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Frontiers in Endocrinology 2024Differences/disorders of sex development (DSD) comprise a large group of rare congenital conditions. 46,XX DSD, excluding congenital adrenal hyperplasia (CAH), represent... (Review)
Review
Differences/disorders of sex development (DSD) comprise a large group of rare congenital conditions. 46,XX DSD, excluding congenital adrenal hyperplasia (CAH), represent only a small number of these diseases. Due to the rarity of non-CAH 46,XX DSD, data on this sex chromosomal aberration were confined to case reports or case series with small numbers of patients. As the literature is still relatively sparse, medical data on the long-term effects of these pathologies remain scarce. In this review, we aim to provide an overview of current data on the long-term follow-up of patients with non-CAH 46,XX DSD, by covering the following topics: quality of life, gender identity, fertility and sexuality, global health, bone and cardiometabolic effects, cancer risk, and mortality. As non-CAH 46,XX DSD is a very rare condition, we have no accurate data on adult QoL assessment for these patients. Various factors may contribute to a legitimate questioning about their gender identity, which may differ from their sex assigned at birth. A significant proportion of gender dysphoria has been reported in various series of 46,XX DSD patients. However, it is difficult to give an accurate prevalence of gender dysphoria and gender reassignment in non-CAH 46,XX DSD because of the rarity of the data. Whatever the aetiology of non-CAH 46,XX DSD, fertility seems to be impaired. On the other hand, sexuality appears preserved in 46,XX men, whereas it is impaired in women with MRKH syndrome before treatment. Although there is still a paucity of data on general health, bone and cardiometabolic effects, and mortality, it would appear that the 46,XX DSD condition is less severely affected than other DSD conditions. Further structured and continued multi-center follow-up is needed to provide more information on the long-term outcome of this very rare non-CAH 46,XX DSD condition.
Topics: Female; Humans; Male; 46, XX Disorders of Sex Development; Adrenal Hyperplasia, Congenital; Disorders of Sex Development; Fertility; Gender Identity; Quality of Life
PubMed: 38752171
DOI: 10.3389/fendo.2024.1372887 -
Current Opinion in Pediatrics Aug 2024Congenital adrenal hyperplasia (CAH) is a relatively common disorder and one of the most challenging conditions seen by pediatric endocrinologists. Poor linear growth in... (Review)
Review
PURPOSE OF REVIEW
Congenital adrenal hyperplasia (CAH) is a relatively common disorder and one of the most challenging conditions seen by pediatric endocrinologists. Poor linear growth in CAH has been recognized for many years. There are new insights to explain this abnormality and shed light on strategies to promote normal growth.
RECENT FINDINGS
Published data suggest that the dose of hydrocortisone during two critical periods of rapid growth, namely infancy and at puberty, has a fundamental effect on growth velocity, and by definition adult height. To prevent over-treatment, hydrocortisone dosage should remain within the range of 10-15 mg/m 2 body surface area per day. Precursor steroids such as 17-hydroxy progesterone (17OHP) should not be suppressed to undetectable levels. In fact, 17OHP should always be measurable, as complete suppression suggests over-treatment.
SUMMARY
CAH is a challenging disorder. High-quality compliance within the consultation setting, with the patient seeing the same specialist at every visit, will be rewarded by improved long-term growth potential. Quality auxological monitoring can avoid phases of growth suppression. New therapy with CRH receptor antagonists may lead to a more nuanced approach by allowing fine tuning of hydrocortisone replacement without the need to suppress ACTH secretion.
Topics: Humans; Adrenal Hyperplasia, Congenital; Child; Adolescent; Hydrocortisone; Body Height; Growth Disorders; Infant; Child, Preschool
PubMed: 38747200
DOI: 10.1097/MOP.0000000000001361 -
Medicine and Pharmacy Reports Apr 2024Congenital adrenal hyperplasia (CAH) is determined in the vast majority of cases by mutations in the gene, which cause the deficiency of the 21 hydroxylase enzyme,...
Approaching fertility in congenital adrenal hyperplasia: exploring P30L mutation-induced 21-hydroxylase deficiency with a presentation between non-classical and simple virilizing phenotypes. A case report.
Congenital adrenal hyperplasia (CAH) is determined in the vast majority of cases by mutations in the gene, which cause the deficiency of the 21 hydroxylase enzyme, which is involved in the synthesis of cortisol and aldosterone. Generally, CAH phenotype and disease severity can be predicted with the genotypes and is related to the residual activity of 21 hydroxylase enzyme. It is divided into classical CAH with salt wasting and simple virilizing forms and non-classical or late-onset CAH forms, respectively. Patients with 21 hydroxylase deficiency, including those with non-classic forms face immense challenges to their fertility. Glucocorticoid therapy has been shown to be useful in obtaining and maintaining a pregnancy among these patients, but it must be used with caution. Given the relevance of CAH in reproductive medicine as well as the diagnostic challenges posed by the phenotypic overlap with polycystic ovary syndrome and by overlap of its own phenotypes (classic CAH-nonclassic CAH), we present the case of a woman with CAH due to 21 hydroxylase deficiency caused by the P30L mutation with a clinical and biochemical presentation between the non-classical form and the classic simple virilizing form. Further, the successful fertility management in this patient and an overview of fertility management in CAH is depicted, as well.
PubMed: 38746038
DOI: 10.15386/mpr-2580 -
Cytokine Jul 2024Polycystic ovarian syndrome (PCOS) is one of the most common (about 5-20%) reproductive disorders in women of reproductive age; it is characterized by polycystic...
AIMS
Polycystic ovarian syndrome (PCOS) is one of the most common (about 5-20%) reproductive disorders in women of reproductive age; it is characterized by polycystic ovaries, hyperandrogenism, and oligo/ anovulation. The levels and expression of ovarian adipokines are deregulated in the PCOS. Apelin is an adipokine that acts through its receptor (APJ) and is known to express in the various tissues including the ovary. It has also been suggested that apelin and APJ could be targeted as therapeutic adjuncts for the management of PCOS. However, no study has been conducted on the management of PCOS by targeting the apelin system. Thus, we aimed to evaluate its impact on combating PCOS-associated ovarian pathogenesis.
METHODS
The current work employed a letrozole-induced-hyperandrogenism PCOS-like mice model to investigate the effects of apelin13 and APJ, antagonist ML221. The PCOS model was induced by oral administration of letrozole (1 mg/kg) for 21 days. A total of four experimental groups were made, control, PCOS control, PCOS + aplein13, and PCOS + ML221. The treatment of apelin13 and ML221 was given from day 22 for two weeks.
KEY FINDINGS
The letrozole-induced PCOS-like features such as hyperandrogenism, cystic follicle, decreased corpus luteum, elevated levels of LH/FSH ratio, and up-regulation of ovarian AR expression were ameliorated by apelin13 and ML221 treatment. However, the PCOS-augmented oxidative stress and apoptosis were suppressed by apelin 13 treatments only. ML221 treatment still showed elevated oxidative stress and stimulated apoptosis as reflected by decreased antioxidant enzymes and increased active caspase3 and Bax expression. The expression of ERs was elevated in all groups except control. Furthermore, the PCOS model showed elevated expression of APJ and apelin13 treatment down-regulated its own receptor. Overall, observing the ovarian histology, corpus luteum formation, and decreased androgen levels by both apelin13 and ML221 showed ameliorative effects on the cystic ovary.
SIGNIFICANCE
Despite the similar morphological observation of ovarian histology, apelin13 and ML221 exhibited opposite effects on oxidative stress and apoptosis. Therefore, apelin13 (which down-regulates APJ) and ML221 (an APJ antagonist) may have suppressed APJ signalling, which would account for our findings on the mitigation of polycystic ovarian syndrome. In conclusion, both apelin13 and ML221 mediated mitigation have different mechanisms, which need further investigation.
Topics: Letrozole; Polycystic Ovary Syndrome; Animals; Female; Apelin Receptors; Mice; Apelin; Ovary; Oxidative Stress; Hyperandrogenism; Apoptosis; Disease Models, Animal
PubMed: 38733946
DOI: 10.1016/j.cyto.2024.156639 -
Gynecological Endocrinology : the... Dec 2024This study aimed to investigate the impact of serum androgen levels on metabolic profiles in patients with polycystic ovary syndrome (PCOS).
OBJECTIVE
This study aimed to investigate the impact of serum androgen levels on metabolic profiles in patients with polycystic ovary syndrome (PCOS).
METHODS
We included 216 patients with PCOS and 216 healthy individuals selected as the control group. According to the measured serum androgen levels, patients with PCOS were divided into the hyperandrogenism group and non-hyperandrogenism group. Clinical metabolic indicators were assessed and compared between the two groups. Additionally, we assessed the correlation between androgen levels and clinical metabolic indicators.
RESULTS
The body mass index, waist-to-hip ratio, mF-G score, and acne score, as well as T, LH, LSH/FSH, FPG, Cr, UA, TG, TC, and LDL-C levels were significantly higher in the PCOS group than in the control group. The incidence of hyperandrogenism and clinical hyperandrogenism in the PCOS group was significantly higher than that in the control group. Regarding clinical hyperandrogenism, hirsutism, acne, and acanthosis nigricans were significantly more common in the PCOS group than in the control group. Serum androgen levels were significantly correlated with the mF-G score, acne score, FSH, glucose concentration at 30 min, glucose concentration at 60 min, glucose concentration at 120 min, FINS, N120, HOMA-IR, HbA1c, AUCG, UA, TG, and hHDL-Clevels.
CONCLUSION
Elevated serum androgen levels are commonly observed in patients with PCOS and are associated with multiple metabolic abnormalities. Therefore, it is recommended to regularly monitor glucose and lipid metabolism-related indicators in patients with PCOS who have elevated androgen levels.
Topics: Humans; Polycystic Ovary Syndrome; Female; Adult; Hyperandrogenism; Androgens; Young Adult; Case-Control Studies; Body Mass Index; Metabolome; Acne Vulgaris; Insulin Resistance
PubMed: 38733359
DOI: 10.1080/09513590.2024.2352136 -
The European Journal of Neuroscience May 2024Previous studies have reported sex differences in cortical gyrification. Since most cortical folding is principally defined in utero, sex chromosomes as well as gonadal...
Previous studies have reported sex differences in cortical gyrification. Since most cortical folding is principally defined in utero, sex chromosomes as well as gonadal hormones are likely to influence sex-specific aspects of local gyrification. Classic congenital adrenal hyperplasia (CAH) causes high levels of androgens during gestation in females, whereas levels in males are largely within the typical male range. Therefore, CAH provides an opportunity to study the possible effects of prenatal androgens on cortical gyrification. Here, we examined the vertex-wise absolute mean curvature-a common estimate for cortical gyrification-in individuals with CAH (33 women and 20 men) and pair-wise matched controls (33 women and 20 men). There was no significant main effect of CAH and no significant CAH-by-sex interaction. However, there was a significant main effect of sex in five cortical regions, where gyrification was increased in women compared to men. These regions were located on the lateral surface of the brain, specifically left middle frontal (rostral and caudal), right inferior frontal, left inferior parietal, and right occipital. There was no cortical region where gyrification was increased in men compared to women. Our findings do not only confirm prior reports of increased cortical gyrification in female brains but also suggest that cortical gyrification is not significantly affected by prenatal androgen exposure. Instead, cortical gyrification might be determined by sex chromosomes either directly or indirectly-the latter potentially by affecting the underlying architecture of the cortex or the size of the intracranial cavity, which is smaller in women.
PubMed: 38733283
DOI: 10.1111/ejn.16391 -
Endocrine May 2024In females with congenital adrenal hyperplasia (CAH), the influence of hyperandrogenism and glucocorticoid supplementation on neurocognition is controversial.
INTRODUCTION
In females with congenital adrenal hyperplasia (CAH), the influence of hyperandrogenism and glucocorticoid supplementation on neurocognition is controversial.
OBJECTIVES
To identify possible differences in visual working memory and verbal memory in adolescent girls with CAH due to 21-hydroxylase deficiency and matched controls. Moreover, to study if any relationship between variables associated with CAH and the scores of the selected memory tests was present.
MATERIAL AND METHODS
In total 39 individuals were studied, female adolescents with CAH and age and pubertal stage matched healthy male and female controls (13 in each group). Sociodemographic, clinical, hormonal, and neurocognitive variables were explored. In female adolescents with CAH, variables related to the disease (age at diagnosis, clinical form, time since diagnosis, and glucocorticoid doses) were correlated with the scores obtained for neurocognitive variables.
RESULTS
The mean age was 13.9 ± 3.3 years. In female adolescents with CAH the results were worse compared to controls in Free Recall (p = 0.039) and in Visual Memory Span score (p = 0.016). Age at diagnosis was negatively correlated to number of hits (p = 0.04), number recalled backward (p = 0.03), Visual Memory Span test score (p = 0.04) and Total Free Recall (p = 0.04), i.e., memory was worse with later diagnosis.
CONCLUSIONS
Female adolescents with CAH had worse visual working memory compared to matched controls, but not in verbal memory. Age at diagnosis was negatively associated with the memory tests.
PubMed: 38727867
DOI: 10.1007/s12020-024-03806-3 -
Acta Paediatrica (Oslo, Norway : 1992) Jul 2024
Topics: Humans; Polycystic Ovary Syndrome; Female; Adolescent; Contraceptives, Oral, Combined; Hyperandrogenism; Androgens
PubMed: 38727034
DOI: 10.1111/apa.17271 -
American Journal of Reproductive... May 2024Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder characterized by oligo-anovulation, hyperandrogenism, and polycystic ovaries, with...
BACKGROUND
Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder characterized by oligo-anovulation, hyperandrogenism, and polycystic ovaries, with hyperandrogenism being the most prominent feature of PCOS patients. However, whether excessive androgens also exist in the ovarian microenvironment of patients with PCOS, and their modulatory role on ovarian immune homeostasis and ovarian function, is not clear.
METHODS
Follicular fluid samples from patients participating in their first in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment were collected. Androgen concentration of follicular fluid was assayed by chemiluminescence, and the macrophage M1:M2 ratio was detected by flow cytometry. In an in vitro model, we examined the regulatory effects of different concentrations of androgen on macrophage differentiation and glucose metabolism levels using qRT-PCR, Simple Western and multi-factor flow cytometry assay. In a co-culture model, we assessed the effect of a hyperandrogenic environment in the presence or absence of macrophages on the function of granulosa cells using qRT-PCR, Simple Western, EdU assay, cell cycle assay, and multi-factor flow cytometry assay.
RESULTS
The results showed that a significantly higher androgen level and M1:M2 ratio in the follicular fluid of PCOS patients with hyperandrogenism. The hyperandrogenic environment promoted the expression of pro-inflammatory and glycolysis-related molecules and inhibited the expression of anti-inflammatory and oxidative phosphorylation-related molecules in macrophages. In the presence of macrophages, a hyperandrogenic environment significantly downregulated the function of granulosa cells.
CONCLUSION
There is a hyperandrogenic microenvironment in the ovary of PCOS patients with hyperandrogenism. Hyperandrogenic microenvironment can promote the activation of ovarian macrophages to M1, which may be associated with the reprogramming of macrophage glucose metabolism. The increased secretion of pro-inflammatory cytokines by macrophages in the hyperandrogenic microenvironment would impair the normal function of granulosa cells and interfere with normal ovarian follicle growth and development.
Topics: Humans; Polycystic Ovary Syndrome; Female; Granulosa Cells; Macrophages; Hyperandrogenism; Adult; Follicular Fluid; Androgens; Cells, Cultured; Macrophage Activation; Cellular Microenvironment; Coculture Techniques; Cell Differentiation
PubMed: 38716832
DOI: 10.1111/aji.13854 -
The Journal of Clinical Endocrinology... May 2024Measuring health-related quality of life (HRQoL) is a crucial aspect of evaluating health care outcomes. Patients with congenital adrenal hyperplasia (CAH) often...
CONTEXT
Measuring health-related quality of life (HRQoL) is a crucial aspect of evaluating health care outcomes. Patients with congenital adrenal hyperplasia (CAH) often self-report deficiencies in HRQoL.
OBJECTIVE
The aim of our study was to develop a disease-specific patient reported outcome (PRO) instrument to evaluate the HRQoL of patients >16 years old with classic congenital adrenal hyperplasia (CAH).
DESIGN, SETTING AND OUTCOMES
Following the FDA guidelines for developing PRO instruments, we developed a conceptual framework for the instrument. A preliminary instrument was created after interviewing a representative sample of 12 patients with CAH between 16 to 68 years old and 3 parents, and obtaining expert feedback from 4 endocrinologists. The instrument was edited after cognitive interviews with 6 patients. Internal consistency of the instrument was evaluated using Cronbach's alpha. Validity was assessed by comparing the scores of our instrument with scores from widely used validated instruments for HRQoL and PRO not specific to CAH.
RESULTS
Sixty-nine patients 16 to 75 years old participated in validating our preliminary instrument. The final questionnaire consists of 44 questions within 7 domains: General Health, Adrenal Insufficiency, Glucocorticoid Excess, Physical Functioning, Mental Health and Cognition, Social Functioning, and Sexual Functioning, with acceptable internal consistency (Chronbach's alpha≥0.6) and validity (r = -0.350 to 0.866).
CONCLUSION
CAHQL is the first validated PRO instrument to capture disease specific HRQoL outcomes in CAH. In addition to its anticipated use in the clinical setting, the instrument could be used to assess the efficacy of novel treatments in development.
PubMed: 38706369
DOI: 10.1210/clinem/dgae309