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Background

In hormonal contraception, two types of hormones are used; estrogens and progestogens. The progestogens are the type of hormone that is mainly responsible for the contraceptive effects. They thicken the cervical mucus, suppress the ovulatory FH surge (at least if the dosage is not too low), and have an anti-proliferative effect on the endometrium resulting in the prevention of possible implantation if the other checkpoints would fail. The estrogen was only added to the formulation by chance. As the pill was developed, John Rock experimented with norethynodrel, developed by Frank Colton in 1952. The daily dose of 10 mg effectively suppressed ovulation in all women, and no breakthrough bleeding occurred. Due to these encouraging results, Rock wanted to further purify the norethynodrel. When he tested his formulation again, breakthrough bleeding occurred. This led to the discovery that the first batch of norethynodrel was contaminated with another hormone, mestranol. Mestranol is a synthetic estrogen, apparently inhibiting breakthrough bleeding. This accidental discovery led to the addition of 150 µg of mestranol to the 10 mg of norethynodrel in the first contraceptive pill, Enovid.

Since then, new progestogens have been developed, allowing to drastically reduce the dose from 10 mg to something in the range around 150 µg. As the use of estrogens is contraindicated for some women due to the well established pro-thrombotic effect, progestogen-only contraceptive pills have been developed. One of the most common ones - at least in western Europe - is Cerazette, containing 75 µg of desogestrel. As already noticed by John Rock in the early 50s, omitting the estrogen leads to a higher risk of breakthrough bleeding. According to MSD, the manufacturer of Cerazette, 20% of users have no breakthrough bleeding at all, and 20% of users have very strong breakthrough bleeding, which is similar to the withdrawal bleeding in combined oral contraceptives. The other 60% of users share physiologic behavior between these two extremes.

Question

I'm struggling with understanding why the estrogen has such an important effect on breakthrough bleeding, and I'm unable to find a good answer to this very question. Estrogens have a proliferative effect on the endometrium, so you'd guess that this could even make things worse, isn't it? If the estrogen competes with the progestogen and the proliferative effect of the estrogen takes over, the endometrium would be able to build up. Wouldn't this mean that breakthrough bleeding could be stronger because now there is more to get rid of?

I would be very pleased if someone could explain this effect in some details and maybe also point to the relevant resources.

  • yes you're thinking correctly, unopposed estrogen causes out of proportion endometrium but it'll eventually shed(perhaps say, after an anovulatory cycle where progesterone will be least), this was earlier referred as dysfunctional uterine bleed, now it's under AUB(abnormal uterine bleed). You see progesterone is important to cause "differentiation and maturation and development of glands" of tissue, estrogen mainly causes proliferation. Have a look on medscape article on abnormal uterine bleeding, or if available you may look for topic AUB in Shaw's Text of Gynecology. – Physicsapproval Aug 7 at 19:13

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