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Biological and epidemiological findings suggest that metabolic factors - insulin, insulin-like growth factor-I (IGF-I) and sex hormone-binding globulin (SHBG) - are involved in the development and promotion of breast cancer. Estrogens, particularly if administered orally, counteract metabolic factors that increase breast cancer risk, i.e. they reduce insulin and IGF-I and increase SHBG. This could contribute toward explaining epidemiological data showing that unopposed oral estrogens do not increase breast cancer risk, or do so only modestly. In contrast to natural progesterone and progesterone-derived progestins, progestins endowed with androgenic (or glucocorticoid) activity negatively influence these metabolic factors, counteracting the favorable effects of estrogens. While most biological and epidemiological findings suggest that natural progesterone does not augment breast cancer risk, available data show an increased risk with synthetic progestins - with the possible exception of progesterone-derived dydrogesterone. Different mechanisms for different progestins could possibly be involved. Differences from progesterone with regard to pharmacokinetics and pharmacodynamics, potency, interaction with the two isoforms of the progesterone receptor, and binding to other steroid receptors could all be relevant. These remain theoretical speculations for the time being, but the possibility that some progestins increase breast cancer risk through their negative influence on metabolic factors cannot be rejected.

Objective: Circulating insulin-like growth factor-I (IGF-I) is mainly produced by the liver under GH stimulation and is influenced by nutrition and insulin. IGF-I bioavailability is regulated by interactions with specific binding proteins (IGFBPs). The objective of this paper is to review available data on modifications of the IGF-I system in menopausal women during HRT, with particular attention on the differential effects of progestins., Method: All available reports on the effects of different forms of HRT have been taken into account., Results: Available data suggest that different kinds of HRT have different effect on the IGF-I system, depending on route of administration, oestrogen dose, basal IGF-I values and type of progestin. Oestrogen administration (oestrogen replacement therapy (ERT)) reduces circulating IGF-I mainly through a hepatocellular effect. The decrease is sharper when oral ERT is used (first pass hepatic effect) and in women with higher basal IGF-I levels. The progestins endowed with androgenic effects--the 19-nortestosterone derivatives and, to a lesser extent, medroxyprogesterone acetate (MPA)--tend to reverse the IGF-I decrease induced by oral oestrogens. In contrast, progestins devoid of androgen-like hepatocellular and metabolic actions (e.g. dydrogesterone) do not interfere with the IGF-I decrease induced by oral oestrogens. Data on the effect of ERT on IGFBP-3 level are not consistent. Oral ERT, via hepatocellular actions (amplified by the first pass hepatic effect) causes a two to three-fold increase in IGFBP-1 levels. Androgenic progestins oppose the IGFBP-1 increase induced by oral oestrogens. Data on the effect of ERT and different progestins on the level of free IGF-I are scant and inconsistent., Conclusion: Even if some aspects need clarification, available data demonstrate that different progestins have differential effects on the circulating IGF-I system.

Objectives: To assess differences in two sequential combined hormone replacement therapy (HRT) products on selected cardiovascular and breast metabolic markers. The products were different concerning the route of administration of estradiol and its combined progestin, either oral or transdermal, and the androgenic properties of progestogens, respectively, dydrogesterone and norethisterone acetate., Methods: One hundred and nineteen healthy non-hysterectomized postmenopausal women were included in this open, multi-center, two parallel group trial. They were randomized to a treatment of six 28-day cycles with oral estradiol sequentially combined with dydrogesterone (oE2/D10) or a sequential combination patch of estradiol plus norethisterone acetate (tdE/NETA). At baseline and after six cycles the high-density lipoprotein cholesterol (HDL-C), the sex hormone binding globulin (SHBG) and the total insulin-like growth factor-I (IGF-I) blood levels were determined by a central laboratory. A total of 89 women were compliant to the protocol., Results: After six cycles, a statistically significant difference (P<0.001) concerning HDL-C, SHBG and IGF-I levels was found between the two treatment groups. The HDL-C levels were increased in the oE2/D10 group and decreased in the tdE/NETA group, with a final difference of about 0.3 mmol/l. The oE2/D10 treatment induced a sharp increase (about 57 mmol/l) in SHBG levels. IGF-I levels decreased with both the products, but the difference in favor of the oE2/D10 treatment was of about 30 ng/ml. Moreover, patients on tdE/NETA with an IGF-I baseline value below the median showed an increase., Conclusion: Oral estradiol sequentially combined with dydrogesterone, a non-androgenic progestogen, induced positive changes of some cardiovascular (HDL-C) and breast (SHBG and IGF-I) metabolic markers. These effects were significantly different from those obtained with a transdermal estradiol associated to an androgenic progestogen.

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.

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.

Unlike parenteral estrogens, oral estrogen administration in menopause causes, through its hepatocellular action, a significant decrease of circulating insulin-like growth factor I (IGF-I) levels; this effect is opposed by the addition of an androgenic progestogen. In vitro studies show that IGF-I is a potent mitogen for 'estrogen responsive' breast cancer cells. Moreover, some findings in breast cancer patients and in women treated with tamoxifen suggest that reduction of circulating IGF-I could be protective to the breast. However, by also considering (1) the potential action on breast cancer cells of IGF-II, (2) the possible consequences of the growth hormone (GH) increase caused by the IGF-I reduction and (3) the fact that in vitro results are not simply transferable to the in vivo condition, other 'scenarios' can be envisaged, besides the favorable one. In support of the latter, there are epidemiologic data which suggest that oral estrogen use could have some favorable peculiarities with regards to breast cancer risk. The associated decrease in circulating IGF-I level could well be one of these peculiarities.

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.

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.