Primary Ovarian Insufficiency: Phenotype and Optimal Treatment

Background: Primary ovarian insufficiency (POI) is an enigmatic condition that affects
~1/10,000 women by age 20. Sometimes referred to as "early menopause," POI is characterized
by estrogen deficiency among other hormonal abnormalities that resemble the menopause. POI is
a serious chronic condition with no cure. The clinical presentation or 'phenotype' in
adolescents is not well understood. Health consequences may include delayed or arrested
puberty, skeletal losses, and the threat to reproductive health. Both the metabolic and
emotional sequelae are substantial, and one of the most concerning is compromised bone
health. The optimal hormone replacement therapy (HRT) regimen for these young women is
debated and practice varies among health providers. Importantly only sparse data exist to
guide clinicians to make evidence-based decisions regarding the management of these patients.
If initiated early, HRT may prevent estrogen-associated bone loss.

Impact: Better understanding of POI may lead to improved treatments for this underserved
population and have significant implications for the treatment of estrogen deficiency in
other populations of adolescents and young women, and for all women going though natural
menopause later in life. Little is known about the effects of HRT on bone health, body
composition, cognition, and health-related quality of life, especially among adolescents.
Understanding how this therapy affects these multiple health outcomes will fill knowledge
gaps regarding treatment for young patients with POI, with potential implications for
adolescents and young women with estrogen deficiency in other clinical settings. We will
define the clinical presentation (i.e., phenotype) of adolescent POI. The pilot data
collected will be used in a future application to the National Institutes of Health, to fund
a larger trial that builds on observations from this initial study. The information gained
from this pediatric model may also provide insights on management of the natural menopause
that occurs in all women later in life.

Methods: Ten adolescents with idiopathic POI (i.e., from unexplained causes) will be
recruited through the CCHMC Teen Health Center, Endocrine or Pediatric/Adolescent Gynecology
Clinics. Ten healthy controls will be recruited from the Teen Health Center. Participants
with POI will receive transdermal estrogen replacement (beginning at 25 µg/patch applied
weekly), with the dose increased at subsequent study visits that will occur at 3, 6, and 12
months. All data collection will take place at the CCHMC Schubert Research Clinic. The
investigators will measure bone density of the central skeleton and body composition by
dual-energy x-ray absorptiometry. To evaluate the peripheral skeleton, bone and muscle
measures will be obtained by peripheral quantitative computed tomography. At each visit, the
participants will have blood drawn to measure circulating hormone levels that are
characteristically altered in adolescents with POI, along with safety assays. Cognitive
functioning will be assessed using standardized tools. Participants will complete quality of
life assessments, along with nutrition and physical activity surveys. Lastly, all
participants will also complete a detailed medical history and health assessment.

Implications/Future Directions: Once the phenotype of adolescent POI is more clearly defined,
a logical next question will be to determine whether negative health outcomes can be
prevented or modified. Data from the proposed trial will guide the design of future
prospective studies that evaluate the effects of traditional treatments (e.g., HRT),
including a longer study to monitor HRT therapy, as well as more experimental treatments
(e.g., skeletal agents) that may benefit young women with this rare condition. In addition,
findings are expected to open avenues of research for adolescents and women with estrogen
deficiency in other clinical settings.

Inclusion Criteria for POI patients

The participant must:

1. Be willing to give informed consent/assent

2. Have a diagnosis of POI based on 2 elevated serum FSH levels obtained >1 month apart

3. Be English-speaking

Exclusion Criteria for POI patients

The participant must not:

1. Have other chronic disease known to affect bone health (e.g., cystic fibrosis, celiac
disease, etc.)

2. Have an identified secondary cause of ovarian insufficiency

3. Have POI in the setting of Turner syndrome, Fanconi Anemia, galactosemia, or Perrault
syndrome (as associated neurological/medical sequelae could confound baseline
measures)

4. Have used medications known to affect bone metabolism over previous 3 months (e.g.
anticonvulsants, chronic use of glucocorticords, Depo-Provera, oral contraceptive
pills)

5. Be currently pregnant (to be confirmed by pregnancy testing)

Inclusion Criteria for Healthy Adolescent Control Participants

The participant must:

1. Be similar in age and race group to the idiopathic POI group

1. Control participants age must be within one year of age from the POI participant
at the time of enrollment. Age may be within one year older or one year younger

2. Race of controls participants will be matched based on race of POI patient
participants

2. Have a BMI within 20% of the BMI of the case-matched participant

3. If postmenarchal, will be regularly menstruating (cycles between 21-35 days)

a. if POI participant is <12.5yrs (mean age of menarche) will match with a pre-
menarchal control participant

4. Be English-speaking

Exclusion Criteria for Healthy Adolescent Control Participants

The participant must not:

1. Have a chronic disease, known to affect bone metabolism (e.g., cystic fibrosis, celiac
disease, sickle cell disease, inflammatory bowel disease etc.)

2. Be receiving medications known to affect bone metabolism over previous three months
(e.g. anticonvulsants, chronic use of glucocorticoids, Depo-Provera, oral
contraceptive pills, etc.)

3. Have a learning disability or a developmental delay

4. Be currently taking any SSRIs, antipsychotics or have any documented problems with
anxiety or depression.

5. Be currently pregnant (as confirmed by pregnancy testing)