Long-term Oral Contraceptives Research Articles

A prospective study of oral contraceptive use and risk of breast cancer (Nurses' Health Study, United States).

Results of previous epidemiologic studies have provided reassurance that there is little, if any, increase in risk of breast cancer with oral contraceptive (OC) use in general. However, in several studies, an increased risk of breast cancer has been observed in two subgroups, young women who used OCs for extended durations and in women who used OCs prior to a first-term pregnancy. We evaluated these relationships using data from the ongoing Nurses' Health Study cohort (United States). We documented 3,383 cases of breast cancer from 1976 to 1992 among 1.6 million person-years of follow-up. We observed no overall relationship between duration of OC use and breast cancer risk, even among women who reported using OCs for 10 or more years (multivariate relative risk [RR] = 1.11, 95 percent confidence interval [CI] = 0.94-1.32). Among women less than 45 years of age, the multivariate RR for using OCs for 10 or more years was 1.07 (CI = 0.70-1.65) compared with never-users. The risk associated with five or more years of OC use prior to a first full-term pregnancy compared with never-use was 0.96 (CI = 0.65-1.43). Among women less than 45 years of age, we observed no evidence of an increased risk with OC use before a first full-term pregnancy (use for five or more years: RR = 0.57, CI = 0.24-1.31). Because of the age distribution of our cohort, we were unable to evaluate these relationships among women less than 40 years of age. Our study provides considerable evidence that long-term past OC use, either overall or prior to a first full-term pregnancy, does not result in any appreciable increase in breast cancer risk in women over 40 years of age.

Beeinflußt die vorangegangene Einnahme oraler Kontrazeptiva das Überleben beim Mammakarzinom?*

The influence of a positive history of oral contraceptive (OC) use on survival of breast cancer was studied in 471 patients. 297 (63%) of them were ever users of OCs and 202 (43%) were long-term users (> or = 49 months). The median follow-up amounted to 56 (6-96) months. Except for a significantly higher frequency of poorly differentiated tumours in OC users (p = 0.01) there was no difference in the distribution of histopathological features between OC users and non-users. Nevertheless, compared to non-users OC user showed a significantly increased 5-year-survival (p = 0.017). This effect was strongly correlated with duration of use (p = 0.004) and time since last use (p = 0.02). The influence of OC use achieved significance after a duration of use of four or more years or in case of OC use at the time of diagnosis. The positive effect persisted in multivariate analyses and was mainly attributed to long-term OC users with tumours of a generally expected poor prognosis.

Breast Cancer Among Young U.S. Women in Relation to Oral Contraceptive Use

While most studies have found no association between oral contraceptive use and breast cancer, several studies of younger women have reported an association with long-term oral contraceptive use. PURPOSE. We studied the relationship of patterns of oral contraceptive use to breast cancer risk among younger women. These women have had oral contraceptives available their entire reproductive lives and are now entering the breast cancer-prone years. A population-based, case-control study of breast cancer was conducted in three counties in western Washington State among women born in 1945 or later, ages 21-45. Case patients were 747 women with breast cancer diagnosed in 1983-1990 and identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry. Control subjects were 961 women identified by random-digit telephone dialing. Subjects were interviewed in person, using pictures of brands of oral contraceptives and calendars of life events as recall aids. There was no increased incidence of breast cancer associated with ever having used oral contraceptives. Because only 8% of this cohort had never used oral contraceptives, short-term users (< 1 year) were combined with never users as the reference group for further analyses. A small increased risk of breast cancer was associated with long duration of oral contraceptive use (odds ratio for > or = 10 years = 1.3; 95% confidence interval [CI] = 0.9-1.9; P for trend = .03), particularly among women aged 35 years or younger (odds ratio for > or = 10 years = 1.7; 95% CI = 0.9-3.1). Breast cancer was also modestly related to oral contraceptive use early in reproductive life (odds ratio for use within 5 years of menarche = 1.3; 95% CI = 1.0-1.8; P for trend = .04) and to use of high-progestin-potency oral contraceptives for at least 1 year (odds ratio = 1.5; 95% CI = 1.1-2.1). These associations were adjusted for age, age at menarche, term pregnancy, induced abortion, and family history of breast cancer. The associations were not further confounded by case-control differences in education, religion, breast feeding of offspring, or infertility; in oral contraceptive contraindications, indications, or complications; or in measures of breast cancer detection such as mammography or breast biopsy. Long-term oral contraceptive use among young women or use beginning near menarche may be associated with a small excess breast cancer risk, possibly due to susceptibility to genetic damage in breast epithelial cells at ages of high breast cell proliferative activity. Future studies should investigate whether the patterns of risk we reported are present as this cohort ages.

Pulsatile luteinizing hormone patterns in long term oral contraceptive users.

Oral contraceptives (OC) inhibit folliculogenesis by a central suppressive action on the release of gonadotropins. To characterize the nature of these central effects, we studied 40 long term OC users on 3 different OCs: two monophasic preparations with 30 micrograms ethinyl estradiol and 150 micrograms l-norgestrel (group 1; n = 15), 150 micrograms desogestrel (group 2; n = 10), and a triphasic formulation containing 30-40 micrograms ethinyl estradiol and 50, 75, and 125 micrograms l-norgestrel (group 3; n = 15). Blood sampling at 10-min intervals during 6-h periods was performed at different moments in the pill cycle. Thirteen healthy volunteers with regular ovulatory cycles served as normal controls. FSH and LH were measured by a sensitive immunoradiometric assay. Pulsatile LH release was observed in all OC users. Mean serum LH and FSH levels, number of LH pulses per 6 h, and the amplitude of LH pulses on day 1 of the pill cycle did not differ from early follicular phase control values. FSH levels were rapidly suppressed from day 2 onward in all three groups, whereas LH levels progressively declined in groups 1 and 2 from day 8 onward. In group 3, however, LH levels were only significantly suppressed after day 13. The number of LH pulses per 6 h decreased in all groups starting on day 2, whereas the amplitude of LH pulses increased. A substantial percentage of LH pulses observed in OC users after day 1 were of low amplitude (< 0.75 IU/L). From these results, we conclude that 1) pulsatile release of LH is maintained during OC use; 2) FSH levels are suppressed equally early and equally effective by all OCs studied; 3) during OC use, the number of LH pulses per 6 h is reduced; 4) modulation of LH pulse amplitudes, and subsequently of serum LH levels, is mainly mediated by a dose- and time-dependent effect of the gestagenic component of the OC; and 5) after the 7-day pill-free interval, a normal early follicular phase pulse pattern is found, even in long term OC users, suggesting that in this period, most of the steroidogenic feedback effects wear off.

Effects of low dose oral contraceptives on very low density and low density lipoprotein metabolism.

Oral contraceptives (OC) raise plasma triglyceride and VLDL levels, which may be of concern, since some conditions characterized by elevated triglycerides are associated with atherosclerosis. To identify the responsible mechanism, we studied 11 healthy premenopausal women, 5 of whom were taking OC containing 0.035 mg ethinyl estradiol, and 6 of whom were not. Their rates of VLDL and LDL metabolism were measured by endogenously labeling apoB, the protein component of VLDL and LDL, by an intravenous infusion of deuterated leucine. OC use had the greatest effect on the large, triglyceride-rich VLDL subfraction (Sf 60-400), increasing plasma levels threefold and production rates fivefold (P < 0.05). Among OC users, small VLDL (Sf 20-60) levels were 2.2 times higher, and production rates were 3.4-fold higher (P < 0.05). The fractional catabolic rates of large and small VLDL were similar among OC users and nonusers. LDL levels and metabolic rates were not significantly different between the two groups. Thus, contemporary low dose OC substantially raise VLDL levels by increasing the production rate of large, triglyceride-rich VLDL, and not by slowing VLDL catabolism. Since VLDL catabolism is not impaired, we speculate that the hypertriglyceridemia induced by OC may be less atherogenic than that of hypertriglyceridemia resulting from impaired lipolysis. This may explain why long-term OC use does not appear to promote atherosclerosis.

Oral Contraceptives and Breast Cancer

Changes in endogenous hormones at various times in life (e.g., early menarche, birth of the 1st child at an advanced maternal age, and late menopause) increase the changes of developing breast cancer. It is reasonable then to expect oral contraceptive (OC) use to increase the risk of breast cancer. It is difficult, however, to prove OC exposure has this effect due to changed OC use patterns plus OCs consist of many different hormones at various doses and compositions. Yet, OC use in the past (even more than 15 years of OC use) had not increased the risk of breast cancer in women of all combined age groups. 3 research groups have identified a small increase in overall risk in low risk women, but unidentified sources of bias or confounding could account for this increased risk. Some recent studies indicate an increased risk of breast cancer with duration of OC use, but the risk depends somewhat on dose of either the estrogen or the progestin. Nonetheless, these findings were weak and inconclusive. Other research shows long-term OC use increases the risk of breast cancer in just young women (under 45 years old). Future epidemiologic studies thus need to address increased breast cancer risk in women under 45 years old who used OCs for a long time. They need to look at whether the risk is due to early use and continues into older age or to longterm use at any time in just young women. Some studies should include women with and without various biological markers of susceptibility. Other studies should measure blood levels of estrogens and progestins in women using the same OCs. BAsed on the information now available, it would be unwise for physicians to warn women against using the highly effective OCs because they do prevent unwanted pregnancy and are protective against ovarian and endometrial cancer.

The risk of breast cancer associated with oral contraception and hormone replacement therapy

Current epidemiologic data from research on the association between combined oral contraceptives (OCs) and breast cancer show that longterm OC use does not significantly increase the risk of developing breast cancer after age 45, but may indeed protect against postmenopausal breast cancer. Yet, older studies with high dose OCs demonstrate a somewhat increased risk (relative risk = 1.5) for young women who have used OCs early and for at least 4 years. Nevertheless, the lack of association even holds true for women with a family history of breast cancer or for those who have benign breast disease. Studies should continue, however, since the OC user cohort is aging and to increase the statistical power of current studies. Standard hormonal replacement therapy consists of a progestin and estrogen. Addition of progestin prevents the risk of endometrial cancer. Some research indicates that it may also protect against breast cancer. However, research from Uppsala, Sweden, suggests that combined estrogen-progestin treatment slightly, but not significantly, increases the breast cancer risk. Further research and longer duration of hormonal replacement therapy should provide clinicians with more information about the breast cancer risk. Individual physicians should inform their patients about concerns raised by the research about hormones and breast cancer, but should be optimistic since the possible risk has not been proven. Some medical associations have already developed guidelines for physicians and included them into continuing medical education programs.

Disturbances in dexamethasone suppression test and lower availability of Ł-tryptophan and tyrosine in early puerperium and in women under contraceptive therapy

This study investigates the function of the hypothalamic-pituitary-adrenal (HPA)-axis and the availability of L-tryptophan and tyrosine to the brain in postpartum women and in women taking long-term oral contraceptives. To this end, we have measured the following parameters in 50 women (i.e. 9 normal controls, 10 women taking oral contraceptives, and 31 postpartum females): plasma cortisol, L-tryptophan, tyrosine and the amino acids (CAA) known to compete with them for transport through the blood-brain barrier. We have determined the effects of 1 mg of dexamethasone on the above-mentioned biological markers in postpartum females. Plasma cortisol and tyrosine were significantly higher and lower, respectively, in puerperium and in women under contraceptive therapy as opposed to normal controls. L-Tryptophan was significantly lower in postpartum females, whilst the L-tryptophan/ CAA ratio did not differ across the three study groups. Postpartum females revealed a significant negative relationship between the availability of L-tryptophan to the brain and postpartum mood, as measured by Zung's Depression and Anxiety Scales and State Anxiety Inventory. Dexamethasone had a significant suppressive effect on L-tryptophan/CAA and tyrosine/CAA ratios, with cortisol non-suppression appearing in 82% of the postpartum females.

Oral contraceptives and breast cancer

Among women in general the risk of breast cancer through 59 years of age does not appear to be affected appreciably by the use of oral contraceptives. Nonetheless, concern continues to be expressed about the effects of early age at first use, long-term duration of use, formulation, and a variety of other factors thought to influence breast cancer risk in the presence of oral contraception. A number of recent studies restricted to young women suggest that long-term use may increase the risk of disease occurring very early, but the present lack of consistent findings in well-conducted epidemiologic studies prevents any certain conclusion with regard to cause-and-effect. However, if an increased risk were indeed present, the most plausible interpretation is that long-term oral contraception promotes earlier clinical manifestation of breast cancer in some women while having no net impact on their lifetime risk of the disease.

Pills, partners and preventive prospects: in‐situ cancer of the cervix

Australian women face a lifetime risk of dying of cervical cancer of 1 in 250. Current epidemiological evidence suggests that the age at 1st sexual intercourse and the number of sexual partners are important risk factors for cervical carcinogenesis. Other risk factors for invasive cervical cancer include cigarette smoking deficiencies of dietary and plasma micronutrients and oral contraceptive (OC) use. The recently documented increased risk of invasive cervical cancer associated with longterm OC use may in part reflect uncontrolled confounding by other factors especially the likely association of OCs with greater exposure of the cervix to infectious agents such as human papillomavirus. Moreover any association of present cancer with past use of OCs may not reflect the risk that is associated with the currently prescribed lower-dose agents. The profiles of risk appear to be similar for invasive carcinoma of the cervix and carcinoma in situ confirming the view that carcinoma in situ is the main precursor lesion for invasive cancer of the cervix. A recent case-control study conducted in Sydney found a 50% increase in the risk of carcinoma in situ in ever users of OCs compared to never users and the risk increased with increasing duration of OC use. The mode of the possible action of OCs on the risk of cervical cancer remains unclear. Recent studies have demonstrated that certain sex steroids directly activate viral DNA that is incorporated into the DNA of epithelial cells and that in vitro interaction occurs between such hormones and human papillomavirus type 16 DNA in the enhanced induction of carcinogenesis in cultured cells. This evidence that a sexually transmitted infectious agent contributes to the etiology of cervical cancer offers a clear direction for preventive action.

Liver diseases related to oral contraceptives.

Any of the parenchymal and mesenchymal constituents of the liver can be adversely affected by oral contraceptive (OC) use. Included among these adverse effects are intrahepatic cholestasis hepatocellular necrosis liver cell adenoma focal nodular hyperplasia hepatocellular carcinoma hepatic angiosarcoma sinusoidal dilatation focal hemorrhagic necrosis hepatic vein thrombosis and portal vein thrombosis. It is important to note however that most of these OC-liver disease associations were recorded during a period when OCs had far higher estrogen content than presently prescribed formulations. It is also important to stress that the direct effects on the liver of combined OCs are generally of little clinical consequence. It is the coincidence of OC use with an underlying possibly latent liver or vascular disease that poses serious dangers. A major concern has been the increased risk of hepatocellular carcinoma in longterm (over 8 years) OC users; however animal studies suggest that OC steroids do not cause hepatocellular carcinoma on their own but rather act as promoters and stimulate the growth of already transformed hepatocytes. Due to the extreme rarity of the underlying liver and vascular diseases that seem to promote adverse hepatic effects in OC users it may not even be justifiable to screen for them before prescribing OCs.

Oral contraceptives and neoplasia: 1987 update

This article reviews the research evidence on the relationship between oral contraceptives (OCs) and neoplasia. More recent epidemiologic studies in this area are considered to have greater validity than earlier studies, largely because of improved assessment of confounding factors. Encouraging has been the finding of a protective effect of OCs on endometrial and ovarian neoplasia: about 2000 cases of endometrial cancer and 1700 cases of ovarian cancer are averted in the US each year as a result of OC use. No consistent association, either adverse or beneficial, has emerged between OCs and breast cancer; however, high-dose combined OCs exert a protective effect on the development of benign breast disease after 2 years of use. Longterm combined OC use appears to be related to the development of benign liver lesions, but the research evidence on the association between OCs and hepatocellular carcinoma remains inconclusive. Of concern is the finding that longterm OC use is associated with an increased risk of cervical neoplasia. The mechanisms by which OCs might exert adverse effects on cervical epithelium are unclear.

Do Oral Contraceptive Agents Affect Nutrient Requirements - Vitamin B-6?

Although vitamin B-6 depletion and repletion studies conducted in the 1970s in small samples indicated that oral contraceptive (OC) use does not increase the requirement for this vitamin, there remain 2 reasons for concern about this issue. The 1st is that concentrations of plasma pyridoxal 5'-phosphate (PLP), the single best indicator of vitamin B-6 status, are depressed in the majority of OC users. This consistent finding is independent of dietary intake of the vitamin. The 2nd reason for concern is the potential effect of longterm OC use on the vitamin B-6 status of pregnant and lactating women. OC use exceeding 30 months has been associated with significantly lower serum concentrations of vitamin B-6 at 5 months gestation and at delivery and with lower Apgar scores; in addition, concentrations of vitamin B-16 in breast milk are lower in OC users than in nonusers. These 2 observations indicate that the requirement for vitamin B-6 is increased, even if only slightly, among OC users. Thus, the vitamin B-6 status should be continually evaluated in OC users, especially those who later desire pregnancy and plan to breastfeed. In addition, efforts should made to improve dietary intake of vitamin B-6 in women of childbearing age.

Increased UDP-glucuronyltransferase in putative preneoplastic foci of human liver after long-term use of oral contraceptives.

Previous research by the authors had suggested that uridine-diphosphate-glucuronyl-transferase (UDP-GT) is a useful preneoplastic marker in chemical carcinogenesis. Recently the authors report that they found typical clear cell foci in a macroscopically normal liver surrounding focal nodular hyperplasia with a 6 cm diameter in a 27-year old woman who had been using oral contraceptives (OCs) containing ethinyl-estradiol and lynestrenol for 9 years. These foci were further characterized by a reduction of canalicular and cytoplasmic ATPase activity an increased glycogen content and a positive immunohistochemical reaction for UDP-GT. OC users develop 2 basic types of benign liver tumors: hepatic adenoma and focal nodular hyperplasia. Hepatic adenoma appears to be caused by OCs whereas the relationship between OC use and focal nodular hyperplasia is less clear. The tumorigenic action of OCs has been ascribed to a promotor action on liver cells; however there is no evidence that OCs are initiators of liver tumors. The case reported shows 2 manifestations of toxic lesions promoted by OC use: the development of focal nodular hyperplasia and enzyme-altered foci comparable to those seen in experimental liver carcinogenesis. Further studies are needed to get more information about the preneoplastic potential of these foci in humans. Since enzyme-altered foci could not be identified in the liver tissue of healthy women these foci may be of prognostic significance in longterm OC users.

Oral contraception and cancer of the female reproductive system.

This paper reviews epidemiologic evidence regarding the association between exposure to oral contraceptives (OCs) and the development of 4 cancers involving the reproductive system: breast, ovarian, endometrial, and cervical. Most knowledge in this area has been derived from cohort or case-control studies. Currently available evidence suggests that OC use does not influence breast cancer risk either adversely or favorably, although there may be a favorable influence on tumor growth. In view of the long latency of effect seen with known risk factors such as radiation exposure, age at menarche, and age at 1st full-term pregnancy, further studies are needed in this area. The epidemiologic evidence consistently supports the prediction that OC use makes the ovaries less susceptible to malignant change, perhaps by a mechanism similar to the protective effect of pregnancies. The magnitude of the effect is considerable, and should have a significant impact on the future incidence of ovarian cancer. In terms of endometrial cancer, there is evidence that sustained estrogenic stimulation unopposed or inadequately opposed by progestogen leads to endometrial hyperplasia and an increased longterm risk of malignancy. In currently used OC formulations, however, the progestogenic component has the predominant effect on the endometrium, and this effect is protective. It remains unknown whether OCs increase cervical cancer risk directly, or whether the association is an indirect one linked to some aspect of sexual behavior that is not being controlled. On the other hand, it seems reasonable to conclude that longterm OC users have an above average risk of cervical cancer and should have regular screening by cervical cytology. It should be kept in mind that recent changes in OC formulations and use patterns render epidemiologic data now available obsolete. It will be many years before sound data will be available on the low-dose estrogen OCs now in almost universal use.

Risk factors for pathologically confirmed benign breast disease.

Between November 1981 and March 1983, data were collected to evaluate risk factors for benign breast lesions in a case-control study based on 288 women with histologically proven benign breast disease, admitted for biopsy to the Tumor Institute of Milan, and 285 age-matched controls. Questions were asked about menstrual and reproductive characteristics, marital status, education, history of various diseases, and lifetime use of oral contraceptives and other hormonal treatments. Nulliparity or low parity, late age at first birth, and late menopause were associated with an increased risk of benign breast disease. The elevated risk associated with late age at first birth was not accounted for by parity. Early age at menarche was associated with an increased risk, but the estimate was not statistically significant. The data do not suggest that the use of oral contraceptives or other female hormones (such as estrogen replacement therapy) is related to the risk of benign breast disease. Risk was apparently lower, however, among current and long-term oral contraceptive users. There was no evidence of a trend with reference to body mass index. The present data indicate a substantial agreement between the risk factors for (pathologically confirmed) benign and malignant breast disease, not only directly, by showing a relationship with parity, age at first birth, and age at menopause, but also indirectly, by failing to produce evidence that greater weight or the use of oral contraceptives has a protective effect.

Breast cancer and oral contraceptive use.

The risk of breast cancer in relation to oral contraceptive use was evaluated in a case-control study of 1191 patients with breast cancer and 5026 control patients. For ever-use compared with never-use, the estimated relative risk of breast cancer was 1.0 (95% confidence interval 0.9-1.2). Use of oral contraceptives for five or more years was not associated with breast cancer, regardless of whether use had ended as much as 10 or more years previously, or more recently. Within categories of women whose baseline risk was elevated, including nulligravidae, premenopausal women, and those with benign breast disease or history of breast cancer in first-degree relatives, the relative risk estimates for five or more years of oral contraceptive use approximated 1.0. For any use before first pregnancy, the relative risk estimate was 1.3, and for use lasting three or more years it was 0.9. These data suggest that long-term oral contraceptive use does not increase the risk of breast cancer even after a latent interval in excess of one decade; nor do oral contraceptives appear to increase the risk within categories of women at relatively high baseline risk.

Plasma pyridoxal phosphate in women taking oral contraceptives since at least five years.

This study was aimed at assessing the need for vitamin B6 in users of oral contraceptives (OCs). There is concern that OC use may alter the function of pyridoxal phosphate (Pal-P) as a co-enzyme in the niacintryptophan pathway. Plasma-Pl was determined in 290 healthy OC users, 275 of whom had been taking OCs for more than 5 years. The normal range is 20-60 nmol/1. Of the 275 longterm OC users, 25 (9%) had Pal-P values below 10 nmol/1 and 117 (43%) had values below 20 nmol/1; 9 had levels above 60 nmol/1. There was no correlation between Pal-P levels and oral glucose tolerance test results. In addition, Pal-P values were determined at onset of OC use, after 3 months, and again after 6 months in the 15 subjects who were not longterm users. 3 of these women showed decreasing values to below normal limits. These results suggest that a minority of women do develop low levels of Pal-P as a result of longterm OC use. Thus, it is recommended that longterm users be advised to increase their comsumption of pyridoxin-rich foods or take vitamin B6 supplements.

Female Breast Cancer

The 3 common diseases of the female breast are cystic hyperplasia, fibroadenoma and carcinoma. In discussing the 3rd and the most common forms of malignant disease, attention is directed to the following: criteria for source data selection (source data for distribution and for risk and etiological factors); distribution of female characteristics, environmental attributes, temporal variation, and a summary of major variables on breast cancer distribution); risk factors (pregnancy, ovarian activity, international variation, benign breast disease, familial aggregation); etiologic hypotheses (effect of contraceptive pill use on benign breast disease and effect of oral contraceptive (OC) use on breast cancer risk); and further hypotheses research. The most common cancer in women, breast cancer usually occurs in the years before the menopause. Factors favoring the development of breast cancer frequently are present early in life. Among women, breast cancer accounts for more than 1 out of very 4 cancers. The age-specific mortality and incidence rates of female cancer increase with age. This pattern is consistently present in both white and black groups. Age-adjusted mortality rates for female breast cancer by place of residence and race for the United States and for each geographic division and state for the 1959-1961 period are presented in table form. An elevated risk of breast cancer associated with long-term OC use has been reported among women with a biopsy diagnosis of benign breast neoplasia prior to the development of breast cancer.

The effect of oral contraceptive steroids and enzyme inducing drugs on sex hormone binding globulin capacity in women [proceedings

An improved assay for sex hormone binding globulin (SHBG) was used to confirm previously published results on the accumulation of SHBG in a group of 3 women starting oral contraceptive therapy with Minovlar. In all 3 women both SHBG and norethisterone concentrations increased 2-3 fold during the first cycle and in a woman studied for 3 months levels were stable by the end of the second cycle. A positive correlation was found between SHBG capacity and norethisterone concentration in all women. An animal model was also developed in which ethinyl estradiol was given orally to rabbits (50 mcg/kg) and goats (500 mcg) for 19 days with blood sample collections on alternate days. No increase in SHBG capactiy in either species was observed. 11 women were investigated to determine the effects of known enzyme-inducing drugs in women taking long-term oral contraception. Long-term therapy with phenobarbitone primidone phenytoin and carbamazepine was combined with an oral contraceptive of either 30 or 50 mcg of ethinyl estradiol. In women taking 30 mcg the SHBG capacity was significantly higher than in controls receiving only the oral contraceptives (P < .05). Similar results occurred in women taking 50 mcg of ethinyl estradiol. 8 women on long-term rifampicin therapy for tuberculosis and who were not on oral contraceptives had SHBG capacity measured 1 month before cessation of therapy and 1 month after stopping rifampicin and the capacity was significantly higher during rifampicin intake (P < .0005). SHBG capacity appears to be increased by drugs known to be enzyme-inducing agents.