Effect of steroid hormones and antihormones on hypothalamic beta-endorphin concentrations in intact and castrated female rats.

The aim of the present study was to evaluate the effects of estrogens and androgens on hypothalamic beta-endorphin (beta-EP) concentrations. Intact or castrated female rats were chronically (2 weeks) treated with estrogen (estradiol benzoate) and/or antiestrogens (clomiphene, cyclophenil or epimestrol), and with androgens (dihydrotestosterone or dehydroepiandrosterone sulphate) and/or antiandrogen (cyproterone acetate). A group of rats treated with vehicle were studied as comparison. The beta-EP concentrations were measured by radioimmunoassay on acidic extracts of rat hypothalami. The administration of clomiphene and cyclophenil significantly reduced hypothalamic beta-EP concentrations in intact rats, while both drugs or estradiol benzoate increased the peptide concentration in castrated rats. Both intact and castrated rats treated with epimestrol showed hypothalamic beta-EP concentrations higher than vehicle treated rats. The estradiol-induced increase of beta-EP was not changed by the concomitant administration of antiestrogens. The administration of dihydrotestosterone significantly decreased beta-EP concentrations in both intact and castrated female rats, while the treatment with dehydroepiandrosterone sulphate only slightly decreased beta-EP levels in intact female rats. The cyproterone acetate-chronically treated rats showed higher beta-EP concentrations than vehicle-treated rats and these changes were reversed by the concomitant addition of dihydrotestosterone or dehydroepiandrosterone sulphate. These results showed that estrogens play a positive role while androgens negatively influence the hypothalamic beta-EP concentrations in female rats, supporting the view that central beta-EP might be a target of gonadal steroid feedback signals.

[Effects of different methods of ovarian stimulation in adult rats]. / Efectos de diferentes métodos de estimulación ovárica en ratas adultas.

The in vitro fecundation programs normally use different ovarian stimulation agents. The purpose of the present study was to compare the effects of some of these agents on indices of ovulation and serum levels of estradiol, progesterone, and FSH. Treatments studied consisted of clomiphene citrate, PMSG alone and in combination with clomiphene citrate, pure human FSH and epimestrol. The data obtained show PMSG alone and PMSG plus clomiphene citrate to be the most effective treatments, in terms of number of oocytes harvested. No differences were noted between serum levels of oestradiol, progesterone and FSH.

Quantitative structure-activity relationships of estrogenic steroids substituted at C14, C15.

The uterotropic activity of thirty 3-methoxyestradiol derivatives is measured and discussed on the basis of X-ray crystallographic results and quantitative structure-activity relationship analyses involving hydrophobic substituent constants pi and f as well as steric parameters Pr and L. In addition, estrogenicity is compared to data of interceptive activity and receptor binding affinity. All the biological data exhibit a high degree of intercorrelation. 17 beta-Hydroxysteroids having 14 alpha configuration reveal a generally better capability of high-affinity binding than those being 14 beta configurated. Between the uterotropic activity and the hydrophobicity of C14, C15 substituents, statistically significant correlations are found which suggest a close contact between the steroidal D-ring subsite and the receptor protein (e.g. for 14 alpha steroids: log UDD = -0.996 pi -0.392; n = 9, r = -0.943, s = 0.235, t = -7.5, alpha less than 0.001). The hydrophobic nature of both 14 alpha and 14 beta medium-sized substituents employed is shown by QSAR regressions to exert a stronger influence than steric effects. Furthermore, there are indications to additional hydrogen bonding and steric repulsion phenomena. As to the receptor-binding models discussed in the literature, it is concluded that the receptor protein has a high conformational flexibility to accommodate very different drug structures all having the common phenolic ring A. But, if an appropriate spacing of steroidal key atoms is recognized by the receptor and, consequently, the steroid-receptor complex is formed, the binding is complemented by hydrophobic interactions also in the D-ring region.

Ultrasound evaluation of the ovarian hyperstimulation syndrome.

282 cycles in 106 women going to be artificially inseminated at the AIED Center in Rome have been studied by means of ultrasound monitoring in order to evaluate the incidence of the ovarian hyperstimulation syndrome. In none of the patients, either in pharmacologically stimulated cycles (82 in 36 women) or in non stimulated cycles (200 in 70 women) moderate or severe hyperstimulation syndrome was reported. Only few mild cases occurred. In the non stimulated group only five cases with mild hyperstimulation occurred (2.5%). 31 pregnancies have been obtained (15.5% of all studied cycles). In the stimulated group 11 cases with signs of mild hyperstimulation occurred (13.4%) and 19 pregnancies were obtained (23.1%) of the stimulated cycles). No twin pregnancy was observed. The only molar pregnancy reported occurred in this group. All signs of hyperstimulation--either in stimulated cycles or in non stimulated patients--regressed spontaneously in the same cycle and anyhow they were not detected by ultrasound monitoring in the subsequent cycle.

A comparative study of clomiphene and epimestrol on plasma progesterone, CBG, TBG and SHBG, and salivary progesterone levels.

The plasma levels of CBG, TBG, SHBG and progesterone, and salivary progesterone levels were measured in eight young ovulatory volunteers. After the control cycle four subjects received 50 mg/day of Clomiphene from days 5 to 9 of the first treatment cycle, and 10 mg/day of Epimestrol from days 5 to 15 of the second treatment cycle. The other four subjects received the treatments in reverse order. Between the two treatments there was one cycle without medication as a "wash-out" period. Plasma and saliva samples were obtained on days +6, +8 and +10 (day of LH peak was denoted by 0), always between 08.00 and 09.00 h. Statistical evaluation was done by means of an analysis of variance (ANOVA), and correlation coefficients were also calculated. Evaluation of data on effects of Clomiphene and Epimestrol on the plasma levels of CBG and salivary progesterone showed that Clomiphene induced a highly significant rise (p less than 0.001) in the CBG levels and decrease (p less than 0.001) in salivary progesterone levels, while no changes were seen following administration of Epimestrol. Both Clomiphene and Epimestrol treatments led towards higher plasma progesterone levels, those following Clomiphene administration being higher. Neither treatment induced significant changes in TBG or SHBG levels. It is concluded that Clomiphene induces significant elevations of CBG and decrease in salivary progesterone, which is thought to reflect the free progesterone fraction and may have significance in relation to a discrepancy between the ovulation and pregnancy rates following Clomiphene therapy.

Epimestrol in treatment of inadequate luteal progesterone secretion.

Seventeen infertile normoprolactinemic women with luteal phase defects were treated with epimestrol. In ten patients, normalization of the impaired luteal phase was achieved. Under epimestrol treatment, periovulatory estradiol concentrations (1077.3 +/- 121.5 pmoles/liter versus 612.7 +/- 64.2 pmoles/liter; mean +/- SEM; P < 0.01) and cervical scores (10.8 +/- 0.3 versus 7.9 +/- 0.38; mean +/- SEM; P < 0.01) were improved, and luteal progesterone (60.0 +/- 9.1 nmoles/liter versus 19.98 +/- 3.14 nmoles/liter; mean +/- SEM; P < 0.001) and estradiol secretioon (813.1 +/- 101.1 pmoles/liter versus 581.9 +/- 73.7 pmoles/liter; mean +/- SEM; P < 0.05) were significantly increased in those women with normalization of the luteal phase as compared with the seven patients in whom epimesterol was without effect. Prolactin levels were elevated in all patients after epimestrol therapy (P < 0.05). Basal LH levels and LH-RH stimulated levels improved following administration of epimestrol (P < 0.01) in the 10 women with normal luteal phases. FSH levels were not significantly affected. Two patients became pregnant. No side effects were noted.

[Epimestrol in the treatment of normoprolactinemic corpus-lutem deficiency (author's transl)]. / Epimestrol in der Behandlung der normoprolaktinämischen Corpus-luteum-Insuffizienz.

The treatment of normoprolactinemic corpus-luteum deficiency with epimestrol is reported. This is a frequent cause of infertility. The clinical and hormonal parameters for the diagnosis and follow-up evaluation of the treatment are described. In the present series 10 of 17 patients with primary infertility and normoprolactinemic corpus-luteum deficiency showed a normalization of the luteal phase. Two pregnancies occured following one cycle of treatment with epimestrol at 5 mg. daily from day 3 to day 12 of the cycle. Epimestrol shows no anti-estrogenic properties in contra-distinction to other ovulation stimulating drugs. The quality of the cervical secretion is therefore not impaired by epimestrol. Side effects or ovarian cysts were not observed.

[Action of epimestrol on pituitary thymidine kinase and gonadotropins in the rat. Comparison with clomiphene and cyclofenil (author's transl)]. / Action de l'épimestrol sur la thymidine kinase hypophysaire et sur les gonadotrophines du rat. Comparaison avec le clomifène et le cyclofénil.

The authors have evaluated the influence of epimestrol on several parameters: pituitary thymidine kinase in immature male rats, FSH and LH contents of pituitary and plasma in immature male and mature female rats, oestrous cycle of female rats. The results are compared with those obtained with clomiphene and cyclofenil. Epimestrol, as well as clomiphene, although at a lesser degree modifies gonadotropins levels; in contrast to clomiphene, in the pituitary thymidine kinase test epimestrol shows an oestrogenic potency but not an anti-oestrogenic one. More over it induces a vaginal cells cornification. These data suggest that epimestrol could be efficient in inducing pregnancy.

Placebo-controlled study of effects of epimestrol on the pituitary-testicular axis in normal men.

Twenty healthy male volunteers were randomly allocated to the treatment with either 15 mg/day of epimestrol or placebo for 10 days. The plasma levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), oestradiol (E2) and prolactin (PRL) were measured before, during and 4 days after the medication by radioimmunoassays. Data were statistically evaluated by means of an analysis of covariance. Circulating LH and FSH, and also T and E2 significantly increased in the epimestrol treated subjects. In the placebo treated subjects no significant changes in the plasma hormone levels were observed. There were no significant changes in the plasma levels of PRL in either group.

Effect of epimestrol on gonadotropin and prolactin plasma levels and response to luteinizing hormone-releasing hormone/thyrotropin-releasing hormone in secondary amenorrhea and oligomenorrhea.

The effects of epimestrol (5 mg every 6 hours for 5 days) on basal levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (Prl), estradiol, progesterone, and dehydroepiandrosterone sulfate, and on the response to LH-releasing hormone (LH-RH) and thyrotropin-releasing hormone (TRH) stimulation, were studied in 18 cases of secondary amenorrhea and oligomenorrhea of hypothalamic-pituitary origin, in three cases of anorexia nervosa, in two cases of long-lasting progestin-induced amenorrhea, and in one case of precocious menopause. The results in the first 18 patients indicate that epimestrol treatment induces a significant increase in LH and Prl levels after 24 hours, while the FSH increase becomes significant only after 4 days of therapy. Twelve hours after discontinuation of treatment, all three hormone levels decreased significantly to values similar to the basal levels, while the pituitary response to LH-RH indicated a much more marked LH secretion than before treatment. A second test, performed 36 hours after the last drug administration, again showed a significantly higher LH response than that found under basal conditions. No significant variations were observed in the FSH response to LH-RH, nor in the Prl response to TRH. These data suggest that epimestrol interferes at the level of the centers responsible for Prl and gonadotropin secretion in the manner of a weak estrogen.

[The importance of hormone examinations in ovulation induction (author's transl)]. / Bedeutung der Hormonuntersuchungen in der Ovulationauslösung.

Those hormone-determination methods were reported by the authors which help to make the ovary response visible for the experts during the ovulation induction. They also dealt with the determination of basal temperature measuring, oestrogen, pregnandiol, progesterone, oestradiol-17beta, FSH, LH, epimestrol and clomiphen. After the routine determination of the above mentioned parameter a preprinted sheet was done, where every treated case was illustrated graphically. From these cases some of the typical ones were shown and analyzed. The determination of hormonal releasing curves characteristic of hyperstimulation, and the importance of these most dangerous complication was emphasized.