The estrogenic activity of synthetic progestins used in oral contraceptives

Abstract

Background. Oral contraceptives (OC) contain an orally active estrogen in combination with an orally active synthetic progestin derived from 19‐nortestosterone. OC have had an enormous positive impact on public health for the past three decades, and in the main, there has been a remarkably low incidence of troublesome side effects. Although estrogens are implicated in an increased incidence of breast and endometrial cancer, epidemiologic studies have not provided convincing evidence to support a direct correlation between OC use and an increase in breast cancer incidence. By contrast, OC do cause a decrease in the incidence of endometrial and ovarian carcinoma. During the past decade, several isolated reports have linked an increased incidence of breast cancer with the use of synthetic progestins. No mechanism for the proliferative potential of progestins has been offered. Therefore, the authors investigated this problem to formulate a hypothesis, based on laboratory data, that might be evaluated in populations at risk. Methods. The synthetic progestins (19‐nortestosterone derivatives) chosen for the study were norethynodrel, norethindrone, norgestrel (levonorgestrel), and gestodene. These were compared with the actions of medroxyprogesterone acetate (MPA). To determine whether the progestins produced their effects via the ER, the cells were transfected with a chloramphenicol acetyl transferase (CAT) reporter gene containing an estrogen response element only activated by ER. Results. The 19‐nortestosterone derivatives all stimulated the growth of estrogen receptor (ER)‐positive but not ER‐negative breast cancer cells in culture. Antiestrogens, but not the antiprogestin mifepristone (also known as RU 486), inhibited progestin‐stimulated cell proliferation. MPA did not stimulate cell proliferation. All the synthetic progestins that increased replication also activated CAT. Activation was blocked by antiestrogens but not by mifepristone; the synthetic progestin MPA was inactive. Conclusions. These studies provided direct evidence that some synthetic progestins exert estrogenic effects through the ER. The results demonstrated that progestins can have a dual effect on estrogen target tissues either to stimulate or differentiate cells. The results suggest that some beneficial estrogen‐like effects could be produced by synthetic progestins (e.g., bone preservation), but epidemiologic studies of OC use should focus of the “total estrogen” content to establish whether some formulations place some groups of women at greater risk of having breast cancer.

An Approach for Using In Vitro and In Silico Data to Identify Pharmaceuticals with Potential (Anti‐)Estrogenic Activity in Aquatic Vertebrates at Environmentally Relevant Concentrations

“…In addition to pharmaceuticals intended to interact with ERs (e.g., EE2, diethylstilbestrol, SERMs), several ligands of other steroid hormone receptors, particularly those associated with PR or AR binding, also exhibited (anti‐)estrogenic activity in the Tox21 assays. This cross‐reactivity has been shown previously in both in vitro (Jordan et al ; Ekena et al ) and in vivo (Brion et al ; Cano‐Nicolau et al ) studies and is likely related to common structural features shared by all steroid hormones (Huang et al ). The interaction of such ligands with ERs has the potential to induce biological effects.…”

“…Tox21 assays. This cross-reactivity has been shown previously in both in vitro (Jordan et al 1993;Ekena et al 1998) and in vivo (Brion et al 2012;Cano-Nicolau et al 2016) studies and is likely related to common structural features shared by all steroid hormones (Huang et al 2010). The interaction of such ligands with ERs has the potential to induce biological effects.…”

Identification of genes involved in growth inhibition of breast cancer cells transduced with estrogen receptor

“…ERβ is poorly expressed in breast tumors [2]. A high percentage of early stage mammary tumors are ERα‐positive and about 50% of these patients respond to anti‐estrogen or endocrine therapy [3,4]. Later stages of breast cancer are more aggressive and refractory to most therapies and this correlates with the ERα‐negative phenotype of these tumors [5].…”

The Role of Hormone Replacement Therapy (HRT) and Tibolone in the Prevention and Treatment of Postmenopausal Osteoporosis

“…A study about the activity of a "pure progestogen" on human osteogenic osteosarcoma cells did not observe any effect on cell proliferation when progestins were added alone to culture, but after the combined administration with 17 -estradiol, a strong action synergistically was confirmed on the proliferation of osteosarcoma cells. Moreover, other studies show that some synthetic progestins produce their effects through the activation of the estrogen receptor (Jordan et al, 1993).…”