Consideraciones en el manejo del adulto con Hiperplasia Suprarrenal congénita clásica por déficit de 21-Hidroxilasa / Management considerations for the adult with congenital adrenal hyperplasia due 21-hydroxylase deficiency

La Hiperplasia Suprarrenal Congénita (HSRC) corresponde a un grupo de defectos genéticos en la síntesis de cortisol. El 95% de ellas son debidas al déficit de 21-hidroxilasa por lo que nos referiremos solo a esta deficiencia. La hiperplasia suprarrenal congénita clásica (HSRC-C) debuta en recién nacidos o lactantes con insuficiencia suprarrenal primaria, diferentes grados de hiperandrogenismo clínico en mujeres y puede coexistir con hipotensión, hiperkalemia e hiponatremia si hay un déficit clínico de aldosterona. El objetivo de este artículo es actualizar el conocimiento y enfoques sugeridos para el manejo de la HSRC-C desde el inicio de sus controles en la etapa adulta. El diagnóstico diferencial en retrospectiva de la HSRC-C y la no clásica (HSRC-NC) a veces resulta difícil ya que esta enfermedad es un espectro fenotípico continuo. La insuficiencia suprarrenal y la dependencia a terapia corticoidal son los eventos principales para diferenciar estas dos patologías que tienen enfoques terapéuticos diferentes. El tratamiento de la HSRC-C en adultos abarca 2 objetivos primarios: la adecuada sustitución de la falla suprarrenal y el control de hiperandrogenismo mediante el uso de corticoides en sus dosis mínimas efectivas. En la mujer existen terapias complementarias para el control del hiperandrogenismo como anticonceptivos y otras que se encuentran en diferentes fases de investigación. Esto permite disminuir las dosis de corticoides en algunos casos. Es importante a la vez abordar tres objetivos secundarios: controlar el riesgo cardiometabólico propio de la enfermedad, evitar el sobre tratamiento corticoidal y manejar la infertilidad. La correcta monitorización del tratamiento en adultos tomando en cuenta los objetivos descritos permite una mejor calidad de vida en estos pacientes. Finalmente el consejo genético debe realizarse en todos los pacientes con HSRC que deseen fertilidad y en sus parejas. El estudio requiere de secuenciación del gen CYP21A2 y debe realizarse en un laboratorio de experiencia.

Congenital Adrenal Hyperplasia (CAH) are a group of genetic defects characterized by impaired cortisol synthesis. 95% of them are due to 21-hydroxylase deficiency. We will discuss only this enzyme's deficiency. Classic congenital adrenal hyperplasia (CAH-C) debuts in newborns or infants with primary adrenal insufficiency, some degree of clinical hyperandrogenism in newborn females, and can coexist with hypotension, hyperkalemia, and hyponatremia if there is a clinical aldosterone deficiency. The objective of this article is to update the knowledge and suggested approaches for the management of CAH-C from the beginning of its controls in the adult stage. The retrospective differential diagnosis of CAH-C and non-classical (CAH-NC) is sometimes difficult because this disease is a continuous phenotypic spectrum. Adrenal insufficiency and dependence on corticosteroid therapy are the main events to differentiate these two pathologies that have different therapeutic approaches. In adults, the treatment of CAH-C must include 2 primary objectives: adequate the replacement of adrenal failure and control of hyperandrogenism, through the use of corticosteroids in their minimum effective doses. In women there are complementary therapies for the control of hyperandrogenism, such as contraceptives and others that are in different phases of research. This makes it possible to reduce the doses of corticosteroids in some cases. It is important at the same time to address three secondary objectives: control the cardiometabolic risk of the disease secondary to corticosteroid treatment, avoid corticosteroid overtreatment and manage infertility. The correct monitoring of treatment in adults and taking in to account the objectives described, allows a better quality of life in these patients. Finally, genetic counseling must be carried out in all patients planning for children, with any type of CAH and in their partners. The study requires sequencing of the CYP21A2 gene and must be performed in a certified laboratory.

Endocrinopathies in paediatric-onset neuromyelitis optica spectrum disorder with aquaporin 4 (AQP4) antibody.

The involvement of the diencephalic regions in neuromyelitis optica spectrum disorder (NMOSD) may lead to endocrinopathies. In this study, we identified the following endocrinopathies in 60% (15/25) of young people with paediatric-onset aquaporin 4-Antibody (AQP4-Ab) NMOSD: morbid obesity ( n = 8), hyperinsulinaemia ( n = 5), hyperandrogenism ( n = 5), amenorrhoea ( n = 5), hyponatraemia ( n = 4), short stature ( n = 3) and central hypothyroidism ( n = 2) irrespective of hypothalamic lesions. Morbid obesity was seen in 88% (7/8) of children of Caribbean origin. As endocrinopathies were prevalent in the majority of paediatric-onset AQP4-Ab NMOSD, endocrine surveillance and in particular early aggressive weight management is required for patients with AQP4-Ab NMOSD.

Androgen excess: Investigations and management.

Androgen excess (AE) is a key feature of polycystic ovary syndrome (PCOS) and results in, or contributes to, the clinical phenotype of these patients. Although AE will contribute to the ovulatory and menstrual dysfunction of these patients, the most recognizable sign of AE includes hirsutism, acne, and androgenic alopecia or female pattern hair loss (FPHL). Evaluation includes not only scoring facial and body terminal hair growth using the modified Ferriman-Gallwey method but also recording and possibly scoring acne and alopecia. Moreover, assessment of biochemical hyperandrogenism is necessary, particularly in patients with unclear or absent hirsutism, and will include assessing total and free testosterone (T), and possibly dehydroepiandrosterone sulfate (DHEAS) and androstenedione, although these latter contribute limitedly to the diagnosis. Assessment of T requires use of the highest quality assays available, generally radioimmunoassays with extraction and chromatography or mass spectrometry preceded by liquid or gas chromatography. Management of clinical hyperandrogenism involves primarily either androgen suppression, with a hormonal combination contraceptive, or androgen blockade, as with an androgen receptor blocker or a 5α-reductase inhibitor, or a combination of the two. Medical treatment should be combined with cosmetic treatment including topical eflornithine hydrochloride and short-term (shaving, chemical depilation, plucking, threading, waxing, and bleaching) and long-term (electrolysis, laser therapy, and intense pulse light therapy) cosmetic treatments. Generally, acne responds to therapy relatively rapidly, whereas hirsutism is slower to respond, with improvements observed as early as 3 months, but routinely only after 6 or 8 months of therapy. Finally, FPHL is the slowest to respond to therapy, if it will at all, and it may take 12 to 18 months of therapy for an observable response.

Reproductive endocrine health in pubertal females with epilepsy on antiepileptic drugs: time to screen?

OBJECTIVES: Although previous studies suggest that valproate (VPA) may induce reproductive endocrine disorders, the effects of newer antiepileptic drugs (AEDs) on reproductive endocrine health have not been widely investigated and compared with those of older AEDs. Therefore, this multicenter cross-sectional study aimed to evaluate the prevalence of reproductive endocrine dysfunctions in pubertal females with epilepsy receiving VPA, lamotrigine (LTG), or levetiracetam (LEV) monotherapy. PATIENTS AND METHODS: Pubertal girls on VPA (n = 11), LTG (n = 8), or LEV (n = 13) monotherapy for at least 6 months were recruited. Healthy sex-matched and age-matched subjects were enrolled as controls (n = 32). Each participant underwent a comprehensive physical examination concerning signs of hyperandrogenism. The Ferriman-Gallwey score of hirsutism was assessed. In addition, all patients completed a standardized questionnaire regarding epilepsy, menstrual cycle, and hirsutism features. Adiposity indices were measured and weight gain was documented for each subject. RESULTS: Hirsutism score, occurrence of hyperandrogenism features, and adiposity indices were significantly higher in the VPA group when compared with LEV and control groups. VPA therapy was more frequently associated with weight gain when compared with LTG and controls, whereas no significant differences with regard to signs of hyperandrogenism were found between VPA and LTG groups. Furthermore, no differences in menstrual disorders were observed between groups. CONCLUSIONS: Pubertal girls with epilepsy receiving VPA monotherapy were more likely to develop signs of hyperandrogenism, that is, hirsutism and acanthosis, than those on LEV or controls. However, no differences in occurrence of menstrual disorders and other reproductive dysfunctions were found between VPA, LTG, LEV, and control groups. These findings do not allow us to clearly determine whether or not VPA, LEV, and LTG monotherapies considerably affect reproductive endocrine health in pubertal girls with epilepsy. Therefore, further prospective studies of larger sample sizes are needed to establish if screening tests should be recommended.

Comparison between effects of myo-inositol and D-chiro-inositol on ovarian function and metabolic factors in women with PCOS.

Myo-inositol and D-chiro-inositol are capable of improving the ovarian function and metabolism of polycystic ovary syndrome (PCOS) patients. The aim of this work is to compare the effects of myo-inositol and D-chiro-inositol in PCOS. We enrolled 50 patients, with homogeneous bio-physical features, affected by PCOS and menstrual irregularities, and we randomly divided them into two groups: 25 were treated with 4 g of myo-inositol/die plus 400 mcg of folic acid/die orally for six months, 25 with 1 g of D-chiro-inositol/die plus 400 mcg of folic acid/die orally for six months. We analyzed in both groups pre-treatment and post-treatment BMI, systolic and diastolic blood pressure, Ferriman-Gallwey score, Cremoncini score, serum LH, LH/FSH ratio, total and free testosterone, dehydroepiandrosterone sulfate (DHEA-S), Δ-4-androstenedione, SHBG, prolactin, glucose/immunoreactive insulin (IRI) ratio, homeostatic model assessment (HOMA) index, and the resumption of regular menstrual cycles. Both the isoforms of inositol were effective in improving ovarian function and metabolism in patients with PCOS, although myo-inositol showed the most marked effect on the metabolic profile, whereas D-chiro-inositol reduced hyperandrogenism better.

Plasma selenium levels in Turkish women with polycystic ovary syndrome.

OBJECTIVE(S): To evaluate selenium (Se) levels in serum and their relation with hyperandrogenism and insulin resistance (IR) in women with polycystic ovary syndrome (PCOS) and in control subjects. STUDY DESIGN: Women with any gynecological problem who presented to the Kahramanmaras Sutcuimam University Medical Faculty Gynecology and Obstetric Outpatient Clinic were invited to participate. Group 1 consisted of 36 cases with a diagnosis of PCOS according to the 2003 Rotterdam Consensus Criteria, and Group 2 (control group) consisted of 33 age- and BMI-matched healthy women. In all cases, serum total testosterone (tT), dihydroepiandrostenedione-sulfate (DHEAS), follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), insulin, glucose (mg/dL), total cholesterol (TC) (mg/dL), high density lipoprotein-cholesterol (HDL-C) (mg/dL), low density lipoprotein-cholesterol (LDL-C) (mg/dL), triglyceride (TG) (mg/dL) and Se levels were measured. RESULTS: The level of FSH was significantly lower, and the levels of LH, E2, tT, and DHEAS were significantly higher in group 1 than in group 2 (p<0.05). The hirsutism score was significantly higher among PCOS women compared to the control group (p<0.05). Although insulin levels and HOMA-IR were markedly increased in the PCOS group compared to the control group, the differences were not significant (p>0.05). The plasma Se level was significantly lower in PCOS women compared to the control group (p<0.05). When we combined the all women in two groups, regarding them as one group (combined group, n=69), a negative correlation between Se and LH and tT was present (p<0.05). CONCLUSION(S): Our results show decreased plasma concentrations of Se and a negative correlation between Se and LH, tT in women with PCOS. These results indicate that Se may play a role in the pathogenesis of PCOS related with hyperandrogenism.

Therapeutic implications of vitamin D and calcium in overweight women with polycystic ovary syndrome.

OBJECTIVE: To assess effects of vitamin D and Calcium (Ca) on hormonal and metabolic milieu of polycystic ovary syndrome (PCOS). DESIGN: Single arm open label trial. METHODS: Twelve overweight and vitamin D deficient women with PCOS underwent a 2 hour oral glucose tolerance testing at baseline and following 3-month supplementation with vitamin D (daily dose of 3533 IU, increased to 8533 IU after the first five participants) and 530 mg elemental Ca daily. MAIN OUTCOME MEASURES: Blood pressure (BP), plasma glucose, insulin, total testosterone (T) androstenedione (A), sex hormone binding globulin, lifestyle parameters were assessed at baseline and following 3-month intervention. Insulin resistance (IR) and area under the curve for glucose and insulin were computed; paired analyses were conducted. RESULTS: Improved serum 25OHD (p < 0.001) and reductions in total T (p = 0.036) and A (p = 0.090) levels were noted following 3-month supplementation, compared to baseline. Significant lowering in BP parameters was seen in participants with baseline BP ≥ 120/80 mmHg (n = 8) and in those with baseline serum 25OHD ≤20 ng/ml (n = 9). Parameters of glucose homeostasis and IR remained unchanged (p > 0.05). CONCLUSIONS: Androgen and BP profiles improved followed three month intervention, suggesting therapeutic implications of vitamin D and Ca in overweight and vitamin D deficient women with PCOS.

Vitamin D in the aetiology and management of polycystic ovary syndrome.

Vitamin D deficiency is common in women with polycystic ovary syndrome (PCOS), with the 67-85% of women with PCOS having serum concentrations of 25-hydroxy vitamin D (25OHD) <20 ng/ml. Vitamin D deficiency may exacerbate symptoms of PCOS, with observational studies showing lower 25OHD levels were associated with insulin resistance, ovulatory and menstrual irregularities, lower pregnancy success, hirsutism, hyperandrogenism, obesity and elevated cardiovascular disease risk factors. There is some, but limited, evidence for beneficial effects of vitamin D supplementation on menstrual dysfunction and insulin resistance in women with PCOS. Vitamin D deficiency may play a role in exacerbating PCOS, and there may be a place for vitamin D supplementation in the management of this syndrome, but current evidence is limited and additional randomized controlled trials are required to confirm the potential benefits of vitamin D supplementation in this population.

Therapeutic effects of calcium & vitamin D supplementation in women with PCOS.

OBJECTIVE: To evaluate the efficacy of calcium & vitamin D supplementation in infertile women suffering from polycystic ovary syndrome (PCOS), and to assess levels of 25-hydroxy vitamin D in these patients. METHODS: In a case control study, 100 infertile PCOS women based on a randomly divided into two groups. Group I (n = 50) were treated with metformin 1500 mg/day, and group II (n = 50) treated with metformin 1500 mg/day plus Calcium 1000 mg/day and Vitamin D 100000 IU/month for 6 months. Patients were followed by transvaginal sonography at first, 3 and 6 months later for evaluating dominant follicle. BMI, menstrual regularity, follicle diameter, pregnancy, serum 25-OH-vitamin D level were matured and compared in two groups. RESULTS: BMI decreased almost significantly (25.49 ± 1.88 vs 26.28 ± 2.15, p: 0.054) in group II. A better improvement was gained in regulating menstrual abnormalities (70% vs 58%, p: 0.211), follicle maturation (28% vs 22%, p: 0.698), and infertility (18% vs 12%, p: 0.401) in group II compared with group I, but these results were not statistically significant. Eighty three percent of all the PCOS patients showed vitamin D deficiency while 35% were severely deficient. The serum 25-OH-vitamin D mean levels were 13.38 ± 6.48 ng/ml. Vitamin D deficiency was recompensed in 74% of the PCOS patients who had taken calcium & vitamin D supplementation. There was no correlation between BMI and 25-OH-VD before and after the treatment (p ≥ 0.01). CONCLUSION: This study showed the positive effects of calcium & vitamin D supplementation on weight loss, follicle maturation, menstrual regularity, and improvement of hyperandrogenism, in infertile women with PCOS.

[Treatment of hyperandrogenism and hyperinsulinemia in PCOS patients with essential amino acids. A pilot clinical study]. / Trattamento dell'perandrogenismo e dell'perinsulinemia con aminoacidi essenziali in pazienti affette da sindrome dell'ovaio policistico. Uno studio pilota.

AIM: Women with polycystic ovary syndrome (PCOS) report frequently hyperinsulinemia. The aim of this study was to evaluate the effects of 16-weeks therapy with essential amino acids supplements on metabolic and clinical indices in PCOS. METHODS: For this study ten women with PCOS and fasting hyperinsulinemia were enrolled. The study comprised 16 weeks of therapy with oral essential amino acids (Aminopril, NAMED, Milan, Italy) administered 4 g twice per day. Body mass index, hirsutism score, serum levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein B, lipoprotein(a), serum adrenal and ovarian androgens, fasting glucose and insulin concentrations, T, DHEAS, gonadotropins, and sex hormone-binding globulin (SHBG), were assessed before and after treatment with essential amino acids. RESULTS: A significant decrease in fasting insulin, total T, luteneizing hormone and follicle-stimulating hormone was reported after amino acids therapy and increase in SHBG, leading to a decrease in the free T index. In addition, a significant reduction in hirsutism score was reported. No significant decrease in mean body mass index and in lipid pattern was reported. CONCLUSION: A decline of insulin after treatment with essential amino acids was observed in women with PCOS as well as total and bioavailable T, leading to significant improvement of clinical symptoms of hyperandrogenism.

[Effects of modified longdan xiegan decoction on hyperandrogenism in patients with polycystic ovary syndrome of stagnant fire in Gan channel type].

OBJECTIVE: To observe the therapeutic effect of modified Longdan Xiegan Decoction (LXD) on hyperandrogenism in patients with polycystic ovary syndrome (POS) of stagnant fire in Gan channel type. METHODS: Forty-eight patients were divided into two groups: the LXD group (25 cases) treated with LXI) for 3 months, and the Diane-35 group (23 cases) with Diane-35. Condition of menstruation, acne, hairiness were observed, basal body temperature (BBT) was measured, and the serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), free testosterone (FT), and androstenedione (A) were detected before and after 3 months' treatment. Meanwhile, adverse reaction was observed. RESULTS: After treatment, the condition of menstrual disorder, acne and single-phase BBT were improved significantly, and serum levels of LH, LH/FSH, FT and A decreased in both groups (P < 0.05), showed insignificant difference between them (P > 0.05). The PRL level dropped in the LXD group (P < 0.05), which significantly lower than that in the Diane-35 group (P < 0.05). There were 3 cases with adverse reaction of irregular colporrhagia and 5 cases with nausea and vomiting in the Diane-35 group, while no adverse reaction in the LXD group occurred. CONCLUSION: Modified LXD could significantly improve the condition in hyperandrogenism patients with POS of stagnant fire in Gan channel type.

[Ovulation induction with adjuvant antiandrogen treatment in Stein-Leventhal syndrome]. / Az ovulatio inductio kiegészítése adjuváns antiandrogén kezeléssel Stein-Leventhal-syndromában.

Ovulation induction with adjuvant antiandrogen treatment was carried out in 50 cycles of 24 hyperandrogenic anovulatory patients. Besides the clomiphene and gonadotrophin (pure FSH) administration on the bases of antiandrogenic effects of the drugs three treatment groups (dexamethasone, sprinolactone and cyproterone acetate) were established. In 40 cases of 50 cycles ovulation were detected and 11 pregnancies occurred. The authors achieved the highest ovulation and pregnancy rate in the group treated with cyproterone acetate. The highest progesterone and the lowest testosterone levels were measured in the same group. According to our investigations adjuvant antiandrogen treatment with cyproterone acetate advisable in the cases of hyperandrongenic conditions.