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Pregnancy alters the disposition and exposure to multiple drugs indicated for pregnancy-related complications. Previous in vitro studies have shown that pregnancy-related hormones (PRHs) alter the expression and function of certain cytochrome P450s (CYPs) in human hepatocytes. However, the impact of PRHs on hepatic concentrations of non-CYP drug-metabolizing enzymes (DMEs) and transport proteins remain largely unknown. In this study, sandwich-cultured human hepatocytes (SCHH) from five female donors were exposed to vehicle or PRHs (estrone, estradiol, estriol, progesterone, cortisol, and placental growth hormone), administered individually or in combination, across a range of physiologically relevant PRH concentrations for 72 h. Absolute concentrations of 33 hepatic non-CYP DMEs and transport proteins were quantified in SCHH membrane fractions using a quantitative targeted absolute proteomics (QTAP) isotope dilution nanoLC-MS/MS method. The data revealed that PRHs altered the absolute protein concentration of various DMEs and transporters in a concentration-, isoform-, and hepatocyte donor-dependent manner. Overall, eight of 33 (24%) proteins exhibited a significant PRH-evoked net change in absolute protein concentration relative to vehicle control (ANOVA p < 0.05) across hepatocyte donors: 1/11 UGTs (9%; UGT1A4), 4/6 other DMEs (67%; CES1, CES2, FMO5, POR), and 3/16 transport proteins (19%; OAT2, OCT3, P-GP). An additional 8 (24%) proteins (UGT1A1, UGT2B4, UGT2B10, FMO3, OCT1, MRP2, MRP3, ENT1) exhibited significant PRH alterations in absolute protein concentration within at least two individual hepatocyte donors. In contrast, 17 (52%) proteins exhibited no discernable impact by PRHs either within or across hepatocyte donors. Collectively, these results provide the first comprehensive quantitative proteomic evaluation of PRH effects on non-CYP DMEs and transport proteins in SCHH and offer mechanistic insight into the altered disposition of drug substrates cleared by these pathways during pregnancy.

Pregnancy results in significant changes in drug pharmacokinetics (PK). While previous studies have elucidated the impact of pregnancy-related hormones (PRH) on mRNA or protein expression and activity of major hepatic metabolizing enzymes, their effect on hepatic drug transporters remains largely unexplored. Therefore, we investigated the effect of a cocktail of PRH on the mRNA expression and activity of hepatic transporters. Plated human hepatocytes (PHH) from 3 premenopausal donors were incubated, in triplicate, for 72 h, with vehicle (DMSO < 0.01%), rifampin (10 μM; positive control) or a cocktail of PRH consisting of estrone, estradiol, estriol, estetrol, progesterone, cortisol, testosterone, oxytocin, and placental growth hormone. The PRH concentrations replicated 0.1×, 1×, or 10× of the plasma concentrations of these hormones observed during each of the three trimesters of pregnancy. After treatment, mRNA expression (quantified by qPCR) of hepatic influx and efflux transporters as well as the activity of influx transporters was quantified (uptake of a selective substrate ± corresponding transporter inhibitor). The data were expressed relative to that in the control (vehicle) group. Significance was evaluated by ANOVA (followed by Dunn's multiple comparisons) or unpaired -test when the within-lot data were analyzed, or repeated measures ANOVA (followed by Dunn's multiple comparisons) or paired -test when data from all 3 lots were analyzed ( < 0.05). In general, a) PRH cocktails significantly induced transporter mRNA expression in the following order OAT2 ≈ NTCP ≈ OCT1 > OATP2B1 and repressed mRNA expression in the following order OATP1B3 > OATP1B1; b) these changes translated into significant induction of OAT2 (T1-T3) and NTCP (T2-T3, in only two lots) activity at the 1× PRH concentration. Compared with the influx transporters, the induction of mRNA expression of efflux transporters was modest, with mRNA expression of MRP2 and BSEP being induced the most. Once these data are verified through probe drug PK studies in pregnancy, they can be populated into physiologically based pharmacokinetic (PBPK) models to predict, for all trimesters of pregnancy, transporter-mediated clearance of any drug that is a substrate of the affected transporters.

Sexual dimorphism refers to differences between biological sexes that extend beyond sexual characteristics. In humans, sexual dimorphism in the immune response has been well demonstrated, with females exhibiting lower infection rates than males for a variety of bacterial, viral, and parasitic pathogens. There is also a substantially increased incidence of autoimmune disease in females compared to males. Together, these trends indicate that females have a heightened immune reactogenicity to both self and non-self-molecular patterns. However, the molecular mechanisms driving the sexually dimorphic immune response are not fully understood. The female sex hormones estrogen and progesterone, as well as the male androgens, such as testosterone, elicit direct effects on the function and inflammatory capacity of immune cells. Several studies have identified a sex-specific transcriptome and methylome, independent of the well-described phenomenon of X-chromosome inactivation, suggesting that sexual dimorphism also occurs at the epigenetic level. Moreover, distinct alterations to the transcriptome and epigenetic landscape occur in synchrony with periods of hormonal change, such as puberty, pregnancy, menopause, and exogenous hormone therapy. These changes are also mirrored by changes in immune cell function. This review will outline the evidence for sex hormones and pregnancy-associated hormones as drivers of epigenetic change, and how this may contribute to the sexual dimorphism. Determining the effects of sex hormones on innate immune function is important for understanding sexually dimorphic autoimmune diseases, sex-specific responses to pathogens and vaccines, and how innate immunity is altered during periods of hormonal change (endogenous or exogenous).

Introduction: Pregnancy increases the clearance of CYP3A4 substrate drugs and pregnancy-related hormones (PRHs) induce hepatic CYP3A4 expression and metabolism. However, it remains unclear to what extent the magnitude of PRH-evoked changes in hepatic CYP3A metabolism varies across multiple substrates. This study quantified the impact of PRHs on CYP3A protein concentrations and buprenorphine metabolism in human hepatocytes, and compared the magnitude of these effects to nifedipine and midazolam metabolism. Methods: Sandwich-cultured human hepatocytes (SCHH) from female donors were exposed to PRHs, administered in combination across a range of physiologically relevant concentrations, for 72 h. Absolute protein concentrations of CYP3A4, CYP3A5, and CYP3A7 in SCHH membrane fractions were quantified by nanoLC-MS/MS, and norbuprenorphine (nor-BUP), dehydro-nifedipine (dehydro-NIF), and 1-hydroxy-midazolam (1-OH-MDZ) formation was evaluated. Results: Compared to control, PRH exposure increased CYP3A4, CYP3A7, and total CYP3A protein concentrations, but not CYP3A5 concentrations, and increased nor-BUP, dehydro-NIF, and 1-OH-MDZ formation in a concentration-dependent manner. The formation of nor-BUP, dehydro-NIF, and 1-OH-MDZ each positively correlated with PRH-mediated changes in total CYP3A protein concentrations. The PRH-evoked increase in nor-BUP formation was evident in all donors; however, the PRH induction of dehydro-NIF and 1-OH-MDZ formation was diminished in a hepatocyte donor with high basal CYP3A5 expression. Discussion: These findings demonstrate that PRHs increase buprenorphine, nifedipine, and midazolam metabolism in SCHH via induction of CYP3A4 and total CYP3A protein concentrations, and the magnitude of these effects vary across hepatocyte donors in a substrate-specific manner. These data provide insight into the contribution of PRH induction of CYP3A4 metabolism to increased buprenorphine clearance during pregnancy.

During female adolescence and pregnancy, rising levels of hormones result in a cyclic source of signals that control the development of mammary tissue. While such alterations are well understood from a whole-gland perspective, the alterations that such hormones bring to organoid cultures derived from mammary glands have yet to be fully mapped. This is of special importance given that organoids are considered suitable systems to understand cross species breast development. Here we utilized single-cell transcriptional profiling to delineate responses of murine and human normal breast organoid systems to female hormones across evolutionary distinct species. Collectively, our study represents a molecular atlas of epithelial dynamics in response to estrogen and pregnancy hormones.

We are witnessing a stark increase in scientific interest in the neurobiological processes associated with pregnancy and maternity. Convergent evidence suggests that around the time of labour, first-time mothers experience a specific pattern of neuroanatomical changes that are associated with maternal behaviour. Here we provide an overview of the human neurobiological adaptations of motherhood, focusing on the interplay between pregnancy-related steroid and peptide hormones, and neuroplasticity in the brain. We discuss which brain plasticity mechanisms might underlie the structural changes detected by MRI, which hormonal systems are likely to contribute to such neuroanatomical changes and how these brain mechanisms may be linked to maternal behaviour. This Review offers an overarching framework that can serve as a roadmap for future investigations.Motherhood in humans is associated with numerous neurobiological adaptations. In this Review, Servin-Barthet et al. focus on the interplay among pregnancy-related hormones, brain plasticity and maternal behaviour and aim to provide a roadmap for future investigations.

Background: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. Methods: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. Results: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. Conclusion: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Background A higher osteoarthritis (OA) risk in females is well-documented, but the causes of this sexual dimorphism remain unclear. This study explores whether this disparity arises from sex differences in development or the sex difference in total reproductive costs of gestation and parental care. Method We tested four hypotheses on the effects of gestation and parental care on OA risk using data from the German Aging Survey (DEAS), controlling for age, education, and comorbidities, as appropriate. We analyzed 2,328 men and 2,359 women with children, and 313 men and 319 women without children. We compared OA risk (1) between childless men and women, (2 and 3) within each sex based on parental status, and (4) by the number of children, stratified by sex. We used logistic regression for each test and calculated adjusted 95% confidence intervals and p-values. First test the effect of sex difference in risk development, while the second and third determine the effect of total reproductive costs in each sex, and the fourth examines the dose-dependent effect of reproductive cost in OA risk development. Results No significant difference in OA risk was found between childless men and women (37% and 44%, respectively, CI = -0.035 to 0.602, p =  0.081). However, women with children had a significantly higher OA risk than childless women (51%, and 44%, respectively, CI = 0.004 to 0.483, p =  0.047). Differences in risk between men with and without children were insignificant ( 43%, and 37%, respectively, CI = -0.069 to 0.432, p =  0.156). OA risk increased significantly with the number of children in women (0.10, CI = 0.03 to 0.179, p =  0.006,) but not in men (0.02, CI = -0.058 to 0.091, p =  0.660,) as the previous experiment also suggests. Conclusion Sexual dimorphism in OA risk appears to be driven by the reproductive costs of gestation and parental care. Our findings highlight the need for finer stratification based on reproductive status to better understand sex differences in disease risks. Plain English summary Osteoarthritis is more common in women than in men. Scientists have long known about this difference, but the reasons behind it are unclear. This study looked at whether the higher risk of osteoarthritis in women is linked to biological differences between the sexes or to pregnancy and parenting. We analyzed data from thousands of men and women in Germany, comparing those with children to those without. We found that childless men and women had similar rates of OA, suggesting that biological sex alone may not explain the difference. However, women with children were more likely to develop osteoarthritis than childless women. The risk of osteoarthritis also increased for women as the number of children they had grew. For men, having children did not seem to affect their osteoarthritis risk. These findings suggest that pregnancy and parenting may play a key role in why women are more likely to develop osteoarthritis. This study highlights the importance of considering reproductive history when studying health differences between men and women. By understanding these factors better, doctors and researchers can work toward improving prevention and treatment for osteoarthritis in men and women. Highlights Women have a higher risk of osteoarthritis (OA) compared to men, but this study found no significant difference in OA risk between childless men and women. Women with children have a significantly higher OA risk than childless women, while parental status does not affect OA risk in men. The number of children is directly associated with increased OA risk in women, but not in men. The sex difference in OA risk appears to be driven by the differential reproductive costs of pregnancy and parental care, rather than differences in biological development between sexes. These findings emphasize the importance of considering reproductive history to better understand sex differences in disease risks.

Cardiac fibrosis is a central determinant of heart failure progression and arises from pathological remodeling characterized by fibroblast activation, myofibroblast differentiation, and excessive extracellular matrix deposition. In contrast, physiological remodeling permits adaptive cardiac growth without net fibrosis. Pregnancy represents an underexplored physiological model of reversible cardiac remodeling. In response to hemodynamic load, the maternal heart undergoes hypertrophic growth that resolves postpartum, constituting a natural paradigm of fibrosis-resistant cardiac adaptation. Pregnancy and lactation are accompanied by profound endocrine and immune reprogramming of maternal tissues. We propose that this hormonal milieu orchestrates coordinated crosstalk among endothelial cells, fibroblasts, and immune cell populations to suppress profibrotic pathways and preserve extracellular matrix homeostasis. Candidate regulators include estrogen, progesterone, prolactin family peptides, relaxin, oxytocin, and components of the renin–angiotensin–aldosterone system. During the postpartum and lactational period, prolactin and oxytocin may further promote reverse remodeling. These hormones likely act by modulating local cytokine and growth factor networks that otherwise drive fibroblast activation. By focusing on non-myocyte cardiac cells and extracellular matrix dynamics, this review positions pregnancy as a translational model to uncover endogenous anti-fibrotic mechanisms and identify novel therapeutic strategies for cardiac fibrosis.

Background To compare pregnancy complications and birth outcomes for women experiencing nausea and vomiting in pregnancy, or nausea only, with symptom-free women. Methods Pregnancies from the Norwegian Mother and Child Cohort Study ( n  = 51 675), a population-based prospective cohort study, were examined. Data on nausea and/or vomiting during gestation and birth outcomes were collected from three questionnaires answered between gestation weeks 15 and 30, and linked with data from the Medical Birth Registry of Norway. Chi-squared tests, one way analysis of variance, multiple linear and logistic regression analyses were used. Results Women with nausea and vomiting (NVP) totalled 17 070 (33 %), while 20 371 (39 %) experienced nausea only (NP), and 14 234 (28 %) were symptom-free (SF). When compared to SF women, NVP and NP women had significantly increased odds for pelvic girdle pain (adjusted odds ratio, aOR, 2.26, 95 % confidence interval, 95 % CI, 2.09–2.43, and aOR 1.90, 95 % CI, 1.76–2.05, respectively) and proteinuria (aOR 1.50, 95 % CI 1.38–1.63, and 1.20, 95 % CI 1.10–1.31, respectively). Women with NVP also had significantly increased odds for high blood pressure (aOR 1.40, 95 % CI 1.17–1.67) and preeclampsia (aOR 1.13, 95 % CI 1.01–1.27). Conversely, the NVP and NP groups had significantly reduced odds for unfavourable birth outcomes such as low birth weight infants (aOR 0.72, 95 % CI 0.60–0.88, and aOR 0.73, 95 % CI 0.60–0.88, respectively) and small for gestational age infants (aOR 0.78, 95 % CI 0.73–0.84, and aOR 0.87, 95 % CI 0.81–0.93, respectively). Conclusions We found that women with NVP and NP are more likely to develop pregnancy complications, yet they display mostly favourable delivery and birth outcomes.