Poseidon and Caeneus: a case of pubertal gender inversion in Greek mythology.

Disorders of sex development (DSDs) are very frequently encountered in ancient Greek mythology. One of the most striking types of DSD described in many myths is gender transformation wherein a female becomes a male or vice versa. Herein, we present via the marvelous myth of Poseidon and Caeneus a case of pubertal gender inversion. A medical interpretation of the myth whereby we attempt to form a diagnosis of this case of DSD is also presented.

Polycystic Ovary Syndrome Physiologic Pathways Implicated Through Clustering of Genetic Loci.

CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder, with disease loci identified from genome-wide association studies (GWAS) having largely unknown relationships to disease pathogenesis. OBJECTIVE: This work aimed to group PCOS GWAS loci into genetic clusters associated with disease pathophysiology. METHODS: Cluster analysis was performed for 60 PCOS-associated genetic variants and 49 traits using GWAS summary statistics. Cluster-specific PCOS partitioned polygenic scores (pPS) were generated and tested for association with clinical phenotypes in the Mass General Brigham Biobank (MGBB, N = 62 252). Associations with clinical outcomes (type 2 diabetes [T2D], coronary artery disease [CAD], and female reproductive traits) were assessed using both GWAS-based pPS (DIAMANTE, N = 898,130, CARDIOGRAM/UKBB, N = 547 261) and individual-level pPS in MGBB. RESULTS: Four PCOS genetic clusters were identified with top loci indicated as following: (i) cluster 1/obesity/insulin resistance (FTO); (ii) cluster 2/hormonal/menstrual cycle changes (FSHB); (iii) cluster 3/blood markers/inflammation (ATXN2/SH2B3); (iv) cluster 4/metabolic changes (MAF, SLC38A11). Cluster pPS were associated with distinct clinical traits: Cluster 1 with increased body mass index (P = 6.6 × 10-29); cluster 2 with increased age of menarche (P = 1.5 × 10-4); cluster 3 with multiple decreased blood markers, including mean platelet volume (P = 3.1 ×10-5); and cluster 4 with increased alkaline phosphatase (P = .007). PCOS genetic clusters GWAS-pPSs were also associated with disease outcomes: cluster 1 pPS with increased T2D (odds ratio [OR] 1.07; P = 7.3 × 10-50), with replication in MGBB all participants (OR 1.09, P = 2.7 × 10-7) and females only (OR 1.11, 4.8 × 10-5). CONCLUSION: Distinct genetic backgrounds in individuals with PCOS may underlie clinical heterogeneity and disease outcomes.

Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms.

Pathogenic SRY-box transcription factor 2 (SOX2) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. We examined exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) for pathogenic SOX2 variants to investigate the underlying pathogenic SOX2 spectrum and its associated phenotypes. We identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes. These variant proteins were tested in vitro to determine whether a causal relationship between IHH and SOX2 exists. We found that Sox2 was highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression in the anteroventral periventricular nucleus of adult female mice. In vitro, shRNA suppression of mouse SOX2 protein in Kiss-expressing cell lines increased the levels of human kisspeptin luciferase (hKiss-luc) transcription, while SOX2 overexpression repressed hKiss-luc transcription. Further, 4 of the identified SOX2 variants prevented this SOX2-mediated repression of hKiss-luc. Together, these data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, attesting to hypothalamic defects in the SOX2 disorder spectrum. Our study describes potentially novel mechanisms contributing to SOX2-related disease and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.

A functional spectrum of PROKR2 mutations identified in isolated hypogonadotropic hypogonadism.

Isolated hypogonadotropic hypogonadism (IHH) is a rare disease with hypogonadism and infertility caused by the defects in embryonic migration of hypothalamic gonadotropin-releasing hormone (GnRH) neurons, hypothalamic GnRH secretion or GnRH signal transduction. PROKR2 gene, encoding a G-protein coupled receptor PROKR2, is one of the most frequently mutated genes identified in IHH patients. However, the functional consequences of several PROKR2 mutants remain elusive. In this study, we systematically analyzed the Gαq, Gαs and ERK1/2 signaling of 23 IHH-associated PROKR2 mutations which are yet to be functionally characterized. We demonstrate that blockage of Gαq, instead of MAPK/ERK pathway, inhibited PROK2-induced migration of PROKR2-expressing cells, implying that PROKR2-related IHH results primarily due to Gαq signaling pathway disruption. Combined with previous reports, we categorized a total of 63 IHH-associated PROKR2 mutations into four distinct groups according Gαq pathway functionality: (i) neutral (N, >80% activity); (ii) low pathogenicity (L, 50-80% activity); (iii) medium pathogenicity (M, 20-50% activity) and (iv) high pathogenicity (H, <20% activity). We further compared the cell-based functional results with in silico mutational prediction programs. Our results indicated that while Sorting Intolerant from Tolerant predictions were accurate for transmembrane region mutations, mutations localized in the intracellular and extracellular domains were accurately predicted by the Combined Annotation Dependent Depletion prediction tool. Our results thus provide a functional database that can be used to guide diagnosis and appropriate genetic counseling in IHH patients with PROKR2 mutations.

Reproductive Phenotypes and Genotypes in Men With IHH.

CONTEXT: Isolated hypogonadotropic hypogonadism (IHH) is phenotypically and genetically heterogeneous. OBJECTIVE: This work aimed to determine the correlation between genotypic severity with pubertal and neuroendocrine phenotypes in IHH men. METHODS: A retrospective study was conducted (1980-2020) examining olfaction (Kallmann syndrome [KS] vs normosmic IHH [nHH]), baseline testicular volume (absent vs partial puberty), neuroendocrine profiling (pulsatile vs apulsatile luteinizing hormone [LH] secretion), and genetic variants in 62 IHH-associated genes through exome sequencing (ES). RESULTS: In total, 242 men (KS: n = 131 [54%], nHH: n = 111 [46%]) were included. Men with absent puberty had significantly lower gonadotropin levels (P < .001) and were more likely to have undetectable LH (P < .001). Logistic regression showed partial puberty as a statistically significant predictor of pulsatile LH secretion (R2 = 0.71, P < .001, OR: 10.8; 95% CI, 3.6-38.6). Serum LH of 2.10 IU/L had a 95% true positive rate for predicting LH pulsatility. Genetic analyses in 204 of 242 IHH men with ES data available revealed 36 of 204 (18%) men carried protein-truncating variants (PTVs) in 12 IHH genes. Men with absent puberty and apulsatile LH were enriched for oligogenic PTVs (P < .001), with variants in ANOS1 being the predominant PTV in this genotype-phenotype association. Men with absent puberty were enriched for ANOS1 PTVs compared to partial puberty counterparts (P = .002). PTVs in other IHH genes imparted more variable reproductive phenotypic severity. CONCLUSION: Partial puberty and LH greater than or equal to 2.10 IU/L are proxies for pulsatile LH secretion. ANOS1 PTVs confer severe reproductive phenotypes. Variable phenotypic severity in the face of severe genetic variants in other IHH genes point to significant neuroendocrine plasticity of the HPG axis in IHH men.

Adrenal aging and its effects on the stress response and immunosenescence.

Normal aging is linked to various endocrine gland changes, including changes in the adrenal glands. Aging is linked to alterations of the hypothalamic-pituitary-adrenal (HPA) axis, including an increase in cortisol levels, a disruption of the negative cortisol feedback, and attenuation of cortisol's diurnal pattern. In addition, secretion of aldosterone and adrenal androgens [dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)] from the adrenal cortex decreases with aging. In this review, we describe normal adrenal function, the adrenal response to stress and immunomodulation in aging individuals as well as the effects of adrenal aging on body composition, metabolic profile, bone health and cognition.

Endocrine disruptors in ancient times and Greek mythology: the spring of Salmacis and the curse of Hermaphroditus.

According to Greek mythology, the spring waters of Salmacis (or Salmakis) feminized the god Hermaphroditus (or Hermaphroditos) and transformed his nature from male to half-male and half-female. The mythical properties of these waters are described in the writings of authors and philosophers of the Hellenistic period. It is evident that the spring of Salmacis and lake actually existed (located in Halicarnassus, today Bodrum, Turkey) and are not the product of poetic imagination. Hence, it could be hypothesized that there were certain natural elements in the waters that had a feminizing effect on the male reproductive axis. We now know, in fact, that naturally occurring environmental agents, also known as endocrine disruptors, can affect the endocrine and reproductive function of both males and females. However, since most endocrine disruptors today are manmade products of the modern industrial lifestyle, the presence and effect of naturally occurring disruptors in times preceding the Industrial Revolution are not widely discussed. It is thus against this background that we seek to formulate a differential diagnosis of male feminization attributable to the effect of natural environmental factors in the form of endocrine disruptors that will have existed in environments round the globe since time immemorial. We conclude that if there had been an accumulation of the mycotoxin zearalenone (ZEA) in the waters of Salmacis, chronic exposure to the lake's water could have resulted in the phenotypic changes described in the Salmacis myth.

Prevalence and Phenotypic Effects of Copy Number Variants in Isolated Hypogonadotropic Hypogonadism.

CONTEXT: The genetic architecture of isolated hypogonadotropic hypogonadism (IHH) has not been completely defined. OBJECTIVE: To determine the role of copy number variants (CNVs) in IHH pathogenicity and define their phenotypic spectrum. METHODS: Exome sequencing (ES) data in IHH probands (n = 1394) (Kallmann syndrome [IHH with anosmia; KS], n = 706; normosmic IHH [nIHH], n = 688) and family members (n = 1092) at the Reproductive Endocrine Unit and the Center for Genomic Medicine of Massachusetts General Hospital were analyzed for CNVs and single nucleotide variants (SNVs)/indels in 62 known IHH genes. IHH subjects without SNVs/indels in known genes were considered "unsolved." Phenotypes associated with CNVs were evaluated through review of patient medical records. A total of 29 CNVs in 13 genes were detected (overall IHH cohort prevalence: ~2%). Almost all (28/29) CNVs occurred in unsolved IHH cases. While some genes (eg, ANOS1 and FGFR1) frequently harbor both CNVs and SNVs/indels, the mutational spectrum of others (eg, CHD7) was restricted to SNVs/indels. Syndromic phenotypes were seen in 83% and 63% of IHH subjects with multigenic and single gene CNVs, respectively. CONCLUSION: CNVs in known genes contribute to ~2% of IHH pathogenesis. Predictably, multigenic contiguous CNVs resulted in syndromic phenotypes. Syndromic phenotypes resulting from single gene CNVs validate pleiotropy of some IHH genes. Genome sequencing approaches are now needed to identify novel genes and/or other elusive variants (eg, noncoding/complex structural variants) that may explain the remaining missing etiology of IHH.

Newly diagnosed diabetes vs. pre-existing diabetes upon admission for COVID-19: Associated factors, short-term outcomes, and long-term glycemic phenotypes.

AIMS: High rates of newly diagnosed diabetes mellitus (NDDM) have been reported in association with coronavirus disease-2019 (COVID-19). Factors associated with NDDM and long-term glycemic outcomes are not known. METHODS: Retrospective review of individuals admitted with COVID-19 and diabetes mellitus (DM; based on labs, diagnoses, outpatient insulin use, or severe inpatient hyperglycemia) between March and September 2020, with follow-up through July 2021. RESULTS: Of 1902 individuals admitted with COVID-19, 594 (31.2%) had DM; 77 (13.0%) of these had NDDM. Compared to pre-existing DM, NDDM was more common in younger patients and less common in those of non-Hispanic White race/ethnicity. Glycemic parameters were lower and inflammatory markers higher in patients with NDDM. In adjusted models, NDDM was associated with lower insulin requirements, longer length of stay, and intensive care unit admission but not death. Of 64 survivors with NDDM, 36 (56.3%) continued to have DM, 26 (40.6%) regressed to normoglycemia or pre-diabetes, and 2 were unable to be classified at a median follow-up of 323 days. CONCLUSIONS: Diabetes diagnosed at COVID-19 presentation is associated with lower glucose but higher inflammatory markers and ICU admission, suggesting stress hyperglycemia as a major physiologic mechanism. Approximately half of such individuals experience regression of DM.

Teenage pregnancies in Western Greece: experience from a university hospital setting.

PURPOSE: Teenage pregnancies have consistently been associated with preterm labor in a wide range of studies. Evidence regarding the incidence and potential complications of teenage pregnancies in Greece is at present scarce. The aim of this study was to evaluate the perinatal outcomes as well as the risk of perinatal and obstetric complications of teenage pregnancies. METHODS: This retrospective study was conducted at the Department of Obstetrics and Gynecology of the University Hospital of Patras, Greece, and all data recorded concerned the year 2019 (January-December). We retrospectively reviewed 643 cases of singleton pregnancies divided into two groups, as follows: Group A included women of average maternal age (AMA) (20-34 years old), and Group B included teenagers, defined as women less than 20 years old. Data regarding demographic and pregnancy characteristics as well as obstetric and neonatal complications were collected. RESULTS: Teenage pregnancies accounted for 6.7% of all deliveries. We detected significantly higher rates of preterm births (p = 0.025), primiparity (p < 0.001), and negative marital status (p < 0.001) in teenage mothers compared to pregnant women of AMA. There were no significant differences concerning other factors between the two groups. CONCLUSIONS: The findings of the present study raise concern regarding the perinatal, obstetric, and social consequences of teenage pregnancies in Greece. Extended studies that will include further information on antenatal care and detailed socioeconomic factors (i.e., level of education, income, and ethnicity) are required to formulate reliable conclusions concerning teenage pregnancies and their effect on maternal and neonatal health.

Impaired Sexual Function in Young Women With PCOS: The Detrimental Effect of Anovulation.

BACKGROUND: Even though polycystic ovary syndrome (PCOS) is a common reproductive disorder affecting young women, its impact on their sexual health is not well known. AIM: To examine the different aspects of female sexuality in young women with PCOS and attempt to associate hormonal changes and ovulatory status with their sexual function. METHODS: Anthropometric characteristics, hormonal levels and sexual function based on the Female Sexual Function Index (FSFI) questionnaire were assessed in 76 young women with PCOS and 133 matched controls. OUTCOMES: Sexual function is significantly impaired in young women with PCOS. RESULTS: Women with PCOS demonstrated lower scores than controls in arousal (5.04 ± 1.19 vs 4.48 ± 1.44, P < .001), lubrication (5.29 ± 1.17 vs 4.69 ± 1.54, P < .001), orgasm (4.78 ± 1.40 vs 4.11 ± 1.61, P = .001), satisfaction (5.22 ± 1.10 vs 4.78 ± 1.31, P = .016), and total score of the FSFI (29.51 ± 5.83 vs 26.76 ± 6.81, P < .001), even after correction for BMI. When corrected for total testosterone, the domains of lubrication, satisfaction, and total score of FSFI remained significantly impaired in women with PCOS (P values .037, .024, & .044 respectively). In multivariate logistic regression analysis, after adjusting for the effect of BMI and hormone levels, dysfunction in orgasm, satisfaction and the total FSFI score were still 3-4 times more common in PCOS (adjusted OR [95% CI]: 3.54, P = .020; 2.96, P = .050; 3.87, P = .027). Even though no statistically significant differences were observed between women with ovulatory PCOS and controls, we detected statistically significant differences in all domains of sexual function apart from pain between controls and PCOS women with anovulation (desire P value .04, arousal P value <.001, lubrication P value <.001, orgasm P value .001, satisfaction P value .001 and FSFI total score P value <.001). CLINICAL IMPLICATIONS: Women with PCOS have compromised sexual function, which is independent of their BMI and highly dependent on their ovulatory status. STRENGTHS AND LIMITATIONS: This is the first study in women with PCOS that implicates anovulation as a risk factor for sexual impairment in PCOS. Further studies are needed to elucidate the mechanisms implicated and to examine the effect of PCOS therapy on the patients' sexual function. CONCLUSION: The adverse effect of PCOS status on the female sexual function is independent of BMI and only partially dependent on hormonal changes characterizing the syndrome. Anovulation appears to be the major determinant of sexual impairment among women with PCOS. Mantzou D, Stamou MI, Armeni AK, et al. Impaired Sexual Function in Young Women With PCOS: The Detrimental Effect of Anovulation. J Sex Med 2021;18:1872-1879.

A manless adultery: the story of Bassa as related in a Marcus Valerius Martialis' epigram.

During the Golden Age of the Roman Empire, Rome was transformed into a magnificent city where architecture, the arts, and commerce flourished. An inconceivable amount of wealth was accumulated by a handful of noble families, while the masses starved. In such a context, moral values inevitably decline, while sexual mores are liberalized and ever more veer towards salacity. This reality was elegantly illustrated in short, often sarcastic poems known as epigrams. Herein, we present a case of a woman with enigmatic appearance of the external genitalia, exhibiting unrestrained homosexual activity, as described in an epigram by Marcus Valerius Martialis (a contemporary poet who lived in the 1st century AD). Based on the information provided in the ancient text, we formulate a differential diagnosis and deduce that this woman was, in fact, a case of congenital adrenal hyperplasia (CAH). To our knowledge, this is the earliest literary description worldwide of a case of CAH as a cause of homosexuality and unquenchable lust.

Leucippus, either male or death: a case of sex reversal by divine intervention.

The concept of metamorphosis (change of form, structure, or substance) is very frequently encountered in Ancient Greek and Roman literature. One of the most striking types of metamorphosis described in many myths is gender transformation, where a man becomes a woman or vice versa. Herein, we present a case of pubertal gender inversion, the marvelous story of the Cretan Leucippus, which not only inspired many ancient writers but also led to the development of a distinct, local, religious cult. A medical interpretation of the myth, whereby we attempt to establish a diagnosis for this case of heterosexual puberty, is also provided.

Hypothalamic Ceramides and the Ovarian Sympathetic System: At the Crossroads of Obesity and Puberty.

Childhood obesity has been linked to early puberty in girls but the mechanism(s) by which overnutrition triggers pubertal onset remain unclear. In a recent issue of Cell Metabolism, Heras et al., 2020 implicate a non-canonical central ceramide to ovarian sympathetic innervation pathway as a novel mediator of obesity-induced pubertal acceleration in female rats.

Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism.

Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency (IGD) IGD is a genetically and clinically heterogeneous disorder. Mutations in many different genes are able to explain ~40% of the causes of IGD, with the rest of cases remaining genetically uncharacterized. While most mutations are inherited in X-linked, autosomal dominant, or autosomal recessive pattern, several IGD genes are shown to interact with each other in an oligogenic manner. In addition, while the genes involved in the pathogenesis of IGD act on either neurodevelopmental or neuroendocrine pathways, a subset of genes are involved in both pathways, acting as "overlap genes". Thus, some IGD genes play the role of the modifier genes or "second hits", providing an explanation for incomplete penetrance and variable expressivity associated with some IGD mutations. The clinical spectrum of IGD includes a variety of disorders including Kallmann Syndrome (KS), i.e. hypogonadotropic hypogonadism with anosmia, and its normosmic variation normosmic idiopathic hypogonadotropic hypogonadism (nIHH), which represent the most severe aspects of the disorder. Apart from these disorders, there are also "milder" and more common reproductive diseases associated with IGD, including hypothalamic amenorrhea (HA), constitutional delay of puberty (CDP) and adult-onset hypogonadotropic hypogonadism (AHH). Interestingly, neurodeveloplmental genes are associated with the KS form of IGD, due to the topographical link between the GnRH neurons and the olfactory placode. On the other hand, neuroendocrine genes are mostly linked to nIHH. However, a great deal of clinical and genetic overlap characterizes the spectrum of the IGD disorders. IGD is also characterized by a wide variety of non-reproductive features, including midline facial defects such as cleft lip and/or palate, renal agenesis, short metacarpals and other bone abnormalities, hearing loss, synkinesia, eye movement abnormalities, poor balance due to cerebellar ataxia, etc. Therefore, genetic screening should be offered in patients with IGD, as it can provide valuable information for genetic counseling and further understanding of IGD.

Sex differentiation with regard to coronary artery disease.

Coronary artery disease was considered a male disease for many years. However, nowadays, coronary artery disease constitutes the leading cause of death in women, although there are a lot of gender-related differences regarding the presentation of acute myocardial infarction, its diagnosis, its treatment, short- and long-term mortality rates, and post-acute myocardial infarction complications. Generally, women have smaller and stiffer hearts and cardiac vessels, suffering a greater extent of atherosclerosis and endothelial and smooth muscle dysfunction. They are usually older than men and they have more comorbidities such as hypertension, renal impairment, and diabetes mellitus. Moreover, female coronary artery disease, the diagnosis of which is more complicated due to more false negative results of some diagnostic methods in women, is more often presented with atypical symptoms and women's symptoms of typical or atypical angina are more severe. Furthermore, women delay significantly more in seeking care and they are more frequently undertreated. Finally, women are associated with generally poorer in-hospital and long-term prognosis having almost two-fold higher early mortality and they are more prone to complications such as bleeding complications, shock, and heart failure, as well as to post-myocardial infarction depression and poorer physical function and mental health. In this review, we discuss these sex-related differences according to current literature.