The variations in oestrogen levels which occur in men with septic shock were determined and analysed in terms of the changes seen in the levels of other steroid hormones of testicular and adrenal origin. The concentrations of the hormones, oestrone (E1), oestradiol (E2), testosterone (T), delta 4-androstenedione (delta 4), cortisol (F) and progesterone (P4) were determined by radioimmunoassay. The serum levels of cholesterol, triglycerides, phospholipids and non-esterified fatty acids (NEFAs) were also determined. Two groups of male septic shock patients were studied within the first 24 h following the admission to the Intensive Care Unit. Group I (n = 24) patients died. Group II (n = 22) patients recovered. Both groups were compared to a control group (n = 44) of healthy men. In group I patients, serum E1 levels were 3900 +/- 900 pmol/l, 12-fold higher than controls (296 +/- 22 pmol/l) [P less than 0.001], serum E2 levels were 880 +/- 170 pmol/l, 6-fold above control levels (158 +/- 30 pmol/l) [P less than 0.001] and serum T levels were 1.7 +/- 0.3 nmol/l, 11-fold lower than in controls (18.7 +/- 1.9 nmol/l) [P less than 0.001]. Serum P4 and F levels were slightly increased (P less than 0.05) and delta 4 androstenedione levels were unchanged. Groups II serum estrogen levels (814 +/- 350 pmol/l) [P less than 0.01] were higher than controls and serum T levels were 2-3 times less than control levels (5.5 +/- 2 nmol/l) [P less than 0.01]. The group II serum P4, F and delta 4 androstenedione levels did not differ from control levels. The levels of cholesterol, triglycerides, phospholipids and NEFAs were all decreased to similar, significant, degrees in both groups of shock patients. The dramatic increase in E1 levels associated with the decrease in T suggests an adrenal-testicular relationship with possible potentiation of aromatization of adrenal or testicular androgens in men in septic shock. The determination of serum E1 and T during septic shock in men could form the basis for prognostic estimations of septic shock severity and for a new therapeutic approach to shock.

OBJECTIVE

To document the relative importance of endogenous sex steroids in modulating the frequency of orgasms, the dominant aspect of sexual behaviour in healthy eugonadal men.

METHODS

Measurement of adrenal and testicular sex steroids in a sample of army recruits and study of their relation to frequency of orgasms ascertained by questionnaire after potential confounding variables were controlled for.

METHODS

Military campus and military hospital laboratories in Athens, Greece.

METHODS

92 consecutively enrolled healthy male recruits aged 18-22 years.

METHODS

Weekly number of orgasms. Serum concentrations of testosterone, dehydroepiandrosterone sulphate, dihydrotestosterone, oestradiol, oestrone, delta-4-androstenedione, and sex hormone binding globulin.

RESULTS

Serum dihydrotestosterone concentration was the only independent hormonal predictor of the frequency of orgasms; an increase in concentration of 1.36 nmol/l (about 2 SD) corresponded to an average increase of one orgasm a week.

CONCLUSIONS

Differences in concentrations of circulating dihydrotestosterone within the normal range may represent a major predictor of sexual activity in healthy young men.

Radioimmunoassays for five oestrogen metabolites in urine are described; they are oestrone 3-glucuronide, oestradiol 3-glucuronide, oestradiol 17 beta-glucuronide, oestriol 3-glucuronide and oestriol 16 alpha-glucuronide. These assays have proved accurate and reliable and can be performed rapidly; they have been carried out directly in diluted menstrual cycle urine and pregnancy urine. No sample pretreatment was required. Preliminary results suggest that clinically useful information can be obtained by performing these assays on random urine specimens.

OBJECTIVE

The impact of the menopause on androgen production is poorly understood. We have investigated the impact of the menopause, as well as other factors such as age, body mass index (BMI) and cigarette smoking, on ovarian and adrenal androgen levels in women aged 40-60 years.

METHODS

Cross-sectional study of blood hormones sampled weekly over one month in volunteer 40-60-year-old women.

METHODS

One hundred and forty-one women, aged between 40 and 60, recruited from community sources (non-clinical), not using hormone replacement or steroidal contraceptives, and with a current sexual partner. Fifty were categorized as premenopausal (ovulating), 37 as perimenopausal and 54 as post-menopausal.

METHODS

The following variables were assessed; menopausal status (based on menstrual history and pattern and plasma progesterone), age, BMI, smoking, oestradiol (E2), oestrone (E1), LH, FSH, total testosterone (TT), androstenedione (A), SHBG, free androgen index (FAI), dihydroepiandrosterone (DHEA), dihydroepiandrosterone sulphate (DHEAS) and cortisol.

RESULTS

are based on multiple regression analysis. TT was positively related to A, BMI and LH. A was negatively related to age and FSH, and positively to DHEA, DHEAS and premenopausal status. SHBG was negatively related to BMI and positively to E1 and non-smoking. DHEA and DHEAS were negatively related to age and were higher in smokers. Both E1 and E2 were related to menopausal status and to FSH. Surprisingly, E2 was negatively related to BMI.

CONCLUSIONS

A variety of factors influence androgen production in this age group. Whereas it is difficult to predict the effect of menopause on androgen levels, LH stimulation of post-menopausal interstitial cells, modulated by a variety of factors including nutrition, and smoking, are likely to be relevant.

Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase-3 (17 beta-HSD-3) deficiency and 5 alpha-reductase-2 (5 alpha-RD-2) deficiency provides natural human genetic models to elucidate androgen actions. To date, five 17 beta-HSD isozymes have been cloned that catalyse the oxidoreduction of androstenedione and testosterone and dihydrotestosterone (DHT), oestrone and oestradiol. Mutations in the isozyme 17 beta-HSD-3 gene are responsible for male pseudohermaphroditism due to 17 beta-HSD deficiency. The type 3 isozyme preferentially catalyses the reduction of androstenedione to testosterone and is primarily expressed in the testes. Fourteen mutations in the 17 beta-HSD-3 gene have been identified from different ethnic groups. Affected males with the 17 beta-HSD-3 gene defect have normal wolffian structures but ambiguous external genitalia at birth. Many are raised as girls but virilize at the time of puberty and adopt a male gender role. Some develop gynaecomastia at puberty, which appears to be related to the testosterone/oestradiol ratio. Two 5 alpha-reductase (5 alpha-RD) isozymes, types 1 and 2, have been identified, which convert testosterone to the more potent androgen DHT. Mutations in the 5 alpha-RD-2 gene cause male pseudohermaphroditism, and 31 mutations in the 5 alpha-RD-2 gene have been reported from various ethnic groups. Such individuals also have normal wolffian structure but ambiguous external genitalia at birth and are raised as girls. Virilization occurs at puberty, often with a gender role change. The prostate remains infantile and facial hair is decreased. Balding has not been reported.

This study evaluated the effects of bisphenol A (BPA) on human endometrial stromal fibroblast (ESF) differentiation and expression of genes involved in oestrogen metabolism. Human ESF from eight hysterectomy specimens were cultured and treated with 5-100 μmol/l of BPA ± oestradiol or 8-br-cAMP for 48 h. mRNA expression was analysed by real-time reverse-transcription PCR. 8-br-cAMP-induced human ESF decidualization was confirmed by expression of insulin-like growth factor binding protein-1 (IGFBP1) and prolactin secretion. Short-term exposure (48 h) decreased human ESF proliferation (P<0.04) not due to apoptosis. High doses of BPA significantly induced IGFBP1 mRNA and protein, decreased P450scc mRNA, reversed the 8-br-cAMP-induced increase in HSD17B2 (oestradiol to oestrone conversion) in a dose-dependent manner and down-regulated HSD17B1 expression (oestrone to oestradiol conversion; P ≤ 0.03). 8-br-cAMP significantly potentiated this effect (P=0.028). BPA had no significant effect on aromatase and PPAR γ expression. The oestrogen-receptor antagonist ICI had no effect on gene expression in BPA-treated cells, and oestrogen receptor α, but not oestrogen receptor β, was significantly down-regulated by high doses of BPA (P=0.028). BPA has an endocrine-disrupting effect on human ESF function and gene expression but the underlying mechanisms appear not to involve oestrogen-mediated pathways.

1. The properties of enzyme activities hydrolysing the sulphate esters of dehydroepiandrosterone, oestrone and p-nitrophenol are reported. The preparation studied was obtained from the microsomal fraction of human placenta by ultrasonic treatment and addition of Triton X-100. 2. The behaviour of the preparation during sedimentation at 105000g and attempts at purification indicated that the activities were particulate. Electron microscopy demonstrated the rupture of vesicular structures approx. 0.5mu in diameter concurrent with the release of activity. 3. The three activities were always associated throughout repeated attempts at separation by sucrose-density-gradient centrifugation and Sephadex-gel filtration. On the basis of kinetic studies, stability studies and treatment with butanol and ribonuclease it was concluded that a separate enzyme is responsible for each of the three activities. Widely varying plots of activity as a function of pH were consistent with this conclusion. 4. On the basis of sensitivity of the enzymes hydrolysing dehydroepiandrosterone sulphate and oestrone sulphate to ribonuclease and sensitivity of all three enzymes to lipase, it was concluded that the three enzymes are bound to a particle containing lipid and RNA. Enzymic activity is dependent on structural integrity of the particle. 5. A spectrophotometric method for the assay of oestrone sulphate hydrolysis is described. 6. Hydrolysis of nitrocatechol sulphate by human placenta under conditions described for arylsulphatases A and B is reported.

To quantify the role of endogenous oestrogen activity in osteoporosis we measured relative metacarpal cortical area (RCA), body mass, serum oestrone, oestradiol, androstenedione, and sex hormone binding globulin (SHBG) in 746 postmenopausal women aged 53 to 76 years, sampled from the general population. The occurrence of fractures and the rate of loss of RCA (delta-RCA) were determined over the previous 9 years. Both RCA and delta-RCA were significantly related to body mass, serum oestrone, oestradiol, and SHBG. The influence of the first three variables appeared to be bone preserving, whereas the latter appeared to be bone wasting. Serum oestradiol, SHBG and body mass proved to have an independent relationship with RCA in multivariate regression analysis. The relationship to delta-RCA was statistically independent for serum SHBG only. Serum androstenedione was unrelated to either RCA or delta-RCA. In the total study population, body mass, serum oestrone, oestradiol and SHBG were not related to the occurrence of fractures over the previous 9 years. In the subgroup of 249 elderly women, aged 65-76 years, SHBG levels were significantly higher for women with type I osteoporotic fractures (vertebral and forearm fractures) as compared to controls. The results suggest a bone wasting influence of SHBG in postmenopausal women, possibly resulting in an increased risk of type I osteoporotic fractures in elderly women.

OBJECTIVE

Oestrogens, androgens and anti-endocrine drugs such as tamoxifen and aminoglutethimide influence plasma insulin-like growth factor-I (IGF-I). IGF-I, in turn, has been found to stimulate the peripheral aromatase in vitro. The aim of this study was to examine relations between sex hormones, IGF-I and insulin-like growth factor binding protein-1 (IGFBP-1) in post-menopausal women with breast cancer.

METHODS

To measure plasma sex steroids, sex hormone binding globulin (SHBG), IGF-I, IGFBP-1, insulin and urinary oestrogen metabolites in post-menopausal women with breast cancer not receiving any endocrine therapy.

METHODS

Thirty-two patients had fasting blood samples obtained between 0800 and 1000 h. A sub-group of 10 patients had 24-hour urine oestrogen metabolites determined.

METHODS

Plasma steroids and proteins were measured by radioimmunoassays. Urinary oestrogens were measured by GC-MS.

RESULTS

SHBG correlated negatively with plasma androstenedione (P < 0.001), insulin (P < 0.001), IGF-I, height and plasma oestrone sulphate (P < 0.025 for all), but positively with plasma IGFBP-1 (P < 0.025). IGFBP-1 correlated negatively with IGF-I (P < 0.001) and the testosterone/SHBG ratio (P < 0.05). Neither IGF-I nor IGFBP-1 correlated with any of the plasma or urinary sex hormones or with the oestrone/androstenedione and oestradiol/testosterone ratios. Multivariate analysis revealed plasma SHBG to correlate positively with IGFBP-1 (P = 0.029) and negatively with insulin (P = 0.031). Plasma IGFBP-1 correlated negatively with IGF-I (P < 0.0001) but not with insulin.

CONCLUSIONS

Our results do not suggest any influence of plasma sex steroids in physiological concentrations on IGF-I or IGFBP-1 in post-menopausal breast cancer patients, nor do they indicate IGF-I at physiological concentrations influences the ratios between plasma oestrogens and their androgen precursors.

A formal memory test was administered to 18 female patients with signs or symptoms of oestrogen deficiency taking part in a double-blind study of piperazine oestrone sulphate. A significant improvement in memory was seen in the treated group compared with the placebo group. The findings are discussed.

This phase II, multicentre, open-label, clinical trial evaluated antitumoral efficacy, tolerability and endocrine effects following 25 mg of treatment with oral exemestane given daily to postmenopausal women with metastatic breast cancer. Eligibility criteria included oestrogen and/or progesterone positivity or a prior response to hormonal therapy if receptor status was unknown; prior failure to tamoxifen therapy; and progressive disease. Patients were divided into three strata: patients who did not respond to tamoxifen or progressed after disease stabilisation (SD) for less than 6 months (stratum 1); patients who, after an initial response or SD lasting at least 6 months, experienced disease progression whilst on tamoxifen (stratum 2); patients with recurrent metastatic disease during or within 12 months of discontinuing adjuvant tamoxifen (stratum 3). Of the 137 patients who received exemestane, 4 experienced a complete response (CR) and 28 a partial response (PR), for an overall response rate of 23%. Another 33 patients had SD for>> or = 24 weeks, resulting in an overall success rate of 47%. The median time to objective response was 16.1 weeks (95% confidence interval (CI) 9.9-24.1). The median response duration was 69.4 weeks, the median duration of overall success 59.1 weeks, the median time to progression (TTP) 25.1 weeks and the median time to treatment failure (TTF) 24 weeks. Response to previous hormonal therapy had little effect on the results, except that there was a trend toward a higher overall success rate in patients who did not respond to previous hormonal therapy. After 8 weeks of therapy, serum levels of oestradiol (E2), oestrone (E1) and oestrone sulphate (E1S) were suppressed to 15.2%, 9.7% and 10.7% of baseline, respectively. The most common adverse events of drug-related or indeterminate cause were hot flushes (14%), dizziness (9%), nausea (8%) and increased sweating (5%). Exemestane had a favourable effect on performance status and tumour-related signs and symptoms, both of which improved or stabilised in approximately 67% and 68% of patients respectively. Exemestane is a unique therapy that is highly active and well tolerated as a new treatment for women with metastatic breast cancer.

4-Hydroxyandrostenedione (4-OHA) is a specific inhibitor of aromatase activity used for the treatment of breast cancer in post-menopausal women. Treatment with 4-OHA has been shown to inhibit the peripheral conversion of androstenedione to oestrone and reduce plasma oestrogen concentrations, but the effect of treatment on breast-tissue oestrone concentrations is not known. We have therefore examined the effect of treatment with 4-OHA on oestrone concentrations in normal and malignant breast tissues and also measured plasma and tissue 4-OHA concentrations. Changes in tumour oestrone concentrations were related to DNA polymerase alpha activity, a marker of cellular proliferation. Blood and breast-tissue samples were obtained before and 36 hr after treatment with 4-OHA. The mean plasma concentration of 4-OHA was 27.9 +/- 19.3 ng/ml, compared with levels of 33.7 +/- 25.6 ng/g for breast tumour and 13.5 +/- 11.5 ng/g for normal breast tissue. There was a significant correlation between 4-OHA concentrations in plasma and normal breast tissue (r = 0.91, p less than 0.001). Treatment with 4-OHA resulted in a significant (p less than 0.02) decrease in breast-tissue oestrone concentrations. For 3/4 tumour samples, a marked decrease in the concentration of oestrone (78 +/- 4%) was associated with a similar decrease (64 +/- 16%) in DNA polymerase alpha activity. It is concluded that treatment with 4-OHA effectively reduces breast-tissue exposure to oestrogen.

Aminoglutethimide without glucocorticoid has been shown to be a clinically effective treatment for postmenopausal breast cancer in low dosage (250 mg day-1). The mechanism of action of this approach is thought to be the inhibition of peripheral aromatase, the enzyme which converts androstenedione to oestrone. The activity of this enzyme was measured in vivo by injection with 3H-androstenedione and 14C-oestrone and found to be 0.20% +/- 0.05 in 5 patients on low dose AG therapy. In comparison with previously published data this demonstrates a 92% inhibition of peripheral aromatase activity confirming aromatase inhibition as a viable aim in the endocrine treatment of breast cancer.

The endocrine effects of low dose (62.5 mg, twice a day) aminoglutethimide (AG), without hydrocortisone (HC), escalating at monthly intervals to a conventional dose of AG (500 mg twice a day) combined with HC, were studied in 33 postmenopausal breast cancer patients. Pretreatment serum concentrations of oestrone (E1) and oestradiol (E2) were significantly suppressed by 62.5 mg of AG twice a day. Although further suppression of E1 appeared to occur with 125 mg of AG twice a day, this was not statistically significant. For E1 and E2, higher doses of AG or combined AG and HC failed to cause further significant suppression compared with that obtained at 125 mg of AG twice a day. Significant rises in serum androstenedione were found with all doses of AG alone, although pretreatment concentrations of androstenedione were not significantly altered by combined AG and HC treatment. Mean pretreatment concentrations of dehydroepiandrosterone sulphate (DHA-S) were significantly suppressed by 62.5 mg of AG twice a day and further marked suppression occurred on combined AG and HC therapy. Serum cortisol, aldosterone and plasma ACTH concentrations showed no significant alterations throughout treatment. Aminoglutethimide is as effective at 125 mg twice a day without HC in its suppression of oestrogen levels as at 500 mg twice a day with HC, and its use in this form warrants clinical evaluation.

Steroid sulphatase (STS) catalyzes the conversion of oestrone sulphate (E1S) to oestrone (E1) and its action in breast tumours makes a major contribution to in situ oestrogen production in this tissue. Although expression of STS mRNA and STS activity are increased in malignant breast tissues compared with that in non-malignant tissues, little is known about the regulation of its expression or activity. In the present study we have used a RT-PCR technique to investigate the regulation of STS mRNA expression in cultured breast tissue fibroblasts and MCF-7 cells. STS mRNA expression was readily detectable in fibroblasts derived from breast tissue proximal to tumours, breast tumour tissue and reduction mammoplasty tissue. For two pre-menopausal subjects, STS mRNA expression was similar in proximal and tumour fibroblasts whereas for a third, post-menopausal subject, expression in breast tumour fibroblasts was 2.4-fold that in proximal fibroblasts. The cytokine tumour necrosis factor alpha (TNFalpha) or the STS inhibitor, 2-methoxyoestrone-3-O-sulphamate, had no effect on STS mRNA expression in fibroblasts. STS mRNA was detectable in MCF-7 cells but neither TNFalpha nor interleukin 6 (IL-6) affected its expression. Transient transfection of COS-1 and MCF-7 cells with a STS cDNA lacking STS 5' and 3' sequences increased activity 17-fold and 2-fold, respectively. TNFalpha plus IL-6 increased STS activity in mock transfected MCF-7 cells and further increased STS activity in transfected MCF-7 cells. This indicates that activation can occur independently of STS promoter and enhancer elements. In conjunction with the lack of regulation of STS mRNA it suggest that TNFalpha and IL-6 may increase STS activity via a post-translational modification of the enzyme or by increasing substrate availability.

Porcine endometrial oestradiol-17 beta dehydrogenase was solubilized from the particulate fraction of homogenates sedimenting between 1200 g and 10,000 g by treatment with 0.4% Brij 35 in neutral buffers. The extracts were processed by successive passage through DEAE-Sepharose, Amberlyte XAD-2 and Blue-Sepharose, and the enzyme was collected from the washed affinity matrix at 0.8 M of a 0-2 M-KCl gradient. A genuine oestrone reductase was eluted at 1.9 M-KCl. The dehydrogenase pool was resolved by butyl-Sepharose chromatography into a major (80%) peak (EDHM) eluted at 0.8 M-(NH4)2SO4 and a very hydrophobic fraction (VHF) recovered at 0.1 M. EDHM was further purified by filtration through Sephadex G-200 and cation-exchange chromatography on Mono S. Sephacryl 300 was used for VHF followed by Mono S. Enrichments from the homogenate amounted to 1074-fold for EDHM and 632-fold for VHF. A single silver-stained band at 32 kDa is seen on SDS/PAGE of EDHM, and VHF contains additional bands at 45 and 80 kDa. Polyclonal antibodies (G436) raised against EDHM and the monoclonal antibody F1 raised against VHF recognize the single 32 kDa band in EDHM and both the 32 kDa and 80 kDa bands in composite VHF. The 45 kDa band of VHF reacts with neither. Monoclonal antibody W1 raised against EDHM only recognizes the 32 kDa peptide of EDHM and VHF. The specific activity for oestradiol oxidation amounts to 4081 mu-units/mg for EDHM and to 2402 mu-units/mg for VHF. Both possess a minimal (1/260) endogenous reductase activity and are devoid of 3 beta, 3 alpha- and 20 alpha-dehydrogenases. We consider EDHM to be authentic oestradiol-17 beta dehydrogenase of porcine endometrium. The composite VHF could reflect the situation of the enzyme in vivo or result from aggregations occurring during processing.

Cigarette smoking is associated with a reduction in the risk for endometrial cancer in post-menopausal women and it has been suggested that this is because smoking has an anti-oestrogenic effect. To investigate this, concentrations of oestrone, oestradiol and oestriol were measured in 24 h urine samples from 167 premenopausal women (53 smokers, 114 non-smokers) and 200 post-menopausal women (54 smokers, 146 non-smokers). Among premenopausal women there were no significant differences in oestrogen excretion between smokers and non-smokers. Among post-menopausal women, geometric mean excretion rates for oestrone and oestradiol did not differ significantly between groups, but oestriol excretion was 19% lower (95% confidence interval -34% to -1%) in smokers than in non-smokers. This may partly explain the reduced risk for endometrial cancer among post-menopausal smokers.

We compared the effect of administering oestradiol via the transdermal or oral routes in six and eight postmenopausal women respectively. Although both treatments achieved similar plasma levels of oestradiol, oral administration led to much greater increases in plasma levels of oestrone and the sulphates and glucuronides of oestradiol, oestrone and oestriol than transdermal treatment (P less than 0.001). Both treatments reduced plasma FSH; from 42 +/- 10 (SE) IU/l to 30 +/- 2 IU/l with oral and from 46 +/- 7 IU/l to 28 +/- 6 IU/l with transdermal treatment. Urine calcium excretion fell from 0.41 +/- 0.06 (molar ratio to creatinine) to 0.17 +/- 0.02 with oral and from 0.25 +/- 0.06 to 0.13 +/- 0.02 with transdermal treatment. Patients' symptoms were improved by both treatments. These changes were related to the plasma oestradiol concentration but not to that of oestrone. Oral, but not transdermal, treatment stimulated hepatic protein synthesis as shown by increased plasma levels of both vitamin-D-binding globulin and sex-hormone-binding globulin. We conclude that although both oral and transdermal oestradiol reduce postmenopausal bone loss, gonadotrophin secretion and symptoms, oral treatment also leads to hepatic stimulation and extensive metabolism of oestradiol, both of which may increase side-effects without conferring additional benefit.

Spectrophotometric and equilibrium-dialysis measurements show that ligandin (glutathione S-transferase B, EC 2.5.1.18) binds monomeric porphyrins at a single site with association constants in the range 10(4)-10(6) litre/mol at pH 7.0. Binding affinities are paralleled by the tendencies of the porphyrins to aggregate, increasing in the order: uroporphyrins I and III less than coproporphyrins I and III approximately haematoporphyrin less than protoporphyrin IX. From this it is deduced that the hydrophobic effect is the predominant driving-force for binding. The porphyrins can be displaced from their binding site on ligandin by bromosulphophthalein and oestrone sulphate. In enzyme inhibition studies, 50% inhibition was brought about by 8 micron-haematoporphyrin and by 1 micron-protoporphyrin IX. In the analysis of the haemotoporphyrin-ligandin system the self-association of haematoporphyrin was studied in detail. It was found to be limited to dimerization in the concentration range 0-200 micron at pH 7.0, 25 degrees C and a dimerization constant of 1.9 x 10(5) litre/mol was determined. Coproporphrin III has a dimerization constant of 5.2 x 10(5) litre/mol under the same conditions.

1. Hydroxylation activities toward steroid hormones were determined for eleven forms of human hepatic cytochrome P450s expressed in yeast Saccharomyces cerevisiae cells. Microsomes were prepared from the yeast cells and assayed for their regioselectivity of hydroxylation toward progesterone, pregnenolone, dehydroepiandrosterone (DHEA) and oestrone. 2. 6 beta-Hydroxylation of progesterone was catalysed most efficiently by CYP3A4, followed by CYP2D6. CYP3A4 showed the highest progesterone 16 alpha-hydroxylation activity, followed by CYP1A1 and CYP2D6. 16 alpha-Hydroxylation of pregnenolone was catalysed efficiently by CYP1A1 and CYP3A4. Only CYP3A4 exhibited 16 alpha-hydroxylase activities toward DHEA and oestrone. 3. Addition of nifedipine, a typical substrate of CYP3A4, inhibited the 6 beta- and 16 alpha-hydroxylation of progesterone by CYP3A4. 4. These results suggest that CYP3A4 and CYP1A1 are responsible for the hydroxylation of these endogenous steroids, as well as xenobiotics, in human liver.

Oestrogens induce the development of female reproductive tissues. Endogenous human oestrogens include oestradiol, oestrone and oestriol. Oestrogen signalling in target tissues is dependent on the tissue concentration of oestrogen and the interaction of oestrogen receptors with an array of cell-specific co-regulator proteins. The diverse mechanisms of oestrogen signalling are complex and incompletely understood. In puberty, oestrogen is derived from both gonadal and peripheral sources. Originally, oestrogen was only thought to drive feminization in females; now, oestrogen is known to be important for pubertal development of males as well. Oestrogen is required for normal maturation of the neuroendocrine-gonadal axis and bone in both sexes, and a variety of other tissues are also responsive to oestrogen. Abnormal puberty can be associated with either excessive or inadequate oestrogen production. Girls deficient in oestrogen should receive replacement in physiological doses. Aromatase inhibitors and anti-oestrogens may prove to be useful therapeutic tools in some types of abnormal puberty.