Feasibility Study for Development of an Early Test for Ovarian Failure

NCT ID: NCT00006156

Last Updated: 2013-05-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 49 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2000-08-31
• Study Completion Date: 2012-01-31

Brief Summary

This purpose of this study is to gain information about normal ovarian function that will be useful in developing a test for early detection of ovarian failure. The ovaries produce female hormones, such as estrogen, that are important in maintaining a woman's health. When the ovaries do not work properly, problems can develop. Unfortunately, there is no test that can detect ovarian failure early in its course. By the time premature ovarian failure is diagnosed in young women, two-thirds have already developed osteopenia (loss of some bone mass) and nearly one in ten have osteoporosis, a greater loss of bone mineral density that weakens bones and increases the risk of fractures.

Women with normal ovarian function ages 18 to 55 and postmenopausal women 60 years of age or older may be eligible for this study. Candidates will be screened with a medical history, physical examination, blood tests and vaginal ultrasound examination. For the ultrasound study, a probe that emits sound waves is inserted into the vagina, and the sound waves are converted to form images of the ovaries. The procedure is done with an empty bladder and takes about 10 minutes. After this screening visit (Visit 1), those enrolled in the study will return to the NIH Clinical Center for the following additional procedures:

Visit 2-Will be scheduled between days 3 and 5 of the menstrual cycle (for women who are still menstruating). Participants will have blood tests to measure hormone levels and to check for pregnancy, and will have another transvaginal ultrasound examination. They will then receive an injection of a synthetic form of follicle stimulating hormone (FSH), a hormone the body makes normally.

Visits 3 and 4-Will be scheduled 24 and 36 hours after the FSH injection given during Visit 2 for collection of blood samples.

Visit 5-Will be scheduled 48 hours after the FSH injection for additional blood sampling and a final transvaginal ultrasound examination.

Detailed Description

This is a pilot project to test the feasibility of developing an FSH stimulation test. There is a need for a sensitive and specific marker to detect ovarian insufficiency early in its course. FSH stimulates inhibin B production by the granulosa cells of the cohort of ovarian follicles; serum inhibin B in turn participates in the negative feedback loop regulating FSH secretion. This protocol is characterizing the normal FSH-stimulated serum inhibin B response to a single subcutaneous injection of 300 IU human recombinant FSH given on day 2 to 4 of the menstrual cycle. In preliminary analysis under this protocol we have demonstrated that FSH-stimulated serum inhibin B levels measured at 24 hours after injection is a more robust marker of functional ovarian age than ovarian follicle count by transvaginal ultrasound, basal serum Mullerian Inhibiting Substance (MIS) levels, or basal serum FSH levels. Multiple regression analysis has revealed that FSH-stimulated inhibin B, FSH-stimulated estradiol, and basal FSH contribute significantly to an ability to predict functional ovarian age (as approximated by chronological age). The resulting regression equation relating these three parameters with age has a correlation coefficient of 0.742 and a coefficient of determination of 0.551. The protocol is now evaluating the reproducibility of this test and the feasibility of generating normative data in young women between the ages of 18 and 25. The results of this study may define parameters that could lead to earlier diagnosis and treatment of premature ovarian insufficiency.

Conditions

Healthy; Premature Ovarian Failure

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Control

Control for FSH stimulation test

Group Type: EXPERIMENTAL

Control

Intervention Type: OTHER

No injection of FSH

Drug: FSH

FSH Stimulation Test

Group Type: EXPERIMENTAL

Drug: FSH

Intervention Type: DRUG

FSH Stimulation Test

Interventions

Control

No injection of FSH

Intervention Type: OTHER

Drug: FSH

FSH Stimulation Test

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

A. Women with normal ovarian function:

Age 18 to 55.

Normal body mass index (18-30 kg/m(2)).

Normal menstrual cycles (between 25-35 days in length).

Ovulatory serum progesterone concentrations (in excess of 6 ng/mL in the menstrual cycle just preceding the study cycle).

B. Postmenopausal women (to serve as negative controls):

Greater than or equal to 60 years of age.

Proven fertility (as evidenced by a history of pregnancy regardless of outcome).

Normal body mass index (18-30 kg/m(2)).

Naturally menopausal: amenorrhea for at least one year; serum FSH greater than 40 IU/mL.

C. Women carriers of FMR1 premutations:

Age 18 to 40.

50 to 200 CGG repeats.

Normal menstrual cycles (between 25-35 days in length).

Have previously had genetic counseling regarding their FMR1 status.

Exclusion Criteria

History of infertility or infertility in a first degree relative.

Acute or chronic disease.

Menopause due to surgery, radiation, or chemotherapy.

Current use of oral contraceptives or hormone replacement therapy, or use of these agents within the previous 3 months.

Use within the previous three months of any medication known to affect the hypothalamic-pituitary-ovarian axis (including over-the-counter and alternative medicines).

History of excessive exercise (greater than 10 hours a week).

Girls will be excluded because there are no data regarding FSH use in children.

Smokers.

Pregnant.

Breast feeding.

Persistent ovarian masses.

History of tumors of the ovary, breast, uterus, hypothalamus, or pituitary.

History of breast or endometrial cancer.

History of hypersensitivity to recombinant FSH or any one of its excipients.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

National Institutes of Health Clinical Center (CC)

NIH

Sponsor Role: collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: lead

Responsible Party

Lawrence Nelson, M.D.

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States

Countries

United States

References

Anasti JN, Kalantaridou SN, Kimzey LM, Defensor RA, Nelson LM. Bone loss in young women with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol. 1998 Jan;91(1):12-5. doi: 10.1016/s0029-7844(97)00583-8.

Reference Type: BACKGROUND

PMID: 9464713 (View on PubMed)

Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol. 1986 Apr;67(4):604-6.

Reference Type: BACKGROUND

PMID: 3960433 (View on PubMed)

Faddy MJ, Gosden RG. A model conforming the decline in follicle numbers to the age of menopause in women. Hum Reprod. 1996 Jul;11(7):1484-6. doi: 10.1093/oxfordjournals.humrep.a019422.

Reference Type: BACKGROUND

PMID: 8671489 (View on PubMed)

Other Identifiers

00-CH-0189

Identifier Type: -

Identifier Source: secondary_id

000189

Identifier Type: -

Identifier Source: org_study_id