Second Chapter
Dr. Álvaro Monterrosa Castro, MD
Lipid metabolism
Alterations in lipid metabolism, related to the use of oral contraceptives, are feared and have always created concern about the possible increase in the risk of cardiovascular disease (13,127). Plasma lipoproteins are the following: VLDL-cholesterol (very low density lipoprotein) that carry triglycerides to peripheral tissues.
LDL-cholesterol (low-density lipoproteins) carry cholesterol to peripheral tissues, with excess lipids being deposited on the arterial walls, thus forming atheromatous plaques.
HDL-cholesterol (high-density lipoprotein) carries excess cholesterol from peripheral tissues to the liver. Normally there is a balance between the components of this transportation system.
VLDL-cholesterol and LDL-cholesterol are considered atherogenic and promote cardiovascular diseases, while HDL-cholesterol are protective and are related to a decreased risk of cardiovascular diseases (127).
Estrogens have a beneficial effect by decreasing LDL cholesterol and increasing HDL cholesterol (83). Androgens have a harmful effect doing the opposite and progestins have important and variable effects apparently related to the dose, androgenic and/or antiestrogenic potency and the type of progestin.
Those progestins with androgenic activity decrease serum levels of protective HDL-cholesterol and if they also increase LDL-cholesterol, they will adversely affect the risk of atherogenesis and ischemic coronary artery disease.
Norgestimate
Norgestimate has potent progestational activity without androgenicity at therapeutic doses, and its progestational and androgenic effects assessed in laboratory assays indicate similarities with natural progesterone (54). Norgestimate and progesterone exhibit a similar affinity for uterine progesterone receptors and weak affinity for androgen receptors (128).
Desogestrel, norgestimate and Gestodene cause a slight increase in the concentration of HDL-cholesterol, while monophasic levonorgestrel pills greatly reduce HDL-cholesterol and induce increases in LDL-cholesterol (60), therefore, the latter are not would recommend to women who have some risk factor for cardiovascular disease.
Levonorgestrel is a progestin with greater androgenic potency and is occasionally associated with the development of acne (60). Combined oral contraceptives with Gestodene have the lowest total dose of progestin.
Women who received norgestimate plus ethinyl estradiol with norgestrel plus ethinyl estradiol
Chapdelaine et al (129) compared changes in the levels of the HDL-cholesterol fraction in women receiving norgestimate plus ethinyl estradiol with norgestrel plus ethinyl estradiol, also monophasic. After two years, women who received the first product showed a statistically significant increase, while users of the other preparation had an appreciable decrease.
The elevation in the HDL-cholesterol fraction contributes to a decrease in the LDL-cholesterol/HDL-cholesterol ratio, which is related to a lower risk of cardiovascular disease.
In turn, Patsch and collaborators (130) assert that the favorable changes observed in the level of HDL cholesterol, with the use of norgestimate plus triphasic ethinyl estradiol, had not been observed in women receiving other triphasic preparations containing levonorgestrel or norethindrone.
Although there are various mechanisms that cause oral contraceptives to have a protective effect on atherogenesis, the increase in HDL-cholesterol and the reduction in LDL-cholesterol may be factors that play an important role.
Lobo et al (127) cite evaluations by Gordon et al who maintain that an increase of 1 mg/dl of HDL-cholesterol is accompanied by a 3.5% reduction in the risk of coronary artery disease. At the same time, a decrease of 1 mg/dl in LDL-cholesterol is associated with a 2% reduction in risk.
The increase in HDL cholesterol levels associated with the use of third-generation pills could lead to the assumption that these new pills would have a favorable cardiovascular effect instead of causing an increase in atherosclerotic risk (127).
(Read Also: Impact on Carbohydrates)
The combination of 30 ug/day of ethinyl estradiol plus 2 mg/day of chlormadinone after six cycles of use induces a 13% increase in HDL-cholesterol and a 17% decrease in LDL-cholesterol.
Metabolic parameters do not appear to be significantly affected by combined oral contraceptives with 20 or 30 Ug/day of ethinyl estradiol (64).
Gestodene, which has greater antigonadotrophic activity than norethindrone, norgestimate, desogestrel or levonorgestrel, which has very low androgenicity and therefore little deleterious effect on lipids, and very minimal estrogenic activity, when used in combination with 20 Ug/day of ethinyl estradiol , provides a hormonal balance very close to ideal, which made it an interesting alternative for the late 20th century.
Studies have been carried out comparing the effects on HDL cholesterol and triglycerides of preparations of 20 and 30 ug/day of ethinyl estradiol, with the same progestin as reference. Brill et al (131) demonstrated that the 20 ug/day compounds show better performance, since they increase HDL cholesterol by 3%, while the 30 ug/day compounds decrease it by 9% after twelve cycles of use.
Microdose oral contraceptives increase triglyceride levels by 64%, while those with 20 ug/day only increase it by 21% after twelve cycles of use.
In a study (73) it was observed that the administration of 15 ug/day of ethinyl estradiol plus 60 ug/day of Gestodene, compared to 20 ug/day of ethinyl estradiol plus 150 ug/day of desogestrel, both preparations significantly decreased the average levels of cholesterol and LDL-cholesterol.
In the group receiving desogestrel, HDL-cholesterol increased significantly and triglyceride levels increased significantly in both groups. There were no clinically important changes, and it is not expected that the magnitude of the modification in lipid levels would generate the appearance of any cardiovascular risk in healthy women.
With the administration of 30 ug/day of ethinyl estradiol plus 2 mg/day of dienogest, the effects that estrogens cause on lipids are not modified, that is, the increase in HDL-cholesterol and the decrease in LDL-cholesterol, since These modifications are carried out by the progestin due to intrinsic androgenicity, and dienogest does not have the binding capacity on androgen receptors (56).
In 2004 Gaspard et al (132) published the results of an open, randomized study in 50 women who were 21.5 +/- 2.0 years of age, weight 56.4 +/- 6.4 kilograms, height 165.1 +/- 5.6 centimeters in height and body mass index of 20.5 +/- 2.0 kg/square meter, to study and compare the influence on lipids and lipoprotein metabolism after 13 cycles of 30 ug/day of ethinyl estradiol plus 3 mg/day of drospirenone with 30 ug/day of ethinyl estradiol plus 150 ug/day of desogestrel.
It was observed that the pill with drospirenone induced an increase in HDL-cholesterol of +12.8%, while the pill with desogestrel did so by +11.8%, results that are very consistent with those found in various evaluations.
HDL-cholesterol plays a positive cardiovascular effect in the transport of cholesterol as well as in the phenomena of “vasomotion” at the endothelial level by inhibiting the oxidation of LDL-cholesterol by stopping the fixation of macrophages, controlling the expression of vascular adhesion cells and regulate the metabolism of thromboxane and prostacyclin.
Various studies have indicated that high levels of HDL-cholesterol are associated with a lower development of cardiovascular events, therefore the two combined oral contraceptives would have a small benefit or at least do not exert a clinical disadvantage(132).
In the same study (132) no significant changes were observed when assessing HDL-2-cholesterol, HDL-3-cholesterol, LDL-cholesterol and VLDL-cholesterol comparing from baseline to the end of the study and neither between the two pills considered.
Triglycerides increased by 73.6% +/- 51.3 with the pill that included drospirenone and 61.3 +/- 44.8% with the desogestrel pill. The elevation of triglycerides is directly related to the dose of estrogen provided.
If the increase is large and persistent, a greater association is observed with pancreatitis if blood levels are greater than 500 mg/dl and cardiovascular phenomena when blood levels are greater than 300 mg/dl. All modern combined oral contraceptives offer the slight elevation observed in the aforementioned study (132), which would lack clinical impact, especially due to the need for the association of elevated triglycerides with the accumulation of VLDL-cholesterol to induce atherogenic processes.
An elevation of APO A-1, APO-A-II, and APO B lipoproteins was also observed with both pills, while a decrease in APO-E and Lipoprotein (a) occurred.
The increase in apolipoproteins APO-A-1, and APO-B, as well as triglycerides are characteristics of the action of ethinyl estradiol on liver function. It is well known that ethinyl estradiol inhibits hepatic lipoprotein lipase and stimulates the synthesis of apolipopreteins.
Elevation of APO-A-1, in accordance with HDL-cholesterol, is considered beneficial in terms of cardiovascular protection.