Fetal hormones and sexual differentiation

The process of fetal sexual differentiation, which involves establishment of genetic sex, differentiation of the gonads, and development of phenotypic sex, is summarized. The morphologic changes that occur in utero that lead to development of the male and female gonads, germ cells, reproductive tracts, and external genitalia are described. Most of the article focuses on the hormones that regulate sexual differentiation and development in utero. The genetic factors that regulate sexual differentiation, which constitute a new and emerging field, also are discussed.     

Sexual differentiation of the human brain: relevance for gender identity, transsexualism and sexual orientation.

Male sexual differentiation of the brain and behavior are thought, on the basis of experiments in rodents, to be caused by androgens, following conversion to estrogens. However, observations in human subjects with genetic and other disorders show that direct effects of testosterone on the developing fetal brain are of major importance for the development of male gender identity and male heterosexual orientation. Solid evidence for the importance of postnatal social factors is lacking. In the human brain, structural diferences have been described that seem to be related to gender identity and sexual orientation.     

Antenatal events causing neonatal brain injury in premature infants

Understanding possible causes of neonatal brain injury is important for perinatal nurses because neonatal brain injury predicts subsequent infant mortality and morbidity in the premature infant. The pathogenesis of the brain injury, germinal matrix/intraventricular hemorrhage and white matter damage, is usually related to a hypoxic event. The hypoxic event may occur in utero, resulting from various conditions, such as maternal infection, maternal alcohol consumption, maternal smoking, placental bleeding disorders, maternal hypercoagulability conditions, metabolic disorders (diabetes and hyperthyroidism), and oligohydramnios. Strategies for prevention beginning before and in pregnancy are needed.     

?strogene im Gehirn

In the brain, estrogens have a variety of functions: they regulate sexual differentiation, sexual behavior, and neuronal activity and demonstrate neuroprotective actions. In neuronal tissue, genomic estrogen effects can be distinguished from rapid, non-genomic effects through cellular signal transduction. The genomic effects are mediated by nuclear estrogen receptors (ER?? and ER??), whereas the non-genomic effects are very likely to depend on membranous ERs. Estrogens are synthesized by aromatase, an enzyme that is expressed in various brain regions. A brain-specific promoter regulates the tissue-specific expression of the aromatase gene. The aromatase activity can rapidly be regulated by phosphorylation and is influenced by neuronal activity. Preclinical studies demonstrate the protective effects of estrogens with respect to neurodegenerative diseases, such as stroke. More research will be necessary in order to close the gap between these preclinical results and data from clinical trials and to develop estrogen therapies for neuronal diseases.     

Multifunctional Pharmacology of Flibanserin: Possible Mechanism of Therapeutic Action in Hypoactive Sexual Desire Disorder

IntroductionFlibanserin is a novel pharmacologic agent in late‐stage clinical testing for hypoactive sexual desire disorder (HSDD) in premenopausal women.AimThe aim of this article is to review the hypothetical mechanism of action of flibanserin in HSDD.MethodsA literature review was conducted of all published works on flibanserin and on related studies of serotonin (5‐HT)_1A receptors and 5‐HT_2A receptors, including their actions on monoamines and on sexual function.Main Outcome MeasuresThe main outcome measures are preclinical pharmacologic actions, especially changes in regional monoamines following treatment with flibanserin.ResultsAt clinically relevant doses, flibanserin acts predominantly at 5‐HT_1A receptors as an agonist and secondarily at 5‐HT_2A receptors as an antagonist. Additional binding actions within an order of magnitude of its 5‐HT_1A affinity, which are not likely to be clinically relevant, include weaker antagonist actions at 5‐HT_2C and 5‐HT_2B receptors, and less defined activity at dopamine (DA) D4 receptors. The 5‐HT_1A actions of flibanserin are only seen postsynaptically, which is unlike other agents such as buspirone that act at presynaptic 5‐HT_1A receptors. Furthermore, the postsynaptic actions of chronic flibanserin administration appear to demonstrate a preference for some populations of postsynaptic 5‐HT receptors, particularly those that are located on the prefrontal cortex (PFC) pyramidal neurons, which regulate monoamine release in certain selective brain regions.ConclusionsThe regional selectivity of flibanserin results in a unique pattern of monoamine modulation. Sustained increases in baseline of DA and norepinephrine (NE) are observed in the PFC, and flibanserin dosing increases DA and NE levels above the basal changes. Conversely, flibanserin induces transient decreases in 5‐HT levels in some brain areas such as the PFC, nucleus accumbens, and hypothalamus, but not in other brain areas such as the hippocampus. Therefore, since DA and NE are excitatory and 5‐HT is inhibitory to sexual desire and arousal, it is tempting to postulate that the actions of flibanserin on serotonin receptors at the PFC pyramidal neurons, resulting in increased DA and NE yet reduced 5‐HT in the PFC, are the mechanistic underpinnings of enhancing sexual desire in HSDD. Stahl SM, Sommer B, and Allers KA. Multifunctional pharmacology of flibanserin: Possible mechanism of therapeutic action in hypoactive sexual desire disorder. J Sex Med 2011;8:15–27.     

REVIEW: New Electroencephalogram (EEG) Neuroimaging Methods of Analyzing Brain Activity Applicable to the Study of Human Sexual Response

IntroductionElectroencephalogram (EEG) combined with brain source localization algorithms is becoming a powerful tool in the neuroimaging study of human cerebral functions.AimThe present article provides a tutorial on the various EEG methods currently used to study the human brain activity, notably during sexual response.Main Outcome MeasuresReview of published literature on standard EEG waveform analyses and most recent electrical neuroimaging techniques (microstate approach and two methods of brain source localization).MethodsRetrospective overview of pertinent literature.ResultsAlthough the standard EEG waveform analyses enable millisecond time-resolution information about the human sexual responses in the brain, less is clear about their related spatial information. Nowadays, the improvement of EEG techniques and statistical approaches allows the visualization of the dynamics of the human sexual response with a higher spatiotemporal resolution. Here, we describe these enhanced techniques and summarize along with an overview of what we have learned from them in terms of chronoarchitecture of sexual response in the human brain. Finally, the speculation on how we may be able to use other enhanced approaches, such as independent component analysis, are also presented.ConclusionsEEG neuroimaging has already been proven as a strong worthwhile research tool. Combining this approach with standard EEG waveform analyses in sexual medicine may provide a better understanding of the neural activity underlying the human sexual response in both healthy and clinical populations. Ortigue S, Patel N, and Bianchi-Demicheli F. New EEG neuroimaging methods of analyzing brain activity applicable to the study of human sexual response. J Sex Med 2009;6:1830–1845.     

The role of testosterone in sexuality and paraphilia--a neurobiological approach. Part I: testosterone and sexuality

IntroductionAntiandrogen therapy has been used for 30 years to treat paraphilic patients and sexual offenders. Yet the therapeutic success of antiandrogens is uncertain. Furthermore, there is still a lack of comprehensive knowledge about the effects of androgen‐lowering therapy in paraphilic patients.AimThis article reviews current neurobiological and clinical knowledge about testosterone and its impact on sexuality, acquired from animal and human basic research. This knowledge may not only enhance our understanding of the great variability of the therapeutic outcome, but could also offer new opportunities to evaluate the effect of androgen‐lowering therapy in paraphilia.MethodsA comprehensive review of the human and animal literature is presented, considering the classical and non‐classical mechanisms of androgens and the androgen brain receptors. Furthermore, the clinical evidence about the impact of testosterone on human sexual behavior is discussed. These are integrated into two current neurobiological theories of sexual behavior, the four‐component model and the dual‐control model.ResultsThe wide distribution of androgen receptors throughout the whole brain and their numerous mechanisms demonstrate that androgens can modulate almost every aspect of sexual behavior—i.e., not only autonomic functions, but also emotional, motivational, and cognitive aspects. Furthermore, testosterone participates in excitatory and inhibitory processes of sexual functions by modulating the activity of mainly dopaminergic neurotransmitter systems.ConclusionsUsing the data presented, we combine the two models and present a new integrated approach to understand the role of testosterone in the excitation and inhibition of sexual function, at the neurochemical, neuroanatomical, and behavioral levels. This knowledge will help us to gain a better understanding of the few and inconsistent data that are currently available concerning (i) the association between testosterone and paraphilic behavior; and (ii) the highly variable effects of antiandrogen therapy, discussed in Part II of this review. Jordan K, Fromberger P, Stolpmann G, and Müller JL. The role of testosterone in sexuality and paraphilia—A neurobiological approach. Part I: Testosterone and Sexuality. J Sex Med 2011;8:2993–3007.     

Functional Magnetic Resonance Imaging Detects Between-Group Differences in Neural Activation Among Men with Delayed Orgasm Compared with Normal Controls: Preliminary Report

BackgroundMechanisms underlying delayed orgasm (DO) are poorly understood; however, known effects of psychotropic medications on sexual function provides a rationale for aberrant central nervous system signaling as a cause.AimTo compare brain activation between men with normal orgasm and those with lifelong DO during sexual stimulation using brain fMRI algorithms.Methods3 subjects with self-reported life-long DO and 6 normal controls were included in this study. The International Index of Erectile Function, Male Sexual Health Questionnaire, and self-reported time to orgasm were used to assess sexual function. Subjects underwent a 3-T fMRI study while viewing 3 video clips: a neutral control (NC), a positive emotional control (EC), and a sexual condition (SC). Each video sequence was repeated 5 times, with 50-second clips presented in a randomized fashion. fMRI data were analyzed in a block design manner to determine areas of differential brain activation between groups. The Allen Brain Atlas of gene expression in the human brain was used to identify signaling pathways in the areas of differential fMRI activation between the DO and control groups.OutcomesThe primary outcome was differential activation of fMRI neural activation between groups.ResultsAnalysis of differential activation in the SC compared with the NC and EC revealed increased activation in the right frontal operculum (P = .003), right prefrontal gyrus (P = .003), and inferior occipital gyrus (P = .003). Increased activation in the right fusiform gyrus of the occipital lobe and the right hippocampus (P = .0004) was seen in the DO group compared with controls. Using the Allen Atlas of Human Brain Expression, we identified corresponding neurotransmitter receptors to this region, including adenosine receptors, muscarinic and nicotinic cholinergic receptors, cannabinoid receptors, and dopamine receptors, among others.Clinical ImplicationsLifelong DO in men may be due to abnormal neurotransmitter signaling leading to poor progression of arousal due to aberrant processing of sexual cues. Identification of neurotransmitter pathways by fMRI will aid the development of pharmacotherapeutic agents.Strengths & LimitationsStrengths of this study include the novel application of functional neuroimaging to investigate the pathogenesis of DO. Limitations include the small sample size, making this study exploratory in nature.ConclusionThis study revealed differences in brain activation on visualization of sexual stimuli in men with a history of DO compared with controls. Identified regions are rich in numerous neurotransmitter receptor subtypes and may be amenable to pharmacologic targeting to identify novel therapies for these men.Flannigan R, Heier L, Voss H, et al. Functional Magnetic Resonance Imaging Detects Between-Group Differences in Neural Activation Among Men with Delayed Orgasm Compared with Normal Controls: Preliminary Report. J Sex Med 2019:16;1246–1254.     

Cardiotocographic and sonographic findings in two cases of antenatally diagnosed intrauterine fetal brain death.

Intrauterine fetal brain death is a rare cause of a fixed fetal heart rate pattern. Seven cases have been previously reported in the literature, but only two of them were diagnosed prenatally and all the newborns died soon after delivery. Two additional cases of antepartum diagnosis of intrauterine fetal brain death, managed expectantly, are reported. We had the unique opportunity to document progressive sonographic cerebral changes during the follow-up period, following the neurological event, while the fetus continued life and growth in utero. The cardiographic and sonographic findings suggesting intrauterine fetal brain death were a prolonged fixed fetal heart rate, even following a vibroacoustic and contraction stress test; an atonic fetus without breathing and body movement; and the appearance of hydramnios and the development of ventriculomegaly.     

Effects of neonatal sexual differentiation, growth hormone and testosterone on thymic weights and thymosin-beta 4 in hypophysectomized rats

Experiments were conducted to analyze the effects of growth hormone and testosterone in conjunction with the effects of neonatal sexual differentiation (via castration of males at days 2 or 11 of age and androgenization of females at day 3 of age) on thymic weight and thymosin-beta 4 concentrations in hypophysectomized rats (day 30 of age). Ten days post-hypophysectomy, hormonal treatments were initiated on males, male castrates, females, and androgenized females. Growth hormone (25 micrograms daily), testosterone propionate (100 micrograms/day), and the combination of the two hormonal treatments were administered for seven days, then thymic weights and blood samples were collected. Administration of growth hormone to hypophysectomized rats increased thymosin-beta 4 concentration in a dose-dependent manner, but injection of testosterone had no effect on thymosin-beta 4 concentrations. Testosterone treatment decreased thymic weights whereas growth hormone increased thymic weights. Hypophysectomized males had increased thymosin-beta 4 concentrations compared with female and neonatally-androgenized female rats. However, hypophysectomy eliminated any thymic weight differences between males and females. The data support a possible endocrine role for the thymus gland and thymic peptides in that they are integrated into the control and support of other endocrine systems. Although differences in thymosin-beta 4 concentrations were noted between males and females, sexual differentiation of the immune system was unaltered by neonatal castration of males or testosterone treatment of females and may indicate sexual differences in immune function are established in utero.     

Neural bases of hypoactive sexual desire disorder in women: an event-related FMRI study

IntroductionAlthough there is an abundant debate regarding the mechanisms sustaining one of the most common sexual complaints among women, i.e., female hypoactive sexual desire disorder (HSDD), little remains known about the specific neural bases of this disorder.AimThe main goal of this study was to determine whether women with HSDD showed differential patterns of activation within the brain network that is active for sexual desire in subjects without HSDD.MethodsA total of 28 right‐handed women participated in this study (mean age 31.1 ± 7.02 years). Thirteen out of the 28 women had HSDD (HSDD participants), while 15 women reported no hypoactive sexual desire disorder (NHSDD participants). Using event‐related functional magnetic resonance imaging (fMRI), we compared the regional cerebral blood flow responses between these two groups of participants, while they were looking at erotic vs. non‐erotic stimuli.Main Outcome MeasureBlood‐oxygenation level dependent (BOLD) signal changes in response to erotic stimuli (compared with non‐erotic stimuli). Statistical Parametric Mapping was used to identify brain regions that demonstrated significant differential activations between stimuli and between groups.ResultsAs expected, behavioral results showed that NHSDD participants rated erotic stimuli significantly higher than HSDD participants did on a 10‐point desirable scale. No rating difference was observed for the non‐erotic stimuli between NHSDD and HSDD participants. Our functional neuroimaging results extended these data by demonstrating two distinct types of neural changes in participants with and without HSDD. In comparison with HSDD participants, participants without HSDD demonstrated more activation in brain areas involved in the processing of erotic stimuli, including intraparietal sulcus, dorsal anterior cingulate gyrus, and ento/perirhinal region. Interestingly, HSDD participants also showed additional activations in brain areas associated with higher order social and cognitive functions, such as inferior parietal lobule, inferior frontal gyrus, and posterior medial occipital gyrus.ConclusionTogether, these findings indicate that HSDD participants do not only show a hypo activation in brain areas mediating sexual desire, but also a different brain network of hyper activation, which might reflect differences in subjective, social, and cognitive interpretations of erotic stimuli. Collectively, these data are in line with the incentive motivation model of sexual functioning. Bianchi‐Demicheli F, Cojan Y, Waber L, Recordon N, Vuilleumier P, and Ortigue S. Neural bases of hypoactive sexual desire disorder in women: An event‐related fMRI study. J Sex Med 2011;8:2546–2559.     

Unusual Presentation of Disorder of Sexual Differentiation

Disorders of sexual differentiation are generally detected in childhood or adolescence. The abdominal gonads may undergo malignant transformation, although the incidence is variable (3–30%), as is the age of presentation with malignancy. We report a case of a Sertoli cell adenoma occurring in an elderly woman who was not previously known to have a disorder of sexual differentiation. A brief review of the complete androgen insensitivity syndrome is made and other possible sexual differentiation disorders presenting with this phenotype are discussed. Histopathologic differential diagnostic pitfalls that can occur in such patients are also discussed. When these conditions are first recognized in adulthood, it is important that the patient's pre-existing sexual identity is not negated on the basis of genotypic results.     

Differential expression and the anti-apoptotic effect of human placental neurotrophins and their receptors

Neurotrophin (NT) is important in the survival, maintenance and differentiation of neuronal tissue, and functions in follicle maturation, tumor growth, angiogenesis and immunomodulation; however, the expression of NT and its receptors (NTR) in human placenta and their influence on fetal growth are unclear. Here we investigated the correlation of NT and NTR in human placenta with uterine environment and fetal growth. TrkB, a NTR, mRNA was expressed on decidual and villous tissue and increased with gestational age, localizing in the trophoblast layer and endothelium by immunohistochemistry. Villous TrkB mRNA was significantly increased in preeclampsia (PE) than in controls and was higher in the normotensive small for gestational age (SGA) placenta, although it was not significant. It was also significantly increased in the small twin of discordant twin pregnancies. Brain-derived neurotrophic factor (BDNF), the main ligand of TrkB, was expressed in membranous chorion and villous tissue and was significantly higher in maternal plasma in normotensive SGA and PE than in controls. TrkB mRNA expression was up-regulated on cultured villous tissue explants and on JEG-3, a choriocarcinoma cell line, by H₂O₂ treatment. BDNF decreased apoptotic cells in H₂O₂-treated JEG-3, indicating that BDNF/TrkB signaling had anti-apoptotic effects against oxidative stress in JEG-3, suggesting a protective role of BDNF/TrkB in human villous tissue under unfavorable conditions in utero.     

Human placental explants in culture: approaches and assessments

Placental explant cultures in vitro are useful for studying tissue functions including cellular uptake, production and release of secretory components, cell interactions, proliferation, growth and differentiation, gene delivery, pharmacology, toxicology, and disease processes. A variety of culture conditions are required to mimic in utero environments at different times of gestation including differing oxygen partial pressures, extracellular matrices and culture medium. Optimization of explant methods is examined for first and third trimester human placental tissue and the biological processes under investigation.     

Factors Influencing the Time of Introduction of Steroidal Contraception in the Breast-Feeding Mother

To ensure infertility whilst breast feeding many mothers ingest steroidal contraceptives. Animal experiments have shown how sexual differentiation of the brain occurs during perinatal life and can be affected by exogenous steroids. The amount of sex steroid secreted in the milk of lactating mothers is very small and dependent on the type of steroid chosen. "On demand" breast feeding is associated with a longer period of lactational amenorrhoea, obviating the necessity for early usage of contraceptives. In view of the possibility that sexual differentiation may be disturbed, it is suggested that, where steroidal contraception is required, the progesterone with the minimal amount of oestrogenic metabolite be used.     

Human rights accountability for maternal death and failure to provide safe, legal abortion: the significance of two ground-breaking CEDAW decisions

In 2011, the Committee on the Elimination of Discrimination against Women (CEDAW) issued two landmark decisions. In Alyne da Silva Pimentel v. Brazil, the first maternal death case decided by an international human rights body, it confirms that States have a human rights obligation to guarantee that all women, irrespective of their income or racial background, have access to timely, non-discriminatory, and appropriate maternal health services. In L.C. v. Peru, concerning a 13-year-old rape victim who was denied a therapeutic abortion and had an operation on her spine delayed that left her seriously disabled as a result, it established that the State should guarantee access to abortion when a woman's physical or mental health is in danger, decriminalise abortion when pregnancy results from rape or sexual abuse, review its restrictive interpretation of therapeutic abortion and establish a mechanism to ensure that reproductive rights are understood and observed in all health care facilities. Both cases affirm that accessible and good quality health services are vital to women's human rights and expand States' obligations in relation to these. They also affirm that States must ensure national accountability for sexual and reproductive health rights, and provide remedies and redress in the event of violations. And they reaffirm the importance of international human rights bodies as sources of accountability for sexual and reproductive rights violations, especially where national accountability is absent or ineffective.     

In utero development of fetal thirst and appetite: potential for programming

Thirst and appetite-mediated ingestive behavior develop and are likely programmed in utero, thus preparing for newborn and adult ingestive behavior. Fetal swallowing activity is markedly different from that of the adult, as spontaneous fetal swallowing occurs at a markedly (six-fold) higher rate compared with spontaneous adult drinking activity. This high rate of fetal swallowing is critical for the regulation of amniotic fluid volume and the development of the fetal gastrointestinal tract. Disordered fetal swallowing has been associated with both a decrease (oligohydramnios) and increase (polyhydramnios) in amniotic fluid volume. Both conditions are associated with a significant increase in perinatal morbidity and mortality, and limited treatment modalities are currently available. The mechanisms underlying the high rate of human fetal swallowing are regulated, in part, by tonic activity of central angiotensin II, glutamate N-methyl-D-aspartate receptors, and neuronal nitric oxide synthase. Fetal hypertonicity-mediated dipsogenesis is likely programmed in utero, as offspring of water-restricted ewes demonstrate a programmed syndrome of plasma hypertonicity, with significant hematologic and cardiovascular alterations. Similar to dipsogenic mechanisms, peripheral and central fetal orexic mechanisms also develop in utero, as demonstrated by increased fetal swallowing after both oral sucrose infusion and central injection of neuropeptide Y. The role of leptin in regulating fetal ingestive behavior is interesting because, contrary to actions in adults, leptin does not suppress fetal ingestive behavior. Teleologically, this may be of value during the newborn period, as unopposed appetite stimulatory mechanisms may facilitate rapid fetal and newborn weight gain. An adverse intrauterine environment, with altered fetal orexic factors during the critical developmental period of fetal life, may alter the normal setpoints of appetitive behavior and potentially lead to programming of adulthood hyperphagia and obesity. Further research is needed to delineate the mechanistic relationship between the intrauterine environment and the development of the setpoints of adult appetite and thirst.     

Can We Deliver Better?

Human childbirth has been described as an “obstetrical dilemma”. Evolution favours enlargement of the foetal brain, whilst bipedal locomotion demands a reduction in pelvic breadth for improvements in biomechanical efficiency. The result of this conflict is a human pelvis incongruous with the dynamics of childbirth. Acute genital distortion at delivery can inflict lasting damage to female pelvic function. Pelvic organ prolapse, urinary, faecal incontinence and sexual dysfunction are long-term sequelae rarely discussed at antenatal care, impacting upon the expectant mother’s ability to make an informed decision. The alternative option is the elective caesarean section, an abdominal incision bypassing the maladies of a vaginal delivery, although not without complications of its own. Childbirth remains an emotive event where evidence-based medicine can be disempowered, and the rising trend to “normalise” birth can disrupt care of the woman. This needs to be maintained in a healthy balance to best provide competent and safe care for women.