All progestins are not created equal
Introduction
A variety of progestins are used in combination with estrogen for hormone replacement therapy (HRT) in postmenopausal women. Progestins are compounds that transform proliferative to secretory endometrium in estrogen-primed uteri. They are administered either continuously combined, sequentially or intermittently during estrogen replacement therapy (ERT) to prevent endometrial hyperplasia. Alternate names for progestin include progestogen, progestagen, gestogen, and gestagen [1].
Progestins differ widely in their chemical structure, pharmacokinetics, and potency. It is important that physicians understand these differences in order to prescribe the optimum type and dose of progestin for HRT.
The objectives of the present review are: (a) to show which progestins are available for therapeutic use and how they differ in chemical structure; (b) to summarize what is known about the metabolism, pharmacokinetics, and potency of progestins; (c) to show that all progestins are not created equal.
Section snippets
Classification of progestins
To understand the pharmacokinetics and potency of progestins, it is helpful to know their chemical structures and how they differ from each other. Table 1 shows a classification scheme for progestins, most of which are used for HRT; their chemical structures are depicted in Fig. 1, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7. Progestins can be divided into natural and synthetic types. There is only one natural progestin and that is progesterone (Fig. 1). Use of the term “natural” here implies that
Metabolism of progestins
The metabolism of progestins is poorly understood. This is due to the fact that relatively few studies on the metabolism of the different progestins have been carried out.
Steroids administered orally undergo hepatic first pass metabolism. The extent to which this occurs varies and depends on the chemical structure of the progestin. Progestins are first subjected to metabolism by bacterial enzymes in the intestine. The metabolized and unmetabolized progestins are then absorbed and enter the
Pharmacokinetics of progestins
Following oral administration of a drug and measurement of the drug or its active metabolite(s) in serum or plasma over a 24-h period, a profile of the administered compound or its metabolite, showing absorption, distribution, and elimination, can be graphed as shown in Fig. 8, Fig. 9, Fig. 10, Fig. 11. These progestin concentrations can be used to calculate a variety of pharmacokinetic parameters; they include maximum concentration (Cmax), the time to reach Cmax, area under the curve (AUC),
Progestin potency
The term “potency” in relation to a drug is controversial and can be confusing. Here, the term is defined as an estimate of a specific effect of a drug. In general, tests of potency can be divided into three types: in vitro receptor binding assays, bioassays, and clinical evaluations. A number of variables are associated with potency tests. However, probably the most important variable is the extrapolation of potency estimates from animals to humans. As an example, Table 6 shows a comparison of
Androgenicity of progestins
In addition to the characteristic progestational activity of progestins, they may also possess anti-estrogenic, androgenic, anti-androgenic, and/or anti-mineralocorticoid activities. The most controversial and confusing of these activities is the androgenicity of certain progestins.
What is an androgenic progestin? It is often defined as a progestin that exhibits androgen-like effects. The two most notable androgenic progestins are levonorgestrel and norethindrone. Primary evidence for their
Conclusion
It is obvious from the present review that progestins differ widely in their chemical structures, structure–function relationships, metabolism, pharmacokinetics, and potency. We can therefore conclude that all progestins are not created equal.
References (39)
- et al.
Use of the name “progestin”
Contraception
(2001) - et al.
Nomenclature of the gonane progestins
Contraception
(1999) - et al.
Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids
Contraception
(1990) - et al.
Medroxyprogesterone acetate in human serum
J. Steroid Biochem.
(1981) - et al.
In vivo conversion of norethesterone and norethisterone acetate to ethinyl estradiol in postmenopausal women
Contraception
(1997) - et al.
The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone
Fertil. Steril.
(1993) - et al.
Radioimmunoassay of serum medroxyprogesterone acetate (Provera) in women following oral and intravaginal administration
Steroids
(1975) - et al.
Plasma concentrations of medroxyprogesterone acetate, estradiol and estrone following oral administration of Klimaxil®, Trisequence®/Provera® and Divina®. A randomized, single-blind, triple cross-over bio-availability study in menopausal women
Maturitas
(1994) - et al.
Pharmacokinetic observations on medroxyprogesterone acetate administered orally and intravaginally
Contraception
(1976) - et al.
Plasma levels and pharmacokinetics of norethindrone and ethinylestradiol administered in solution and as tablets to women
Contraception
(1983)
Intraindividual comparison of pharmacokinetic parameters of d-norgestrel, lynestrenol and cyproterone acetate in 6 women
Contraception
The relative bioavailability of levonorgestrel and ethinyl estradiol administered as a low-dose combination oral contraceptive
Contraception
Pharmacokinetic comparison of two triphasic oral contraceptive formulations containing levonorgestrel and ethinylestradiol
Contraception
Levonorgestrel and ethinylestradiol in women—studies with Ovran and Ovranette
Contraception
Investigations of pharmacokinetics of levonorgestrel to specific consideration of a possible first pass effect in women
Contraception
Serum levels of 3-ketodesogestrel after oral administration of desogestrel and 3-ketodesogestrel
Contraception
Serum pharmacokinetics of orally administered desogestrel and binding of contraceptive progestogens to sex hormone-binding globulin
Am. J. Obstet. Gynecol.
Plasma concentrations of 3-ketodesogestrel after oral administration of desogestrel and intravenous administration of 3-ketodesogestrel
Contraception
The pharmacokinetics of ethinyl estradiol in the presence and absence of gestodene and desogestrel
Contraception
Cited by (180)
Hormone-based models for comparing menstrual cycle and hormonal contraceptive effects on human resting-state functional connectivity
2022, Frontiers in NeuroendocrinologyModeling hormonal contraception in female rats: A framework for studies in behavioral neurobiology
2022, Frontiers in NeuroendocrinologyCitation Excerpt :Progestins are sometimes classified according to the generation they were released publicly as contraceptives (Petitti, 2003). However, others classify progestin generations according to when the progestin was first synthesized and their molecular structure (Giatti et al., 2016; Sitruk-Ware, 2008; Stanczyk, 2003). As a result, the classification of progestins by generation in the literature is often inconsistent.
Establishment of a steroid binding assay for membrane progesterone receptor alpha (PAQR7) by using graphene quantum dots (GQDs)
2022, Biochemical and Biophysical Research CommunicationsPharmacokinetics, metabolism and serum concentrations of progestins used in contraception
2021, Pharmacology and Therapeutics