The onset of puberty is complex and not well understood, but is characterized by sleep-entrained increases of luteinizing hormone (LH) [by inference gonadotropin releasing hormone (GnRH)] secretion in early puberty. This diurnal pattern of GnRH secretion changes as puberty progresses-night time LH secretion remains unchanged but daytime LH pulse frequency gradually increases by late puberty. These day-night changes may be critical for regulation of normal gonadotropin secretion across puberty since rapid and slow GnRH pulse frequencies favor LH and follicle stimulating hormone (FSH) synthesis and secretion respectively. The mechanisms controlling day-night variations of GnRH secretion are currently unknown. Progesterone (P) provides negative feedback to the GnRH pulse generator and is its major regulator in adult women. In a small study in early pubertal girls we have shown that exogenous P suppresses day time LH pulses (awake) while having no effect on nocturnal LH secretion. Endogenous P levels increase overnight by two fold in early pubertal girls with peak levels occurring in the morning. We therefore propose that P regulates the diurnal secretion of GnRH by feedback inhibition in early puberty and this effect is dependent on the sleep-wake cycle. However this does not explain the progressive increase in the day time GnRH pulse frequency during pubertal maturation. P mediated feedback inhibition of the GnRH pulse generator is impaired in the presence of hyperandrogenemia (HA) in adult women and can be restored by the antiandrogen Flutamide. Of interest, testosterone (T) levels progressively increase from early to late puberty in normal girls, which coincides with the increasing day time LH pulsatility. We therefore hypothesize that the increasing levels of T during normal pubertal maturation leads to impaired P mediated inhibition of the GnRH pulse generator during the day time (awake). In girls with HA, this phenomenon may occur early in puberty, resulting in increased day time GnRH secretion and predisposing them to development of polycystic ovarian syndrome (PCOS). PCOS is a common disorder effecting about 7% of reproductive age women, characterized by HA, rapid frequency LH (GnRH) pulse secretion, insulin resistance, metabolic syndrome and is the leading cause of female infertility. We propose the following aims to test our hypotheses.
Aim 1 will determine the effects of near-physiological concentrations of P in suppressing daytime (awake) LH (GnRH) pulse frequency during early and late puberty.
Aim 2 will assess whether HA alters normal day-night GnRH (LH) pulse frequency patterns across pubertal maturation and if so can this be reversed by treatment with an antiandrogen. These studies will help us understand regulation of the GnRH pulse generator during sleep-wake cycles in normal pubertal maturation. They will also provide insight into the effect of HA on diurnal regulation of GnRH pulse patterns across puberty in normal and obese (HA) girls. An improved understanding of the early predisposition of obese girls with HA to the development of PCOS will enhance development of better preventive and therapeutic measures.

Public Health Relevance

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive age women characterized by elevated luteinizing hormone (LH) and testosterone levels, impaired ovulation and cysts on the ovaries resulting in significant morbidity including abnormal hair growth, acne, irregular menses, infertility, and an increased risk for diabetes, obesity and the metabolic syndrome. PCOS likely begins in puberty when girls develop certain hormonal abnormalities similar to those seen in adult women with PCOS. This research will study the role of progesterone in regulating the day-night (wake-sleep) pattern of gonadotropin releasing hormone (GnRH) and LH secretion in normal and hyperandrogenemic girls across puberty with the hope that an improved understanding of hormonal abnormalities during puberty will aid in the prevention and treatment of the disorder.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F06-T (20))
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Winer, Karen
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University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
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