Biomedical subjects
Publications and source records attributed to F Kuttenn.
From 1993 to 1995, 82 donors have permitted the retrieval of 810 oocytes allowing to obtain 411 embryos. 95 receiving couples have been included : 30 obtained a pregnancy, 7 abandoned and 38 are waiting for a transfer. The rate of pregnancies by transfer is superior to the one observed with the transfer of frozen embryos (40.5% versus 27%).
Polycystic ovary syndrome (PCOS) is an association of oligomenorrhoea, anovulation, hyperandrogenism, obesity and enlarged polycystic ovaries. It provides a model of loss of cyclic ovarian function. It is classical to distinguish between type I and type II PCOS. In type I, the primary mechanism seems to be hypothalamic dysfunction, which causes an increase in the frequency and amplitude of LH pulses, with diminished FSH release. LH hypersecretion stimulates ovarian stroma hyperplasia while FSH insufficiency results in the failure of folliculare maturation and hence anovulation. Aromatization of androgens to oestrogens is responsible for permanent oestrogen overproduction, which favours LH hypersecretion. Type II PCOS is more frequent and may have multiple causes (local, endocrine, systemic, iatrogenic) that interfere with the gonadotropic axis and alter the FSH/LH ratio. The most efficient treatment of hirsutism is cyproterone acetate which alone has both antiandrogenic and antigonadotropic properties. Clomifene citrate remains the "first choice" treatment of infertility associated with anovulation.
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The frequency of 12 different mutations of the steroid 21-hydroxylase gene (CYP21) was investigated in 129 French patients affected by congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency. Eighty-nine percent of the CAH chromosomes were characterized. The most frequent mutations were a C-G substitution in intron 2, the deletion of the CYP21 gene and a T-A substitution in exon 4 in the severe form of the disease, and a G-T substitution in exon 7 in the nonclassic form. The correlation between the genotypes and the clinical forms of the disease showed marked variation in the phenotype from a single genotype, suggesting that individual variation and undetected additional mutations on the same CAH chromosome accounted for the phenotype. In 65 informative meioses of CAH families, no de novo mutation was found.
The proto-oncogene c-myc is involved in the stimulation of cell proliferation, and its expression is known to be stimulated by estradiol (E2) in human breast cancer cell lines and various non-cancerous E2-dependent tissues. However, little information is currently available concerning its expression and regulation in normal human breast tissue. We therefore studied c-myc expression and hormone modulation in normal human breast epithelial (HBE) cells in culture, routinely obtained in our laboratory and which remain hormone-dependent. On these normal HBE cells, E2 induced a biphasic increase in c-myc mRNA level, with a first peak as early as 30 min, and a secondary increase after 2 h of treatment; this stimulation was dose-dependent, with an optimal concentration of 10 nM E2. Its primary action is probably at the transcriptional level since the half-life of c-myc mRNA measured in the presence of actinomycin D (12 +/- 3 min) was not modified by E2 treatment. In addition, E2 stimulation of c-myc mRNA does not require protein synthesis since it was not suppressed by cycloheximide treatment. Western blot studies of c-myc protein in HBE cells revealed the same biphasic pattern of stimulation, with a first peak after 60 min and a second one after 2 h of E2 treatment. In conclusion, the c-myc proto-oncogene is expressed in normal HBE cells, as in breast cancer cells. Moreover, E2 stimulates c-myc expression which, therefore, may partly mediate the growth-promoting effect of E2.
The aim of this study was to find out whether the dysfunction of aldosterone pathway, previously proposed as a marker of secretory adrenal carcinoma, is also found in nonsecretory adrenal carcinomas, which pose even more difficult diagnostic problems even for patients with hypertension accompanied or not by hypokalemia. The exploration consisted of using the same method (RIA preceded by a chromatographic step) to determine the plasma levels of the following steroids in the mineral corticosteroid pathway: deoxycorticosterone (DOC), 18-hydroxydeoxycorticosterone (18-OHDOC), corticosterone (B), 18 hydroxycorticosterone (18 OH B), and aldosterone. The subjects included 16 adults, each presenting with an endocrinologically asymptomatic adrenal mass associated for some patients with hypokalemia and hypertension (8 with adrenal carcinoma, 2 with adrenal metastasis from other forms of cancer, and 6 adenomas). These results show that even in nonsecretory adrenal carcinoma, there is a dysfunction of the aldosterone pathway, which can be evaluated from the ratio between aldosterone and the substrate of 11 beta hydroxylase (DOC) and its derivative (18-OH DOC). This study suggests that exploration of mineralocorticosteroid pathway can be used as a hormonal marker of adrenal carcinoma for both secretory and non-secretory malignant masses.
Previous reports demonstrated that prolactin receptors (PRL-R) are widely expressed on cells of the immune system. We analyzed a possible regulation of PRL-R expression on human mononucleated blood cells by prolactin (PRL) itself. PRL-R expression was analyzed by immunofluorescence on T and B lymphocytes and monocytes from peripheral blood mononucleated cells (PBMC) of patients with hyperprolactinemia or acromegaly compared with sex- and age-matched control subjects. The frequency of PRL-R positive cells and the intensity of PRL-R expression was only modified among the CD8+ T cell population of hyperprolactinemic patients with macroadenoma. No correlation was reported between PRL-R expression and circulating PRL levels. The percentage of PRL-R+ cells on B or T lymphocytes and monocytes as well as the capacity of PBMC to proliferate in response to T cell mitogens were not significantly different in bromocriptine-treated compared with untreated patients. These findings suggest that factors other than pituitary PRL play the major role in regulating PRL-R expression on cells of the immune system.
Tamoxifen, a synthetic antiestrogen widely used for the treatment of breast cancer, is also being proposed for the prevention of this cancer among women at high risk for the disease. Such an approach requires an objective and accurate evaluation, not only of the expected beneficial effects, but also of the potential iatrogenic side effects which could result from the administration of this drug to a population of healthy women. The present article summarizes our present knowledge which results from studies, all carried out on women with breast cancer: we review the side effects on the female genital apparatus, the ovarian and non ovarian endocrine side effects, the effects on cardio-vascular and thromboembolic risks, on bone metabolism and on ocular and hepatic side effects. The potential carcinogenic role is only briefly mentioned since it has already been the subject of a publication in this journal.
Lymphangiomyomatosis is a rare disease which affects young women of childbearing age. Ten women with pulmonary lymphangiomyomatosis were treated with antiestrogen therapy from 3 to 9 years (mean time of treatment: 5.3 years). Efficacy of treatment was evaluated by clinical, radiological, pulmonary function testing response as well as the overall long-term outcome. Four patients died of respiratory failure after 3, 5, 5 and 9 years of treatment. Of the 6 patients remaining alive, respiratory function deteriorated in 4 cases after a transient period of mild improvement lasting 3 years in 2 cases. Two patients appeared stable after 3 and 7 years of treatment. Without a control group, although a longer time of survival along these last years, it seems difficult to impute this benefit to the sole antiestrogen treatment and the overall long term prognosis of the disease remains really uncertain.
In most androgen target tissues, the first step of androgen action is the 5 alpha-reduction of testosterone to DHT which binds to the androgen receptor with an affinity 3 to 4 fold higher than testosterone. Two genes, encoding two isozymes of 5 alpha-reductase (5 alpha-R) have been cloned. The two isoforms, 5 alpha-R1 and 5 alpha-R 2 are located on chromosomes 5 and 2 respectively and differ in optimal pH, substrate and inhibitor affinities and tissue expression. 5 alpha-R 2 is responsible for sexual differentiation. It is the major form expressed in the prostate where it seems necessary for embryonic growth and development. 5 alpha-reductase deficiency results in androgen insensitivity due to abnormal 5 alpha-R 2. Affected patients are XY individuals with a very peculiar form of male pseudohermaphroditism: they have feminine genitalia at birth and masculinize at puberty. 29 mutations, spanning the whole coding portion of the gene, have been described; correlation between mutations and enzyme activity have led to the suggestion that both the N- and the C-terminal end of the gene are involved in substrate binding, whereas the cofactor binding-site is located in the C-terminus. In contrast to androgen insensitivity due to 5 alpha-reductase deficiency, increased 5 alpha-reductase activity can result in androgen hypersensitivity as described in idiopathic hirsutism or benign prostatic hyperplasia. In these case 5 alpha-R 1 could possibly be involved.
Androgen insensitivity syndromes are suspected in XY subjects with normal testosterone secretion presenting with absent or severely impaired androgen dependent sexual differentiation. Such clinical features suggest an abnormality of the androgen receptor, necessary step in the transmission of the hormonal message. The androgen receptor is a member of the steroid/thyroid nuclear receptors superfamily. It is a soluble protein of 919 amino acids, divided in independent functional domains responsible for the various functions of the receptor:hormone and DNA binding, and transcriptional activation. The highest concentration of androgen receptor is found, in both sexes, in tissues resulting from primary or secondary sexual differentiation. Cloning of the androgen receptor and use of molecular biology techniques have led to a new classification of androgen insensitivity syndromes. In complete forms (complete androgen insensitivity:CAI) the phenotype is feminine. In receptor negative CAI (Rc-: complete loss of hormone binding), molecular abnormalities include rare, partial or complete, deletions of the gene, or, more frequently, single point mutations in the hormone binding domain, leading to a functionally inactive receptor. Identification and characterization of these mutations provide valuable information regarding the functional importance of specific amino acids of the androgen receptor. In receptor positive CAI (RC+: conserved hormone binding capacity), abnormalities have been reported in the DNA binding domain (deletion of a zinc finger, single point mutations), but also in the hormone binding domain, thus distinguishing between the hormone binding activity and the transcriptional activation activity of this domain. Partial insensitivity syndromes are characterized by an ambiguous and extremely variable phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)
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Etymologically meaning "cessation of menstruation", the menopause is in fact a phenomenon which occurs over several years and can be divided into two phases: a period of "pre"-menopause, approximately from the age of 40 to 50, during which ovulation becomes increasingly less frequent, leads to decreased fertility and progesterone deficiency (luteal insufficiency), whereas the confirmed "menopause", which occurs between the age of 50 and 55, is the disappearance of all follicles, leading to estrogen deprivation. The risk associated with the "pre"-menopause is an "unopposed estrogen effect", with its cellular effects on target-tissues. The problem of confirmed menopause is decreased tissue trophicity, not only of the genital area, but of the body in general (skin, bone, blood vessels, etc.) as a consequence of estrogen deprivation. Replacement therapy is the logical treatment: progestins during the "pre"-menopause, estrogens in combination with progestins once "menopause" is confirmed.
The treatment of menopause must meet efficacy, safety, simplicity and adaptability criteria. To achieve optimal benefit-to-risk ratio, treatment must be instituted and followed up with consideration to 1) the patient herself and 2) the type of treatment: molecule, dose, route of administration, sequence, duration, etc. The stage of menopause must be determined, since the deficiency, and hence replacement therapy, involves progestins in the years just before menopause, and estrogens in postmenopausal women. Cellular contra-indications (history of breast or endometrial cancer) concern all estrogens, whereas metabolic or thromboembolic contra-indications concern only oral estrogens. Which progestin? there is a consensus in favor of progesterone or one of its close derivatives (dydrogesterone, pregnane or norpregnane). Continuous or discontinuous treatment? Discontinuous treatment, closer to normal physiology, causes menstrual bleeding in 15 to 20% of patients, whereas continuous treatment, proposed to avoid menstruations, leads to irregular bleeding in 30 to 70% of the cases, bleeding which calls for additional and constraining investigations, and would be dangerous to ignore! Among the proposed formulations, the best will be the one which allows for individually tailored adjustment according to signs of estrogen overdosage or underdosage. Treatment may be instituted at any age of post-menopause, and need not be limited over time, unless a contra-indication develops.
Although rare, thyroid hormone resistance syndrome should be suspected on a biological profile combining high thyroid hormone and non-suppressed TSH plasma levels. Resistance to thyroid hormone can be classified into 3 forms: generalized, pituitary and peripheral, all three showing tissue resistance heterogeneity from one person to another, and from one tissue to another in the same subject. In the generalized and pituitary forms, thyroid hormone levels are high with paradoxically normal or increased TSH levels. The TRH test still stimulates TSH secretion, and only the highest doses of T3 successfully suppress TSH secretion. In the generalized form, euthyroidism is usual, whereas in the pituitary form hyperthyroidism requires treatment in order to lower TSH secretion. In the peripheral form, various symptoms of thyroid hormone deficiency may be observed, contrasting with normal T3, T4 and TSH serum levels, and requiring supraphysiological doses of T3 for correction. In most cases, familial occurrence can be evidenced, with an autosomal dominant or sometimes recessive mode of inheritance. Genetic analysis has identified, in the generalized form, more than 10 mutations of the thyroid hormone receptor beta gene, all resulting in an alteration in the T3 binding domain of the receptor. In the autosomal dominant form, tissue resistance may result from a "dominant inhibitory effect" of the normal receptor function by the mutant receptor. All these thyroid hormone resistance syndromes constitute exceptional models for studying the mechanisms of action of thyroid hormones. Simultaneous observations of the mutated receptors with various clinical and biological phenotypes should further our understanding of thyroid hormone receptor function.
Fertility was evaluated in 53 female patients with late-onset adrenal hyperplasia (LAH) due to 21-hydroxylase deficiency. The majority of patients (n = 33) were seen for isolated postpubertal hirsutism, 9 patients consulted for sterility, and 11 for irregular menstrual cycles. At the time of diagnosis, the ages of patients ranged from 15-40 yr (mean +/- SD, 24.6 +/- 5.2). No patient had major signs of virilization. The plasma 17-hydroxyprogesterone level was higher than normal in all patients (26.8 +/- 18.9 nmol/L; range, 3.4-139.4) and dramatically increased to 140.1 +/- 80.6 nmol/L (range, 35.2-324.2) after ACTH treatment. Plasma androgen levels were high (testosterone, 3.25 +/- 2.03 nmol/L; delta 4-androstenedione, 13.65 +/- 5.60 nmol/L). Plasma basal and LHRH-stimulated values were normal for FSH and high for LH. Basal and TRH-stimulated plasma PRL levels were normal. Among these 53 LAH patients, only 20 desired a pregnancy. These had a total of 38 pregnancies. Ten patients became pregnant before the diagnosis of LAH and without any treatment; they had a total of 18 pregnancies, 12 of which were successful. Moreover, 19 normal pregnancies without any spontaneous abortion were carried to term by 14 of 16 hydrocortisone-treated patients. One patient needed the association of one cure of clomiphene citrate. Hypofertility in LAH patients seems, therefore, to be relative. Its mechanism is hormonal, with anovulation or dysovulation, due to the continuous steroid feedback of adrenal origin on the hypothalamo-pituitary axis. Hydrocortisone is the appropriate treatment in most cases, reducing adrenal androgen overproduction and relieving hypothalamic-pituitary gonadotropin function, thereby making possible cyclic ovarian activity and ovulations.
Lymphangiomyomatosis is a rare disease which affects young women of childbearing age. Eight women with pulmonary LAM were treated with antiestrogen therapy and were monitored by blood estrogen measurements along with clinical hypoestrogenic symptoms. Treatment ranged from three to nine years. The response to therapy was evaluated by the clinical course, chest x-ray films, pulmonary function tests and overall long-term outcome. Three patients died of respiratory failure after three, five and nine years of treatment. Of the five patients remaining alive, respiratory function deteriorated in four cases, after a transient period of mild improvement lasting three years in two cases. The last patient appeared stable after three years of follow-up. Time course ranged from 4 to 17 years. However, without a control group, we cannot determine whether or not the apparent improvement of the natural time course was due to the hormonal treatment.