For hormonal contraception (hormonal contraceptives), estrogen-progestin combination preparations are predominantly used; more rarely, drugs containing only a progestin are used. They are used orally, transdermally (“through the skin“), vaginally (“via the vagina”), intrauterinally (intrauterine device/coil), subdermally (implant/hormone implant; contraceptive sticks) and intramuscularly (“into the muscle”) (depot preparation). The different compositions, dosages and methods of application allow an individual choice for the user, even in the case of risks or illnesses, but they also include sometimes very different side effects that must be taken into account when prescribing. Estrogens
- Synthetic estrogens:
- Ethinylestradiol (EE) is a synthetic estrogen used in most contraceptives. It is much more potent than natural estrogen. The ethynyl group (ethynylation) causes stabilization and prolonged mobilization and thus increased biological availability of estrogen.
- Mestranol, a prodrug* of ethinyl estradiol, which is metabolized (metabolized) in the liver to ethinyl estradiol, is no longer used today because of the individually very different conversion in most countries, as well as Germany.
- Natural estrogen
- Estradiol valerate, an ester, is a prodrug of bioidentical synthetic estradiol with valeric acid. The latter ensures good absorption in the intestine and is metabolized in the liver to estradiol and valeric acid.
* Inactive or low active pharmacological substance referred to, which is converted into an active substance only by metabolism in the organism.
Progestins
Progestins (synonyms: progestagens, progestogens, progestins) are substances that cause secretory transformation of the endometrium. There is an abundance of progestogens, many of which are derived from progesterone or testosterone and, as a single substance, from spironolactone.
- The natural progestin progesterone is not suitable for ovulation inhibition (inhibition of ovulation) (it is used only during pregnancy and for postmenopausal hormone therapy).
- Of synthetic progestins, there are a variety that are used both for contraception, postmenopausal hormone therapy (period that begins when menstruation has been absent for at least a year) and also for gynecological diseases
- For contraception, they are used as combination therapy with ethinyl estradiol or estradiol valerate
- As progestogen monotherapy in the mini-pill, the “morning-after pill”, in intrauterine devices (IUDs), in the subdermal implant, in the three-month injection
Listed here from the variety are only progestins contained in contraceptives (contraceptive drugs):
Progesterone derivatives
- 17-alpha-medroxyprogesterone derivatives (pregnanes).
- Chlormadinone acetate (CMA)
- Cyproterone acetate (CPA)
- Medroxyprogesterone acetate (MPA)
- 19-Norprogesterone derivatives (19-norpregnans).
- Nomegestrol acetate (NOMAG) (Nomegestrol).
Testosterone derivatives
- 19-Nortestosterone derivatives (Estrane).
- Dienogest (DNG)
- Lynestrenol (LYN) (prodrug of norethisterone).
- Norethisterone (NET)
- Norethisterone acetate (NETA) (prodrug of norethisterone).
- 19-Nortestosterone derivatives (13-ethylgonanes).
- Desogestrel (DSG) (prodrug of etonogestrel = 3-keto-desogestrel).
- Etonogestrel (ENG) (3-keto desogestrel).
- Gestodene (GSD)
- Levonorgestrel (LNG) (active metabolite of norgestimate).
- Norelgestromin (NGM) (active metabolite of norgestimate).
- Norgestimate (NGT) (prodrug of norelgestromin and levonorgestrel).
Spironolactone derivatives
- Drospirenone (DRSP)
Progestin generations
The progestogens are divided into three generations according to the period of development (early sixties, seventies, eighties). However, this refers only to the nortestosterone derivatives. All other progestins are referred to as unclassified.
- First generation: dienogest, norethisterone, norethisterone acetate, lynestrenol (prodrug of norethisterone) (no longer commercially available in Germany).
- Second generation: Levonorgestrel, Norgestrel (no longer commercially available in Germany, racemate of Levonorgestrel).
- Third generation: desogestrel, etonogestrel, gestodene, norelgestromin, norgestimate
- Unclassified progestogens: cyproterone acetate, drospirenone, medroxyprogesterone acetate, nomegestrol acetate.
Progestogens have a wide spectrum of effects (androgenic, antiandrogenic, glucocorticoid, antimineralocorticoid, estrogenic partial effects (see Table 1), which must be considered in the indication, especially from the point of view of side effects and diseases. Contraceptive mechanism of action
The main mechanism of contraception is inhibition of ovulation. This is primarily effected by the dose and type of progestin. The estrogen primarily serves to stabilize the cycle. In combination preparations, estrogens and progestins complement each other by acting centrally synergistically, inhibiting the release of gonadotropins (sex hormones that stimulate the function of the gonads) and thus impairing follicle maturation (egg maturation).In practice, the ovulation-inhibiting dose of progestins is usually chosen to be significantly higher than necessary, which has the advantage that the dose of ethinylestradiol can be reduced, leading to a reduction in estrogenic side effects. Estrogens
The contraceptive effects of estrogens are induced
- Centrally by suppression of the
- Hypothalamic GnRH release.
- Pituitary FSH, LH secretion
- peripherally by inhibition of
- Follicle maturation (oocyte maturation).
- Ovulation (ovulation)
- Corpus luteum formation (corpus luteum formation).
Progestins
The contraceptive effect of progestogens is induced
- Centrally by suppression
- Of the hypothalamic GnRH release.
- Of the inhibition of the LH peak in combination with ethinylestradiol
- Peripheral
- In combination with ethinyl estradiol
- By inhibiting follicle maturation (egg maturation).
- independently by
- Antagonizing estrogen action on the endometrium (uterine lining) → inhibiting nidation.
- Thickening of cervical mucus → impermeability to sperm (seminal cells).
- Decrease in tubal motility (mobility of the fallopian tubes).
- Changes in the tubal mucosa
- Blockade of capacitation of the spermatozoa* ?
- In combination with ethinyl estradiol
* Physiological maturation process of sperm cells in the female genital tract, without which fertilization of the egg is not possible.
Ovulation inhibitory dose of progestogens.
Table 1: Ovulation inhibitory dose of selected progestogens.
| Progestin | Dose mg/d |
| Chlormadinone acetate (chlormadinone) (CMA) | 1,7 |
| Cyproterone acetate (cyproterone) (CPA). | 1,0 |
| Desogestrel (DSG) (act. metab. = etonogestrel = 3-keto-desogestrel). | 0,06 |
| Dienogest (DNG) | 1,0 |
| Drospirenone (DRSP) | 2,0 |
| Etonogestrel (ENG) (3-keto-desogestrel). | 0,06 |
| Gestodene (GSD) | 0,04 |
| Levonorgestrel (LNG) | 0,06 |
| Lynestrenol (LYN) (prodrug of norethisterone). | 2,0 |
| Medroxyprogesterone acetate (MPA) (medroxyprogesterone). | 50 |
| Nomegestrol acetate (Nomegestrol) (NOMAC) | 1,25 |
| Norelgestromin (NGM) (act.Metabolized from norgestimate) | 0,2 |
| Norethisterone (NET) | 0,4 |
| Norethisterone acetate (NETA) | 0,5 |
| Norgestimate (NGT) (prodrug of norelgestromin and levonorgestrel). | 0,2 |
Progestin partial effects
Table 2: Progestin partial effects
| Estrogen | Antiestrogen | Androgen | Antiandrogen | Glucocorticoid | Antimineralocorticoid | |
| CMA | – | + | – | + | + | – |
| CPA | – | + | – | + | + | – |
| DSG | – | + | + | – | – | – |
| ENG | – | + | + | – | – | – |
| DNG | – | +/- | – | + | – | – |
| DRSP | – | – | – | + | – | + |
| GSD | – | + | + | – | (+) | – |
| LNG | – | + | + | – | – | – |
| LYN | + | + | + | – | – | – |
| MPA | – | + | (+) | – | + | – |
| NET/NETA | + | + | + | – | – | – |
| NGM/NGT | – | + | + | – | – | – |
| NOMAC | – | + | – | + | – | – |
CMA: chlormadinone, CPA: cyproterone, DSG: desogestrel (active metabolite of etonogestrel), ENG: etonogestrel (prodrug of desogestrel), DNG: dienogest, DRSP: drospirenone, GSD: gestodene, LNG: levonorgestrel, LYN: lynestrenol (prodrug of norethisterone), MPA: Medroxyprogesterone acetate, NET: norethisterone, NETA: norethisterone acetate, NGM: norelgestromin (active metabolite of NGT), NGT: norgestimate (prodrug of norelgestromin and levonorgestrel), NOMAC: nomegestrol acetate, +: effective, (+): weakly effective, – not effective.
Forms of hormonal contraceptives
Medicines for hormonal contraception usually contain a combination of estrogen (ethinyl estradiol or, more recently, estradiol valerate) and various progestins or progestogens as monopreparations. They can be applied orally, transdermally, intrauterine or subcutaneously. Combination preparations
Oral combination preparations
- Single-phase preparations: the dosage of estrogens and progestins is constant in each application (oral, transdermal, vaginal).
- Multi-phase preparations (step, sequence preparations) (oral): the dosage of estrogens and progestins is in 2 or 3 stages (phases) in adaptation to the natural cycle. Background: attempt to better tolerability, associated with fewer side effects.
In commerce are
- Two-step preparations (two-phase preparations).
- Long cycle: 91-day pack, 84 combination tablets, followed by 7 low-dose ethinyl estradiol. Bleeding occurs during this phase. The new cycle is started after taking the last tablet
- 7/15/ six day intake-free interval.
- 11/11/ six days intake-free interval
- Three-step preparations (three-phase preparations).
- 6/5/10/ seven-day intake-free interval.
- 7/7/7/ seven days ingestion-free interval
- Four-step preparations (four-phase preparations).
- Long-cycle preparationsIn addition to the personal desire to have periods as infrequently as possible, the preferred indications are the following conditions: Endometriosis (occurrence of endometrium (uterine lining) extrauterine (outside the uterine cavity), for example in or on the ovaries (ovaries), tubes (fallopian tubes), urinary bladder or intestines), premenstrual syndrome (PMS), hypermenorrhea (bleeding is too heavy (> 80 ml); usually the affected person consumes more than five pads/tampons per day), polycystic ovary syndrome (PCOS; symptom complex characterized by hormonal dysfunction of the ovaries) and migraine. ) and migraine.Intake errors also occur less frequently in the long cycle.There are two types:
- Long cycle preparations
- With hormone-free interval (HFI) (Evaluna, Velmari).
- Without hormone-free interval (HFI) (Seasonique)* .
Currently (2019), three long cycle preparations are approved in Germany
- Evaluna (30 µg ethinyl estradiol + 150 µg levonorgestrel.) Taken for 84 days, followed by a seven-day take-free interval).
- Seasonique (30 µg ethinylestradiol + 150 µg levonorgestrel for 84 days, followed by seven tablets 10 µg ethinylestradiol. In the estrogen-only phase, menstruation occurs).
- Velmari (20 µg ethinyl estradiol + 3 mg drospirenone. Taken several times for at least 24 days, maximum 120 days. After the end of intake, four days break).
- Off-label use: any approved single-phase preparation of 21 tablets, which can be taken continuously for a desired period, followed by a seven-day break.
- <* Taking without a hormone-free interval is preferred for symptoms that may occur due to hormone withdrawal during the break in exogenous hormone application e.g. dysmenorrhea/regular pain, premenstrual syndrome, menstruation-associated headaches, irritability.
- Transdermal combination products.
- Patch: ethinyl estradiol/norelgestromin. Change patch on days 8 and 15. Do not wear patch from day 22. The patch-free interval must not exceed seven days.
- Vaginal combination preparations
- Vaginal release system (vaginal ring): ethinylestradiol/etonogestrel. Removal of ring after 21 days. After 7-day break insertion of a new ring.
- Micropill
- As micropills are so-called low-hormone pills with less than 50 µg ethinyl estradiol in a pill called.
- Ultra-low-dose pills
- Are pills whose tablets contain only 20 µg of ethinyl estradiol or estradiol.
Caveat: The term minipill and micropill are often confused with each other. Monopreparations
- Oral progestogen monopreparations
Minipill
Minipills contain the progestogens desogestrel or levonorgestrel. Both must be taken daily. The effect occurs only 14 days after starting to take the pill. If taken incorrectly, there is a risk of pregnancy for about seven days during unprotected intercourse.Mode of action.
- Solidification of the cervical secretion.
- Remodeling of the endometrium, which impedes nidation.
Desogestrel has an additional ovulation-inhibiting effect and can be taken up to 12 hours delayed. The pill on the market contains 75 µg, an ovulation-inhibiting dose increased by 1.25 times. Levonorgestrel must always be taken at the same time of day if possible. Any delay must not exceed 3 hours. (Lynestrenol is no longer on the market).
“Morning-after pill”, post-capital pill.
Two oral medications are available
- Levonorgestrel, 1.5 mg (PIDANA).
- Take no later than 72 hours (three days) after unprotected intercourse. The effect depends on the time of taking. The later the intake the lower the effect.
- Mechanism of action: suppression of the mitcyclic LH surge. This prevents or postpones ovulation (ovulation). After ovulation has occurred, that is, after fertilization has occurred, levonorgestrel is no longer effective. (An emergency contraceptive with two tablets of levonorgestrel with 0.75 mg each, that should be taken at intervals of 12 hours, is not on sale in Germany).
- Ulipristal acetate 30 mg (UPA) (Ulipristal) (EllaOne): it is a progesterone receptor modulator.
- Take up to 120 hours (five days) after unprotected intercourse.
- Mechanism of action: suppression of LH surge for up to five days. After ovulation has occurred, ie after fertilization has occurred Ulipristal is no longer effective.
Notice:
- Both emergency contraceptives do not induce abortion bleeding. Therefore, it cannot be considered a success. If menstruation remains absent for more than a week after the expected date, a pregnancy test must be performed.
- Taking during breastfeeding: both preparations pass into breast milk. Therefore, breastfeeding should be done before taking them.
- Breastfeeding break for
- Levonorgestrel: 8 hours
- Ulipristal: one week
- Breastfeeding break for
For emergency contraception, the copper IUD can also be used up to 120 hours after unprotected sexual intercourse (see emergency contraception (interception)). It prevents implantation of the fertilized egg and can be left intrauterine as a contraceptive if desired. Hormonal IUDs (intrauterine devices (IUDs), intrauterine systems).
- The hormonal IUDs on the market contain.
- Levonorgestrel
- 13.5 mg (effective for up to three years)
- 19.5 mg (effective for up to five years)
- 52 mg (effective up to five years)
- Levonorgestrel
Implants (contraceptive rods).
- In Germany, an implant with etonogestrel (3-keto-desogestrel) is on the market, which is effective for up to three years.
- Outside Germany, there are hormone implants containing the progestogens megestrol acetate, norethisterone, norgestrinone or etonogestrel, which are effective for a period of 1-5 years depending on the progestogen.
Injections (three-month injection).
- The injection on the market contains.
- Medroxyprogesterone acetate at 104 mg and is effective for up to three months
- (no longer on the market are (medroxyprogesterone acetate 150 mg, norethisterone antate 200 mg).
