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.

Plasma 3 beta-hydroxy-delta 5-steroids in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

There is little information about the plasma concentrations of 3 beta-hydroxy-delta 5-steroids (delta 5-steroids) in untreated patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. To further study the delta 5 pathway, we measured plasma levels of delta 5- and delta 4-steroids in 21 adult patients with different degrees of 21-hydroxylase deficiency (11 salt-wasters, 5 simple virilizers, and 5 patients with the nonclassical form of the disease). In all patients, investigations were performed after withdrawal of steroid treatment for at least 10 days. In addition, catheterization of gonadal and adrenal veins was performed in two salt-wasting male patients displaying bilateral testicular tumors to study adrenal secretion of delta 5- and delta 4-steroids. In one of them, surgical resection of the intratesticular adrenal rests gave the opportunity to measure 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activity. In all untreated patients, an increase in plasma delta 4-steroids was observed. In contrast, although plasma levels of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were not significantly modified in simple virilizers, a paradoxical decrease in all delta 5-steroids was observed in salt-wasters. Catheterization of the adrenal veins confirmed the decrease in delta 5-steroids, particularly DHEA and DHEAS. The androstenedione/DHEA ratio was increased in all patients proportionally to the severity of the disease, suggesting an increase in adrenal 3 beta HSD. In vitro analysis of 3 beta HSD activity showed a 4-fold increase in intratesticular adrenal tissue compared to that in normal adrenals. A positive correlation between the androstenedione/DHEA ratio and plasma ACTH levels was observed, suggesting a long term stimulatory effect of ACTH on 3 beta HSD. Angiotensin-II could have an additive effect on ACTH-induced 3 beta HSD activity.

[Treatment of acromegaly with a new slow release somatostatin analog, lanreotide]. / Traitement de l'acromégalie par un nouvel analogue de la somatostatine, le lanréotide à action prolongée.

Treatment of Acromegaly has been improved by the development of the somatostatin analogs characterized by an increased specificity and longer duration of action. One of these analogs-Lanreotide- (Somatuline) is supplied under a slow release formulation and does not require several daily injections like other analogs presently available. The clinical pharmacodynamic studies that have been conducted in healthy and acromegalic patients show that the i.m. injection of a single dose of this slow-release formulation leads to a significant decrease of the plasma GH and IGF-1 levels. This effect lasts at least 14 days. The Lanreotide slow-release formulation has been used to treat 123 acromegalic patients who presented with a still evolutive disease after conventional therapy. The product was given at a 30 mg-dose every 10 or 14 days during a 3-to 24-month period. This treatment led to a reduction of the symptoms and to a decrease of GH hypersecretion. GH and IGF-1 levels have been normalized respectively in 46% and 32% of the patients. The observed results allow to conclude to an immediate efficacy of the treatment (without escape sign). The adverse drug events are minor and transitory. The antitumor effects are modest and inconstant. The slow release formulation seems to provide the patients with a better quality of life, as compared to the several daily injections.

Failure of combined follicle-stimulating hormone-testosterone administration to initiate and/or maintain spermatogenesis in men with hypogonadotropic hypogonadism.

In men with hypogonadotropic hypogonadism, prolonged treatment with LH and FSH induces spermatogenesis. To compare the respective role of exogenous testosterone and intratesticular testosterone on the induction and maintenance of spermatogenesis, 10 men with hypogonadotropic hypogonadism and without history of cryptorchidism were studied. They were treated with human gonadotropins (hMG; 150 IU FSH and LH and 1500 IU hCG, im, three times weekly) or pure FSH (150 IU, im, three times a week) and testosterone (T: 250 mg, im, once a week). Five men were treated first with hMG-hCG and then with pure FSH plus T. The other five men started with pure FSH plus T. Each treatment period lasted 24 months. In all men, hMG-hCG induced spermatogenesis after 24 months, with normal motility and quality. The combination of pure FSH and T was not able to induce spermatogenesis after 24 months. In addition, sperm count dropped dramatically to 0.3 +/- 0.1 x 10(6)/mL within 3 months and to 0 after 6 months when pure FSH and T followed [corrected] hMG-hCG. Plasma T levels were increased by both treatments, but significantly more after pure FSH and T (35.3 +/- 5.2 nmol/L) than after hMG-hCG (20.4 +/- 5.2 nmol/L; P < 0.05). Plasma estradiol levels after treatment with pure FSH and T were also increased, but the difference from those obtained during hMG-hCG treatment was not significant. In conclusion, in men with complete gonadotropin deficiency, FSH and exogenous T are not able to induce spermatogenesis. Furthermore, spermatogenesis induced by LH plus FSH (hMG-hCG) cannot be maintained when exogenous T replaced LH in the regimen. Thus, exogenous T is unable to replace LH (and intratesticular T) to induce spermatogenesis. These data are noteworthy in the prospect of male contraception after a complete blockade of gonadotropin activity.

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). DESIGN AND SUBJECTS: Ten women, aged 28-35 years, using an intrauterine device for contraception, were selected for this study. All women had idiopathic hirsutism with or without acne and seborrhoea. Flutamide was administered orally in a dose of 250 mg twice daily for 1 year. Basal body temperature was recorded and pelvic ultrasonography performed before and every 3 months during treatment. LH pulse frequency and amplitude (Cluster analysis) and basal and GnRH-stimulated plasma LH and FSH levels were determined on day 5 of the cycle prior to flutamide treatment, and after 6 and 12 months of therapy. Plasma total testosterone (T), non-SHBG bound T, androstenedione (A), dehydroepiandrosterone sulphate (DHEAS), androstanediol glucuronide (3 alpha-diol G) and sex hormone binding globulin (SHBG) levels were measured before and every 3 months during therapy, on day 5 of the cycle. Plasma oestradiol and progesterone levels were determined on day 22 of the studied cycles. RESULTS: Disappearance of acne and seborrhoea occurred after 2 months with a marked improvement of hirsutism at 6 months. At 12 months, hirsutism had disappeared with a Ferriman and Gallwey score < 7. No adverse side-effects, apart from transient diarrhoea in two patients, were reported with this flutamide dose. None of the patients had any disturbance of menstrual cycles which remained ovulatory. The pure anti-androgen flutamide induced no significant change in LH pulsatile profile, nor in LH and FSH responsiveness to GnRH. Plasma concentrations of steroids were not altered. Plasma SHBG and 3 alpha-diol G levels did not change during flutamide treatment. CONCLUSION: Flutamide, which interacts only with the androgen receptor, is effective for hirsutism, acne and seborrhoea, and does not disturb menstrual cyclicity or ovulation. It may represent a treatment of choice for essential hirsutism in women using safe contraceptive methods.

Xp22.3 deletions in isolated familial Kallmann's syndrome.

Several familial cases of Kallmann's syndrome (KS) have been reported, among which the X-chromosome-linked mode of inheritance is the most frequent. The gene responsible for the X-linked KS has been localized to the terminal part of the X-chromosome short arm (Xp22.3 region), immediately proximal to the steroid sulfatase gene responsible for X-linked ichthyosis. Large deletions of this region have been previously shown in patients affected with both X-linked ichthyosis and KS. We report here the search for Xp22.3 deletions in 20 unrelated males affected with isolated X-linked KS. Only 2 deletions were found using Southern blot analysis, indicating that large deletions are uncommon in patients affected with KS alone. Both deletions were shown to include the entire KAL gene responsible for X-linked KS. The patients carrying these deletions exhibit additional clinical anomalies, which are discussed: unilateral renal aplasia, unilateral absence of vas deferens, mirror movements, and sensory neural hearing loss.

Evaluation of acromegaly by measurement of 24-hourly urinary growth hormone excretion.

Twenty-four hourly urinary growth hormone excretion (24-h uGH) has been quantified using a combination of ultrafiltration and conventional immunoradiometric assay. Twenty-four hourly uGH was measured in 20 normal adults and in 42 patients with acromegaly (9 untreated, 28 treated but with above-normal IGF-I levels, and 5 treated and cured). The means and ranges were as follows: 3.7 (1-9) ng/24 h for normals and 160 (40-540), 66 (2-380) and 5.2 (4-8) ng/24 h for the three groups of acromegalic patients, respectively. Ten patients with pituitary adenomas without acromegaly had 24-h uGH within the normal range. Twenty-four hourly uGH therefore gives a clear differentiation between controls and untreated patients. Log-transformed values for subjects with acromegaly showed significant correlations between 24-h uGH and levels of IGF-I (r = 0.63, p < 0.01), fasting plasma GH (r = 0.92, p < 0.001) and plasma GH after glucose loading (r = 0.85, p < 0.001). Twenty-four hourly uGH was also determined in three acromegalic patients before and during SMS 201-995 therapy. Twenty-four hourly uGH reflected the corresponding changes in mean levels for hourly sampling over 12 h of plasma GH and IGF-I and in clinical signs after 3-6 months of therapy. The results of this study indicate that 24-h uGH is an accurate indicator of GH secretion in acromegalic patients and could therefore be used both in diagnosis and in monitoring the progress of therapy in these patients.