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The associations between age at menarche and the hormonal patterns of adolescent menstrual cycles were investigated to obtain information as to why early menarche is an important risk factor for breast cancer. An initial group of 200 schoolgirls, 7-17 yr old, was investigated longitudinally 3 times at 1.5-yr intervals. A serum progesterone concentration in the latter part of the cycle exceeding 6.4 nmol/liter (2.0 ng/ml) was considered to signify an ovulatory cycle, and a concentration less than 1.6 nmol/liter (0.5 ng/ml) an anovulatory cycle. The frequency of ovulation depended significantly on both the time since menarche and the age at menarche (P less than 0.001 for both variables). Early menarche was associated with early onset of ovulatory cycles. The times from menarche until 50% of the cycles were ovulatory were about 1, 3, and 4.5 yr when the ages at menarche were less than 12.0, 12.0-12.9, and more than or equal to 13.0 yr, respectively. Girls with a menarcheal age below 12.0 yr had higher serum estradiol but lower testosterone and dehydroepiandrosterone concentrations than subjects with later menarche. The estradiol to dehydroepiandrosterone ratio was already higher before menarche in subjects who displayed early menarche during follow-up. These findings show that the increase in adrenal androgen secretion was mainly related to chronological age and was not affected by the time of menarche. The demonstration of early ovulation after early menarche is in conflict with the estrogen-window hypothesis suggesting a longer duration of anovulatory cycles to explain the increased risk of breast cancer after early menarche. Other theories should therefore be considered, among them the following: 1) high serum progesterone concentration in association with normal or high serum estradiol at puberty increases the risk, 2) only the early and relatively high estrogen concentrations are important, or 3) the estrogen to androgen ratio is the critical factor, with androgens having a protective effect.

Early menarche is a risk factor for breast cancer. In a longitudinal manner, we have investigated the endocrine features of girls with early menarche. This study extends our investigations to the third decade of life in a cohort of girls followed up for 13 years. The group studied comprised 44 women, 20-31 years of age. Eleven women had had their menarche before 12.0 years, 14 women at 12.0-12.9 years and 19 women at 13.0 years or more. The women who had had early menarche had higher serum oestradiol concentrations during the follicular phase of the menstrual cycle than the women who had had their menarche later. The serum oestradiol concentrations increased rapidly at the beginning of cycle in these "early menarche" women. If there is a threshold which serum oestradiol concentrations must exceed to increase the risk of breast cancer, then these women have more days at risk than other women. In addition, the serum SHBG (sex-hormone-binding globulin) concentration was about 30% lower in the follicular-phase specimens of the women who had had their menarche before 12.0 years compared with those who had had their menarche at 13.0 years. Our data therefore indicate that women with early menarche are subject to a high degree of oestrogen stimulation at least until approximately 30 years of age. Our findings may have important consequences for the design of intervention programs for breast cancer prevention.

17 beta-Hydroxysteroid dehydrogenase (17HSD) isoenzymes catalyse the interconversion between highly active 17 beta-hydroxy- and low-activity 17-keto-steroids and thereby regulate the biological activity of sex steroids. The present study was carried out to characterize 17HSD activity and the expression of 17HSD type 1 and 2 isoenzymes in several human cell types and tissues. The data indicate that in cultured cells the direction of 17HSD activity is exclusively determined by the expression of these distinct isoenzymes. The intracellular environment could not modulate the direction of the enzyme activities in any of the cell types analysed. 17HSD type 1 acts as a reductase converting oestrone into oestradiol, whereas 17HSD type 2 possesses oxidative activity inactivating oestradiol by converting it into oestrone. The data, furthermore, suggest that of the two 17HSD type 1 mRNAs (1.3 and 2.3 kb), expression of the 1.3 kb mRNA is related to enzyme concentration in all the cell types studied. This mRNA is principally expressed in cells of placental and ovarian origin, but is also present in malignant breast epithelial cells. In contrast, 17HSD type 2 is more widely expressed. It is present in several oestradiol-metabolizing tissues as well as in some target cells of sex steroid action. The opposite reaction directions observed in the cultured cells, together with differences in the distribution of the isoenzymes, suggest that type 1 is involved in oestradiol production in females while type 2 plays a role in the inactivation of this sex steroid in peripheral tissues, both in females and in males. However, some examples exist of simultaneous expression of both enzymes in the same cell type or tissue.

CDNA clones for 17β‐hydroxysteroid dehydrogenase (17‐HSD; EC 1.1.1.62) were isolated from a placental λgt11 expression library using polyclonal antibodies against placental 17‐HSD. The largest cDNA contained 1325 nucleotides, consisting of a short 5′‐noncoding segment, a coding segment of 987 nucleotides terminated by a TAA codon, and a 329 nucleotide long 3′‐noncoding segment. The open reading frame encoded a polypeptide of 327 amino acid residues with a predicted M r of 34853. The amino acid sequence of 23 N‐terminal amino acids determined from purified 17‐HSD agreed with the sequence deduced from cDNA. The deduced amino acid sequence also contained two peptides previously characterized from the proposed catalytic area of placental 17‐HSD.

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Dietary estrogens are believed to exert their estrogenic or antiestrogenic (chemopreventive) action in estrogen responsive cells by interacting with the estrogen receptor (ER). The present study was undertaken to evaluate a direct role of ER in estrogenic or antiestrogenic activities of three dietary estrogens (coumestrol, genistein and zearalenone). HeLa cells were transiently co-transfected with an expression vector for ER and an estrogen-responsive reporter gene construct. Coumestrol, genistein, and zearalenone all increased the activity of the reporter gene, only in the presence of the ER, and the activation was blocked with the ER antagonist ICI 164,384, demonstrating an ER-specific, agonist response. In addition, in MCF-7 cells, coumestrol and zearalenone increased the expression of the estrogen-responsive pS2 gene. Coumestrol and genistein inhibited the purified estrogen-specific 17ß-hydroxysteroid oxidoreductase enzyme and the conversion of estrone to 17ß-estradiol in T-47D cells, which contain this enzyme. However, they did not inhibit the estrone-induced proliferation of T-47D cells. In conclusion, coumestrol, genistein, and zearalenone are all potent estrogens in vitro, and they act through ER mediated mechanism. Our findings give no evidence to support the idea that these compounds act as antiestrogens through competition for the binding sites of ER or by inhibition of the conversion of estrone to 17ß-estradiol in breast cancer cells, since this effect was nullified by their agonist action on cell proliferation. Therefore, their suggested chemopreventive action in estrogen-related cancers must be mediated through other mechanisms.ImagesFigure 2. AFigure 2. BFigure 2. CFigure 2. DFigure 2. EFigure 3. AFigure 3. BFigure 4. AFigure 4. BFigure 4. CFigure 4. DFigure 4. EFigure 5.Figure 6.Figure 7.Figure 8.Figure 9. AFigure 9. BFigure 9. C

The biological activity of certain estrogens and androgens is modulated by enzymes called 17p-hydroxysteroid dehydrogenases (I~P-HSDS), which catalyze the interconversion between less active 17-oxosteroid and more active 17P-hydroxysteroid forms. In the present report, we describe cloning of mouse 17P-HSD type-I cDNA from an ovarian library generated from 4,4'-( 1,2-diethyl-I ,2-ethenediyl)bisphenol-(diethylstiIbestro1)-treated mice, and characterization of the corresponding enzyme. The open reading frame of the mouse 17P-HSD type-1 cDNA encodes a peptide of 344 amino acid residues with a predicted molecular mass of 3678.5 Da. The mouse 17P-HSD type-1 enzyme shares 63 % and 93 % overall identity with human and rat 17P-HSD type-I enzymes, respectively, and the most striking differences between the mouse and human type-1 enzymes are between the amino acid residues 197 and 230 and in the carboxy terminus of the enzymes. Similarly to the human 17P-HSD type-I enzyme, the mouse type-I enzyme primarily catalyzes reductive reactions from 17-0x0 forms to 17P-hydroxy forms in intact cultured cells, but unlike the human type-I enzyme, the mouse enzyme does not prefer phenolic over neutral substrates. Thus, mouse 17P-HSD type 1 catalyzes reduction of androst-4-ene-3,17-dione (androstenedione) to 17P-hydroxyandrost-4-en-3-one (testosterone) as efficiently as 3P-hydroxyestra-l,3,.5(10)-trien-17-one (estrone) to estra-1,3,5(10)-triene-3~,17~-diol (estradiol). 17P-HSD type 1 is predominantly expressed in mouse ovaries, in which it is located in granulosa cells.Keywords: 17-hydroxysteroid dehydrogenases ; cloning ; mouse; estrogen ; B1 repetitive sequence.17P-Hydroxysteroid dehydrogenases (17p-HSDs) catalyze the conversion of neutral and phenolic 17-oxosteroids to 17P-hydroxysteroids and vice versa. Both androgens and estrogens are biologically more active in their l7P-hydroxy configurations, such as 17P-hydroxyandrost-4-en-3-one (testosterone) and estra-1,3,S(10)-triene-3~,17~-diol (estradiol), than in their 17-0x0 configuration. Thus, 17P-HSDs, along with other steroidogenic enzymes such as 3P-hydroxysteroid dehydrogenases and Sa-reductases, modulate the biological activity of the sex steroids.