Role Of Progestogens Research Articles

The Role of Progestogens in Menopausal Hormone Therapy.

Progestogens are steroid compounds that have the ability to induce secretory transformation in the endometrium and are utilized in menopausal hormone therapy to prevent endometrial hyperplasia and endometrial cancer. Progestogens can be derived from 21-carbon or 19-carbon steroid cytoskeletons and thus have different properties and metabolic effects beyond the progestational effects on the endometrium. This limited review will focus on the available progestogens utilized in combination hormone therapy including progesterone, medroxyprogesterone acetate, norethindrone, norethindrone acetate, levonorgestrel, and drospirenone. The impact of progestogens on a variety of target tissues including the endometrium, breast, cardiovascular system, brain, and bone, will be reviewed. Last, the current clinical regimens that can be utilized by clinicians will be discussed.

Endogenous Progestogens and Colorectal Cancer Risk among Postmenopausal Women.

The role of progestogens in colorectal cancer development is poorly characterized. To address this, our group developed a highly sensitive assay to measure concentrations of seven markers of endogenous progestogen metabolism among postmenopausal women. The markers were measured in baseline serum collected from postmenopausal women in a case-cohort study within the breast and bone follow-up to the fracture intervention trial (B∼FIT). We followed women not using exogenous hormones at baseline (1992-1993) for up to 12 years: 187 women with incident colorectal cancer diagnosed during follow-up and a subcohort of 495 women selected on strata of age and clinical center. We used adjusted Cox regression models with robust variance to estimate risk for colorectal cancer [hazard ratios (HR), 95% confidence intervals (CI)]. High concentrations of pregnenolone and progesterone were not associated with colorectal cancer [quintile(Q)5 versus Q1: pregnenolone HR, 0.71, 95% CI, 0.40-1.25; progesterone HR, 1.25; 95% CI, 0.71-2.22]. A trend of increasing risk was suggested, but statistically imprecise across quintiles of 17-hydroxypregnenolone (Q2 to Q5 HRs, 0.75-1.44; P trend, 0.06). We used sensitive and reliable assays to measure multiple circulating markers of progestogen metabolism. Progestogens were generally unassociated with colorectal cancer risk in postmenopausal women. Our findings are consistent with most prior research on circulating endogenous sex hormones, which taken together suggest that sex hormones may not be major drivers of colorectal carcinogenesis in postmenopausal women.

Role of progestogens in women at risk for spontaneous preterm birth: the final word?

Preterm birth is defined by WHO as delivery before 37 weeks of gestation. 1 WHO: recommended definitions, terminology and format for statistical tables related to the perinatal period and use of a new certificate for cause of perinatal deaths, modifications recommended by FIGO as amended October 14, 1976. Acta Obstet Gynecol Scand. 1977; 56: 247-253 PubMed Google Scholar It is one of the most common pregnancy complications, with an estimated global rate of 10·6% in 2014, equating to an estimated 14·84 million live preterm births. 2 Chawanpaiboon S Vogel JP Moller AB et al. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. Lancet Glob Health. 2019; 7: 37-46 Summary Full Text Full Text PDF PubMed Scopus (962) Google Scholar Preterm birth considerably increases risk of neonatal morbidity and mortality, including long-term sequelae, and can result in long-term health and financial implications for families. 3 Goldenberg RL Culhane JF Iams J Romero R The epidemiology and etiology of preterm birth. Lancet. 2008; 371: 75-84 Summary Full Text Full Text PDF PubMed Scopus (4622) Google Scholar Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trialsVaginal progesterone and 17-OHPC both reduced birth before 34 weeks' gestation in high-risk singleton pregnancies. Given increased underlying risk, absolute risk reduction is greater for women with a short cervix, hence treatment might be most useful for these women. Evidence for oral progesterone is insufficient to support its use. Shared decision making with woman with high-risk singleton pregnancies should discuss an individual's risk, potential benefits, harms and practicalities of intervention. Full-Text PDF

Effects of oral contraceptives on thyroid function and vice versa.

Thyroid gland dysfunction represents an epidemiologically relevant disease in the female gender, where treatment with oral contraceptives (OCs) is frequently prescribed. Although OCs are able to impact the thyroid gland function, scanty data have been released on this matter so far. The aim of this article was to review how hormonal OCs, including estrogen- or progesterone-only containing medications, interact with the hepatic production of thyroid-binding globulin (TBG) and, consequently, their effects on serum levels of thyroxine (T4) and triiodothyronine (T3). We also reviewed the effect of Levo-T4 (LT4) administration in women taking OCs and how they influence the thyroid function in both euthyroid women and in those receiving LT4. The estrogenic component of the pills is capable of increasing various liver proteins, such as TBG, sex hormone-binding protein (SHBG) and coagulation factors. On the other hand, the role of progestogens is to modulate estrogen-dependent effects mainly through their anti-androgenic action. In fact, a reduction in the effects of androgens is useful to keep the thromboembolic and cardiovascular risks low, whereas OCs increase it especially in women with subclinical hypothyroidism or in those treated with LT4. Accordingly, subclinical hypothyroidism is known to be associated with a higher mean platelet volume than normal and this increases cardiovascular risk due to platelet hyperactivity caused by incomplete thrombocytopoietic maturation.

Review on role of progestogen (dydrogesterone) in the prevention of gestational hypertension.

Gestational hypertension remains one of the main causes of maternal deaths all over the world. Attempts to reduce/prevent the incidence had failed due to lack of understanding of the disease's aetiology. One of the early roles of natural progesterone in the first trimester of pregnancy is to promote formation of wide-calibre spiral vessels that invade into the myometrial layer of the gravid uterus. Theoretically, this will prevent or reduce the incidence of gestational hypertension in the latter half of the pregnancy. The progestogen, dydrogesterone, has similar molecular structure and properties to natural progesterone. A pilot study was undertaken on primigravidae, who have higher risk of developing gestational hypertension. They were supplemented with dydrogesterone in the first trimester (Study Group) and compared with a similar number of primigravidae (Control Group) without supplementation with the progestogen. The incidence of gestational hypertension was significantly lower in the Study Group as compared to the Control Group (1.7% vs. 12.9%, respectively, p<0.001). The incidence of foetal distress was also significantly lower in the Study Group compared to the Control Group (4.3% vs. 18.1%, respectively, p<0.001). Supplementation of the progestogen, dydrogesterone, in the first trimester to primigravidae has shown great potential in reducing or preventing the incidence of gestational hypertension.

The role of progestogens in obstetrics practice

Objective: in this paper reviews the evidence for safety and efficacy of use of any progestogens in each of these indications. Progestogens may be use for the prevention of preterm labour, but not only for therapy spontaneous abortion.

Drospirenone- and levonorgestrel-containing oral contraceptives and the risk of gallbladder disease

BackgroundStudies have found an association between the use of estrogen-containing oral contraceptives (OCs) and the risk of gallbladder disease. This study evaluated this relation as well as the role of progestogen on the risk of gallbladder disease among users of drospirenone-containing OCs compared to users of levonorgestrel-containing OCs. Study DesignDatabase: The UK General Practice Research Database.We conducted a nested case–control analysis among women aged 14 to 60 years during 2001 through 2008 who had ever received drospirenone- or levonorgestrel-containing OCs. Cases were women with a first diagnosis of gallbladder disease during the study period. Women who received a study OC within 6 months of the index date were exposed. All other women were nonexposed. We matched two controls to each case on year of birth, index date, amount of recorded history and general practice attended. ResultsThe adjusted odds ratio for gallbladder disease comparing drospirenone and levonorgestrel OCs to nonexposure were 0.9 [95% confidence interval (CI) 0.7–1.1] and 1.0 (95% CI 0.9–1.1), respectively. ConclusionsThere is no evidence in these data that drospirenone- or levonorgestrel-containing OC use confers an increased risk of gallbladder disease compared to women not currently exposed to an OC. Nor is use of drospirenone OCs associated with a higher risk of gallbladder disease than use of levonorgestrel-containing OCs.

The Role of Progestogens in Regulating Matrix Metalloproteinase Activity in Macrophages and Microglial Cells

Although the systemic effects of progestogens have been extensively studied, little is known in regards to the cellular effects of these compounds. Using a cellular model for vascular (macrophages) and brain (microglial) cells, we studied the effects of various progestogens, either alone or in combination with 17β-estradiol (E(2)) on the activity of matrix metalloproteinase-9 (MMP-9), a proteolytic enzyme involved in vascular remodeling and plaque destabilization in cardiovascular events, blood-brain barrier breakdown in stroke and brain regeneration and neurovascular remodeling during repair phases of brain injury. In the absence of E(2), medroxyprogesterone acetate (MPA), a synthetic progestogen and progesterone (PG) metabolites tended to increase MMP-9 enzyme activity in macrophages and microglial cells, whereas PG decreased such activity in macrophages; exceptions being that MPA and the PG metabolite, pregnanediol (Pdiol) had no effect on macrophage MMP-9 enzyme activity and PG had no effect on microglial cell MMP-9 enzyme activity. In the presence of E(2), an opposite affect was observed whereby MPA and the PG metabolites tended to decrease MMP-9 enzyme activity from macrophages and microglial cells, whereas PG had no effect; exceptions being that MPA and Pdiol had no effect on macrophage MMP-9 enzyme activity. In conclusion, these results demonstrate that the effects of PG, PG metabolites and MPA on MMP-9 enzyme activity differ across vascular and brain cells when administered alone or in combination with E(2) which could have important mechanistic implications for hormone therapy.

Effects of estradiol and progestogens on tumor-necrosis factor-alpha-induced changes of biochemical markers for breast cancer growth and metastasis

Background. Epidemiological data suggest an enhanced breast cancer risk during estrogen/progestogen therapy as compared to estrogen monotherapy in postmenopausal women. The underlying mechanism, however, still remains unknown. Estrogens are known to be mitogenic agents for benign and cancerous breast epithelial cells whereas the role of progestogens is unclear. Tumor-associated macrophages play a crucial role in tumor growth and metastasis due to the synthesis of various cytokines such as tumor necrosis factor-α (TNF-α), which can stimulate the synthesis of proliferative and angiogenic factors in tumor cells. In an in vitro model we investigated the influence of estradiol and estradiol/progestogens combinations on the changes of TNF-α- induced markers.Methods. MCF-7 cells, a human estrogen- and progesterone-receptor-positive human breast cancer cell line, were used for the experiments. Estradiol (E2), at a concentration of 0.1 nM, and the progestogens progesterone (P), norethisterone (NET) and medroxyprogesterone acetate (MPA), each at concentrations of 0.01 to 1 μM, were tested alone and in combination. The cells were incubated for 4 days and the markers monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were measured in the supernatant by enzyme-linked immunosorbent assay.Results. E2 in combination with TNF-α elicited significant increases in MCP-1 and VEGF concentrations compared with TNF-α alone. For the progestogens alone an increase of MCP-1 was observed for NET, whereas MPA induced a decrease. An increase of VEGF was observed for all progestogens, the effect being greatest for MPA. No changes were found for MMP-9. In combinations with E2, the E2-induced increase of MCP-1 was reduced by NET and MPA and the increase of VEGF was diminished by P and NET, but not by MPA. The E2-induced decrease of MMP-9 was not antagonized by P and NET, but completely abolished by MPA.Conclusion. Our results indicate that E2 may have a stimulating effect on pre-existing tumor growth and metastasis. This effect seems to be influenced by progestogens in a different manner. Thus the choice of progestogen addition to estrogen therapy may be important, especially since different effects can occur in the case of pre-existing tumor cells.

Potential role of progestogens in the control of adipose tissue and salt sensitivity via interaction with the mineralocorticoid receptor

Beside their role in the control of water and electrolyte homeostasis, recent data clearly indicate that aldosterone and the mineralocorticoid receptor (MR) are involved in adipocyte biology. It has been recently shown that aldosterone promotes white and brown adipocyte differentiation in vitro through specific activation of the MR. In addition, a non-epithelial pro-inflammatory role for MR activation has been recently inferred from studies on mineralocorticoid/salt administration in experimental animal models and from clinical studies. The mineralocorticoid system could hence represent a potential target for new therapeutic strategies in obesity and the metabolic syndrome.Progesterone has high affinity for the MR and is a natural antagonist of aldosterone. Differently from classic synthetic progestins, which are devoid of antimineralocorticoid properties, progesterone and new progestogens show remarkable antimineralocorticoid effects.Here, we discuss the potential role of the antimineralocorticoid properties of progestogens in the control of body weight, adipose tissue proliferation and salt sensitivity; their therapeutic use in postmenopausal women, as well as in women affected by polycystic ovary syndrome, may open new and unexpected possibilities in the treatment of related metabolic disorders.

Use of the etonogestrel-releasing implant is associated with hypoactivation of the coagulation cascade

The role of progestogens in haemostasis is controversial. Our objective is to evaluate the haemostatic effects of an etonogestrel-releasing implant. This open-label, self-controlled, longitudinal study involved 20 healthy women receiving subcutaneous etonogestrel-releasing implants. At baseline, 1, 3 and 6 months, we measured the following: activated partial thromboplastin time; prothrombin time; thrombin time; fibrinogen; coagulation factors II, V, VII, VIII, IX, X and XI; von Willebrand factor; activated protein C (APC); antithrombin; free protein S; plasminogen activator inhibitor type 1 (PAI-1); alpha2-antiplasmin; thrombin-antithrombin (TAT) complex; prothrombin fragment 1 + 2 (F1 + 2); D-dimers; APC resistance. Statistical analyses included the Friedman test and ANOVA. Levels of APC (P < 0.01), factor II (P = 0.02), factor VII (P = 0.006), factor X (P = 0.01) and F1 + 2 (P < 0.001) were reduced, whereas those of PAI-1 (P = 0.01) and factor XI (P = 0.006) were transitory increased. All of these values, however, remained within normal ranges. Surprisingly, TAT concentrations fell below the normal range (P < 0.001). Our findings suggest that the etonogestrel-releasing implant does not induce a prothrombotic pattern during the first six months of use, and that its use is associated with a reduction in thrombin generation.

Norethisterone acetate in combination with estrogen: Effects on the skeleton and other organs: A review

This article is focused on the use of norethisterone acetate as progestogen in hormone replacement therapy. Emphasis is made on the fact that the primary reason for adding a progestogen to hormone replacement therapy is to protect the endometrium against hyperplasia. In this paper we review data that demonstrate that hormone replacement therapy that includes norethisterone acetate has positive effects on the postmenopausal bone metabolism and that it increases bone mass more than expected and more than treatment with alendronate. All available evidence is reviewed to show that norethisterone acetate, if given in the correct dosage, does not influence serum lipids and lipoproteins in any negative way. It is furthermore shown that norethisterone acetate seems to be superior compared to other progestogens to provide optimum bleeding control and endometrial protection. Also, hormone replacement therapy combinations with norethisterone acetate efficiently alleviate hot flushes. Hormone replacement therapy and the risk of breast cancer and the role of progestogens are discussed. (Am J Obstet Gynecol 2002;187:1101-16.)

Hormone replacement therapy: the perspectives for the 21st century

Nowadays different lines of evidence demonstrate the benefits of postmenopausal hormone replacement therapy (HRT). HRT is extremely effective in treating subjective symptoms and can really improve the quality of life of climacteric women. HRT and dementia: Estrogens are potentially relevant to the pathogenesis and treatment of Alzheimer's disease. The effects of different progestogens on cognitive functions and Alzheimer's disease are largely unknown. The prevention of Alzheimer disease might be a major indication to long term HRT. Large prospective, randomized trials will confirm these preliminary data. HRT and osteoporosis: HRT has been strongly correlated with higher bone mineral density and lower fracture incidence. Definite answers in terms of minimum effective dosages, timing and duration of HRT for fracture prevention are needed. HRT and cardiovascular disease: Different lines of evidence suggest that HRT can exert cardioprotective effects with substantial reduction of morbidity and mortality for cardiovascular disease in postmenopausal women. The effects and the role of progestogens in cardiovascular disease prevention are still debated. Prospective, randomized, controlled studies are needed to assess the impact of different HRT regimens on cardiovascular events. HRT and cancer: The major issue in the relationship between HRT and cancer is breast cancer. Long-term and current HRT use are followed by a slight, though significant increase in the risk of breast cancer. Progestogens can modify the cellular response of normal as well as cancer breasts. The possible protective effect of continuous progestogen addition is very interesting and needs further investigation. Alternative to classical HRT: Selective estrogen receptor modulators (SERM). SERMs such as raloxifene (RAL) are a new class of drugs that exert site specific estrogenic or antiestrogenic effects in different target tissues. RAL prevents bone loss and reduces serum cholesterol in postmenopausal women. In contrast to estrogen RAL does not stimulate breast or uterine tissues. In vitro RAL is highly effective at inhibiting the growth of estrogen-dependent breast adenocarcinoma cells. SERMs are expected to represent a major breakthrough for postmenopausal health. Conclusion: HRT can be offered either as a preventive tool or as individualized care on the basis of personal needs. New therapeutic options like the SERMs will offer a substantial medical advancement for the treatment of postmenopausal women.

Tamoxifen and the female genital tract.

Ugwumadu AHN, Carmichael P, Neven P. Tamoxifen and the female genital tract. Int J Gynecol Cancer 1998; 8: 6-15. Tamoxifen was originally developed by Imperial Chemical Industries (England) (ICI) in 1966 as an anti-estrogenic contraceptive. Ironically, it found a role in the treatment of anovulatory infertility, but its most important application to date is in adjuvant hormonotherapy for breast cancer. Tamoxifen has a complex and poorly understood mix of estrogenic and anti-estrogenic properties with variable and contrasting effects on hormone-sensitive target tissues, such as the endometrium. This article reviews the gynecologic lesions associated with tamoxifen therapy and discusses the merits and acceptability of endometrial surveillance tests and the role of progestogens.

Effect of Oral Contraceptives on Haemostasis Variables

Combined oral contraceptives (COCs) have effects on a large number of haemostasis variables. We have summarised literature data on effects of COCs containing 30-35 micrograms ethinyl estradiol for the third generation of progestogens (PGs): desogestrel, gestodene and norgestimate. It is concluded that about 15 variables show a shift in distribution of the order of magnitude of their interindividual variation coefficient. When comparing the third generation of PGs with the second one (norgestrel, levonorgestrel) stronger increases are noted for the former for some haemostatic variables. Also differences between desogestrel and gestodene for factor VII were apparent. It indicates that the role of PGs in the effects of COCs is significant and their design may in addition to reduction of oestrogen dosage be important in reducing haemostatic complications. The survey on molecular and cellular mechanisms by which the sex steroids might operate showed a great lack of knowledge. Only for factor XII has a functional oestrogen response element in the DNA definitely been identified. The study of molecular markers of coagulation and fibrinolysis have shown a distinct increased activation of coagulation (F 1 + 2, FPA) and fibrinolysis (PAP), and an increased fibrin turn-over (increased FDPs); platelet products are not found increased (beta TG, PF-4). The increase in fibrinolysis represent a counterforce, but individual changes in variables in coagulation and fibrinolysis do not correlate indicating independent effects and no evidence for a individually regulated balance. A first step in further research might be in understanding the increase in coagulation activation (F 1 + 2) which has so far not been satisfactorily related to changes in blood concentrations of haemostatic factors and possibly local factors.

Antagonism of oestrogen-induced prolactin release by medroxyprogesterone acetate

Previous studies conducted at our clinic suggested that the administration of hormone replacement therapy (HRT) in postmenopausal women could result in the inhibition of oestrogen-induced prolactin (PRL) release. The aim of this study was to determine how the pituitary function is affected by the sequential addition of medroxyprogesterone acetate (MPA) to oestrogen replacement therapy. Twenty-one postmenopausal women receiving no other medication were treated with a standard dose (0.625 mg/day) of conjugated equine oestrogens (CEE) for a period of 24 days, plus 5 mg/day MPA added sequentially during the last 12 days of the oestrogen therapy. Blood samples were collected before treatment, during oestrogen and oestrogen-progestogen administration and after cessation of treatment. Folliclestimulating hormone (FSH), luteinizing hormone (LH), 17β-oestradiol (E 2) and PRL levels were studied. During treatment gonadotrophin concentrations decreased significantly, while after cessation of HRT the levels of FSH and LH increased. These gonadotrophin fluctuations indicated a sharp rise in E 2 levels during therapy and a significant decrease during the treatment-free period. PRL levels were found to be higher during CEE therapy, but they fell when patients received CEE in combination with MPA. These observations suggest that the role of progestogens in a variety of experimental and clinically relevant situations needs to be investigated not only as regards their direct action but also their modulation of the effect of oestrogen.

A risk-benefit appraisal of transdermal estradiol therapy.

Estrogen replacement therapy (ERT) is very effective in relieving many menopausal symptoms such as hot flushes, night sweats, urogenital atrophy and psychological disturbances. Moreover, it is effective in the prevention of postmenopausal osteoporosis and has a favourable effect on some risk factors for cardiovascular disease in the long term, via several mechanisms including mediating effects on the lipid profile. Most of these beneficial effects are maintained with transdermal estradiol therapy, involving the use of a cutaneous delivery system attached to the skin which delivers a controlled rate of estradiol over a period of up to 4 days. However, the clear demonstration of a favourable effect on some risk factors for cardiovascular disease remains to be established. Transdermal administration of estradiol appears to be at least as effective as oral conjugated estrogen therapy on most of the end-points which have been evaluated, but allows a lower dose to be used, avoiding some of the metabolic adverse effects experienced with oral treatment. Endocrinological adverse effects, such as breast tenderness, breakthrough bleeding and fluid retention, are similar in both treatments, and can be minimised by dose adjustments in most cases. The most common adverse effects related to transdermal therapy are local skin reactions at the site of application. These are usually mild and transient in nature, and can be overcome by changing the site of application. Serious risks of transdermal therapy appear to be the same as those for other forms of ERT, namely an increased risk of endometrial hyperplasia and cancer with estrogen therapy alone. However, combination therapy involving the sequential administration of a progestogen has been shown to substantially reduce the risk of endometrial proliferation. The potential increased risk of breast cancer has been controversial and appears to be minimal with ERT. The role of progestogens on breast cancer risk remains controversial, but the data to date do not indicate any significant change in risk when progestogens are added to ERT.

Oestrogen and Progestogen Synergistically Stimulate Human and Rat Osteoblast Proliferation

Oestrogens play an important role in bone metabolism; they preserve bone mass after the menopause. Their action in bone has recently been shown to be, partly, a direct one, as oestrogen receptors and their effects have been demonstrated in bone cells. The role of progestogens in bone metabolism is less clear. In this study it has been shown that 17 beta-oestradiol exerts only a small, although not significant, stimulatory action with regard to SaOS-2 human osteosarcoma cell proliferation. A pure progestogen (Org 2058) has no effect when added alone. In combination with 17 beta-oestradiol, however, it has a highly synergistic action on SaOS-2 cell proliferation. The same effect was observed in primary rat osteoblasts, showing that this synergism is a general phenomenon in osteoblastic cells. High numbers of oestrogen and progestogen receptors have been demonstrated in SaOS-2 cells, indicating that the effects of these steroids are mediated via the normal route of steroid receptors. These data provide a cellular basis for the clinically recognized positive effect of oestrogen/progestogen combinations on bone formation.

Oestrogen and progestogen synergistically stimulate human and rat osteoblast proliferation.

Oestrogens play an important role in bone metabolism; they preserve bone mass after the menopause. Their action in bone has recently been shown to be, partly, a direct one, as oestrogen receptors and their effects have been demonstrated in bone cells. The role of progestogens in bone metabolism is less clear. In this study it has been shown that 17 beta-oestradiol exerts only a small, although not significant, stimulatory action with regard to SaOS-2 human osteosarcoma cell proliferation. A pure progestogen (Org 2058) has no effect when added alone. In combination with 17 beta-oestradiol, however, it has a highly synergistic action on SaOS-2 cell proliferation. The same effect was observed in primary rat osteoblasts, showing that this synergism is a general phenomenon in osteoblastic cells. High numbers of oestrogen and progestogen receptors have been demonstrated in SaOS-2 cells, indicating that the effects of these steroids are mediated via the normal route of steroid receptors. These data provide a cellular basis for the clinically recognized positive effect of oestrogen/progestogen combinations on bone formation.

Role of progestogens in the prevention of breast cancer

The incidence of breast cancer has continued to decrease each year at Wilford Hall United States Air Force Medical Center with the ever-increasing use of combined progestogen-oestrogen replacement therapy over the past 12 yr. By 1983, the overall incidence of breast cancer had fallen to 53.9:100000. The lowest rate for the 9 yr of a prospective study to 1983 was seen among the oestrogen-progestogen users (66.8:100000) although it was also slightly reduced in both the unopposed oestrogen users (142.3:100000 and the oestrogen vaginal cream users (116.3:100000). The incidence was significanlty lower in both the oestrogen-progestogen users and the oestrogen users ( P ⩽ 0.01) as compared with untreated women (343.5:100000). These data further strengthen the growing evidence that the addition of progestogen to oestrogen decreases the risk of mammary malignancy.