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Background For many women finding the right contraceptive method can be challenging and consistent and correct use over a lifetime is difficult. Even remembering to take a birth control pill every day can be a challenge. The primary objective of this study was to evaluate women's experience with a weekly ethinylestradiol/norelgestromin contraceptive patch (EE/NGMN patch), given new technologies recently developed in hormonal contraception to increase women's options in avoiding daily dosing. Methods In 24 Italian sites, 207 women received the EE/NGMN patch for up to 6 cycles. At study end, overall satisfaction and preference, as well as compliance, efficacy and safety, were evaluated. Results 175 women (84.5%) completed the study. The overall satisfaction rate was 88%; convenience and once-a-week frequency of the patch were especially appreciated. At baseline, 82 women (39.4%) were using a contraceptive method, mainly oral contraceptives and barrier methods, but only 45.1% were very satisfied/satisfied; after 6 months with the patch, 86.3% of this subset was very satisfied/satisfied. Considering the method used in the 3 months before the study entry, 78.1% strongly preferred/preferred the patch, for convenience (53.9%), ease of use/simplicity (28.9%), fewer (9.2%) and less severe (2.6%) side effects. Compliance was very high: 1034/1110 cycles (93.2%) were completed with perfect compliance and the mean subject's compliance score was 90%. One on-therapy pregnancy occurred. The patch was safe and well tolerated: adverse events frequency was low, with predominantly single reports of each event. Most of them started and subsided during cycle 1. Conclusion This study demonstrated that the EE/NGMN patch is associated with high satisfaction levels and excellent compliance. At study end, the majority of women indicated that they would continue using the patch.

Diffusion of [14C] megestrol acetate from polydimethylsiloxane (PDS) implants was studied in ten human volunteers during a period of one year. In vitro diffusion rates for each capsule were measured in 100 ml of distilled water changed every 24 hours, until constant diffusion was reached. After insertion of 3 capsules in the subcutaneous tissue of the left arm, approximately 60 to 70 per cent of the total radioactivity excreted daily was present in the urine. Throughout the experiment, diffusion was calculated on the basis of total urinary radioactive metabolites excreted daily. At the beginning of the experiment, the faecal plus urinary radioactivity recovered approached the values obtained under in vitro conditions. However, on subsequent days, a rapid decrease in the diffusion of megestrol acetate from the implants was noticed. Two months after insertion of the capsules, the daily diffusion was decreased to approximately 50 per cent of the initial values. After the third month, the excretion of urinary metabolites, and therefore the diffusion from the implants, becomes more uniform and stable; from the fourth month onwards the release can be considered as practically constant up to one year. Nine out of ten volunteers behaved in the same way; the tenth subject showed the same excretion pattern but the absolute excretion values were significantly (P < 0.01) lower than the average. It is concluded that the in vitro incubation is a reliable way of calculating the in vivo diffusion from PDS capsules inserted in the human, although, for all practical purposes, effective levels attained in the body will be only half of this value. With this important limitation diffusion in the human of megestrol acetate embedded in PDS, can be considered to be constant.

One female and one male foetus were perfused at midpregnancy with 17β-oestradiol-16-14C,17α-3H and metabolites were isolated in a radiochemically homogeneous form from the perfusates and various foetal tissues. The 3H/14C ratio of the perfused material was 60.2. Unconjugated and conjugated 17β-oestradiol and oestrone were isolated from all tissues studied. The 3H/14C ratio of the oestradiol isolated from all tissues, except the liver, agreed with the perfused one. The oestrone isolated from different sources did not contain any 3H-label. Unconjugated oestriol and conjugated oestriol, 16-epi-oestriol, 16α-hydroxy-oestrone, 16-oxo-oestradiol and 15α-hydroxy-oestradiol were isolated from the extracts of the livers. No 3H-label was present in 16α-hydroxy-oestrone, and only traces, if any, in 16-oxo-oestradiol. On the other hand, the isotopic ratios of 16-epi-oestriol, oestriol and 15α-hydroxy-oestradiol were between 1.5 and 5.0. It is concluded that a small but significant part of the oestriol, 16-epi-oestriol and 15α-hydroxy-oestradiol synthesized by the foetal liver is formed via a direct hydroxylation of oestradiol.

Three midgestation placentas were perfused at laparotomy during fifteen minutes with tracer amounts of [1,2-3H] testosterone [35S] sulphate sodium salt, and metabolites present in the placentas, perfusates and maternal urine specimens were analyzed. Most of the radioactive material administered was present in the placentas and perfusates; approximately 2% of it was recovered from the urine. More than 99.5% of the radioactive material recovered from the placentas and the perfusates was in a water soluble (conjugated) form. No unconjugated testosterone was found in these sources. Radiochemically homogeneous [1,2-3H] testosterone [35S] sulphate was isolated from the placentas, perfusates and urine specimens collected during the first 24 hours of experiment. The isotopic ratio of the conjugate isolated from these sources was very similar to that of the perfused material. Seventy per cent of the double labelled radioactive material recovered from the Day 1 urine samples was radiochemically homogeneous testosterone sulphate. The relative amounts of testosterone sulphate present in the Day 2 and Day 3 urine specimens showed a gradual decrease. This decrease was associated with an increase in tritium to sulphur-35 ratio. From the pooled extracts of all urine specimens, small amounts of exclusively tritium labelled conjugated 5α-androsterone and 5β-androsterone were also isolated. No 17β-oestradiol 17-sulphate was detected in any of the sources studied. It is concluded that little, if any, testosterone sulphate is hydrolyzed by the midgestation human placenta, and that a considerable part of the testosterone sulphate secreted by the foetus is transferred across the placenta to the mother in an unchanged form. The major part of the transferred testosterone sulphate is excreted in the urine; a smaller part of it undergoes hydrolysis with a subsequent metabolism of the steroid moiety.

Four female and four male previable human foetuses (18th to 21st week of gestation) were perfused with a combination of 3H-labelled testosterone (T) and 14C-labelled androst-4-ene-3,17-dione (A) and the principal unconjugated products of dehydrogenation and reduction as well as testosterone sulphate were studied in the perfusates and various foetal tissues. 14C-labelled T derived from the metabolism of perfused A, and 3H-labelled A, originating from the perfused T, were isolated from all sources studied; as much as 2.1% of the administered A was isolated in the form of T-14C and 3.6% of the administered T was isolated as A-3H. No statistically significant sex difference was found in the interconversion of T and A; however, the extent of interconversion in one female foetus differed highly significantly (P < 0.001) from that taking place in all other foetuses. The isotopic ratios of the re-isolated A and T indicated that the interconversion was complete in the liver, partial in the gastrointestinal tract and rather limited in all other tissues. No reduction products were detected in the adrenals. From the other tissues the following unconjugated 5β-reduction products were isolated: 5β-androstane-3,17-dione from the gastrointestinal tract, liver and perfusates, 3α-hydroxy-5β-androstan-17-one (gastrointestinal tract, liver, carcass and perfusates), 5β-androstane-3α,17β-diol (liver), 17β-hydroxy-5β-androstan-3-one (liver). The following unconjugated 5α-reduction products were isolated: 5α-androstane-3,17-dione (gastrointestinal tract, liver, lungs, carcass and perfusates), 3α-hydroxy-5α-androstan-17-one (gastrointestinal tract, liver, lungs, carcass and perfusates), 3β-hydroxy-5α-androstan-17-one (lungs, carcass and perfusates), and 17β-hydroxy-5α-androstan-3-one (lungs, carcass and perfusates). The 5β-forms were predominant in the liver, their quantity exceeding that of 5α-forms by at least a factor of 100, the 5α-forms dominated the pattern in all other tissues. A sex difference in the reductive metabolism of A and T could not be ascertained. Testosterone sulphate was a major metabolite in the gastrointestinal tract and adrenals, but was not detected in the liver. On the basis of the isotopic ratios of the isolated compounds a concept is presented describing the principal pathways of the reductive metabolism of A and T in various tissues of human foetuses at midpregnancy.

Previable foetuses were perfused with 3H-labelled testosterone (T) plus 14C-labelled androstenedione (A), or with 3H-labelled dehydroepiandrosterone plus 14C-labelled A. In addition, in two experiments half of the liver and one adrenal of foetuses perfused with 3H-labelled A were incubated with 14C-labelled A. From the various tissues several products of aromatisation and hydroxylation were isolated in a radiochemically homogeneous form. Oestrogens were present only in the extracts of livers and in the perfusates. From the livers oestrone, 17β-oestradiol, 15α-hydroxy-oestradiol and oestriol were isolated. Following reduction with KBH4 of the fraction containing 16epi-oestriol together with ring D hydroxy-ketones, 15α-hydroxy-oestradiol, oestriol and 16epi-oestriol were isolated. These oestrogens, which were present exclusively as conjugated material, were only formed from A and T, but not from dehydroepiandrosterone. Conjugated oestrone, but no 17β-oestradiol was isolated from the perfusates. No oestrogens were detected in the extracts of the adrenals, not even following the perfusion and subsequent incubation with large amounts of A. Oestrogens were also absent from the combined extracts of all other foetal tissues. Unconjugated 11β-hydroxy-androstenedione was isolated from the adrenals as the principal metabolite of A both in the perfusion and incubation studies. It was also isolated from the perfusates. Conjugated 11β-hydroxy-testosterone was isolated from the adrenals as a major metabolite of T. No unconjugated 1 1β-hydroxy-testosterone was detected in any of the perfusion or incubation experiments. Little, if any adrenosterone was present in the adrenals. However, this compound was isolated from the extracts of the lungs and residual tissues. No qualitative sex difference was found in the formation of any of the compounds isolated. The formation of 15- and 16-oxygenated oestrogens by the liver was contrasted by the absence of 15α-hydroxy-androstenedione, 15α-hydroxy-testosterone, 16α-hydroxy-androstenedione, or 16α-hydroxy-testosterone from any of the tissues. Lack of 16α-hydroxylation of A was also demonstrated following the incubation of A with homogenates of adrenals and livers. It is concluded that: aromatisation in the foetal organism takes place only in the liver and exclusively from α,β-unsaturated 3-ketosteroids, part of the conjugated oestrogen formed by the foetal liver is released into the foeto-placental circulation, mainly, if not entirely, in a ketonic form, 15α- and 16α-hydroxylation of A and T is preceded by aromatisation and takes place only in the liver, part of the A secreted by the placenta to the foetus is returned to the placenta in the form of 11β-hydroxy-androstenedione.

In order to study the temporal relations in the biogenesis of testosterone, decapsulated testes of adult mice were incubated with carbon-14-labelled sodium acetate and attempts were made to isolate the most likely intermediates. Considerable quantities of radiochemically homogeneous squalene, lanosterol, cholesterol, testosterone and androstenedione, but no pregnenolone, progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, pregnenolone sulphate or dehydroepiandrosterone sulphate were isolated. The same pattern of incorporation was found when gradually increasing amounts of non-labelled pregnenolone, progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, dehydroepiandrosterone sulphate or testosterone were added to the system as "trapping agents" or when Leydig cell preparations rather than decapsulated testes were used. The presence of 10 mIU of HCG greatly enhanced the de novo formation of testosterone, androstenedione and 5α-dihydrotestosterone but did not change the pattern of acetate incorporation. Radioimmunoassays of the incubation medium with or without added HCG, and carried out at different periods of time indicated the presence of gradually increasing amounts of testosterone and androstenedione together with some 5α-dihydrotestosterone, whereas only trace amounts of pregnenolone, progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone and dehydroepiandrosterone were present. An analysis of the incubated testes revealed that the addition of HCG significantly enhanced the content of testosterone, androstenedione and 5α-dihydrotestosterone. Little or no increase was observed as far as pregnenolone, progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone or dehydroepiandrosterone were concerned. It is concluded that decapsulated testes of mice synthesize de novo testosterone from sodium acetate under conditions in which the formation of pregnenolone, progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, pregnenolone sulphate and 17-hydroxypregnenolone sulphate cannot be demonstrated.

A newborn anencephalic monster was injected with carbon-14 labelled dehydroepiandrosterone and tritium labelled androstenedione and metabolites recovered from various tissues and blood specimens were analysed. Dehydroepiandrosterone was readily converted to dehydroepiandrosterone sulphate in all tissues studied. Furthermore, unconjugated as well as conjugated 5-androstene-3β,17β-diol and conjugated 16α-hydroxy-dehydroepiandrosterone were isolated from the liver. Very little, if any, of the injected dehydroepiandrosterone was converted to Δ4-3-ketosteroids, ring A reduction products or oestrogens. On the other hand, androstenedione was rapidly metabolized to testosterone, a variety of unconjugated and conjugated reduction products and conjugated oestrogens. From the different tissues, the following unconjugated compounds were isolated in a radiochemically homogenous form: testosterone (liver, blood, kidneys, gastrointestinal tract, lungs, thymus), 5β-androstanedione (liver), 5β-androsterone (liver, blood, kidneys, gastrointestinal tract, lungs, thymus), epi-5β-androsterone (liver), 5β-androstane-3α,17β-diol and 5α-androstanedione (blood, combined extract of all organs), 5α-androsterone (liver, blood, kidneys, gastrointestinal tract, lungs, thymus), 5α-dihydrotestosterone (combined foetal organs except the liver) and epi-5α-androsterone (blood and combined foetal organs except the liver). From the solvolysed conjugated fraction, the following steroids were isolated: 5β-androstane-3α,17β-diol (liver), 5β-androsterone (liver, blood, kidneys, gastrointestinal tract, lungs, thymus), epi-5β-androsterone (liver), 5α-androsterone (liver, blood, kidneys, gastrointestinal tract, lungs, thymus), testosterone (liver, blood, kidneys, gastrointestinal tract, lungs, thymus). The 5β-forms were predominant in the liver, whereas the 5α-forms dominated the pattern in all other tissues studied, including the blood. The data indicate that the androgen metabolism of the anencephalic monster studied, did not differ qualitatively from that of midterm foetuses.

Background: Every year 30% of individuals above age 65 fall, and falls are the principal cause of bone fractures. To reduce fracture incidence requires both prevention of falls and maintenance of bone strength. Methods: PubMed searches were performed, for studies of the epidemiology of fractures, bone physiology, endocrine effects, osteoporosis measurement, genetics, prevention and effectiveness. Topic summaries were presented to the Workshop Group and omissions or disagreements were resolved by discussion. Results: Ageing reduces bone strength in post-menopausal women because estrogen deficiency causes accelerated bone resorption. Bone mineral density (BMD) decreased more than 2.5 standard deviation below the mean of healthy young adults defines osteoporosis, a condition associated with an increased risk of fractures. Risk factors such as age and previous fracture are combined with BMD for a more accurate prediction of fracture risk. The most widely used assessment tool is FRAX™ which combines clinical risk factors and femoral neck BMD. General preventive measures include physical exercise to reduce the risk of falling and vitamin D to facilitate calcium absorption. Pharmacological interventions consist mainly in the administration of inhibitors of bone resorption. Randomized controlled trials show treatment improves BMD, and may reduce the relative fracture risk by about 50% for vertebral, 20-25% for non-vertebral and up to 40% for hip fractures although the absolute risk reductions are much lower. Conclusions: Although diagnosis of osteoporosis is an important step, the threshold for treatment to prevent fractures depends on additional clinical risk factors. None of the presently available treatment options provide complete fracture prevention.