Progestins and breast cancer hallmarks: The role of the ERK1/2 and JNK pathways in estrogen receptor positive breast cancer cells.

Progestins used in hormonal contraceptives and menopausal hormone therapy (MHT) have been linked to increased breast cancer risk. Whether the association holds for all progestins is unclear and the underlying mechanisms remain poorly understood. We directly compared the effects of four progestins (medroxyprogesterone acetate (MPA), norethisterone acetate (NET-A), levonorgestrel (LNG) and drospirenone (DRSP)) to each other and the natural progestogen progesterone (P) on selected cancer hallmarks.

Progesterone receptor isoform ratios influence the transcriptional activity of progestins via the progesterone receptor.

Progestins (synthetic progestogens) are progesterone receptor (PR) ligands used globally by women in both hormonal contraception and menopausal hormone therapy. Although four generations of unique progestins have been developed, studies seldom distinguish between the activities of progestins via the two functionally distinct PR isoforms, PR-A and PR-B. Moreover, not much is known about the action of progestins in breast cancer tumors where PR-A is mostly overexpressed relative to PR-B.

The transcriptional activity of progestins used in contraception and menopausal hormone therapy via progesterone receptor A is dependent on the density of the receptor.

Studies directly comparing the efficacies and potencies of multiple progestins used in contraception and menopausal hormone therapy (MHT) in parallel via human progesterone receptor isoform A (PR-A) in the same model system are limited, and how these parameters are influenced by the density of PR-A are unclear. This is surprising as it is known that the expression levels of PR-A vary in different tissues and diseases. We thus determined for the first time the relative efficacies and potencies for transactivation of the natural PR ligand, progesterone (P), the PR-specific agonist promegestone (R5020), and selected progestins from all four generations in parallel via different densities of PR-A overexpressed in the MDA-MB-231 breast cancer cell line.

Upregulation of an estrogen receptor-regulated gene by first generation progestins requires both the progesterone receptor and estrogen receptor alpha.

Progestins, synthetic compounds designed to mimic the activity of natural progesterone (P), are used globally in menopausal hormone therapy. Although the older progestins medroxyprogesterone acetate (MPA) and norethisterone (NET) have been implicated in increased breast cancer risk, little is known regarding newer progestins, and no significant risk has been associated with P. Considering that breast cancer is the leading cause of mortality in women, establishing which progestins increase breast cancer incidence and elucidating the underlying mechanisms is a global priority.

Differential off-target glucocorticoid activity of progestins used in endocrine therapy.

The glucocorticoid receptor (GR) regulates transcription of genes involved in multiple processes. Medroxyprogesterone acetate (MPA), widely used in the injectable contraceptive Depo-MPA (DMPA), has off-target effects via the GR, which may result in side-effects in endocrine therapy. However, very little is known about the GR activity of other progestins used in endocrine therapy.

11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool.

Androgens are the obligatory precursors of estrogens. In humans, classic androgen biosynthesis yields testosterone, thought to represent the predominant circulating active androgen both in men and women. However, recent work has shown that 11-ketotestosterone, derived from the newly described 11-oxygenated androgen biosynthesis pathway, makes a substantial contribution to the active androgen pool in women.

Pharmacokinetics, metabolism and serum concentrations of progestins used in contraception.

Many different forms of hormonal contraception are used by millions of women worldwide. These contraceptives differ in the dose and type of synthetic progestogenic compound (progestin) used, as well as the route of administration and whether or not they contain estrogenic compounds. There is an increasing awareness that different forms of contraception and different progestins have different side-effect profiles, in particular their cardiovascular effects, effects on reproductive cancers and susceptibility to infectious diseases.

Characterisation of progestins used in hormonal contraception and progesterone via the progesterone receptor.

Different progestogens are widely used in hormonal therapy and mediate their therapeutic actions via the progesterone receptor (PR). Little published data exist on their relative efficacies and potencies via the PR, while those available may be confounded by off-target receptors, different methodologies and model systems. We performed dose-response analysis to investigate the efficacies and potencies for transcription of progesterone and several progestins widely used in contraception via the B isoform of human PR (PR-B).

A direct comparison of the transcriptional activities of progestins used in contraception and menopausal hormone therapy via the mineralocorticoid receptor.

A variety of structurally and functionally distinct progestins is used in contraception and menopausal hormone therapy (MHT). Some progestins elicit off-target effects by binding to steroid receptors other than the progesterone receptor, which may impact their therapeutic and side-effect profiles. We directly compared the binding affinities, efficacies and potencies of selected progestins via the mineralocorticoid receptor (MR).

Differential metabolism of clinically-relevant progestogens in cell lines and tissue: Implications for biological mechanisms.

Steroid hormones regulate a variety of physiological processes, including reproductive function, and are widely used in hormonal therapy. Synthetic progestogens, or progestins, were designed to mimic progesterone (P) for use in contraception and hormonal replacement therapy in women. Medroxyprogesterone acetate (MPA) and norethisterone (NET) are the most widely used injectable contraceptives in the developing world, while other progestins such as levonorgestrel (LNG), etonogestrel (ETG) and nestorone (NES) are used in or being developed for other forms of contraception.

Hormone Therapy and Breast Cancer: Emerging Steroid Receptor Mechanisms.

Although hormone therapy is widely used by millions of women to relieve symptoms of menopause, it has been associated with several side-effects such as coronary heart disease, stroke and increased invasive breast cancer risk. These side-effects have caused many women to seek alternatives to conventional hormone therapy, including the controversial custom-compounded bioidentical hormone therapy suggested to not increase breast cancer risk. Historically estrogens and the estrogen receptor were considered the principal factors promoting breast cancer development and progression, however, a role for other members of the steroid receptor family in breast cancer pathogenesis is now evident, with emerging studies revealing an interplay between some steroid receptors.

A comparative characterization of estrogens used in hormone therapy via estrogen receptor (ER)-α and -β.

Conventional hormone therapy (HT) containing estrogens such as ethinylestradiol (EE) have been associated with an increased risk of breast cancer and cardiovascular disease resulting in women seeking safer alternatives that are claimed to have fewer health risks. One such alternative gaining popularity, is custom-compounded bioidentical (b)HT formulations containing bioidentical estradiol (bE) and estriol (bE). However, the preparation of these custom-compounded estrogens is not regulated, and depending on the route of synthesis, steroid mixtures with differing activities may be produced.

Comparing the androgenic and estrogenic properties of progestins used in contraception and hormone therapy.

Progestins used in endocrine therapies bind to multiple steroid receptors and are associated with several side-effects. It is thus important to understand the relationship between steroid receptor cross-reactivity and the side-effect profile of progestins. In cell lines that express negligible levels of steroid receptors, we report for the first time the binding affinities, potencies and efficacies of selected progestins from different generations determined in parallel.

Fourth-Generation Progestins Inhibit 3β-Hydroxysteroid Dehydrogenase Type 2 and Modulate the Biosynthesis of Endogenous Steroids.

Progestins used in contraception and hormone replacement therapy are synthetic compounds designed to mimic the actions of the natural hormone progesterone and are classed into four consecutive generations. The biological actions of progestins are primarily determined by their interactions with steroid receptors, and factors such as metabolism, pharmacokinetics, bioavailability and the regulation of endogenous steroid hormone biosynthesis are often overlooked. Although some studies have investigated the effects of select progestins on a few steroidogenic enzymes, studies comparing the effects of progestins from different generations are lacking.

The metabolic fate and receptor interaction of 16α-hydroxyprogesterone and its 5α-reduced metabolite, 16α-hydroxy-dihydroprogesterone.

16α-hydroxyprogesterone (16OHP4) is not well characterised in terms of metabolism and receptor interaction. We therefore investigated its metabolism by adrenal CYP11B and peripheral steroidogenic enzymes, SRD5A and AKR1C2. UHPLC-MS/MS analyses identified novel steroids: the biosynthesis of 4-pregnen-11β,16α-diol-3,20-dione catalysed by CYP11B2; the 5α-reduction of the latter and 16OHP4 catalysed by SRD5A yielding 5α-pregnan-11β,16α-diol-3,20-diovne and 5α-pregnan-16α-ol-3,20-dione (16OH-DHP4); and 16OH-DHP4 converted by AKR1C2 to 5α-pregnan-3α,16α-diol-20-one.

Progestins used in endocrine therapy and the implications for the biosynthesis and metabolism of endogenous steroid hormones.

Steroidogenesis refers to the de novo synthesis of steroid hormones from cholesterol by a number of sequential enzyme catalysed reactions in the adrenal and the gonads. In addition, circulating steroid hormone precursors are further metabolised in selected peripheral tissues. It has been suggested that the biosynthesis of endogenous steroid hormones can be modulated by progestins, used widely by women in female reproductive medicine.

Medroxyprogesterone acetate differentially regulates interleukin (IL)-12 and IL-10 in a human ectocervical epithelial cell line in a glucocorticoid receptor (GR)-dependent manner.

Medroxyprogesterone acetate (MPA), designed to mimic the actions of the endogenous hormone progesterone (P4), is extensively used by women as a contraceptive and in hormone replacement therapy. However, little is known about the steroid receptor-mediated molecular mechanisms of action of MPA in the female genital tract. In this study, we investigated the regulation of the pro-inflammatory cytokine, interleukin (IL)-12, and the anti-inflammatory cytokine IL-10, by MPA versus P4, in an in vitro cell culture model of the female ectocervical environment.