Pharmacodynamics of combined estrogen–progestin oral contraceptives: 4. Effects on uterine and cervical epithelia

ABSTRACT

Introduction: Steroid hormones are responsible for specific changes in the endometrium during the menstrual cycle, when they are sequentially secreted and, because of this, in the early days sequential combined oral contraceptive regimens were utilized. The same basic concept has been utilized with multi-phasic regimens, in order to produce endometrial pictures mimicking the normal cycle.

Areas covered: The Endometrial effects of progestins and estrogens; combined monophasic high- (50 μg), medium- (30 μg), low- (20 μg), ultralow- (15 μg) estrogen content; sequential regimens; multiphasic combinations; treatment schedules.

Cervical effects of combined high-dose and sequential combinations, including evidence for an increase in malignant lesions.

Expert opinion: Overall, combined oral contraceptives (COCs) inhibit normal proliferative changes and the endometrium becomes thin, narrow, with widely spaced glands and pre-decidual changes in the stroma. During the first few cycles the progestin induces a coexistence of proliferative and secretory features; with time, the picture changes because the progestin induces a down-regulation of estrogen receptors, resulting in tortuous glands similar to those in the secretory phase, but characterized by a quiescent, atrophic glandular epithelium.

In the cervical epithelium, under the influence of high-dose COCs, endocervical glands became hypersecretory and in some instances, distinctive type of atypical polypoid endocervical hyperplasia is found.

KEYWORDS:

• Combined oral contraceptives
• sequential oral contraceptives
• monophasic
• polyphasic regimens
• endometrium
• cervix

Article highlights

• Different progestins exert diverse biological activities and actions on the endometrium.

• In general, sequential regimens produce an overall endometrial picture closer to the physiological one. However, they had to be abandoned because of an increased risk of endometrial cancer.

• Non-sequential regimens (with different dosages, or schedule of administration) result in a variety of morphological endometrial pictures, ranging from an atrophic endometrium to an almost normal secretory activity.

• The use of natural estrogens (micronized 17β-estradiol, estradiol valerate, estetrol) in a COC is a promising development; unfortunately, no specific studies have so far addressed the issue of their effect on the endometrium.

• High-dose COC produces alterations of the cervical epithelium, including a hyper-secretive status of endocervical glands; in some cases, these modifications result in an atypical polypoid endocervical hyperplasia. These lesions, however, have been considered benign.

• There is evidence of an increased risk of cervical neoplasia in COC users. At the same time, the relationship between the use of COCs, the presence of HPV infection, and cervical malignancies needs to be further clarified.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.