The ovariectomized rat model of postmenopausal bone loss

Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats.

Cycle frequency, length, and vaginal cytology were measured longitudinally in three cohorts of singly housed virgin mice staggered across a 3-year interval. The age profiles of these parameters were qualitatively similar, but quantitatively different, among cohorts. Cycle frequency was initially low (Phase I), due to prolonged cycles and late-starting cycles, and did not peak (Phase II) until mice were 3-5 months old. Phase II lasted for 7-10 months, depending on the cohort. Thereafter cycle frequency declined steadily (Phase III). The average age of cessation of cyclicity varied among cohorts, occurring between 13 and 16 months of age. Age changes in cycle length paralleled those of cycle frequency. During Phase II, median cycle length was less than 5 days and variance was lowest. During Phases I and III, variance was about twofold greater and median cycle length was greater than 5 days. Although median cycle length remained stable for several months during Phase II, the peak period of 4-day cycles was much shorter. In all cohorts, 4-day cycles did not peak until 7-8 months of age and began to decline by 9 months. The decrease in 4-day cycles was associated with a progressive lengthening of cycles-first from 4 to 5 days, then to longer cycles. The fraction of cycles with extended cornification (greater than 2 days) increased with advancing age from less than 0.35 during the initial period of cycle lengthening to a maximum of 0.60. The observation that the initial phase o cycle prolongation was not usually associated with extended cornification is consistent with earlier evidence that this period is characterized by a delayed, rather than prolonged, preovulatory rise of estradiol. However, the increased fraction of prolonged cycles with extended cornification at later ages suggests that the preovulatory elevation of estradiol may ultimately be prolonged.

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A longitudinal study of estrous cyclicity in aging C57BL/6J mice: I. Cycle frequency, length and vaginal cytology.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose etiology is presently unknown. Probably the most consistent and widespread deficit seen in this syndrome is that of the basal forebrain cholinergic system. We have previously demonstrated that estradiol (E2) modulates the function of these neurons and plays a role in their maintenance by preventing the ovariectomy-induced decrease in choline acetyltransferase activity. It has been postulated that the lack of neurotrophic support may contribute at least in part to degeneration of cholinergic neurons in AD. As such, it is hypothesized that E2 may affect cholinergic function by modulating the levels of certain neurotrophic factors. We have shown that 3 months after ovariectomy (OVX) there was a significant reduction in NGF messenger RNA (mRNA) levels. In the present study, we extended the hypothesis that E2 may serve a neurotrophomodulatory role by assessing the effect of OVX and E2 replacement on brain-derived nerve factor (BDNF) mRN...

The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague-Dawley rats.

Background Many clinicians and patients believe that endometriosis-associated pain is due to the lesions. Yet causality remains an enigma, because pain symptoms attributed to endometriosis occur in women without endometriosis and because pain symptoms and severity correlate poorly with lesion characteristics. Most research and reviews focus on the lesions, not the pain. This review starts with the recognition that the experience of pain is determined by the central nervous system (CNS) and focuses on the pain symptoms. Methods Comprehensive searches of Pubmed, Medline and Embase were conducted for current basic and clinical research on chronic pelvic pain and endometriosis. The information was mutually interpreted by a basic scientist and a clinical researcher, both in the field of endometriosis. The goal was to develop new ways to conceptualize how endometriosis contributes to pain symptoms in the context of current treatments and the reproductive tract. Results Endometriotic lesions can develop their own nerve supply, thereby creating a direct and two-way interaction between lesions and the CNS. This engagement provides a mechanism by which the dynamic and hormonally responsive nervous system is brought directly into play to produce a variety of individual differences in pain that can, in some women, become independent of the disease itself. Conclusions Major advances in improving understanding and alleviating pain in endometriosis will likely occur if the focus changes from lesions to pain. In turn, how endometriosis affects the CNS would be best examined in the context of mechanisms underlying other chronic pain conditions.

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Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications

Longitudinal studies were performed in a colony of aging female rats,from 4-33 months of age,to determine the chronologicalchange inreproductive patterns and the changes in sex steroid, prolactin and gonadotropin secretionassociatedwith different reproductive states. The present study demonstrates that the incidence (65%) of irregular estrous cycles in aging rats increased abruptly from 10-12 months of age. Subsequently, female rats became chronically anovulatory with persistentvaginalcornificationsand theirovariescontained developed follicles but no corpora lutea. The highest incidence (65%) of constant estrous (CE) rats occurred at the age of about 19 months. During the anovulatory state, CE rats displayed low to medium levels of serum estradiol, estrone, testosterone and androstenedione, low levels of progesterone and minimal levels of 20nhydroxyprogesterone. Preovulatory increasesin gonadotropin and prolactin release,similar to those seen in young cycling ratson proestrus,were not observed in CE rats.Whereas serum basal LH levels remained unaltered, morning FSH levelswere increased in CE rats.The lattermay account for the persistent follicular development in aging rats during chronic anovulatory state. Serum basal prolactin levels were normal in CE rats during the early phase (11-16 months of age) of the anovulatory state, but were subsequently increased 3 to 4-fold beyond 24 months of age. Moreover, ovariectomy at a young age prevented the increased pituitary prolactin release in old female rats. These results suggest that continuous exposure to medium levels of estrogens, particularly in the presence of sustained low progesterone secretion, may alter pituitary secretion of prolactin in aging rats. With further advance of age and following many months of anovulatory function, aging female rats exhibited ovulatory activity at irregular intervals. After each ovulation, formed corpora lutea were maintained for a prolonged period, presumably due in part to the existing high prolactin levels in the circulation of older female rats. These corpora lutea in old “pseudopregnant (PSP)” rats were functional as indicated by active secretion of progestins, with 20a-hydroxyprogesterone levels greater than those of progesterone in the circulation. These results indicate that the ovaries of aging rats retain their functional capacity to develop follicles and corpora lutea and to secrete steroid hormones. Although the cause(s) responsible for cessation of normal ovulatory cycles in aging female rats is unknown, the present study demonstrates that the chronic anovulatory state in aging female rats is characterized by significantly reduced ovarian secretion and the lack of cyclic increases in pituitary gonadotropin and prolactmn release. The causal relationships between the decreased ovarian steroid production and the absence of preovulatory surges of gonadotropin release in aging CE rats remain to be determined.

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Chronological Changes in Sex Steroid, Gonadotropin and Prolactin Secretion in Aging Female Rats Displaying Different Reproductive States

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Changes in Uterine Estrogen Receptor and Morphology in Aging Female Rats

This study was designed to determine whether chronic anovulation in old constant estrous rats is associated with alternations in gonadotropin binding and/or aromatase enzyme activity of granulosa cells. Granulosa cells, isolated from mature Graafian follicles of old constant estrous rats (25-26 months of age) and young proesrrous rats (4-5 months of age), were tested for their capacity of 1) bind human 1’ 2 �Il iodo-chorionic gonadotropin specifically and to 2) aromatize androstenedione into estrogens. Scatchard plot analysis of binding data indicated specific, high affinity, hCG receptor sites on granulosa cells of both young and old rats and there was no significant difference in the binding parameters between the two groups. The apparent dissociation constant (Kd) of the high affinity receptor was 4.3 (±0.6) X 10’ ‘ M and 5.0 (±0.7) X 10’’ ‘ M for granulosa cells from young and old rats, respectively. The number of hCG binding sites/granulosa cell was determined to be 8,772 (±708) and 10,408 (±1,854) from young and old rats, respectively. The aromatase activity was comparable in granulosa cells of young and old rats. After a 5 h incubation with increasing concentrations of androstenedione, a dose related increase in estrogen

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K. H. Lu

Papers

Chronological Changes in Sex Steroid, Gonadotropin and Prolactin Secretion in Aging Female Rats Displaying Different Reproductive States

Changes in Uterine Estrogen Receptor and Morphology in Aging Female Rats

Gonadotropin Binding and Aromatase Activity in Granulosa Cells of Young Proestrous and Old Constant Estrous Rats