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The development of oral contraceptives in the 1960s revolutionized how women perceive menstruation which catapulted the development of this drug as one of the most used and researched pharmaceuticals on the market. Oral contraceptives gave women control over the timing and symptoms associated with menstruation as well as a 0.03% chance of pregnancy with perfect use. In addition, as the drug evolved through the decades the risk of adverse effects are reduced without compromising its efficacy. These characteristics create an attractive alternative to being subjected to the discomforts of pre-menstrual symptoms, unpredictable cycles, and pregnancy woes. This article will discuss how the hormones involved in combined oral contraceptives prevent ovulation and conception through analyzing different studies on the most common medications.
In the 1960s, the first combined oral contraceptives contained high doses, greater than 50Âµg, of estrogen and progesterone. But such high doses increase a woman's chance of developing pulmonary embolism, venous and arterial thromboembolism, cerebral thrombosis, and ishaemic heart disease (Russell et al 1967). Modern oral contraceptives contain 20-35Âµg of ethinyl estradiol which is the most commonly used estrogen. "Estradiol is the major estrogen produced by the ovary but its use is limited due to poor absorption when taken in a non-micronized form." (Wright et al 2008) But with the addition of an ethinyl group, the compound becomes orally active requiring a lower dosage to be just as effective.
Also the progesterone component in combined oral contraceptives have not decreased significantly in dosage over the last forty years they have undergone different waves of transformations to reduce any adverse effects. In the first generation, norethynodrel was the most common in the 1960s and is metabolized by the body into norgestrel and levonorgesterel. Levonorgesterel was later isolated as the second generation of progesterones. The third generation of progesterones involve desogersterel and norgestimate which is metabolized into levonorgesterel in the body. In a study by Kulier et al, all three generations were combined with less than 50 Âµg of ethinyl estradiol and compared to one another based on effectiveness, cycle control, and side effects. The conclusion of this study indicated that "the third and second generation progestogens are preferred over first generation in all indices of acceptability." (Kulier et al 2004) Although third generation progestogens are preferred, the second generation levonorgesterel is the most commonly used compound in modern day combined oral contraceptives.
The main focus of combined oral contraceptives is to inhibit ovulations from occurring in order to prevent pregnancy through a variety of mechanisms. In a study done by Hemrik et al, evidence supports that combined oral contraceptives, specifically ethinyl estradiol, work at the level of the hypothalamus in the hypothalamo-pituitary-gonadal axis. A large dose of GnRH (gonadatrophin releasing hormone) was injected into women taking the same combined oral contraceptives for at least 3 months. After four days of pulsatile GnRH stimulation, an increase in endogenous LH (lutenizing hormone), FSH (follicle stimulating hormone), and endogenous estradiol levels were observed. Also follicle like structures appeared in the ovaries of some subject but regressed once GnRH stimulation ended. Once GnRH treatments ceased LH, FSH, and endogenous estradiol levels decreased back to normal levels associated with taking combined oral contraceptives. These results demonstrate that the anterior pituitary is functionally capable of producing gonadatropins because the organ is still sensitive to GnRH while on combined oral contraceptives. The study concluded that combined oral contraceptives work at the level of the hypothalamus suppressing GnRH release and not at the anterior pituitary directly.
Ethinyl estradiol acts on the hypothalamus via a negative feedback system which is dominant in the follicular and luteal phase of the menstrual cycle. In the follicular phase, estrogen levels are low and by increasing these steroids in the body from ingesting combined oral contraceptives, the hypothalamus stops producing GnRH which prevents the anterior pituitary gland from secreting LH and FSH and then the ovaries do not receive the signal to produce estrogens in order to keep estrogen levels in a well defined limit. For ovulation to occur two events need to happen: high estrogen levels to stimulate kisspeptin neurons in the AVPV (anteroventral paraventricular nucleus) and circadian signal from the SVN (suprachiasmatic neuron). Kisspeptin neurons in AVPV have receptors for estrogen so when estrogen increases it stimulates the AVPV to release kisspeptin which upregulates the release of GnRH and ultimately causes the LH surge as positive feedback becomes more dominant. But if estrogen levels are not high enough, which can be due to combined oral contraceptives, they bind to neurons in the arcuate nucleus which favors a low kisspeptin release and ultimately a regular day to day release of GnRH. During ovulation cells change in the median eminence, a highly vascularized area that allows communication between the hypothalamus and the anterior pituitary, to allow more GnRH to enter the portal system of blood vessels to the anterior pituitary. But ethinyl estradiol keeps the level of estrogens low and that causes tight junctions in the portal system to form preventing GnRH from entering the portal system and affecting the anterior pituitary. Essentially what combined oral contraceptives are doing during the active pill cycle is extending the follicular phase by preventing ovulation while still allowing the luteal phase to continue during the hormone free intervals of the placebo cycle.
According to Baerwald et al's analysis of literature on ovarian follicular development, "ovarian follicular development is not completely inhibited during standard use of combined oral contraceptives" (Baerwald et Al 2004) which means that combined oral contraceptives primarily prevent pregnancy via the hypothalamus and not the ovaries. In a study done by Van Heusden et al, ten follicles greater than 10mm, which is considered a dominant follicle, developed on the third day of taking the combined oral contraceptive in seven of the thirty-six women despite suppressed levels of LH, FSH and endogenous estradiol. This is important because the early stages of ovarian follicular development are sensitive to LH and FSH but are not dependent on these gonadatrophins until the final days leading up to ovulation. Because follicles were observed, the ovaries are still functioning while the women are on combined oral contraceptives.
During the hormone free interval, the effects of combined oral contraceptives decrease and the hypothalamo-pituitary-gonadal axis can regain some function until the next cycle of active pills. In a study done by Keuhl et al, a group of women were assign to take a 21/7 day regimen for two months and then they were given a 168/7 day extended phase of combine oral contraceptives in order to compare the effect each treatment had on hormone levels. In both treatments the results during the hormone free interval were very similar, "FSH has been shown to increase on days 3-4 of the hormone free interval, allowing follicular recruitment and estradiol production." (Keul et al 2008) Because of the FSH increase during the hormone free interval, it is especially risky for women who extend this interval by missing a pill or starting their treatments on Sundays rather than day 1 of the menstruation cycle. These women increase the follicular growth to a potentially ovulatory diameter . In order to prevent ovulation, the dose of ethinyl estradiol must be low enough to prevent adverse side effects but still high enough to decrease FSH levels and suppress follicular growth at the start of a new active pill cycle.
Although it has been discussed that combined oral contraceptives primarily inhibit ovulation via the hypothalamus, there are many secondary mechanism on cervical permeability and uterine endometrial receptivity to ensure optimal protection against an unwanted pregnancy. In a study done by Winfried et al, the ovarian activity in women taking combined oral contraceptives for three cycles were monitored. If follicular activity was present, uterine endometrial thickness and permeability of cervical mucus of those women were examined. They observed that "the quality of cervical mucus was minimal in more than 95% of all cycles during all treatments of combined oral contraceptive". (Winfried et al 1997) If cervical mucus is too thick or not abundant, due to high levels of progesterone from the combined oral contraceptives, the sperm can not travel through the cervix to the uterus and up the fallopian tube to meet the ovum if it was released. The study also revealed the endometrial thickness to be lower than 8 mm in majority of the women demonstrating the impaired endometrial receptivity. If the endometrium is not thick enough then the blastocyst will not have a sufficient amount of tissue to burrow in to during implantation and ultimately the blastocyst will not be able to release the hormones necessary to maintain the corpus luteum into the mother's circulatory system and the blastocyst will die. In all the studies analyzed in this article ovulation did not occur but it is a reassuring point that there are multiple levels of protection.