Sex differences in lower urinary tract biology and physiology

Females and males differ significantly in gross anatomy and physiology of the lower urinary tract, and these differences are commonly discussed in the medical and scientific literature. However, less attention is dedicated to investigating the varied development, function, and biology between females and males on a cellular level. Recognizing that cell biology is not uniform, especially in the lower urinary tract of females and males, is crucial for providing context and relevance for diverse fields of biomedical investigation. This review serves to characterize the current understanding of biological sex differences between female and male lower urinary tracts, while identifying areas for future research. First, the differences in overall cell populations are discussed in the detrusor smooth muscle, urothelium, and trigone. Second, the urethra is discussed, including anatomic discussions of the female and male urethra followed by discussions of cellular differences in the urothelial and muscular layers. The pelvic floor is then reviewed, followed by an examination of the sex differences in hormonal regulation, the urinary tract microbiome, and the reticuloendothelial system. Understanding the complex and dynamic development, anatomy, and physiology of the lower urinary tract should be contextualized by the sex differences described in this review.     

Sex differences in prostaglandin metabolism.

Prostaglandin E2 (PGE2), PGF2alfa and PGD2 were synthetized from [1-¹⁴C]-arachidonic acid by rat kidney medulla microsomal fraction. The formation of each prostaglandin was significantly less in female animals than in males. The rate of inactivation of [³H]-PGF2alfa by kidney cortex cytosol was almost linear with the time of incubation during the first 30 min. The production of PGF2alfa metabolite (13,14-dihydro-15-keto PGF2alfa) was higher in male rats than in females.     

Sex differences in human urinary steroid metabolic profiles determined by gas chromatography

Fifty-two 24-hr urine collections from healthy male and female adults were analyzed by a new gas chromatographic method. High-resolution open tubular glass capillary columns with a coating of SE-30 liquid phase containing a dispersion of small particles of silanized silicic acid (Silanox) were employed. The components were analyzed as methoxime-trimethylsilyl ether derivatives. Seventeen urinary steroid metabolites were quantified through use of an internal reference compound. The results are interpreted as delineating two different types of steroid metabolism for premenopausal females: one group displays metabolic profiles closely resembling those of males. The biologic origin of this effect is not known, but it may be due to either late fetal or neonatal hormonal effects.     

Sex differences in cocaine-induced behavioral sensitization.

To further understand how sex differences affect the development and maintenance of sensitization, 48 adult Fischer rats (24 female and 24 male) received chronic administration (14 days) of cocaine (15 mg/kg, i.p.) or saline or a challenge dose (7 days after chronic cocaine administration). Sex differences were observed in the development and maintenance of cocaine-induced total locomotor, ambulatory and rearing activity. Although, overall cocaine administration increased stereotypic activity in both male and female rats, female rats had significantly higher stereotypic activity than male rats across the three behavioral test days (1, 7 and 14). Female rats had statistically significant higher benzoylecognine levels after acute cocaine administration than male rats. However, no differences between male and female rats in benzoylecognine plasma levels were observed after chronic and challenge doses of cocaine administration. Interestingly, after acute and challenge cocaine administration, corticosterone levels were significantly higher in female rats when compared to male rats. This study confirms previous reports that there are sex differences in the behavioral response to cocaine. Moreover, this study expands previous studies by demonstrating that sex differences occur in only certain aspects of cocaine-induced behavioral activation and the development and maintenance of cocaine-induced behavioral sensitization.     

Sex differences in dog corpus callosum.

Human studies reported sex differences in size and shape of the corpus callosum. These observations have been contested. The purpose of the present study is to investigate possible sex differences in the corpus callosum of dogs. The entire brains including the medulla from 12 female and 9 male adult mongrel dogs were removed and weighed. Total and partial area measurements of the callosum were made from photographic tracings of its outline. The callosum was partitioned into 3 regions; anterior half, posterior half, posterior one-fifth. The total corpus callosum, anterior half, posterior half, and posterior fifth or splenium areas were measured. Sex differences were found. The anterior half, the posterior half, the posterior fifth, and the total callosum were significantly greater in absolute area in males than in females.     

Sex differences of plasma cholinesterase in the rat.

Plasma cholinesterase activity of adult female HAN-Wistar rats was found to be 5.5-fold higher than that of adult male rats kept under constant specified pathogen-free (SPF) conditions up to their 870th day of life.     

Sex differences in kidney mineral concentrations and urinary albumin excretion in rats given high-phosphorus feed

We examined sex differences in kidney mineral concentrations and urinary albumin excretion in rats given feed containing various phosphorus (P) levels. With feed that was 0.6%, 0.9%, 1.2%, and 1.5% P, kidney calcium and P concentrations were higher in female rats than in male rats. With 1.2% or 1.5% P, urinary albumin excretion was higher in the female rats. The sex of the animal affected the kidney mineral concentrations and urinary albumin excretion in rats with a high P intake.     

Sex differences in autoimmune diseases

Women are more susceptible to a variety of autoimmune diseases including systemic lupus erythematosus (SLE), multiple sclerosis (MS), primary biliary cirrhosis, rheumatoid arthritis and Hashimoto's thyroiditis. This increased susceptibility in females compared to males is also present in animal models of autoimmune diseases such as spontaneous SLE in (NZBxNZW)F1 and NZM.2328 mice, experimental autoimmune encephalomyelitis (EAE) in SJL mice, thyroiditis, Sjogren's syndrome in MRL/Mp-lpr/lpr mice and diabetes in non-obese diabetic mice. Indeed, being female confers a greater risk of developing these diseases than any single genetic or environmental risk factor discovered to date. Understanding how the state of being female so profoundly affects autoimmune disease susceptibility would accomplish two major goals. First, it would lead to an insight into the major pathways of disease pathogenesis and, secondly, it would likely lead to novel treatments which would disrupt such pathways.     

Abnormal levels of urinary catecholamines in dystrophic mice and hamsters.

Twenty-four-hour urine was collected from normal and dystrophic mice and hamsters for catecholamine determinations. A new method of analysis was used whereby 3,4-dihydroxyphenylalanine (DOPA), dopamine (DA), norepinephrine (NE), and epinephrine (E) were measured simultaneously. The procedure is based on a combination of liquid-solid extraction, cation exchange chromatography, and controlled potential electrochemistry. The results of these experiments indicated that while DA levels were similar in both normal and pathological animal urine, DOPA levels decreased slightly in the dystrophic mouse but not the hamster, and NE and E levels in dystrophic groups were two and four times greater than normal in both species. The data supports the concept of biochemical alterations in tissue other than muscle. While not necessarily supportive to catecholamine abnormality as the primary cause of muscular dystrophy, the present data cast doubt that this disease is a primary muscle disease.     

Sex differences in primary hypertension

Men have higher blood pressure than women through much of life regardless of race and ethnicity. This is a robust and highly conserved sex difference that it is also observed across species including dogs, rats, mice and chickens and it is found in induced, genetic and transgenic animal models of hypertension. Not only do the differences between the ovarian and testicular hormonal milieu contribute to this sexual dimorphism in blood pressure, the sex chromosomes also play a role in and of themselves. This review primarily focuses on epidemiological studies of blood pressure in men and women and experimental models of hypertension in both sexes. Gaps in current knowledge regarding what underlie male-female differences in blood pressure control are discussed. Elucidating the mechanisms underlying sex differences in hypertension may lead to the development of anti-hypertensives tailored to one's sex and ultimately to improved therapeutic strategies for treating this disease and preventing its devastating consequences.     

Sex differences in adrenocortical structure and function. XI

Summary Adrenal glands from orchectomized and ovariectomized rats, with and without replacement therapy, and also from intact controls of both sexes, were examined by autoradiography with ³H-thymidine. The labelling index after 1 or 2 nucleoside injections was higher in the zona glomerulosa of females than in male rats, while no differences were found in the fascicular and reticular zones. Orchiectomy increased the labelling index in the fascicular and reticular zones, an effect prevented by testosterone. Ovariectomy did not change the labelling index, while estradiol lowered it in the zona glomerulosa. Duration of the S phase was longer in the zona fasciculata cells of males than in females. Both orchiectomy and testosterone shortened this phase in cells of the zona fasciculata and zona reticularis. Ovariectomy prolonged the S phase in the zona fasciculata and shortened this time in the reticular zone, an effect reversed by estradiol.In the glomerular and fascicular zones, cell cycle time was longer in males than in females. Orchiectomy shortened this time in all adrenocortical zones, an effect reversed by testosterone. Ovariectomy shortened cell cycle time in the glomerular and reticular zones and prolonged it in the zona fasciculata; these effects were reversed by estradiol. Turnover rate in adrenocortical cells was markedly higher in females than in males, a difference due to testosterone which markedly decreased turnover rate.     

Epinephrine sulfation in the forearm: Arteriovenous differences in free and conjugated catecholamines.

Simultaneously drawn arterial and forearm venous levels of free and sulfate conjugated epinephrine and norepinephrine were measured in 8 subjects in order to study the role of skeletal muscle in catecholamine sulfation. A sensitive radioenzymatic assay was used. The average free epinephrine level was 46% lower in venous than in arterial blood (p<0.023) while average sulfated epinephrine level was 37% higher (p<0.016). These findings suggest that epinephrine sulfation is occurring in the forearm, most likely in skeletal muscle. The mean venous free norepinephrine level was 21% higher than the mean arterial level (p<0.055) presumably reflecting release from sympathetic nerve terminals. No evidence of norepinephrine sulfation or deconjugation in skeletal muscle was found.