blood and urine samples, ovarian ultrasonography and an endometrial biopsy taken on days 21-24 of the third treatment cycle were used to monitor the cycles. Treatment inhibited ovulation during the 3 treatment cycles in 5 women. The regimen was partially effective in 3 women and totally ineffective in another 2 women. Ovulation was confirmed in 11 of the 30 treated cycles, and, in these 11, the luteinizing (LH) peak and follicular rupture occurred during MPA treatment periods. Out of 19 anovulatory cycles, 16 had no increase in progesterone levels and another 3 developed a luteinized unruptured follicle. Among the anovulatory cycles, 3 cycles presented a biphasic hormonal profile. In these 3 cycles the luteal phase progesterone level were much lower than in baseline cycles and they were associated with unruptured follicles. The other 16 cycles had a monophasic hormonal profile with no increase in progesterone levels in spite of a delayed rise in LH level. Progestin administration induced secretory changes in the endometrium, but irregular or delayed development was found. Only 9 post-treatment cycles were followed and 5 of these were ovulatory, 1 of them without a detectable LH midcycle peak. Regular withdrawal bleeding occurred in all subjects. These data indicate that the sequential regimen can suppress ovulation while maintaining regular bleeding, but increased efficacy is needed for phase II clinical trials.

Smoking and cycle control among oral contraceptive users.

OBJECTIVE: Because cigarette smoking has a variety of antiestrogenic actions, we investigated the possibility that smoking may adversely affect spotting and bleeding among women using oral contraceptives. STUDY DESIGN: Three open-label, randomized clinical trials involving 16,506 cycles among 2956 oral contraceptive users were performed. RESULTS: Smokers reported a consistently higher frequency of spotting or bleeding than did nonsmokers. After recency and consistency of oral contraceptive use and progestin component were controlled for, smokers were, on average, 47% more likely to have spotting or bleeding than nonsmokers were over six cycles of oral contraceptive use, with higher levels of smoking associated with a greater frequency of spotting or bleeding. By the sixth cycle women who smoked > or = 16 cigarettes per day were almost three times more likely to have spotting or bleeding than were nonsmokers. CONCLUSION: Cigarette smoking adversely affects cycle control among oral contraceptive users, possibly by increasing estrogen catabolism. Although these findings also raise the possibility that oral contraceptive efficacy may also be impaired in smokers, an immediate concern is that oral contraceptive users who have spotting and bleeding are more likely to discontinue their use, placing them at risk of unintended pregnancy.

PIP: Three open-label, randomized clinical trials involving 16,506 cycles among 2956 oral contraceptive (OC) users were conducted in order to investigate whether smoking may adversely affect spotting and bleeding among women using OCs. Included were 1480 women and 8292 cycles of experience with gestodene preparations, 1384 women and 7691 cycles with OCs containing desogestrel, and 92 women and 523 cycles with the norgestimate preparation. Among smokers, the proportion who reported spotting or bleeding varied from 59% in the first cycle to 14% in the sixth cycle, averaging 23%. In contrast, the proportion of nonsmokers who reported bleeding ranged from 52% in the first cycle to 9% in the sixth cycle, averaging 19% for all six cycles. Although the proportion of smokers and nonsmokers with spotting or bleeding decreased significantly with time (p = .000), nonsmokers had a slight but consistent increase in spotting or bleeding for each cycle after the first, whereas spotting or bleeding in smokers decreased during the first two cycles and remained constant thereafter. After recency and consistency of OC use and progestin components were controlled for, smokers were 47% more likely to have spotting or bleeding than nonsmokers over six cycles of OC use with higher levels of smoking associated with a greater frequency of spotting or bleeding. By the sixth cycle women who smoked or= 16 cigarettes/day were almost three times more likely to have spotting or bleeding than nonsmokers. For women with any smoking, the relative risk (RR) was elevated for every cycle, with the difference being significant in five of six cycles. The RR for any smoking varied from 1.30 in the first cycle (an increase in risk of 30% compared with nonsmokers) to 1.86 (86% increase) by cycle six. Cigarette smoking adversely affects cycle control among OC users, possibly by increasing estrogen catabolism. Women who have spotting or bleeding are more likely to discontinue OC use, which places them at increased risk of unintended pregnancy.

Oral contraceptives in women with systemic lupus erythematosus.

Oral contraceptives (OCs) are generally not prescribed for women with SLE due to the widely-held view that they may activate disease. This practice is based on the greater incidence of SLE in women than in men, biologic abnormalities od estrogen metabolism, murine models of lupus, several anecdotes of patients having disease flares while receiving exogenous hormones, and a single retrospective study in patients with pre-existing renal disease. In contrast, recent retrospective patient surveys, albeit limited by the absence of formal analyses of disease activity, suggest that the rate of flare is not significantly increased in patients taking OCs. The preexisting data are insufficient to warrant the dismissal of a potentially important birth control option in a disease which predominantly affects women in their reproductive years and whose fertility is not altered by the disease. In counseling patients regarding lupus and pregnancy, there are clinical predictors of pregnancy outcome; patients in remission tend to do well. The same principles may be true regarding advice on the use of OCs; patients with inactive or stable/moderate disease and at low risk for thrombosis may benefit without a change in lupus activity. OCs with the lowest estrogen content should be used and consideration given to progestin only pills in situations where there is some risk of increased clotting. Large prospective double-blind placebo-controlled studies inclusive of all ethnic groups should provide the basis for more definitive recommendations.

Safety implications of transferring the oral contraceptive from prescription-only to over-the-counter status.

The idea of making oral contraceptives available without prescription has a long history, and has been recently revived in the US and the UK. High dose oral contraceptives have generally been replaced by low dose formulations and, subsequently, most cardiovascular risks have been reduced and a protection against ovarian and uterine cancers has been consistently demonstrated. Oral contraceptive compliance, however, continues to be a problem, but there is no reason to assume that wise practice would be any more or less if oral contraceptives were available over-the-counter (OTC). Some countries have introduced alternatives to prescription-only oral contraceptives, whereby nurses, midwives, social workers and/or pharmacists are incorporated into the distribution process. This article concludes that the balance of risks and benefits is in favour of OTC access for oral contraceptives.

PIP: US and UK Family planning providers have revived the debate of whether or not to make oral contraceptives (OCs) available over-the-counter. Decreased hormone doses in OCs have reduced most cardiovascular risk and protect against ovarian and uterine cancers. An advantage of progestogen-only pills is that they can be used safely by smokers and breast-feeding women. In the US, an OC prescription provides many women from minority groups and single mothers who receive OCs from family planning programs with their only access to health care. Since the cost of an OC prescription is so high, women receiving subsidized OCs tend not to switch to other methods. User compliance remains a problem even with prescription. One study found a failure rate of up to 11% for OC users younger than 18. Poor user compliance would as likely be a problem if OCs were available over-the-counter. Two public health specialists with the University of California, Berkeley, echo the recommendation that emergency contraception (2 high-dose OC pills initially followed by 2 more pills 12 hours later) should be available without prescription, which can be managed separately from the routine use of OCs. Pharmacists could be trained to explain OCs, discuss possible contraindications, and provide reference materials to potential OC users. Nurses, midwives, or social workers could be responsible for OC prescription. In the UK, nurses can already prescribe drugs more complicated and potentially dangerous than OCs. Making OCs available over-the-counter could improve women's health, make OCs more easily available, free some professional and financial resources that might then focus on other areas (e.g., diagnosis and treatment of sexually transmitted diseases in the young), and boost confidence of OC users. If OCs are on the shelf next to aspirin and antihistamines, they will be perceived, as they well should be, as a well-tolerated, easy-to-use medicine.

The progestin-only pills and the levonorgestrel-releasing IUD: two progestin-only contraceptives.

PIP: The author reviewed available study findings in the literature to evaluate the merits, disadvantages, and unsettled issues of progestin-only contraceptive pills (POPs) and the newly developed levonorgestrel-releasing (LNG) IUD. The mechanism of POP action and the brands marketed are first considered, followed by discussion of safety considerations, efficacy and compliance, side effects, clinical acceptability, continuation patterns, the advantages of using POPs, current use, and issues to be addressed. The author then discusses the LNG IUD in sections on its mode of action, studies used for evaluation, safety considerations, clinical performance, noncontraceptive effects, and use perspectives and issues to be addressed. The benefits of POPs outweigh their risks, especially for lactating and/or postpartum women, with available information suggesting that POPs are at least as safe as, if not safer than, combined oral contraceptives (COCs). The incidence of nonmenstrual systemic side effects in POP users, such as headaches, nausea, vomiting, and dizziness, tend to be milder, and their incidence may have been overreported in previous studies. However, for POPs to be as effective as COCs, strict compliance is required. Moreover, compared to COCs, POPs are more likely to cause menstrual disturbances in the first few months of use.^ieng

Desogestrel, norgestimate, and gestodene: the newer progestins.

OBJECTIVE: To review and compare the newer progestins desogestrel, norgestimate, and gestodene with regard to chemistry, pharmacokinetics, efficacy, and tolerability. DATA SOURCES: Primary literature on desogestrel, norgestimate, and gestodene was identified from a comprehensive MEDLINE English-literature search from 1984 through 1994, with additional studies selected by review of the references. Indexing terms included progestins, desogestrel, gestodene, norgestimate, levonorgestrel, and norgestrel. STUDY SELECTION: Only human clinical and pharmacokinetic trials performed in Europe, Canada, and the US were included. DATA EXTRACTION: All available data from human studies were reviewed; both comparative and noncomparative studies were included because of the paucity of direct comparative information available. DATA SYNTHESIS: The newer progestins were designed to minimize the adverse effects (e.g., acne, hirsuitism, nausea, carbohydrate and lipid metabolism changes) observed with older oral contraceptives (OCs) while maintaining efficacy and good menstrual cycle control. Desogestrel, norgestimate, and gestodene have minimal amounts of androgenicity and antiestrogenic potential. All of these agents are pharmacokinetically similar to older agents: they are highly bioavailable when administered orally, hepatically metabolized, and obtain steady-state concentrations after 8-10 days of continuous administration. The newer agents have similar Pearl Indexes and slightly better cycle control. Furthermore, the new progestins appear to cause fewer adverse effects, such as acne and hirsuitism, and similar rates of weight gain, blood pressure changes, and lipid and carbohydrate metabolism changes. CONCLUSIONS: Desogestrel, norgestimate, and gestodene appear to offer clinical advantages because of their decreased androgenicity. Women whose cycles are currently well controlled with other OCs should not be switched to a newer progestin. However, any of the combination OC products that contain these progestins may be prescribed for women intolerant of older agents or to first-time users of OCs. The newer progestins appear to be efficacious and offer similar cycle control, improved safety and tolerability profiles, and comparable price with the older agents.

PIP: The objective was to review and compare the chemistry, pharmacokinetics, efficacy, and tolerability of the newer progestins desogestrel, norgestimate, and gestodene. Data sources were primary literature on desogestrel, norgestimate, and gestodene identified from a comprehensive MEDLINE English-literature search from 1984 through 1994, with additional studies selected by review of the references. Only human clinical and pharmacokinetic trials performed in Europe, Canada, and the US were included. All available data from human studies were reviewed; both comparative and noncomparative studies were included. The newer progestins were designed to minimize the adverse effects (e.g., acne, hirsutism, nausea, blood pressure elevation, carbohydrate and lipid metabolism changes, hemostatic changes) observed with older oral contraceptives (OCs) while maintaining efficacy and good menstrual cycle control. Desogestrel, norgestimate, and gestodene have minimal amounts of androgenicity and antiestrogenic potential. All of these agents are highly bioavailable when administered orally, hepatically metabolized, and obtain steady-state concentrations after 8-10 days of continuous administration. These agents have similar Pearl Indexes and slightly better cycle control than older agents. They appear to cause fewer adverse effects such as acne and hirsutism, and similar rates of weight gain, blood pressure changes, and lipid and carbohydrate metabolism changes. Desogestrel, norgestimate, and gestodene appear to offer clinical advantages because of their decreased androgenicity; however, available data are based on relatively small studies of short duration. Women whose cycles are currently well controlled with other OCs should not be switched to a newer progestin. However, any of the combination OC products that contain these progestins may be prescribed for women intolerant of older agents or to first-time users of OCs because of their apparent efficacy, improved cycle control, superior safety, tolerability, and comparable prices. Patients who have significant acne or hirsutism with older products and diabetic women may experience clinically significant benefit with the newer agents.

[Oral contraceptives: APF takes a position]. / Contraceptivos orais: APF toma posicao.

PIP: The Portuguese Association of Family Planning has learned about a study of the World Health Organization that associated certain types of combined oral contraceptives (OCs) with an increased risk of cardiovascular diseases, notably deep venous thrombosis. The position of the International Medical Advisory Panel (IMAP) of the IPPF, however, was that such conclusions were not definitive and new studies should be conducted to confirm or refute these conclusions. Furthermore, since the risk is rare, those using OCs should have regular medical examinations. For the majority of OC users the benefits outweigh the risks. The author of one of the two studies that hinted at the cardiovascular risks of third-generation progestagens stated that the British authorities incorrectly interpreted the data, which were preliminary. In fact, these data suggest that the new generation of OCs protects against cardiac attack and associated mortality. Even the WHO took the position that these results should be confirmed by independent studies. The polemic mounted when the British authorities issued an alert about the possible negative effects of seven types of OCs containing progestagens which putatively doubled the risk of venous thrombosis. This was based on the findings of three studies: two of them were incomplete, one was done at the initiative of the WHO, one was carried out in Europe, and the third one was done in the UK. At the meeting of the Committee of Pharmaceutical Specialties of the European Agency of Medicaments in October 1995 in London the position was taken that it is not appropriate to withdraw such OCs; investigators should analyze these data in depth and perform new studies; the three companies that manufacture such OCs should submit more information by the end of 1995; and physicians should take into account thromboembolic risk factors when prescribing such OCs.^ieng

POPs less widely used.

Progestin-only pills (POPs) are less widely used and available than combined pills. For example, the U.S. Agency for International Development (USAID) shipped only 3 million packets of POPs worldwide in 1994, compared with 62 million packets of combined pills, according to Mark Rilling, program analyst with USAID's Office of Population. While USAID considers POPs to be an acceptable contraceptive option for some women and intends to continue providing them, the worldwide market for them is small, Rilling says. The London-based International Planned Parenthood Federation (IPPF) reports a similar trend. IPPF shipped 16 times more combined pills than POPs during 1994, says Dr. Carlos Huezo, the organization's medical director. New efforts to clarify the role of progestin-only pills may make them more acceptable. For example, new studies have provided additional evidence that POPs do not harm breastfed infants whose mothers use them. A new label that reflects these findings, and clarifies other distinctions from combined pills, is being developed for POPs by the U.S. Food and Drug Administration, based on a draft developed by FHI. The pills also are being more actively promoted among some family planning organizations, and may prove useful for community-based distribution.

Metabolic parameter, bleeding, and weight changes in U.S. women using progestin only contraceptives.

Our objective was to determine the effect of progestin-only contraceptives on metabolic parameters, bleeding patterns, and weight changes during the first year of use. Seventy-one women (> 95% Caucasian), who were advised regarding contraception alternatives, self-selected levonorgestrel implants (n = 44), depo-medroxyprogesterone acetate (n = 22), or oral norethindrone (n = 5). One year later, 11 levonorgestrel implant and five depomedroxyprogesterone acetate patients were randomly selected to compare (pre- and post-progestin use) levels of cholesterol, triglycerides, low density lipoprotein (LDL), high density lipoprotein (HDL), very low density lipoprotein (VLDL), apolipoproteins A-1 and B-100, bilirubin, and sex hormone binding globulin. Monthly bleeding and spotting records were kept in each group. Body weights were also monitored in each group. No statistically significant differences in metabolic parameters were found between pre- and post-progestin use in the levonorgestrel implant and depo-medroxyprogesterone acetate groups. Continued bleeding patterns were more prominent in the levonorgestrel implant and oral norethindrone groups than in patients receiving depo-medroxyprogesterone acetate. No significant weight gain was detected in any group. No changes in metabolic parameters or weight were noted over the one year of use of levonorgestrel implants or depo-medroxyprogesterone acetate. Depo-medroxyprogesterone acetate had the highest incidence of amenorrhea.

PIP: During March 1991-April 1992, health workers recruited 71 women aged 16-43 (98% Caucasian) attending the University of Utah Obstetrics and Gynecology Clinic for a clinical study examining metabolic parameters, menstruation disorders, and changes in weight after 12 months of use of a progestin-only contraceptive. The progestin-only contraceptives (number of women using each) included Norplant contraceptive implants (44), Depo-Provera (22), and a mini-pill (norethindrone) (5). Metabolic parameters were total cholesterol, triglycerides, high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL), sex hormone binding globulin, apolipoprotein A-1, apolipoprotein B-100, and total and direct bilirubin. The only groups investigated for metabolic parameters were Norplant users and Depo-Provera users. Metabolic parameters did not change significantly after progestin use. No group experienced significant weight gain. However, one woman gained more than 60 pounds in the Norplant group and one woman gained more than 40 pounds in the Depo-Provera group. Depo-Provera users had significantly fewer total days of blood loss than Norplant users during months 5-12 (p 0.02) and mini-pill users during months 6-10 (p 0.04). Mini-pill users and Norplant users had similar bleeding patterns, except during months 11-12, when Norplant users had more bleeding than mini-pill users (e.g., month 12, 9 vs. 0 days). The total days of blood loss was 8.7 for Norplant users, 3.5 for Depo-Provera users, and 10.2 for mini-pill users. Less than 10% of Norplant users and mini-pill users experienced amenorrhea, while amenorrhea increased after 120 days in Depo-Provera users (p 0.001). After 1 year, the Norplant and mini-pill groups had more excessive prolonged (10 days) bleeding than the Depo-Provera group (29% and 50%, respectively, vs. 11%).

Is time-interval between mini-pill ingestion and breastfeeding essential?

A study was conducted on four alternate days over an eight-day period in a group of 12 healthy, 20-35 year old exclusively breast feeding women who were interested in weaning their infants. On each study day the women ingested 150 micrograms levonorgestrel. Maternal blood and milk samples were collected at 2, 4, 6, and 8 hr intervals after LNG ingestion on the 1st, 3rd, 5th, and 8th day. A time-dependent decrease in maternal serum and increase in breast milk levels of LNG were observed. Maintaining a time interval between mini-pill intake and breastfeeding results in higher levels of LNG in breast milk, thereby exposing the infant to a bolus of LNG in a "single-delayed" feed.

PIP: In India over an 8-day period, 12 healthy, lactating women aged 20-35 (body mass index, 21-23) who took a mini-pill with 150 mcg levonorgestrel (LNG) (Microlut) daily provided blood and breast milk samples over increasing time intervals between LNG ingestion and sample-taking. The researchers wanted to determine whether a time interval between maternal LNG ingestion and breast feeding delivers less LNG to the breast milk and the infant. Regardless of the time interval, about 10% of the LNG in the blood was transferred to the breast milk. The observed LNG levels in the breast milk were higher than the expected LNG levels, except at a 2-hour interval. Maternal sera LNG levels decreased as the time intervals increased (1198 pg/ml at 2 hours, 995 at 4 hours, 476 at 6 hours, and 340 at 8 hours), while the LNG levels in breast milk increased (100, 180, 250, and 330 pg/ml, respectively). The researchers explained the decrease in maternal levels by metabolism of LNG by the mother's liver, but they could not account for the increase of LNG in the breast milk. These findings show that maintaining a time interval between maternal ingestion of LNG and breast feeding increases LNG in breast milk, exposing the infant to a bolus of LNG in one delayed feed.