Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT01425541 |
| Other study ID # |
8588 |
| Secondary ID |
JCM010U54HD02893 |
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 2000 |
| Est. completion date |
August 2025 |
Study information
| Verified date |
November 2023 |
| Source |
University of Virginia |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Girls with high levels of the male hormone testosterone often develop polycystic ovary
syndrome (PCOS) as adults. Women with PCOS often have irregular menstrual periods, excess
facial and body hair, and weight gain. Women with PCOS also have difficulty becoming
pregnant. Some, girls with high levels of male hormone will develop normal hormone levels as
they grow up. Most girls continue to have high levels of male hormone as adults. In addition,
girls with elevated levels of male hormones often have lower fertility rates in adulthood. In
this study the investigators will aim to discover the effect of 7 days of estrogen and
progesterone on GnRH pulses in girls and women with the goal of understanding how and why
some girls and women have higher levels of male hormone and the causes of PCOS. If
investigators understand the causes of these disorders, they may be able to better treat them
and perhaps even learn how to prevent the development of PCOS.
Description:
Adolescent hyperandrogenemia (excess androgen production) occurring before or during early
puberty appears to be a precursor to adult polycystic ovary syndrome (PCOS). PCOS affects
about 6% of women of childbearing age in the United States. Those who suffer from this
disorder often experience irregular menstrual periods, excess facial and body hair, and
weight gain. PCOS is also a leading cause of infertility. Women with PCOS often report
irregular menstrual cycles as adolescents. A study of adolescents with menstrual
irregularities showed that some subjects normalize endocrine function as they mature, while a
majority maintained hyperandrogenism in conjunction with high levels of luteinizing hormone
(LH) and polycystic ovaries. In addition, girls with high levels of serum androgens often
have lower fertility rates in adulthood.
We propose that adult PCOS, and perhaps adolescent hyperandrogenemia, are due in part to
dysregulation of pituitary and ovarian hormones. Synthesis and secretion of LH and follicle
stimulating hormone (FSH) are primarily regulated by gonadotropin releasing hormone (GnRH).
Both LH and FSH are secreted by the same gonadotrope cell, and the frequency of stimulation
of this cell by GnRH in part determines which hormone is released. In primates, rapid GnRH
frequencies (approx. 1 pulse/ hour) favor LH secretion whereas slower GnRH stimuli (1 pulse/
3 hours or less) favor FSH release. In normal women, the cyclical rise and fall in hormone
levels control follicular maturation and ovulation. Early studies showed an initial
predominance of FSH in the follicular phase, with a subsequent rise in estradiol (E2). In the
late follicular phase, LH increases as a consequence of increased GnRH secretion. Following
ovulation, rising levels of E2 and P then reduce GnRH pulse frequency, allowing a rise in FSH
for the next cycle of follicular maturation.
One feature of adult PCOS is increased mean serum levels of LH and increased LH pulse
frequency, presumably due to increased stimulation of the pituitary by excess hypothalamic
secretion of GnRH. Since women with PCOS maintain high levels of LH and low levels of FSH,
follicle maturation and ovulation do not occur normally. Girls with hyperandrogenemia in
adolescence also have an increased frequency of LH pulses when compared to age matched
controls.
If hyperandrogenemic adolescents could be treated effectively before or during pubertal
maturation, development of clinical PCOS as an adult could potentially be avoided. One
proposed cause of both hyperandrogenemia and PCOS is a defect in GnRH pulse modulation, which
normally happens as puberty progresses. GnRH is secreted by a part of the brain called the
hypothalamus. In normal pubertal maturation the increase in GnRH pulse secretion during sleep
stimulates LH and ovarian E2 and P secretion. Feedback of these hormones reduces GnRH pulses
during daytime hours, initiating cycles of ovarian-hypothalamic feedback regulation which
mature into the patterns seen in normal ovulatory cycles. Recent studies have shown that E2
and P can slow LH pulses in adult women with PCOS, but higher concentrations of P are needed
to inhibit LH pulse frequency. If hypothalamic (GnRH pulse generator) sensitivity to
inhibition by P is reduced during pubertal maturation, the low levels of P present during the
initial development of ovarian cyclicity may not be adequate to suppress GnRH/LH pulse
secretion. This could lead to LH excess and relative FSH deficiency. Administering oral doses
of P in early adolescence may compensate and restore normal ovarian-hypothalamic feedback. In
turn, increasing amounts of naturally secreted P in subsequent cycles could eventually
normalize the system.
The long term goal of this line of investigation is to determine if E2 and P treatment of
adolescents with hyperandrogenemia can slow the GnRH pulse generator to promote FSH
production and the advent of normal menstrual cycles. As an initial step we propose to
determine if the GnRH pulse generator is relatively insensitive to E2 and P inhibition in
hyperandrogenemic adolescent girls.
