HRT and breast cancer risk: a clue for interpreting the available data.

Epidemiological and biological data on HRT and breast cancer risk are reviewed. Some aspects deserve consideration. (1) The majority of epidemiological data have been gathered from populations where high estrogen doses (> or = 1.25 mg daily of conjugated estrogens) were used as first line therapy. (2) HRT does not increase the risk in overweight women, even in the series in which a risk increase (in longterm users) is found. This could be as a result of the fact that oral estrogens, through their metabolic and hepatocellular effects, reverse some biological features of obesity (e.g. increased insulin-like growth factor I activity and decreased sex hormone binding globulin level) which potentially increase breast cancer risk, so balancing the estrogen stimulation. (3) The progestin addition seems to increase the risk when the 19 nor-testosterone derivatives are used. These androgenic compounds contrast the metabolic and hepatocellular effects of oral estrogens. To sum up, the possibility does exist that even the longterm use of oral estrogens at the right ('low') dose, with the addition of a non-androgenic progestin, will be shown to be associated with a very limited breast cancer risk increase.

Insulin-like growth factor I (IGF-I) serum level modifications during transdermal estradiol treatment in postmenopausal women: a possible bimodal effect depending on basal IGF-I values.

The objective of this study was to determine the influence of transdermal estradiol administration on insulin-like growth factor I (IGF-I) serum level in a series larger than those published to date. Thirty-nine postmenopausal women with vasomotor symptoms were studied; blood samples (after overnight fast) were obtained just before and at the 6th month of treatment with transdermal estradiol 0.05 mg/day, and serum levels of IGF-I, growth hormone and sex hormone binding globulin (SHBG) were evaluated. Sixteen of the 39 women did not show variations of IGF-I values (group A), while 11 showed an increase (group B) and 12 showed a decrease (group C) by at least 20% with transdermal estradiol treatment. IGF-I basal levels were higher in group C as compared to group A (p < 0.05) and to group B (p < 0.01), intermediate in group A, and lower in group B. Group C showed a significant increase of SHBG values with transdermal estradiol treatment. Transdermal estradiol seems to induce a bimodal effect on IGF-I serum levels, depending on IGF-I basal values. This could be caused by a different responsivity to estrogen action on the liver (the major site of circulating IGF-I production) and also, possibly, by a different degree in insulin sensitivity changes caused by estrogen.

Lipid profile during hormone replacement therapy: effect of different progestins?

Oral estrogens cause a decrease of low density lipoprotein cholesterol (LDL-chol.) and, especially an increase of high density lipoprotein cholesterol (HDL-chol.) levels, which both have potentially favorable effects; they also cause a triglyceride level increase, which probably has no clinical relevance except in cases with basal hypertriglyceridemia. Transdermal estradiol causes generally a minor decrease in LDL-chol. and minor increase HDL-chol. levels, with no increase or even decrease in triglyceride levels. The addition of androgenic progestins at conventionally used doses, while not interfering with LDL-chol. variations, causes a HDL-chol. decrease, which contrasts the effect of oral estrogens and completely reverses the effect of transdermal estradiol. On the contrary, the addition of a non androgenic progestin does not interfere with any of the estrogen induced lipid profile modifications.

Effect of progestins on IGF-I serum level in estrogen-treated postmenopausal women.

Insulin-like growth factor I (IGF-I) has a role in the whole-body anabolism and promotes both normal and abnormal cell growth in several tissues. Although IGF-I is also synthesized locally at numerous other sites, the liver does constitute the major site of its synthesis, and circulating IGF-I is mainly of hepatic derivation. The production of IGF-I is stimulated by growth hormone (GH), the secretion of which is influenced by circulating IGF-I level through a negative feed-back mechanism. Oral estrogen treatment causes a significant decrease of the IGF-I serum level, probably through a hepatocellular effect due to the first hepatic passage. Treatment with transdermal estradiol (tdE2) at the currently used doses does not cause, on average, substantial variations in the IGF-I serum level. The addition of an androgenic progestin--with strong hepatocellular actions, opposite to those of estrogen--completely reverses the IGF-I decrease induced by oral estrogens, and even causes a trend to IGF-I increase when tdE2 is used. Conversely, the addition of a non androgenic progestin, like dydrogesterone, does not cause interference with the estrogen effect.

Androgenic progestogens oppose the decrease of insulin-like growth factor I serum level induced by conjugated oestrogens in postmenopausal women. Preliminary report.

Oral oestrogen treatment in postmenopausal women causes a decrease of insulin-like growth factor I (IGF-I) serum level, probably through a hepatocellular effect. To explore the possibility that the androgenic progestogens oppose this effect, serum IGF-I and sex hormone binding globulin (SHBG) were evaluated in two groups of patients treated respectively with oral conjugated oestrogens (oCE) or transdermal oestradiol (tdE2), in a first phase with the addition of dydrogesterone (DYDR), a non-androgenic progestogen, and subsequently with the addition of norethisterone acetate (NETA). With respect to basal values, treatment with oCE+DYDR caused an increase of SHBG (P < 0.002) and a decrease of IGF-I serum levels (P < 0.05); the shift to NETA addition opposed both effects: SHBG levels decreased partially but significantly (P < 0.01 vs. oCE + DYDR) and IGF-I returned to basal values with a significant increase with respect to the oCE + DYDR phase (P < 0.02). No changes were observed in the tdE2 + DYDR treated women; in this group the shift to NETA addition caused a significant decrease of SHBG values (P < 0.001 vs. before treatment and vs. tdE2 + DYDR phase) and a slight increase of IGF-I values. These differential effects on IGF-I and SHBG serum levels might be relevant as far as breast cancer risk is concerned.

Long-term hormone replacement treatment in menopause: new choices, old apprehensions, recent findings.

In recent years there has been an increase in the use of parenteral oestradiol as an alternative to the conventional oral preparations used in hormone replacement treatment (HRT) in menopause, such as conjugated equine oestrogens (CEE). The latter have been subject in the past to apprehensions, partly due to misunderstanding and oversimplification but also in relation to problems that have arisen during the history of HRT, for example the increase in endometrial cancer risk deriving from the use of non-progestogen-opposed treatment. However, confidence in long-term HRT comes from the epidemiological findings, which refer mainly to the use of oral CEE unopposed by progestogen: a reduced risk of osteoporotic fractures and of cardiovascular disease, and a very limited risk of breast cancer. Oral oestrogens produce marked hepatocellular effects. These effects are, on the whole, favourable from the point of view of cardiovascular risk. In addition, it cannot be excluded that some hepatocellular effects of oral oestrogen, for example increased sex hormone binding globulin levels and reduced circulating insulin-like growth factor I activity, offer protection to the breast. As progestogen supplementation is needed in non-hysterectomized women, priority should be given to preparations, such as progesterone or dydrogesterone, that feature good endometrial activity without opposing oestrogen hepatocellular effects.

Differential effects of oral conjugated estrogens and transdermal estradiol on insulin-like growth factor 1, growth hormone and sex hormone binding globulin serum levels.

In postmenopausal women oral ethinylestradiol causes a reduction in circulating insulin-like growth factor 1 (IGF-1) and an increase in serum growth hormone levels. There are no data on the effect of conjugated estrogens, the preparation most often used in estrogen replacement treatment (ERT), on these parameters. We evaluated serum IGF-1 and growth hormone levels, together with the levels of sex hormone binding globulin (SHBG), an indicator of estrogen hepatocellular action, before and after 6 months of ERT in two comparable groups of postmenopausal women. Sixteen women were treated with oral conjugated estrogens, 0.625 mg/day, and 14 with transdermal estradiol, 0.05 mg/day. In the women treated with oral conjugated estrogens, an increase in SHBG (p < 0.001), a decrease in IGF-1 (p < 0.001) and an increase in growth hormone (p < 0.05) serum levels were observed. No such effects were seen with the use of transdermal estradiol, devoid of hepatocellular effects. Undoubtedly, oral conjugated estrogens, 0.625 mg/day, through a hepatocellular effect, cause marked modifications in the IGF-1/growth hormone axis, which may have clinical relevance. For instance, the decreased IGF-1 level, together with the increased level of SHBG, might provide some explanation of the favorable epidemiological data on breast cancer risk in women receiving oral conjugated estrogens.