The role of steroid hormones in regulating vaginal smooth muscle contractility was investigated. Rabbits were kept intact or ovariectomized. After 2 weeks, animals were continuously infused with vehicle or supraphysiological levels of testosterone (100 μg/day), or estradiol (200 μg/day), for an additional 2 weeks. The distal vaginal tissue was used to assess contractility in organ baths and changes in tissue structure were assessed by histology. Ovariectomized animals infused with vehicle exhibited significant atrophy of the muscularis and decreased epithelial height, resulting in thinning of the vaginal wall. Estradiol infusion increased epithelial height, comparable to that of intact animals, but only partially restored the muscularis layer. In contrast, testosterone infusion completely restored the muscularis layer, but only partially restored the epithelial height. In vaginal tissue strips contracted with norepinephrine and treated with bretylium, electrical field stimulation (EFS) caused frequency-dependent relaxation that was slightly attenuated with vehicle, significantly inhibited with estradiol and significantly enhanced with testosterone. VIP-induced relaxation was slightly attenuated in tissues from vehicle and estradiol-infused groups, but was enhanced in tissues from testosterone-infused animals. Contraction elicited by EFS or exogenous norepinephrine was not significantly altered with ovariectomy or steroid hormone infusion when data were normalized to potassium contraction. However, the tissue from testosterone-infused animals developed significantly greater contractile force to norepinephrine. These observations suggest that steroid hormones may be important regulators of vaginal tissue structure and contractility.
Female sexual arousal is characterized by increased genital blood flow, genital sensation and vaginal lubrication.1,2,3 During the early phases of genital arousal, the proximal two-thirds of the vagina lengthens and increases in volume, followed by constriction of the distal third.3 Thus, it has been suggested that vasodilation of the blood vessels within the vagina and relaxation of the nonvascular vaginal smooth muscle are important events during the genital arousal response. However, the physiological mechanisms regulating these processes have not been well characterized. Histological studies of vaginal innervation have demonstrated the presence of adrenergic and cholinergic nerve fibers as well as those containing neuropeptide Y, vasoactive intestinal polypeptide (VIP), nitric oxide synthase, calcitonin gene-related peptide (CGRP) and substance P.4,5,6,7,8 While recent studies have begun to demonstrate the involvement of adrenergic, cholinergic and nonadrenergic, noncholinergic neurotransmitters in regulating vaginal smooth muscle tone, the precise roles of these neurotransmitters in regulating vaginal contractility and blood flow are yet to be determined.9,10,11
Steroid hormones are critical for maintaining the integrity of female genital tissue structure and function.12,13,14,15,16,17 The thickness and rugae of the vaginal wall, as well as vaginal lubrication, are estrogen dependent.18,19 In addition, estrogens have been shown to enhance genital sensation and maintain blood flow.15,20,21,22 While androgens have been shown to enhance sexual interest, genital sensation, orgasmic responses and sexual satisfaction, it remains unclear how androgens modulate genital tissue physiology.23,24,25,26
The vaginal wall consists of three distinct layers—the mucosa, the muscularis and the adventitia. The muscularis is comprised of poorly delineated, inner circular and outer longitudinal bundles of smooth muscle. Sex steroid hormones may regulate distinct physiological pathways in the various cellular components of the vaginal wall. While the effects of estradiol on the vaginal mucosa have been well investigated, the regulatory effects of estrogens and androgens on vaginal nonvascular smooth muscle have received limited attention. This study was undertaken to investigate the effects of estrogen and androgen on vaginal smooth muscle contractility and vaginal tissue structure. Hormonal manipulations were performed in vivo and physiological studies with vaginal tissue strips were carried out in organ baths to assess smooth muscle responses to electric field stimulation and exogenous vasoactive agents.
All protocols were approved by the Institutional Animal Care and Use Committee at the Boston University School of Medicine. Female New Zealand White rabbits (4.5–5.0 kg) were either kept intact (I, n=4) or ovariectomized. At 2 weeks post-ovariectomy, animals were treated for an additional 2-week period with polyethylene glycol vehicle (average mol. wt.=300; V, n=7), testosterone (T, n=6), estradiol (E, n=7), dihydrotestosterone (DHT, n=6), delta-5-androstenediol (Adiol, n=6) or dehydroepiandrosterone (DHEA, n=4). Hormonal treatment of ovariectomized animals was carried out by implanting osmotic infusion pumps (model 2002; Alzet, Palo Alto, CA, USA) subcutaneously between the scapulae using aseptic technique. The delivery rates of the steroid hormones were 200 μg/day for estradiol, 100 μg/day for testosterone, 100 μg/day for DHT, 250 μg/day for Adiol and 1000 μg/day for DHEA. After the hormone replacement period, animals were euthanized and vaginal tissues were removed. Longitudinal vaginal tissue strips were taken from the distal (lower) half of the vagina and ranged from 10 to 15 mm in length. The introitus region was excluded. All layers of the vagina were maintained intact and included the epithelium. Tissue strips were used immediately for organ bath studies.
Organ bath studies
Rabbit vaginal strips were mounted onto tissue supports, attached to tension transducers (model FT03; Grass Instruments, Quincy, MA, USA) and immersed in 25 ml baths of physiological salt solution (PSS; 118.3 mM NaCl, 4.7 mM KCl, 0.6 mM MgSO4, 1.2 mM KH2PO4, 2.5 mM CaCl2, 25 mM NaHCO3, 0.026 mM CaNa2EDTA, 11.1 mM glucose) maintained at 37°C and aerated with 5% CO2, 20% O2 and 75% N2. The tissue strips were progressively stretched and periodically contracted with 2 μM norepinephrine until optimal isometric tension was achieved. Vaginal tissues were then subjected to several different protocols, as described below. For each rabbit, each protocol was repeated in 2–3 separate tissue strips.
(a) Electrical field stimulation was used to elicit neurogenic responses. For contractile responses, tissue strips at basal tone were stimulated with a train of square waves at varying frequencies (0.5–40 Hz), for a period of 20 s. Each square wave had an amplitude of 10 V and a duration of 0.5 ms. Similar parameters have previously been shown to stimulate responses in vaginal tissue, which were completely inhibited by tetrodotoxin.11 Data for neurogenic contraction were expressed as a percentage of the contraction induced by PSS containing 120 mM K+ (K+-PSS) or as the contractile force in milliNewtons (mN). For relaxatory responses, vaginal tissue strips were contracted with 2 μM norepinephrine and elec-trical field stimulation was carried out in the presence of 10 μM bretylium to inhibit norepinephrine release from adrenergic nerves. Neurogenic relaxation was expressed as a percentage of the tone induced by norepinephrine with 100% relaxation, defined as the loss in tone caused by a combination of 10 μM sodium nitroprusside and 10 μM papaverine HCl.
(b) Vaginal tissue strips at optimal isometric tension were exposed to increasing concentra-tions of exogenous contractile or relaxatory agents. For contraction response studies, tissues were exposed to increasing concentrations (10−9–10−5 M) of norepinephrine and data were ex-pressed as a percentage of K+-PSS-induced contraction or as the force of contraction in mN. For relaxation-response studies, the tissues were contracted with 2 μM norepinephrine and then exposed to increasing concentrations (10−9–10−6 M) of VIP (Peptides International, Louisville, KY, USA). The data were expressed as a percentage of the tone induced by norepinephrine with 100% relaxation defined as the loss in tone caused by a combination of 10 μM nitroprusside and 10 μM papaverine.
Histology of vaginal tissue
Vaginal tissue was harvested from intact and ovariectomized rabbits infused with vehicle, estradiol or testosterone (n=3 for each group). Full-thickness tissue samples were fixed in phosphate-buffered 4% paraformaldehyde (pH 7.4). After fixation, the tissue samples were rinsed in phosphate-buffered saline and dehydrated in graded ethanol solutions (70–100%). Tissues were then washed with two changes of CitriSolv (Fisher Scientific, Pittsburgh, PA, USA) for 15 min each, and then immersed in three paraffin baths under vacuum for 30 min each, before being placed in block molds. Tissue sections (6 μm thick) were applied to Superfrost Plus glass slides (Fisher Scientific, Pittsburgh, PA, USA) and allowed to dry on a warming tray overnight. Slides were deparaffinized with two changes of CitriSolv (5 min each), rehydrated with graded ethanol solutions (100–70%) and washed with phosphate-buffered saline and then with distilled water. Deparaffinized tissue sections were subjected to routine hematoxylin and eosin staining. Slides were dehydrated with graded ethanol solutions and CitriSolv, and coverslipped with Permount (Fisher Scientific, Pittsburgh, PA, USA).
All data were analyzed by one-way analysis of variance (ANOVA) and Bartlett's test for equal variances. If the ANOVA P-value was less than 0.05, the data were analyzed by the Tukey–Kramer multiple paired comparison test.27 Differences between paired comparisons were considered statistically significant when P-values were less than 0.05. In cases where sample variances were determined to be significantly different, data were transformed by taking the logarithm (base 10) of each value to normalize variances and the ANOVA was repeated. If the comparison of the mean values approached but did not reach statistical significance and the trends were consistently observed in each animal, it was concluded that the effect was real. Dose responses to norepinephrine and VIP were compared by determining the EC50 values and the ‘area under the curve’ (AUC) for each experiment. AUC for each dose response was approximated by determining the sum of responses over the entire range of doses. Determination of EC50 values and statistical analyses were performed using GraphPad Prism version 3.02 for Windows (GraphPad Software, San Diego, CA, USA). For histology, vaginal tissue sections were examined for qualitative morphological changes in the epithelium and muscularis. For each animal, 12 random tissue sections (three fields per section) were examined. In addition, epithelial height was measured in three separate tissue sections from each group (three fields per section).
Vaginal tissue histology
Histological examination of vaginal tissue from intact rabbits indicated the presence of a single layer of columnar epithelial cells of uniform height and a well-defined muscularis with closely packed fascicles (Figure 1). In contrast, ovariectomized animals infused with vehicle demonstrated an overall thinning of the vaginal wall with muscle bundles that appeared smaller and more dispersed, indicating significant muscular atrophy. The vaginal epithelium of ovariectomized rabbits was also thinner with minimal cytoplasmic volume when compared to intact rabbits (Figures 1 and 2). In ovariectomized, testosterone-infused rabbits, the overall structure and thickness of the muscularis layer was similar to intact animals. The epithelial cell height was greater than that of vehicle-infused rabbits, but remained significantly smaller than intact rabbits. Also, the lamina propria appeared to be thicker in testosterone-infused rabbits than in intact rabbits. Estradiol-infused ovariectomized rabbits exhibited normal vaginal epithelia with average cell heights that were not significantly different from intact animals (Figures 1 and 2). In visual fields of equal area and magnification, we consistently observed that both the inner circular and outer longitudinal muscle layers were visible in the vaginal tissue from estrogen-infused rabbits. However, in the same visual fields, only a portion of the inner circular muscle layer is visible in vaginal tissue from intact or testosterone-infused rabbits. Thus, while estradiol-infused ovariectomized rabbits had a more developed muscularis layer than vehicle-infused rabbits, the overall thickness of the muscularis was less than that observed in intact or testosterone-infused ovariectomized animals.
EFS-induced relaxation in vaginal smooth muscle
Vaginal tissue contracted with exogenous norepinephrine and treated with the adrenergic nerve blocker bretylium exhibited frequency-dependent relaxation to EFS (Figure 3a). Although not reaching statistical significance, vaginal tissue from ovariectomized rabbits consistently exhibited attenuated relaxation to EFS. EFS-induced relaxation was significantly inhibited in estradiol-infused ovariectomized animals, whereas testosterone infusion significantly enhanced EFS-induced relaxation (Figure 3a). Interestingly, vaginal tissue from ovariectomized rabbits infused with DHT, delta-5-androstenediol or DHEA also exhibited significantly enhanced EFS-induced relaxation when compared to the tissue from intact animals (data not shown).
VIP-induced relaxation in vaginal smooth muscle
Vaginal tissue strips contracted with exogenous norepinephrine relaxed to VIP in a dose-dependent manner (Figure 3b). Tissues from ovariectomized animals treated with vehicle or estradiol exhibited reduced relaxation to VIP. Although the total AUC values for vehicle- and estradiol-infused groups were not significantly different from the intact group, EC50 values were significantly greater (Table 1), indicating an attenuated relaxation response. In contrast, testosterone enhanced VIP-induced relaxation, significantly decreasing the EC50 value relative to both the intact and vehicle groups (Table 1). Similar to EFS-induced relaxation, the vaginal tissue from DHT-, delta-5-androstenediol- or DHEA-infused ovariectomized rabbits also exhibited significantly enhanced relaxation to VIP relative to the tissue from intact animals (data not shown).
Electrical field stimulation (EFS)-induced contraction in vaginal smooth muscle
The magnitude of contraction caused by EFS in vaginal tissue was frequency dependent. However, contractile responses were observed to be highly variable between individual tissue strips. When responses were normalized as a percentage of 120 mM K+-PSS-induced contraction, ovariectomy in the absence or presence of steroid hormone replacement did not significantly change the contractile response (Figure 4a). However, some trends could be observed between the treatment groups. The mean contractile response (%K+-PSS-induced contraction) was consistently lower in ovariectomized animals when compared to the control group. When data were expressed as contractile force, testosterone- and estradiol-infused groups contracted more forcefully relative to intact or vehicle-infused groups (Figure 4b).
Norepinephrine-induced contraction in vaginal smooth muscle
Exogenous norepinephrine caused dose-dependent contraction in vaginal tissue strips. When data were normalized to K+-PSS-induced contraction, neither the AUC nor the EC50 values were significantly different between the treatment groups (Figure 5a and Table 2). However, when data were expressed as contractile force, the AUC for the testosterone-infused group was significantly greater than the intact group (Figure 5b and Table 2). Vehicle- and estradiol-infused groups had intermediate AUC values, but were not significantly different from the intact group. Interestingly, EC50 values for ovariectomized groups with or without steroid hormone infusion were significantly lower than for the intact group (see Table 2). Further, vaginal tissue from testosterone-infused ovariectomized rabbits had EC50 values that were significantly lower than either vehicle- or estradiol-infused rabbits.
Our data suggest that steroid hormones can influence vaginal tissue contractility, as well as growth. Histological examination confirmed that steroid hormones can mediate extensive tissue remodeling in the vagina. In addition to their well-known effects on vaginal mucosal growth, estrogens have been shown to increase vascularization in the vagina.12,15 The effects of estradiol on the muscularis layer of the vagina remain unclear. While estrogens inhibit proliferation in vascular smooth muscle cells, they have been shown to promote smooth muscle proliferation in the seminal vesicle.28,29,30,31 Thus, the effects of estrogens on smooth muscle cell growth appear to be tissue specific. In our study, we found that estradiol promoted vaginal smooth muscle growth, but not to the same extent as testosterone. Since animals were infused with hormone 2 weeks after ovariectomy, it is also likely that estradiol infusion prevented additional loss of smooth muscle that would have occurred during the third and fourth weeks after ovariectomy.
The regulation of vaginal contractility by steroid hormones was most apparent with mechanisms mediating smooth muscle relaxation. We observed that estradiol diminished the relaxatory response caused by EFS or exogenous VIP, while testosterone enhanced or normalized these responses. Further, DHT, delta-5-androstenediol and DHEA had similar effects to testosterone, indicating that other androgens or androgen precursors are equally effective in facilitating neurogenic or VIP-induced relaxation. These alterations may be explained by either increased neurogenic input or upregulation in the number or affinity of neurotransmitter receptors mediating relaxation. Although the main neurotransmitter mediating relaxation of the rabbit vaginal muscularis is yet to be identified,11 similar mechanisms have been demonstrated in other tissues with VIP. Various studies in breast cancer cells, uterus, oviduct, pituitary and seminal vesicle have shown that estrogens and androgens can modulate VIP content, the number of VIP immunoreactive cells and the number and affinity of VIP receptors.32,33,34,35,36
Estrogen and progesterone also have been shown to influence myometrial myosin light-chain kinase activity and uterine connective tissue-remodeling processes.37,38 Thus, steroid hormones may also cause intracellular alterations in vaginal smooth muscle contractile pathways or extracellular changes in matrix proteins that affect the material properties of vaginal tissue. Interestingly, the attenuating effect of estradiol on EFS- and VIP-induced relaxation is not antagonized by progesterone or testosterone (unpublished data). Instead, relaxation responses are further attenuated. Thus, the combined effects of steroid hormones in the vagina may not be accurately predicted by examining responses to treatment with individual hormones.
When data were normalized, neurogenic contraction in the distal vagina was not significantly influenced by supraphysiological concentrations of estradiol or testosterone. However, when data were not normalized, we observed a small, but consistent trend that vaginal tissue from testosterone- and estradiol-infused rabbits contracted with greater force than tissue from intact or vehicle-infused rabbits. Since the duration of hormone treatment in ovariectomized rabbits was only 2 weeks, trends in EFS-induced contraction that were observed in our study may have become more apparent at longer time intervals of hormone replacement. Compared to the vehicle-infused group, more forceful contractions in the hormone-infused groups are consistent with the histological findings (increased thickness of muscularis layer). However, vaginal tissue from intact rabbits generated the same amount of force as tissue from vehicle-infused ovariectomized rabbits. It is likely that hormonal regulation of vaginal contractility is complex and involves factors in addition to the amount of nonvascular smooth muscle within the muscularis layer.
On the other hand, estradiol has been shown to increase the number of adrenergic nerve fibers and norepinephrine content in rabbit vagina.39,40 These changes seem to accompany the overall tissue growth, without any overt effects on the density of innervation. Thus, mechanisms that maintain the density of adrenergic innervation in the vagina may make this organ resistant to changes in neurogenic contraction. The contractile response to exogenous norepinephrine was also resistant to change with hormonal manipulation. Small but significant differences were only observed when data were expressed in terms of force. Clear potentiation was only observed in the tissue from ovariectomized rabbits infused with testosterone.
The main source of estrogens and androgens in rabbits are the ovaries. Thus, ovariectomy in this animal model leads to near-complete sex steroid deprivation and allows investigation of the effects of hormonal treatment on target tissues. Also, since the female rabbit is an induced ovulator and remains in diestrus until mounted by a male, the complicating effects of the estrus cycle are not present in this animal model. However, this lack of an ovarian cycle may also produce differences in the response to sex steroid hormones. Another important caveat with regard to our findings is that, while plasma concentrations of hormones were not measured in this study, limited pilot studies suggest that the doses of steroid hormones used to treat ovariectomized animals result in supraphysiological plasma concentrations (unpublished data; eg plasma estradiol concentrations were 33.7±5.3 pg/ml for intact rabbits, 20.9±0.8 pg/ml in vehicle-infused ovariectomized rabbits and 469.0±86.1 pg/ml in estradiol-infused ovariectomized rabbits). This is an important consideration, given the multiple and dose-dependent effects of steroid hormones in many tissues.
In conclusion, our findings suggest that estrogens and androgens may be important regulators of vaginal tissue growth and contractility. Estrogens are important for maintaining epithelial health in the vagina, while androgens appear to be critical for maintaining the relaxatory response to endogenous neurotransmitters. Interestingly, contractile responses to adrenergic input may be largely resistant to change by steroid hormones. Further biochemical, histological and physiological studies are needed to elucidate the numerous and complex actions of steroid hormones in genital tissues and female sexual function.
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This work was supported by grants DK56846 (AMT) and DK02696 (NNK) from the National Institute of Diabetes and Digestive and Kidney Diseases and by The American Foundation for Urologic Disease (RM).
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Kim, N., Min, K., Pessina, M. et al. Effects of ovariectomy and steroid hormones on vaginal smooth muscle contractility. Int J Impot Res 16, 43–50 (2004). https://doi.org/10.1038/sj.ijir.3901138
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