Adrenal Hyperplasia Among Young People With PCOS

Polycystic ovarian syndrome (PCOS) is a heterogeneous group of disorders presenting with
hyperandrogenism in adolescents and young women. The etiology of this condition remains
unknown, despite its many identified links to insulin resistance, hypertension and metabolic
syndrome, as well as its potential connection to the various forms of congenital adrenal
hyperplasia (CAH).

The adrenal glands are the only source in the body of adrenocortical steroids. In normal
physiology, the pituitary hormone ACTH regulates the secretion of glucocorticoids, while the
secretion of mineralocorticoids is controlled by the renin-angiotensin system. In addition to
these two steroids, the adrenal gland secretes lesser amounts of intermediate metabolites of
these steroids, as well as the sex-steroids DHEA, DHEAS, androstenedione, testosterone,
estrogen, and estrone. Dysregulated secretion of any of these hormones can be caused by the
development of hyperplasia of the adrenocortical tissue, which may be mild and lead to
specific clinical syndromes depending on the identity of the secreted hormones. Bilateral
adrenocortical hyperplasia (BAH) is now an increasingly diagnosed cause of adrenal
dysfunction.

We propose that there is a subgroup of patients with PCOS who actually have non-CAH primary
forms of BAH. To investigate this possibility, we propose to study the
hypothalamic-pituitary-adrenal axis (HPAA) over the next 2 years in 120 young girls and women
(ages 16 to 25 years) that we will compare to 30 age- and race-matched normal females.
Patients will be recruited primarily (although not exclusively) from a busy New York City
clinic run by the Pediatric Endocrine Division at the Infants and Children's Hospital of
Brooklyn at Maimonides and SUNY Downstate. All patients will undergo standard testing of the
HPAA including oral low- and high-dose dexamethasone (DEX)-suppression testing (Liddle s
test). Paradoxical rise of cortisol and/or other steroid metabolites in response to DEX is
considered a sensitive test for the diagnosis of BAH. Patients with such responses will be
molecularly investigated for the known causes of BAH (GNAS, PRKAR1A, PDE11A, PDE8B and other
mutations).

The first goal of this study is to identify any possible contributions of the BAH phenotypes
and genotypes to the pathophysiology of PCOS, a yet unknown factor in the etiology of this
multifaceted disorder. The second goal is to perform a comparative analysis of the expression
of large sets of genes in cells of these patients using gene arrays and other genetic
analyses. This study will generate important information about the molecular pathways that
are affected in this subgroup of patients with PCOS. Thirdly, this study will also allow for
the collection of DNA from affected and non-affected relatives of the patients to perform
genetic studies and identify causative genetic defects. Finally, the study is expected to
lead to new diagnostic and therapeutic methods for at least certain forms of PCOS.

- INCLUSION CRITERIA FOR PATIENTS:

Women 16-24 years old with PCOS defined as biochemical hyperandrogenism with associated
findings of either menstrual irregularity and /or polycystic ovaries on ultrasound;
hyperandrogenism defined as elevation of any of the following androgens: free testosterone,
total testosterone, DHEAS, DHEA, 17 0H progesterone, androstenedione, 17OH pregnenolone; a
polycystic ovary on ultrasound should either have 12 follicles measuring 2-9 mm in
diameter, or have an increased ovarian volume of 10 CC or greater; menstrual irregularity
defined as: Amenorrhea refers to absence of bleeding for at least three usual cycle
lengths; oligomenorrhea refers to bleeding that occurs at an interval greater than 35 days.

We would like patients to have oligomenorrhea for at least six usual cycle lengths.
Patients have to be off oral contraceptive pills or any other medications that alter
steroidogenesis for at least one month prior to participating in the study

INCLUSION CRITERIA FOR CONTROLS:

Women 18-25 years old with normal menstrual function; they have to be off oral
contraceptive pills or any other medications that alter steroidogenesis for at least one
month prior to participating in the study.

EXCLUSION CRITERIA FOR PATIENTS:

Patients who have hyperandrogenism due to 21 hydroxylase deficiency non- classic adrenal
hyperplasia androgen secreting neoplasms

Women with known or suspected androgenic/anabolic drug use

Women with severe insulin resistance-acanthosis nigricans syndrome; Fasting insulin levels
are obtained to rule out syndromes of severe insulin resistance and hyperandrogenism; if
insulin is above 80 mU/mL in the fasting state, and/or >300 mU/mL following a 2- or 3-hour
oral glucose tolerance test (obtained elsewhere), patients are not eligible.

Women with thyroid dysfunction, hyperprolactinemia, (defined as prolactin level greater
than or equal to 3 times the upper reference limit), less than 2 years post menarche, and
patients on medications that alter steroidogenesis such as oral contraceptive pills, for
less than a month prior to the date of inclusion in the study. (see above: patients have to
be off oral contraceptive pills or any other medications that alter steroidogenesis for at
least one month prior to participating in the study)

Women with prior history of pregnancy.

EXCLUSION CRITERIA FOR CONTROLS:

Young women with hyperandrogenemia, hirsutism or known adrenal tumors or other endocrine
diseases, patients on multiple medications, known insulin resistance, or any other chronic
or acute illness are not eligible as controls for this study.