How Does the Progestogen-only Pill Work?

Modern contraceptives have many mechanisms of action; some are combined hormonal contraceptives, some are progestogen-only, while others are intrauterine devices which release either copper or hormones. Implants, patches, and rings are also available, all of which are hormone-releasing.

The effects of the progestin-only pill (POP) are multiple. The progestin contained in these pills belongs to one of two families, the estranes and the gonanes.

Gonanes have greater intrinsic progestational activity than the estranes, and can therefore be administered in lower doses.

POP generations

The first-generation POP comprise estranes, including:

• norethisterone
• norethindrone
• ethynodiol diacetate
• lynestrenol
• norethynodrel

The second-generation gonanes:

• levonorgestrel
• norgestrel

The third-generation gonanes:

• desogestrel
• gestodene
• norgestimate

Newer progestins

• drospironene, which is a spironolactone derivative
• dienogest
• nestorone
• nomegestrel acetate
• trimegestone

The first and second-generation POP must be taken every day, with not more than a three hour difference between the time of ingestion on successive days.

The third-generation pill has a margin of 12 hours before it loses its efficacy. With newer progestogens, such as drospirenone, 24-hour delays during a cycle have not been shown to interfere with the inhibition of ovulation in that cycle.

Second- and third-generation progestins are associated with better patient satisfaction due to lower incidence of menstrual disturbances. Third-generation progestogens have also shown a greater contraceptive efficacy of up to 97 percent, which is comparable to that of combined oral contraceptives.

Modes of action of POP

Progestogen-only pills have multiple biological effects on the female body. Depending on the nature of the progestogen, the primary mechanism of contraception differs from one pill to the other, and also from the combined oral contraceptive pill.

• inhibition of follicular development
• inhibition of ovulation
• suppression of corpus luteum formation
• changes in the nature of the cervical mucus which inhibits the passage of sperms into the uterine cavity
• effects on the endometrium which affect implantation, at least in theory

Inhibition of ovulation

Progestins lead to a suppression of luteinizing hormone (LH) secretion, by producing a negative feedback on the synthesis and release of the gonadotropin-releasing hormone (GnRH) from the hypothalamus. This leads to the absence of the FSH and LH surge, which is essential to mature the developing dominant follicle, and trigger the event of ovulation.

With conventional POP, 60 percent of cycles are anovulatory. However, desogestrel-containing POP has been shown to suppress ovulation in 97 percent of cycles, making this the primary mechanism of action.

Midcycle peaks of FSH and LH are dampened, especially before the rise in progesterone, compared to the woman’s pretreatment cycles. Thus the mean FSH and LH levels are not much altered, but the peak values were noticeably lower.

Four types of reaction to POP have been noted:

• complete suppression of estradiol and progesterone secretion, signaling inhibition of ovulatory activity
• cyclic follicular development but without corpus luteum formation
• normal follicular growth but poor luteal phase activity
• no alteration in hormone production - most pregnancies may occur in this group

Cervical mucus changes

Cervical mucus changes are not always the most important mode of action but are the first to take place, occurring so rapidly as to provide contraceptive protection almost instantly if POP is begun within the first five days of the menstrual cycle.

In the first half of the normal menstrual cycle, estrogen causes the cervical mucus to become progressively thinner, alkaline, and clear, culminating in the production of copious, watery, ‘egg-white’ mucus around the time of ovulation. This allows the free passage of sperm from the cervix into the uterine cavity to achieve fertilization.

However, after this brief window of opportunity, the secretion of progesterone causes the mucus to become thick, white, and opaque, with a sticky consistency. The volume is greatly reduced to about 40 ml, while the viscosity and leukocyte content increases. Spinnbarkeit and ferning effects are almost lost, due to high cross-linking by siliac acid.
 

This is impermeable to sperm penetration. This effect is claimed to be the primary mechanism in the case of first- and second-generation low-dose POP, since many ovulatory cycles do occur with these pills, and because it occurs with very low concentrations of progesterone, unlike the other actions.

It is also the most short-lived mechanism of protection because the mucus becomes permeable to sperm within less than 24 hours of ingestion of the POP. This is responsible for the short window of protection after missing a pill. The other mechanisms then take on significance in maintaining protection.

Effects on fallopian tubes

Progestins cause a slowing of smooth muscle contractility and tubal motility as a result. Ciliary action is also reduced. This may contribute to the failure of fertilization, as the rate of progress of sperm and oocytes through the fallopian tubes is altered, along with sperm capacitation and sperm migration. This may be the reason for the higher incidence of ectopic gestation in POP users who become pregnant.

Endometrial effects

Progesterone normally leads to maturation and a secretory change in an already proliferated endometrium, prepared by the prior action of estrogen in the first half of the cycle. However, when the progestin-only pill is administered, the constant low level of a progestogen leads to the development of endometrial thinning with scanty and atrophied glands and very much reduced synthesis of progesterone receptors, which is hostile towards the implantation of a fertilized ovum.

The exposure of the endometrium to progestogen without prior priming by estrogen, in the case of the POP, contributes to endometrial instability. Dilated veins grow below the endometrial surface. These findings may be responsible for irregular or breakthrough bleeding with POP

POP acts through various combinations of these modes of action, but the variation between them depends to a large extent on the individual and the situation. Different organs react in different ways to the presence of low-dose progestogen, irrespective of the response of other organs. However, they may complement and potentiate the contraceptive effect.

Clinically, it is important to understand that scanty menstrual bleeding does not indicate lack of ovulation, although breakthrough bleeding occurs only with inhibition of ovulation. Many types of luteal phase dysfunction may accompany ovulation, such as low LH levels, short luteal phase and low levels of progesterone, and low estradiol levels.

This may further enhance contraceptive efficacy by reducing the rate of progress through the fallopian tube, as well as by hindering proper implantation. It is also possible that normal oocyte maturation is not taking place due to the abnormal hormonal milieu.

The slowed movement of the ovum through the fallopian tubes is presumably responsible for the occurrence of ectopic pregnancies. The implications of the bleeding patterns of POP users are not yet clear, with some studies reporting that bleeding patterns were most regular in women who ovulate, others not. The suppression of proliferation in the endometrium likewise may or may not be associated with intermenstrual bleeding.

Conclusion

Progestin-only pills prevent conception in several independent ways. They prevent ovulation in about half of cycles, smooth the midcycle LH and FSH peaks, slow the movement of the ovum through the fallopian tubes, thicken the cervical mucus to prevent sperm penetration, and alter the endometrium. The culmination of these effects makes the endometrium unfavorable for implantation. The significance of intermenstrual bleeding while on POPS has not been determined.

References

1. https://www.ncbi.nlm.nih.gov/pubmed/10561657
2. https://courses.washington.edu/conj/bess/contraception/contraception.htm
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2621397/
4. https://www.ncbi.nlm.nih.gov/pubmed/10226677