Feasibility Study for Development of an Early Test for Ovarian Failure
Feasibility Study for Development of an Early Test for Ovarian Failure
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.
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.
-  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.