Progestins in the menopause in healthy women and breast cancer patients

At present, more than 200 progestin compounds are synthetized, but their biological effects are different: this is function of their structure, receptor affinity, metabolic transformations, the target tissues considered, dose. The action of progestins in breast cancer is controversial; some studies indicate an increase in breast cancer incidence, others show no differences, and yet others indicate a decrease. Many studies agree that treatment with progestins plus estrogens at a low dose and during a limited period (less than 5 years) can have beneficial effects in peri- and post-menopausal women. It was demonstrated that various progestins (e.g. nomegestrol acetate, medrogestone, promegestone), as well as tibolone and its metabolites, can block the enzymes involved in estradiol bioformation (sulfatase, 17β-hydroxysteroid dehydrogenase) in breast cancer. Progesterone is converted into various metabolic products: in normal breast tissue the transformation is mainly to 4-ene derivatives, whereas in the tumor tissue 5α-pregane derivatives are predominant. Aromatase activity is the last step in the formation of estrogens by the conversion of androgens. In recent studies it was shown that 20α-dihydroprogesterone, a metabolite found mainly in normal breast tissue and having anti-proliferative properties, can act as an anti-aromatase agent. The data suggest the possible utilization of this compound in breast cancer prevention. In conclusion, in order to clarify and better understand the response of progestins in breast cancer (incidence and mortality), as well as in hormone replacement therapy or in endocrine dysfunction, new clinical trials are necessary using other progestins in function of the dose and period of treatment.     

Paracrine overexpression of insulin-like growth factor-1 enhances mammary tumorigenesis in vivo

Insulin-like growth factor-1 (IGF-1) stimulates proliferation, regulates tissue development, protects against apoptosis, and promotes the malignant phenotype in the breast and other organs. Some epidemiological studies have linked high circulating levels of IGF-1 with an increased risk of breast cancer. To study the role of IGF-1 in mammary tumorigenesis in vivo, we used transgenic mice in which overexpression of IGF-1 is under the control of the bovine keratin 5 (BK5) promoter and is directed to either the myoepithelial or basal cells in a variety of organs, including the mammary gland. This model closely recapitulates the paracrine exposure of breast epithelium to stromal IGF-1 seen in women. Histologically, mammary glands from transgenic mice were hyperplastic and highly vascularized. Mammary glands from prepubertal transgenic mice had significantly increased ductal proliferation compared with wild-type tissues, although this difference was not maintained after puberty. Transgenic mice also had increased susceptibility to mammary carcinogenesis, and 74% of the BK5.IGF-1 mice treated with 7,12-dimethylbenz[a]anthracene (20 μg/day) developed mammary tumors compared with 29% of the wild-type mice. Interestingly, 31% of the vehicle-treated BK5.IGF-1 animals, but none of the wild-type animals, spontaneously developed mammary cancer. The mammary tumors were moderately differentiated adenocarcinomas that expressed functional, nuclear estrogen receptor at both the protein and mRNA levels. These data support the hypothesis that tissue overexpression of IGF-1 stimulates mammary tumorigenesis.     

On the possible role of mammary-derived growth hormone in human breast cancer

The incidence of breast cancer has risen worldwide, especially in countries where it used to be low, very probably as a result of economic prosperity and changes in life-style. In women, the available data have resulted in the concept of progression from normal breast development to cancer through precursor lesions sensitive to hormones and growth factors that can be produced locally in the mammary gland, acting as paracrine or autocrine stimulating agents. The local endocrine environment in the breast can be different from the situation in the circulation. In the dog, growth hormone (GH) can be produced locally in the mammary glands and its production can be stimulated by progestins. This GH probably plays a paracrine role in the progesterone-induced proliferation and differentiation of mammary epithelium. There is increasing evidence that the local mammary progestin/GH-axis is operational not only in dogs but also in human breast cancer. No data are yet available on the production of mammary-derived GH in women.     

Expression of growth hormone in canine mammary tissue and mammary tumors. Evidence for a potential autocrine/paracrine stimulatory loop.

The role of progestins in the pathogenesis of breast cancer in women remains controversial. To advance this discussion, we report the demonstration and localization of progestin-induced biosynthesis of growth hormone (GH) in canine mammary gland tissue. Nontumorous mammary tissues and tumors, both benign and malignant, were obtained from private household dogs. Immunoreactive GH was localized in mammary epithelial cells and correlated with the presence of GH mRNA. Local synthesis of GH was also proven immunoelectron microscopically by demonstrating GH-containing secretory granules. Cellular GH production in nontumorous tissues was more extensive during the progesterone-dominated luteal phase of the ovarian cycle or during exposure to synthetic progestins than during anestrus. GH was also associated with areas of hyperplastic mammary epithelium, which may indicate that locally produced GH enhances proliferation, acting in an autocrine and/or paracrine manner. In 41 of 44 tumors, GH was present. Of 3 GH-negative tumor samples, 2 were from progestin-depleted, castrated bitches. In nonmalignant mammary tissues, GH production is stimulated by progesterone and synthetic progestins interacting with progesterone receptors. In some progesterone-receptor-negative malignant tumors, GH expression was found, indicating loss of this control. Progestin-induced GH probably participates in the cyclic development of the mammary gland but may promote mammary tumorigenesis by stimulating proliferation of susceptible, and sometimes transformed, mammary epithelial cells.     

In situ phosphorylation of Akt and ERK1/2 in rat mammary gland, colon, and liver following treatment with human insulin and IGF-1

High doses of insulin and the insulin analog AspB10 have been reported to increase mammary tumor incidence in female rats likely via receptor-mediated mechanisms, possibly involving enhanced IGF-1 receptor activation. However, insulin and IGF-1 receptor functionality and intracellular signaling in the rat mammary gland in vivo is essentially unexplored. The authors investigated the effect of a single subcutaneous dose of 600 nmol/kg human insulin or IGF-1 on Akt and ERK1/2 phosphorylation in rat liver, colon, and mammary gland. Rat tissues were examined by Western blotting and immunohistochemistry by phosphorylation-specific antibodies. Insulin as well as IGF-1 caused Akt phosphorylation in mammary epithelial cells, with myoepithelial and basal epithelial cells being most sensitive. IGF-1 caused stronger Akt phosphorylation than insulin in mammary gland epithelial cells. Phosphorylation of ERK1/2 was not influenced by insulin or IGF-1. Rather, in liver and mammary gland P-ERK1/2 appeared to correlate with estrous cycling, supporting that ERK1/2 has important physiological roles in these two organs. In short, these findings supported that the rat mammary gland epithelium expresses functional insulin and IGF-1 receptors and that phosphorylation of Akt as well as ERK1/2 may be of value in understanding the effects of exogenous insulin in the rat mammary gland and colon.     

Differential effects of progestins on breast tissue enzymes

There is substantial evidence that mammary cancer tissue contains all the enzymes responsible for the local biosynthesis of estradiol (E2) from circulating precursors. Two principal pathways are implicated in the final steps of E2 formation in breast cancer tissue: the 'aromatase pathway' that transforms androgens into estrogens and the 'sulfatase pathway' that converts estrone sulfate (E1S) into estrone (E1) via estrone sulfatase. The final step is the conversion of weak E1 to potent biologically active E2 via reductive 17beta-hydroxysteroid dehydrogenase type 1 activity. It is also well established that steroid sulfotransferases, which convert estrogens into their sulfates, are present in breast cancer tissues. One of the possible means of blocking E2 effects in breast cancer is to use anti-estrogens, which act by binding to the estrogen receptor (ER). Another option is to block E2 using anti-enzymes (anti-sulfatase, anti-aromatase, or anti-17beta-hydroxysteroid dehydrogenase (17beta-HSD). Various progestins (e.g. promegestone, nomegestrol acetate, medrogestone, 17-deacetyl norgestimate, dydrogesterone and its 20-dihydro derivative), as well as tibolone and its metabolites, have been shown to inhibit estrone sulfatase and 17beta-hydroxysteroid dehydrogenase. Some progestins and tibolone can also stimulate sulfotransferase activity. These various progestins may therefore provide a new option for the treatment of breast cancer.     

Comparative analysis of the uterine and mammary gland effects of progesterone and medroxyprogesterone acetate

Objectives

In combined hormone replacement therapy (HRT) progestins are used to inhibit estradiol-activated uterine epithelial cell proliferation. In comparison to estradiol-only therapy, combined HRT leads to enhanced proliferation of mammary epithelial cells. In a quantitative mouse model, we assessed the balance between uterine and undesired mammary gland effects for two progestins that are widely used in HRT, progesterone and medroxyprogesterone acetate.

Study design

Mice were ovariectomized and after 14 days they were treated subcutaneously with either vehicle, estradiol (100 ng) or estradiol plus increasing doses of progesterone or medroxyprogesterone acetate for three weeks.

Main outcome measures

Measures for progestogenic mammary gland activity were stimulation of side-branching and stimulation of epithelial cell proliferation. Progestogenic activity in the uterus was assessed by measuring inhibition of estradiol-activated uterine epithelial cell proliferation. ED₅₀ and ID₅₀ values for the distinct readouts were obtained and dissociation factors for uterine versus mammary gland activity were calculated.

Results

MPA demonstrated uterine activity and mitogenic activity in the mammary gland at the same doses. In contrast, progesterone showed uterine activity at doses lower than those leading to significant stimulation of epithelial cell proliferation in the mammary gland.

Conclusions

Progestins do not behave the same. Use of the natural hormone progesterone, but not MPA, in combined hormone therapy might offer a safety window between uterine effects and undesired proliferative activity in the mammary gland.     

Antiestrogen action of progesterone in the breast

This review analyzes recent data from international literature concerning the antiestrogen action of progesterone, progestins and the antiprogesterone RU 486 at the level of mammary cells in culture from either breast cancer lines or normal breast obtained from reduction mammoplasties. Most data indicate that progesterone, progestins and even RU 486 have a strong antiestrogen effect on breast cell appreciated by the decrease of estradiol receptor content, the decrease of cell multiplication and the stimulation of 17 beta-hydroxysteroid activity which may be considered as a marker of breast cell differentiation dependent of progesterone receptor.     

Insulin analogues may accelerate progression of diabetic retinopathy after impairment of inner blood-retinal barrier

Diabetic retinopathy regresses after spontaneous infarction or surgical ablation of pituitary gland. Growth hormone deficiency seems to be a protective factor for development of diabetic retinopathy in dwarfs. Despite the same glycemic control, development of diabetic retinopathy is significantly higher in pubertal subjects than pre-pubertal subjects. These evidences indicate a strong relationship between growth hormone and progression of diabetic retinopathy. Insulin like growth factor-1 (IGF-1) is the most important mediator of effects of growth hormone (GH). It stimulates IGF-1 receptor. Insulin analogues also stimulate IGF-1 receptor. Therefore insulin analogues may show similar effects like growth hormone and deteriorate diabetic retinopathy. However we suggest that impairment degree of inner blood-retinal barrier should be considered for this claim. We hypothesize that insulin analogues have dual effects (beneficial and worsening) depending on stage of impairment of inner blood-retinal barrier. Insulin analogues protect pericytes and blood-retinal barrier by decreasing blood glucose level. Analogues may pass into the retinal tissue in very low amounts when inner blood-retinal barrier is intact. Therefore, insulin analogues may not deteriorate diabetic retinopathy but also have beneficial effect by protecting blood-retinal barrier at this stage. However, they may pass into the retinal tissue in much more amounts when inner blood-retinal barrier impairs. Analogues may deteriorate cellular composition of retina through stimulation of IGF-1 receptors. A number of different cell types, including glia, retinal pigment epithelial cells and fibroblast-like cells have been identified in diabetic epiretinal tissues. Insulin analogues may cause proliferation in these cells. A type of glial cell named Non-astrocytic Inner Retinal Glia-like (NIRG) cell was identified to be stimulated and proliferate by IGF-1. IGF has been reported to generate traction force in retinal pigment epitelium (RPE) and mullerian cells. Mullerian cells also support inner blood-retinal barrier. Insulin analogues may cause proliferation in glial cells and generate traction force in RPE and mullerian cells by stimulating IGF-1 receptor. These effects of analogues may increase after deterioration of inner blood-retinal barrier and cause structural changes in retinal tissue. Deterioration of cellular structure may contribute to impairment of inner blood-retinal barrier, facilitate anjiogenesis and influence vitreoretinal interface. Therefore we suggest that insulin analogues should be used carefully after impairment of inner blood-retinal barrier. Analogues that bind with lesser affinity to IGF-1 receptor should be chosen after impairment. Pharmacologic agents may be developed to antagonize effect of insulin analogues on IGF-1 receptors.     

Exogenous progestagens and the human breast

The role of progestins (or progestagens) on the breast tissue remains controversial. However, according to the molecule and the duration of application, cell differentiation and apoptosis may predominate over proliferation. Progestins are also used as second-line agents for the treatment of metastatic breast cancer. In young women with benign breast disease, long-term treatment with 19-nortestosterone progestins had a trend to decrease breast cancer risk contrarily to what was observed in postmenopausal women receiving estrogens. Several compounds with progestational activity have been used for HRT. Small differences in the structure of the molecules may lead to pronounced differences in activities, some progestins exerting androgenic effects and some exerting estrogenic or glucocorticoid like activities. While most progestins do not bind to the estrogen receptors, it has been shown that some androgenic progestins stimulate MCF7 cells proliferation while progestins derived from progesterone did not induce cell multiplication in the same cell lines. Therefore, different progestins may induce different effects on the breast cells. Whether the progestins available to date are able to bind specifically to the progesterone receptors PR-A or PR-B and whether this is of clinical relevance to breast cell proliferation is still unclear. Although the relationship between progestin use and breast cancer risk is still the subject of debate and controversy, the data reported to date suggest that 5 years of treatment carry a low risk but further duration of use increases the risk. Further studies are still needed, randomised long-term prospective studies as well as from the laboratory, especially to determine whether a sequential or continuous regimen would be preferable as far as breast-cell response and apoptosis are concerned, and what are the effects of the various molecules used for HRT.     

Isoflavones--safe food additives or dangerous drugs?

The sales volume of products containing isoflavone has increased since the publication of the Women's Health Initiative. The many apparently contradictory results published on the effects of isoflavones on a variety of estrogen-regulated organs point to both beneficial as well as adverse effects on human health. It is of particular importance that psychovegetative climacteric complaints such as hot flushes are, if at all, only slightly influenced by isoflavones. The substances appear to have weak anti-osteoporotic effect. Their anti-atherosclerotic action is debatable, as not all authors find any beneficial effect on lipids. Most importantly, there is dispute as to whether isoflavones derived from soy or red clover have negative, positive or any effect at all on the mammary gland or endometrium. It is beyond any doubt that soy products may have cancer preventing properties in a variety of organs including the mammary gland. However, these properties may only be exerted if the developing organ was under the influence of isoflavones during childhood and puberty. This may also explain the often quoted "Japanese Phenomenon", the fact that breast cancer occurs to a lesser extent in Japanese women. When administered to isoflavone "inexperienced" women at the time of menopause, the phytoestrogens appear to share the same effects as estrogen used in classical preparations for hormone replacement therapy, i.e. they may stimulate the proliferation of endometrial and mammary gland tissue with at present unknown and unpredictable risk to these organs. Therefore, the following question arises for the clinician: Why should soy or red clover products containing isoflavone be recommended, if the positive effects are only negligible but the adverse effects serious?     

Progesterone receptor isoform functions in normal breast development and breast cancer

Progesterone acting through two isoforms of the progesterone receptor (PR), PRA and PRB, regulates proliferation and differentiation in the normal mammary gland in mouse, rat, and human. Progesterone and PR have also been implicated in the etiology and pathogenesis of human breast cancer. The focus of this review is recent advances in understanding the role of the PR isoform-specific functions in the normal breast and in breast cancer. Also discussed is information obtained from rodent studies and their relevance to our understanding of the role of progestins in breast cancer etiology.     

Insulin analogues may accelerate progression of diabetic retinopathy after impairment of inner blood-retinal barrier

Diabetic retinopathy regresses after spontaneous infarction or surgical ablation of pituitary gland. Growth hormone deficiency seems to be a protective factor for development of diabetic retinopathy in dwarfs. Despite the same glycemic control, development of diabetic retinopathy is significantly higher in pubertal subjects than pre-pubertal subjects. These evidences indicate a strong relationship between growth hormone and progression of diabetic retinopathy. Insulin like growth factor-1 (IGF-1) is the most important mediator of effects of growth hormone (GH). It stimulates IGF-1 receptor. Insulin analogues also stimulate IGF-1 receptor. Therefore insulin analogues may show similar effects like growth hormone and deteriorate diabetic retinopathy. However we suggest that impairment degree of inner blood-retinal barrier should be considered for this claim. We hypothesize that insulin analogues have dual effects (beneficial and worsening) depending on stage of impairment of inner blood-retinal barrier. Insulin analogues protect pericytes and blood-retinal barrier by decreasing blood glucose level. Analogues may pass into the retinal tissue in very low amounts when inner blood-retinal barrier is intact. Therefore, insulin analogues may not deteriorate diabetic retinopathy but also have beneficial effect by protecting blood-retinal barrier at this stage. However, they may pass into the retinal tissue in much more amounts when inner blood-retinal barrier impairs. Analogues may deteriorate cellular composition of retina through stimulation of IGF-1 receptors. A number of different cell types, including glia, retinal pigment epithelial cells and fibroblast-like cells have been identified in diabetic epiretinal tissues. Insulin analogues may cause proliferation in these cells. A type of glial cell named Non-astrocytic Inner Retinal Glia-like (NIRG) cell was identified to be stimulated and proliferate by IGF-1. IGF has been reported to generate traction force in retinal pigment epitelium (RPE) and mullerian cells. Mullerian cells also support inner blood-retinal barrier. Insulin analogues may cause proliferation in glial cells and generate traction force in RPE and mullerian cells by stimulating IGF-1 receptor. These effects of analogues may increase after deterioration of inner blood-retinal barrier and cause structural changes in retinal tissue. Deterioration of cellular structure may contribute to impairment of inner blood-retinal barrier, facilitate anjiogenesis and influence vitreoretinal interface. Therefore we suggest that insulin analogues should be used carefully after impairment of inner blood-retinal barrier. Analogues that bind with lesser affinity to IGF-1 receptor should be chosen after impairment. Pharmacologic agents may be developed to antagonize effect of insulin analogues on IGF-1 receptors.     

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.     

Leptin receptor signaling supports cancer cell metabolism through suppression of mitochondrial respiration in vivo

Obesity represents a risk factor for certain types of cancer. Leptin, a hormone predominantly produced by adipocytes, is elevated in the obese state. In the context of breast cancer, leptin derived from local adipocytes is present at high concentrations within the mammary gland. A direct physiological role of peripheral leptin action in the tumor microenvironment in vivo has not yet been examined. Here, we report that mice deficient in the peripheral leptin receptor, while harboring an intact central leptin signaling pathway, develop a fully mature ductal epithelium, a phenomenon not observed in db/db mice to date. In the context of the MMTV-PyMT mammary tumor model, the lack of peripheral leptin receptors attenuated tumor progression and metastasis through a reduction of the ERK1/2 and Jak2/STAT3 pathways. These are tumor cell-autonomous properties, independent of the metabolic state of the host. In the absence of leptin receptor signaling, the metabolic phenotype is less reliant on aerobic glycolysis and displays an enhanced capacity for β-oxidation, in contrast to nontransformed cells. Leptin receptor-free tumor cells display reduced STAT3 tyrosine phosphorylation on residue Y705 but have increased serine phosphorylation on residue S727, consistent with preserved mitochondrial function in the absence of the leptin receptor. Therefore, local leptin action within the mammary gland is a critical mediator, linking obesity and dysfunctional adipose tissue with aggressive tumor growth.     

Effects of progestins of human proliferative endometrium: an in vitro model of potential clinical relevance

Endometrium biopsy is a useful indicator of endometrium proliferation and is clinically relevant to diagnose cell proliferation and to evaluate response to progestin treatment and to monitor hormone replacement therapy. The aim of our study was to investigate the in vitro effects of progesterone and synthetic progestins on endometrium explants with a particular focus on estradiol receptor (ER) and progesterone receptor (PR) expression which reflects through cell secretion the hormone treatment efficiency. Most widely used progestagens belonging to three distinctive groups were investigated, i.e, medroxyprogesterone acetate (MPA), norethindrone acetate (NOR) and nomegestrol acetate (TX) which are respectively pregnane, 19-nortestosterone and norpregnane derivatives. We used organ culture from human proliferative endometrium, in which tissue integrity, particularly gland/stroma relationships are preserved. Progestins induce epithelial cell secretion and most effects were observed at the highest concentration tested (10(-7) M) and by TX and MPA on homogeneous and on heterogeneous (including also secretory glands) proliferative endometrium respectively. In these conditions, ER as well as PR expression were decreased on both glandular and stromal cells. In contrast, progesterone at 10(-7) M significantly decreased only PR, in glands and in stroma of homogeneous proliferative endometrium, and just in stroma of heterogeneous endometrium. NOR exhibited less effects. At lower concentrations (10(-8) M, 10(-9) M), significantly less effects were observed by synthetic progestins on proliferative endometrium. The experiments show that the different types of progestins do not exhibit in vitro similar effects. Since progestins variably act on proliferative endometrium, the exposure of endometrium explants to progestins may be a useful tool to predict clinical response to hormone therapy (individual "hormonogram") and to monitor endometrium proliferation.     

Progestins in HRT: Sufferance or desire?

While the benefits of progestins in hormonal replacement therapy are well recognized as far as endometrial protection is concerned the data on breast tissue and the cardiovascular system are contentious. Following the Women's Health Initiative study, the Million Women Study and The Women's International Study of Long-duration (O)estrogen after Menopause the question can be raised: When dealing with optimal hormonal therapy after the menopause, is the progestin component accepted here on sufferance or is it desired? The answer is partly made up by the fact that the recent epidemiological data may have been not only wrongly translated in relation to the clinical settings, but also to the whole class of therapies. The various progestins available for hormonal therapy exert different partial effects at cellular level according to the biochemical composition. Due to the structural differences the progestins result in a variety of tissue transforming changes as well as metabolic and hemostatic changes. Since no single test or algorithm presently serves as golden standard for all desired hormonal effects the least changes or no changes from the premenopausal physiology may often be advantageous. In our opinion targeting this goal includes a sustained desire for an estrogen/progestin combination as optimal future hormone therapy. Moreover the strategy not only includes evaluation of the specific steroidal formula, but also a titration of the dose and choosing the optimal route of administration. With special reference to cardiovascular disease this review therefore makes a plea for differentiating between the array of chemically and functionally distinct progestins used therapeutically after the menopause in combination therapy.     

Steroidal hormones and proliferation, differentiation and apoptosis in breast cells

The impact of estrogens (E) and progestins (P) on the breast is crucial. Recent epidemiological studies raised a great concern concerning breast cancer risk and hormone replacement therapy (HRT). However, the effects of HRT in breast tissue remain unclear. Biological data predominantly show that P are antiproliferative and proapoptotic at least for normal breast cells. These antiproliferative effects of P are well described at the cellular level. Whereas E2 increases the level of the various cyclins involved in the cell cycle progression and decreases the cyclin kinase inhibitors, p21 and p27, progestins act in an opposite manner. In addition, they both modulate the phosphorylated rate of Rb involved into the S phase progression. Various proteins of the apoptotic cascade are also targets for E2 and P. We showed that bcl-2, p53 and caspase 3 are oppositely modulated by E2 and P in normal and breast cancer cell cultures. It is very possible that in vivo the balance between E2/P, the type of P, specific phenotypes could explain increasing risk during HRT, which appears to be mainly a promoter effect on preexisting transformed cells.     

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.     

Stem Cells and the Stem Cell Niche in the Breast: An Integrated Hormonal and Developmental Perspective

The mammary gland is a unique organ in that it undergoes most of its development after birth under the control of systemic hormones. Whereas in most other organs stem cells divide in response to local stimuli, to replace lost cells, in the mammary gland large numbers of cells need to be generated at specific times during puberty, estrous cycles and pregnancy to generate new tissue structures. This puts special demands on the mammary stem cells and requires coordination of local events with systemic needs. Our aim is to understand how the female reproductive hormones control mammary gland development and influence tumorigenesis. We have shown that steroid hormones act in a paracrine fashion in the mammary gland delegating different functions to locally produced factors. These in turn, affect cell–cell interactions that result in changes of cell behavior required for morphogenesis and differentiation. Here, we discuss how these hormonally regulated paracrine interactions may impinge on stem cells and the stem cell niche and how this integration of signals adds extra levels of complexity to current mammary stem cell models. We propose a model whereby the stem cell niches change depending on the developmental stages and the hormonal milieu. According to this model, repeated hormone stimulation of stem cells and their niches in the course of menstrual cycles may be an important early event in breast carcinogenesis and may explain the conundrum why breast cancer risk increases with the number of menstrual cycles experienced prior to a first pregnancy.