Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.

An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are reviewed. Specific issues in individuals with Klinefelter syndrome or androgen insensitivity syndrome are considered. The expert panel recommends that pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team. Children with a known condition should be followed from the age of 8 years for girls and 9 years for boys. Puberty induction should be individualised but considered at 11 years in girls and 12 years in boys. Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders or congenital pituitary deficiencies. The transition of these young adults highlights the importance of a multidisciplinary approach, to discuss both medical issues and social and psychological issues that arise in the context of these chronic conditions.

[Syndrome Of 46, XX Male With Sex-Determining Region Of Y (SRY) Chromosome Missing, Bilateral Gynecomastia And Complete Virilization: About A Case]. / Le Syndrome Du 46, XX Male Avec Absence Du Gene Sex-Determining Region Of Y (SRY) Chromosome, A Propos D'un Cas.

Absent SRY gonadal dysgenesis (negative) is the set of clinical and biological manifestations linked to the lack of development of the testes in humans. Authors report the first case of gonadal dysgenesis SRY-negative 46, XX male with gynecomastia documented in Mali. CASE OBSERVATION: This is a 15 years old boy of a deaf-mute brother, no family consanguinity. He was referred to the hospital because of severe bilateral gynecomastia. Hypergonado-tropic hypogonadism condition was investigated by hormonal laboratory assessment and the result of cytogenetic analysis carried out in France revealed a karyotype SRY-negative 46, XX isch Yp11, 3. The patient received psychological assistance and substitutive treatment based on testosterone. Reconstructive surgery was also conducted to correct urogenital malformations. CONCLUSION: Diagnosis of 46, XX male syndrome is rare and need cytogenetic analysis. In Mali, cost and availability of this technique make diagnosis difficult and care inadequate for patients.

La dysgénésie gonadique à SRY absent (négatif) est l'ensemble des manifestations clinico-biologiques liées à l'absence de développement des testicules chez l'homme. Les auteurs rapportent le premier cas de dysgénésie gonadique type 46, XX male à SRY Négative avec gynécomastie documenté au Mali. OBSERVATION: Il s'agissait d'un jeune garçon de 15 ans, avec antécédents d'un frère sourd-muet, sans consanguinité familiale, qui a consulté pour gynécomastie bilatérale marquée. Devant l'hypogonadisme hypergonadotrope objectivé sur le bilan hormonal, une étude cytogénétique réalisée en France a montré un caryotype à 46, XX isch Yp 11,3 à SRY Négative. La prise en charge repose sur une assistance psychologique, le traitement substitutif en testostérone et la chirurgie réparatrice des malformations uro-génitales. CONCLUSION: Le diagnostic du syndrome 46, XX mâle est rare et le diagnostic est cytogénétique. Le coût et l'accessibilité de cette technique au Mali rendent le diagnostic difficile et la prise en charge inefficiente.

Impact of cancer chemotherapy before ovarian cortex cryopreservation on ovarian tissue transplantation.

STUDY QUESTION: How efficacious is transplantation of ovarian cortex previously exposed to chemotherapy? SUMMARY ANSWER: Prior exposure to chemotherapy did not disrupt the function of cryopreserved ovarian tissue after transplantation. WHAT IS KNOWN ALREADY: Ovarian tissue cryopreservation (OTC) followed by ovarian tissue transplantation (OTT) is an efficacious technique for restoration of female fertility. At least 130 children have been born following this procedure. To date, little is known about the efficacy of OTT in patients exposed to cancer chemotherapy prior to OTC. STUDY DESIGN, SIZE, DURATION: This study evaluates the recovery of ovarian function and fertility in 31 consecutive patients who had received OTT, between 2005 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Thirty one patients, wanting children, were transplanted with autologous ovarian cortex, among which 22 patients (71%) had been exposed to chemotherapy before OTC. Recovery of ovarian function was considered total once menstruation occurred. Ovarian function recovery (OFR), ovarian graft survival, and incidence of pregnancy were related to previous chemotherapy exposure, type of chemotherapy and graft characteristics (number of grafted fragments and follicular density). MAIN RESULTS AND ROLE OF CHANCE: The amount of ovarian tissue collected was the only parameter to show any significant change between patients with versus without previous chemotherapy. At 1 year after OTT, the cumulative incidence of OFR was 83% (93% in patients exposed to chemotherapy and 67% in others (P = 0.14)). A low follicular density (<0.3 foll/mm2) in the transplant and a low number of grafted fragments (<16) were significantly associated with a delayed OFR. Graft survival at 2 years after OTT was 77%. It was significantly lower in patients exposed to bifunctional alkylating agents before ovarian cryopreservation and in patients with a low follicular density. The proportion of women who succeeded in having at least one live birth was 23% in the total population, 0% (0/9) in the group 'no previous chemotherapy', and 32% (7/22) in the group 'previous chemotherapy'. The cumulative incidence of pregnancy (Kaplan-Meier) at 3 years after OTT was 36% overall and 49% in case of previous chemotherapy, with no difference related to previous chemotherapy exposure. In total there were 13 pregnancies and 8 births in 7 patients. LIMITATIONS, REASONS FOR CAUTION: The pathology in the two groups of patients was not comparable. In the group of patients who had chemotherapy before OTC, there were 95% of hematological malignancies. In the group of patients who did not have chemotherapy before OTC only 1 out of 9 patients had a malignant hematological disease while 44% had some pathology affecting the ovaries. Few women are available for study and only large changes are likely to have statistical significance. WIDER IMPLICATIONS OF THE FINDINGS: These results suggest that prior cancer chemotherapy should no longer be considered a limitation to cryopreservation of ovarian tissue and current recommendations in this regard should be revised. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Agence de la Biomédecine (France's biomedical office). There are no competing interests to report. TRIAL REGISTRATION NUMBER: NCT02184806.

MRI follow-up is unnecessary in patients with macroprolactinomas and long-term normal prolactin levels on dopamine agonist treatment.

OBJECTIVE: Both antitumor and antisecretory efficacies of dopamine agonists (DA) make them the first-line treatment of macroprolactinomas. However, there is no guideline for MRI follow-up once prolactin is controlled. The aim of our study was to determine whether a regular MRI follow-up was necessary in patients with long-term normal prolactin levels under DA. PATIENTS AND METHODS: We conducted a retrospective multicenter study (Marseille, Paris La Pitie Salpetriere and Nancy, France; Liege, Belgium) including patients with macroprolactinomas (largest diameter: >10 mm and baseline prolactin level: >100 ng/mL) treated by dopamine agonists, and regularly followed (pituitary MRI and prolactin levels) during at least 48 months once normal prolactin level was obtained. RESULTS: In total, 115 patients were included (63 men and 52 women; mean age at diagnosis: 36.3 years). Mean baseline prolactin level was 2224 ± 6839 ng/mL. No significant increase of tumor volume was observed during the follow-up. Of the 21 patients (18%) who presented asymptomatic hemorrhagic changes of the macroprolactinoma on MRI, 2 had a tumor increase (2 and 7 mm in the largest size). Both were treated by cabergoline (1 mg/week) with normal prolactin levels obtained for 6 and 24 months. For both patients, no further growth was observed on MRI during follow-up at the same dose of cabergoline. CONCLUSION: No significant increase of tumor size was observed in our patients with controlled prolactin levels on DA. MRI follow-up thus appears unnecessary in patients with biologically controlled macroprolactinomas.

Deletion of CPEB1 Gene: A Rare but Recurrent Cause of Premature Ovarian Insufficiency.

CONTEXT: Premature ovarian insufficiency (POI) may be secondary to chemotherapy, radiotherapy, or environmental factors. Genetic causes are identified in 20-25% of cases, but most POI cases remain idiopathic. OBJECTIVE: This study aimed to identify new genes involved in POI and to characterize the implication of CPEB1 gene in POI. DESIGN AND SETTING: This was a case report and cohort study replicate conducted in academic medical centers. PATIENTS AND METHODS: A deletion including CPEB1 gene was first identified in a patient with primary amenorrhea. Secondly, 191 sporadic POI cases and 68 familial POI cases were included. For each patient, karyotype was normal and FMR1 premutation was excluded. Search for CPEB1 deletions was performed by quantitative multiplex PCR of short fluorescent fragments or DNA microarray analysis. Gene sequencing of CPEB1 was performed for 95 patients. RESULTS: We identified three patients carrying a microdeletion in band 15q25.2. The proximal breakpoint, for the three patients, falls within a low-copy repeat region disrupting the CPEB1 gene, which represents a strong candidate gene for POI as it is known to be implicated in oocyte meiosis. No mutation was identified by sequencing CPEB1 gene. Therefore, heterozygous deletion of CPEB1 gene leading to haploinsufficiency could be responsible for POI in humans. CONCLUSION: Microdeletions of CPEB1 were identified in 1.3% of patients with POI, whereas no mutation was identified. This microdeletion is rare but recurrent as it is mediated by nonallelic homologous recombination due to the existence of low-copy repeats in the region. This result demonstrates the importance of DNA microarray analysis in etiological evaluation and counseling of patients with POI.

Endocrine Manifestations in a Monocentric Cohort of 64 Patients With Erdheim-Chester Disease.

CONTEXT: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterized by infiltration of foamy histiocytes in multiple organs. Endocrine involvement has mostly been described in case reports. OBJECTIVE: We performed systematic endocrine evaluation in a large cohort of patients with ECD. DESIGN: This was a single-center observational study conducted between October 2007 and May 2013. SETTING: The evaluation was conducted in Pitié-Salpêtrière Hospital (Paris, France), a tertiary care hospital. PATIENTS: Sixty-four consecutive patients with ECD (sex ratio, 3.6; mean age, 57.6 years [range, 20-80 years]). Thirty-six patients had follow-up assessments. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Clinical, biological, and morphological evaluations of pituitary, gonadal, adrenal, and thyroid functions, as well as metabolic evaluation, were performed. RESULTS: Diabetes insipidus was found in 33.3% of patients, frequently as the first manifestation of ECD. Anterior pituitary dysfunction was found in 91.3% of patients with full anterior pituitary evaluation, including somatotropic deficiency (78.6%), hyperprolactinemia (44.1%), gonadotropic deficiency (22.2%), thyrotropic deficiency (9.5%), and corticotropic deficiency (3.1%). Thirty-five patients (54.7%) had ≥2 anterior pituitary dysfunctional axes, rising to 69.6% (16 of 23) when only patients with complete evaluations were considered. Two patients had panhypopituitarism. Infiltration of the pituitary and stalk was found with magnetic resonance imaging in 24.4% of patients. Testicular insufficiency was found in 53.1% of patients, with sonographic testicular infiltration in 29% of men, mostly bilateral. Computed tomography adrenal infiltration was found in 39.1% of patients, and 1 case of adrenal insufficiency was observed. No patient was free of endocrine hormonal or morphological involvement. Endocrine dysfunctions were most often permanent, and new deficits appeared during follow-up. CONCLUSION: Endocrine involvement is very frequent in ECD and should be evaluated carefully at diagnosis and during follow-up.

Childhood craniopharyngioma: hypothalamus-sparing surgery decreases the risk of obesity.

CONTEXT: Craniopharyngioma is a brain tumor whose high local recurrence rate has for a long time led to a preference for extensive surgery. Limited surgery minimizing hypothalamic damage may decrease the severe obesity rate at the expense of the need for radiotherapy to complete the treatment. OBJECTIVE: We compared weight gain and local recurrence rates after extensive resection surgery (ERS) and hypothalamus-sparing surgery (HSS). DESIGN: Our observational study compared a historical cohort managed with ERS between 1985 and 2002 to a prospective cohort managed with HSS between 2002 and 2010. SETTING: The patients were treated in a pediatric teaching hospital in Paris, France. PATIENTS: Thirty-seven boys and 23 girls were managed with ERS (median age, 8 years); 38 boys and 27 girls were managed with HSS (median age, 9.3 years). MAIN OUTCOME MEASURES: Data were collected before and 6 months to 7 years after surgery. Body mass index (BMI) Z-score was used to assess obesity and the number of surgical procedures to assess local recurrence rate. RESULTS: Mean BMI Z-score before surgery was comparable in the 2 cohorts (0.756 after ERS vs 0.747 after HSS; P = .528). At any time after surgery, mean BMI Z-score was significantly lower after HSS (eg, 1.889 SD vs 2.915 SD, P = .004 at 1 year). At last follow-up, the HSS cohort had a significantly lower prevalence of severe obesity (28% vs 54%, P < .05) and higher prevalence of normal BMI (38% vs 17%, P < .01). Mean number of surgical procedures was not significantly different in the 2 cohorts. CONCLUSIONS: Hypothalamus-sparing surgery decreases the occurrence of severe obesity without increasing the local recurrence rate.

A hereditary moyamoya syndrome with multisystemic manifestations.

OBJECTIVE: We report a detailed description of a family affected by a hereditary multisystem disorder associated with moyamoya syndrome. METHODS: In this family case report, we evaluated 9 members of the same family originating from Algeria. Investigations included neuroimaging, cardiologic and ophthalmologic evaluation, hormonal testing, hemoglobin electrophoresis, chromosomal karyotyping, muscle biopsy for morphology, immunohistochemistry and enzyme assays, mtDNA mutation screening, and haplotype analysis of 2 loci previously linked to moyamoya, on chromosomes 10 (ACTA2) and 17. RESULTS: Five males related through a maternal lineage were affected, suggesting an X-linked inheritance. Four of them had symptomatic moyamoya syndrome with an onset of acute neurologic manifestations between 4 and 32 years. Hypergonadotropic hypogonadism, azoospermia, short stature of postnatal onset (-2 to -4 SD in adulthood), premature graying of hair, and dysmorphism were present in all patients. The other features of the disease included early cataract in 4, dilated cardiomyopathy in 3, and partial growth hormone deficiency in 2 members. Muscle biopsy data did not reveal signs of a mitochondrial disorder. All conditions known to be associated with moyamoya syndrome such as Down syndrome, neurofibromatosis, and sickle cell disease were excluded. We also excluded linkage to the 2 loci previously reported to be involved in autosomal dominant syndromic and nonsyndromic moyamoya. Carrier females had normal phenotype and clinical history. CONCLUSIONS: These data strongly suggest that this family is affected by a hereditary moyamoya multisystem disorder with X-linked recessive pattern of inheritance.

Prolactin and human tumourogenesis.

The involvement of prolactin in human tumourogenesis has been long debated. The reason is that the evidence supporting the role of circulating prolactin in promoting breast cancer was mainly obtained using rodent models, whereas most of the studies performed in human species in the 1980s have remained inconclusive. Things have now started to change because two alternative mechanisms of prolactin actions in tumour growth have emerged since the beginning of the 21st Century. The first involves locally-produced prolactin, which acts by an autocrine/paracrine mechanism. Genetically-modified mouse models have demonstrated the tumourigenic potential of local prolactin on the prostate and the mammary gland, and arguments are now emerging in humans also. The second mechanism involves genetic variants of the receptor. Although no genetic disorder has been reported for prolactin or its receptor, a variant of the prolactin receptor exhibiting constitutive activity has been recently identified in patients presenting with breast tumours, suggesting that sustained prolactin signalling may participate in breast tumourogenesis. Recent data regarding these two nonclassical mechanisms of prolactin action are discussed. Finally, we address the question of their inhibition in future cancer therapy, both in light of other findings that have revealed novel actions of prolactin in breast cancer cells, and with respect to the compounds currently available to target prolactin receptor signalling.

[Phenotype-genotype correlation in mutations of the gonadotrophin receptor gene in women]. / Corrélation phénotype-génotype des mutations des récepteurs des gonadotrophines chez la femme.

Different mutations have been described in LH and FSH genes as well as in their receptors. These mutations are either activating (gain of function), or inhibiting (loss of function). Activating mutations are expressed as a dominant trait, thus in the heterozygous state, whereas inhibiting mutations are only expressed when both alleles bear the mutation. Inactivating mutations of FSH receptor gene, in women, are associated with primary ovarian insufficiency. Inactivating mutations of LH receptor gene have also been described, most often in XX patients whose families also include cases of male pseudohermaphrodism. Clinically, these women suffer from primary amenorrhea but with normal development of breasts and the hair system. Infertility is constant. LH blood levels are increased, estradiol blood levels are those encountered at the beginning of the follicular phase (50-70 pg/ml). The discovery of these mutations allows a better understanding of some genotypes and is helpful in advancing our knowledge of these receptors.

[Congenital hypogonadotropic hypogonadism]. / Hypogonadisme hypogonadotrope congénital.

Congenital hypogonadotropic hypogonadism is defined by reduced steroid hormone synthesis and secretion due to low LH and FSH secretion. It is a rare disease with an unknown prevalence (about 1/5000). It results from a fetal defect in GnRH neuron migration, a defect of pituitary development or from a functional defect of the hypothalamopituitary axis between GnRH neurons and gonadotropic cells. The diagnosis should be considered at birth in males with micropenis, during adolescence in case of delayed puberty or absent puberty, and during adulthood in case of infertility. It may be restricted to the gonadotropic axis, combined with other endocrine system defects or be part of a complex syndrome. Several gene defects have now been described. Molecular studies should be performed to confirm the diagnosis and to help provide appropriate genetic counseling. Treatment to induce puberty should be provided at adolescence, followed by hormonal substitution treatment during adulthood. Specific infertility treatment may also be proposed but patients with the dominant form of gonadotropic deficiency should be informed of the risk of transmission.

Molecular pathology of the FSH receptor: new insights into FSH physiology.

Manipulations of mouse genome have helped to elucidate gonadotrophin function but important differences subsist between rodent and human reproduction. Studies of patients with mutations of gonadotrophins or gonadotrophin receptors genes allow understanding their physiological effects in humans. The correlation of the clinical phenotypes of patients with in vitro studies of the mutated receptor residual function and histological and immunohistological studies of the ovarian biopsies permits to understand which stages of follicular development are under FSH control. Total FSH receptor (FSHR) inactivation causes infertility with an early block of follicular maturation remarkably associated with abundant small follicles as in prepubertal ovaries and demonstrates the absolute requirement of FSH for follicular development starting from the primary stage. Partial FSHR inactivation, characterized by normal-sized ovaries, can sustain follicular development up to the early antral stages but incremental levels of FSH stimulation seem to be required for antral follicular growth before selection. These findings contrast with the traditional view of an initial gonadotrophin-independent follicular growth prior to the preantral-early antral stages. The presence of numerous reserve follicles in the ovaries of these patients may permit a future treatment of their infertility. The study of reduced FSHbeta or FSHR activity in genetically modified male mice models and in men suggests a minor impact of the FSHR on masculine fertility. Further studies on patients with a demonstrated total FSHbeta or FSHR inactivation are required to elucidate reported differences in spermatogenesis impairment. Finally, the studies of mutations of gonadotrophins and their receptors demonstrate differences in gonadotrophin function between genetically modified rodents and humans which suggest prudence in extrapolating observations in rodents to human reproduction. Ovarian hyperstimulation syndrome (OHSS) can infrequently arise spontaneously during pregnancy, but most often it is an iatrogenic complication of ovarian stimulation treatments with ovulation drugs for in vitro fertilization. The first genetic cause of familial recurrent spontaneous OHSS was identified as a broadening specificity of the FSHR for hCG due to naturally occurring heterozygous mutations located unexpectedly in the transmembrane domain of the FSHR. Broadening specificity of a G protein-coupled receptor is extremely rare. These observations led to the identification of the etiology of this previously unexplained syndrome and permitted to conceive novel models of FSHR activation. Susceptibility to iatrogenic OHSS or its clinical severity may be associated with FSHR polymorphisms with slightly different activities in vivo as suggested by several studies. The study of larger cohorts is needed to evaluate the clinical impact of these observations in the management of patients undergoing IVF protocols.

[Management of families at high risk for hereditary breast-ovarian cancers: the endocrinologist's point of view]. / Attitude pratique devant une famille à haut risque de cancer du sein et/ou de l'ovaire: le point de vue de l'endocrinologue.

Most cancers have a sporadic physiopathology, but approximately 5 to 10% of breast cancers and 10% of ovarian cancers involve a genetic predisposition. Sometimes, the gene involved in these hereditary cancers can be identified (usually BRCA1 or 2), but most of the time it remains unknown. However, all women considered at high risk, because of their familial history, must be identified so they can be provided with the most adequate care, since the probability is very high that they develop such a cancer in the future. Fortunately, effective strategies have been developed to reduce this risk. Early detection of breast cancer is possible and prophylactic treatments (chemoprevention and prophylactic surgery) exist for both breast and ovarian cancers. Another reason why it is essential that these high risk women are identified is that treatment for hereditary cancers differs in some ways from that of sporadic cancers. It is best that counseling be given in an interdisciplinary cancer genetic clinic, where all practionners are aware of the latest data and guidelines.

Evaluation of different markers of the ovarian reserve in patients presenting with premature ovarian failure.

Premature ovarian failure (POF) is a heterogeneous syndrome, possibly due to mutations of genes involved in the normal development of the ovary and/or the follicles. Based essentially on animal models, these mutations are associated with various ovarian histological phenotypes, from a complete absence of to a partial follicular maturation. The aims of our work were in one hand to determine if ovarian histology, compared to pelvic ultrasonography, would be helpful either in identifying which patients display an impaired follicular growth or in the orientation of the POF etiology; on the other hand, since developing follicles up to the antral stage are reported in POF and that Anti-Müllerian hormone (AMH) might be a good indicator of follicular presence, we decided to determine whether AMH should be a better marker to determine the presence of an ovarian reserve in POF patients. To try to answer to the first question, we studied first 166 patients suffering from POF with a normal karyotype. Vaginal ultrasonography (US) was performed in 134 patients and an ovarian biopsy was obtained in 67 women. The presence of follicles suggested at US was confirmed at histology in only 56% of the patients. Ovarian histology led to the distinction of two phenotypes (a) small-sized ovaries, deprived of follicles, and (b) normal-sized ovaries with partial follicular maturation. To confirm the value of ovarian biopsies, samples from 20 normal women have been studied, confirming that ovarian biopsy at random allow reliable assessment of follicular activity. To try to answer to the second question of our work, a cross sectional study analyzing serum AMH, ovarian histology and AMH immunoexpression in 48 POF patients, was performed. Serum AMH was significantly higher in women with more than 5 follicles at ovarian histology. Ovarian AMH immunostaining revealed a normal AMH expression in POF preantral follicles but a decrease expression at the early antral stages. In conclusion, ovarian histology appears to be a reliable tool to appreciate the follicular reserve, and helpful and complementary to clinical and hormonal phenotyping in order to orient the search for various genetic causes of POF syndrome. Finally, AMH levels in POF patients could identify women with persistent follicles.

Luteinizing hormone pulsatility in patients with major ovarian hyperandrogenism.

Hyperandrogenism and ovulatory dysfunction are common in women with either polycystic ovary (PCOS) or ovarian virilizing tumor. However, contrasting with the numerous studies that have extensively described gonadotropin secretory abnormalities, principally increased LH pulse amplitude and frequency, few studies have concerned gonadotropin secretion in patients with ovarian virilizing tumors; low gonadotropin levels have occasionally been reported, but never extensively studied. The goal of the present study was to further evaluate the pulsatility of LH secretion in women with ovarian virilizing tumor compared with that of PCOS patients. Eighteen women with major hyperandrogenism (plasma testosterone level >1.2 ng/ml) were studied (5 women with ovarian virilizing tumor, 13 women with PCOS, and 10 control women). Mean plasma LH level, LH pulse number and amplitude were dramatically low in patients with ovarian tumors when compared to both PCOS (p<0.001) and controls (p<0.001). In case of major hyperandrogenism, LH pulse pattern differs markedly between women with ovarian virilizing tumor or PCOS, suggesting different mechanisms of hypothalamic or pituitary feedback.

Hormonal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

During childhood, the main aims of the medical treatment of congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency, are to prevent salt loss and virilization and to achieve normal stature and normal puberty. As such, there is a narrow therapeutic window through which the intended results can be achieved. In adulthood, the clinical management has received little attention, but recent studies have shown the relevance of long-term follow-up of these patients. Indeed, long-term evaluation of adult CAH patients enables the identification of multiple clinical, hormonal and metabolic abnormalities as bone mineral density alteration, overweight and disturbed reproductive functions. In women with classic CAH, low fertility rate is reported, and is probably the consequence of multiple factors, including neuroendocrine and hormonal factors, feminizing surgery, and psychological factors. Men with CAH may present hypogonadism either through the effect of adrenal rests or from suppression of gonadotropins resulting in infertility. These patients should therefore be carefully followed-up, from childhood through to adulthood, to avoid these complications and to ensure treatment compliance and tight control of the adrenal androgens, by multidisciplinary teams who have knowledge of CAH.

Prolactinoma and estrogens: pregnancy, contraception and hormonal replacement therapy.

The stimulatory role of estrogen on prolactin secretion and on proliferation of lactotropic cells is well established in terms of physiology but could this phenomenon be extended to include harmful effects of estrogens on prolactinoma? The aim of this review is to provide an up-to-date assessment of this subject with regard to pregnancy, use of contraceptive pills and postmenopausal hormone replacement therapy. Dopamine agonists allow women presenting prolactinoma to recover their ovulation cycles and become pregnant. There is no adverse data concerning the safety of dopamine agonists such as bromocriptine, if the woman is treated during the first trimester of pregnancy but there is little information regarding the most recent treatments such as cabergoline or quinagolide. In women with microadenomas, pregnancy generally has little impact on their adenoma, delivery is normal and breast-feeding is allowed. Concerning macroprolactinomas, tumor progression during pregnancy is possible and endocrine follow-up remains necessary. Contraceptive pills containing estrogen and progestins are currently the best-tolerated and the most effective contraception. This type of contraceptive has long been avoided in patients presenting prolactinoma. While the literature has little to say on this subject and provides no adverse information, professional experience suggests that this attitude should be amended and that women presenting microprolactinoma should be allowed to use current contraceptive pills (containing 30 microg or less of ethinyl estradiol). The most important problem to overcome with this type of prescription, which masks the clinical consequences of hyperprolactinemia, is the possibility of overlooking hypophyseal disease that could result from this approach. The problem of macroprolactinoma is different; the possibility of prescribing contraceptive pills must be evaluated on a case-by-case basis and the impact of the drug on the adenoma must be very closely monitored. Estrogen replacement therapy in patients presenting hypogonadism should be attempted in patients with a history of prolactinoma and standard-monitoring precautions should be taken. In menopausal women, when replacement therapy is desirable, the presence of a microprolactinoma should not by itself avoid this prescription.

Serum anti-Müllerian hormone expression in women with premature ovarian failure.

BACKGROUND: Premature ovarian failure (POF) is generally irreversible. However, developing follicles up to the antral stage are reported in POF and anti-Müllerian hormone (AMH) might be a good indicator of follicular presence. This study analysed serum AMH, ovarian histology and AMH immunoexpression in POF patients. METHODS: A cross-sectional study of 48 POF patients in an Endocrinology Department setting. Patients had an ovarian biopsy simultaneously with serum AMH sampling and/or ovarian AMH immunostaining. RESULTS: Mean serum AMH was 1.04 +/- 1.66 ng/ml. Serum AMH was significantly higher in women with 15 or more follicles at ovarian histology (P = 0.001). Comparison of ovarian AMH immunostaining from POF patients and 10 normal controls revealed a normal AMH expression in POF pre-antral follicles, but a decreased expression at the early antral stages. Serum AMH was undetectable in 77% of the patients with 0-5 AMH immunopositive follicles and detectable in 100% of the patients with more than 15 AMH immunopositive follicles. CONCLUSIONS: AMH levels in POF patients could identify women with persistent follicles. The decrease of AMH immunoexpression in POF antral follicles could suggest a defect of antral development.