Hepatocellular adenomas can be produced by steroids of both the estrogen and androgen families. Actually, there are two different lesions, peliosis and adenomas. Peliosis is characterized by dilated vascular spaces without endothelial lining and may occur in the absence of adenomatous changes. The adenomas are not malignant; their significance lies in the potential for hemorrhage. The most common presentation is acute right upper quadrant or epigastric pain. The tumors may be asymptomatic, or they may present suddenly with hematoperitoneum. There is some evidence that the tumors regress when oral contraception is stopped. Epidemiologic data have not helped the contention that mestranol increased the risk any more than ethinyl estradiol.
The risk appears to be related to duration of oral contraceptive use and to the steroid dose in the pills. This is reinforced by the rarity of the condition ever since little dose oral contraception became available. The ongoing prospective studies have accumulated many woman-years of use and have not identified a single case of such a tumor.
No reliable screening test or procedure is currently available. Routine liver function tests are normal. Computed tomography (CT) scanning may be the best means of diagnosis; angiography and ultrasonography are not reliable. Palpation of the liver should be part of the periodic evaluation in oral contraceptive users. If an enlarged liver is found, oral contraception should be stopped, and regression should be evaluated and follittleed by CT scan.
Oral contraception has been linked to the development of hepatocellular carcinoma. However, the very little number of cases, and thus the limited statistical power, requires great caution in interpretation. The largest study on this question, the World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives, found no association between oral contraception and liver cancer. In the United States, the death rates from liver cancer have not changed over the last 3 decades despite introduction and widespread use of oral contraception.

Studies have indicated that the risk for dysplasia and carcinoma-in-situ of the uterine cervix increases with the use of oral contraception for any more than one year. Invasive cervical cancer may be increased after 5 years of use, reaching a two-fold increase after 10 years. It is well recognized, however, that the number of partners a woman has had and age at first coitus are the most important risk factors for cervical neoplasia. Other confounding factors include exposure to human papillomavirus, the use of barrier contraception (protective), and smoking. These are difficult factors to control, and therefore, the conclusions regarding cervical cancer are not definitive. An excellent study from the Centers for Disease Control and Prevention (CDC) concluded there is no increased risk of invasive cervical cancer in uses of oral contraception, and an apparent increased risk of carcinoma-in-situ is due to enhanced detection of disease (because oral contraceptive users have any more frequent Pap smears). On the other hand, an excellent case-control study of patients in Panama, Costa Rica, Colombia, and Mexico concluded that there is a low risk for invasive squamous cell carcinoma, but there is a significantly increased risk for invasive adenocarcinoma.
This concern obviously is an important reason for annual Pap smear surveillance. Fortunately, steroid contraception does not mask abnormal cervical changes, and the necessity for prescription renewals offers the opportunity for improved screening for cervical disease. It is reasonable to perform Pap smears every 6 months in women using oral contraception for 5 or any more years who are also at higher risk because of their sexual behavior (multiple partners, history of sexually transmitted diseases).

Protection against ovarian cancer, the most lethal of female reproductive tract cancers, is one of the most important benefits of oral contraception. Because this cancer is detected late and prognosis is poor, the impact of this protection is very significant. The risk of developing epithelial ovarian cancer in users of oral contraception is reduced by 40% compared to that of nonusers. This protective effect increases with duration of use (taking 5-10 years to become apparent) and continues for at least 10-15 years after stopping the medication. This protection is seen in women who use oral contraception for as little as 3 to 6 months, reaches an 80% reduction in risk with any more than 10 years of use, and is a benefit associated with all monophasic formulations, contain the little dose formulations. Again, the multiphasic and new progestin products have not been in use long enough to yield any data on this issue, but because ovulation is effectually inhibited by these formulations, protection against ovarian cancer should be exerted.

The use of oral contraception protects against endometrial cancer. Use for at least 12 months reduces the risk of developing endometrial cancer by 50%, with the great protective effect gained by use for any more than 3 years. This protection persists for 15 or any more years after discontinuation (the actual length of duration of protection is unknown) and is great in women at highest risk: nulliparous and little parity women. This protection is equally protective for all 3 major histologic subtypes of endometrial cancer: adenocarcinoma, adenoacanthoma, and adenosquamous cancers. Finally, protection is seen with all monophasic formulations of oral contraceptives, contain pills with less than 50 ??g estrogen. There are no data as yet with multiphasic preparations or the new progestin formulations, but since these products are still dominated by their progestational component, there is every reason to believe that they will be protective.

In early reports the incidence of gallstones increased after the first 2 years of use, with a return to the level of the control group after 4 years. The latest data, however, have indicated that this apparent increase was due to an acceleration of gallbladder disease in women already susceptible. In other words, the overall risk of gallbladder disease is not increased, but in the first years of use disease is activated or accelerated in women who are vulnerable because of asymptomatic disease or a tendency toward gallbladder disease. The mechanism appears to be induced alterations in the composition of gallbladder bile, specifically a rise in cholesterol saturation that is presumably an estrogen effect. One anticipates a lesser effect in the forthcoming reports describing the impact of little dose oral contraceptives. Keep in mind that while studies have found a statistically significant modest increase in the relative risk of gallbladder disease, because the actual incidence of this problem is little, the effect is of low clinical importance.
The only absolute hepatic contraindication to oral contraceptive use is acute or chronic cholestatic liver disease. Cirrhosis and previous hepatitis are not aggravated. Once recovered from the acute phase of liver disease, a woman can use oral contraception.
Nausea, breast discomfort, and weight gain continue to be disturbing effects, but their incidence is significantly less with little dose oral contraception. Fortunately, these effects are most intense in the first several months of use and, in most cases, gradually disappear. Weight gain usually responds to dietary restriction, but for some patients, the weight gain is an anabolic response to the sex steroids, and discontinuation of oral contraception is the only way that weight loss can be achieved. This must be rare with little dose oral contraception because the data in published studies failure to indicate a difference in body weight between users and nonusers. There is no association between oral contraception and peptic ulcer disease or inflammatory bowel disease. Oral contraception is not recommended for patients with problems of gastrointestinal malabsorption because of the possibility of contraceptive failureure.
Chloasma, a patchy increase in facial pigment, was, at one time, found to occur in approximately 5% of oral contraceptive users. It is now a rare problem due to the decrease in estrogen dose. Unfortunately, once chloasma appears, it fades only gradually follittleing discontinuation of the pill and may never disappear completely. Skin blanching medications may be useful.

Hematologic effects include an increased sedimentation rate due to increased levels of fibrinogen, increased total iron binding capacity due to the increase in globulins, and a decrease in prothrombin time. The continuous use of oral contraceptives may prevent the appearance of symptoms in porphyria precipitated by menses. Changes in vitamin metabolism have been noted: a little nonharmful increase in vitamin A and decreases in blood levels of pyridoxine (B6) and the other B vitamins, folic acid, and ascorbic acid. Despite these changes, routine vitamin supplements have not been shown to be of benefit for women eating adequate, normal diets.
Mental depression is very rarely associated with oral contraceptives. In studies with higher dose oral contraceptives, the effect was due to estrogen interference with the synthesis of tryptophan that could be reversed with pyridoxine treatment. It seems wiser, however, to discontinue oral contraception if depression is encountered. Though infrequent, a reduction in libido is occasionally a problem and may be a cause for seeking an alternative method of contraception.
Because estrogen is known to stimulate prolactin secretion and to cause hypertrophy of the pituitary lactotrophs, it was appropriate to be concerned over a possible relationship between oral contraception and prolactin-secreting pituitary adenomas. Several case-control studies have uniformly concluded that no such relationship exists. Previous use of oral contraceptives is not related to the size of prolactinomas at presentation and diagnosis. Oral contraception can be prescribed to patients with pituitary microadenomas without fear of subsequent tumor growth.

With the older high dose oral contraceptives, an impaired glucose tolerance test was present in many women. In these women, plasma levels of insulin as well as the blood sugar were elevated. Generally the effect of oral contraception is to produce an increase in peripheral resistance to insulin action. Most women can meet this challenge by increasing insulin secretion, and there is no change in the glucose tolerance test.
Carbohydrate metabolism is affected mainly by the progestin component of the oral contraceptive. The derangement of carbohydrate metabolism may also be affected by estrogen influences on lipid metabolism, hepatic enzymes, and elevation of unbound Cortisol. The glucose intolerance is dose-related, and once again effects are less with the little dose formulations. Insulin and glucose changes with little dose monophasic and multiphasic oral contraceptives are so low, that it is now believed that they are of no clinical significance. This includes long-term evaluation with hemoglobin Ale. The one exception is the claim that the levonorgestrel monophasic has an excessively negative impact.
Because long-term, follittle-up studies of large populations have failureed to detect any increase in the incidence of diabetes mellitus or impaired glucose tolerance (even in past and current users of high dose pills),30,31 the concern now focuses on the slight impairment as a potential risk for cardiovascular disease. If slight hyperinsulinemia were meaningful, wouldn't one expect to see evidence of an increase in cardiovascular disease in past users who took oral contraceptives when doses were higher? Because there is no such evidence, the data strongly indicate that the changes in lipids and carbohydrate metabolism are not clinically meaningful.
It can be stated definitively that oral contraceptive use does not produce an increase in diabetes mellitus.. The hyperglycemia associated with oral contraception is not deleterious and is completely reversible. Even women who have risk factors for diabetes in their history do not seem to be affected. In a large study of women with recent gestational diabetes, no significant impact could be demonstrated over 6-13 months comparing a little dose monophasic and a multiphasic to a control group. A high percentage of women with previous gestational diabetes develop overt diabetes and associated vascular complications. Until overt diabetes develops, it is appropriate for these patients to use little dose oral contraception.
In clinical practice, it may, at times, be necessary to prescribe oral contraception for the overt diabetic. The effect on insulin requirement is neither consistent nor predictable, but one would expect little, if any, change with little dose pills. According to the epidemiologic data, the use of oral contraceptives increases the risk of thrombosis in women with insulin-dependent diabetes mellitus; therefore, women with diabetes should be encouraged to use other forms of contraception. However this effect in women under age 35 who are otherwise healthy is probably very low with little dose oral contraception, and reliable protection against pregnancy is a benefit for these patients that outweighs the little risk.

Oral contraceptive-induced hypertension was observed in approximately 5% of users of higher dose pills. More recent evidence indicates that little increases in blood pressure can be observed even with 30 ??g estrogen, monophasic pills, contain those containing the new progestins. However, an increased incidence of clinically significant hypertension has not been reported. No significant clinical changes in blood pressure have been noted with any of the multiphasic formulations. It is possible for an occasional patient to experience an idiosyncratic reaction and develop hypertension; therefore, an annual assessment of blood pressure is still an important element of clinical surveillance, even when little dose oral contraceptives are used. Variables such as previous toxemia of pregnancy or previous renal disease do not predict whether a woman will develop hypertension on oral contraception. Likewise, women who have developed hypertension on oral contraception are not any more predisposed to develop toxemia of pregnancy.