Serum C-19 steroid sulphates in females with clinical hyperandrogenism

Serum sulphates of 5-androstene-3 beta, 17 beta-diol (5-ADIOL-S), 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-DIOL-S) and dehydroepiandrosterone (DHEA-S), as well as unconjugated androstenedione (AD), testosterone (T) and 17 alpha-hydroxyprogesterone (17OHP), sex hormone binding globulin (SHBG) and the free androgen index (FAI) were measured by specific radioimmunoassay in girls with premature adrenarche (n = 9-16), and in hirsute women with (1) late onset 21 hydroxylase deficiency (n = 14), (2) polycystic ovarian disease (n = 28) and (3) idiopathic hirsutism (n = 74). Levels were also determined in females with androgenic alopecia (n = 35-45), in normal prepubertal girls (n = 9-14) and in normal adult women (n = 50-73). Mean serum concentrations of 5-ADIOL-S, 3 alpha-DIOL-S, DHEA-S, AD, T, and FAI were elevated and SHBG depressed, in all patient groups compared with controls, except for DHEA-S and T in patients with alopecia. We conclude that in addition to DHEA-S, 5-ADIOL-S may have a role as a pro-hormone in the synthesis of more potent androgens (T, DHT) in peripheral tissues such as skin; in addition, 3 alpha-DIOL-S may be a marker of peripheral androgen metabolism.     

Cyproterone acetate diminishes sexual activity in male rabbits.

Cyproterone acetate (CA) was injected daily in eleven rabbits for 3 weeks at a dose of 20 mg/day, and for a further week at a dose of 40 mg/day. After 3 weeks of treatment, the ejaculation frequency was reduced but other measures of sexual behaviour were not significantly changed. There was no reduction in the fructose concentration of the semen, but the volume of the ejaculates decreased. The vesicular glands from the experimental animals showed histological changes typical of those occurring after castration. It was concluded that CA reduced the activity of at least one of the accessory sex glands as well as sexual behaviour. This lends support to the current hypothesis that the endocrine regulation of rabbit sexual behaviour differs from that of the rat.     

Teratogenic effects of cyproterone acetate and medroxyprogesterone treatment during the pre- and postimplantation period of mouse embryos. II. Cyproterone acetate and medroxyprogesterone acetate treatment before implantation in vivo and in vitro

The study was performed to investigate direct embryotoxic effects of maternal progestin treatment during the preimplantation period. In the first experiment pregnant mice received a single subcutaneous injection of either cyproterone acetate (CA) or medroxyprogesterone acetate (MPA) on day 2 of pregnancy (5-600 mg/kg). In a second experiment four-cell embryos were exposed to CA or MPA in vitro (3 or 30 micrograms/ml medium). Our results revealed: (1) After maternal treatment the number of live embryos was reduced after the highest CA dose. Development into blastocysts was inhibited in a dose-related manner after CA but not after MPA. The number of cells in morulae, blastocysts, and of the inner cell mass (ICM) of late blastocysts was not affected. (2) When morulae and blastocysts were cultured in vitro after maternal treatment, hatching, attachment, and trophoblast outgrowth were inhibited after high doses, but development and differentiation of the ICM were inhibited even after low doses. (3) Application of 30 micrograms/ml of CA or MPA in vitro was directly embryolethal. Three micrograms/ml did not affect development into blastocysts, but ICM development and differentiation were again inhibited during subsequent culture in hormone-free medium. (4) Qualitative protein synthesis was altered in morulae and blastocysts 24 hours after maternal CA treatment. According to our results high doses of progestins are embryotoxic before implantation, low doses have delayed effects on embryonic development that are particularly evident after implantation in vitro.     

Bromocriptine treatment in anovulation with decreased ratio of follicle stimulating hormone to luteinizing hormone and with hyperandrogenism

Twenty-six anovulatory women of polycystic ovarian (PCO)-type were treated with bromocriptine (Br) at a daily dose of 5 mg for 2 months. Ovulatory cycles were resumed in 18 (69.2%) women (Br-responders). No difference between pretreatment serum levels of FSH, LH, PRL and estradiol and FSH/LH ratios in Br-responders and nonresponders was observed. The geometric mean of circulating androstenedione (A-dione) in Br-responders (2.58 ng/ml) appeared higher than that in nonresponders (2.11 ng/ml) but was not statistically significant. The geometric mean of dehydroepiandtrosterone sulfate (DHEA-S) in Br-responders (1652 ng/ml) was lower (p less than 0.01) than that in nonresponders (2582 ng/ml). The ratio of DHEA-S to A-dione (D/A ratio) exhibited a highly significant between-group difference (p less than 0.001) (646 and 1222 for Br-responders and nonresponders, respectively). Br-nonresponders with high DHEA-S levels and D/A ratios tended to hyperproduction of adrenal androgen, and Br-responders with high A-dione levels and low D/A ratios to hyperproduction of ovarian androgen. The present study indicates that Br is effective in PCO-type women presumably with ovarian androgen hyperproduction. The efficacy of Br, when applied to PCO-type women, could be predicted with their D/A ratios.     

Investigative strategy of hyperandrogenism in women

Investigative procedures in the assessment of female hyperandrogenism are reviewed. Based on their experience, the authors suggest an inexpensive investigative strategy in hyperandrogenic females consisting of the following: the first step depends upon the clinical symptoms--in cases of hirsutism with regular menstrual cycles, plasma testosterone (T) and plasma dehydroepiandrosterone sulfate (DHA-S) are assayed, and the basal body temperature chart is recorded. In cases of hirsutism with irregular or anovulatory menstrual cycles, in addition to T and DHA-S, plasma 17-hydroxyprogesterone and urinary-free cortisol are assayed. In case of anovulation without hirsutism, T and DHA-S are assayed, and the LHRH test is performed. The results of this first investigation allow to attribute to the woman one of the six following hormone profiles: (1) metabolic hyperadrenalism; (2) tumoral hyperandrogenism; (3) 21-hydroxylase defect; (4) nontumoral DHA-S increase; (5) nontumoral ovarian hyperandrogenism; (6) idiopathic hirsutism. The additional investigative procedures required in each of these groups are detailed.     

Strategic approach of hyperandrogenism in women

Based on the results of the laboratory screening of 35 hirsute patients, a strategic approach of hyperandrogenism is proposed. The determination of plasma concentration of total testosterone (T), androstenedione (A) and dehydroepiandrosterone sulfate (DHEAS) appeared to be the basic investigation before to further explore the adrenal (ACTH test) and/or ovarian (gonadotropin measurements) androgen secretion. Together with the clinical findings, plasma T, A and DHEAS levels generally bring evidence of androgen-secreting tumors or polycystic ovaries, or suggest the possibility of adrenal hyperplasia. In the other cases, only the determination of plasma unbound T level is useful for demonstrating the hyperandrogenism. Finally in patients with 'so-called' idiopathic hirsutism, while evidence of excessive androgen production can be obtained by the laboratory screening, the origin of this hyperandrogenism remains uncertain in most cases.     

Management of hyperandrogenism in adolescent girls.

Hyperandrogenism in adolescent girls can be a troubling problem because of the difficulty in establishing a diagnosis and in prescribing appropriate therapy. Androgen excess in adolescent patients encompasses a spectrum of clinical presentations, including acne, hirsutism, oligomenorrhea, amenorrhea, virilism, and ovarian cysts. Androgen excess is a clinical and chemical feature of idiopathic hirsutism, late-onset forms of congenital adrenal hyperplasia, and polycystic ovarian disease; in some cases, functional hyperandrogenism is discussed. We recommend screening for hyperandrogenism by measuring blood levels of testosterone, dehydroepiandrosterone sulfate, and delta 4-androstenedione, while others propose a first dexamethasone suppression test for evaluation of free testosterone, dehydroepiandrosterone sulfate, and cortisol. Treatment will be chosen according to particular symptoms such as acne, hirsutism, obesity, or oligomenorrhea.     

Rhythmic Variations of Pharmacokinetic Processes of Cyproterone Acetate in Rabbits

A study about the influence of administration time on pharmacokinetics of Cyproterone acetate in rabbits was performed. Thirty animals were distributed in six groups, each corresponding to a different time: 2, 6, 10, 14, 18 and 22 hours after light onset (HALO). Rabbits received a single intravenous administration of 4 mg kg^-1 Cyproterone acetate. Blood samples were taken and processed by high performance liquid chromatography. Plasmatic data were fitted to a biexponential equation. Concentration at zero time (Co), concentration at zero time extrapolated from the distribution phase (A), hybrid constant for distribution phase and its half life, volume of the central compartment (V_c), volume of distribution at steady state (V_ss), constants for transferring the drug from the central compartment to the exterior (K₁₀) and from the central to the peripheral compartment presented chronobiological variations (p < 0.05) and were fitted to a cosine equation. The following parameters adjusted to circadian rhythms: Co (Acrophase: 1.72 HALO); A (Acrophase: 4.09 HALO); V_c (Acrophase: 11.92 HALO); V_ss (Acrophase: 10.12 HALO) and K₁₀ (Acrophase: 3.59 HALO). It was concluded that pharmacokinetics of intravenously injected CPA in rabbits would behave in a different, though predictable, manner according to the animal's biological clock.     

Metabolism of adenosine and thymidine in healthy females of different ages and females with mastopathies

The activity of thymidine kinase, thymidine phosphorylase, adenosine deaminase and 5'-nucleotidase of AMP was studied in tissues of 39 healthy females, as well as blood serum and lymphocytes of 60 healthy females, as well as in 50 patients with fibrocavernous mastopathy aged as 23-70. Comparative determination of adenosine metabolism enzymes activity in lymphocytes was carried out simultaneously with studying some immunological indexes in the organism of the same-aged healthy females and ones with mastopathy. It was revealed that age-related changes in the activity of thymidine kinase in blood serum reflected the analogous changes in enzyme activity in tissues of the healthy women. A direct correlation was established between thymidine kinase activity and age both in the healthy females and those with mastopathy. A significant decrease in activity of thymidine phosphorylase was demonstrated in blood serum of the patients with mastopathy in the age 46-60. Determined 4-fold increase in the activity of adenosine deaminase in serum was accompanied by decreased enzyme activity in lymphocytes and decreased Lymphocyte Blast Transformation Index in the same age range. Changes of immunological status are more expressed in T-system of immunity. The revealed metabolic changes in DNA-precursors metabolism in the patients with mastopathy aged as 46-60 might be one of the reasons of increased risk of oncological disease in this age group.     

Synchronization of estrus following 7 or 9 day treatment with chlormadinone acetate (CAP)

Synchronization of estrus and fertility were determined in a series of 8 trials. Various levels of chlormadinone acetate (CAP) were fed for either 7 or 9 days. An injection of 5 mg of estradiol valerate and CAP was given at the start of the feeding period. In some trials estradiol 17β was injected near the end of the feeding period. In trial 1, 98% of the CAP-treated heifers were in estrus in a 5-day period, but only 46% conceived at first service compared to 80% in the non-synchronized heifers (P<.01).In trials 2 through 6, 0.25 mg estradiol 17β injected either 60 or 72 hours after the last CAP feeding reduced the interval to ovulation in heifers that ovulated. However, use of estradiol 17β reduced the number of heifers ovulating in most trials.In trials 7 and 8, estrus was effectively synchronized with either 7- or 9-day feeding of 7.5 or 10 mg of CAP daily followed by .5 mg estradiol 17β, 72 hours after the last CAP feeding. Pregnancy rates at first service varied from 21 to 45% in heifers in the synchronized groups, compared to 58% in the controls in trial 7 (P<.05). In trial 8 pregnancy rates at 1st service varied from 29 to 47% in treated heifers compared to 72% in controls (P<.01).In this series of trials, fertility was reduced from 24 to 43% with the use of CAP and estradiol valerate. Conception rates at first service were not improved by varying the length of feeding (7 or 9 days), level of CAP (7.5 or 10 mg) or by attempting to reduce the variation in ovulation time with estradiol 17β. None of the combinations of these three drugs used increased fertility in these trials.     

Glatiramer acetate treatment of multiple sclerosis: an immunological perspective

Glatiramer acetate (GA) has been used as an immunomodulatory agent for the treatment of relapsing-remitting multiple sclerosis (MS) in the United States since 1996. It is currently one of two first-line agents for use in the treatment of relapsing-remitting MS. GA was the first agent to be used in the treatment of MS that was developed using the animal model of MS called experimental autoimmune encephalomyelitis. In this commentary, we examine the development of GA as a treatment for MS and discuss its mechanism of action as suggested by recent studies using modern immunologic methods.     

XY females with enzyme deficiencies of steroid metabolism

Summary The literature on XY females with enzyme deficiencies (17-hydroxylase, 17-reductase and 17, 20-desmolase) is reviewed. The main features of these individuals are briefly compared with those of XY females with pure gonadal dysgenesis and with testicular feminization.     

Male chimpanzees prefer mating with old females

Cross-cultural studies indicate that women's sexual attractiveness generally peaks before motherhood and declines with age. Cues of female youth are thought to be attractive because humans maintain long-term pair bonds, making reproductive value (i.e. future reproductive potential) particularly important to males. Menopause is believed to exaggerate this preference for youth by limiting women's future fertility. This theory predicts that in species lacking long-term pair bonds and menopause, males should not exhibit a preference for young mates. We tested this prediction by studying male preferences in our closest living relative, the chimpanzee (Pan troglodytes). We show that despite their promiscuous mating system, chimpanzee males, like humans, prefer some females over others. However, in contrast to humans, chimpanzee males prefer older, not younger, females. These data robustly discriminate patterns of male mate choice between humans and chimpanzees. Given that the human lineage evolved from a chimpanzee-like ancestor, they indicate that male preference for youth is a derived human feature, likely adapted from a tendency to form unusually long term mating bonds.     

Formation of 2-cyanomethylenecyclohexyl acetate by incubation of acetate with slices of jojoba cotyledons

E-2-cyanomethylene-4,5-dimethoxy-3-hydroxycyclohexyl acetate was isolated and characterized from the incubation of either developing or germinating joj