Patient case: 54-year-old male with Gastric cancer. Genetic variant: PIK3CA (E545K). Other conditions: Depression.

Clinical trial: The Effects of Aging and Estrogen on the Brain

Summary: The purpose of this study is to study the effects of aging and estrogen on the brain. Specifically, this study will look how the hypothalamus signals the pituitary gland to secrete reproductive hormones and how that changes with aging.

Detailed description: Although it is clear that loss of ovarian function plays a major role in the menopause in women, there is evidence from animal studies that primary age-related hypothalamic and pituitary changes may also contribute to reproductive aging. In women, the transition to menopause is characterized by a dynamic period of markedly changing hypothalamic-pituitary feedback from the aging ovary. Complete cessation of ovarian function results in the loss of negative feedback of ovarian steroids and inhibin on the hypothalamic and pituitary components of the reproductive axis. An increase in serum levels of LH, FSH and FAS occurs in postmenopausal women with removal of negative ovarian feedback. However, levels of LH, FSH and FAS after menopause decline steadily as a function of age in most though not all studies.
  A series of studies from our laboratory conducted over the past several years have specifically addressed the effect of age on the neuroendocrine components of the reproductive system. In our studies in young and old postmenopausal women, we have confirmed a marked decrease in serum levels of all three secretory products of the gonadotrope with age. This age-related decline in gonadotrope secretion does not appear to result from a decrease in the overall amount of GnRH secreted or the amount of GnRH secreted per bolus although GnRH pulse frequency does slow with aging.
  Using high doses of a GnRH antagonist to achieve complete blockade of the GnRH receptor we have examined the degree to which GnRH contributes to the secretion of LH and FSH (vis a vis other potential controlling factors, such as the activin/follistatin system or the putative FSHRH). The degree to which GnRH contributes to the secretion of LH and FSH is not changed following menopause, but its contribution to secretion of FAS is relatively increased. Preliminary data would suggest that following menopause there is no independent age-related change in the degree to which GnRH contributes to secretion of any of the gonadotropins.
  An increase in gonadotropin clearance may theoretically contribute to the decline in serum gonadotropin levels following menopause, but this is unlikely to be the case. It is known that there are isoforms of LH and FSH, which differ in their carbohydrate structure, and that changes in carbohydrate composition can alter plasma clearance. Heterogeneous populations of both FSH and LH can be separated into 20 to 30 isoforms each on the basis of charge differences in their molecular structure. A shift to more acidic isoforms of FSH has been documented in postmenopausal compared to normally cycling women in our own and previous studies. More acidic forms of human FSH clear more slowly when injected into mice. While impacting on hormone clearance, we have not found changes in in vitro bioactivity of these altered isoforms of FSH. In studies in which the GnRH receptor was blocked using a high dose of a GnRH antagonist, we have now shown that the serum half-life of LH is markedly prolonged in postmenopausal women. We have also shown that, as with FSH, there is a shift to more acidic forms following the menopause. Gonadal steroid administration is associated with a shift to less acidic forms of LH and FSH making it most likely that changes in isoform composition of these hormones with menopause are related to changes in the gonadal steroid milieu. To date we have no evidence that age has any additional influence on the clearance of LH after menopause. As opposed to effects on the intact gonadotropins, menopause does not alter plasma disappearance of FAS. Taken together, these studies suggest that the loss of gonadal feedback following menopause alters the forms of both LH and FSH secreted and may contribute to the overall increase in LH and FSH in postmenopausal women. However, there is no evidence that an increase in gonadotropin clearance contributes to the decline in serum gonadotropin levels with aging after menopause.
  In women, the transition to menopause is characterized by a dynamic period of markedly changing hypothalamic-pituitary feedback from the aging ovary. In the rodent, aging is associated with decreased in vitro secretion of LH and reduced LHb mRNA in pituitary cells from old compared with mature castrate males and females. The decrease in baseline and GnRH-stimulated LH, FSH and FAS secretion from dispersed pituitary cells from old compared with mature castrate male rats suggests that a decrease in the functional capacity of the gonadotrope contributes to this decrease, but there has been no systematic examination of potential changes in gonadotrope number with aging in any animal species.
  In women, potential changes in the ability of the pituitary to respond to GnRH as a function of aging have been examined using either the amplitude of endogenous LH pulses or the response to exogenous GnRH, with variable results. Rossmanith found both an absolute and relative decrease in response to exogenous GnRH in one study and an absolute, but not a relative decrease with age in a second study. Lambalk et al. found a decreased response with years post menopause, but paradoxically, an increased response to GnRH with chronological age in postmenopausal women. Although not universally found, a decrease in absolute pulse amplitude as a function of age has been observed in some studies although there was generally no change with age when amplitude is expressed in relation to mean levels. Unfortunately, there are significant disadvantages of both methods used to assess the functional capacity of the pituitary. LH pulse amplitude in response to endogenous GnRH secretion integrates both hypothalamic and pituitary effects of aging while the response to exogenous GnRH is dependent on the preceding interpulse interval which is both variable and influenced by age itself. Thus, although the bulk of the evidence points to an age-related decrease in the ability of the pituitary to secrete gonadotropins, improved methodologies are required to fully address this issue in postmenopausal women.
  While there is ample evidence for negative feedback regulation of gonadotropin secretion with low doses of estrogen, the site of action is less clear. In the rat model ovariectomy is associated with increased LH and FSH secretion and increased expression of LH, FSH and mRNA which is reversed by the addition of estradiol. The post-castration increases in gonadotropin subunits are associated with an increase in the number of cells expressing LH, an increase in cell size and an increase in the amount of expression per cell. Similar effects of ovariectomy and estradiol replacement on gonadotropin expression have been demonstrated in the sheep. In women, studies have shown less of a decline in gonadotropin levels with estrogen replacement in older women suggestive of a decreased sensitivity to estrogen negative feedback with age. Evidence demonstrating the effects of estrogen negative feedback on the neuroendocrine system has been inconsistent with studies demonstrating either a decrease or lack of change in GnRH pulse amplitude and/or frequency. Our studies in young and old postmenopausal women have shown a significant decrease in GnRH pulse amplitude rather than frequency with estrogen replacement. These studies do, however, suggest that the pituitary contributes to the estrogen-induced decline in gonadotropin secretion both indirectly, secondary to steroid-related changes in GnRH, and directly, as indicated by several lines of evidence establishing a direct estrogen negative feedback effect at the pituitary level. Although previous studies have been controversial, our own preliminary data suggests that estrogen negative feedback is increased with aging. A month of physiologic estrogen administration in postmenopausal women was associated with significant inhibition of pituitary responsiveness to graded doses of GnRH. These results stand in contrast to the results of our FDG-PET studies which support a hypothalamic, but not a pituitary site of estrogen negative feedback 24 hours after the onset of low dose estrogen infusion, similar to results of previous studies which revealed a hypothalamic site of estrogen negative feedback alone by administration of tamoxifen to normal and GnRH deficient women. One interpretation of these results is that inhibition of LH associated with short-term (24 hour) exposure to low-dose estrogen is mediated at the hypothalamus alone, while with more prolonged (28 days) exposure to similar low levels of estrogen, both hypothalamic and direct pituitary effects contribute to LH inhibition. The current protocol will determine the sensitivity of the pituitary and the secretory response of the gonadotrope under controlled conditions with or without estrogen feedback in young and old postmenopausal women. Furthermore, estrogen feedback will be assessed after short-term versus prolonged estrogen exposure.

Eligibility: Inclusion Criteria:
  -  45-55 or 70-80 years old
  -  History of natural menopause defined by the absence of menses for at least 12 months (or history of surgical menopause defined as bilateral oophorectomy) and a FSH level >26 IU/L
  -  On no hormonal medication or herbal supplements and/or over the counter menopause therapy for a minimum of 2 months prior to study
  -  Normal TSH, PRL, factor V, and CBC
  -  Normal BUN and Creatinine (< 2 times the upper limit of normal)
  -  BMI ≤ 30
  -  Non-smokers or smoke less than 10 cigarettes/day
  Exclusion Criteria:
  -  Absolute contraindications to the use of physiologic replacement doses of estrogen, including a negative screening mammogram within the past 24 months
  -  History of coronary artery disease
  -  On medications thought to act centrally on the GnRH pulse generator
  -  Past history of hypersensitivity or allergy to narcotics, vancomycin, muscle relaxants, aspirin, and/or anaphylactic reaction(s) to other drugs
  -  Prior history of breast cancer and/or blood clots

Relevance to patient case: not relevant