Follicle Stimulating Hormone (FSH) Glycosylation in Women: Effect of Estradiol

NCT ID: NCT03868202

Last Updated: 2019-07-12

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE2

Total Enrollment

10 participants

Study Classification

INTERVENTIONAL

Study Start Date

2019-07-03

Study Completion Date

2020-01-31

Brief Summary

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This clinical trial is an investigational research study to determine the ratio of glycosylated FSH21/FSH24 in premenopausal women and postmenopausal women as well as determining if estradiol can increase this ratio in postmenopausal women.

Detailed Description

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Follicle Stimulating Hormone (FSH), is secreted by the pituitary gland at the base of the brain, and is the primary stimulus for growth of the ovarian follicle that contains the egg. Glycosylation, or adding glucose, to FSH is critical for its bioactivity on stimulating the ovarian follicle. The FSH with less glycosylation (FSH21) has a higher affinity for the FSH receptor and activates more pathways than does fully-glycosylated FSH (FSH24). Previous studies showed pituitaries from young women contain a high ratio of FSH21/FSH24 while pituitaries from older and postmenopausal women have a lower ratio of FSH21/FSH24. The investigators hypothesize that the higher FSH21/FSH24 ratio found in young women is responsible for normal follicle growth.

This study is intended to provide the first determination of systemic changes in the ratio of FSH21/FSH24 and determine if estradiol increases the FSH21/FSH24 ratio in the first morning urine of women. To take part in this study, the participant must be willing to collect the first morning urine on particular mornings of the menstrual cycle and be available for blood draws on those mornings. Additionally for postmenopausal participants, the participant must be willing to use topical estrogen, EstroGel©, for 14 days and be willing to collect the first morning urine on particular mornings and again be available for blood draws on those mornings. For the postmenopausal participants with an intact uterus, the participants must be willing to take an oral progestin, micronized progesterone, for 12 days following the completion of the study.

Conditions

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Follicle Stimulating Hormone Glycosylation Urinary FSH21/FSH24 Ratio Estradiol Effect

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

SCREENING

Blinding Strategy

NONE

Study Groups

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Premenopausal women

Participants will bring into clinic their first voided urine of the day on cycle days 9, 12 and 15 in a urinary collection kit that will be given. A urine dip stick will be performed on the samples. Each time they bring in a sample, they will have a serum blood draw for estradiol and FSH.

Group Type NO_INTERVENTION

No interventions assigned to this group

Postmenopausal women

Participants will bring into clinic their first voided urine of the day on assigned days 1, 4 and 7 in a urinary collection kit that will be given. A urine dip stick will be performed on the samples. Each time they bring in a sample, they will have a serum blood draw for estradiol and FSH. The participants will then be started on EstroGel© for 14 days from day 7-21. During that time that they are on EstroGel©, the participants will bring into clinic their first voided urine of the day on assigned days 15, 18, and 21 in a urinary collection kit that will be given. A urine dip stick will be performed on the samples. Each time they bring in a sample, they will have a serum blood draw for estradiol and FSH. After the last urinary collection and blood draw, they will discontinue the EstroGel and be started on micronized progesterone if they have a uterus for 12 days.

Group Type ACTIVE_COMPARATOR

Estradiol Transdermal Product

Intervention Type DRUG

Hormone replacement therapy will be given to postmenopausal women for up to 1 month.

Interventions

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Estradiol Transdermal Product

Hormone replacement therapy will be given to postmenopausal women for up to 1 month.

Intervention Type DRUG

Other Intervention Names

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Micronized progesterone

Eligibility Criteria

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Inclusion Criteria

Premenopausal (Age 20-30):

1. Age between 20 - 30 years old
2. Not on oral, transdermal or vaginal hormonal contraception with last use greater than 2 months (non-hormonal IUD okay)
3. At least 6 weeks after removal of subdermal contraceptive implant
4. At least 9 months from the last hormonal contraceptive injection
5. Regular menses with a 26-32 day interval
6. Willingness to abstain from heterosexual intercourse or use barrier contraception during the study
7. No serious medical illness
8. Not on medication(s) effecting ovarian function
9. Screening ultrasound on cycle day 12-14 with at least 1 follicle measuring \>12mm.
10. Normal pap smear within the last 3 years, if indicated (report needed)

Postmenopausal (Age 45-60):

1. Age between 45-60 years old
2. Last spontaneous menstrual period \>1 year
3. Vaginal pH \> 5.0
4. No contraindications to hormonal replacement therapy
5. No major medical condition/current medication(s) that would impact use of hormone replacement therapy
6. Never have been on hormone replacement therapy or last use greater than 6 months
7. Mammogram within the last 1 year that is normal (report needed)
8. Pap smear within the last 3-5 years that is normal (report needed)
9. Willing to use hormone replacement therapy

Exclusion Criteria

Premenopausal (Age 20-30):

1. Uncorrected endocrinopathy affecting ovarian function (i.e.: Prolactinoma, thyroid disease)
2. Medications affecting the hypothalamic-pituitary-ovarian axis.
3. Screening ultrasound with no follicles measuring ≥11 mm
4. History of pelvic surgery
5. Current abnormal pap smear requiring intervention

Postmenopausal (Age 45-60):

1. Last menstrual period \<1 year
2. Contraindication to hormone replacement therapy
3. Use of exogenous hormone replacement therapy in the last 6 months
4. Significant medical disease or current medication use that can impact estrogen metabolism
5. Unwilling or unable to use transdermal estrogen and oral progestin.
6. Allergy to transdermal estrogen and oral progestin.
7. Unexplained vaginal bleeding within the last 6 months.
Minimum Eligible Age

20 Years

Maximum Eligible Age

55 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

Yes

Sponsors

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Wichita State University

OTHER

Sponsor Role collaborator

Eastern Virginia Medical School

OTHER

Sponsor Role lead

Responsible Party

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Reem Sabouni

Principal Investigator, Fellow of Reproductive Endocrinology and Infertility

Responsibility Role PRINCIPAL_INVESTIGATOR

Locations

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Jones Institute for Reproductive Medicine

Norfolk, Virginia, United States

Site Status RECRUITING

Countries

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United States

Central Contacts

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Reem Sabouni, MD

Role: CONTACT

757-446-7100

David F Archer, MD

Role: CONTACT

757-446-7444

Facility Contacts

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Abby Peele

Role: primary

Reem Sabouni, MD

Role: backup

References

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Hunzicker-Dunn ME, Lopez-Biladeau B, Law NC, Fiedler SE, Carr DW, Maizels ET. PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells. Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):E2979-88. doi: 10.1073/pnas.1205661109. Epub 2012 Oct 8.

Reference Type BACKGROUND
PMID: 23045700 (View on PubMed)

Santoro N, Randolph JF Jr. Reproductive hormones and the menopause transition. Obstet Gynecol Clin North Am. 2011 Sep;38(3):455-66. doi: 10.1016/j.ogc.2011.05.004.

Reference Type BACKGROUND
PMID: 21961713 (View on PubMed)

Bousfield GR, Butnev VY, Butnev VY, Hiromasa Y, Harvey DJ, May JV. Hypo-glycosylated human follicle-stimulating hormone (hFSH(21/18)) is much more active in vitro than fully-glycosylated hFSH (hFSH(24)). Mol Cell Endocrinol. 2014 Feb 15;382(2):989-97. doi: 10.1016/j.mce.2013.11.008. Epub 2013 Dec 1.

Reference Type BACKGROUND
PMID: 24291635 (View on PubMed)

Bousfield GR, Butnev VY, Rueda-Santos MA, Brown A, Hall AS, Harvey DJ. Macro- and Micro-heterogeneity in Pituitary and Urinary Follicle-Stimulating Hormone Glycosylation. J Glycomics Lipidomics. 2014;4:1000125. doi: 10.4172/2153-0637.1000125.

Reference Type BACKGROUND
PMID: 25722940 (View on PubMed)

Wang H, May J, Butnev V, Shuai B, May JV, Bousfield GR, Kumar TR. Evaluation of in vivo bioactivities of recombinant hypo- (FSH21/18) and fully- (FSH24) glycosylated human FSH glycoforms in Fshb null mice. Mol Cell Endocrinol. 2016 Dec 5;437:224-236. doi: 10.1016/j.mce.2016.08.031. Epub 2016 Aug 22.

Reference Type BACKGROUND
PMID: 27561202 (View on PubMed)

Klein NA, Illingworth PJ, Groome NP, McNeilly AS, Battaglia DE, Soules MR. Decreased inhibin B secretion is associated with the monotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles. J Clin Endocrinol Metab. 1996 Jul;81(7):2742-5. doi: 10.1210/jcem.81.7.8675606.

Reference Type BACKGROUND
PMID: 8675606 (View on PubMed)

Andreasson B, Bostofte E. Influence of 2 mg estradiol-17 beta on circulating FSH, LH, total and unconjugated estradiol levels in post-menopausal women. Acta Obstet Gynecol Scand. 1981;60(6):555-8. doi: 10.3109/00016348109155485.

Reference Type BACKGROUND
PMID: 6801915 (View on PubMed)

Bunyavejchevin S, Panthong C, Limpaphayom KK. Serum estradiol and follicle-stimulating hormone levels in Thai women post total abdominal hysterectomy and bilateral oophorectomy using oral 17 beta-estradiol. J Med Assoc Thai. 2002 Jan;85(1):58-62.

Reference Type BACKGROUND
PMID: 12075721 (View on PubMed)

Fahraeus L, Larsson-Cohn U. Oestrogens, gonadotrophins and SHBG during oral and cutaneous administration of oestradiol-17 beta to menopausal women. Acta Endocrinol (Copenh). 1982 Dec;101(4):592-6. doi: 10.1530/acta.0.1010592.

Reference Type BACKGROUND
PMID: 6818806 (View on PubMed)

Robyn C, Vekemans M. Influence of low dose oestrogen on circulating prolactin. LH and FSH levels in post-menopausal women. Acta Endocrinol (Copenh). 1976 Sep;83(1):9-14. doi: 10.1530/acta.0.0830009.

Reference Type BACKGROUND
PMID: 989226 (View on PubMed)

Wide L, Naessen 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. doi: 10.1111/j.1365-2265.1994.tb02513.x.

Reference Type BACKGROUND
PMID: 8033370 (View on PubMed)

Bousfield GR, Butnev VY, Walton WJ, Nguyen VT, Huneidi J, Singh V, Kolli VS, Harvey DJ, Rance NE. All-or-none N-glycosylation in primate follicle-stimulating hormone beta-subunits. Mol Cell Endocrinol. 2007 Jan 2;260-262:40-8. doi: 10.1016/j.mce.2006.02.017. Epub 2006 Oct 31.

Reference Type BACKGROUND
PMID: 17079072 (View on PubMed)

Archer DF, Pickar JH, MacAllister DC, Warren MP. Transdermal estradiol gel for the treatment of symptomatic postmenopausal women. Menopause. 2012 Jun;19(6):622-9. doi: 10.1097/gme.0b013e31823b8867.

Reference Type BACKGROUND
PMID: 22282101 (View on PubMed)

Other Identifiers

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19-03-FB-0058-EVMS

Identifier Type: -

Identifier Source: org_study_id

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