Estrogens, progestins, and headache.

PIP: Migraine headaches appear to be linked to the menstrual cycle and the use of oral contraceptives (OCs). Migraine attacks occur during menses in 60% of women and appear to be related to the withdrawal of estrogen. The fluctuations in estrogen levels associated with migraine headaches produce biochemical changes in prostaglandin production, prolactin release, and opoid regulation. Treatment seeks to interrupt the pathophysiological sequence of menstrual-related migraine through the administration of nonsteroidal anti-inflammatory drugs, ergotamine, or, in refractory cases, hormonal agents. The frequency of migraine decreases with age, but tends either to regress or worsen during menopause. In some cases, estrogen replacement therapy for menopausal symptoms produces headache and it may be necessary to reduce the estrogen dose or change from conjugated estrogen to pure estradiol or estrone. The incidence and severity of migraines are also affected by OC use. OCs may trigger migraine episodes and exacerbate or alleviate pre-existing headache. This variable response seems to be a result of individual differences in intrinsic estrogen neuronal response. Although migraine itself may be a risk factor in stroke, there is no evidence that this risk is increased in migrainers who use OCs.^ieng

The effect of oral contraceptive use and pregnancy on the daily rhythm of cortisol and cortisone.

The effect of oral contraceptives and of pregnancy on the daily rhythm of cortisol, and its metabolite cortisone in plasma and saliva has been investigated. In both conditions the total plasma cortisol levels were raised to the same extent, the mean values in saliva in the oral contraceptive users being intermediate between those in pregnancy and in the controls, particularly in the morning. Salivary cortisone levels were more related to salivary cortisol than to total plasma cortisone which exhibited a rather flat daily rhythm. There was a shift in peak values for salivary cortisol and cortisone towards late morning: this may be due to a delay in the daily activation of the hypothalamic-pituitary-adrenal axis in these patients.

PIP: The daily rhythm of plasma free cortisol and its metabolite cortisone in pregnancy or during oral contraceptive (OC) use was investigated in 10 pregnant women, 11 users of low-dose OCs, and 12 nonpregnant controls who were not using OCs. Radioimmunoassay was performed in the analysis of citric-acid stimulated saliva samples collected from 5 AM to midnight at 1-2-hour intervals and plasma samples were obtained from 10 women. Both pregnancy and OC use were found to produce significantly elevated levels of salivary cortisol and cortisone as well as a delay in the peak time of each hormone. The plasma analyses revealed significant increases in cortisol concentrations in both pregnant women and OC users, but plasma concentrations of cortisone increased only in pregnant women. Peak concentrations of salivary and total plasma cortisol were significantly higher in the first half of pregnancy, while cortisone was significantly higher during the second half of pregnancy. The shift in the peak of cortisone and cortisol values was from about 7 AM in control to 8 AM during pregnancy, with OC users in an intermediate position. Unexpectedly, the values for free plasma cortisol were normal during the afternoon but raised in saliva. It is postulated that the observed shifts in the peak time of the daily rhythm of cortisol and cortisone during pregnancy and OC use reflect an estrogen-induced increased synthesis of corticosteroid-binding globulin. Of interest would be a 24-hour measurement of these two hormones in saliva, free plasma, and total plasma.

Interactions of oestrogens and hours of sleep on cortisol, FSH, LH, and prolactin in hypogonadal women.

The effects of conjugated oestrogens 0.625 mg and placebo on adrenal and pituitary hormones were compared in 10 postmenopausal women during their sleep by means of double blind prospective crossover study. On placebo, the women had nocturnal variations in LH, prolactin and cortisol concentrations. However, oestrogen administration selectively blunted LH and prolactin changes, but not the rise in cortisol.

PIP: A double-blind, crossover, prospective study was carried out in 10 postmenopausal women to assess the effects of conjugated estrogen therapy and placebos on adrenal and pituitary hormones during their sleep. Nocturnal hormones levels of FSH, LH, Prl and cortisol concentrations during sleep were measured in women on estrogen replacement therapy both with and without the exogenous estrogen administration. Firstly, the study shows that postmenopausal women maintain the predictable nocturnal variation in prolactin, LH, and cortisol during sleep similar to premenopausal women. Administration of .625 mg conjugated estrogen blunted prolactin and LH variability, inducing a pattern similar to that observed in prepubertal girls and some women with gonadal dysgenesis. The estrogen did not affect the rise in cortisol levels. There was no correlation between the stage of sleep and the various hormone levels observed. Compared to the placebo patients, those on estrogens had a significant increase in total REM sleep, a significant decrease in sleep latency.

Pharmacokinetics of oestrogens and progestogens.

There are large inter- and intra-individual variations in the serum concentrations of natural and synthetic sex steroids irrespective of the route of administration. Oral ingestion of steroids has a stronger effect on hepatic metabolism than parenteral administration, as the local concentration in liver sinusoids are 4-5 times higher during the first liver passage. Oestradiol and oestrone are interconvertible, dependent on the local concentrations in liver and target organs, and oestrone sulphate serves as a large reservoir. The oestrone/oestradiol ratio has no physiological significance, as oestrone is only a weak oestrogen. Oestrone is both a precursor and a metabolite of oestradiol. Oestriol is extensively conjugated after oral administration. Therefore, the oestriol serum levels are similar after oral intake of 10 mg and after vaginal application of 0.5 mg oestriol resulting in similar systemic effectiveness. Conjugated oestrogens can easily enter the hepatocytes but are hormonally active only after hydrolyzation into the parent steroids. Ethinylestradiol which exerts strong effects on hepatic metabolism and inhibits metabolizing enzymes, should not be used for hormone replacement therapy. Among the progestogens, the progesterone derivatives have less effects on liver metabolism than the norethisterone derivatives (13-methyl-gonanes and 13-ethyl-gonanes). The highly potent 13-ethyl-gonanes are effective at very low doses, because of a slow inactivation and elimination rate due to the ethinyl group.

Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy.

The concept of bioavailability is discussed with particular references to the sex steroids. Problems encountered in the measurement of bioavailability of these steroids and the various factors that may affect their bioavailability are briefly described. Information regarding the bioavailability of the estrogens and gestogens, some of which are prodrugs, used in oral contraception and hormone replacement therapy is summarized and the implications regarding the clinical use of these steroids are discussed.

PIP: This review examines the bioavailability of sex steroids used in oral contraceptives and hormone replacement therapy and the implications of the clinical use of these steroids. These steroids include the estrogens (estradiol, estrogen sulfates, ethinyl estradiol) and the gestogens (progesterone, norethisterone, levonorgestrel, desogestrel, gestodene, norgestimate, and medroxyprogesterone acetate). The naturally occurring sex steroids are estradiol, estrogen sulfates, and progesterone or their derivatives. The synthetic sex steroids are ethinyl estradiol, norethisterone, levonorgestrel, desogestrel, gestodene, norgestimate, and medroxyprogesterone acetate. Factors influencing bioavailability of these sex steroids revolve around drug formulation (dosage form, disintegration rate, and dissolution rate), drug characteristics (chemical properties and stability in the gastrointestinal tract), user's characteristics (gastrointestinal and hepatic functions), and possibly smoking, diet, and other drugs. A wide variation exists in the bioavailability values both within any study and between the different studies with the same steroid. Possible reasons for the variability include experimental error, a small number of subjects, the rate and extent of absorption of the compound, the compound's rate of metabolism and elimination (especially hepatic metabolism and elimination), differences in dose, and interaction between the estrogen and the gestogen. Some of the synthetic sex steroids are prodrugs.

Oral contraceptive-induced lupus erythematosus in a Japanese woman.

A case of oral contraceptive-induced lupus erythematosus (LE) was reported. Erythematous skin lesions were noticed on hypothenor sites of palms and acral sites of pedes. Abnormal laboratory findings included an elevated ESR, CRP and weakly positive anti-nuclear antibodies. Skin biopsy specimens from involved skin showed Clq deposits at the dermo-epidermal junction. LE-like symptoms were considered to be induced by oral contraceptives, because her symptoms disappeared after the oral contraceptives were discontinued.

PIP: A case is presented of a 37-year-old Japanese woman who presented to the hospital with arthralgia of the extremities and erythema of the hypothenar and thenar extremities. Also present were pain, swelling of the extremities, general malaise, and erythematous lesions. Abnormal laboratory findings included an elevated erythrocyte sedimentation rate, proteinuria, and weakly positive antinuclear antibodies. A biopsy from the erythematous lesion of the palm revealed mild inflammation of the lymphocytes around dermal small vessels. In addition, the lupus band test was positive in uninvolved skin sites. A month prior to the onset of symptoms, the patient had begun taking an oral contraceptive (OC) that contained 0.5 mg of etynodil acetate and 0.1 mg of mestranol. All symptoms disappeared within 2 weeks of discontinuation of OC use and the laboratory findings returned to normal. This is assumed to be a case of drug-induced lupus erythematosus. Estradiol has been demonstrated to play a significant role in the development of skin lesions in lupus erythematosus, and the estrogen in OCs may trigger a lupus episode. However, this is only the 4th case of OC-induced lupus reported from Japan.

Pharmacology of estrogens and estrogen-induced effects on nonreproductive organs and systems.

The classification of estrogens based on chemical structure and origin is presented. The metabolism of endogenous estrogens and the postulated mechanism of action of steroid hormones are reviewed. Specific effects of estrogen on bone, kidney and coagulation are also discussed.

PIP: This article reviews the effects of estrogens on protein production by the liver, lipid metabolism, bone maturation and structure, and mineral metabolism. Also presented is a comparison of natural steroidal estrogens (estradiol, estrone, conjugated estrogens, and equine estrogens), synthetic steroidal estrogens (esters and 17-alpha-ethinyl estradiol), and nonsteroidal estrogens (diethylstilbestrol, dienestrol, and chlorotrianisene). Delivery of estrogens by different routes produces different effects. However, the metabolic changes that occur from enzyme induction within hepatic tissue are probably related to the type and dosage of estrogen rather than to the route of administration. Preparations containing estrogens that occur naturally in humans have the least exaggerated potency in the hepatic system relative to their estrogenicity, while conjugated estrogens that contain a mixture of equine estrogens are 2-3 times more potent in the hepatic system and ethinyl estradiol and diethylstilbestrol demonstrate a hepatic potency that is 4-18 fold greater than their estrogen potency. Estrogen is believed to induce a hypercoagulation state associated with both oral contraceptive (OC) use and pregnancy, but the clinical significance of increased levels of clotting factors remains undetermined. Estrogen appears to inhibit bone resorption in postmenopausal women and improve calcium balance. Although estrogen receptors are present in the kidney, their physiologic significance remains unknown. Estrogen does cause an increase in levels of plasma renin substrate, plasma renin activity, and angiotensin. Estrogen-induced increases in angiotensin, leading to renal sodium retention, appear to be the mechanism underlying the association of OCs with hypertension.

Oestrogens and host resistance.

PIP: The literature is searched for references to studies dealing with the immunobiological effects of pregnancy and other instances of increased estrogenic production in humans and various animal species. In the human female, the estrogen-related metabolic changes associated with pregnancy and reproduction have widespread effects on host tolerance of the fetus and diseases where host resistance is involved. These changes facilitate fetal survival. They also lower bodily resistance to viral and bacterial infections. Acute inflammation may be stimulated and chronic inflammation inhibited by pregnancy, both of which effects are mediated by estrogens. It is speculated that some aspects of host resistance are increased while others are decreased, maintaining an overall balance.^ieng

Estrogens and breast cancer: present position.

Oestrogen is probably involved in breast cancer in two main ways: (1) in the aetiology of the disease as a promoting substance rather than as a carcinogen; (2) in stimulating the growth of at least some established breast cancers, acting through the oestrogen receptor. Successful modes of endocrine therapy would then be interpreted as interfering with (a) the supply of oestrogen to the tumour (b) the nuclear events in oestrogen action or (c) receptor replenishment.

PIP: Estrogens can be involved in breast cancer in the following 2 ways: 1) as a promoting rather than a carcinogenic agent in the formation of breast cancers; and 2) as a stimulant to the growth of established breast tumors through the estrogen receptor. The evidence linking estrogen with the etiology of breast cancer is, however, largely circumstantial. Successful endocrine therapy would interfere with the supply of estrogen to the tumor, the nuclear events in estrogen action, or receptor replenishment. The minimal criterion for therapeutic success with endogenous estrogen therapy is to effect a reduction in hormone levels. Only tumors with endocrine sensitivity, indicating the presence of estrogen receptors, will respond, it is believed. The absence of estrogen receptors predicts failure for this type of therapy. Studies have shown that the estrogenic components of OCs (oral contraceptives) do not lead to an increased risk of breast cancer except perhaps in a small subgroup of women already at high risk.

Ovarian hormones and gingivitis.

PIP: Elevated plasma concentrations of the ovarian hormones--estrogen and progestins--during pregnancy, puberty, the menstrual cycle, and oral contraceptive (OC) use are associated with an increased incidence of gingival inflammation and exudate. Gingivitis is induced by the micro- organisms that compose subgingival plaque, particularly anaerobic organisms. The ovarian hormones both stimulate bacterial growth and promote the inflammatory process. In the presence of sex hormones, the metabolic breakdown of folate is increased, leading to a folate deficiency that enhances the inflammatory destruction of oral tissue. Gingivitis occurs in an estimated 60-75% of pregnancy women, but the numbers of gingivitis-producing bacteria decrease toward the end of pregnancy and the gingival tissues return to their previous state. In OC users, on the other hand, inflammation of the gingiva is chronic and may increase over time. If gingivitis is already present at the onset of pregnancy or OC use, the inflammation will become progressively more severe. Although these effects cannot be avoided, ovarian hormone- induced gingivitis can be substantially minimized of low plaque levels exist at the beginning of pregnancy or pill initiation.^ieng

Interactions with oral contraceptives.

The interaction of a range of different factors with the pharmacologic activity of oral contraceptives is reviewed. Pharmacokinetic interactions with oral contraceptives may occur (1) during absorption and extrahepatic circulation, (2) by interfering with protein binding, and (3) during hepatic metabolism. The hepatic mixed function oxidase system, which is mainly responsible for the metabolism of oral contraceptives, is affected by several different factors and is easily induced. Nutrition affects the activity of many drugs, but information regarding oral contraceptives is meager. Both pharmacokinetic and pharmacodynamic interactions, which may be synergistic or antagonistic, between the estrogen and gestagen components of oral contraceptives, are important, but there is no correlation between the rate of metabolism of the two components. Evidence suggests that some anticonvulsant, antibiotic, and antibacterial drugs may reduce the efficacy of oral contraceptives. Instances of interactions of other therapeutic agents are reported infrequently. The incidence of serious interactions is low and does not appear to have been reduced with low-dose oral contraceptives, probably because of large intersubject variability in the pharmacokinetics of oral contraceptives.

PIP: Pharmacokinetic interactions between oral contraceptives (OCs) and other drugs and nutrients may occur during absorption and extrahepatic circulation, through interference with protein binding, and during hepatic metabolism. However, the most significant locus of drug interaction is the mixed function oxidase system of the liver endoplasmic reticulum. Increased activity of the mixed function oxidase system produced by other drugs tends to reduce the half-life of elimination of sex steroids and consequently of their serum concentrations and biological effect. At the same time, OC administration generally has an inhibitory effect on the metabolism of other drugs and consequent reductions in their pharmacologic activity. The rate of drug metabolism will vary according to genetic and environmental factors such as diet, alcohol use, smoking, and pathologic conditions. Although the influence of nutrition on the absorption and bioavailability of contraceptive steroids has not yet researched adequately, high-protein diets appear to stimulate the activity of the hepatic drug-oxidizing system and increase the metabolism of other drugs. Pharmacokinetic and pharmacodynamic interactions between the estrogen and gestogen components of OCs may be synergistic or antagonistic, but no correlation has been found between the rate of metabolism of the 2 steroids as reflected in their elimination half-lives. Despite evidence that some anticonvulsant, antibiotic, and antibacterial drugs reduce the efficacy of OCs, this interaction is severe enough to lead to OC failure in less than 5% of cases. It can be postulated that women in whom drug interactions lead to contraceptive failure are fast metabolizers or have liver enzyme systems especially susceptible to induction.

Gastrointestinal disease and oral contraception.

Oral contraceptive steroids play a major role in modern family planning. With the present tendency to decrease the doses of both estrogens and progestogens, any factor that reduces the bioavailability of the lower-dose preparations may have an impact on contraceptive protection. Although ethinyl estradiol, the most commonly used oral estrogen, is liable to an enterohepatic circulation as unchanged drug, the commonly used progestogens are not. At present, no convincing evidence exists in the human subject that disruption of the enterohepatic circulation by antibiotics or antacids does reduce contraceptive efficacy of the pill. Oral contraceptive steroids are mainly absorbed from the small bowel, and contraceptive efficacy depends on its absorptive capacity. Enhanced passage of gastrointestinal contents or impaired absorption may thus contribute to contraceptive failures in patients who have chronic inflammatory disease, diarrhea, ileostomy, or jejunoileal bypass.

PIP: THe recent trend toward decreased dosages of estrogen and progestogen in oral contraceptives (OCs) makes it especially important that attention be directed toward additional factors-- dietary factors, gastrointestinal disturbances or diseases, or drugs that interact with OCs--that may further reduce the bioavailability of steroids and thus compromise contraceptive protection. At present, there is no evidence that antibiotics interfere with OC steroids at the level of enterohepatic circulation; also unlikely is a clinically significant interaction between OCs and antacids. Unlike estrogens, progestogens do not undergo enterohepatic recirculation as unchanged drugs; presumably due to the lack of direct conjugation at the 17 position. Thus, no impact on contraceptive efficacy is produced by disruptions in progestogen metabolism. On the other hand, there is an ample body of research suggesting a link between OCs and chronic inflammatory bowel disease, especially Crohn's disease. The finding of reduced bioavailability of estrogen and progestogen in women who have undergone jejunoileostomy demonstrates that OCs are mainly absorbed in the small bowel and that contraceptive efficacy is related to its absorptive capacity. Overall, it is recommended that careful attention be given to OC acceptors with chronic inflammatory disease, non-colonic diarrhea, ileostomy, and jejunoileal bypass.

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.

High progesterone receptor concentration in a variant of the ZR-75-1 human breast cancer cell line adapted to growth in oestrogen free conditions.

Culture of ZR-75-1 human breast cancer cells for 5 days in the absence of oestrogens (phenol red-free medium supplemented with dextran coated charcoal stripped 5% fetal calf serum) resulted in a slowing of growth rate and loss of progesterone receptors. Oestradiol at 10(-9) M markedly stimulated growth and progesterone receptor synthesis over a 5-day period. While medroxyprogesterone acetate (10(-10) to 10(-6) M) inhibited growth of ZR-75-1 cells growing in complete medium, in the short-term absence of oestrogens low concentrations were growth stimulatory. Cells deprived of oestrogens for 5 days retained sensitivity to growth inhibition by 4-hydroxy tamoxifen. ZR-75-1 cells were also adapted to growth in the absence of oestrogens over a 5-month period. These cells (ZR-PR-LT) failed to express binding sites characteristic of the type 1 oestrogen receptor but progesterone receptor expression was at a level normally associated with oestrogen induction. Adapted cells were growth inhibited by oestradiol, 4-hydroxy tamoxifen and medroxyprogesterone acetate, but despite elevated progesterone receptor expression the progestin was only marginally more inhibitory than in the parent line. Our data indicate a poor quantitative relationship between response to progestins in vitro and progesterone receptor concentration and support previous findings that acquisition of an oestrogen independent phenotype does not necessarily result in resistance to anti-oestrogens.

PIP: After an initial response to hormonal therapy, breast cancer patients whose tumors are positive for the presence of estrogen receptors and progesterone receptors become resistant to this treatment, either because of the development of antiestrogen withdrawal. Within 5 days of transfer to an estrogen-free medium, proliferation of ZR-75-1 cells slowed dramatically and there was a loss of progesterone receptors. Also over a 5-day period, estradiol markedly stimulated growth and progesterone receptor synthesis. Medroxyprogesterone acetate inhibited the growth of ZR-75-1 cells in complete medium, low concentrations in the absence of estrogen were growth stimulatory in the short run. Cells deprived of estrogen for 5 days were still sensitive to growth inhibition by 4-hydroxy tamoxifen. Although ZR-PR-LT cells failed to demonstrate binding sites characteristic of the type 1 estrogen receptor, progesterone receptor expression was at a level consistent with estrogen induction. Adapted cells were growth inhibited by estradiol, 4-hydroxy tamoxifen, and medroxyprogesterone acetate, but the progestin was only slightly more inhibitory than in the parent line. Overall, these findings suggest a poor quantitative relationship between the in vitro response to progestins and progesterone receptor concentration and confirm previous findings that the acquisition of an estrogen-independent phenotype does not necessarily lead to antiestrogen resistance.

Oral contraceptive use and risk of colorectal cancer.

To evaluate the relation between oral contraceptives and colon and rectal cancer, we analyzed combined data from two case-control studies conducted in six Italian regions between 1985 and 1996. The studies included 803 women with incident colon cancer, 429 with rectal cancer, and 2,793 controls with acute, nonneoplastic, nondigestive, non-hormone-related disorders. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) from unconditional multiple logistic regression equations, including terms for age, center/study period, education, family history of colorectal cancer, menopausal status, age at menopause, parity, use of hormone replacement therapy, body mass index [weight (kg) per height squared (m2)], and total energy intake. Ever-use of oral contraceptives was inversely associated with colon cancer (OR = 0.63; 95% CI = 0.45-0.87) and rectal cancer (OR = 0.66; 95% CI = 0.43-1.01). Duration of use of oral contraceptives was inversely related to risk of colon but not rectal cancer. This study suggests that women who have ever used oral contraceptives are at lower risk of colon and rectal cancer.

PIP: The 15 cohort and case-control studies published to date on the association between oral contraceptive (OC) use and colorectal cancer have yielded conflicting results; 7 revealed a reduced cancer risk among OC users, 6 showed no association, and 2 reported some increased risk. The present analysis combined data from a multicenter case-control study, conducted in 6 Italian regions in 1992-96 with data from a 1985-91 study in northern Italy, yielding a total of 803 women with colon cancer (median age, 61 years), 429 cases of rectal cancer (median age, 62 years), and 2793 controls (median age, 57 years). 59 women with colon cancer (7.3%) and 323 controls (11.6%) reported ever-use of OCs (odds ratio (OR), 0.63; 95% confidence interval (CI), 0.45-0.87). OC use for more than 24 months further decreased this risk (OR, 0.52; 95% CI, 0.32-0.85). The protection conferred by OC use was similar when the origin of the neoplasm was in the ascending, transverse, or descending colon. An inverse association was also found between ever-use of OCs and rectal cancer (OR, 0.66; 95% CI, 0.43-1.01), but there was no association with duration of OC use. For colon and rectal cancers combined, a 36% reduction in cancer risk was present among ever-users of OCs (OR, 0.64; 95% CI, 0.49-0.85). These findings are consistent with the descriptive epidemiology of colorectal cancer, the bile acid hypothesis, and experimental findings on estrogen receptors and the colorectal cancer pathway.

Estrogen replacement therapy: indications and complications.

Estrogen replacement therapy is one of the most controversial issues in the field of reproductive medicine. Indications for its use include hot flashes, vaginal atrophy, and risk of osteoporosis. Risk of heart disease may also be an indication but this use has not been firmly established. The role of estrogen replacement therapy in aging changes of skin needs clarification. Complications of therapy include endometrial cancer, breast cancer, hypertension, hyperlipidemia, and gallbladder disease. The last three complications presumably result from hepatic actions of estrogen replacement therapy.

PIP: Indications and complications of estrogen replacement therapy are discussed in this edited transcription of a conference held at the UCLA School of Medicine. Although many of the symptoms of loss of ovarian function can be corrected by estrogen replacement therapy, several potentially harmful side effects are associated with the administration of estrogen. Hot flashes, the most common menopausal symptom for which women seek treatment, may continue over extended periods of time and the loss of ovarian feedback signals. Several types of evidence indicate that hot flashes are centrally rather than peripherally mediated disturbances, and it now appears that the hypothalamic factors which stimulate pulsatile release of luteinizing hormone play an integral role in initiation of hot flashes. The fact that the extent of estrogen deficiency differs among postmenopausal women may explain why all women do not have hot flashes. The effects of body size on estrogen production and plasma protein binding appear to be significant variables modulating the extent of estrogen deficiency and hypothalamic function. Other studies suggest that calcitonin and gonadal steroids are linked in the pathogenesis and treatment of osteoporosis, but the mechanism of action of estrogen replacement therapy in the treatment of osteoporosis has not been elucidated. Most investigations have failed to show the presence of estrogen receptors in bone. It is likely that the term osteoporosis includes heterogeneous skeletal disorders and that both sex hormones and calcemic hormones are important in pathogenesis. Further research is required on the possible effect of estrogen replacement therapy in decreasing relative risk of arteriosclerotic heart disease. Vaginal atrophy is an accepted indication for estrogen replacement, but its use for skin indications should not be recommended until a beneficial cosmetic effect is shown. Complications of estrogen replacement include endometrial cancer, breast cancer, hypertension, hyperlipidemia, and gallbladder disease, the latter 3 apparently resulting from hepatic action of estrogen replacement therapy. Because of the enhanced hepatic action of orally administered estrogen, other routes of administration are being explored. Additional research is needed to define the risk-benefit ratio of estrogen replacement therapy.

Oral contraceptives and benign tumors of the liver.

PIP: The prevalence of benign tumors of the liver in users of oral contraceptives (OCs) has increased to the point that they must be considered in the differential diagnosis of a variety of symptoms in women at risk. It is important to distinguish hepatic adenoma from focal nodular hyperplasia because the former may be complicated by severe hemorrhage and is clearly linked to prolonged OC use. The annual incidence of hepatic adenoma has been estimated at 3.4 cases/100,000 OC users. Focal nodular hyperplasia generally appears as a single nodule (78%) measuring less than 5 cm in diameter (84%). On cut section there is a characteristic central, stellate, fibrous core that radiates to the periphery of the lesion, dividing the tumor into a number of nodules. Proliferating bile ducts and inflammatory cells are often seen in the fibrous areas. Hepatic adenoma is easily distinguished by gross and microscopic inspection. It usually appears as a single (71%), large (36% larger than 10 cm), fleshy tumor without any internal structure. The absence of bile ducts is noteworthy. Data show strong association between OCs and the development of hepatic adenoma but no association with focal nodular hyperplasia. If women use OCs for more than 6 years, hepatic adenoma is 25 times more likely to develop than in nonusers. Patients with hepatic adenoma usually present with life-threatening hemorrhage as the initial manifestation of the tumor. Hormonal factors are very important in the pathogenesis and clinical presentation of hepatic adenoma; hemorrhage frequently occurs in association with menstruation. By contrast, patients with focal nodular hyperplasia generally have no symptoms and the prognosis is excellent. Use of OCs should be stopped in all patients who may have hepatic tumors because tumor regression usually occurs after withdrawal of the drug. Evidence indicates that synthetic estrogens do not cause tumors directly but can enhance the growth of neoplastic cells.^ieng

The canalization of cervical mucus in the human fertility.

PIP: Canalization of cervical mucus from 31 patients at the obstetric/gynecologic clinic at the Universita Cattolica del S. Cuore in Rome, Italy has studied to determine the biochemical basis of canalization and its dependence on estrogen, to study the action on the canalization of hormones used to induce ovulation, and to correlate fern pattern and canalization. Cervical mucus was collected daily and applied to a glass slide, covered with an object cover, and allowed to dry. The typical arrangement of the dendritic crystals and the presence of channels among them were confirmed. Depending on the phase of the ovulatory cycle, the crystals differed in direction and in number. The number of channels consistently increased as estradiol levels increased during the proliferative phase. This happened in both natural and induced ovulatory cycles. The cervical mucus of patients with primary amenorrhea canalized when treated with estrogens. The channels ran parallel to each other. Yet, during the secretory phase, the number of channels fell rapidly and the channels were lined up in a crisscross fashion. This suggested that sperm penetration is dependent on the orientation of mucus crystals. Indeed in vitro studies showed that spermatozoa enter the periovulatory mucus in tightly packed files as if the mucus allowed only passage in this linear formation. The biophysical characteristics of canalization paralleled those of ferning. Moreover, like ferning, the presence of essential salts and proteins induced canalization. It is concluded that canalization can be used to accurately measure estradiol levels and thus to detect ovulation.^ieng

[Hormonal contraception and substitution therapy: the importance of progestogen for cardiovascular diseases]. / Hormonale Kontrazeption und Substitutionstherapie: Die Bedeutung des Gestagens für kardiovaskuläre Erkrankungen.

Epidemiological data have demonstrated, that the progestogen component of oral contraceptives is involved in the development of hypertension, ischaemic heart diseases and stroke. It had been suggested, that atherosclerotic lesions due to the unfavourable effect on lipid metabolism of progestogens with androgenic properties, play a causal role. It has, however, been shown, that there is no development of atherosclerosis despite reduced HDL and elevated LDL, presumably because of the induction of hepatic LDL- and remnant-receptors by the strong effect of ethinyl-oestradiol upon the liver. A series of experimental and clinical findings indicates that vasospasms caused by the vasoconstrictory effect of progestogens are involved in the development of arterial thromboses. In postmenopausal women, the additional administration of progestogens to the oestrogen treatment may trigger ischaemic diseases, particularly in the presence of vascular lesions. Oestrogens exercise a pronounced vasodilatory effect and stabilize the vascular tonus--through changes in the responsiveness of endothelium and smooth muscle cells to vasoactive compounds, through modulation of neurotransmitter release from nerve endings, and through direct blocking of calcium channels. The effects depend essentially on an intact endothelium. By a direct action on the vascular wall, progestogens increase the sensitivity of arteries to vasoconstrictory compounds and reduce blood flow. As aldosterone increases the number of beta-adrenergic receptors in the arterial smooth muscle cells and thus act vasodilatorily, it cannot be excluded, that progestogens with high affinity to the aldosterone receptor and antimineralocorticoid properties, may exert a strong vasoconstrictory effect.(ABSTRACT TRUNCATED AT 400 WORDS)

PIP: Epidemiological data have revealed that the progestogen in oral contraceptives (OCs) is involved in hypertension, ischemic heart diseases, and stroke. Atherosclerotic lesions were implicated owing to the androgenic properties of progestogens. However, atherosclerosis did not develop despite reduced high density lipoprotein (HDL) and elevated low density lipoprotein (LDL), presumably because of the strong effect of ethinyl estradiol (EE) upon induction of hepatic LDL- and remnant-receptors. A series of findings indicate that vasospasms caused by the effect of progestogens are involved in arterial thromboses. In postmenopausal women, the addition of progestogens to the estrogen treatment may trigger ischemic diseases. Estrogens exert a vasodilatory effect and stabilize the vascular tonus through the responsiveness of the endothelium, neurotransmitter release, and direct blocking of calcium channels. Progestogens increase the sensitivity of arteries to vasoconstrictory compounds and reduce blood flow. In women treated with ovulation inhibitors, and EE-induced activation of the renin-angiotensin-aldosterone system was observed. Aldosterone acts vasodilatorily, while progestogens with high affinity to the aldosterone receptor may exert a strong vasoconstrictory effect. If vascular lesions are present, the vasoconstrictory action of progestogens may cause acute ischemic attacks. Therefore, the lowest effective dose of the progestogen has to be used for replacement therapy. In hysterectomized women, the extra administration of progestogens should be avoided and in women with arterial diseases they should be prescribed with discretion. Additional progestogens given for 14 days 3 months apart may suffice for the prevention of endometrial hyperplasia. Both the EE and progestogen doses in OCs should be reduced. Progestogen-dominant ovulation inhibitors should be restricted to cases with an additional indication.

Pharmacokinetics of gestagens: some problems.

Various approaches to studying the pharmacokinetics of gestagens and the factors that influence derivation of the parameters are described with levonorgestrel used as an example. Published studies of the pharmacokinetics of levonorgestrel are reviewed, and new information is presented regarding intra- and intersubject variation. Differences between various formulations of levonorgestrel are apparent when the formulations are compared in the same subjects. There is also a marked difference in the parameters when derived under single-dose or steady-state conditions. The role of sex hormone-binding globulin in the metabolism of levonorgestrel is questioned. Large intra- and inter-subject variations in the parameters exist, and a subject may show a large month-to-month variation when one levonorgestrel formulation is used and smaller variations when another formulation is used. This wide variability in the pharmacokinetic parameters, problems that arise in the derivation and interpretation of the parameters, the biologic significance of most of these parameters, and their lack of correlation with pharmacodynamic responses severely limit the usefulness of pharmacokinetic studies of the gestagens.

PIP: The results of previously published studies of the pharmacokinetics of levonorgestrel (LNG), a widely used gestagen, were tabulated, reviewed, and subjected to new analyses. The mean half-life of elimination, usually calculated using two-compartment open modeling, ranged from 8 to 18 hours. Such large variations in half-life of elimination have been noted in studies of other steroid contraceptives as well. Recalculation of half-life of elimination by simply plotting the 8- and 24-hour serum concentrations against time yielded values in general agreement with those obtained with the original investigators' pharmacokinetic values. The pharmacokinetics of gestagens are influenced not only by dose and formulation but also by high levels of intrasubject and intersubject variation. In most studies, sampling is not continued beyond 24 hours, and this may cause an underestimation of half-life, particularly for long-lived gestagens. Another common parameter, mean pharmacokinetic bioavailability of LNG (as calculated by the area under the curve method), ranged from 20 to 35 ng/ml/hour in patients given 150 mcg of LNG with 30 mcg of ethinyl estradiol. Bioavailability increased with higher doses. Since half of the LNG in serum is bound to sex hormone-binding globulin (SHBG), changes in the serum concentration of this protein may affect LNG pharmacokinetics. Estrogens induced SHBG. Some investigators have proposed that the higher LNG levels observed in serum when a gestagen is administered together with an estrogen is due to increased amounts of SHBG in serum. However, a number of studies have shown that estrogens administered with gestagens do not induce SHBG and may actually decrease its concentration. In general, studies of the pharmacokinetics of estrogens report a high degree of variation in common pharmacokinetic parameters, as well as a frequent lack of correlation with biologic response. This raises the question of whether these types of studies are providing useful information.