| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Regular Article |
a Institute of Toxicology and Environmental Health, University of California, Davis, California 95616
b California Regional Primate Research Center, University of California, Davis, California 95616
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
aging, estradiol, FSH, ovary, ovulatory cycle, pituitary, progesterone, seasonal reproduction
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Only an animal model is likely to provide access to the materials and experimental interventions needed to fully understand the physiologic basis of menopause and related symptoms. The ideal animal model is one that can be monitored using the same daily urine sampling and methods of urinary hormone measurements already applied to women. Using this approach with a nonhuman primate model, Gilardi et al. [4] reported that the laboratory macaque (Macaca mulatta) exhibited a menopausal transition similar to that of the human female, and suggested that the female macaque may provide an animal model for study of the physiologic bases of perimenopausal symptoms observed in humans.
Gilardi et al. [4] described the perimenopausal transition in the macaque, but not all of the same endocrine changes were observed in the macaque as have been described in studies characterizing the human perimenopausal transition [3, 4]. Before complete cessation of cyclic ovarian function, which is common to both humans and macaques, a prolonged period abnormal ovarian function is observed in humans. Specific hormonal events, commonly described as occurring in women during this time period, however, were not documented by Gilardi et al. [4] as occurring in the macaque. For example, a progressive rise in the follicular phase of FSH baseline and episodes of hyperestrinism described in the human [2, 3] were not observed in the macaque. The absence of this hormonal event suggests that the macaque and human differ in terms of specific endocrine events during the climacteric, and these differences may detract from the usefulness of the macaque as a model for human perimenopause.
Because the Gilardi et al. study [4] was performed on a relatively small number of animals during only a portion of the year, the macaque menopausal transition may have been incompletely characterized by the existing data. Like the Walker study [5], the present study was performed to further elucidate the similarities and differences between the human and nonhuman primate perimenopausal transition. Walker [5] measured serum LH and estradiol over a 52-wk period to dissociate seasonal acyclicity from endocrine events characteristic of the climacteric. The present study investigated the characterization of ovarian and pituitary function during the menopausal transition in the female macaque by monitoring ovarian steroid and FSH excretion using daily urine collections, also throughout a complete year. In addition, early follicular phase inhibin ß circulating concentrations were measured.
The primary objective of this study was to determine if seasonal changes in pituitary function prevent complete FSH escape and hyperestrinism in perimenopausal macaque females. The working hypothesis was that seasonal changes in hypothalamic and pituitary function modulate pituitary function during the perimenopause, attenuating FSH escape and hyperestrinism in the macaque female. If true, these relationships need to be considered when using the macaque model to conduct studies relevant to the human perimenopause. The secondary objective was to determine if the onset of the perimenopausal transition in the macaque is temporally related to somatic aging by simultaneously measuring circulating dehydroepiandrosterone sulfate (DHEAS) levels.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Twenty intact, female rhesus macaques were selected for this study based on their general health and age (18–26 yr). One female was killed during the study after being diagnosed with a colonic adenocarcinoma. The final number of study subjects, therefore, was 19. Each female was housed individually indoors with a photoperiod of 12L:12D and in accord with American Association for Accreditation of Laboratory Animal Care standards. Daily urine samples were collected from each individual female for approximately 1 yr. Samples were collected from December 1997 to February 1999. Urine collection was conducted in the following manner: A clean pan was placed below the cage each evening to obtain the urine produced overnight, minus evaporation. The collection pan was removed each morning, and 3.0 ml of urine were collected in plastic syringes and injected (without needles) into a 12 mm x 75 mm polystyrene test tube. The tube was then centrifuged (3000 x g for 10 min), decanted into 12 mm x 75 mm polypropylene cryogenic vials, and stored frozen at -20°C until analyzed.
The breeding season for rhesus monkeys (both indoors and outdoors) at the California Regional Primate Research Center runs roughly from September through February, with the majority of conceptions occurring from October through December. Outdoor documentation consists of the round-up weight sheets on which palpation results are noted, ultrasound records (when performed, usually for clinical reasons), and conception termination records for those animals whose pregnancies were not detected by either of the two previous methods. The nonbreeding season in this study is defined as those months during which reduced fertility is expected in this colony, or March through August.
Each female was visually monitored for vaginal bleeding. Two blood samples were collected during the intervals of 3–5 days and 10–12 days following the onset of vaginal bleed. Females were restrained in metabolic squeeze-cages, and blood was collected by venipuncture. Whole blood was allowed to clot, followed by centrifugation at 3000 x g for 10 min. Serum was decanted into 12 mm x 75 mm polypropylene cryogenic vials and stored frozen at -20°C until analyzed. Selected serum samples that best represented Days 3–5 of each menstrual cycle were analyzed for inhibin ß and DHEAS concentrations.
To test whether the assay employed in this study was capable of detecting increased urinary FSHß subunit, a subset of the study animals was monitored after removing ovarian negative feedback to the hypothalamus and pituitary by surgical removal of the ovaries. This subset included four females (age, 20.8–26.3 yr) that were ovariectomized approximately 6.5 mo following cessation of the initial collection period. Six months after ovariectomy, daily urine samples were collected on these subjects as described above. These daily urine samples were analyzed for estrogen and progesterone urinary metabolites, which indicated by the estrogen levels obtained that some hormone-producing ovarian tissue remained in two of the four females. Consequently, these two females were removed from the analyses presented here.
To demonstrate that increasing FSHß immediately heightens ovarian estrogen production and that the resultant rise of estrogen metabolites is detectable by the urinary E1C assay employed in this study, an additional three mature females (age, 6.8–10.9 yr) were treated with exogenous FSH (rFSH; Organon, West Orange, NJ). Each female received 75 U of FSH on Days 4–10 following onset of the previous menstrual bleed. Urine samples were collected daily, as described above, during and after treatment and were analyzed for urinary estrogen excretion.
Assays
All urine samples were analyzed for urinary estrogen and creatinine, and a subset was analyzed for estrogen and progesterone metabolites, and follicle stimulating hormone (FSHß subunit) as previously reported [6, 7]. Briefly, urinary estrogen and progesterone metabolites were measured by enzyme immunoassay (EIA). The progesterone metabolite antibody used for assaying urine samples was Hygeia pregnanediol-3-glucuronide (PdG) (Waltham, MA), monoclonal PG-1, and the estrogen metabolite antibody R522 (estrone conjugate [E1C] antibody) [5]. Urine samples were diluted 1:50 (v/v) in distilled water and added with halving dilutions of standards (estrone conjugate standards, 6.25–200 pg/well; PdG, 9.765–1250 pg/well) and two duplicate internal controls to previously antibody-coated Nunc Maxisorb 96-well microtiter plates (Applied Scientific, San Francisco, CA). Buffer and the appropriate enzyme label were then added (estrone glucuronide or PdG horse radish peroxidase). Plates were incubated at 4°C for a minimum of 12 h. After incubation, plates were washed and tapped dry, after which 0.1 ml of substrate was added to all wells. Plates were placed on a shaker for 30–60 min (until the desired color was reached). Plates were read on a spectrophotometer with a test filter of 405 nm and a reference filter of 650 nm.
The FSHß subunit ELISA was applied according to the method described by Todd et al. [7]. Briefly, urine samples were prepared for assay by boiling for 2 min to dissociate dimers. Undiluted urine samples were added with standards (39–5000 pg/ml) and two duplicate internal controls to previously antibody-coated and blocked Nunc Maxisorb 96-well microtiter plates. Buffer was also added, and the plates were left to incubate for a minimum of 6 h at room temperature. Following the first incubation, plates were washed,. and 0.2 ml of R9517 polyclonal rabbit anti-rFSH was added. Plates were then left at room temperature to incubate overnight or for 12–18 h. After the second incubation, plates were washed, and 0.2 ml of biotinylated goat anti-rabbit IgG was added (product no. 170-6401; Bio-Rad, Richmond, CA). Plates were incubated for 2–5 h at room temperature. After the third incubation, plates were washed, and 0.2 ml of alkaline phosphatase streptavidin was added. Plates were then incubated for 1 h at room temperature. After the fourth incubation, plates were washed, and 0.2 ml of 0.5 mg/ml p-nitrophenyl phosphate (Sigma Chemical Co., St. Louis, MO) in substrate buffer was added (1.0 mM MgCl 2 and 1.0 M diethanolamine-HCl, pH 9.0). Plates were kept at room temperature for 30–60 min (until the desired color was reached). Plates were read on a spectrophotometer with a test filter of 405 nm and a reference filter of 650 nm. All urinary assay results were indexed by creatinine (Cr) to compensate for variation in urine sample concentration [8].
The interassay coefficients of variation for the estrone conjugate EIA were 7% and 9% at 31% and 72% binding, respectively, for duplicate control samples on the E1C standard curve. The 50% binding for the E1C EIA averaged 31 pg/well (n = 504). The interassay coefficients of variation for the PdG EIA were 9% at 37% binding and 12% at 71% binding (n = 252). The 50% binding for the PdG EIA averaged 48 pg/well (n = 252). The interassay coefficients of variation for the FSHß subunit ELISAs were 14.10% and 19.37% for low and high controls, respectively.
Serum samples were analyzed for inhibin ß and DHEAS using commercially available assay kits. Inhibin ß was measured using an ELISA kit from Serotec (Harlan Bioproducts, Indianapolis, IN). The DHEAS was measured using an RIA kit (Diagnostic Products Corporation, Los Angeles, CA). All samples were analyzed according to the respective manufacturer's instructions without modification.
Data Analysis
Ovulatory menstrual cycles were identified using a modification of the method described by Gilardi et al. [4]. Daily E1C and PdG metabolite excretion profiles for each intermenstrual interval were examined visually. A normal ovulatory intermenstrual interval was designated as such when a sustained rise of PdG, lasting for 
5 days, was observed and when this rise in PdG was immediately preceded by a sharp increase in E1C, coincident with a discrete FSHß peak. An episode of vaginal bleeding following the sustained PdG elevation completed the "normal" designation. If a sustained increase in PdG was observed in the absence of a visually observed episode of vaginal bleeding, Hemastix Reagent Strips (Fisher Scientific, Santa Clara, CA) were used to determine the presence of occult blood in the urine sample. Intervals (long or short) between episodes of vaginal bleeding that did not also exhibit sequential E1C and FSHß peaks were categorized as anovulatory cycles with breakthrough bleeding events. Ovarian cycles that exhibited prolonged periods of baseline E1C in the absence of an elevation in PdG (>15 days), that exhibited shortened periods of elevated PdG excretion (<5 days), or that were of very short duration between episodes of vaginal bleeding (<22 days) were categorized as abnormal cycles.
The normal entrainment of FSH was defined using the FSHß subunit profiles of four premenopausal monkeys as assessed by Todd et al. [7] using methods identical to those of the present study. The ability of the FSHß subunit assay to detect elevations in baseline was validated by monitoring animals following ovariectomy. The ability of the E1C assay to detect a full range of estrogen production was confirmed by monitoring intact animals treated with rFSH to assess ovarian responsiveness to FSH.
Standard descriptive statistics were derived for steroid and protein hormone values (e.g., mean, SD, SEM, coefficients of variation), and data were tested for intergroup differences. Normality and equal variance of log-transformed group data for serum inhibin ß and urinary FSHß were tested by one-way ANOVA. If passed, differences between groups were compared by multiple-comparison procedures (Dunnett method, 
= 0.05) using group 1 as the control. For DHEAS, normality and equal variance of group distributions were tested by two-way, repeated-measures ANOVA, and differences between groups were compared (Student-Newman-Keuls method, = 0.05). Statistical tests were performed with SigmaStat [9].
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
|
|
|
|
Mean FSHß subunit levels in the four groups and in ovariectomized females are shown in Table 2. Grouped FSHß data passed the normality test (P > 0.200) and the equal variance test (P = 0.012). The differences in the mean values among the different groups were greater than would be expected by chance (P = 0.001). Multiple comparisons indicated a statistically significant difference in urinary FSHß subunit levels in groups 3 and 4 and ovariectomized females compared to group 1, but no difference between groups 1 and 2. Mean urinary FSHß levels increased from 192.61 pg/mg Cr in group 1 to 1315.59 pg/mg Cr in group 3 to 3218.30 pg/mg Cr in group 4. Basal urinary estrogen metabolite levels were not observed to decrease until ovarian cycles became abnormal and FSHß levels began to rise.
|
The FSHß subunit profiles of the four ovariectomized females that exhibited elevated levels were recruited from the original study group of 19 monkeys. Before ovariectomy, the mean concentration of urinary FSHß for the four females was 200 pg/mg Cr (SD, ±150), with a range of 10–1480 pg/mg Cr (n = 1535). In contrast, the mean concentration of urinary FSHß values in the two females without residual ovarian tissue 6 mo after ovariectomy was 1191.17 pg/mg Cr (SD, ±650), with a range of 280–3340 pg/mg Cr (n = 120). All but six sample values from these two monkeys after ovariectomy were greater than two SD above the average values obtained for this group before surgery (i.e., >500 pg/mg Cr).
The E1C measurements of urinary metabolites were used to assess ovarian responsiveness to FSH in intact monkeys treated with rFSH. All treated monkeys exhibited a marked and sustained rise in urinary E1C concentrations. A response to treatment was detected as E1C levels increased to 500 to >2000 ng/mg Cr per day within 3–7 days after treatment (data not shown).
Mean circulating inhibin ß levels in the four groups and in ovariectomized females are shown in Table 2. Grouped inhibin ß data passed the normality test (P > 0.194) and the equal variance test (P = 0.346). The differences in the mean values among the different groups were greater than would be expected by chance (P = 0.046). Whereas multiple comparisons between groups only indicated statistically significant differences in urinary inhibin ß means between group 1 and the ovariectomized group (P < 0.05), a trend toward decreased inhibin secretion, however, was apparent from aged females with normal cycles, aged females with abnormal cycles, anovulatory aged females, and finally, ovariectomized females. Mean circulating inhibin ß levels were similar in groups 1 and 2 (130.30 and 127.52 pg/ml, respectively) and lower in groups 3 and 4 (101.39 and 55.31 pg/ml, respectively). None of the intact groups, however, were as low as the ovariectomized females (30.24 pg/ml).
Mean circulating DHEAS levels showed an increase from 1.26 µg/dl in group 1 to 1.92 µg/dl in group 2 to 3.07 µg/dl in group 3 to 3.84 µg/dl in group 4. These group differences, although apparently large, were not statistically significant, perhaps due to the small sample sizes and large variances. Within groups, somatic aging was indicated by a general decrease in DHEAS level over the 1-yr study period, but this decrease was statistically significant only for anovulatory or group 4 females.
Finally, the nonbreeding season was associated with the highest number of abnormal cycles. Coincidentally, the onset of complete ovarian senescence in the macaque was more likely to occur during that time (i.e., females that ceased abnormal cycling and became anovulatory were less likely to exhibit ovarian activity in the next breeding season and more likely to exhibit permanent ovarian quiescence). Aged female macaques that showed menstrual cycle irregularities during the breeding season, in other words, were less likely to return to ovarian cyclicity and exhibited permanent ovarian quiescence following the nonbreeding season.
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Several previously published studies have described 4–6 mo of daily hormone patterns for women [2, 3] and nonhuman primate species [5, 10–14]. Seasonal changes in the hypothalamic-pituitary-ovarian axis may be an important consideration when developing a nonhuman primate model for the human menopausal transition. The human female has no perceptible seasonality. In contrast, some laboratory macaque species, including the rhesus, exhibit an annual nonbreeding season under seminatural outdoor conditions. Macaques exposed to natural lighting and temperatures conceive early during the fall and winter months or, if not allowed to breed, continue to have several ovulatory cycles. This pattern has also been seen in laboratory-house macaques, which have shown an increase in anovulation and short luteal phases during the summer months, with year-round vaginal bleeding episodes (i.e., menstruation) [15]. Under controlled light and temperature, 22% of macaque females maintained their ovarian cyclicity with ovulations, as determined by laparotomy, but showed greater variability in cycle length than was seen in cycles occurring during the winter months [16]. The number of ovulations (or normal ovarian cycles) that a female has annually may relate to body condition [17], because low-body-weight females living under outdoor conditions that cease ovulating early in the season have lower serum estradiol levels with normal FSH and LH levels at the first ovulation of the breeding season than their heavier counterparts [18].
Other investigators have experimentally evaluated the impact of seasonal changes on estradiol negative feedback on LH inhibition at both the gonadal and nongonadal level in nonhuman primates. Wilson et al. [19] demonstrated that circulating bioactive LH exhibited a lower baseline with reduced pulse frequency in the summer versus the fall months in ovariectomized female macaques. The addition of exogenous estrogen had a greater effect in suppressing baseline LH in the summer compared to the fall months. It was concluded from these studies that estradiol's ability to suppress LH was the result of seasonal changes, either at the level of the hypothalamus, which reduced steroid-induced GnRH, or at the level of the pituitary, through increased sensitivity to the negative feedback on LH secretion. In addition, because estrogen challenge has been shown by Daily and Neill [15] to elicit FSH and LH surges during the summer months, summer infertility is also associated with insufficient follicular development as a component of anovulation. Results from the present study are consistent with observations by Daily and Neill, because most females exhibited 1) a failure to ovulate during summer months, 2) a lack of estrogen increases indicative of follicular development, and 3) a monotonic FSHß excretion profile. Within individual females, basal estrogen excretion profiles were not lower during the summer, however, compared to the fall and winter months, and FSHß excretion levels were not elevated during the summer anovulatory period. Taken together, these results indicate that a failure of follicles to mature normally during the summer months may be an additional component of seasonality in laboratory macaques.
It is possible that events such as the hyperestrinism observed in women approaching menopause [2, 3] were simply not observed by Gilardi et al. [4], because a small number of rhesus macaques in that study were followed during a segment of the year in which FSH was unable to escape from reduced negative feedback. The design of the present study, in which ovarian steroid hormones and FSHß were monitored throughout the year, revealed seasonal effects that are consistent with the failure to observe FSH escape as a consequence of a delay in development of a dominant follicle. This would be true, however, only during the nonbreeding or summer months in some animals.
The present data confirm the findings of Gilardi et al. [4] and others [20, 21]. Some older macaque females begin to exhibit abnormal ovarian function as early as 18 yr of age, but others may continue to have normal menstrual cycles until, or even after, 25 yr of age. As with women, normal and abnormal menstrual cycles in the macaque were interspersed during this late premenopausal period. Given this similarity between the monkey and the human, the failure to observe a rise in baseline FSH during the early and midfollicular phase of the menstrual cycle in monkeys approaching menopause was somewhat surprising, because such an increase occurs during the human menopausal transition [22–24]. Because no such pattern of increase in FSHß excretion was observed in this study, the failure to observe episodes of hyperestrinism in perimenopausal macaques should not be surprising. Our validation of estrogen stimulation with rFSH indicates that even small or transient increases in estrogen production would have been detected with the methods employed. Thus, the failure to observe increased E1C concentrations confirms the failure of FSH to stimulate hyperestrinism in any of the intact females in the present study as well as in that of Gilardi et al. [4]. Furthermore, the failure to observe hyperestrinism does not appear to result from a decreased annual or seasonal change in pituitary "drive," because FSHß did not increase during the normal breeding season.
In general, the nonbreeding season (March–August) had the greatest number of abnormal cycles (Table 1). Although limited, the current data also suggest that onset of complete senescence was more likely to occur during the nonbreeding season than during other times of the year, because two (of three) females with primarily abnormal, shifting to anovulatory cycles (group 3) during the first breeding season did not initiate cycles of any type during the following breeding season. The other female in group 3 began the next season with an abnormal cycle, followed by two normal cycles, and then complete cessation. A seasonal effect on the progression of ovarian events during the menopausal transition in the rhesus macaque may be possible, which also is consistent with reduced pituitary drive during the spring and summer months. The possible seasonal effects suggested by the present study do not explain the fact that elevations of FSH and episodic hyperestrinism were never observed in aged macaques during the breeding season (or during the winter months). Urinary FSHß measurements indicated that pituitary escape did not occur episodically during the breeding season in animals that were clearly experiencing abnormal menstrual cycles associated with age. Similarly, FSHß baseline levels did not exhibit a significant increase following complete cessation of cyclic ovarian function in group 2, but they did rise in group 3 and group 4 (following ovariectomy). Monkeys of an even greater age (25–30 yr) might have exhibited the expected characteristics that were missing in the monkeys studied here. Yet, in the life-history perspective of Pavelka and Fedigan [25], all female Japanese macaques studied exhibited reproductive termination after 25 yr, and the 2.9% of the population reaching that advanced age exhibited outward signs of weakness and general deterioration, unlike healthy menopausal women of middle age. As suggested by Hodgen et al. [20], the results presented here similarly suggest that, unlike the human, the macaque ovary can maintain relatively normal restraint on FSH secretion even after its ability to produce normal cyclic sex-steroid profiles has been lost. Most likely, this restraint prevents the episodes of hyperestrinism observed in women.
An association between decreased DHEAS and diseases of aging, including those of the menopausal transition, has been shown [26–29]. Recently, Kemnitz et al. [30] suggested an age-related increase in DHEAS in female (and male) macaques between 0.5 and 36 yr of age. This observation was confirmed in the study presented here, as indicated by a general decline in DHEAS levels in groups during the study period. The data presented here, however, also suggest that DHEAS levels exhibit increases related to ovarian status. Decreases in ovarian steroidogenesis might cause increases in adrenal steroid production, but we have no evidence that these endocrine events are, in fact, related.
It is beyond the scope of this paper to explain the physiologic basis for differences observed between the macaque and human in terms of the endocrine events associated with perimenopause, but recent studies have strongly suggested that the rise in FSH observed during the perimenopausal transition of women is more closely associated with circulating inhibin ß levels, not with the reduction of estradiol [24]. The E1C levels did decline, and sustained PdG elevations disappeared, following cessation of ovarian activity in some animals in this study. This loss of cyclic ovarian production of sex steroids was not associated, however, with a rise in FSHß. In contrast, a complete removal of ovarian tissue was associated with a statistically significant increase in FSHß excretion. In contrast to the human, then, it appears that ovarian inhibin ß production continues in the absence of follicle recruitment and cyclic sex-steroid production to maintain and entrain FSH secretion during perimenopause in the macaque.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 Supported by NIH 1R03AG14853. Additional funding was provided by California Regional Primate Research Center base grant RR00169. 
2 Correspondence: Susan E. Shideler, I.T.E.H., University of California, One Shields Avenue, Davis, CA 95616-8615. FAX: 530 752 5300; seshideler{at}ucdavis.edu
Accepted: July 24, 2001.
Received: August 25, 2000.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  G. F. Weinbauer, M. Niehoff, M. Niehaus, S. Srivastav, A. Fuchs, E. Van Esch, and J. M. Cline Physiology and Endocrinology of the Ovarian Cycle in Macaques Toxicol Pathol, December 1, 2008; 36(7_suppl): 7S - 23S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Buse, M. Zoller, and E. Van Esch The Macaque Ovary, with Special Reference to the Cynomolgus Macaque (Macaca fascicularis) Toxicol Pathol, December 1, 2008; 36(7_suppl): 24S - 66S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Walker and J. G. Herndon Menopause in Nonhuman Primates? Biol Reprod, September 1, 2008; 79(3): 398 - 406. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Schumacher, R. Guennoun, A. Ghoumari, C. Massaad, F. Robert, M. El-Etr, Y. Akwa, K. Rajkowski, and E.-E. Baulieu Novel Perspectives for Progesterone in Hormone Replacement Therapy, with Special Reference to the Nervous System Endocr. Rev., June 1, 2007; 28(4): 387 - 439. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Gagliardi, J. R Liukkonen, K. M Phillippi-Falkenstein, R. M Harrison, and H M. Kubisch Age as a determinant of reproductive success among captive female rhesus macaques (Macaca mulatta) Reproduction, April 1, 2007; 133(4): 819 - 826. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Wierman, R. Basson, S. R. Davis, S. Khosla, K. K. Miller, W. Rosner, and N. Santoro Androgen Therapy in Women: An Endocrine Society Clinical Practice Guideline J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3697 - 3710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Downs and H. F. Urbanski Neuroendocrine Changes in the Aging Reproductive Axis of Female Rhesus Macaques (Macaca mulatta) Biol Reprod, October 1, 2006; 75(4): 539 - 546. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Wu, M. B. Zelinski, D. K. Ingram, and M. A. Ottinger Ovarian Aging and Menopause: Current Theories, Hypotheses, and Research Models Experimental Biology and Medicine, December 1, 2005; 230(11): 818 - 828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.M. Nichols, B.D. Bavister, C.A. Brenner, P.J. Didier, R.M. Harrison, and H.M. Kubisch Ovarian senescence in the rhesus monkey (Macaca mulatta) Hum. Reprod., January 1, 2005; 20(1): 79 - 83. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Garai, S. Vilagi, I. Repasy, M. Koppan, and J. Bodis Short communication: seasonal onset of menopause? Hum. Reprod., July 1, 2004; 19(7): 1666 - 1667. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Tang, W. G.M. Janssen, J. Hao, J. A. Roberts, H. McKay, B. Lasley, P. B. Allen, P. Greengard, P. R. Rapp, J. H. Kordower, et al. Estrogen Replacement Increases Spinophilin-immunoreactive Spine Number in the Prefrontal Cortex of Female Rhesus Monkeys Cereb Cortex, February 1, 2004; 14(2): 215 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. X. Lu, Z. Ma, S. Moser, T. G. Evans, and C. J. Miller Effects of Ovarian Steroids on Immunoglobulin-Secreting Cell Function in Healthy Women Clin. Vaccine Immunol., September 1, 2003; 10(5): 944 - 949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. L. Bellino and P. M. Wise Nonhuman Primate Models of Menopause Workshop Biol Reprod, January 1, 2003; 68(1): 10 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-H. Lue, B. L. Lasley, L. S. Laughlin, R. S. Swerdloff, A. P. S. Hikim, A. Leung, J. W. Overstreet, and C. Wang Mild Testicular Hyperthermia Induces Profound Transitional Spermatogenic Suppression Through Increased Germ Cell Apoptosis in Adult Cynomolgus Monkeys (Macaca fascicularis)( J Androl, November 1, 2002; 23(6): 799 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. Lasley, N. Santoro, J. F. Randolf, E. B. Gold, S. Crawford, G. Weiss, D. S. McConnell, and M. F. Sowers The Relationship of Circulating Dehydroepiandrosterone, Testosterone, and Estradiol to Stages of the Menopausal Transition and Ethnicity J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3760 - 3767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Schramm, A. M. Paprocki, and B. D. Bavister Features associated with reproductive ageing in female rhesus monkeys Hum. Reprod., June 1, 2002; 17(6): 1597 - 1603. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
