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ANDROGENS AND HYPOTHALAMIC SENSITIVITY TO PROGESTERONE FEEDBACK IN FEMALE PUBERTY

Award Number: F32HD055014
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2007
PERIOD OF PERFORMANCE END DATE: 05/31/2009

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ANDROGENS AND HYPOTHALAMIC SENSITIVITY TO PROGESTERONE FEEDBACK IN FEMALE PUBERTY - DESCRIPTION (provided by applicant): Women with polycystic ovary syndrome (PCOS) have elevated plasma LH and persistently rapid GnRH pulse frequency. They also require higher levels of progesterone (P) to suppress LH(GnRH) pulse frequency than normal controls. Treatment with the androgen receptor blocker flutamide restores hypothalamic sensitivity to P in women with PCOS, indicating that androgens mediate hypothalamic P insensitivity. In normal girls, hypothalamic sensitivity to estradiol (E2) and P diminishes as puberty advances, while testosterone (T) levels rise 5-fold. We propose that this rise in T may cause a progressive reduction in the sensitivity of the GnRH pulse generator to P feedback during normal female puberty. This process may be exaggerated in girls with hyperandrogenemia (HA), perhaps explaining the rapid LH(GnRH) pulses and accelerated maturation of the LH(GnRH) pulse pattern seen in adolescent HA. Preliminary results in adolescents suggest that while overall HA girls have reduced hypothalamic P sensitivity similar to women with PCOS, some girls maintain P sensitivity despite equivalent degrees of HA. The HA girls who maintain P sensitivity trend towards younger gynecologic age, suggesting a possible role for duration of androgen exposure, and, to date, are all Hispanic, suggesting a possible role for genetic factors. One genetic candidate for the variable effects of elevated androgens on hypothalamic P sensitivity is the androgen receptor (AR) polymorphic trinucleotide (CAG) repeat region. CAG repeat length is inversely correlated with transactivation activity of the AR, with longer CAG repeat length conferring reduced receptor activity. The distribution of CAG repeat length varies among racial and ethnic groups, with Hispanics tending to have longer CAG repeat length than Caucasians or African-Americans. Thus, Hispanics may have reduced androgen action, potentially explaining why the Hispanic girls maintained hypothalamic P sensitivity despite the presence of elevated plasma androgens. We plan to assess hypothalamic sensitivity to P feedback by measuring LH pulsatility before and after 7 d of oral E2 and P in normal and HA girls at all pubertal stages. In normal girls, we will assess the evolution of P sensitivity during puberty. In HA girls, we will assess the effect of duration of androgen exposure and androgen blockade on P sensitivity. In addition, we will determine the AR CAG repeat length in all subjects and assess whether AR CAG repeat length modulates androgen effects on hypothalamic P sensitivity. PCOS affects 6-7% of women and is a leading cause of infertility. Better understanding the causes of PCOS will hopefully lead to improved screening, prevention, and treatment of the disorder.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2008 ( Subtotal = $51,812 )
2008	2008	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Child Health and Human Development Extramural Research	000	2	5/9/2008	NON-COMPETING CONTINUATION	$51,812
														Subtotal = $51,812

Issue Date FY: 2007 ( Subtotal = $53,931 )
2007	2007	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Child Health and Human Development Extramural Research	000	1	2/23/2007	NEW	$53,931
														Subtotal = $53,931

Grand Total All Awards = $105,743

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ANDROGENS AND HYPOTHALAMIC SENSITIVITY TO PROGESTERONE FEEDBACK IN FEMALE PUBERTY

Award Number: F32HD055014

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2007

PERIOD OF PERFORMANCE END DATE: 05/31/2009

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