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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.

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  • 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. Aug 7, 2020 at 19:13

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The question refers to the finding that "(...) breakthrough bleeding is much more common with progestogen-only methods", see Wikipedia, Hormonal Contraception and inquires about how adding estrogen to progestogen-only pills apparently prevents breakthrough bleeding, as this seems a paradox because estrogen 1. builds up the placenta (the more the build-up, the more the bleeding, presumably) and 2. does not maintain the placenta (as progesterone does, thus preventing bleeding).

The question's argument is confirmed by a comment, see above:

"(...) unopposed estrogen causes out of proportion endometrium but it'll eventually shed."

Some answer is to be found in Wikipedia, Hormonal contraception:

"Estrogen was originally included in oral contraceptives for better cycle control (to stabilize the endometrium and thereby reduce the incidence of breakthrough bleeding)..."

As this answer (as many other sources) lacks explanation the following reasoning tries to explain what is known and what is yet unclear about the mechanism of action of estrogen in "combined" hormonal contraceptive.

First, some basic knowledge (from University of Berkeley):

"Estrogen:

Negative feedback:

  • occurs during follicular phases when estrogen levels are still low.

Positive feedback:

  • occurs at high concentrations near the end of the follicular phase, estrogen becomes a positive inducer of the anterior pituitary
  • positive feedback triggers the anterior pituitary to release more FSH and LH
  • more FSH and LH cause the ovary to produce more estrogen
  • the ensuing LH surge is responsible for ovulation"

Second, a summary of the following as the question turned out to be a difficult one, with several issues in science yet unresolved:

Estrogen combined to progesterone may compensate for a lack of estrogen caused by supplemented progesterone, the latter reducing the secretion of follicle-stimulating hormone thus preventing ovulation (cp. question's text) and, at the same time, by absence of FSH, not inducing the production of estrogen . Estrogen's regulatory role in the menstrual cycle might include the upholding of the production of progesterone (peaks of estrogen ask for such of progesterone, see quote highlighted above, LH known to induce progesterone production). Supplementation of estrogen might thus prevent any lack of progesterone as supplemented progesterone may downregulate its very production.

Third, explanatory text:

One basic understanding (cp. the comment above) is that it is the lack, the drop, of the progesterone level that causes the bleeding. There is no hormone or signaling molecule that actively initiates bleeding; it is the drop of production of progesterone the function of which is maintenance of (non-bleeding) placenta. As the question and the comment suggest this mechanism applies to estrogene in the same way, which asks for some explanation of the finding that estrogen is able to reduce breakthrough bleeding (as estrogen differs from progesterone in that respect, as it does not maintain the placenta, thereby preventing bleeding).

There is a second basic concept: the regulation of progesterone axis by the estrogen axis, to be distinguished by the feedback regulation of both hormones based on the hormones FSH and LH. Interestingly, feedback works via action of hypothalamic gonadotropin-releasing hormone which is one single hormone acting on both axis, the "pulse" of secretion deciding if the progesterone or estrogen axis is addressed.

Estrogen and progesteron are both dependent on stimulating hormones, i.e. follicle-stimulating hormone, FSH, and luteinizing hormone, LH. Any rise in estrogen or progesterone (by a regulatory feedback loop that uses the inhibin hormones acting on hypothalamus production of gonadotropin releasing hormone) is able to decrease its very production, and, second, there is an order of succession: the production of FSH consecutively leads to the production of LH; there is an "axis" FSH/LH, of estrogen followed by progesterone (in spite of almost simultaneous peaks of FSH and LH at the time of ovulation FSH (ovum) precedes LH (placenta). If there is no new ovulation there will be no new placenta. Estrogen as well as progesteron, in that feedback loop, seem to act on hypothalamic gonado-releasing hormone, thus up- und downregulating each other via FH and FSH homones.

See Wikipedia: "High-dose progestogen-only contraceptives, (...), completely inhibit follicular development and ovulation.": A progesterone-only pill, as it is able to inhibit the production of FSH may by inhibiting pathways decrease its own production (feedback reglation in a strict sense). However, it seem very likely that it downregulates estrogens "peak" function, thus its function to induce (non-supplemented) progesterone rises and possible decrease production. Conversely, the supplementation of estrogen may uphold the production of progesteron thus preventing shedding in case of lack of supplementation.

By suppressing FSH (known action of contraception, "at least when in high dosis", cp. question above) progesterone seems to be able to inhibit estron and and its own upregulation, thus production. Any drop of progesterone that is has been supplemented thus possibly leads to "non-maintainance" of the placenta by diminished substituting production.

As a result, this answer is:

Supplementation of estrogen may uphold the production of progesterone to compensate any drop in levels of supplemented progesterone thus preventing breakthrough bleeding.

Final remark: Any better answer must be simpler...

Edit:

Search results confirm that there does exist a direct effect of estrogen on production and secretion of progesterone:

"(...) circulating estrogen levels rise (...), they stimulate the hypothalamo-pituitary axis. This estrogen positive feedback is pivotal to stimulate the luteinizing hormone (LH) surge required for ovulation and luteinization of ovarian follicles. ... "Together, these data strongly suggest that estrogen enhances neuroprogesterone synthesis in the hypothalamus that is involved in the positive feedback regulating the LH surge.", see Micevych et al., The luteinizing hormone surge is preceded by an estrogen-induced increase of hypothalamic progesterone in ovariectomized and adrenalectomized rats, Neuroendocrinology 2003 Jul;78(1):29-35

Popular-scientific pages do not explain the mechanisms, e.g.

BBC, Hormones in human reproduction: "The oral contraceptive, which is known as the pill, contains oestrogen or progesterone. These hormones inhibit the production of FSH, and eggs cannot mature."

For some scientific explanation, see e.g.

Reed et al., The Normal Menstrual Cycle and the Control of Ovulation:

"Declining steroid production by the corpus luteum (...) for follicle stimulating hormone (FSH) to rise during the last few days of the menstrual cycle (...). Another influential factor on the FSH level in the late luteal phase is related to an increase in GnRH pulsatile secretion secondary to a decline in both estradiol and progesterone levels (...). This elevation in FSH allows for the recruitment of a cohort of ovarian follicles (...)"

However,Lesoon/Mahesh, Stimulatory and inhibitory effects of progesterone on FSH secretion by the anterior pituitary found: "These results indicate that the anterior pituitary is a major site of action of progesterone in the release of FSH and that 5 alpha-reduction of progesterone plays an important role in FSH release."

Even if the latter finding does not contractict the stated role of estrogen and progesteron, it doesn't surprise that the search result for action of progesteron in hormonal contraception inter alia is:

"Does progesterone affect the mechanism of ovulation?"

"The role of progesterone (P) in the mechanism of ovulation is controversial at best. (...)"

See also, in the context of postmenopausal breakthrough bleeding the conclusion of van de Weijer et al., Relationship of estradiol levels to breakthrough bleeding during continuous combined hormone replacement therapy, 1999:

"The occurrence of breakthrough bleeding during continuous combined hormone replacement therapy with estradiol and dydrogesterone in postmenopausal women was related to serum estradiol levels and not to dydrogesterone levels. Further studies are needed to test the hypothesis that estrogen is a major factor in the incidence of bleeding(...).

There is a related question on Stackexchange Biology: Use of progesterone in preventing ovulation?.

Last not least, some hint at Wikipedia on Human chorionic gonadotropin:

"Human chorionic gonadotropin interacts with the LHCG receptor of the ovary and promotes the maintenance of the corpus luteum for the maternal recognition of pregnancy at the beginning of pregnancy. This allows the corpus luteum to secrete the hormone progesterone during the first trimester."

Progesterone levels that correspond to those during pregnancy thus lack corresponding chorionic gonadotropin. That may also be meant by stating: "Estrogen was originally included in oral contraceptives for better cycle control", see above.

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    Do you realize you've edited this answer 18 times, and each time you do so the question gets bumped to the front page, displacing more recent questions? Could you possibly try to edit your answers offline until you have them right and then post them once?
    – Carey Gregory
    May 6, 2022 at 1:14
  • Thank you for your kind comment. I didn't even know that there is a review process, as I found out at meta: "Why can people edit my posts? How does editing work?". There, the bumping is not connotated being bad; on the other hand, please give some hint about how to edit offline, I shall do it, I will. May 6, 2022 at 6:09
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    Edits are perfectly fine and encouraged even, but not dozens of edits because that just keeps bumping the same question back to the top of the queue. Try to keep it to one or two edits, not 18. By editing offline I simply meant typing your answer into a text editor and then reviewing and editing that document until you've got it the way you want it. Then you can copy and paste that text as your answer.
    – Carey Gregory
    May 6, 2022 at 13:26
  • Thank you very much for so kindly and comprehensively informing. I promise to play by that rule. Again, thank you. May 7, 2022 at 12:26

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