Gilbert Schaison

Termination of early pregnancy by the progesterone antagonist RU 486 (Mifepristone).

We studied the effects of the progesterone antagonist RU 486 in 100 women with early, unwanted pregnancy (within 10 days of the expected onset of the missed menstrual period). Thirty-four women received oral doses of 400 mg (in four days), 26 received 600 mg (in four days), and 40 received 800 mg (in two days). Uterine bleeding occurred in all patients within four days of the first dose and continued for 5 to 17 days. In 85 of the women, a dramatic decrease in the plasma chorionic gonadotropin level was observed on day 6, and an empty uterus was confirmed by ultrasonography on day 13. Hence, these women were considered to have had a complete abortion. Fifteen subjects had persistently elevated plasma chorionic gonadotropin levels on day 6 and were considered not to have responded to RU 486. They all had uterine evacuation, which was facilitated by a softening of the cervix. The percentage of women with complete abortion was similar in all dosage groups. Furthermore, plasma levels of immunoreactive RU 486 were similar in subjects with and without complete abortion. The only important side effect observed in the responders was prolonged uterine bleeding in 18 percent, but neither blood transfusion nor curettage was required. We conclude that RU 486 is an effective and safe method for termination of very early pregnancy but that it should be used only under close medical supervision.

Functional hypothalamic amenorrhoea: a partial and reversible gonadotrophin deficiency of nutritional origin.

Functional hypothalamic amenorrhoea (FHA) is a consequence of low dietary intake as observed in two major pathophysiological conditions, anorexia nervosa and/or intensive physical exercise. The aim of the present study was to assess in women with FHA and normal body mass index (BMI) and apparently normal daily activities, the degree of impairment of GnRH secretion, its nutritional origin and its reversibility.

The impact of a pure anti-androgen (flutamide) on LH, FSH, androgens and clinical status in idiopathic hirsutism

OBJECTIVES We assessed in women the effects of androgen suppression on gonadotrophin secretion and the therapeutic efficacy of the pure anti‐androgen flutamide (2‐methyl‐N‐[4‐nitro‐3‐(trifluoromethyl)phenyl]‐propanamide).

Vascular reactivity in acromegalic patients: preliminary evidence for regional endothelial dysfunction and increased sympathetic vasoconstriction

Hypertension is found in one‐third of acromegalic patients. An heterogenous distribution of cardiac output has been recently demonstrated in acromegalic patients with an increased blood flow at the level of the upper limb, suggesting that acromegalic patients may have some degree of endothelial dysfunction. Elsewhere, studies involving hypopituitary GH‐deficient adults have shown that GH and/or IGF‐I may have direct effect on endothelial function.

Improvement of hypocalcemic cardiomyopathy by correction of serum calcium level.

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Efficacy and Tolerability of the Long-Acting Somatostatin Analog Lanreotide in Acromegaly. A 12-Month Multicenter Study of 58 Acromegalic Patients

Objective: To determine the effects of the new somatostatin analogue, lanreotide, in its prolonged released form (PR), in patients with acromegaly.Design: Prospective open multicenter non comparative study.Setting: Thirty-three university-affiliated medical centers.Patients: One hundred sixteen acromegalic patients with active disease, of whom 58 patients complied with the protocol and completed the 12-month period treatment.Intervention: Lanreotide PR treatment was started at a dose of 30 mg intramuscularly every 14 days. If integrated mean plasma GH levels were not below 5 μg/L and/or IGF-I levels were not normalized after one month of treatment, injections were given every 10 days. The duration of the study was 12 months.Results: After one month of treatment mean plasma GH and IGF-I levels had fallen from 10.7 ± 11.1 μg/L (mean ± SD; range, 2.6 – 74.8 μg/L; median, 7 μg/L) and 718 ± 270 μg/L (range 338 – 1440 μg/L; median, 645 μg/L), respectively, to 7.8 ± 10.1 μg/L and 575 ± 252 μg/L, respectively. Thirty patients (22%) had plasma GH levels below 2.5 μg/L, and 8 patients (16%) had age-adjusted normal plasma IGF-I levels. At the sixth month of treatment mean plasma GH levels of 2.5 μg/L or less, and normal plasma IGF-I levels were observed in 33%, and 33% of patients, respectively. At the twelvth month of treatment, these percentages were 41%, and 41%, respectively. The interval between two injections was shortened (one injection every 10 days) in 8 of the 58 patients (13%) at the second month of treatment, and at the end of the study, 70% of patients required 3 injections per month. The most frequent adverse event elicited by enquiry was transient diarrhea (76% of patients), followed by abdominal pain (62%) and pain at the injection site (59%). Based on the analysis of a subgroup of 46 patients who had at least a measurement of fecal fat content after day 0 of the study, a non significant increase (from 4.2 ± 3.4 to 5.1 ± 4.3 g/24h, p = 0.3) in mean steatorrhea was observed during treatment. Before treatment, steatorrhea was present in 9 (19%) patients. During the study, 15 additional patients (32%) developed persistent steatorrhea, and there was a transient increase in fecal fat content above 6 g/24 h in another 11 patients. After exclusion of the 7 patients (12%) with gallstones at enrolment, new gallstones were diagnosed in 6 out of 50 patients (12%) during the study.Conclusion: Two or three monthly injections of lanreotide PR decreased GH concentration to less than 2.5 μg/L and normalized IGF-I levels in 41% of patients treated during 12 months. The good tolerability of this treatment, and the reduction in the frequency of injections, plus the sustained drug serum concentrations, confirm the usefulness of this new somatostatin analog formulation.

Percutaneous dihydrotestosterone treatment

Various forms of androgen replacement therapy are readily available for the treatment of hypogonadism in men (Cantril et al. 1984). The commonly used long-acting, injected, testosterone esters produce wide variations of serum androgen concentrations with high levels soon after the injection and subnormal levels after 15 days (Snyder et al. 1980). In addition, an elevation in the estradioltestosterone ratio can cause gynecomastia in some men. Oral therapy requires the administration of multiple daily doses of testosterone. Some of the preparations which are 17α-alkylated androgens such as fluoxymesterone and methyltestosterone produce severe hepatotoxicity and should not be used on a long-term basis. Testosterone undecanoate produces only short-lived testosterone peaks and thus requires repeated doses. Testosterone incorporated into microspheres may be slowly and steadily released from the intramuscular site over extended periods of time. Finally, a transdermal testosterone delivery system, when applied at the appropriate dose and on the appropriate part of the body, has been shown to be an effective and new modality for the treatment of male hypogonadism. Daily application of a patch, containing 10 mg of testosterone, applied to the scrotal skin brings the serum testosterone levels in the normal range, increases the DHT levels into the supranormal range while the estradiol levels remain low (Bals-Pratsch et al. 1986 and 1988; Ahmed et al. 1988).

Hypogonadotropic hypogonadism as a model of post-natal testicular anti-Müllerian hormone secretion in humans

The pituitary gonadotropins are the main regulators of testicular hormonal secretion in humans. Hypogonadotropic hypogonadism (HH), characterized by the absence of secretion of endogenous gonadotropins is therefore a convenient model to asses the respective effects of luteinizing hormone (LH) (or human chorionic gonadotropin (hCG)), exogenous testosterone (T) and FSH on gonadal function. In order to investigate the hormonal control of AMH secretion in man, serum AMH levels were measured in adult patients with congenital HH (CHH) and with post-pubertal acquired HH (AHH) either untreated, during hCG or T therapy. In untreated CHH patients, serum AMH levels were significantly higher than in normal men and similar to those previously reported in prepubertal boys indicating the absence of pubertal maturation of Sertoli cells. In men with AHH, serum AMH levels were also significantly increased when compared to healthy men, but less than in CHH because a persistent testicular T secretion in these patients with less complete gonadotropin deficiency. The high AMH levels in AHH suggest that the post-pubertal suppression of AMH is a reversible phenomenon. In HH patients, hCG treatment induced an increase of plasma T associated with a dramatic decrease of serum AMH, whereas the similar increase in plasma T levels obtained with exogenous T induced only a partial decrease of serum AMH. This dissociation was related to the higher intratesticular T induced by hCG. Taken together, our results confirms the clinical relevance of previous data obtained in rodent models concerning the hormonal regulation of AMH secretion.

Primary adrenal and thyroid insufficiencies associated with hypopituitarism: a diagnostic challenge.

Polyglandular syndromes have been described for many years but only one case of panhypopituitarism with adrenal and thyroid insufficiencies has been documented. We present a 69‐year‐old woman with the initial diagnosis of idiopathic primary hypopituitarism. An associated primary adrenal disease was suspected on low plasma aldosterone and increased plasma renin values during unjustified withdrawal of treatment. The complete absence of cortisol response to long‐term ACTH administration confirmed the diagnosis. In addition, primary hypothyroidism was demonstrated by the absence of radioiodine uptake by the thyroid gland and the inability to increase T4 secretion after repeated TSH injections. The pattern of hypopituitarism and the coexistence of both adrenal and thyroid deficiencies provide strong evidence for the diagnosis of autoimmune polyglandular syndrome with hypophysitis.

RU 486 in Women with Normal or Anovulatory Cyles

The antiprogesterone steroid RU 486 was given orally to 32 normally cycling women for four days, starting on the fourth day after the basal body temperature shift. Uterine bleeding occurred on the third day of RU 486 administration in all 14 women treated with 100 mg per day, in seven out of the eight women treated with 50 mg, and in eight out of ten women receiving 25 mg per day. Luteal regression was observed in eight women treated with 100 mg per day, in three treated with 50 mg, and in two receiving 25 mg per day. Plasma LH was measured every 15 minutes from 0800 h to 1200 h for five days in 17 patients. Mean levels decreased, and its computerized pulsatile release disappeared in seven of the eight subjects treated with 100 mg, in two out of four receiving 50 mg, and in one out of five treated with 25 mg. RU 486 had no effect when given to five patients with anovulatory cycles for four days, starting on day 18 of their cycle.