This review comprises the pharmacokinetics and pharmacodynamics of natural and synthetic estrogens and progestogens used in contraception and therapy, with special consideration of hormone replacement therapy. The paper describes the mechanisms of action, the relation between structure and hormonal activity, differences in hormonal pattern and potency, peculiarities in the properties of certain steroids, tissue-specific effects, and the metabolism of the available estrogens and progestogens. The influence of the route of administration on pharmacokinetics, hormonal activity and metabolism is presented, and the effects of oral and transdermal treatment with estrogens on tissues, clinical and serum parameters are compared. The effects of oral, transdermal (patch and gel), intranasal, sublingual, buccal, vaginal, subcutaneous and intramuscular administration of estrogens, as well as of oral, vaginal, transdermal, intranasal, buccal, intramuscular and intrauterine application of progestogens are discussed. The various types of progestogens, their receptor interaction, hormonal pattern and the hormonal activity of certain metabolites are described in detail. The structural formulae, serum concentrations, binding affinities to steroid receptors and serum binding globulins, and the relative potencies of the available estrogens and progestins are presented. Differences in the tissue-specific effects of the various compounds and regimens and their potential implications with the risks and benefits of hormone replacement therapy are discussed.

https://www.hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric.pdf

Pharmacology of estrogens and progestogens: influence of different routes of administration.

The coumarin (benzopyran-2-one, or chromen-2-one) ring system, present in natural products (such as the anticoagulant warfarin) that display interesting pharmacological properties, has intrigued chemists and medicinal chemists for decades to explore the natural coumarins or synthetic analogs for their applicability as drugs. Many molecules based on the coumarin ring system have been synthesized utilizing innovative synthetic techniques. The diversity oriented synthetic routes have led to interesting derivatives including the furanocoumarins, pyranocoumarins, and coumarin sulfamates (COUMATES), which have been found to be useful in photochemotherapy, antitumor and anti-HIV therapy, and as stimulants for central nervous system, antibacterials, anti-inflammatory, anti-coagulants, and dyes. Of particular interest in breast cancer chemotherapy, some coumarins and their active metabolite 7-hydroxycoumarin analogs have shown sulfatase and aromatase inhibitory activities. Coumarin based selective estrogen receptor modulators (SERMs) and coumarin-estrogen conjugates have also been described as potential antibreast cancer agents. Since breast cancer is the second leading cause of death in American women behind lung cancer, there is a strong impetus to identify potential new drug treatments for breast cancer. Therefore, the objective of this review is to focus on important coumarin analogs with antibreast cancer activities, highlight their mechanisms of action and structure-activity relationships on selected receptors in breast tissues, and the different methods that have been applied in the construction of these pharmacologically important coumarin analogs.

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

Pharmacological profile of progestins.

The progestins have different pharmacologic properties depending upon the parent molecule, usually testosterone or progesterone (P), from which they are derived. Very small structural changes in the parent molecule may induce considerable differences in the activity of the derivative. In hormonal contraceptives, progestins represent the major agent designed for suppressing ovulation and are used in combination with estrogen (E) usually ethinyl-estradiol (EE). The development of new generations of progestins with improved selectivity profiles has been a great challenge. Steroidal and nonsteroidal progesterone receptor (PR) agonists have been synthesized as well, although the latter are still in a very early stage of development. Several new progestins, have been synthesized in the last two decades. These include dienogest (DNG), drospirenone (DRSP), Nestorone (NES), nomegestrol acetate (NOMAc) and trimegestone (TMG). These new progestins have been designed to have no androgenic or estrogenic actions and to be closer in activity to the physiological hormone P. DRSP differs from the classic progestins as it is derived from spirolactone. It is essentially an antimineralocorticoid steroid with no androgenic effect but a partial antiandrogenic effect. The antiovulatory potency of the different progestins varies. TMG and NES are the most potent progestins synthesized to date, followed by two of the older progestins, keto-desogestrel (keto-DSG) and levonorgestrel (LNG). The new molecules TMG, DRSP and DNG also have antiandrogenic activity. Striking differences exist regarding the side effects among the progestins and the combination with EE leads to other reactions related to the E itself and whether the associated progestin counterbalances, more or less, the estrogenic action. The 19-norprogesterone molecules and the new molecules DRSP and DNG are not androgenic and, therefore, have no negative effect on the lipid profile. Given their pharmacological properties, it is likely that the new progestins may have neutral effects on metabolic or vascular risks. However, this hypothesis must be confirmed in large clinical trials.

/pdf/new-progestagens-for-contraceptive-use-50pggn2ft1.pdf

New progestagens for contraceptive use

Prostate cancer is the most common malignancy in Western societies and the second most common cause of male cancerrelated death in the UK and USA, accounting for ≈ 12% of all male cancer-related deaths [1,2]. When confined to the prostate gland, the disease is curable with local therapy (radical prostatectomy, external beam radiotherapy, brachytherapy or cryotherapy). However, despite the use of PSA for screening, in 15–33% of men local therapy fails and they develop incurable metastatic disease [3,4]. Activation of the androgen receptor (AR) by androgenic steroids including testosterone and its more potent 5 α -reduced metabolite, 5 α -dihydrotestosterone (DHT), regulates the transcription of a diverse range of target genes involved in prostate cell proliferation, differentiation, and apoptosis [5]. Androgen deprivation by medical or surgical castration remains the mainstay of treatment and > 90% of men with metastatic prostate cancer initially respond rapidly and often dramatically to castration, with improvements in bone pain, regression of soft tissue metastasis, and steep declines in PSA level. However, the duration of response is frequently short (12–33 months) and in almost all patients is followed by the emergence of castration-resistant prostate cancer (CRPC) that, untreated, is invariably fatal within 9–12 months [3]. Systemic chemotherapy with docetaxel for patients with CRPC confers a modest survival advantage (2–3 months) and is effective for palliating symptoms [6], but the duration and rate of response is limited. Other chemotherapy, e.g. mitoxantrone, has not been shown to improve survival but might help with symptom control [6]. There is an urgent need for new agents that provide palliation and improve survival.

Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer

Nomegestrol acetate (NOM-Ac; TX 066, 17 alpha-acetoxy-6-methyl-19-nor-4,6-pregnadiene-3,20-dione, CAS 58652-20-3), a 19-nor-progesterone derivative showed a significant antiandrogenic effect on ventral prostate and seminal vesicles weights of immature castrated rats treated with testosterone. However, this effect was 20 times less potent than that of cyproterone acetate (CYP-Ac). In contrast to norethindrone acetate, a 19-nor-testosterone derivative. NOM-Ac was totally devoid of androgenic effect on male accessory sex organs. Relative binding affinity against 3H-testosterone for androgen receptor of rat ventral prostate showed an IC50 of 22.6 +/- 4.0 and 21.1 +/- 5.3 nmol/l for NOM-Ac and CYP-Ac, respectively, while Dixon analysis disclosed a Ki of 7.58 +/- 0.94 and 4.30 +/- 0.17 nmol/l. Then, Scatchard plot analysis of 3H-NOM-Ac binding revealed a KD of 20.9 +/- 3.1 nmol/l and a Bmax of 217 +/- 27 fmol/mg protein.

Antiandrogenic properties of nomegestrol acetate.

17 alpha-Acetoxy-6-methyl-19-nor-4,6-pregna-diene-3,20-dione (TX 066) has the pharmacological profile of a pure progestogen with no side effect such as androgenic activity. Its pituitary suppressing effect is relatively weak, as is also its antiestrogenic activity. It possesses a powerful antiandrogenic effect, which, in addition to the classic uses for progestogens, may make TX 066 useful in the treatment of certain diseases such as prostatic hypertrophy or the Stein-Leventhal syndrome.

The pharmacological profile of TX 066 (17 alpha-acetoxy-6-methyl-19-nor-4,6-pregna-diene-3,20-dione), a new oral progestative.

An overview of nomegestrol acetate selective receptor binding and lack of estrogenic action on hormone-dependent cancer cells.

In vitro and in vivo models for the evaluation of potent inhibitors of male rat 17α-hydroxylase/C17,20-lyase

19-Norprogesterone (19-NOR-P) is a potent progestagen in mammals by s.c. injection, but is almost inactive when given p.o. In the rat, 19-NOR-P also shows marked salt-retaining and hypertensive effects, consistent with its high affinity for mineralocorticoid receptors (MR). We synthetized recently some p.o. active 19-NOR-P derivatives, and have examined the extent to which the structural changes made on the parent compound can modify the affinity for MR and the salt-retaining potency. Compared with aldosterone, 19-NOR-P has a 47% affinity for rat renal cytosolic MR, decreasing to 13% with alpha-hydroxylation on C-17 (17 alpha-OH-19-NOR-P). The addition of a methyl group combined with the formation of a double bond at C-6 led to nomegestrol, the relative affinity of which was 1.2%. Binding was almost abolished completely (0.23%) by acetylation of the 17 alpha-OH group (nomegestrol-acetate). A single s.c. injection of 19-NOR-P, 20 micrograms/animal, induced a marked decline of [Na+]/[K+] ratio in urine of adrenalectomized male rats. The antinatriuretic effect was still observed after a 11-day period of daily administrations of the same dosage. 17 alpha-OH-19-NOR-P decreased the [Na+]/[K+] ratio only at a high p.o. dose (2500 micrograms/animal). NOM-Ac did not affect the [Na+]/[K+] ratio after a single s.c. or p.o. administration, but increased it at the end of a 11-day p.o. treatment. Thus, the chemical modifications that lead to potent p.o. active progestins derived from 19-NOR-P induce stepwise reductions in the affinity for MR and of the mineralocorticoid effects of the parent compound.

P Bonnet

Papers

Antiandrogenic properties of nomegestrol acetate.

The pharmacological profile of TX 066 (17 alpha-acetoxy-6-methyl-19-nor-4,6-pregna-diene-3,20-dione), a new oral progestative.

An overview of nomegestrol acetate selective receptor binding and lack of estrogenic action on hormone-dependent cancer cells.

In vitro and in vivo models for the evaluation of potent inhibitors of male rat 17α-hydroxylase/C17,20-lyase

Extinction of mineralocorticoid effects in 19-norprogesterone derivatives: structure-activity relationships.