Progestinas y cáncer de mama en terapia de reemplazo hormonal: cómo actúan y qué alternativas son más seguras / Progestins and breast cancer in hormone replacement therapy: how do they work, and what alternatives are safer

En algunos estudios se ha asociado a la terapia de reemplazo hormonal (TRH) con estrógenos y progestinas a un mayor riesgo de cáncer de mama que la terapia con estrógenos solos. Sin embargo, dependiendo de su naturaleza algunas progestinas serían más seguras que otras. Se buscaron y analizaron artículos atingentes al tema en las bases de datos Google Scholar, PubMed, Science, SciELO y Cochrane, introduciendo los siguientes términos: terapia de reemplazo hormonal y cáncer de mama, progestinas y cáncer de mama, receptor de progesterona. Específicamente se ha asociado a las progestinas sintéticas acetato de medroxiprogesterona, noretisterona y levonorgestrel con un mayor riesgo de cáncer de mama, no así a la progesterona natural, a la progesterona oral micronizada ni a la didrogesterona. La progesterona natural, progesterona micronizada y didrogesterona serían más seguras en TRH para evitar el desarrollo de cáncer de mama, lo que estaría dado por la mayor especificidad en su acción.

In some studies, hormone replacement therapy (HRT) with estrogens and progestins has been associated with a higher risk of breast cancer than therapy with estrogens alone. However, depending on their nature, some progestins may be safer than others. This article analyzes the mode of action of progesterone in breast tissue and also the role of some progestins in the development of this pathology. Articles related to the subject were searched for and analyzed in Google Scholar, PubMed, Science, SciELO and Cochrane databases, introducing the following terms: hormone replacement therapy and breast cancer, progestins and breast cancer, progesterone receptor. Specifically, synthetic progestins medroxyprogesterone acetate, norethisterone, and levonorgestrel have been associated with an increased risk of breast cancer, but not natural progesterone, micronized oral progesterone, or dydrogesterone. Natural progesterone, micronized progesterone and dydrogesterone would be safer in HRT to prevent the development of breast cancer, which would be due to the greater specificity of their action.

Efficacy of Different Progestins in Women With Advanced Endometriosis Undergoing Controlled Ovarian Hyperstimulation for in vitro Fertilization-A Single-Center Non-inferiority Randomized Controlled Trial.

Object: Is it possible to use different progestins cotreatment with human menopausal gonadotrophin (hMG) in women with advanced endometriosis but normal ovulation during controlled ovarian hyperstimulation (COH) in vitro fertilization (IVF)? Whether different progestins treatments can be an alternative choice for women with severe endometriosis in considering IVF/ICSI treatment remains unknown? Design: Non-inferiority randomized clinical trial. Setting: Tertiary-care academic medical center. Population: Four hundred and fifty infertile patients with severe endometriosis undergoing IVF/ICSI between May 2016 and March 2017. Methods: Four hundred and fifty infertile patients with severe endometriosis undergoing IVF/ICSI were randomized to: medroxyprogesterone acetate +hMG; dydrogesterone +hMG; and progesterone +hMG. Ovulation was induced with a gonadotropin-releasing hormone agonist (GnRH-a) and chorionic gonadotropin (hCG). Viable embryos were cryopreserved for later transfer. Main Outcome Measures: The primary endpoint outcome was the number of oocytes retrieved. Secondary indicators included the incidence of a premature surge in luteinizing hormone (LH), the number of viable embryos, and clinical pregnancy outcomes. Results: The number of oocytes retrieved was higher in the medroxyprogesterone acetate +hMG group than the two other groups (9.3 ± 5.7 vs. 8.0 ± 4.5 vs. 7.8 ± 5.2, P = 0.021). LH levels were suppressed after a 6-day progestin treatment in the medroxyprogesterone acetate +hMG and dydrogesterone +hMG groups, but there was a rebound of LH values in the progesterone +hMG group. No premature LH surge and ovarian hyperstimulation syndrome (OHSS) occurred. No significant differences among the three groups were observed in fertilization and pregnancy outcomes. Conclusion: It is mandatory to point out that our conclusions are valid for patients with ovarian advanced endometriosis but normal ovarian functions. These results suggest three different progestins protocols are equivalent in terms of pregnancy outcomes for women with advanced endometriosis. PPOS protocol can be an alternative choice for women with severe endometriosis and normal ovarian reserve in IVF/ICSI treatment. These methods could be tested with other populations of women with endometriosis. Clinical Trial Registration: www.ClinicalTrials.gov, identifier:ChiCTR-OIN-16008529. Trial registration date: 2014-05-25. Date of first patient enrollment: May 2016.

New progestagens for contraceptive use.

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.

Progestagênios e terapia de reposição hormonal / Hormone replacement therapy and progestogens

O uso da terapia de reposição hormonal aumentou nos últimos 20 anos principalmente devido ao alívio dos problemas causados por deprivação estrogênica apresentada pelas mulheres nesse período da vida, como também pelos possíveis efeitos preventivos sobre condições degenerativas crônicas, confirmadas por estudos observacionais. Entretanto, a partir da publicação de dois grandes estudos clínicos randomizados e controlados, Heart and Estrogen/Progestagen Replacement Study e Women Health Initiative, colocou-se em dúvida a real eficácia da terapia de reposição hormonal. Esses estudos evidenciaram resultados adversos com o hormonioterapia no regime de estrogênio e progestagênio administrados de forma contínua. Segundo alguns autores, um ponto importante relacionado com os resultados adversos, tem sido o uso dos progestagênios. Sabe-se que em mulheres não histerectomizadas sua utilização previne o risco de hiperplasia e câncer do endométrio. Porém, grande parte dos efeitos colaterais da terapia de reposição hormonal, se deve ao emprego dos progestagênios, além de reduzir alguns dos benefícios promovidos pelos estrogênios. Para que se faça uma escolha adequada de qual substância utilizar, minimizando os efeitos adversos, é importante conhecer os tipos de progestagênios e seus mecanismos de ação, seus efeitos sobre o perfil lipídico, sobre o metabolismo dos carboidratos e o risco cardiovascular. Entre os novos compostos lançados em nosso meio, há a drosperinona, cujo uso atual se restringe à contracepção; a trimegestona e a didrogesterona, ambos usados na terapia de reposição hormonal. Acreditamos que o grande avanço da terapia de reposição estará na redução da dose dos hormônios utilizada, no emprego de regimes não tradicionais de proteção endometrial, como a utilização de progestogênio a cada dois ou três meses associado à terapia de reposição estrogênica. Com essas modificações, espera-se reduzir os possíveis efeitos adversos associados à reposição hormonal em mulheres na pós-menopausa, aumentando assim a adesão ao tratamento

Impact of clinically relevant progestins on the neural effects of estradiol and the signaling pathways involved.

The natural ovarian hormone progesterone functions as an effective neuroprotective agent. However, in its native state it is not an efficient therapeutic compound because of its poor bioavailability. Thus, for practical therapeutic usage it became necessary to develop orally active progestogens for use in hormone therapy. We have shown that not all progestogens are equal in their ability to modulate neuronal survival and markers of neuronal plasticity. Thus, one cannot assume that all hormone therapies will perform the same, and it is crucial to determine the neural effects and interactions with estradiol of synthetic progestins used in place of natural progesterone. We have analyzed a number of clinically relevant progestins for neuroprotective efficacy. These in vitro analyses of neuroprotective efficacy could serve as a predictive index of clinical efficacy for progestins to protect against degenerative insults that lead to Alzheimer's disease. To aid in such therapeutic development, we determined the chemical structural features that predict progestin efficacy in the brain and showed that binding affinity does not predict neuroprotective efficacy or the direction of effect and thus cannot be used as an indicator of neurological benefit. In contrast, there was a set of common features of ligand-receptor interactions that are correlative and hopefully predictive of neuroprotective efficacy. Elucidation of the sites and targets of progestogen action should have a clear impact on both the use of hormone therapy for the prevention of neurodegenerative disease and the future design of target-specific hormone therapy formulations.

Progestogen therapies: differences in clinical effects?

A large number of estrogen/progestogen preparations are available for the treatment of estrogen-deficiency symptoms. These preparations differ in the route of administration, the type and dose of both the estrogen and progestogen. The only indication for the addition of a progestogen is endometrial protection, but, depending on its chemical structure, a progestogen can either enhance (e.g. hot flushes, gonadotropin release, breast-epithelial proliferation and bone mineral density) or antagonize (e.g. endometrium, arterial wall, lipid metabolism, hepatic protein synthesis and mood) the effects of the estrogen component. Available progestogens differ largely in their hormonal pattern and, in addition to their progestogenic and antiestrogenic action on the endometrium, they can exert androgenic, antiandrogenic, glucocorticoid and/or antimineralocorticoid effects. There are no comprehensive trials comparing directly the modulating effects of the various progestogens, and clinical and epidemiological data do not allow a definite conclusion on the clinical relevance of differences between progestogens.

Classification and pharmacology of progestins.

Besides the natural progestin, progesterone, there are different classes of progestins, such as retroprogesterone (i.e. dydrogesterone), progesterone derivatives (i.e. medrogestone) 17alpha-hydroxyprogesterone derivatives (i.e. chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate), 19-norprogesterone derivatives (i.e. nomegestrol, promegestone, trimegestone, nesterone), 19-nortestosterone derivatives norethisterone (NET), lynestrenol, levonorgestrel, desogestrel, gestodene, norgestimate, dienogest) and spironolactone derivatives (i.e. drospirenone). Some of the synthetic progestins are prodrugs, which need to be metabolized to become active compounds. Besides the progestogenic effect, which is in common for all progestins, there is a wide range of biological effects, which are different for the various progestins and have to be taken into account, when medical treatment is considered.

Newer progestogens.

OBJECTIVE: To review the literature on the most recent progestogens to be developed, to provide clinical comparisons with older progestogens and to look at the potential of products not yet marketed. DATA SOURCES: Searches of Medline and Popline together with requests for bibliographies from the Population Council, Wyeth-Ayerst Research and Schering Health Care. STUDY SELECTION: Information from technical papers was used to ascertain the metabolic characteristics and receptor binding affinities of the compounds. Previous reviews were scrutinised in order to make comparisons with older compounds. Any available trials were examined to ascertain efficacy, bleeding patterns and tolerability, more weight being given to comparative trials. DISCUSSION: Five progestogens have been developed in the last decade. They are all devoid of androgenic activity; some have antiandrogenic activity. Combined oral contraceptive (COC) pills containing dienogest and drospirenone are already marketed. Nomegestrol and nestorone have been extensively studied as subdermal implants. CONCLUSIONS: Newer progestogens used in combination with oestrogen behave very similarly to existing products. Progestogen-only products using new progestogens have potential for significantly better tolerability due to their lack of androgenic activity.

Poison prevention packaging requirements; exemption of hormone replacement therapy products. Final rule.

The Commission is amending its child-resistant packaging requirements to exempt hormone replacement therapy ("HRT") products containing one or more progestogen or estrogen substances. Current exemptions cover some HRT products, but not others. This rule would uniformly exempt from child resistant packaging requirements all HRT products that rely solely on the activity of one or more progestogen or estrogen substances.

Progestogens in hormonal replacement therapy: new molecules, risks, and benefits.

While the benefits of progestogen use in hormone replacement therapy (HRT) are well recognized as far as endometrial protection is concerned, their risks and drawbacks have generated controversial articles. Several risks are attributed to progestogens as a class-effect; however, the progestogens used in HRT have varying pharmacological properties and do not induce the same side effects. Natural progesterone (P) and some of its derivatives, such as the 19-norprogesterones (Nestorone, nomegestrol acetate, trimegestone), do not bind to the androgen receptor and, hence, do not exert androgenic side effects. Newly synthesized molecules such as drospirenone or dienogest have no androgenic effect but do have a partial antiandrogenic effect. Drospirenone derives from spironolactone and binds to the mineralocorticoid receptor. When the cardiovascular risk factors are considered, some molecules with a higher androgenic potency than others attenuate the beneficial effects of estrogens on the lipid profile as well as the vasomotion. On the other hand, other progestogens devoid of androgenic properties do not exert these deleterious effects. The epidemiological data do not suggest any negative effect of the progestogens administered together with estrogens on cardiovascular morbidity or mortality. However, recent results suggest that in women with established coronary heart disease, HRT may not protect against further heart attacks when the progestogen selected possesses androgenic properties. The data related to the progestogen effect on breast tissue has been interpreted differently from country to country. However, it has been admitted that, according to the type of progestogen used and the dose and duration of its application, a predominant antiproliferative effect is observed in the human breast cells. As far as breast cancer risk is concerned, most epidemiological studies do not suggest any significant difference between the estrogens given alone or combined with progestogens in HRT. Complying with the classic contraindications of HRT and selecting molecules devoid of estrogenic, androgenic, or glucocorticoid effect should allow a larger use of the progestins without any major drawback.

Biological effects of progestins in breast cancer.

The action of progestins is derived from many factors: structure, affinity for the progesterone receptor or for other steroid receptors, the target tissue considered, the biological response, the experimental conditions, the dose and metabolic transformation. The proliferative response to progestins in human breast cancer cells is contradictory: some progestins inhibit, others stimulate, have no effect at all, or have a dual action. For instance, medroxyprogesterone acetate has a stimulatory effect on breast cancer cells after a short period of treatment, but this effect becomes inhibitory when treatment is prolonged. It has been demonstrated that, in hormone-dependent breast cancer cells, various progestins (nomegestrol acetate, medrogestone, promegestone) are potent sulfatase inhibitory agents. The progestins can also involve the inhibition of the mRNA expression of this enzyme. In another series of studies it was also demonstrated that some progestins are very active in inhibiting 17beta-hydroxysteroid dehydrogenase for the conversion of estrone to estradiol. More recently it was observed that the progestins promegestone and medrogestone stimulate sulfotransferase for the formation of estrogen sulfates. Consequently, the action of progestins in blocking estradiol formation via sulfatase, or in stimulating the effect on sulfotransferase activity, can open interesting and new possibilities in clinical applications in breast cancer.

Progestins and breast cancer.

In the last years there has been an extraordinary development in the synthesis of new progestins. These compounds are classified, in agreement with their structure, in various groups which include progesterone, retroprogesterones, 17alpha-hydroxyprogesterones, 19-norprogesterones, 17alpha-hydroxyprogesterone derivatives, androstane and estrane derivatives. The action of progestins is a function of many factors: its structure, affinity to the progesterone receptor or to other steroid receptors, the target tissue considered, the biological response, the experimental conditions, dose, and metabolic transformation. The information on the action of progestins in breast cancer patients is very limited. Positive response with the progestins: medroxyprogesterone acetate and megestrol acetate was obtained in post-menopausal patients with advanced breast cancer. However, extensive information on the effect of progestins was obtained in in vitro studies using hormone-dependent and hormone-independent human mammary cancer cell lines. It was demonstrated that in the hormone-dependent breast cancer cells, various progestins (nomegestrol acetate, tibolone, medrogestone, promegestone) are potent sulfatase inhibitory agents. The progestins can also involve the inhibition of mRNA of this enzyme. In another series of studies it was also demonstrated that various progestins are very active in inhibiting the 17beta-hydroxysteroid dehydrogenase for the conversion of estrone to estradiol. More recently it was observed that the progestins promegestone or medrogestone stimulate the sulfotransferase for the formation of estrogen sulfates. Consequently, the blockage in the formation of estradiol via sulfatase, or the stimulatory effect on sulfotransferase activity, by progestins can open interesting and new possibilities in clinical applications in breast cancer.

[Hormone replacement therapy in the climacteric]. / Terapia de sustitución hormonal en el climaterio.

Menopause is the physiologic state that is a consequence of the cessation of ovarian function. A large number of vasomotor, psychological and gynecological symptoms have been associated with menopause. Hormonal replacement therapy is effective in treating these conditions. The use of estrogens and progestins including dosages, routes of administration and their advantages and disadvantages are reviewed in this article. In addition, hormonal replacement therapy may reduce the risk of atherosclerosis and prevent the osteoporosis of climateric women. Hormonal therapy is associated with side effects but they do not contraindicate its use.