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Endocrinology Vol. 138, No. 1 143-148
Copyright © 1997 by The Endocrine Society

ARTICLES

Abnormal Estrous Cyclicity and Behavioral Hyporesponsiveness to Ovarian Hormones in Genetically Obese Zucker Female Rats1

Carrie Lynn Marín Bivens and Deborah H. Olster

Department of Psychology, University of California, Santa Barbara, California 93106

Address all correspondence and requests for reprints to: Dr. Deborah H. Olster, Department of Psychology, University of California, Santa Barbara, California 93106. E-mail: olster{at}psych.ucsb.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Obese Zucker female rats are infertile. The present study was designed to assess estrous cyclicity in adult, ovary-intact, lean and obese Zucker rats and to compare reproductive behaviors induced by exogenous steroid hormones in ovariectomized (ovx) lean and obese Zucker rats. The majority (90%) of obese rats had incomplete cycles in comparison with the normal, 4-day cycles displayed by lean Zucker rats. After ovariectomy, all rats were treated with estradiol benzoate (EB, 15–100 µg/kg) or EB plus progesterone (P, 2–20 mg/kg), and tested for sexual receptivity and proceptivity (PRO). At the highest EB dose, obese Zucker females displayed lordosis less frequently than lean rats (lordosis quotient, LQ, 8 ± 6% vs. 32 ± 13%, respectively). At the lowest doses of EB plus P, lean females were extremely receptive and proceptive (LQ = 93 ± 4%, PRO = 6.2 ± 2 bouts/min). Zucker obese females, in contrast, were only slightly receptive (LQ = 26 ± 11%) and showed less PRO than lean rats (PRO = 2.4 ± 0.6 bouts/min). Increasing the dose of either EB or P, administered in combination with the lowest dose of the other hormone, produced receptivity and PRO in obese Zucker females that were comparable with those observed in lean rats. Serum estradiol and P levels in ovx obese rats were either equivalent to or higher than those in the ovx lean rats when both were given the same doses of hormones. These data suggest that considerably higher doses and serum concentrations of EB and/or P are required to elicit robust lordosis and PRO in ovx obese Zucker than in lean rats. This behavioral hyporesponsiveness to sex steroid hormones may contribute to infertility in the obese Zucker female rat.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
FOOD availability is a regulator of reproduction in mammals. Food restriction in female rats delays pubertal onset (1, 2, 3), suppresses pulsatile gonadotropin secretion (1, 3), induces abnormal estrous cycles (3), and inhibits reproductive behavior (3). Although the link between undernutrition and suppressed reproductive function is well established, the connection between obesity and infertility has not been as thoroughly explored.

The obesity in Zucker rats is inherited as a Mendelian, homozygous recessive trait (fa/fa) (4). Genetically obese Zucker rats have several endocrine and metabolic abnormalities, including low metabolic rate (5), hyperinsulinemia (6, 7), corticosterone overproduction (8, 9), and infertility (4). Obese rats are produced typically by breeding heterozygous (+/fa) lean rats (4) (Charles River Laboratories, personal communication; Harlan Sprague Dawley, personal communication) or by breeding heterozygous (+/fa) females with fertile obese (fa/fa) male rats (R. Oates-O’Brien, University of California, Davis, personal communication). However, only a few male obese Zucker rats are fertile (4, 10), and all obese Zucker female rats are infertile (4). Obese female rats have delayed puberty, as indicated by delayed vaginal opening (11, 12, 13), subsequent abnormal estrous cyclicity (11, 12, 14), undeveloped uteri and lack of deciduomata formation (11, 15), a lack of mechanically induced pseudopregnancy, and low pituitary weight (15). Only a small subset of obese Zucker rats displays normal estrous cycles (14, 16, 17) and shows normal pseudopregnancy and deciduomata responses (16).

Ovary-intact and PMS-treated, obese Zucker, female rats display less reproductive behavior than their lean counterparts (4, 11, 15). This evidence suggests that obese Zucker female rats may be behaviorally hyporesponsive to the inductive effects of gonadal steroid hormones. To test this hypothesis, we compared reproductive behavior induced by exogenous steroid hormones in ovariectomized (ovx) lean and obese Zucker rats. Serum steroid hormones were measured after estradiol benzoate (EB) and progesterone (P) treatment to rule out the possibility that low circulating hormone levels in steroid-treated, obese rats could have produced suboptimal reproductive behaviors.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Nine-week-old, heterozygous, lean (fa/+, n = 10) and obese (fa/fa, n = 21) female rats were purchased from the Department of Nutrition, University of California, Davis, CA. Sexually experienced, Long-Evans, male rats (4–6 months old, 500–670 g, from Charles River Laboratories, Wilmington, MA) were used as stimulus males for the behavioral tests. All animals were housed singly in a room with ambient temperature at 22–23 C and a 14-h light/10-h dark photoperiod (lights on 2300 h–1300 h). They were given unlimited access to food (Rodent Chow no. 5001, PMI Feeds, St. Louis, MO) and water. All procedures were approved by the University of California, Santa Barbara Animal Care Council, and followed the guidelines established by the NIH Guide for the Care and Use of Laboratory Animals.

Estrous cycles, hormone treatments, and behavioral testing
After a 1-week recovery period from traveling, vaginal smears were collected each morning (1000 h) by lavage from all females for 2 weeks to determine estrous cyclicity (18). In this classification, the term metestrus is omitted and replaced with diestrus I because metestrus has a rather short duration and is not consistently observed. The investigator classified all vaginal smears without knowledge of genotype. After estrous cyclicity data were collected, the female rats were anesthetized with 33.3 mg/kg ketamine (im) plus 6.7 mg/kg xylazine (im) and were ovx bilaterally with caution to prevent excessive adipose tissue removal. Behavioral testing began after all rats returned, at least, to their presurgical weights (16 days post surgery).

Ovx lean females received EB (Sigma, St. Louis, MO; 15, 50, 100 µg/kg sc) dissolved in sesame oil, followed 24 h later by P (Sigma; 2 mg/kg sc) dissolved in propylene glycol. Obese females received either EB (15, 50, 100 µg/kg sc) followed 24 h later by P (2 mg/kg sc; n = 10), or EB (15 µg/kg sc) followed 24 h later by P (2, 4, 20 mg/kg sc; n = 11). The different hormone doses were given to all animals in a counterbalanced order, with a 2-week recovery period between hormone treatments. Animals were tested for the display of reproductive behaviors in response to stimulus males, which were physically larger than obese females, immediately before and 4 h after P treatment. A dim red light (25 W) provided illumination during testing (1400–2200 h). Reproductive behaviors were observed in clear Plexiglas cylinders (46 cm x 92 cm, American Plastics Corp., Camarillo, CA) with pine shavings on the floor. Sexual receptivity was quantified by lordosis quotient (LQ, positive lordosis responses/number of mounts x 100%) and lordosis rating [LR, average degree of arching of the back using the following criteria: 0 = no lordosis, 1 = slight, 2 = moderate, 3 = strong dorsioflexion; (19)]. Proceptivity (PRO) rate was measured as the frequency of ear-wiggling and hop-darting bouts. The observer was unaware of treatment conditions during these behavioral observations.

Blood collection
Another group of ovx lean (n = 10) and obese (n = 12) rats were catheterized in the right jugular vein using the anesthesia described previously. The catheters were made from 0.025"-id x 0.047"-od silicon rubber tubing (Sil-Med Corp., Tauton, MA). The catheter extended 34 mm into the jugular vein, was led sc around the shoulder to the back of the neck, protruded 2.5 cm from the neck, and was sealed with a stainless steel pin. The catheters were flushed daily with heparin (100 IU/ml in 0.9% saline) to maintain patency. At the onset of the dark phase, 2 days after catheterization, a 0.5-ml blood sample was removed and replaced with 0.5 ml sterile 0.9% saline. Next, the rats were treated with either 15 or 50 µg/kg EB, sc. Every 4 h post injection, a 0.5-ml blood sample was collected and replaced with 0.5 ml sterile 0.9% saline, without restraining the rats. If catheters failed, samples were collected from the tail vein, with restraint. After the seventh blood sample was collected (i.e. 24 h after EB injection), either 2 or 4 mg/kg P was injected sc. Four hours later, a final 2-ml blood sample was collected. A dim red light (25 W) provided illumination during the dark phase of the photoperiod, and noise was minimized. Sera were harvested and stored at -20 C until used in RIAs.

RIA
Serum estradiol and P levels were measured in duplicate 50-µl samples by RIA using Coat-A-Count RIA kits (Diagnostics Products Corp., Costa Mesa, CA). We first verified that these kits do not require extraction or chromatography, even from hyperlipidemic serum samples (data not shown). For the estradiol RIA, the assay sensitivity was 8 pg/ml and the intra- and interassay coefficients were 2.4% and 7.3%, respectively (n = 4 assays). The sensitivity for the P RIA was 0.02 ng/ml and the intra- and interassay coefficients were 0.8% and 3.6%, respectively (n = 2 assays).

Data analysis
Estrous cyclicity data were analyzed by chi-square analysis for normal estrous cycles (normal = 4- to 5-day cycles, abnormal = diestrus > 2 days, prolonged estrus, or incomplete cyclicity). Mixed-measures ANOVA and post hoc comparisons were used to analyze the RIA data and proceptive behavioral data for effects of genotype, hormone dose, and time, when appropriate. Friedman’s two-way ANOVA and multiple comparisons (hormone dose effects) and Mann-Whitney U test (genotype effects) were used to evaluate the sexual receptivity data (20). The criterion for statistical significance was P < 0.05 for all tests. The statistical software program BMDP (1993 version, programs 2V, 4V, 7D, 3S) was used for all analyses.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Estrous cyclicity
All ovary-intact lean rats had normal, 4-day estrous cycles, whereas only 10% of the obese rats had normal cycles (Fig. 1Go, {chi}2 = 8081, P < 0.05). Representative examples of abnormal cycles are shown in Fig. 1Go. Most (75%) obese rats displayed alternating single days of estrus and multiple days of diestrus, whereas some were in constant diestrus (15%). Oddly, one rat had a backward cycle, with estrus followed by proestrus instead of diestrus (Fig. 1Go).



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  		Figure 1. Patterns of representative daily vaginal smears with percent lean and obese Zucker rats displaying that specific vaginal smear pattern. All lean rats displayed normal 4-day estrous cycles, whereas most obese rats exhibited aberrant cycles. P, proestrus; E, estrus; D1, 1st day of diestrus; D2, 2nd day of diestrus.

 
Sex behavior
After injection of EB alone, lordosis responses were low in both lean and obese ovx rats. At the highest dose of EB, obese rats displayed lordosis less frequently than the lean rats (Fig. 2Go, Mann-Whitney U = 81.5, P < 0.05). When the obese rats displayed estradiol-induced sexual receptivity, it was less robust than that observed in lean rats, as assessed by LR (Fig. 2Go, Mann-Whitney U = 85.5, P < 0.05). Proceptive behaviors were never observed in either group after treatment with EB alone.



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  		Figure 2. LQ (top) and LR (bottom) in ovx lean and obese females after various doses of EB. **, P < 0.01; *, P < 0.05 vs. lean rats at same EB dose.

 
At the lowest doses of EB (15 µg/kg) plus P (2 mg/kg), lean rats were significantly more receptive and proceptive than obese rats [Fig. 3Go, LQ, Mann-Whitney U = 102, P < 0.05; LR, Mann-Whitney U = 99.0, P < 0.05; PRO, F (1, 19) = 5.31, P < 0.05]. Increasing the dose of EB while keeping the P dose constant induced LQs, but not LRs, in obese rats comparable with those observed in lean rats treated with the same dose of hormones (Fig. 3Go, LR, Mann-Whitney U = 80.00, P > 0.1; LQ, Mann-Whitney U = 91.0, P < 0.05). Proceptive behaviors were lower in obese rats after either the lowest (15 µg/kg) or the highest (100 µg/kg) EB dose combined with 2 mg/kg P [F (1, 19) = 5.31, P < 0.05]. Increasing the P dose, while keeping EB at the lowest dose, enhanced sexual receptivity (both LQ and LR) and PRO in obese rats to the level displayed by lean rats receiving any dose of EB plus 2 mg/kg P (Fig. 3Go, Mann-Whitney U = 66.00, P > 0.05).



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  		Figure 3. LQ (top), LR (middle) and PRO rate (bottom) in ovx lean and obese females after treatment with varying doses of EB plus P. **, P < 0.01; *, P < 0.05 vs. lean rats receiving the same hormone dose.

 
Circulating steroid hormones
Baseline levels of circulating estradiol did not differ in ovx lean and obese rats. After injection of either EB dose, serum estradiol levels peaked at 4–8 h and declined gradually in both lean and obese rats. Strikingly, obese rats had substantially higher serum estradiol concentrations at each time point than lean rats when treated with the same dose of EB [Fig 4Go., F (1, 14) = 43.45, P < 0.05].



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  		Figure 4. Serum estradiol concentrations (top) and serum P concentrations (bottom) in ovx lean and obese females after treatment with EB (15 or 50 µg/kg) or P (2 or 4 mg/kg). **, P < 0.01; *, P < 0.05 vs. lean rats receiving the same hormone dose and at the same time point.

 
Baseline levels of P were higher in obese rats as compared with lean rats [F(1, 14) = 7.14, P < 0.05]. Four h after injecting the lowest P dose (2 mg/kg), serum P levels increased from baseline and were similar in lean and obese rats (Tukey’s post hoc comparison P > 0.05). However, four h after injection of the higher P dose (4 mg/kg), obese rats had higher serum P levels than lean rats [F (1, 14) = 7.14, P < 0.05].


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Estrous cyclicity
The vaginal smear data confirm previous findings that estrous cyclicity is abnormal in obese Zucker rats (11, 12, 14). Although obese rats exhibited prolonged diestrus, the abnormality may not be simply an increase in cycle length, as previously suggested, because many animals seemed to skip stages. Alternatively, the stages may be shortened so that a daily vaginal lavage misses a short stage. These findings suggest abnormal endogenous steroid production in obese rats, possibly in response to abnormal gonadotropin secretion or impaired vaginal epithelial response to estradiol. Endogenous steroid production in obese rats with normal 4-day cycles is similar to that found in ovary-intact lean rats but has yet to be measured in abnormally cycling obese rats (14). Yet, few (10%) obese rats in our study showed normal, 4-day estrous cycles.

Steroid-induced, reproductive behavior
Besides abnormal estrous cyclicity, obese Zucker rats were behaviorally hyporesponsive to the effects of exogenous steroid hormones. Obese rats displayed significantly less P-facilitated receptivity and PRO at the lowest combined doses of EB plus P, a hormonal regimen that induced maximal reproductive behavior in lean rats. Raising the EB dose, while maintaining the P dose constant, induced receptivity in obese rats to levels similar to those seen in lean rats. Maintaining the lowest EB dose and raising the P dose increased both receptivity and PRO in obese rats to levels similar to those observed in lean rats. This finding is not surprising because P facilitates solicitation behaviors in estradiol-primed, ovx rats (21).

These results suggest that considerably higher doses of estradiol and P are necessary to elicit robust sexual receptivity and PRO in ovx obese rats as compared with lean rats. This may be part of a general hyporesponsiveness of obese Zucker female rats to ovarian hormones. Not only are female obese rats hyporesponsive to gonadal steroid hormone effects on sex behavior, they are hyporesponsive to estradiol’s suppressive effects on feeding (22, 23) and body weight (23). Yet, ovariectomy increases body weight (23), feeding (23), and gonadotropin secretion (11) in obese Zucker rats, suggesting that obese rats secrete estradiol and that both their hypothalamic-pituitary axis and neural systems mediating-feeding behavior are sensitive to it.

The behavioral hyporesponsiveness of obese Zucker females after exogenous hormone treatment was not caused by lower serum concentrations of hormones. Circulating concentrations of estradiol after EB injection were higher in obese than in lean rats. After the lowest EB dose (15 µg/kg), serum estradiol levels observed in both lean and obese Zucker rats were within physiological levels for female rats on the night of proestrus (14, 24). Serum P levels after P injection were equivalent or higher in obese rats, although their baseline P levels were 50% higher than those observed in ovx lean females. Presumably, the adrenal glands, which are overactive in obese rats, overproduce progestins (8, 9, 25, 26). Obese rats sequester less 3H-P in adipose tissue than lean rats (27), which may contribute to their elevated serum P levels. Although serum estradiol and P levels achieved by injections of the same doses were equivalent or higher in obese rats, it is possible that abnormalities in sex hormone-binding proteins could alter free steroid hormone levels and subsequent induction of sexual behavior. We cannot address this possibility because we used estradiol and P RIAs that measured total serum steroid hormones.

Estrogen receptors and estrogen-induced progestin receptors in specific diencephalic brain areas mediate the effects of estradiol and P on reproductive behaviors (28). Cytosol estrogen receptor concentrations in the whole hypothalamus and preoptic area are similar in lean and obese Zucker rats (29). Additionally, sufficient estradiol apparently reaches the brain in obese rats because EB treatment (5 µg sc) induces greater concentrations of cytosol progestin receptors in the preoptic area and hypothalamus of obese than in those of lean Zucker rats (30). Binding affinities for cytosol estrogen and progestin receptors seem comparable between lean and obese genotypes (27, 29). Although hypothalamic cytosol estrogen and progestin receptors seem functional in obese rats, it is possible that cell nuclear estrogen and progestin receptor accumulation may be inadequate.

There are many other documented abnormalities in obese Zucker rats that might contribute to reproductive dysfunction. For instance, the overactive hypothalamic-pituitary-adrenal axis (8, 9, 25, 26) in obese Zucker rats may lead to diminished reproductive capacity. CRH can suppress sex behavior in female rats when injected into the mediobasal hypothalamus and midbrain central gray (31). Short-term administration of CRH suppresses LH release in ovx rats, which presumably could lead to abnormal estrous cyclicity (32). However, obese rats have similar CRH and CRH messenger RNA (mRNA) levels in the paraventricular nucleus of the hypothalamus and lower CRH levels in the median eminence and pituitary as compared with lean rats (33, 34, 35). Thus, it seems unlikely that CRH release or overproduction in the hypothalamus leads to their behavioral hyporesponsiveness to exogenous steroid hormones. Corticosterone overproduction, which occurs in obese Zucker rats, could disrupt reproductive behaviors because chronic corticosterone treatment decreases sexual receptivity in female rats (36, 37, 38).

Another feasible explanation, although counterintuitive, for the abnormal physiological and behavioral responses in obese Zucker rats to exogenous steroid hormone treatment, is that obese Zucker rats behave similarly to calorically deprived, instead of calorically abundant, rodents. For example, both obese Zucker rats and food-deprived animals have similar food intake patterns (i.e. large meals, slight increase in meal frequency), have increased neuropeptide Y (NPY) levels and synthesis in the hypothalamus (39, 40, 41), are hyporesponsive to the inductive effects of exogenous steroid hormones on reproductive behavior (42), and have elevated circulating estradiol and P after treatment with exogenous steroid hormones (43). However, food deprivation does alter concentrations of estrogen and progestin receptors in the hypothalamus and preoptic area (44, 45). These similar behavioral and physiological responses between food-deprived rodents and obese Zucker rats suggest that obese Zucker rats may respond as if they exist in a state of starvation.

Finally, the abnormal estrous cyclicity and behavioral hyporesponsiveness to sex-steroid hormones displayed by obese rats may be triggered by hyperactive neurotransmitter systems that are inhibitory to reproductive behavior and estrous cyclicity, such as NPY and endogenous opioids. NPY mRNA is overproduced in the arcuate nucleus of female obese Zucker rats (39), which probably contributes to the higher tissue levels of NPY in other diencephalic areas such as the ventromedial hypothalamus (41), medial preoptic area (40), paraventricular nucleus (40, 41), and suprachiasmatic nucleus (40, 41). NPY overproduction in obese Zucker rats may be produced by dysfunctional negative-feedback mechanisms of both leptin and insulin on NPY synthesis (46, 47, 48). Chronic injection of NPY in female rats disrupts estrous cyclicity by prolonging diestrus (49). Intraventricular injections of NPY suppress sexual receptivity and PRO in either estrogen- or estrogen-plus-P-primed, spayed female rats (50). Likewise, the concentration of the endogenous opioid, ß-endorphin, and its precursor, POMC, is higher in whole brain and pituitary of obese, as compared with lean, Zucker rats (25, 51, 52). ß-endorphin regulates gonadotropin secretion (53), and its disruption could lead to abnormal estrous cyclicity. Furthermore, peripheral and central ß-endorphin injections suppress sexual behavior in female rats (54, 55, 56). Work from this laboratory suggests that destruction of the arcuate nucleus of the hypothalamus, where both NPY and ß-endorphin are produced, decreases body weight and feeding and increases sex behavior in obese Zucker rats (57). These data support the hypothesis that overproduction of NPY or opioids may contribute to behavioral hyporesponsiveness to gonadal steroid hormones observed in obese rats.

In conclusion, we have documented that estrous cyclicity is abnormal in most genetically obese Zucker rats. We found that steroid-treated ovx obese rats are behaviorally hyporesponsive to doses of exogenous steroid hormones that induce maximal responsiveness in lean rats. Considerably higher doses and circulating concentrations of estradiol and P are required to elicit robust sexual receptivity and PRO in ovx obese Zucker rats. This behavioral hyporesponsiveness to ovarian hormones may contribute to infertility in the obese Zucker female rat.


   Acknowledgments
 
Our gratitude and appreciation are bestowed to Jack B. Calderone and Tara Marchand for their editorial commentary on previous versions of this manuscript.


   Footnotes
 
1 This work was supported by NIH Grant HD-28636 (to D.H.O.) and a predoctoral Minority Fellowship in Neuroscience from the American Psychological Association (to C.L.M.B.). Back

Received June 10, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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