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

Media scan. Hormone replacement therapy and breast cancer risk. Commentary.

PIP: A study published in the Journal of the American Medical Association (JAMA) found that combined hormone replacement therapy (HRT) is associated with a higher risk of acquiring breast cancer than is estrogen replacement therapy (ERT). A 20% increased relative risk (RR) with ERT and a 40% increased relative risk with combined HRT among current and recent users versus never-users were reported. This paper presents the comments of Dr. Joseph W. Goldzieher, associate editor of The Contraception Report, on the JAMA study and evidence on combined HRT and breast cancer. Goldzieher notes that in the JAMA study the 95% confidence limits of the RR of ERT (1.0-1.4) and combined HRT (1.1-1.8) overlap completely, indicating no important difference. Other similar studies also have confidence limits that overlap completely, subsequently demonstrating its insignificance. Hence, it is clear that the overall RR of breast cancer related to ERT or combined HRT ranges from small to nil.^ieng

Single-monthly-dose vitamin D supplementation in elderly patients.

OBJECTIVE: To determine the serum levels of calcidiol and calcitriol in 2 men and in 21 postmenopausal, primarily elderly women receiving hormone replacement therapy, orally administered calcium citrate, and an additional supplement of 50,000 IU of vitamin D (1.25 mg of cholecalciferol) once monthly for various periods. METHODS: We determined plasma calcidiol and calcitriol levels at various times, ranging from -1 to +60 days after intake of a single dose of 1.25 mg of vitamin D in 10 initial or short-term users (1 to 6 months) and in 13 women who had been using this monthly regimen for several years. The primary concerns were the safety and adequacy of the blood levels achieved with a regimen that encouraged compliance. RESULTS: In long-term users of monthly vitamin D regimens, calcidiol levels were usually slightly in excess of the upper limit of normal (that is, >52 ng/mL [>130 nmol/L]) at all times throughout the month; in contrast, calcitriol levels exceeded the normal range (8 to 52 pg/mL [19 to 125 pmol/L]) only once in 18 samplings. In short-term users, calcidiol levels exceeded the normal range only once shortly after intake, and no calcitriol level exceeded the normal range. CONCLUSION: Once-a-month dosage of 50,000 IU (1.25 mg) of vitamin D in elderly women receiving hormone replacement therapy plus supplemental calcium and uncontrolled generic multivitamin intake yields calcitriol levels within the normal range, even after years of use of this regimen. Calcidiol levels exceeded the normal range at all times in long-term users but only once in short-term users. Calcidiol concentrations, however, were found to be far below levels (>150 ng/mL [>375 nmol/L]) that might produce hypercalciuria or hypercalcemia.

Natural family planning: suitability of the CUE method for defining the time of ovulation.

The purpose of this study was to compare the CUE method for family planning with the Ovulation Detection Method for defining the fertile phase of the menstrual cycle. We evaluated 42 cycles from 10 women in Monterrey, Mexico, who were monitored by basal body temperatures, urinary LH, pelvic ultrasound, and the CUE monitor. The fertile phase of the cycle was adequately defined in all cycles using the CUE method, and in 35 cycles (83.3%) by the Ovulation Method. Using our protocol, the period of recommended abstinence with the CUE method is 9 days and with the Ovulation Method 11 days. The CUE method accurately defines the fertile phase of the menstrual cycle, thus improving the predictability of ovulation for women who use natural methods of birth control.

PIP: To evaluate the potential utility of the CUE method in natural family planning (NFP), this method was compared with a standard NFP technique, the Ovulation Method, in 39 cycles of 10 women from Monterrey, Mexico. All women had more than 2 years' experience with the Ovulation Method. In the CUE method, ovulation prediction is based on a peak in salivary electrical resistance and its confirmation by a rise in vaginal resistance as monitored by a hand-held electronic instrument attached to a specially designed sensor. The CUE method defined the fertile period of all 39 cycles adequately, while the Ovulation Method resulted in incorrect definition of the fertile phase in 4 (10%) of 39 cycles. The salivary peak predicted ovulation an average of 8 days in advance of its occurrence and the increase in vaginal readings in the periovulatory period was seen within 1 day of follicle collapse in all subjects. The duration of abstinence required by the CUE method would have averaged 9.0 +or- 1.5 days (range, 6-13 days). In contrast, the average duration of abstinence associated with the Ovulation Method was 11.0 +or- 2.9 days (range, 6-16 days). 82% of cycles monitored by the CUE method compared with only 53% of those monitored by the Ovulation Method would have required a period of abstinence of 10 days or less. The simplicity and objectivity of the CUE method, combined with its requirement for fewer days of abstinence, offer the potential for improving NFP compliance and continuation.

Oral contraceptive side effects: where's the beef?

The initial report is reviewed, as well as the results of subsequent investigations, and the current status of the following side effects attributed to the use of oral contraceptives: subjective symptoms such as mood and libido changes, also headache; melanoma; gallbladder disease; liver tumors, sickle cell disease exacerbation; teratogenesis; "post-Pill" amenorrhea; atherogenesis; and diminished carbohydrate tolerance. In many instances a cause-and-effect relationship appears to be incorrect or highly improbable. In other instances the side effects are clinically insignificant or so rare as to be of minimal importance. Yet they continue to be listed by various authorities as validated side effects or relative contraindications to oral contraceptive use. This, in turn, limits the access of many women to a highly effective form of contraception. This re-examination of past history is intended to modernize our concepts of the safety of this modality.

PIP: The authors review the evidence regarding a number of important adverse reactions attributed to oral contraceptive (OC) use, identify the original claim and subsequent documentation, and form a current opinion on the validity of existing claims. This examination was conducted in hopes of modernizing concepts on the safety of OC use. Mood and libido changes, as well as headache; melanoma; gallbladder disease; liver tumors; the exacerbation of sickle cell disease; teratogenesis; "post-Pill" amenorrhea; atherogenesis; and diminished carbohydrate tolerance have been attributed as side effects related to the use of OCs. A cause-and-effect relationship, however, in many instances appears to be false or highly unlikely. In other instances, the side effects are clinically insignificant or so rare as to be of minimal importance. These side effects nonetheless continue to be listed by various authorities as valid or relative contraindications to OC use. Such indications only limit the access of many women to this highly effective form of contraception.

When is it safe to switch from oral contraceptives to hormonal replacement therapy?

Women may continue to use oral contraceptives (OCs) into their 40's and 50's, but to date no method has been evaluated to ascertain their ovarian status, i.e., whether fertility and estrogen production have diminished sufficiently so they could be safely switched to hormonal replacement therapy. A group of 12 postmenopausal women who had been, for long periods of time, on a regimen of 3 back-to-back packages (i.e., 63 days on, 7 days off) of low-dose oral contraceptives have been studied. Secondly, a group of 9 perimenopausal women aged 36 to 47 were examined in the same manner. The third group consisted of early reproductive age women (arbitrarily divided into subsets aged 17-25 and 26-35 using low-dose OCs in the customary regimen) as normal controls. Blood samples were obtained on the last day of a pill cycle and at 7 days off the pill. In some menopausal women, blood samples were obtained at both 7 and 14 days off OCs. Serum was assayed by RIA for estradiol, FSH and LH. As expected in the young reproductive age women, estradiol levels increase at one week off the pill, together with a rebound in FSH and LH to follicular phase levels. In the perimenopausal group, there was a sharp distinction based on age. The women over 40 showed a more marked rise in FSH while those aged 36-40 showed a distinctly lesser response. Estradiol levels were variable, but tended to show some age grouping. Little diagnostic separation was observed for LH. In postmenopausal women, FSH levels were not always elevated at one week post-pill, and even in a second trial with sampling at one and two weeks off the OC, not all postmenopausal women showed a "menopausal" increase in FSH. The more uniform feature was that estradiol levels never increased above basal values. The study found that serum estradiol levels increase after a week off the pill in controls, but are unchanged at one and two weeks in the menopausal group. FSH levels rebound normally in reproductive age women and usually, but not always, increase substantially in postmenopausal women. After two weeks off OCs, an increased FSH and/or no change in basal estradiol levels is strong evidence that it is now safe (contraceptively speaking) to switch from OCs to standard hormone replacement regimens.

PIP: Women may continue to use oral contraceptives (OC) into their 40s and 50s. No method has, however, been evaluated to determine whether fertility and estrogen production have diminished enough so that they could safely switch to hormonal replacement therapy. The authors studied a group of 12 postmenopausal women who had been, for long periods of time, on a regimen of three back-to-back packages of low-dose OCs, and a group of nine perimenopausal women aged 36-47 years. Women aged 17-25 and 26-35 years using low-dose OCs in the customary regimen were used as normal controls. Blood samples were taken on the last day of a pill cycle and at 7 days off the pill. In some menopausal women, blood samples were obtained at both 7 and 14 days off OCs. Serum was assayed by RIA for estradiol, FSH, and LH. The study found that serum estradiol levels increase after a week off the pill in controls, but are unchanged at one and two weeks in the menopausal group. FSH levels rebound normally in reproductive-age women and usually, but not always, increase substantially in postmenopausal women. After two weeks off OCs, an increased FSH and/or no change in basal estradiol levels is strong evidence that it is now safe to switch from OCs to standard hormone replacement regimens.

Are low-dose oral contraceptives safer and better?

It is widely believed that the use of low-dose oral contraceptives decreases thrombotic risks, compared with higher-dose oral contraceptives. Two recent epidemiologic studies infer a lower risk with 30 to 35 mcg than with 50 mcg estrogen oral contraceptives. However, as with prior studies from which similar conclusions were drawn, these studies have major flaws, the worst being that all 50 mcg oral contraceptives are lumped together, whereas 50 mcg mestranol oral contraceptives are actually bioequivalent to 35 mcg ethinyl estradiol oral contraceptives, thus confounding all such studies. Moreover, while rare thrombotic events have received inordinate attention, the major protective effect against endometrial and ovarian cancer that has been shown in older studies among users of oral contraceptives containing > or = 50 mcg ethinyl estradiol or > or = 80 mcg mestranol are almost totally ignored. The theoretical benefits of using lower-dose oral contraceptives have not been demonstrated, whereas the protection against these types of reproductive cancer have been shown repeatedly with high-dose oral contraceptives but not, to date, with lower-dose oral contraceptives. Such protection may be diminished by lowering the oral contraceptive dosage. Should every woman of reproductive age use high-dose oral contraceptives for 2 years? Are we throwing out the baby with the bath water?

Sexual behavior, contraception and the risk of contracting HIV.

Recently, concern has been expressed on a possible association between the use of oral contraceptive pills (OCs) and an increased risk of contracting the HIV infection. As a consequence it has been postulated that a low prevalence of condom use due to widespread utilization of oral contraceptive pills would result in an acceleration of the spread of AIDS. The International Committee for Research in Reproduction (ICRR) a group of eleven experts in the field of gynecology, endocrinology and contraception, wishes to comment on the concerns raised about OC use and AIDS.

The history of steroidal contraceptive development: the estrogens.

PIP: Our understanding of estrogenic activity began in 1912, when Adler and Fellner in Vienna and Iscovesco in Paris obtained the first ovarian extracts and Haberlandt concluded that ovarian interstitial tissue inhibits ovulation during pregnancy, through the 1920s when Fellner produced sterility in rabbits and mice and Allen and Doisy isolated crystalline estrone. By 1930, Reiprich correctly assigned the antifertility action of the estrogens to pituitary inhibition. The testing of estrogenic materials for a variety of gynecological disorders continued in the 1930s, with researchers seemingly unaware of the earlier ovulation inhibition work. In 1936, Kurzrok predicted the prospects for hormonal sterilization in a paper that was largely ignored. Research continued on the use of estrogen to treat dysmenorrhea by inhibiting ovulation. At this point, contraception was not one of the many possible applications of this procedure under consideration. In 1945, Albright identified the potential of ovulation-inhibiting doses of estrogen as a contraceptive. His suggestion was also doomed to oblivion. Since none of the estrogens at that time were consistent in their ovulation-inhibiting effect, clinical trials would have been disastrous. In 1960, clinical trials with the 19-norprogestins took place in Mexico City. The oral contraceptives (OCs) were "contaminated" with mestranol, and research revealed that the ethinyl group has a special role in potentiating gonadotropin-suppressing action. This led to the development of "sequential" OCs, which in turn were replaced by monophasic formulations of lower dosage. By 1975, the dosages were reduced even further. Debates over proper dosage were confounded by the fact that mestranol must be demethylated to become biologically active. It is now known that plasma ethinyl estradiol levels are comparable from a single oral dose of 50 mcg mestranol and from 35 mcg ethinyl estradiol. Current research continues with the 11 beta-methoxy ethinyl estradiol, which is 10 times as potent as ethinyl estradiol and has some unusual metabolic features because it does not form oxidative metabolites.^ieng

Selected aspects of polycystic ovarian disease.

Although there is general agreement about the polycystic ovary as an anatomic entity, a classic description of an associated syndrome remains elusive. This lack of definition, however, has not impeded clinical investigation. This article focuses on the diagnosis, pathogenesis, hypotheses, and treatment of polycystic ovarian disease.

PIP: Ultrasonography provides physicians much information for the epidemiology and diagnosis of polycystic ovarian disease (PCOD)--a yet to be defined associated syndrome. For example, some physicians used it to reveal that 92% of women with hirsutism and regular menstrual cycles had PCOD. Considerable research exists on the link between insulin resistance. PCOD, and hyperandrogenism. Some results confirm the link while others do not. Abnormal gonadotropin dynamics are 1 of the most consistent characteristics of PCOD. Researchers have conceived various hypotheses for PCOD. A long-lived hypothesis is that elevated estrone levels which occur regularly in PCOD increase the sensitization of pituitary luteinizing hormone (LH) secretion and reduces secretion of follicle stimulating hormone to the gonadotropin releasing hormone stimulus. Another hypothesis is that progesterone deficiency facilitates PCOD. Various PCOD treatments exist. Physicians have treated PCOD with clomiphene citrate or nighttime small doses of corticosteroids for 20-30 years. Recent observations indicate the dexamethasone has a longer half life than prednisone or prednisolone. Since almost 50% of women with PCOD are obese, weight reduction has beneficial effects. Administration of progesterone is a possible treatment that is often ignored. Several clinical studies have included administration of bromocriptine to women with PCOD since a sizable number of such women have high levels of prolactin indicating a possible dopamine deficiency. The studies with bromocriptine have not showed much promise. Evidence suggests that administering oral contraceptives to premenopausal women with PCOD may reduce their risk of later developing ovarian cancer. Gonadotropin and gonadotropin releasing hormone therapies are possible means of inducing ovulation in PCOD women. Various physicians have used laparoscopy to apply different techniques to induce ovulation in women with PCOD. These techniques included sharp puncture, electric current, and laser vaporization or endocoagulation of the cysts.

Qualitative differences in estrogenic/antiestrogenic effects of clomiphene and zuclomiphene.

Depending upon the rat assay end point, the estrogenic or antiestrogenic activity of clomiphene (CC) or its isomer, zuclomiphene (Zu), varies considerably. For uterine/body weight ratio, Zu = estradiol greater than CC; for the estrogenic effect on uterine epithelium, Zu greater than estradiol = CC; higher CC doses were antiestrogenic. For endometrial stroma, Zu = estradiol much greater than CC. In the effect of estrogen receptor, low-dose CC = estradiol; high-dose CC was antiestrogenic. For Zu, both doses were about equal and highly antiestrogenic. Essentially the same was seen with progesterone receptor. For plasma LH suppression, Zu much greater than CC much greater than estradiol; but for plasma FSH, estradiol much greater than CC = Zu. The intrinsic estrogenicity of these compounds was made more apparent by the castrate status of the rats. This spectrum of activities may make it possible to select estrogenic or antiestrogenic activities for clinical purposes, depending upon the end-organ effect desired.

A short-term comparison of the effects of clomiphene citrate and conjugated equine estrogen in menopausal/castrate women.

An attempt was made to assess the potential role for an antiestrogen in the hormone replacement therapy of menopausal women who have a contraindication to estrogen use. Two groups of menopausal or castrate women were given either conjugated equine estrogen or clomiphene citrate in a cyclic manner for 25 days each month for 3 months. The effects were measured after 3 months and compared with baseline values. Clomiphene lowered FSH slightly, but had no effect on subjective vasomotor symptoms. With respect to bone metabolism, it produced no change in plasma parathyroid hormone level, whereas estrogen lowered it; both compound lowered serum calcium but clomiphene had less effect. The hydroxyproline/creatinine ratio was decreased more by clomiphene than by the estrogen. These findings are consistent with a beneficial effect on bone. Clomiphene had no adverse effects on clotting parameters and showed effects similar to those of conjugated equine estrogens on certain measures of lipid metabolism.

Thirty years of hormonal contraception: an historical perspective.

PIP: In 1919, a German scientist placed ovaries from pregnant rabbits under the skin of other female rabbits making them infertile. Later he injected extracts from pregnant cow corpora lutea into rabbits also making them infertile. In 1931, he states that hormonal sterilization is the ideal birth control. Yet, it was another 30 years before the first hormonal contraceptive was available. Estrogenic research led another German scientist to conclude that estrogen inhibits the pituitary gland. This resulted in more steroid research. Many obstacles existed, however; e.g. it took 4000 gallons of urine to extract a minute amount of androsterone and almost a ton of bull testicles and identify progesterone. Schering was able to synthesize it from ox bile, resulting in high-priced monopoly. Marker later synthesized it from a Mexican yam causing the price of progesterone to drop rapidly from dollars to cents per gram. Other scientists struggled to also develop estrogenic substances. By 1940, some physicians used estrogens to suppress ovulation. Despite this evidence, few physicians considered using them for contraceptive purposes because, like abortion, contraception was taboo. Instead political activists (e.g., Margaret Sanger) addressed synthetic hormones' potential for contraception. Their persistence encouraged some researchers to isolate compounds and to conduct clinical trials with oral contraceptives (OCs). The older OCs posed a deep vein thrombosis risk. The lower-dosed OCs no longer carry this risk. There has also been some evidence, albeit inconclusive, that OCs increase, the risk of breast cancer. 30 years later, physicians still are reluctant to address contraception. The Catholic Church and conservative economists are against contraceptives. The economists fear that smaller populations reduce markets. In many developing countries another obstacle to contraceptives is the cultural norm to produce many children.^ieng

Pharmacokinetics of ethinyl estradiol and mestranol.

Pharmacokinetally, a 50 micrograms oral dose of mestranol (which itself is inactive) is bioequivalent to a 35 micrograms dose of ethinyl estradiol. Physiologically, mestranol ranges from 50% to 100% of the activity of ethinyl estradiol, depending on the endpoint chosen. Compounds such as these, which are metabolized with a first-pass effect and are enterohepatically recirculated, demonstrate large interindividual and intraindividual variability in their pharmacokinetics. Thus a given dose of ethinyl estradiol in one person may produce an effect equivalent to a substantially larger (or smaller) dose in another person. This wide variability confounds efforts to establish tight dose-response relationships, a point rarely considered in clinical or epidemiologic studies of these compounds. The circulating levels of ethinyl estradiol sulfates may be higher than those of free ethinyl estradiol itself. It has been thought that these sulfates represent a "reservoir" of ethinyl estradiol. Our studies show that this idea is untenable because the half-life of the sulfates is not long enough for such an effect. Differences in the pharmacokinetics of ethinyl estradiol and mestranol have been observed in studies of various populations. The reality of these group differences is affirmed by analyses of urinary metabolite patterns.

Management of menopause when estrogen cannot be used.

Estrogen deficiency, whether surgically induced or as a consequence of natural ovarian failure, has destructive effects on many organ systems. With current levels of life expectancy, untreated women may expect to spend a third of their lifetime in this state. Appropriate estrogen replacement therapy (ERT) can avert (if started promptly) or ameliorate these devastating consequences, some of which (osteoporotic fractures, increased cardiovascular morbidity) can be lethal. Nevertheless, from 10 to 20% of postmenopausal women may have significant contraindications to ERT. Treatment of symptoms and improving the quality of life is imperative, yet many physicians abjure intervention, for reasons which are not entirely clear. Recent studies of conventional intervention with sedatives or tranquilisers show results equivalent to placebo therapy. On the other hand, specific agents with demonstrated effectiveness are available for management of the major estrogen-deficiency effects, although none of them are truly adequate replacement for the effect of estrogen itself.

Selected aspects of the pharmacokinetics and metabolism of ethinyl estrogens and their clinical implications.

Careful studies in an adequate sample of subjects show a very marked degree of variability in the pharmacokinetics of ethinyl estradiol--specifically, in parameters such as area under the curve, half-life, and time to peak. This variability is seen in differences between different populations, as well as from one individual to another. These studies also show variability in area under the curve and other parameters in the same person from time to time. Such differences may equal or exceed the differences between low dose (35 micrograms) and high-dose (50 micrograms) formulations. The levels of plasma ethinyl estradiol produced by a 50 micrograms dose of mestranol are similar to those from 35 micrograms of ethinyl estradiol. Thus a high-dose pill may be no higher than a low-dose pill if the nature of the estrogen is not kept in mind. Qualitative differences in the oxidative metabolites of estrogens may be of significance with respect to oncogenic potential.

PIP: The variability in the pharmacokinetics of ethinyl estradiol (EE) is pronounced, especially regarding such parameters as area under the curve, half-life, and time to peak. This variability shows up in different populations, different individuals, or in the same individual, and can even exceed the differences between low dose (35 mcg) and high- dose (50 mcg) formulations. 50 mcg of mestranol and 35 mcg of ethinyl estradiol both produce similar plasma EE levels. Qualitative differences in the oxidative metabolites of estrogens may be of significance with respect to oncogenic potential. The pharmacokinetic differences of EE whether caused by dietary, ethnic, or other factors are not merely differences in gastric absorption or renal excretion. Studies on kinetics and bioavailability showed that after oral administration of EE 3-sulfate only about 20% appeared as free EE in the blood, while EE 17-sulfate produced about half this amount. Individual variation showed a large spread both for plasma total EE sulfate levels and free EE. The pharmacokinetics of three 1 mg norethindrone/35 mcg EE and three 1 mg norethindrone/50 mcg mestranol formulations were analyzed and the mean values, standard deviations, and highest and lowest individual plasma patterns of the 3 EE preparations were indistinguishable. The administration of 50 mcg of mestranol resulted in an average area under the curve EE of 963 +- 544, whereas the dose 35 mcg of EE produced an area under the curve of 1036 +- 483, thus 35 mcg of EE proved to be a stronger dose than 50 mcg of mestranol. Inter- and intraindividual variability was demonstrated in a study: 24 patients received 35 mcg EE formulations and 27 others received 50 mcg mestranol agents. 3 identical formulations by different manufacturers proved to be bioequivalent. Extreme values ranged from -79% to +134% of the mean of the 3 determinations per individual. Clinical implications of these findings are that plasma EE levels engendered by 35 mcg EE may be indistinguishable from those produced by 50 mcg in another person. 2 to 3 mcg of moxestrol (the 11 beta-methoxy derivative of EE) is an effective contraceptive, as it is 10 times as potent as EE. Exposure of certain cell clones to estradiol, EE, and stilbestrol causes formation in vitro to foci of transformed (neoplastic) cells. However, moxestrol did not produce such cell transformation and these oxidative metabolites increased with estradiol or EE but not with moxestrol. This does not prove the oncogenic role of estrogens in humans, but it offers a new approach in the development of safer estrogens.