Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women

OBJECTIVE: During the past few years serious concern has been raised about the safety of combined estrogen/progestogen hormone therapy, in particular about its effects on the breast. Several observations suggest that androgens may counteract the proliferative effects of estrogen and progestogen in the mammary gland. Thus, we aimed to study the effects of testosterone addition on breast cell proliferation during postmenopausal estrogen/progestogen therapy. DESIGN: We conducted a 6-month prospective, randomized, double-blind, placebo-controlled study. A total of 99 postmenopausal women were given continuous combined estradiol 2 mg/norethisterone acetate 1 mg and were equally randomly assigned to receive additional treatment with either a testosterone patch releasing 300 microg/24 hours or a placebo patch. Breast cells were collected by fine needle aspiration biopsy at baseline and after 6 months, and the main outcome measure was the percentage of proliferating breast cells positively stained by the Ki-67/MIB-1 antibody. RESULTS: A total of 88 women, 47 receiving active treatment and 41 in the placebo group, completed the study. In the placebo group there was a more than fivefold increase (P<0.001) in total breast cell proliferation from baseline (median 1.1%) to 6 months (median 6.2%). During testosterone addition, no significant increase was recorded (1.6% vs 2.0%). The different effects of the two treatments were apparent in both epithelial and stromal cells. CONCLUSIONS: Addition of testosterone may counteract breast cell proliferation as induced by estrogen/progestogen therapy in postmenopausal women.     

Lessons to be learned from animal studies on hormones and the breast

The relation of hormone use by postmenopausal women to breast cancer risk has been controversial and unclear. A recent large randomized trial, the Women's Health Initiative (WHI) and a large observational study (Million Women Study) provided somewhat conflicting answers. The WHI found an increased incidence of breast cancer among women given hormone therapy (conjugated equine estrogen plus medroxyprogesterone acetate) but no increase in those given estrogen only therapy (conjugated equine estrogen alone). Whereas, the Million Women Study found an increased breast cancer risk among the estrogen plus progestin and the estrogen only users. This review brings comparative perspective to the issue of the effects of estrogen plus progestin versus estrogen only effects on breast cancer and is focused particularly on nonhuman primates. Although data from rodents is mixed, studies of monkeys suggest that estrogen only treatment has little or no effect on breast cell proliferation, and by inference, on breast cancer risk. On the other hand, data from both mouse and monkey studies strongly support the conclusion that the co-administration of a progestogen with an estrogen markedly increases breast cell proliferation and the potential for breast cancer promotion.     

Postmenopausal testosterone therapy and breast cancer risk

Background: Testosterone therapy is being increasingly used in the management of postmenopausal women. However, as clinical trials have demonstrated a significantly increased risk of breast cancer with oral combined estrogen–progestin therapy, there is a need to ascertain the risk of including testosterone in such regimens. Objective: Evaluation of experimental and epidemiological studies pertaining to the role of testosterone in breast cancer. Design: Literature review. Setting: The Jean Hailes Foundation, Research Unit. Main Outcome Measures: Mammary epithelial proliferation, apoptosis and breast cancer. Results: In experimental studies, testosterone action is anti-proliferative and pro-apoptotic, and mediated via the AR, despite the potential for testosterone to be aromatized to estrogen. Animal studies suggest that testosterone may serve as a natural, endogenous protector of the breast and limit mitogenic and cancer promoting effects of estrogen on mammary epithelium. In premenopausal women, elevated testosterone is not associated with greater breast cancer risk. The risk of breast cancer is also not increased in women with polycystic ovary syndrome who have chronic estrogen exposure and androgen excess. However, in postmenopausal women, who are oestrogen deplete and have increased adipose aromatase activity, higher testosterone has been associated with greater breast cancer risk. Conclusion: Available data indicate the inclusion of testosterone in estrogen–progestin regimens has the potential to ameliorate the stimulating effects of hormones on the breast. However, testosterone therapy alone cannot be recommended for estrogen deplete women because of the potential risk of enhanced aromatisation to estrogen in this setting.     

Progestogens in postmenopausal hormone therapy and the risk of breast cancer

Hormone therapy is the treatment of choice for the alleviation of menopausal symptoms and the treatment of urogenital atrophy. In women with an intact uterus a progestogen must be added to estrogen therapy to prevent endometrial hyperplasia and cancer. There is a wide variety of marketed progestogens which differ in their pharmacological properties according to their structure. Convincing evidence from both clinical trials and epidemiological studies indicates that combined estrogen–progestogen therapy confers a higher risk of breast cancer compared to estrogen monotherapy. Concerning the different types of progestogens, data from large observational studies suggest that natural progesterone and dydrogesterone are associated with a lower risk of breast cancer compared with the other progestins. Observational studies, furthermore, indicate that sequential estrogen–progestogen regimens may lead to a lower risk elevation compared to continuous regimens. The effect of tibolone on breast cancer is unclear. Concluding, both the type of the progestogen and the mode of HT administration may have an impact on breast cancer risk.     

Lessons to be learned from clinical studies on hormones and the breast

Estrogen is a well-known mitogen in human breast epithelium but the action of progestogen is complex and incompletely understood. During the last years, accumulating data from animal, clinical and observational studies suggest a proliferative effect in breast tissue when progestogen is added to estrogen. Findings in surrogate markers like breast density add to clinical and epidemiological reports indicating that continuous combined HRT may carry a higher risk of breast cancer than treatment with estrogen alone. Whether the results are valid for all progestogens remains to elucidated. It is also clear that not all women respond in the same way to the same treatment and the biological basis for the marked individual variation in breast response has to be clarified. Further knowledge about the role of androgens and of the impact of different treatment regimens is important and prospective randomized clinical studies are needed.     

A physiologic role for testosterone in limiting estrogenic stimulation of the breast

OBJECTIVE: The normal ovary produces abundant testosterone in addition to estradiol (E(2)) and progesterone, but usually only the latter two hormones are "replaced" in the treatment of ovarian failure and menopause. Some clinical and genetic evidence suggests, however, that endogenous androgens normally inhibit estrogen-induced mammary epithelial proliferation (MEP) and thereby may protect against breast cancer. DESIGN: To investigate the role of endogenous androgen in regulating mammary epithelial proliferation, normal-cycling rhesus monkeys were treated with flutamide, an androgen receptor antagonist. To evaluate the effect of physiological testosterone (T) supplementation of estrogen replacement therapy, ovariectomized monkeys were treated with E(2), E(2) plus progesterone, E(2) plus T, or vehicle. RESULTS: We show that androgen receptor blockade in normal female monkeys results in a more than twofold increase in MEP, indicating that endogenous androgens normally inhibit MEP. Moreover, we show that addition of a small, physiological dose of T to standard estrogen therapy almost completely attenuates estrogen-induced increases in MEP in the ovariectomized monkey, suggesting that the increased breast cancer risk associated with estrogen treatment could be reduced by T supplementation. Testosterone reduces mammary epithelial estrogen receptor (ER) alpha and increases ERbeta expression, resulting in a marked reversal of the ERalpha/beta ratio found in the estrogen-treated monkey. Moreover, T treatment is associated with a significant reduction in mammary epithelial MYC expression, suggesting that T's antiestrogenic effects at the mammary gland involve alterations in ER signaling to MYC. CONCLUSIONS: These findings suggest that treatment with a balanced formulation including all ovarian hormones may prevent or reduce estrogenic cancer risk in the treatment of girls and women with ovarian failure.     

Mechanisms of sex steroids. Future developments

The discussion on the risks of hormone therapy supports the search for alternative drugs such as selective estrogen receptor modulators (SERMs). These compounds are suitable for special preventive goals, but cannot be expected to replace the use of estrogens in patients with estrogen deficiency. The development of selective progesterone receptor modulators (SPRMs) which has to resolve various problems, might be a promising approach. Hormone replacement therapy (HRT) with natural estrogens remains the measure of choice for treatment of symptoms caused by estrogen deficiency. Recent findings suggest that the additional progestogen which is used for the protection of the endometrium, plays a crucial role with regard to the risk of breast cancer and cardiovascular disease. As surrogate parameters cannot predict the extent of risks, suitable tools for the selection of progestogens with the least potential for causing adverse effects, are urgently needed. Experimental, clinical and epidemiological data suggest that the elevation in breast cancer risk is due to the proliferative effect of estrogens on breast tissue which is largely enhanced by progestogens. A short-term in vivo-test might be helpful for the evaluation of proliferative effects of estrogen–progestogen preparations. Similarly, a strictly standardized in vivo-test for the assessment of the atherogenic potential of estrogen–progestogen preparations might help to select the preparations with the lowest risk for ischemic diseases. The available data suggest that it is probably not the androgenic but the glucocorticoid activity of a progestogen which plays a role in the development of cardiovascular disease. Progestogens with glucocorticoid effects may up-regulate the thrombin receptor in the vessel wall which is involved in the development of atherosclerosis and stimulation of extrinsic coagulation.     

Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy

OBJECTIVE: There is now convincing evidence that usual hormone therapy for ovarian failure increases the risk for breast cancer. We have previously shown that ovarian androgens normally protect mammary epithelial cells from excessive estrogenic stimulation, and therefore we hypothesized that the addition of testosterone to usual hormone therapy might protect women from breast cancer. DESIGN: This was a retrospective, observational study that followed 508 postmenopausal women receiving testosterone in addition to usual hormone therapy in South Australia. Breast cancer status was ascertained by mammography at the initiation of testosterone treatment and biannually thereafter. The average age at the start of follow-up was 56.4 years, and the mean duration of follow-up was 5.8 years. Breast cancer incidence in this group was compared with that of untreated women and women using usual hormone therapy reported in the medical literature and to age-specific local population rates. RESULTS: There were seven cases of invasive breast cancer in this population of testosterone users, for an incidence of 238 per 100,000 woman-years. The rate for estrogen/progestin and testosterone users was 293 per 100,000 woman-years--substantially less than women receiving estrogen/pro-gestin in the Women's Health Initiative study (380 per 100,000 woman-years) or in the "Million Women" Study (521 per 100,000 woman-years). The breast cancer rate in our testosterone users was closest to that reported for hormone therapy never-users in the latter study (283 per 100,000 woman-years), and their age-standardized rate was the same as for the general population in South Australia. CONCLUSIONS: These observations suggest that the addition of testosterone to conventional hormone therapy for postmenopausal women does not increase and may indeed reduce the hormone therapy-associated breast cancer risk-thereby returning the incidence to the normal rates observed in the general, untreated population.     

Progestogen deficiency and endometrial cancer risk

There is a close relationship between the amount of estogen and progesterone secreted by the ovary from puberty to menopause and the development of hyperplastic endometrium of all types and finally endometrial cancer. The endogenous endocrine pattern reflects progesterone deficiency (corpus luteum deficiency). Such deficiency can also develop when treatment with exogenous estrogen and progestogen is done and a deficiency of the progestogen in comparison to the used estrogen is induced in pre- and postmenopausal women. This risk is particular accentuated in the climacteric female when the endocrine milieu was unfavorable in the years before (menstrual cycle disorders, PCOS, obesity, no full-term pregnancy, no breast feeding, etc.).However, there are the additional factors, which modify the biological end result: “Progestogen deficiency”. One main factor is the level of SHBG determined by the amount of free, biologically active estradiol. A low level of SHBG is for instance induced by high body weight. Therefore, the amount of overweight correlates with increased risk of endometrial hyperplasia and finally endometrial cancer. In addition, increasing body weight negatively affects proper ovarian function leading to corpus luteum deficiency and this in addition increases the risk of endometrial cancer. The classical risk increase for endometrial cancer is associated with oligomenorrhea or polymenorrhea combined with corpus luteum deficiency or anovulation. Therefore, women with PCOS are at increased risk for endometrial cancer in the pre- and postmenopausal years. Examples from the therapeutic point of view have been the risk increase found with biphasic estrogen high-dosed oral contraceptives with a long estrogen phase and a short progestogen phase. In climacteric females estrogen-only treatment results in a predictable increase in endometrial cancer risk. Therefore, it is mandatory to use estrogen/progestogen combinations. The lowest risk is achieved when a continuous estrogen/progestogen regimen is used. In addition, the lowest dose of estrogens for the individual woman should be chosen.     

Hormones and breast cancer

The incidence of breast cancer in women varies with age, mammarygland mass and exposure to endogenous and exogenous hormones.Age is the single most important factor and if, as projected,32% of women will be aged >60 years by 2050, world breast cancerincidence will exceed the current 10⁶ per year. Hormonal influencesthat affect growth of the mammary gland increase the risk ofbreast cancer; for example earlier menarche and later menopause.Childbearing protects against later development of breast cancer,and breastfeeding further decreases the risk. The breast cancerrisk declines more with increasing total duration of breastfeeding.Exposure to hormonal contraceptives has been evaluated in acombined reanalysis of data from 51 epidemiological studies.There is a small transient increase in the relative risk ofbreast cancer among users of oral contraceptives but, sinceuse typically occurs at young ages when breast cancer is relativelyrare, such an increase would have little effect on overall incidencerates. In contrast, exposure to menopause hormone treatmentoccurs when the baseline risk of breast cancer is higher, andepidemiological studies and randomized controlled trials consistentlyfind an increase in breast cancer risk with exposure to combinedestrogen and progestogen. Women with a family history of breastcancer in first degree relatives have an increased risk of breastcancer but there is no evidence to suggest that this differsaccording to a woman's use of oral contraceptives or menopausehormone treatment. Selective estrogen receptor modulators areuseful in the treatment and/or prevention of breast cancer dependingon the specific agonist or antagonist effects on estrogen targettissues.     

Tibolone: clinical recommendations and practical guidelines. A report of the International Tibolone Consensus Group

An international multidisciplinary panel of experts in the management of the menopause met at the 4th Amsterdam Menopause Symposium in October 2004 to determine the specific place of tibolone, a synthetic steroid with a unique clinical profile, within the wide range of currently available postmenopausal therapy options. The consensus was that tibolone is a valuable treatment option for women with climacteric complaints. As well as relieving vasomotor symptoms, tibolone has positive effects on sexual well-being and mood, and improves vaginal atrophy and urogenital symptoms. Prevention of bone loss with tibolone is comparable to that seen with estrogen therapy (ET) and estrogen/progestogen therapy (EPT). As tibolone rarely causes endometrial proliferation, no additional progestogen is required. It also has good tolerability, being associated with a low incidence of vaginal bleeding and of breast pain. Tibolone does not increase mammographic density. Absolute numbers of women at increased risk for breast cancer are estimated to be low or absent with both tibolone and ET, and the risk with tibolone should be significantly lower than that with EPT. Tibolone might therefore be preferable to EPT in certain women who have not been hysterectomised. Based on the evidence available, the panel proposed a number of subgroups of postmenopausal women with vasomotor symptoms in whom tibolone might have added value; these included women with sexual dysfunction, mood disorders, fibroids and urogenital complaints, as well as those with breast tenderness or high mammographic breast density with EPT use.     

Rationale for use of lower estrogen doses for postmenopausal hormone therapy

In placebo-controlled clinical trials low dose estrogens have been shown to reduce hot flashes an average of 65%. Low dosage is effective in preventing bone loss in early menopause and both low and ultralow estrogen dosages can prevent bone loss among women many years beyond menopause. Epidemiological studies indicate less risk of cardiovascular disease and venous thromboembolism in women who use low dose estrogens compared to standard dose. Low dosages of estrogens are less likely to produce unacceptable side effects, such as vaginal bleeding or breast tenderness. When prescribing low dosage estrogen, one can safely use less progestogen, either less daily dosage or less frequent cycles. Older women on ultralow estrogen may not require regular progestogen because the endometrium is not stimulated. In conclusion, there is a strong rationale for use of lower estrogen dosage in HT. Low dosage estrogen can relieve vasomotor symptoms and can prevent postmenopausal bone loss. Women taking low dosages of estrogens are less likely to have unacceptable side effects, such as vaginal bleeding or breast tenderness. Moreover, the potential harm caused by standard dosages of estrogen with progestin, including coronary heart disease, venous thromboembolism, stroke, and breast cancer may be mitigated by use of lower estrogen doses that do not require daily or monthly progestin opposition.     

Sexual hormone on the human mammary carcinoma cells in vitro (author's transl)

The effects of estradiol-17 beta and testosterone on cultures of human breast cancer cells from 10 patients are described. Testosterone produced a significant decrease in the rate of cell proliferation of sex-chromatin-positive cells, while no effect of estrogen could be observed. Sex-chromatin-negative cells appeared to be independent of the 2 hormones. A significant decrease in the number of cells in cultures derived from postmenopausal patients was noted after testosterone application. Sex-chromatin-positive cells in cultures treated with either hormone were frequently abnormal in shape, with pycnotic and lytic aspects and nuclear abnormalities; sex-chromatin-negative cells showed similar abnormalities even more frequenlty.     

Effect of statins combined with estradiol on the proliferation of human receptor-positive and receptor-negative breast cancer cells

OBJECTIVE: Combination of a statin plus estrogen may reveal benefits on the cardiovascular system in postmenopausal women by additively ameliorating both the lipid profile and vascular function. Long-term therapy with estrogens, however, is associated with an increase of breast cancer risk. In contrast, evidence is accumulating that statins may inhibit carcinogenesis because of their central action on important cellular functions. It is of special clinical interest whether a statin/estrogen combination may reduce the most undesired side effect of estrogen therapy, that is, an increase in breast cancer risk. Therefore, in the present in vitro study, for the first time we have compared the effect of five statins on the proliferation of human breast cancer cells alone and in the presence of stimulatory estradiol (E(2)). DESIGN: As cell models, the receptor-positive cell line MCF-7 and the receptor-negative cell line MDA-MB 231 were used. The statins atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin were tested in the concentration range of 1.6 microm to 50 microm alone and in the range of 0.01 nm to 10 microm in combination with E(2). Cell proliferation was measured after 4 days by the adenosinetriphosphate-chemosensitivity test. RESULTS: All statins except pravastatin were able to significantly inhibit dose dependently the cell proliferation of both cell lines. The inhibitory values were between 10% and 90%, whereby the potency was greater in the case of receptor-negative cancer cells. A significant difference in the efficacy of the statins was observed for MCF-7 cells, in which atorvastatin was less effective than the other statins. In contrast, in the presence of E(2), the statins showed similar antiproliferative actions in MCF-7 cells when tested in the concentration range of 0.01 nm to 10 microm. A reduction of cell proliferation of less than 10% was observed at the lower concentrations and between 15% and 25% at the highest concentration of 10 microm. CONCLUSIONS: The present data indicate that statins can inhibit the proliferation of receptor-positive and -negative human breast cancer cells but failed to completely abrogate the E(2)-induced proliferation of receptor-positive breast cancer cells. Clinical trials, however, are necessary to prove this anticarcinogenic action of statins.     

性激素替代治疗与乳腺癌

目前世界范围内乳腺癌发病率呈上升趋势Ｍａｒｉａｎｎｅ指出１９８５年时医学家估计全世界每年出现７２万新病例，预计至２０００年每年将出现１００万新病例［１］之所以出现乳癌发病率增长，其原因是与妇女平均寿命的提高有关，因为４０岁以上妇女乳腺癌的发生率升高...     

Current status of hormone therapy and breast cancer

This editorial comments on two similar reviews of the literature on breast cancer and post-menopausal hormone therapies (HTs), puts the results in clinical perspective and suggests where they direct future research and clinical management. Although epidemiological studies have suggested increased breast cancer risk for all menopausal HT regimens, unopposed oral estrogen regimens have not been associated with any increased risk in recent randomized placebo controlled trials (RCTs). Added progestogen after 5 years of combined HT in RCTs increases the risk of breast cancer by four cases per 10,000 per annum. As yet there is no evidence of different risk by progestogen type, dose or route. Theoretically local intrauterine progestogen may not give the same risk, but long-term trials are required. The commentary addresses the responsibility of the media in presenting levels of risk to the public, moving towards safer regimens, safer therapies, appropriate patient choice and, in particular, correct timing of HT where it is prescribed around menopause. This is in contrast to many of the trials when HT was administered after the potential climacteric window of therapeutic opportunity. The current main indication for HT remains for menopausal symptom control where it improves quality of life. HT may be required for many years. The informed woman should decide on HT based on her personal benefits and risks, which should include all aspects of her health.     

The case for less-than-monthly progestogen in women on HT: is transvaginal ultrasound the key?

Unopposed estrogen (previously called ERT, now referred to as ET) increases a patient's risk of endometrial cancer. The addition of a progestogen to estrogen (previously called HRT, now referred to as HT) will decrease that additional risk of endometrial cancer although it will not eliminate it. Initially this was always done in a sequential fashion. More recently, continuous-combined HT, utilizing daily progestogen, has been popularized. Increasingly, published data points to progestogen and estrogen together causing an increase in the risk of breast cancer two to three times above that of estrogen alone. In the past, less-than-monthly progestogen has been attempted. It results in less bleeding, as well as some simple hyperplasia. Transvaginal ultrasound has a very poor positive predictive value (4% for serious endometrial disease and 9% for any endometrial disease) but a very high negative predictive value (99%) when the echo is distinct, and thin (<5 mm). Thus, patients with an initial thin distinct endometrial echo can begin with unopposed estrogen. At 3 months, they get a progestogen withdrawal of 12 days and the endometrial echo is measured again. If thin and distinct (<5 mm), the interval between progestogen withdrawals can be further increased and in some women potentially eliminated. If the echo is not sufficiently thin, although this does not necessarily indicate anything more than proliferative endometrium, those patients may require either monthly progestogen or continuous-combined HT. The advantage for the successful patient is less progestogen exposure, as little as 24 days per year in most patients, and less bleeding (although because the majority will bleed, the patient has to be willing to accept a withdrawal bleed that she has planned and can control the timing of by when she chooses to take the progestogen). The patient should have an easily visible thin endometrial echo before initiation. Some women will not lend themselves to a reliable assessment of the endometrial echo (at least not without saline infusion enhancement). Examples of such patients are those with an axial uterus, coexisting fibroids, marked obesity, and previous endometrial ablation. Such an approach will allow a large number of patients whose initial endometrial echo is easily visualized to minimize their progestogen dose.     

In vivo and in vitro evidence that PPARγ ligands are antagonists of leptin signaling in breast cancer

Obesity is a major risk factor for the development and progression of breast cancer. Leptin, a cytokine mainly produced by adipocytes, plays a crucial role in mammary carcinogenesis and is elevated in hyperinsulinemia and insulin resistance. The antidiabetic thiazolidinediones inhibit leptin gene expression through ligand activation of the peroxisome proliferator-activated receptor-γ (PPARγ) and exert antiproliferative and apoptotic effects on breast carcinoma. In this study, we investigated the ability of PPARγ ligands to counteract leptin stimulatory effects on breast cancer growth in either in vivo or in vitro models. The results show that activation of PPARγ prevented the development of leptin-induced MCF-7 tumor xenografts and inhibited the increased cell-cell aggregation and proliferation observed on leptin exposure. PPARγ ligands abrogated the leptin-induced up-regulation of leptin gene expression and its receptors in breast cancer. PPARγ-mediated repression of leptin gene involved the recruitment of nuclear receptor corepressor protein and silencing mediator of retinoid and thyroid hormone receptors corepressors on the glucocorticoid responsive element site in the leptin gene expression regulatory region in the presence of glucocorticoid receptor and PPARγ. In addition, PPARγ ligands inhibited leptin signaling mediated by MAPK/STAT3/Akt phosphorylation and counteracted leptin stimulatory effect on estrogen signaling. These findings suggest that PPARγ ligands may have potential therapeutic benefits in the treatment of breast cancer.     

Differential effects of sex steroids on T and B cells: modulation of cell cycle phase distribution, apoptosis and bcl-2 protein levels.

Sex steroids have dramatic and differential effects on classic endocrine organ proliferation and apoptosis. In this investigation we sought to delineate similar effects of sex steroids on proliferation, cell cycle phase and apoptosis in lymphocyte cell lines as models for T and B cells. Estrogen and testosterone inhibited T cell line proliferation, induced accumulation of cells in S/G(2)M phases of the cell cycle, and increased apoptosis in a concentration- and time-dependent manner. There was a more modest effect of estrogen and testosterone on cell cycling and apoptosis in B lymphocyte cell lines, suggesting that estrogen and testosterone are inhibitory to T but not B cell lines. In comparison, progesterone induced cytostasis and modestly increased apoptosis in both T and B cell lines. Estrogen and testosterone were not antagonistic or synergistic to each other in their effects on cell cycle phase distribution, and only minimally synergistic for apoptosis. In contrast, progesterone antagonized cell cycle and apoptotic effects of estrogen in T cells. Estrogen-induced cell cycle and apoptotic effects in T cell lines were associated with suppression of bcl-2 protein levels, which were unaffected in Raji B cells. Progesterone also antagonized the estrogen-induced changes in T cell bcl-2 protein levels. These results suggest that there may be significant and differential sex steroid effects on T and B lymphocytes that may be important to sexual dichotomies in immune and autoimmune responses.