NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

Cover of Holland-Frei Cancer Medicine

Holland-Frei Cancer Medicine. 5th edition.

Show details

Chapter 57Progestins

, MD, PhD and , PhD.

Progestins, as a class of sex steroids, are associated with a remarkable spectrum of responses in diverse tissues. Most but not all of these responses are the result of the molecular interaction of the steroid with the progesterone receptor (PR), which can be demonstrated in target cells. Progesterone interaction with its receptor is only the first phase of a complex series of events involved in the regulatory mechanisms that determine the response to this hormone. In addition to the sequence of events in the assembly of a preinitiation complex of RNA polymerase II (pol-II) and general transcription factors, a series of proteins serve to modulate the response to progestins in target tissues in health and disease. These proteins that modulate transcriptional activity are referred to as co-regulators (co-activators, co-repressors, and co-integrators), and they produce a series of protein-DNA, protein-RNA and protein-protein interactions to either enhance or repress gene transcription. This complex interaction of progesterone receptor with bound progestin and co-regulator proteins provides potential selectivity to the interaction with promoter and response elements in different tissues.1,2

Steroid receptor-signaling co-regulator protein interaction and function provide a partial explanation of how target tissues function differently under specific physiologic conditions and disease states. Progestin function should no longer be regarded as limited to that of differentiation sex steroids. It is critical to provide molecular mechanisms to explain how some tissues respond to progestins with cell proliferation whereas in other tissues, the same progestins inhibit proliferation and are associated with cell differentiation. We have yet to account for the dramatic differences in progesterone-induced changes observed in tissues such as the breast and uterus. These differences are seen in both epithelial and stromal elements and seemed paradoxical prior to the recognition of the complexity of the co-regulatory proteins’ role in steroid hormone signaling.1,2 Progestins also alter glandular epithelium and smooth muscle in other organs and tissues, including effects on vascular repair and fibrosis, as well as reticuloendothelial elements. Proliferation of breast epithelium is associated with progesterone3 whereas in the uterus, estrogen is dominant in proliferation and progesterone inhibits proliferation.4 Despite this diametric effect on proliferation in these organs, progestins affect secretory differentiation and activity in both tissues after estrogen priming.

Pharmacology

Progestins are properly classified as natural or synthetic. Progesterone is the dominant naturally occurring progestin. Progesterone occupies a position early in the scheme of the synthetic pathway involving the conversion of precursor cholesterol to the production of adrenal cortex-derived hormones, including androgens, progestins, and estrogens. After menopause, in the absence of hormone replacement, the adrenal becomes the principal source of sex steroids. In the premenopausal woman, progesterone is principally derived from the corpus luteum of the ovary, but in pregnancy after the 8th week of gestation, the placental progesterone production greatly exceeds ovarian-derived progesterone. The placental trophoblast is the dominant cell responsible for progesterone production by the placenta. The development of a secretory endometrium in which the blastocyst can implant requires progesterone. Progesterone is synthesized by the adrenals through conversion of pregnenolone. Progesterone levels of 25 ng/mL are usual in the luteal phase of the menstrual cycle while levels to 150 ng/mL are seen in late pregnancy. High levels of progesterone (in the range of 100–150 ng/mL) are associated with tissue responses that have implications for treatment of other conditions. Progesterone inhibits T lymphocyte cell-mediated immune response, prostaglandin formation, and smooth-muscle contractility.5

The principal pharmacologic uses of progestins are in contraception and in conjunction with estrogen in postmenopausal hormone replacement therapy, where progestins are employed to minimize the risk of uterine cancer associated with estrogen-only therapy.6 Progestins are also widely employed to treat metastatic endometrial and breast cancer.7 The recommendation for progestin addition to estrogen replacement therapy in the climacteric places new emphasis on understanding the mechanism of progesterone action in settings other than contraception, particularly in populations with an increased risk of endometrial and breast cancer.4,8 In premenopausal women, progestins and antiprogestins are used predominantly in contraceptive preparations, which have been the focus of the greatest effort toward understanding the pharmacology and mechanism of action of progesterone as well as various synthetic progestins and antiprogestins.9 Progestins are often used alone in selected women with climacteric symptoms who are advised not to take estrogens. Progestins are used in the endocrine treatment of uterine and breast cancer with clinically proven antineoplastic properties.7,10 Progestins have also been of therapeutic benefit in meningiomas,11 pulmonary lymphangiomyomatosis,12 uterine leiomyomas,13 and endometriosis14 producing tumor stabilization or reduction, disease remission, or disease inhibition. Some degree of antineoplastic effects has also been suggested in other neoplasms, such as ovarian carcinoma,15 esophageal carcinoma,16 cervical carcinoma,17 and endometrial stromal sarcoma,18 but controlled clinical trials have not proven the efficacy of progesterone in these tumors.

Progesterone is poorly absorbed when given orally although transdermal administration has shown some efficacy.19 When injected, progesterone must be administered with an oil carrier. A number of synthetic progestins are available which are well absorbed in the gastrointestinal tract. Synthetic progestins are derivatives of the steroid structure of either progesterone or testosterone. This derivative relationship provides the basis for the classification of the synthetic progestins. The synthetic progestins most often encountered include 17-hydroxyprogesterone, medroxyprogesterone (Provera), medroxyprogesterone acetate, megestrol acetate (Megace), norethindrone, norethindrone enanthate, norethindrone acetate, norethynodrel, norgestrel, desogestrel, and gestodene. In view of their importance in contraception and their therapeutic use in the climacteric and in neoplastic disease, new synthetic progestational compounds are under continued development and evaluation.

The poor absorption of progesterone has been overcome with some of the synthetic derivative progestins but at the cost of adverse effects on plasma lipid levels,20 and alternate derivatives or alternate administration routes continue to be sought.19,20 Medroxyprogesterone given as a single intramuscular injection of 25 to 50 mg shows an effect on estrogen-stimulated endometrium for just over 2 weeks although increases in basal body temperature from such treatment may last 6 weeks or more. Depo-Provera has a period of action that is considerably longer. Oral medroxyprogesterone and oral megestrol acetate are well absorbed. Medroxyprogesterone produces a luteal effect in anovulatory patients, with an oral dose of 5 to 10 mg daily for 5 days. A dose of 5 to 10 mg/day for 10 days is typically recommended for anovulatory patients and in programs of cyclic estrogen-progesterone therapy for the climacteric. If daily progesterone is used in conjunction with estrogen replacement, a dose of 2.5 mg daily is recommended.

A 19-norsteroid, RU 486, is an antiprogesterone that has been used clinically in the last several years for its effects on pregnancy. This compound is effectively absorbed orally and appears to bind to the progesterone receptor with high affinity and to effect altered co-regulator protein interaction after binding. RU 486 also has significant antiglucocorticoid activity as well as weak antiandrogen activity, being an effective contragestational agent.21

Quantitative increases in progesterone-receptor concentration in target cells are induced by preovulatory estrogen surges.22 This has the effect of priming target cells to respond to the progesterone rise produced by the corpus luteum after ovulation. Loss of the function of the corpus luteum (luteolysis) is associated with a rapid decrease of progesterone and estradiol. Associated with this rapid decrease of progesterone and estrogen is the disintegration of the endometrium. Since progesterone activity is dependent on intact functional progesterone receptor, one molecular mechanism likely involved in RU 486 action is a modulation of PR function. RU 486 enhances the binding of heat shock protein-90 (hsp-90) to the PR-altering co-regulator interaction and reducing progesterone-receptor-induced transcriptional stimulation.1,2,23 When bound to the PR, the hsp-90 produces an inactive configuration, preventing interaction with co-activators and with the target genes.1,2

In addition to the epithelial effects of progesterone, effects on bone metabolism, water retention, lipid metabolism, and the central nervous system must all be considered in developing treatment strategies using progestins.24,25

Basic Mechanism of PR Ligand-Dependent Transcription

Function of Activation Factors and Heat Shock Proteins

Progesterone functions in RNA transcription regulation through a complex series of interactions that is initiated by binding of the hormone to its cognate receptor.1,2 The receptor after ligand binding is either a homodimer or heterodimer. When the ligand is bound, heat shock proteins 90, 70, and 20 (hsp-90/70/20) are released.26,27 It is clear that in the absence of progesterone, the progesterone receptor is functionally inactive and is associated with chaperone protein hsp-90.1,2,26,27 The chaperone function of the hsp-90 is intimately associated with inactivity of the steroid receptor. The activation of the progesterone receptor directly involves its binding to its conserved activation function AF-2 at the carboxyl end of the progesterone receptor. This interaction modifies the molecular constraints, including the release of the hsp-90. The modifications, including release of the chaperone protein(s) and co-repressor proteins as well as binding of co-activator proteins, permit enhanced access to the DNA-binding domain. The results from the laboratory of D.R. Ciocca, suggest that in human breast cancers, a heat shock protein designated hsp-27 may be involved in cell growth, arrest, and enhanced differentiation.28 The heat shock protein hsp-70 also appears be involved in cell proliferation. In the absence of progesterone, the PR is functionally inactive.

The function of the heat shock protein has also been associated with cell death or apoptosis as well as differentiation.1,2 The synthesis of hsp-27 is modulated in the endometrium during different phases of the menstrual cycle. The synthesis of hsp-90 that stabilizes the inactive form of the receptor is modulated by environmental or other stress, resulting in increased cellular concentrations. Higher concentrations of the hsp-90 appear to suppress sex-steroid receptor-dependent transcription in general.29,30

Structure of the DNA-Binding Domain

The DNA-binding domain (DBD) of all of the receptors that are known to respond to lipophilic signals is a highly conserved sequence.1,2 The consensus sequence cores involved in DNA binding are composed of 66 amino acids that include nine perfectly conserved cysteines. There are two zinc fingers, each of which has one zinc coordinated with four cysteines. One of these fingers appears to be involved in dimer formation, and the other is needed for recognition of progesterone response elements (PREs) of the DNA of progesterone-responsive genes in a complex series of reactions.31–35 Trans-activation appears to be a positive modification that unmasks the DBD.34 Steroid receptors function as dimers, with one of the fingers interacting in the wide DNA groove while the other maintains the dimer configuration.31

Function of PR Co-regulators (Co-activators and Co-repressors) on Transcription

On binding of progesterone, the progesterone receptor changes its conformation in the ligand-binding domain (LBD) in such a way to enable changes in the complex of co-regulators, including the release of co-repressors and the recruitment of co-activators. The modulation of transcription activity is influenced by the interaction with coregulators that include steroid-receptor co-activator-1 (SRC-1) and related proteins, transcription intermediary factor-2 (TIF-2), and glucocorticoid receptor-interacting protein-1 (GRIP-1). The SRC-1 interacts between the N-terminal activation (AF-1) and the C-terminal AF-2 of the PR. This serves to emphasize that SRC-1 functions to synergize the amino terminal AF-1 and the carboxyl terminal AF-2 of the progesterone receptor. This enhanced transcription is referred to as transactivation.2

PR has been shown to contain a repressor domain that binds to a co-repressor when the PR is bound by hormone antagonists. An example is the antagonist RU 486, which negatively interacts with the general transcription factors (GTFs), resulting in an inactive receptor-ligand complex. Thus, it is proposed that co-activators function by interacting with GTFs to activate target gene transcription whereas co-repressors interact with the same GTFs to inactivate the receptor-ligand complex. In both situations, the heat shock proteins 90, 70, and others are dissociated from the PR complex when this PR complex binds either co-activators or co-repressors. This suggests that the function of the co-regulators is to modulate the interaction of the GTFs and the hormone response elements (HRE) in the transcription of specific genes at the TATA promoter.2

Co-repressor binding is associated with a conformation of the receptor that prevents the complex from binding to its DNA-binding element in the DBD. Even though the receptor can be shown to dimerize after ligand binding, unless the co-repressor is displaced, transcription is not stimulated. Numerous reviews are available with regard to many of the details of the function of receptor-ligand interactions.2,36–38

Potential Function of the Co-activator SRC-1 on Chromatin Remodeling

Steroid hormones have long been known to affect chromatin structure. As the chromatin complex, eukaryotic DNA is efficiently packaged into arrays of nucleosomes that contain about 145 base pairs of DNA tightly wrapped as 1.7 turns around a histone octamer.39 This complex is likely to remain inaccessible to the steroid receptor as a ligand-bound receptor-transcription complex. The DNA nucleosome histone octamer complex is held together through the positively charged histones and the negative DNA residues. Recent evidence has shown that the SRC-1 has enzymatic activity as a histone acetyltransferase, as does (cyclic adenosine monophosphate response element binding) CREB-binding protein (CBP).40 This dual function as a co-activator and nucleosome charge modifier suggests that it likely to have an additional essential function to provide the essential physical access to the chromosome-specific DNA-promoter origin.41 Thus, the SRC-1 enhances the ligand-dependent and receptor-dependent and cell-free transcription of chromatin.42

Specific Target Selection of Progesterone Function

Target cells not only must distinguish progesterone in the presence of other steroids, present in small amounts, but also must distinguish progesterone from other hydrophobic molecules that are frequently found in 100-fold or greater excess. Thus, while progesterone may affect a number of physiologic processes, such a high degree of discrimination is limited to differentiated cells that possess PR proteins and PREs in their genome.1,2,43

PR is a prototypic member of a superfamily of transcriptional regulatory proteins. The target gene mRNA-level regulation is primarily dependent on progesterone activation of PR that results in a complex series of events.1,2 As with other members of this superfamily, activated PR acquires the capacity to modulate the activity of specific target genes. Some target genes are under the regulation of both PR and glucocorticoid receptor (GR). Such genes include estrogen receptor, human metallothionein IIA,44 uteroglobulin, vitellogenin,45 and human pregnancy-specific beta-glycoprotein.46 The molecular mechanisms to provide discrimination are dependent on highly specific protein-DNA interactions that involve specific amino acid residues of the PR and nucleotide residues of the target genes. The amino acid residues of the PR are defined as the DBD, and the DNA elements of these target genes as PREs. The PRE sequences of a whole network of target genes are recognized by the trans-activated PR.47 These PRE gene sequences are further characterized as enhancer-like in that neither their precise orientation nor their position appears to be critical. The PREs recognized by the DBD are confined, however, to the 59 upstream end of the genes, near the promoter regions of all progesterone-responsive target genes.48 This feature of hormone induction is common to the whole superfamily of steroid receptors.1 The progesterone-PR complex activates the positively charged cysteine-rich amino acid residues of the DBD, which in turn function to increase its binding affinity for specific PRE residues of target genes. This activation is often referred to as trans-activation, denoting that its function spans many amino acid residues. The response mechanism is dependent on the steps, beginning with hormone recognition, followed by activation of the DBD, and then interaction of the DBD with chromosomal DNA target-gene progesterone-responsive element sequences.

Analyses of the DNA sequences also demonstrate that most progesterone-responsive target genes have not only multiple PRE copies but also other HREs, including, in particular, GREs. Many of these HREs have the capacity to modify the function of the PR. This knowledge of the existence of multiple PRE and HRE elements in combination provides for the first time a plausible mechanism to account for the clinical observation that both the dose and prior hormone history have a profound effect on the clinical response of patients’ tumors to hormone manipulation. As a specific example, it is frequently observed that the administration of different levels of progesterone enhances the cooperative binding to HREs, and that a number of hormone combinations both down- and up-regulate progesterone-responsive genes.

Progesterone Receptor Function and PR Mutations

Progesterone response is dependent on the presence of functionally intact PR. Progestin-induced activity is only initiated when the steroid is bound to the carboxy terminal or progesterone-binding domain (PBD) to induce trans-activation at the DBD.1,2 An absence of hormone response will result from either the absence of the PR or its failure to bind the steroid-binding domain (SBD). The physical presence of PR by immunology does not assure that its response to ligand is assured. Point mutations or total deletions in the SBD of the PR can occur. There is also evidence of mutations in nonfunctional sequences as well as inactive receptor as a consequence of mutations in what are now recognized as co-regulator binding sites.49

Functional Significance of the Presence of Multiple PR Isoforms

In humans, PR is composed of two progesterone-binding proteins, PRA (PRα) and PRB (PRβ). The expression of the human PR is reported to be controlled by two promoters that direct the synthesis of mRNA transcripts encoding the two receptor proteins. The PRα is N-terminally truncated by 164 amino acid residues and therefore is slightly smaller than PRβ.50 The PRα and PRβ co-express in the same cells and appear to be synthesized in equal proportions. There are reports of what appears to be functional differences between PRα and PRβ in the transcriptional activation of target genes.51 In breast cancers, PRα is expressed at high levels in some tumors, with the suggestion that PRα may act as a transdominant inhibitor of PRβ. Two distinct estrogen-regulated promoters generate transcripts that encode PRα and PRβ, as functionally different.52

Function of Estrogen-Induced PR Synthesis

In breast epithelial tissue, differentiation is dependent on the synthesis and activation of both PR and estrogen receptor (ER). The synthesis of either PR or ER requires both a specific signal response and a permissive chromosomal configuration in the region of the steroid-receptor gene. This permissive state requires that a number of nuclear events have occurred, including the synthesis of trans-activating nuclear proteins, demethylation of the DNA, estrogen modulation of PR, and postsynthetic modification of a number of specific nuclear proteins.53 PR and ER activation, then, are dependent not only on receptor synthesis and ligand-binding affinity but equally on associations with at least a spectrum of additional proteins, including a 45-kD and a 35-kD protein and several classes of transcription-specific protein stimulators (TSPS).

Tissue-Specific Modulation of Receptor Activity

The progesterone response mediated by trans-activated PR represents critical interactions with chromatin and its complement of associated proteins. Most abundant among these are the histones39 and the HMG1 and HMG2 chromosomal proteins,54 which have been shown to interact directly with steroid receptors. These proteins are postsynthetically modified by both histone kinases and acetylases.55

PR not only functions in its binding to cis-activating PREs at the 59 upstream DNA sequences of a number of progesterone-responsive genes, it also has the capacity to function as a down-regulator of the synthesis of other hormone receptors (HRs), e.g., ER.56,57 PR should be considered a target gene for estrogen response in that a functional ER is required to up-regulate the synthesis of PR.58 This mechanism may also account for the modulation of PR synthesis in response to glucocorticoid modulating the binding affinity of PREs on PR target genes.

Postsynthetic modifications involve both subtle alterations in the PR structure and cis- and trans-activating factors. Modifications include (a) phosphorylation and acetylation of chromosomal proteins such as histones HMG1 and HMG2, (b) postsynthetic modification of the binding of heat shock proteins to PR, (c) phosphorylation of both of these proteins, and (d) co-regulator-associated enzymatic activities. In addition to the multiple cis-activating components described for HRE, trans-activating elements are also required for RNA transcription critical for the hormone response.59

Progesterone Receptor as a Member of the Superfamily of Receptor Proteins

The superfamily of receptor proteins that interact with many lipophilic ligands have a number of features in common with PR.60 Early studies using proteolytic digestion of progesterone receptor proteins demonstrated a loss of DNA binding in spite of retention of the specific ligand binding. These proteolytic receptor digests were referred to as meroreceptor fragments. A number of highly conserved regions for the receptor protein genes have been observed through cloning of receptor proteins. The structures of the receptor proteins for progesterone, estrogen, and glucocorticoid show a striking homology with other hydrophobic signal proteins, including thyroid receptor, retinoic acid receptors, and vitamin D3 receptor.

Intracellular Localization and Postsynthetic Modifications

Progesterone is a hydrophobic signal and is thus unrestricted by plasma or nuclear membranes, being free to diffuse through membranes to interact with specific proteins that are confined to humans. Whereas it is clear that the specificity attained by a hydrophilic signal is dependent on its interaction with cell surface receptors, the precise intracellular localization of all hydrophobic steroid molecules is unresolved. The use of antireceptor antibodies to PR and ER demonstrates these proteins in the nucleus whereas immunoreactive GR in the absence of ligand is found in the cytoplasm. After complexing with their specific ligands, all steroid receptors are detected only in the nucleus. The presence of the specific ligand is a primary signal for nuclear translocation.

Clinical Observations on Progestin Receptor and Target Tissue Responses to Progestins

Progesterone is associated with a number of clinically important responses in a variety of tissues. Among these are progestins’ critical role in the support of the products of conception; the differentiation of the endometrium and the promotion of the secretory phase of the endometrium; the maturation and cornification of the vaginal mucosal epithelium; the suppression of ovulation; the inhibition of gonadotropin release; the proliferation of breast epithelium and the induction of secretory activity in breast epithelium; and a natriuretic effect on the kidneys. A number of these biologic effects of progesterone are seen only in concert with priming of the target tissues with estrogen, whereas other effects appear to be interrelated with the actions of other steroid hormones, peptide hormones, and/or growth factors. Both progesterone and estrogen influence the response when superpharmacologic doses are used. Possible interactions between progesterone, estrogen, and growth factors must be taken into account when constructing treatment strategies.

Uterus

Normal Uterus

The cyclic response of the uterus to estrogen and progesterone is among the best-studied examples of hormonal modulation of tissue response. There is clear evidence for cyclic regulation of ER and PR proteins in the endometrial epithelium, the myometrium, and the endometrial stroma. The induction of PR by estrogen has been shown both in vitro and in vivo. An increase in PR at the end of the proliferative phase of the menstrual cycle occurs in the stromal/myometrial tissue 24 to 48 hours before the observed peak of PR levels in endometrial epithelial tissue.14 This cyclic change can be aborted by the administration of 10 mg of Provera for 5 to 10 days, associated with regression of the epithelium. Epithelial hyperplasia of the uterus exposed to progestins first shows acanthomatous or squamous metaplastic changes (changes wherein the cells resemble squamous cells) followed by secretory differentiation and finally regression of the hyperplastic change, with eventual atrophy after 10 to 14 days.

Uterine Carcinoma

Uterine carcinoma is a localized disease in the majority of cases. There is a severalfold increased incidence of adenocarcinoma of the uterus when a woman is given unopposed estrogen in physiologic doses, and this increased frequency is reduced to that of the population not receiving estrogen, if progestins are also given. Progestins can be effectively given in several ways. Among these options is that progestins be given for the last 10 days of the estrogen-replacement cycle or at a lower dose throughout the cycle.

When diagnosed, adenocarcinoma of the uterus is cured by local therapy in 80% of cases. In the event of recurrence, exogenous progestin is an effective treatment in a significant fraction of cases: more than 30% of patients with recurrent disease demonstrate objective response to exogenous progestins. ER and PR can be measured in these tumors, and the presence of these receptors correlates with differentiation of the tumor, prognosis for the patient, and response to progestins. The duration of response is not predicted by the presence of receptor and varies from months to years. Tumors that lack ER and PR respond objectively to progestins in fewer than 10% of cases. Tumors that have been treated with radiotherapy have a greater tendency to be progesterone receptor negative than tumors that have not been treated with radiation. Because of the low toxicity of progestins, a trial of progestin therapy is often warranted even if receptors have not been measured in the tumor or appear to be absent in recurrent or inoperable endometrial carcinoma.

The effective use of progestins in treating endometrial hyperplasia associated with unopposed estrogen and in patients with receptor-rich well-differentiated adenocarcinomas further supports the role of progestins in suppressing proliferation of the endometrium. The use of hormone therapy has readily demonstrable effects on endometrial histology.39

Other Neoplasms of the Uterus

Pharmacologic progestin has a clearly beneficial effect on uterine leiomyomas, and significant levels of PR have been demonstrated in these proliferations of mesenchymal origin.13 Uterine sarcomas, including stromal sarcomas and leiomyosarcomas, have a variable response to progesterone.18 PR is not consistently observed in these tumors.

PR has been reported in some studies of squamous carcinoma of the uterine cervix (up to 41% of tumors).17 Cervical epithelial maturation was correlated with progesterone secretion (ovulation). PR was not found in the majority of tumors in other studies, and no firm evidence for clinical or histologic correlation of the presence of PR has been shown.

Breast

Normal Breast

Progestin response in the human breast is complex and influences both proliferation and differentiated function. The luteal phase of the menstrual cycle (progesterone dominant) is characterized both by active secretion and by the peak of proliferative activity in the normal breast.8 Epidemiologic data appear to implicate progestins in proliferative disorders and cancers of the breast in a more direct fashion than had been previously thought.8 It has been recognized from the earliest studies of ER and PR in breast epithelial systems that progesterone action, mediated through PR, resulted in down-regulation of the ER in breast epithelium. This observation suggested that the influence of estrogen would be to stimulate proliferation of the breast epithelium, and that the effect of progesterone might be to inhibit proliferation, similar to the effect seen in the uterus. While the effect on regulation of ER appears to be similar, the effect of progestins and specifically progesterone in physiologic amounts is not similar. The assumption that progestins will act to reduce estrogen-associated proliferative change does not appear to be valid. This must be considered in recommending sex steroid replacement therapy in the climacteric. Thought should be given to the fact that adding progestin to estrogen replacement therapy does not reduce the risk of breast cancer. It remains clear that ovarian hormones are critical to breast cancer risk, and that in women who have had surgical oophorectomy, even daily unopposed conjugated estrogens in a dose up to 1.25 mg does not produce risk comparable to that associated with prolonged years of normal menstrual cycles in the climacteric.

Breast Cancer

PRs have been studied extensively in cancerous human breast tissue. Patients whose tumors are PR positive have a higher probability of responding to endocrine therapy (not necessarily progestins) and in most series show a somewhat better prognosis with respect to both survival and disease-free interval.61 Considerable controversy exists with respect to the effect of menstrual cycle phase at surgery on the evaluation of tissue for receptor, as well as to whether there is an effect of this timing on prognosis.62–64 PR, in contrast to ER, does not show increasing levels with increasing age of the population studied.58

Progestin therapy for metastatic breast cancer has been used principally as a second- or third-line therapy following selective estrogen receptor modifiers such as tamoxifen. The principal progestin used for metastatic breast cancer has been megestrol acetate. The response of metastatic breast cancer to megestrol is predicted by the presence of ER and/or PR but is best predicted by the observation of objective response to prior hormonal therapy. One of the more interesting aspects of progestin therapy for metastatic breast cancer is the observation of a dose-response increase in efficacy. Patients who have relapsed or progressed on conventional therapeutic doses of medroxyprogesterone (100–200 mg/day) or megestrol (160 mg/day) may show additional response with increased dose (to 2,000 mg/day for medroxyprogesterone or to 1,600 mg/day for megestrol). A beneficial side effect of the progestin is increased appetite and weight gain although some of the weight gain can be associated with fluid retention.2 The mechanism of the increased appetite and actual weight gain is poorly understood although this property of appetite enhancement has been used clinically to treat cancer-associated anorexia and cachexia. There are a number of other central nervous system effects of progestins that have been characterized, including beneficial effects on climacteric symptoms.25

Other Tumors of the Breast

Progesterone receptors have been reported in fibroadenomas, cystosarcoma phyllodes, and breast sarcomas. There is no convincing evidence for a biologic response to progestin manipulation of either cystosarcoma phyllodes or stromal sarcoma of the breast.

Ovary

Epidemiologic data have shown an effect on the incidence of ovarian epithelial carcinoma in patients who have used estrogen-progesterone preparations to inhibit ovulation. PR is observed in 30 to 40% of ovarian carcinomas.15 While some studies have observed a trend toward better survival in patients with PR-positive carcinomas, no convincing data to indicate objective response to progestin therapy have been reported.

Other Tissues

PR and response to progestins have been repeatedly reported in meningiomas and pulmonary lymphangioleiomyomatosis, renal cell carcinomas, and squamous cell carcinoma of the head and neck. The presence of PRs in meningiomas is consistently observed, and clinical trials have shown response to progestins. In squamous cell carcinoma of the head and neck, the presence of progestin receptors has been detected, but in these tumors, as in renal cell carcinoma, objective response to progestin treatment has not been convincingly shown. In contrast, progestin therapy has become an important option in the treatment of pulmonary lymphangioleiomyomatosis, which was a uniformly fatal condition before progestin-hormonal therapy was shown to be effective.12 In cases in which pulmonary lymphangiomyomatosis is treated early in the course of the disease, before extensive chylous effusion is present, objective response to continued progesterone therapy is noted in the majority of patients. This response appears to require that the progestin be continued. Responses at greater than 5 years have been observed; in some patients, however, the disease progresses after a period of remission despite continued progesterone.

Conclusion

The different responses that progestins induce in specific target tissues and how such differences can exist in the face of what appears to involve the same progesterone receptor isoforms, the same ligand, and the same or similar progesterone response elements has emerged as a critical area for understanding the role of progestins in the oncology of breast and endometrium. The broad spectrum of tissue response to progesterone has been shown to involve subtle differences in the competition of the liganded progesterone receptor for an array of co-regulators in the signaling pathway.1,2,65 The progesterone receptor-chromatin interaction is only part of what determines the differentiated function induced by progesterone. Many of the molecular details of progesterone induction of specific gene activation of RNA transcription have now been identified while others remain elusive. Access to the ligand-binding-domain steroid (hydrophobic pocket) requires changes in the helix 12 amino-terminal region of the PR as a result of interaction with activation factors (AF-1). Co-activators, co-repressors, isoforms, and postsynthetic modifications all contribute to the complex regulation of response to these steroids. Progestins also influence cell proliferation and can be seen to play a role in the treatment of a number of neoplasms, primarily those of the endometrium and breast. The molecular mechanisms involved in progestin treatment response are complex, and enhanced understanding of these complex signaling systems will greatly aid new treatment development and design involving this remarkable class of sex steroids.

References

1.
McKenna N J, Lanz R B, O’Malley B W. Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev. 1999;20:321–344. [PubMed: 10368774]
2.
Shibata H, Spencer T E, Onate S A. et al. Role of co-activators and co-repressors in the mechanism of steroid/thyroid receptor action [review] Recent Prog Horm Res. 1997;52:141–164. [PubMed: 9238851]
3.
Anderson T, Howell A, Williams G. Oral contraceptive use increases proliferation and decreases oestrogen receptor content of epithelial cells in the normal human breast. Int J Cancer. 1991;48:206–210. [PubMed: 2019467]
4.
Brinton L A, Hoover R N. Estrogen replacement therapy and endometrial cancer risk. Unresolved issues. Obstet Gynecol. 1993;81:265–271. [PubMed: 8380913]
5.
Szekeres-Bartho J, Barakonyi A, Polgar B. et al. The role of gamma delta T cells in progesterone mediated immunomodulation during pregnancy: a review. Am J Reprod Immunol. 1999;42:44–48. [PubMed: 10429766]
6.
Grady O, Rubin, SM, Petitti D B. et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016–1021. [PubMed: 1443971]
7.
Robertson J F R, Williams M R, Todd J. et al. Factors predicting the response of patients with advanced breast cancer to endocrine (Megace) therapy. Eur J Clin Oncol. 1989;25:469–475. [PubMed: 2703001]
8.
McCarty K S Jr. Proliferative stimuli in the normal breast: estrogens or progestins. Hum Pathol. 1989;20:1137. [PubMed: 2591942]
9.
Baulieu E E. A novel approach to human fertility control: contragestion by the anti-progesterone RU 486. Eur J Obstet Gynecol Reprod Biol. 1988;28:125. [PubMed: 3402651]
10.
Nyholm H C. Estrogen and progesterone receptors in endometrial cancer. Clinicopathological correlations and prognostic significance [review] APMIS Suppl. 1996;65:5–33. [PubMed: 8944054]
11.
Halper J, Colvard D S, Scheithauer B W. et al. Estrogen and progesterone receptors in meningiomas: comparison of nuclear binding, dextran-coated charcoal and immunoperoxidase staining assays. Neurosurgery. 1989;25:546. [PubMed: 2477767]
12.
Berger U, Khaghani A, Pomerance A. et al. Pulmonary lymphangioleiomyomatosis and steroid RE receptors. An immunocytochemical study. Am J Clin Pathol. 1990;93:609. [PubMed: 2183584]
13.
Maheux R. Treatment of uterine leiomyomata: past, present and future. Horm Res. 1989;32:125. [PubMed: 2693323]
14.
Lessey B A, Metzger D A, Haney A F, McCarty K S Jr. Immunohistochemical analysis of estrogen and progesterone receptors in endometriosis: comparison with normal endometrium during the menstrual cycle and the effect of medical therapy. Fertil Steril. 1989;51:409–515. [PubMed: 2646155]
15.
Harding M, Cowan S, Hole D. et al. Estrogen and progesterone receptors in ovarian cancer. Cancer. 1990;65:486. [PubMed: 2297640]
16.
Berg N J, Colvard D S, Neel H B III. et al. Progesterone receptors in carcinomas of the upper aerodigestive tract. Otolaryngol Head Neck Surg. 1989;101:527. [PubMed: 2512530]
17.
Hunter R E, Longcope C, Keough P. Steroid hormone receptors in carcinoma of the cervix. Cancer. 1987;60:392. [PubMed: 3594376]
18.
Keen C E, Phillip G. Progestin-induced regression in low-grade endometrial stromal sarcoma. Case report and literature review. Br J Obstet Gynaecol. 1989;96:1435. [PubMed: 2695158]
19.
Crook D, Crust M P, Gangar K F. et al. Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on serum lipids and lipoproteins. Am J Obstet Gynecol. 1992;166:950–955. [PubMed: 1550171]
20.
Ottosson U B, Johansson B G, Schoultz B. Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: a comparison between progestogens and natural progesterone. Am J Obstet Gynecol. 1985;151:746–750. [PubMed: 3976784]
21.
Baulieu E E. Contragestion and other clinical applications of RU 486, and antiprogesterone at the receptor. Science. 1989;245:1351. [PubMed: 2781282]
22.
Gasc J M, Baulieu E E. Regulation by estradiol of the progesterone receptor in the hypothalamus and pituitary: an immunohistochemical study in the chicken. Endocrinology. 1988;122:1357. [PubMed: 3126035]
23.
Baulieu E E. RU 486 (an anti-steroid hormone) receptor structure and heat shock protein mol. wt. 90,000 (hsp 90) Hum Reprod. 1988;3:541. [PubMed: 3292573]
24.
Tremollieres F, Pouilles J M, Ribot C. Effect of long-term administration of progestogen on post menopausal bone loss: result of a two-year, controlled randomized study. Clin Endocrinol (Oxf) 1993;38:627–631. [PubMed: 8334749]
25.
Lobo R A, Gibbons W E. The role of progestin therapy in breast disease and central nervous system function. J Reprod Med. 1982;27:515. [PubMed: 6813466]
26.
Kang K I, Meng X, Devin-Leclerc J. et al. The molecular chaperone Hsp90 can negatively regulate the activity of a glucocorticosteroid-dependent promoter. Proc Natl Acad Sci U S A. 1999;96:1439–1444. [PMC free article: PMC15481] [PubMed: 9990042]
27.
Devin-Leclerc J, Meng X, Delahaye F. et al. Interaction and dissociation by ligands of estrogen receptor and Hsp90: the antiestrogen RU 58668 induces a protein synthesis-dependent clustering of the receptor in the cytoplasm. Mol Endocrinol. 1998;12:842–854. [PubMed: 9626660]
28.
Vargas-Roig L M, Fanelli M A, Lopez L A. et al. Heat shock proteins and cell proliferation in human breast cancer biopsy samples. Cancer Detect Prev. 1997;21:441–451. [PubMed: 9307847]
29.
Sabbah M, Radanyi C, Rredeuilh G, Baulieu E E. The 90 kDa heat-shock protein (hsp90) modulates the binding of the oestrogen receptor to its cognate DNA. Biochem J. 1996;314:205–213. [PMC free article: PMC1217026] [PubMed: 8660284]
30.
Pratt WB, Redmond T, Sanchez ER, et al. Speculations on the role of the 90 kDA heat shock protein in glucocorticoid receptor transport and function. In: Carlstedt-Duke J, Eriksson H, Gustafsson JA, editors. The steroid/thyroid hormone receptor family and gene regulation. Basel: Birkhauser Verlag; 1989. p. 109–126.
31.
Evans R M, Hollenberg S M. Zinc fingers: gilt by association. Cell. 1988;52:1. [PubMed: 3125980]
32.
Miesfeld R L. The structure and function of steroid receptor proteins. Crit Rev Biochem Mol Biol. 1989;24:101. [PubMed: 2651007]
33.
Green S, Chambon P. Nuclear receptors enhance our understanding of transcription regulation. Trends Genet. 1988;4:309. [PubMed: 2853466]
34.
Power R F, Conneely O M, McDonnell D P M. et al. High level expression of a truncated chicken progesterone receptor in Escherichia coli. J Biol Chem. 1990;265:1419. [PubMed: 2153132]
35.
Conneely O M, Dobson A D, Carson M A. et al. Structure-function relationships of the chicken progesterone receptor. Biochem Soc Trans. 1988;16:683. [PubMed: 2466711]
36.
Carson-Jurica M A, Schrader W T, O’Malley B W. Steroid receptor family: structure and functions. Endocr Rev. 1990;11:201. [PubMed: 2194782]
37.
O’Malley B W. The steroid receptor superfamily: more excitement predicted for the future. Mol Endocrinol. 1990;4:353. [PubMed: 2188115]
38.
Moore D D. Promiscuous behavior in the steroid hormone receptor superfamily. Trends Neurosci. 1989;12:165. [PubMed: 2472686]
39.
Kelner D N, McCarty K S Sr. Porcine liver nuclear histone acetyltransferase: partial purification and basic properties. J Biol Chem. 1984;259:3413. [PubMed: 6706965]
40.
Spencer T E, Jenster G, Burcin M M. et al. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature. 1997;389:194–198. [PubMed: 9296499]
41.
Wolffe A P, Hayes J J. Chromatin disruption and modification [review] Nucleic Acids Res. 1999;27:711–720. [PMC free article: PMC148238] [PubMed: 9889264]
42.
Liu Z, Wong J, Tsai S Y. et al. Steroid receptor coactivator-1 (SRC-1) enhances ligand-dependent and receptor-dependent cell-free transcription of chromatin. Proc Natl Acad Sci U S A. 1999;96:9485–9490. [PMC free article: PMC22235] [PubMed: 10449719]
43.
Klein-Hitpass L, Tsai S Y, Weigel N L. et al. The progesterone receptor stimulates cell-free transcription by enhancing the formation of a stable preinitiation complex. Cell. 1990;60:247. [PubMed: 2153462]
44.
Slater E P, Cato A C, Karin M. et al. Progesterone induction of metallothionein-IIA gene expression. Mol Endocrinol. 1988;2:485. [PubMed: 2843758]
45.
Wahli W. Evolution and expression of vitellogenin genes. Trends Genet. 1988;4:227. [PubMed: 3072724]
46.
Chilton B S, Mani S K, Bullock D W. Servomechanism of prolactin and progesterone in regulating uterine gene expression. Mol Endocrinol. 1988;2:1169. [PubMed: 3216859]
47.
Evans R M, Hollenberg S M. Cooperative and positional independent trans-activation domains of the human glucocorticoid receptor. Cold Spring Harb Symp Quant Biol. 1988;53:813. [PubMed: 3254785]
48.
Dean D C, Knoll B J, Riser M E, O’Malley B W. A 59-flanking sequence essential for progesterone regulation of an ovalbumin fusion gene. Nature. 1983;305:551. [PubMed: 6621702]
49.
Dobson A D, Conneely O M, Beattie W. et al. Mutational analysis of the chicken progesterone receptor. J Biol Chem. 1989;264:4207. [PubMed: 2917996]
50.
Conneely O M, Kettelberger D M, Tsai M J. et al. The chicken progesterone receptor A and B isoforms are products of an alternate translation initiation event. J Biol Chem. 1989;264:14062. [PubMed: 2760059]
51.
McGowan E, Clarke C. Effect of overexpression of progesterone receptor A on endogenous progestin-sensitive endpoints in breast cancer cells. Mol Endocrinol. 1999;13:1657–1671. [PubMed: 10517668]
52.
Kastner P, Krust A, Turcotte B. et al. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J. 1990;9:1603. [PMC free article: PMC551856] [PubMed: 2328727]
53.
Horwitz K B, Francis M D, Weill Hormone dependent covalent modification and processing of human progesterone receptors in the nucleus. DNA. 1985;4:451–460. [PubMed: 4092571]
54.
Bernues J, Querol E. Non-random reconstitution of HMG1 and HMG2 in chromatin. Determination of the histone contacts. Biochim Biophys Acta. 1989;1008:52–61. [PubMed: 2719962]
55.
Mold D E, McCarty K S Sr. A chinese hamster ovary cell histone deacetylase that is associated with a unique class of mononucleosomes. Biochemistry. 1987;26:8257. [PubMed: 3442654]
56.
Nardulli A M, Greene G L, O’Malley B W, Katzenellenbogen B S. Regulation of progesterone receptor messenger ribonucleic acid and protein levels in mcf-7 cells by estradiol: analysis of estrogen’s effect on progesterone receptor synthesis and degradation. Endocrinology. 1988;122:935. [PubMed: 3342760]
57.
Ree A H, Landmark B F, Eskild W. et al. Autologous down-regulation of messenger ribonucleic acid protein levels for estrogen receptors in MCF-7 cells: an inverse correlation to progesterone receptor levels. Endocrinology. 1989;124:2577. [PubMed: 2651098]
58.
McCarty K S Jr, Silva J S, Cox E B. et al. Relationship of age and menopausal status to estrogen receptor content in primary carcinoma of the breast. Ann Surg. 1983;197:123–130. [PMC free article: PMC1353098] [PubMed: 6824366]
59.
Kumar V, Green S, Stack G. et al. Functional domains of the human estrogen receptor. Cell. 1987;51:941–948. [PubMed: 3690665]
60.
Gronemeyer H. The chicken progesterone receptor. In: Gronemeyer H, Ellis H, editors. Affinity labelling and cloning of steroid and thyroid hormone receptors. Ellis Morwood, NY; 1988. p. 55–67.
61.
Osborne C K. Steroid hormone receptors in breast cancer management. Breast Cancer Res Treat. 1998;51:227–238. [PubMed: 10068081]
62.
Bawde R A, Gregory W M, Chaudary M A. et al. Timing of surgery during the menstrual cycle and survival of premenopausal women with operable breast cancer. Lancet. 1991;337:1261–1264. [PubMed: 1674070]
63.
McGuire W L, Hilsenbeck S, Clark G M. Optimal mastectomy timing. J Natl Cancer Inst. 1992;84:346–348. [PubMed: 1738187]
64.
Nathan B, Bates T, Anbazhagan R. et al. Timing of surgery for breast cancer in relation to the menstrual cycle and survival of premenopausal women. Br J Surg. 1993;80:43–48. [PubMed: 8428290]
65.
Lange C A, Richer J, Horwitz K B. Hypothesis: progesterone primes breast cancer cells for cross-talk with proliferative or antiproliferative signals [review] Mol Endocrinol. 1999;13:829–836. [PubMed: 10379882]
© 2000, BC Decker Inc.
Bookshelf ID: NBK20835
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...