The Effects of Aging and Estrogen on the Brain - Full Text View

Purpose

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.

Condition	Intervention	Phase
Healthy	Drug: GnRH Drug: NAL-GLU GnRH antagonist Drug: Estrogen patch (Climara)	Phase 2 Phase 3


Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Intervention Model: Crossover Assignment Masking: Open Label
Official Title:	Pituitary Contribution to the Decline in Gonadotropin Secretion With Age

Resource links provided by NLM:

MedlinePlus related topics: Pituitary Disorders

Drug Information available for: Estradiol Estradiol cypionate Estradiol valerate Estradiol acetate Estradiol hemihydrate

U.S. FDA Resources

Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:

pituitary response after GnRH stimulation; LH, FSH and FAS, the peak amplitude, and area under the curve for each GnRH dose per study group [ Time Frame: after each 28-hour admission ] [ Designated as safety issue: No ]


Estimated Enrollment:	60
Study Start Date:	January 2002
Estimated Study Completion Date:	January 2018
Primary Completion Date:	January 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1 Postmenopausal women 45-55 years old	Drug: GnRH GnRH doses of 25, 75, 250 and 750 ng/kg will be given IV every 4 hr in random order, with the exception that the highest dose will always be administered last Drug: NAL-GLU GnRH antagonist a single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg Drug: Estrogen patch (Climara) transdermal estrogen patches (Climara 0.05mg/day, changing the patch every 86 hr)
Experimental: 2 Postmenopausal women 70-80 years old	Drug: GnRH GnRH doses of 25, 75, 250 and 750 ng/kg will be given IV every 4 hr in random order, with the exception that the highest dose will always be administered last Drug: NAL-GLU GnRH antagonist a single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg Drug: Estrogen patch (Climara) transdermal estrogen patches (Climara 0.05mg/day, changing the patch every 86 hr)

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Eligibility


Ages Eligible for Study:	45 Years to 80 Years (Adult, Senior)
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

Criteria

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00386022

Locations


United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114

Sponsors and Collaborators

Massachusetts General Hospital

National Institute on Aging (NIA)

Investigators


Principal Investigator:	Janet E Hall, M.D.	Massachusetts General Hospital

More Information

Additional Information:

MGH Reproductive Endocrine Unit This link exits the ClinicalTrials.gov site

Reproductive Endocrine Unit research studies This link exits the ClinicalTrials.gov site

Publications:

Rossmanith WG, Scherbaum WA, Lauritzen C. Gonadotropin secretion during aging in postmenopausal women. Neuroendocrinology. 1991 Sep;54(3):211-8.

Chakravarti S, Collins WP, Forecast JD, Newton JR, Oram DH, Studd JW. Hormonal profiles after the menopause. Br Med J. 1976 Oct 2;2(6039):784-7.

Kwekkeboom DJ, de Jong FH, van Hemert AM, Vandenbroucke JP, Valkenburg HA, Lamberts SW. Serum gonadotropins and alpha-subunit decline in aging normal postmenopausal women. J Clin Endocrinol Metab. 1990 Apr;70(4):944-50.

Scaglia H, Medina M, Pinto-Ferreira AL, Vázques G, Gual C, Pérez-Palacios G. Pituitary LH and FSH secretion and responsiveness in women of old age. Acta Endocrinol (Copenh). 1976 Apr;81(4):673-9.

Hall JE, Lavoie HB, Marsh EE, Martin KA. Decrease in gonadotropin-releasing hormone (GnRH) pulse frequency with aging in postmenopausal women. J Clin Endocrinol Metab. 2000 May;85(5):1794-800.

Gill S, Sharpless JL, Bo-Abbas Y, Hall JE. Hypothalamic effects of gonadal steroid replacement in postmenopausal women: Quantity of GnRH. Proc The Endocrine Society 82nd Annual Meeting 395:P3-1636, 2000.

Sharpless JL, Supko JG, Martin KA, Hall JE. Disappearance of endogenous luteinizing hormone is prolonged in postmenopausal women. J Clin Endocrinol Metab. 1999 Feb;84(2):688-94.

Wide L, Wide M. Higher plasma disappearance rate in the mouse for pituitary follicle-stimulating hormone of young women compared to that of men and elderly women. J Clin Endocrinol Metab. 1984 Mar;58(3):426-9.

Hall JE, Sluss PM, Eriksson K, Sharpless JL, Wide L. Less basic isoforms of endogenous luteinizing hormone (LH) in postmenopausal women result in prolonged plasma disappearance. Proc The Endocrine Society 81st Annual Meeting 292: P2-54, 1999.

Wide L, Naessén T. 17 beta-oestradiol counteracts the formation of the more acidic isoforms of follicle-stimulating hormone and luteinizing hormone after menopause. Clin Endocrinol (Oxf). 1994 Jun;40(6):783-9.

Blackman MR, Mukherjee A, Tsitouras PD, Harman SM. Decreased in vitro secretion of LH, FSH, and free alpha-subunits by pituitary cells from old male rats. Am J Physiol. 1985 Aug;249(2 Pt 1):E145-51.

Riegle GD, Meites J, Miller AE, Wood SM. Effect of aging on hypothalamic LH-releasing and prolactin inhibiting activities and pituitary responsiveness to LHRH in the male laboratory rat. J Gerontol. 1977 Jan;32(1):13-8.

Tang LK, Tang FY. LH responses to LHRH, DBcAMP, and 17 beta-estradiol in cultures derived from aged rats. Am J Physiol. 1981 May;240(5):E510-8.

Stewart DA, Blackman MR, Kowatch MA, Danner DB, Roth GS. Discordant effects of aging on prolactin and luteinizing hormone-beta messenger ribonucleic acid levels in the female rat. Endocrinology. 1990 Feb;126(2):773-8.

Rossmanith WG, Reichelt C, Scherbaum WA. Neuroendocrinology of aging in humans: attenuated sensitivity to sex steroid feedback in elderly postmenopausal women. Neuroendocrinology. 1994 Apr;59(4):355-62.

Lambalk CB, de Boer L, Schoute E, Popp-Snyders C, Schoemaker J. Post-menopausal and chronological age have divergent effects on pituitary and hypothalamic function in episodic gonadotrophin secretion. Clin Endocrinol (Oxf). 1997 Apr;46(4):439-43.

Alexander SE, Aksel S, Hazelton JM, Yeoman RR, Gilmore SM. The effect of aging on hypothalamic function in oophorectomized women. Am J Obstet Gynecol. 1990 Feb;162(2):446-9.

Rossmanith WG, Handke-Vesely A, Wirth U, Scherbaum WA. Does the gonadotropin pulsatility of postmenopausal women represent the unrestrained hypothalamic-pituitary activity? Eur J Endocrinol. 1994 May;130(5):485-93.

Genazzani AD, Petraglia F, Sgarbi L, Montanini V, Hartmann B, Surico N, Biolcati A, Volpe A, Genazzani AR. Difference of LH and FSH secretory characteristics and degree of concordance between postmenopausal and aging women. Maturitas. 1997 Mar;26(2):133-8.

Santoro N, Banwell T, Tortoriello D, Lieman H, Adel T, Skurnick J. Effects of aging and gonadal failure on the hypothalamic-pituitary axis in women. Am J Obstet Gynecol. 1998 Apr;178(4):732-41.

O'Dea LS, Finkelstein JS, Schoenfeld DA, Butler JP, Crowley WF Jr. Interpulse interval of GnRH stimulation independently modulates LH secretion. Am J Physiol. 1989 Apr;256(4 Pt 1):E510-5.

Gharib SD, Wierman ME, Shupnik MA, Chin WW. Molecular biology of the pituitary gonadotropins. Endocr Rev. 1990 Feb;11(1):177-99. Review.

Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev. 1999 Jun;20(3):358-417. Review. Erratum in: Endocr Rev 1999 Aug;20(4):459.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Shaw ND, Histed SN, Srouji SS, Yang J, Lee H, Hall JE. Estrogen negative feedback on gonadotropin secretion: evidence for a direct pituitary effect in women. J Clin Endocrinol Metab. 2010 Apr;95(4):1955-61. doi: 10.1210/jc.2009-2108. Epub 2010 Feb 4.

Shaw ND, Srouji SS, Histed SN, McCurnin KE, Hall JE. Aging attenuates the pituitary response to gonadotropin-releasing hormone. J Clin Endocrinol Metab. 2009 Sep;94(9):3259-64. doi: 10.1210/jc.2009-0526. Epub 2009 Jun 23.


Responsible Party:	Janet E. Hall, MD, Associate Physician, Massachusetts General Hospital
ClinicalTrials.gov Identifier:	NCT00386022 History of Changes
Other Study ID Numbers:	2000-P-002498 R01AG013241
Study First Received:	October 6, 2006
Last Updated:	November 5, 2013
Health Authority:	United States: Food and Drug Administration United States: Institutional Review Board

Keywords provided by Massachusetts General Hospital:


Gonadotropin-releasing hormone Estrogens postmenopausal women Pituitary hormones

Additional relevant MeSH terms:


Estrogens Estradiol Polyestradiol phosphate Estradiol 3-benzoate Estradiol 17 beta-cypionate Estradiol valerate LHRH, N-Ac-2-Nal(1)-4-Cl-Phe(2)-3-Pal(3)-Arg(5)-Glu(6)-AlaNH2(10)-	Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Contraceptive Agents Reproductive Control Agents Contraceptive Agents, Female Hormone Antagonists

ClinicalTrials.gov processed this record on September 28, 2016