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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 12 4637-4644
Copyright © 1999 by The Endocrine Society

Original Studies

Vasopressin and Oxytocin Neurons of the Human Supraoptic and Paraventricular Nucleus; Size Changes in Relation to Age and Sex

Tatjana A. Ishunina and Dick F. Swaab

Netherlands Institute for Brain Research (T.A.I., D.F.S.), 1105 AZ Amsterdam, The Netherlands; and the Department of Histology and Embryology, Kursk State Medical University (T.A.I.), Kursk, Russia 305033

Address all correspondence and requests for reprints to: Prof. Dr. D. F. Swaab, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands. E-mail: t.eikelboom{at}nih.knaw.nl


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei consist of arginine vasopressin (AVP)- and oxytocin (OT)-synthesizing neurons that send projections to the neurohypophysis, whereas the PVN also projects to other brain areas. A growing body of evidence in animals suggests the presence of sex differences in the vasopressinergic and oxytocinergic systems. The present study was aimed at determining whether the sizes of AVP and OT neurons in the human SON and PVN show sex differences, as earlier studies demonstrated that a change in neuronal size is a sensitive parameter for activity. The minimal and maximal diameters were determined to estimate the volumes of cell somata and cell nuclei in AVP and OT neurons stained with an antibody against human glycoprotein-(22–39), a part of the AVP precursor, and a monoclonal anti-OT antibody in 15 men and 17 women ranging in age from 29–94 yr. The AVP neurons appeared to be larger in young men than in young women (<=50 yr old). In elderly women (>50 yr old) AVP cell size considerably exceeded that in young women. In elderly men AVP neurons were larger than in young men and elderly women, although these differences were not significant. In addition, AVP cell size correlated positively with age in women but not in men. No significant differences were found in the AVP cell nucleus volumes among all four groups studied. Sex differences in the size of the PVN vasopressin neurons were pronounced at the left side (P = 0.048) and absent at the right side (P = 0.368), indicating the presence of functional lateralization in this nucleus. No difference was found in any morphometric parameter of OT neurons in the PVN among the 4 groups studied. Thus, our data demonstrate sex differences in the size of the AVP neurons, and thus in their function, that are age and probably also side dependent and the absence of such changes in OT neurons in the PVN. These data provide a basis for the reported higher AVP plasma levels in men compared to women.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE NEUROPEPTIDES arginine vasopressin (AVP) and oxytocin (OT) serve both as peripheral hormones and as neurotransmitters or neuromodulators in the brain. In the hypothalamus AVP and OT are synthesized in the paired supraoptic (SON), paraventricular (PVN), and accessory nuclei by neurosecretory neurons that range from magnocellular to parvocellular. AVP is also produced by parvocellular neurons in the suprachiasmatic nucleus (1). The neurosecretory neurons of the PVN and SON transport AVP and OT to the neurohypophysis where they are either stored or released into the blood stream (1, 2, 3). Hormonal actions of AVP include regulation of plasma volume and osmolality (1, 4) and, in the liver, promotion of glycogenolysis (5). In the brain, AVP is involved in the regulation of body temperature (4), blood pressure (6), brain development (7, 8), and circadian rhythmicity (1) as well as in modulation of memory (9). AVP was also shown to be released during sexual arousal (10). The role of OT in the processes of lactation and parturition is well documented (1, 11). In addition, it has central functions, such as facilitation of the maternal behavior (12) and lordosis (13), and inhibition of learning and memory (14). OT was shown to be released at the time of ejaculation (10), plasma OT levels were significantly increased during sexual arousal both in men and in women (15), and the number of OT neurons in the PVN was decreased in Prader-Willy syndrome, indicating a role in eating behavior (16). Both AVP and OT are important for social attachment (17).

A growing body of evidence indicates the presence of sex differences in the vasopressinergic and oxytocinergic systems in mammals. In female mice the number of OT cells and OT-immunostained axons and the amount of OT in the hypothalamus were larger than in males (18). In the rat the volume of the SON, the sizes of AVP neurons (19), the areas of their rough endoplasmic reticulum, and the sizes of their nucleoli (20) were larger in males than in females. In male golden hamsters 50% more AVP-immunoreactive neurons were found in the medial and lateral subdivisions of the SON than in females (21), all indications of a higher activity of AVP neurons in males than in females. In agreement with these signs of increased activity of AVP neurons in males, plasma levels of AVP were shown to be sexually dimorphic in rats (22, 23) and humans (24, 25), where they were reported to be higher in males. It should be noted, however, that the latter studies did not measure the main part of the AVP in human plasma that is bound to platelets (26). Our aim was to investigate the possible presence of sex differences in the activity of vasopressinergic and oxytocinergic neurons of the human SON and PVN using the size of neurons as a sensitive parameter for functional differences (27, 28). Special attention was paid to the effect of age and lateralization.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissue collection

Brains (mean weight, 1285 ± 29 g, mean ± SEM; mean postmortem delay, 18 ± 3 h) from 32 control subjects (15 males and 17 females) without a primary neurological or psychiatric disease, ranging in age from 29–94 yr (57 ± 3 yr) were obtained at autopsy (see Ref. 28 for clinicopathological information). The brains in the Netherlands Brain Bank are donated by patients that have given their informed consent for a brain autopsy and the use of the brain tissue and medical files for research purposes. The hypothalami were dissected and fixed in 4% formaldehyde in phosphate-buffered saline (pH 7.4) at room temperature for about 2 months (75 ± 26 days). The fixed hypothalami were dehydrated in graded ethanols, embedded in paraffin, and cut serially in 6-µm coronal sections. For anatomical orientation, every 50th section was mounted on chrome-aluminum sulfate-coated glass slides, deparaffinized, hydrated, and stained with thionine (0.5%).

Immunocytochemistry

Two consecutive sections in the middle of the SON from each subject were stained with antisera recognizing AVP neurons [Boris-Y-2, directed against the human glycoprotein-(22–39), a part of the AVP precursor] (29, 30). Immunocytochemical staining was performed by the following protocol. Sections were hydrated and incubated for 1 h at room temperature and overnight at 4 C with Boris-Y-2 (1:1000 dilution) in Tris-buffered saline (0.05 mol/L Tris and 0.5 mol/L NaCl, pH 7.6) containing 0.5% Triton X-100. All subsequent incubations were performed at room temperature for 1 h. The sections were washed in Tris-buffered saline (0.05 mol/L Tris and 0.9% NaCl, pH 7.6) and incubated with goat antirabbit serum (Betsy; 1:100 dilution) in Tris-buffered saline-Triton X-100. After washing in Tris-buffered saline, sections were incubated with peroxidase-antiperoxidase (1:1000 dilution) in Tris-buffered saline-Triton X-100. Finally, the sections were washed in 0.05 mol/L Tris-HCl, pH 7.6, and stained with 0.5 mg/ml 3–3'-diaminobenzidine (Sigma) in 0.05 mol/L Tris, pH 7.6, containing 0.01% H2O2 and 0.2% nickel ammonium sulfate at room temperature for 10 min. After rinsing in distilled water the sections were dehydrated via ethanol and mounted in Entellan (Merck & Co., Rahway, NJ). For staining OT neurons in adjacent sections, the monoclonal antibody (A1–28) (31) was used. After rehydration, sections were incubated with 1) A1–28 (1:200), 2) biotinylated sheep antimouse IgG (1:100), 3) avidin-biotin-horseradish peroxidase (Vector elite kit, Vector Laboratories, Inc., Burlingame, CA; 1:800) in 0.05 mol/L Tris, 0.5 m saline, and 0.5% Triton X-100, pH 7.6; subsequently incubated with 0.5 mg/ml 3–3'-diaminobenzidine in TBS containing 0.01% H2O2, followed by dehydration in graded ethanols and xylene and coverslipping with Entellan.

Quantification of neuronal parameters

As the shape of the neuron is ellipsoide, it necessitated the measurements of two axis for an appropriate estimation of the neuron volume. The shortest (Dmin) and largest (Dmax) diameters of cell somata crossing under the angle of 900 were measured in immunocytochemically stained AVP and OT neurons with a nucleolus by means of an ocular micrometer. Cell somata volumes (Vcs) were subsequently calculated according to the formula of a prolate spheroid {pi} a b2/6, where a is the Dmax, and b is the Dmin. Cell nucleus volumes (Vcn) were calculated using the formula of the sphere volume 4{pi} r3/3 (32), where r is the radius of the sphere. Dmin and Dmax as well as the corresponding cell volume were calculated for each neuron separately.

Statistical methods

The differences in the mean Dmin, Dmax, Vcs, and Vcn between males and females were tested using the Kruskal-Wallis multiple comparisons test. To test the correlation between age of the subjects and mean Dmin, Dmax, Vcs, and Vcn, Spearman’s correlation test was used. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Immunocytochemistry resulted in a clear cytoplasmic staining of AVP and OT-ergic neurons in the SON, PVN, and accessory nuclei. In the SON OT cells were mostly concentrated in a cap on top of the dorsolateral part that was otherwise predominantly vasopressinergic. OT cells were also found diffusely distributed among AVP neurons in the ventromedial subdivision of the SON. In the PVN OT neurons were scattered among AVP cells. Microscopic analysis revealed that the size of AVP neurons in both nuclei was larger in young males than in young females and was larger in old women than in young women ( Figs. 1–3GoGoGo). Subsequent quantitative analysis was performed in two different age groups subdivided around the median age of the menopause, which is about 50 yr (33). As the majority of OT cells are located in the PVN, whereas relatively few OT cells are localized in the dorsolateral part of the SON, and scattered OT cells are present in the accessory neurosecretory groups (1), OT-ergic cells were measured only in the PVN.



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  		Figure 1. Immunocytochemical staining of vasopressinergic neurons in the SON (A–F). Note the difference between a young man (A and B) and a young woman (C and D) and between a young woman (C and D) and an elderly woman (E and F). Bar: A, C, and E, 400 µm; B, D, and F, 40 µm.

 


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  		Figure 2. Immunocytochemical staining of vasopressinergic neurons in the PVN. Note the difference between a young man (A and B), a young woman (C and D), and an old woman (E and F). Bar: A, C, and E, 400 µm; B, D, and F, 40 µm.

 


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  		Figure 3. No difference in staining was present among the four groups in the size of OT-ergic neurons in the PVN (A–H) in a young man (A and B), a young woman (C and D), an elderly man (E and F), and an elderly woman (G and H). Bar: A, C, E, and G, 400 µm; B, D, F, and H, 40 µm.

 
A total of 2480 AVP neurons was measured in the SON (55 ± 0.9/patient), whereas 2138 (AVP-ergic) neurons (49 ± 1.1/patient) and 2068 (OT-ergic) neurons (51 ± 1.3/patient) were analyzed in the PVN. There was a significant correlation between age and the Dmin of AVP-ergic neurons in the PVN when all patients were pooled (r = 0.408; P = 0.031). After subdivision of the subjects into females and males, women showed a significant (r = 0.508; P = 0.037) positive correlation between the Dmax and age in the SON and between the Vcs (r = 0.592; P = 0.02) and the Dmin (r = 0.624; P = 0.013) and age in the AVP-ergic neurons in the PVN. No significant correlations with age were found in men.

In the SON the Kruskal-Wallis test showed that there was a significant difference in the Dmax of AVP-ergic neurons among the four groups (P = 0.009). This parameter was significantly (P = 0.001) larger in young males than in young females (<=50 yr old) and was larger in elderly women (>50 ys old) than in young women (P = 0.003; Table 1Go and Fig. 1Go).


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  		Table 1. Mean ± SEM of cell size parameters in AVP neurons in different age groups in the SON

 
In the AVP-ergic PVN the Kruskal-Wallis test showed that Vcs (P = 0.017) and Dmin (P = 0.01) were significantly different among the four groups. The Mann-Whitney test further demonstrated that Vcs and Dmin were significantly larger in young males than in young females (P = 0.041). Each of these parameters was larger in elderly women than in young women (P = 0.003 and P = 0.002 respectively; Table 2Go and Figs. 2Go and 4Go).


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  		Table 2. Mean ± SEM of cell size parameters in AVP neurons in different age groups in the PVN

 


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  		Figure 4. Graph depicting sex and age differences in cell somata volumes in the PVN. AVP neurons are larger in young men than in young women (P = 0.041) and are larger in old women than in young women (P = 0.003). No such difference is present in OT neurons, which are obviously smaller than AVP cells (P = 0.0001).

 
No significant differences in Vcn among the four groups were observed in either of the nuclei.

In 13 patients in whom both the left and right halves of the hypothalamus were available (26 sections for the left and 26 for the right side), there was a trend for left-right asymmetry in the PVN of males, as the Vcs of AVP-ergic neurons were larger in the left part than in the right (P = 0.057). As a result, the sex differences in the size of the AVP neurons in the PVN of those patients was prominent in the left side (P = 0.048) and absent in the right side (P = 0.368). In the SON no evidence for left-right asymmetry was observed (Fig. 5Go).



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  		Figure 5. Graph depicting differences in AVP cell somata volumes between the left and right parts of the SON and PVN. The Mann-Whitney test showed that there is a trend for left-right asymmetry in the PVN in men (P = 0.057). As a result, sex differences in the PVN were pronounced at the left side (P = 0.048) and absent at the right side (P = 0.368).

 
Interestingly, age and sex differences in the size of AVP neurons in the SON manifested in the maximal neuronal diameter, whereas in the PVN sex differences were found in the minimal diameter of the neurons.

In the oxytocinergic population of the PVN the Kruskal-Wallis test showed that none of the studied parameters was different among the four groups (Table 3Go and Fig. 3Go), no correlation was present between the cell size and age, and no evidence for a left-right asymmetry was observed. In the PVN, OT cells were smaller than AVP-ergic cells (P = 0.0001; Fig. 4Go).


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  		Table 3. Mean ± SEM of cell size parameters in OT neurons in different age groups in the PVN

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The size of SON and PVN neurons is a sensitive measure of their activity (27, 28). In the present study we confirmed, using other parameters, earlier observations that showed a sex-dependent activation of neurons in the human SON and PVN with age based upon an increase in the size of the Golgi apparatus and of the cell surface as determined by image analysis (28, 34). In the present paper we studied the activity changes for the first time in immunocytochemically defined AVP and OT neurons. In addition, we described for the first time sex differences in the size of AVP neurons in the human PVN, indicating a higher activity in young males than in young females and the lack of any sex- or age-related differences in OT neurons. There are various measures for neuronal activity in postmortem material. The most sensitive of them seem to be the size of the Golgi apparatus and cell size (28). In situ hybridization for AVP messenger ribonucleic acid did not give a good indication of activity changes (35). It appeared, moreover, to be difficult to combine the staining of the Golgi apparatus area with immunocytochemical identification of the cell type. Therefore, we have chosen for the present study to measure the cell size in immunocytochemically identified AVP and OT neurons. It should also be noted that the image analysis measurements that we used in the former study (28) did not distinguish the size of the long and short cell body diameters, which appeared to be differentially changed in relation to age and sex in the SON and PVN, possibly in relation to the microscopic orientation of AVP neurons within the hypothalamus. In a previous study we found that the cell profiles in the SON were larger in young males than in young females and that they were larger in old women than in young women (28). In the present study we performed a more detailed analysis, using other quantitative parameters, such as Vcs, Vcn, Dmin, and Dmax and included for the first time both vasopressinergic and oxytocinergic populations of the PVN. It appeared from the present work that AVP-ergic neurons show an age-dependent pattern of sex differences not only in the SON but also in the PVN. The AVP neurons in the PVN were also larger in young males, suggesting the higher activity in these neurons, compared to those in young females, and were larger in old women than in young women, whereas the size of OT neurons did not differ among the four groups studied.

The observed sex differences in AVP neurons may have various functional implications. Our morphometric data and the animal experimental literature agree with the finding that plasma AVP levels are higher in male rats (22, 23) and in male humans (24, 25). There are also sex differences at the level of the target organ of AVP. It is known from the literature that the pressor action of AVP is greater in male rats than in nonestrous females (36) and that the antidiuretic response to AVP is significantly greater in intact males than in intact nonestrous females (37). Gonadectomy was without effect on both the pressor response to AVP (38) and the antidiuretic potency of AVP in male rats (37), but in gonadectomized female rats both effects were enhanced to a level similar to that observed in intact males (37, 38). There are various factors that may contribute to the sex differences in AVP neurons. Several studies demonstrated that the secretion of AVP is influenced by circulating levels of gonadal steroids, particularly estrogens, as plasma AVP levels vary during the estrous cycle in the rat (22, 39), during the menstrual cycle in the human (40), and after gonadectomy in rats (22). Moreover, the expression of the AVP gene in the rat brain is affected by variations in estrogen levels during the estrous cycle, gestation, and lactation (41). Estrogens decrease the antidiuretic (42) and pressor (43) responses to AVP in the female rat, an effect that was significantly enhanced in ovariectomized animals. Gonadotropins may also influence the neurosecretory activity in the rat SON and PVN when administered systemically (44) and after local implantation (45). It has been shown that in the rat ovariectomy activates the neurosecretory neurons in the SON and PVN, and the administration of estrogens to the ovariectomized rat causes a decreased activity of neurons in the SON and PVN. This effect was reversed after the additional administration of gonadotropins (39, 44). In support of an inhibitory action of ovarian hormones on the AVP neurons are our data on the 46-yr-old female (patient 80002) who had a bilateral ovariectomy 22 months before her death because of an ovarian carcinoma and who showed larger AVP cell sizes in the SON (Vcs = 2330 µm3) and especially in the PVN (Vcs = 2021 µm3) than other females of her age group.The present study in humans confirms the observations mentioned above by demonstrating a higher activity of AVP neurons in postmenopausal women with increased gonadotropin levels (33). The exclusion of the patient with ovarian carcinoma (no. 80002) did not influence the results.

Our data show that AVP neurons in both SON and PVN are larger in postmenopausal women than in young females, and the menopause is associated with the hypersecretion of gonadotropins from the pituitary as a response to a decreased secretion of ovarian sex steroids (33). The observation of patient 80002 and our results from the present and earlier studies (28) suggest the existence of an inhibitory role of estrogens on the activity of AVP neurons in the human SON and PVN. Such an effect may be mediated via a number of mechanisms. One of them is a direct action of estrogens on the genomic level in the PVN and SON neurons mediated by estrogen receptor ß (ERß) (46, 47). The localization of ERß on identified AVP neurons in the human hypothalamus has, however, not yet been performed. Another possible way, as shown in rat (48), is that estrogens may regulate the activity of magnocellular AVP and OT neurons in an indirect, transsynaptic manner by influencing the activity of neurons projecting to the SON from the estrogen-receptive lamina terminalis and preoptic area. Another line of research has proposed that the activation of AVP neurons during aging is a compensating mechanism for a decreased responsiveness to AVP in the aged kidney that is due to a decrease in renal AVP receptors (49, 50). In conclusion, the possible explanations of the mechanism of the sex-dependent age-related activation of AVP neurons are at present manyfold and need further research.

We found sex differences in the PVN in the cell size of AVP-ergic neurons and not of OT-ergic ones, suggesting a selective effect of gonadal steroids, particularly of estrogens, on AVP neurons. Yet, there is much evidence that estrogens affect OT cells. Serum OT levels vary during the menstrual cycle (51, 52). Estrogens in rats has been reported to enhance OT gene expression (53, 54), peptide content (55), and secretion (56). The OT gene contains several estrogen response elements in rats (57) and humans (58). OT neurons in the rat express ERß immunoreactivity (47, 59), showing the potential of direct regulation of OT neurons by estrogens via ERß. In our study, however, we did not find any sex or age differences in the size of OT-ergic neurons in contrast to AVP neurons, consistent with an earlier report in which the total number of neurons expressing OT in the human PVN did not change in the course of aging (60). The lack of changes in the size of the OT neurons might either mean that this subpopulation of OT neurons is not affected by long term changes in estrogen levels or that functional changes in this group of neurons are not readily reflected in changes in cell size in the smaller oxytocin neurons (61). Follow-up studies with other measures of neuronal activity, such as in situ hybridization for oxytocin messenger ribonucleic acid, should clarify this point.

A surprising observation was made concerning a left-right asymmetry in the PVN, where there was a trend for the AVP cell somata volumes to be larger on the left side of the PVN compared to those on the right side in men, and as a result, sex differences were prominent between left parts and absent between right parts. This is consistent with an earlier report (62) in which a significant lateralization was found for TRH in the human PVN. The left-right difference may result directly from the effect of estrogens on the development of hypothalamic lateralization (63). On the other hand, the asymmetry in the activity of AVP neurons may also be indirectly caused by the asymmetrical distribution of neurotransmitters in the human brain (64), such as {gamma}-aminobutyric acid (GABA), that is, in an opposite way from the activity of the AVP neurons, related to age and has right side prevalence in the brain (64). Indeed, the observation that GABA levels decrease with age in man (64, 65) while it appears to have a striking inhibitory effect on AVP release in the PVN (66) and SON (67) make it an interesting potential factor involved in the age- and lateralization-related control of AVP neuronal activity. As the inhibitory effect of GABA decreases with aging (64, 65), AVP neurons would become more active during the course of aging, as was indeed found earlier by the increased size of the Golgi apparatus (28, 34) and in the present study for the cell size. It should be noted also that a lateralization of the SON would not have many functional implications, as it contains mainly neurosecretory neurons releasing their products into the bloodstream, whereas the PVN also has projections into the brain (1). The lateralization we observed in the AVP-ergic PVN seems to be a part of the global, more lateralized, brain organization in men than in women (68).

In conclusion, our results show the existence of age-dependent sex differences in AVP neurons in the human SON and PVN, which are suggested to have a side preference in the PVN and an absence of any age- or sex-related differences in oxytocinergic cells in the PVN. In addition, the presence of lateralization of AVP neuron activity in the PVN seems to raise the general point that for studies of sex differences in the human brain, potential left-right differences should be taken into account.


   Acknowledgments
 
Brains were obtained from the Netherlands Brain Bank, Amsterdam (coordinator Dr. R. Ravid). The integrity of the brain of the controls was investigated by Dr. W. Kamphorst or Prof. Dr. P. van der Valk of the Pathological Institute of the Free University, Amsterdam. We also thank Mr. B. Fisser and Ms. U. Unmehopa (Netherlands Institute for Brain Research) for their technical help in the processing of brain tissues, Ms. U. Unmehopa also for the graphic help, W. G. North (Dartmouth Medical School, Lebanon, NH) for providing us with the Boris-Y-2 antiserum, Dr. A. Hou-Yu (Columbia University, New York, NY) for the generous gift of the OT antibody (A1–28), Mr. G. Van der Meulen for the photography, Dr. M. A. Hofman for statistical advice and critical revision of the manuscript, and Mrs. W. Verweij for secretarial help.

Received April 30, 1999.

Revised July 13, 1999.

Accepted August 24, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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