THE EFFECTS OF ENDOCRINE DISRUPTORS ON FEMALE GONADAL AXIS: AN UPDATE.

Endocrine disruptors (EDs) are considered to have an impact on the function of reproductive axis at different levels as well on reproductive organs in both sexes. Complexity of female reproductive system influenced with various stressors including EDs lead to morphological and functional alterations. This is resulting in modulation of neuroendocrine regulation with consequent developmental irregularities and derangements, causative infertility, endometriosis as well as premature ovarian insufficiency or polycystic ovary syndrome. A number of experimental clues was obtained on female animal models using various EDs such as synthetic estrogens and phytoestrogens, neurotransmitters, pesticides or various chemicals. These substances lead towards consequent derangement of the neuroendocrine control of reproduction from early phases of reproductive development towards different phases of adult reproductive period. This text will address some novel insights into the effects of EDs on neuroendocrine regulation of gonadal axis, effects on ovaries as well on endometrium during implantation period.

The effect of metformin and myoinositol on metabolic outcomes in women with polycystic ovary syndrome: role of body mass and adiponectin in a randomized controlled trial.

PURPOSE: To compare the effects of insulin sensitizers metformin (MET) and myo-inositol (MI) on adiponectin levels and metabolic characteristics in women with polycystic ovary syndrome (PCOS) with respect to their body mass index (BMI). METHODS: In this open label, parallel randomized clinical trial, 66 women with PCOS (33 normal-weight and 33 overweight/obese) were randomized to either MI (4 g/day) or MET (1500 mg/day) for a period of 6 months. Serum concentration of adiponectin, hormonal and metabolic laboratory outcomes and clinical assessment of BMI, body composition and Ferriman-Gallwey score (FG score) were evaluated before and after treatment. RESULTS: After the 6-month intervention, comparison between MET and MI in time to treatment analysis showed no significant differences between the two treatments for all analyzed parameters. Only borderline significantly lower AUC glucose was found in the MET group in comparison to the MI group (p = 0.071). The main effect of treatment was shown for glucose concentration at 120 min OGTT (p = 0.032) and testosterone (p = 0.002). The main effect of time was shown for body mass (p = 0.004), waist circumference (p < 0.001), BMI (p = 0.003), body fat mass (p = 0.001), adiponectin (p = 0.020), fasting glucose (p = 0.001), testosterone (p = 0.015), SHBG (p = 0.013), 17OH progesterone (p = 0.008), LH (p = 0.004) and estradiol (p = 0.014). CONCLUSION: Our study showed similar effects of MET and MI on BMI, body composition, hormonal profile, metabolism of glucose and insulin, and adiponectin level. The two insulin sensitizers, MET and MI, were useful in reducing BMI and improving body composition without significant differences between the two treatments in PCOS women. TRIAL REGISTRATION: ISRCTN13199265. Trial registration date: 14.04.2021. (ISRCTN Registry), retrospectively registered.

THE EFFECT OF MYOINOSITOL AND METFORMIN ON CARDIOVASCULAR RISK FACTORS IN WOMEN WITH POLYCYSTIC OVARY SYNDROME: A RANDOMIZED CONTROLLED TRIAL.

CONTEXT: Cardiovascular risk is increased in women with polycystic ovary syndrome (PCOS). Do insulin sensitizing agents such as metformin (MET) and myoinositol (MI) ameliorate biomarkers of cardiovascular risk? OBJECTIVE: To compare the effects of MET and MI on blood pressure, lipid profile and high sensitive C-reactive protein (hs-CRP) in women with PCOS in respect to their body mass index (BMI). DESIGN: Open label, parallel randomized, single center study. SUBJECTS AND METHODS: Sixty six women with PCOS (33 normal-weight and 33 overweight/obese) were randomized to either MI (4 g/day) or MET (1500 mg/day) for a period of 6 months. Serum concentration of hormones, lipid profile, oxidized LDL (ox-LDL), hs-CRP, blood pressure measurement and clinical assessment of BMI, waist circumference (WC) and Ferriman Gallwey score (FG score) were performed before and after treatment. RESULTS: Thirty patients in each group completed the trial. Compared with MET, MI significantly decreased diastolic blood pressure (DBP) (p=0.036) and significantly increased serum hs-CRP (p=0.043). No differences between groups in total cholesterol (TC), HDL-cholesterol, LDL-cholesterol, ox-LDL and triglycerides were reported after 6 months. Treatment with MI reduced BMI (p=0.037), WC (p=0.005), DBP (p=0.021) and TC (p=0.008). During MET treatment a significant decrease in BMI (p=0.005), WC (p=0.004), FG score (p=0.001), testosterone (p=0.013) and free androgen index (FAI) (p=0.006) was observed. CONCLUSIONS: Our study showed an advantage of MI in reduction of DBP and TC thus predicting favorable metabolic and cardiovascular outcomes in PCOS women. MET more effectively decrease indices of hyperandrogenism.

Liraglutide administration improves hormonal/metabolic profile and reproductive features in women with HAIR-AN syndrome.

SUMMARY: HAIR-AN syndrome, the coexistence of Hirsutism, Insulin Resistance (IR) and Acanthosis Nigricans, constitutes a rare nosologic entity. It is characterized from clinical and biochemical hyperandrogenism accompanied with severe insulin resistance, chronic anovulation and metabolic abnormalities. Literally, HAIR-AN represents an extreme case of polycystic ovary syndrome (PCOS). In everyday practice, the management of HAIR-AN constitutes a therapeutic challenge with the available pharmaceutical agents. Specifically, the degree of IR cannot be significantly ameliorated with metformin administration, whereas oral contraceptives chronic administration is associated with worsening of metabolic profile. Liraglutide and exenatide, in combination with metformin, have been introduced in the management of significantly obese women with PCOS with satisfactory results. Based on this notion, we prescribed liraglutide in five women with HAIR-AN. In all participants a significant improvement regarding the degree of IR, fat depositions, androgen levels and the pattern of menstrual cycle was observed, with minimal weight loss. Furthermore, one woman became pregnant during liraglutide treatment giving birth to a healthy child. Accordingly, we conclude that liraglutide constitutes an effective alternative in the management of women with HAIR-AN. LEARNING POINTS: HAIR-AN management is challenging and classic therapeutic regimens are ineffective. Literally HAIR-AN syndrome, the coexistence of Hirsutism, Insulin Resistance and Acanthosis Nigricans, represents an extreme case of polycystic ovary syndrome. In cases of HAIR-AN, liraglutide constitutes an effective and safe choice.

Insulin resistance, androgens, and lipids are gradually improved in an age-dependent manner in lean women with polycystic ovary syndrome: insights from a large Caucasian cohort.

PURPOSE: Polycystic ovary syndrome (PCOS), considered a lifelong condition, manifests mainly as a cluster of hyperandrogenic symptoms during the early reproductive years, with the affected woman gradually developing an adverse cardiometabolic profile over the years. However, some data point to the possibility of differences in the evolution of PCOS according to a woman's weight. The aim of the present study was to evaluate the metabolic and hormonal profiles of women with PCOS over time. METHODS: A total of 763 lean women with PCOS (BMI 20-25 kg/m2) and 376 controls were included. The study group was further divided into three age groups representing women post-adolescence, of reproductive age, and of late reproductive age. All subjects were assessed clinically, biochemically, and hormonally. RESULTS: Waist circumference, lipids, androgens, and insulin resistance index (homeostasis model assessment of IR index (HOMA-IR)) were significantly higher in the PCOS group compared with controls. Age subgroup analysis showed a progressive decrease of HOMA-IR and waist circumference, and lipid levels were comparable between PCOS and controls in all age groups. Androgens remained significantly higher in PCOS, but they gradually decreased through time. A significant negative association of age with waist circumference, androgens, insulin, and HOMA-IR was revealed. Univariate and multivariate regression analysis disclosed a strong correlation of HOMA-IR with age (p = 0.014, ß - 0.19, SE coefficient 0.008) as a single parameter or in combination with total cholesterol (TC) (p < 0.001, age: ß - 0.023, SE 0.10; TC: ß 0.084, SE 0.027). CONCLUSION: Insulin resistance, androgens, and lipids are gradually improved in an age-dependent manner in lean PCOS women. We hypothesize that if these women do not gain weight with the passage of time, there is a high probability that their cardiometabolic risk will be attenuated.

DIAGNOSIS OF ENDOCRINE DISEASE: Drug-induced endocrinopathies and diabetes: a combo-endocrinology overview.

In the currently overwhelming era of polypharmacy, the balance of the dynamic and delicate endocrine system can easily be disturbed by interfering pharmaceutical agents like medications. Drugs can cause endocrine abnormalities via different mechanisms, including direct alteration of hormone production, changes in the regulation of the feedback axis, on hormonal transport, binding and signaling, as well as similar changes to counter-regulatory hormone systems. Furthermore, drugs can interfere with the hormonal assays, leading to erroneous laboratory results that disorientate clinicians from the right diagnosis. The purpose of this review is to cover a contemporary topic, the drug-induced endocrinopathies, which was presented in the monothematic annual Combo Endo Course 2018. This challenging part of endocrinology is constantly expanding particularly during the last decade, with the new oncological therapeutic agents, targeting novel molecular pathways in the process of malignancies. In this new context of drug-induced endocrine disease, clinicians should be aware that drugs can cause endocrine abnormalities via different mechanisms and mimic a variety of clinical scenarios. Therefore, it is extremely important for clinicians not only to promptly recognize drug-induced hormonal and metabolic abnormalities, but also to address the therapeutic issues for timely intervention.

The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene.

BACKGROUND: Nonclassical congenital adrenal hyperplasia (NC-CAH) is caused by mutations of the CYP21A2 gene. The clinical manifestations and hormonal derangements of NC-CAH are quite variable. OBJECTIVES: (i) To define the phenotype and its relation to genotype according to gender and age and (ii) to evaluate the validity of currently applied hormonal criteria for establishing the diagnosis of NC-CAH. PATIENTS AND METHODS: The clinical, hormonal and molecular data of 280 subjects (235 female) with NC-CAH and a median age of 17·6 years were analysed. CYP21A2 genotyping was performed in all subjects. RESULTS: The majority of females aged less than 8 years presented with premature pubarche (88·3%), while those older than 8 presented with a polycystic ovary-like phenotype (63·2%). A total of 7·7% of the females and 51·1% of the males were asymptomatic at the time of diagnosis. In the total group, 50·4% of the subjects were compound heterozygotes for one classical (C) and one nonclassical (NC) mutation, while 46% of the alleles studied carried the p.V281L mutation. Basal 17OHP values were below 6 nm (2 ng/ml) in 2·1% of the subjects with NC-CAH, but none had peak 17OHP values post-ACTH lower than 30 nm (10 ng/ml). CONCLUSIONS: NC-CAH has a variable phenotype depending on the age, gender and the presence of a classical mutation. A peak cut-off value of 17OHP post-ACTH lower than 30 nm excludes the diagnosis of NC-CAH, whereas basal 17OHP <6 nm may represent a false-negative result. A significant number of patients harboured a classical mutation, a finding which requires genotyping of the partner for genetic counselling.

"Menstrual irregularities in PCOS. Does it matter when it starts?".

BACKGROUND: PCOS is presented by a broad spectrum of menstrual irregularities appearing often at puberty or later on during the reproductive years in women suffering from this multifaceted syndrome. To our knowledge, there is no evidence to suggest whether the time of onset of menstrual irregularities (peri or post pubertal) indicates a differential metabolic and/or hormonal profile as well as ovarian ultrasonographic findings, in adulthood in women with PCOS. AIM OF THE STUDY: To compare anthropometric, hormonal-metabolic profile and ultrasound findings in PCOS women with peripubertal onset of menstrual disorders with the corresponding data obtained from PCOS patients with post pubertal onset of menstrual irregularities, matched for BMI and age. PATIENTS-METHODS: 89 PCOS women were evaluated cross-sectionally at the age of 25 years. In 49 subjects menstrual irregularities were present from menarche, whereas in 40 women the irregularities appeared at least 3 years post menarche. RESULTS: Anthropometric parameters were comparable between the 2 groups. The 2 groups did not differ on metabolic and hormonal profile as well as ovarian ultrasound findings. CONCLUSIONS: These data indicate that the timing of menstrual irregularities, do not appear to have an impact, on hormonal/metabolic profile and ovarian ultrasound morphology in patients diagnosed with PCOS, later in life.

Low free plasma levels of retinol-binding protein 4 in insulin-resistant subjects with polycystic ovary syndrome.

BACKGROUND: It has been shown in animals and in humans that retinol-binding protein 4 (RBP4) production from adipose tissue leads to generalized insulin resistance (IR). A more sensitive marker of circulating RBP4 is free plasma RBP4 expressed by RBP4 to transthyretin (TTR) ratio, since in circulation RBP4 is bound to TTR. AIM: To investigate RBP4 levels in insulin-resistant women with polycystic ovary syndrome (PCOS) and to estimate free plasma RBP4 expressed by RBP4/TTR ratio. SUBJECTS AND METHODS: Thirty-five PCOS subjects were compared with 45 controls matched for age and body mass index (BMI). In each subject, fasting values of glucose, insulin, gonadotropins, estradiol, androgens, C-reactive protein (CRP), RBP4, and TTR were determined. RESULTS: PCOS subjects in comparison to controls were more insulin-resistant [homeostasis model assessment for IR (HOMA-IR): 2.6+/-0.3 vs 1.9+/-0.1, p=0.043], and presented lower RBP4 levels (28.3+/-1.1 vs 32.4+/-1.2 microg/ml, p=0.021) and RBP4/TTR ratio (0.26+/-0.01 vs 0.31+/-0.01, p=0.0014). When RBP4 and RBP4/TTR values where stratified according to BMI status (obese, overweight, and lean subjects), it was noticed that both RBP4 and RBP4/TTR values in lean PCOS were significantly lower than in controls (RBP4: 25.0+/-5.5 vs 34.1+/-9.0 microg/ml, p=0.0063, RBP4/TTR: 0.25+/-0.3 vs 0.35+/-0.1, p=0.016). No correlation was observed between RBP4 and RBP4/TTR with any hormonal or metabolic parameter including BMI. CONCLUSIONS: RBP4 and free plasma RBP4 expressed as RBP4/TTR ratio are statistically and significantly lower in insulin-resistant PCOS subjects in comparison to controls. Therefore, our findings do not confirm a link between IR, neither with RBP4 nor with free plasma RBP4 levels. The significance of these findings remains to be elucidated, since RBP4 might prove to have different actions, like other adipokines, from humans and rodents.

Obesity and attenuated adiposity rebound in children with congenital hypothyroidism. Normalization of BMI values in adolescents.

An earlier adiposity rebound, suggestive of adult obesity, has been reported in children with congenital hypothyroidism. We undertook this study to evaluate the effect of congenital hypothyroidism on: 1) the timing of adiposity rebound, 2) the long-term prognosis of BMI status, and 3) the factors potentially affecting adiposity in subjects with congenital hypothyroidism. We found that in children with congenital hypothyroidism the BMI values were higher during the first years of life compared to normal population, but subsequently normalized. After the initial rise of BMI, the decline (nadir) and subsequent rise (adiposity rebound), usually occurring in normal children at an age greater than 30 months, was less evident in our group of children with congenital hypothyroidism. The severity of hypothyroidism affected BMI values at 6 and 12, but not at 36 months of age. In conclusion, in children with congenital hypothyroidism, 1) the high BMI values in early childhood normalize in adolescence, and 2) the normally expected BMI fluctuations during the first years of life are attenuated. These findings constitute indirect evidence that thyroid function during fetal and neonatal life affects BMI status during the first years of life.

Brown tumor of the fibula: unusual presentation of an uncommon manifestation. Report of a case and review of the literature.

Brown tumors are erosive bony lesions caused by rapid osteoclastic activity and peritrabecular fibrosis due to hyperparathyroidism, resulting in a local destructive phenomenon. Although brown tumors are the most pathognomonic sign of hyperparathyroidism, they are very rarely observed at present as a result of early detection of hypercalcemia and elevated parathyroid hormone levels. The rare appearance of this entity in everyday practice is troublesome for both patients and physicians, because whenever it emerges, diagnosis could be mistaken for a giant cell tumor of the bone. However, clinical, biochemical, and radiologic findings can easily guide the diagnosis if one considers the full continuum of findings and their association with subject's medical history, instead of focusing only on bone lesion. In this report we present a case of brown tumor in the fibula with a short literature review, whose aggressive presentation and unawareness of the skeletal findings of hyperparathyroidism puzzled the caring doctors. This case illustrates the need for continuous vigilance of any physician, regardless of his specialty or his position in medical services structures.

Reduced insulin secretion in normoglycaemic patients with beta-thalassaemia major.

AIMS: To assess insulin sensitivity and secretion in the fasting state in regularly transfused patients with beta-thalassaemia major with normal glucose response during an oral glucose tolerance test and to estimate its possible relation to iron overload. METHODS: We measured fasting glucose, insulin and C-peptide levels in 24 patients with beta-thalassaemia major and 18 control subjects matched for age and body mass index. Insulin sensitivity and insulin release index were calculated according to the homeostasis model assessment (HOMA). Correlations with age, body mass index and serum ferritin were also calculated. RESULTS: Fasting glucose levels in patients were increased compared with control subjects (5.5 +/- 0.12 vs. 4.7 +/- 0.13 mmol/l, mean +/- SEM, P < 0.001). Pancreatic B-cell insulin secretion in the fasting state (estimated by SC(HOMA)) was lower in thalassaemic patients (SC(HOMA) 88.5 +/- 11.11 vs. 184.3 +/- 23.72 in control subjects, P < 0.001). Patients were then divided into those with impaired (IFG) and normal (NFG) fasting glucose. SC(HOMA) was higher in the patients with NFG compared with those with IFG patients (110.6 +/- 17.63 vs. 66.3 +/- 10.88, respectively, P < 0.05) but estimated insulin sensitivity (ISI(HOMA)) was similar. Plasma values of C-peptide correlated positively with ferritin (r = 0.42, P = 0.04) and SC(HOMA) (r = 0.45, P = 0.02) and negatively with ISI(HOMA) (r = -0.43, P = 0.03). CONCLUSIONS: These results support the concept that impaired B-cell function, as reflected by a reduction in the insulin secretion index, is present in beta-thalassaemic patients with normoglycaemia before changes in oral glucose tolerance tests are apparent.

Pituitary size fluctuation in long-term MR studies of PROP1 deficient patients: A persistent pathophysiological mechanism?

Inactivating PROP1 gene alterations are responsible for over 50% of familial combined pituitary hormone deficiency cases. Pituitary enlargement followed by regression and subnormal pituitary size has been documented in a number of PROP1 deficient patients. Data derived from PROP1 deficient mice (Ames dwarfs) have revealed some of the underlying cellular mechanisms. Nevertheless, long-term magnetic resonance imaging (MRI) findings in two PROP1 deficient patients suggest the evolution of pituitary pathology as more complex and persistent than previously described. Patient A had enlarged pituitary gland (pituitary height: 9-10 mm), demonstrated by serial MRI carried out from age 5 to 8.5 yr, small pituitary gland (4 mm) at age 10 yr and pituitary enlargement (11 mm) at age 19 yr. Patient B had a pituitary gland of normal size at age 7 yr (5 mm), whereas at age 14.3 and 16.3 yr, an enlarged pituitary gland was disclosed (10 and 11 mm, respectively). Both series of events are suggestive of a persistent pathophysiological mechanism in the pituitary gland of patients with PROP1 gene defects. Therefore, long-term pituitary follow-up by MRI in such patients may be necessary even in the case of a small or normal pituitary gland. It must be noted that current data from the Ames dwarf mouse cannot fully explain the observed pituitary size fluctuation.

Prevalence of thyroid dysfunction in Turner's syndrome: a long-term follow-up study and brief literature review.

Thyroid dysfunction, especially hypothyroidism caused by Hashimoto's thyroiditis is more frequently observed in girls with Turner's syndrome (TS). The aim of the present study was to evaluate prevalence, etiology, karyotype distribution and age at onset of thyroid pathology in girls with TS. Data recorded in 84 girls with TS attending our clinic were analyzed. The mean age +/- standard deviation [SD] at their initial evaluation was 10.3 +/- 3.7 years (range, 0.5 to 19 years) and the mean period of observation was 8.4 +/- 4.4 years. The thyroid function had been evaluated at least once per year in all patients and thyroid autoantibodies (ATA) were available in 51 (60.7%). Hypothyroidism was detected in 24% of the studied subjects and hyperthyroidism in 2.5%. Elevated values of thyroid autoantibodies were detected in 42% of girls with TS, whose ATA had been determined, and 65% had hypothyroidism. Thyroid dysfunction was first noted after the age of 8 years with no difference in the distribution of new cases at the different ages or pubertal stages. There was no difference in the incidence of thyroid dysfunction related to the type of karyotype abnormality. Thyroid dysfunction is more frequently encountered in girls with TS (hypothyroidism: 24% in the total group and 65% in those with positive ATA, hyperthyroidism: 2.5%). Thyroid dysfunction was observed after the age of 8 years with no difference in the occurrence of new cases in the various age groups thereafter. Hence, thyroid function should be evaluated yearly in girls with TS past the age of 8 years and more frequently in those with positive thyroid autoantibodies.

Effects of estrogen deprivation due to breast cancer treatment.

Breast cancer is one of the main life-threatening diseases that a woman may have to face during her lifetime. The increasing incidence of breast neoplasia reported over the last few decades has led to widespread screening of women resulting in early diagnosis. One common but challenging question for most doctors, after the surgical excision of the lesion, is determination of the ideal adjuvant therapy for their patients for the achievement of maximum life expectancy with the best quality of life. Since the beginning of the last century, the knowledge that breast cancer arises from hormone-responsive tissues has long made use of hormone-blocking agents in the beneficial treatment of breast neoplasia. The discovery of new molecules with endocrine actions has rendered the use of adjuvant therapy in a tailor-made pattern too complicated, as these agents have a different mode of action, different adverse effects and probably different indications. The aim of the present review is to clarify these issues, analyzing the mechanism of action of available drugs and their actions on specific areas of uncertainty: cognitive function, cardiovascular system, urogenital tract, bone metabolism, weight gain, hot flushes and premature menopause. Regarding the efficacy of adjuvant therapy, there has been particular focus on the multiple hormonal-induced consequences of each regimen in order to provide the clinician with the available data for choosing the ideal therapy for the patient.

Human growth hormone and gonadotropin releasing hormone analog combination therapy increases predicted height in short normal girls.

The "short normal" child constitutes a real challenge for the pediatric endocrinologist. In a subgroup of short normal children, puberty starts at a normal age but with low height, and hence, the final height is expected to be quite compromised. Efforts to improve the outcome in this group have been made in the past with equivocal results. We present the growth data of 8 short girls with normal growth hormone values on provocative testing and low height at puberty initiation. At intervention the height and the stage of puberty were 129.3 +/- 5 cm and II to III, respectively, and the predicted height was 148.8 +/- 2.6 cm. Gonadotropin releasing hormone analog, triptorelin (3.6 +/- 0.5 microg/kg/day) and growth hormone (0.5 IU/kg/week) were used in different sequential order and simultaneously in each child. The mean total treatment period was 47.6 +/- 11.2 months. The mean predicted and the mean final height in the total group were 148.8 +/- 2.6 and 154.5 +/- 3.6 cm, respectively (p:0.028). The final height did not differ from the target height (154.8 +/- 8 cm versus 154.5 +/- 3.6 cm), while in 4 children, the final height was greater than the target height. The height gain (delta Final height - Predicted height) was 5.7 +/- 1.3 cm. If we analyze separately the girls in whom growth hormone was started first and gonadotropin releasing hormone analog followed versus those who started the analog first, the delta Final height - Predicted height was 8 +/- 3 cm in the former and 4.8 +/- 3.1 cm in the latter (p:0.03). It seemed that the difference was accounted for by duration of growth hormone therapy (51.3 +/- 10.6 months versus 28.6 +/- 10.6 months) (p:0.026), rather than by other factors. In conclusion, under the conditions of the present study, the combination of puberty arrest and growth hormone therapy significantly improved predicted height. The most significant determinant of the height gain was the duration of growth hormone therapy.

Insufficient adrenarche in patients with combined pituitary hormone deficiency caused by a PROP-1 gene defect.

Adrenarche was evaluated in five patients, aged 17.4 +/- 3 years, with combined pituitary hormone deficiency (CPHD), caused by a PROP-1 gene defect. Adrenocorticotrophic hormone (ACTH), cortisol and dehydroepiandrosterone sulfate (DHEAS) were determined prior to and following the administration of corticotropin-releasing hormone (CRH) in four of the five patients, while only basal values of ACTH, cortisol and DHEAS were determined in the fifth. In the four patients in whom a CRH test was carried out, the mean basal values of cortisol, ACTH and DHEAS were 289 +/- 140 nmol/l, 4.5 +/- 1.7 pmol/l and 0.26 +/- 0.36 micromol/l, respectively. The corresponding post-CRH peak values were 584 +/- 204 nmol/l, 12.7 +/- 3.9 pmol/l and 0.43 +/- 0.41 micromol/l. In the fifth patient, basal ACTH, cortisol and DHEAS values were 4 pmol/l, 411 nmol/l, and 2.33 micromol/l, respectively. Thus the basal and post CRH values of DHEAS (a marker of adrenarche) were low for age, while basal and post-CRH cortisol and ACTH values were within normal limits. For the interpretation of these findings two hypotheses can be proposed: 1) The PROP-1 gene is only expressed in the pituitary, and the role of PROP-1 is related to the maturation of the cells which synthesize the presumed adrenal androgen stimulating hormone (AASH). 2) The PROP-1 gene is also expressed in the adrenal cortex and, when defective, the zona reticularis does not function appropriately. Regardless of the interpretation