Susan K. Blank

Maturation of Luteinizing Hormone (Gonadotropin-Releasing Hormone) Secretion across Puberty: Evidence for Altered Regulation in Obese Peripubertal Girls

CONTEXT Peripubertal obesity (body mass index-for-age >or= 95%) in girls is associated with hyperandrogenemia. LH likely contributes to this relationship, but overnight LH secretion in obese girls is poorly characterized. OBJECTIVE The aim of the study was to evaluate LH pulse characteristics in obese girls throughout pubertal maturation. DESIGN We conducted a cross-sectional analysis. SETTING The study was performed in a general clinical research center. PARTICIPANTS Eight nonobese and five obese Tanner 1-2 girls participated, as well as 32 nonobese and 12 obese Tanner 3-5 girls. INTERVENTION Blood samples were collected every 10 min overnight (from 1900 to 0700 h). MAIN OUTCOME MEASURES LH pulse frequency, amplitude, and mean LH were measured in three 4-h time blocks (block 1, 1900-2300 h; block 2, 2300-0300 h; and block 3, 0300-0700 h). RESULTS Tanner stage 1-2 nonobese girls demonstrated nocturnal increases of LH frequency (P < 0.01, block 1 vs. 2) and mean LH (P < 0.05, block 1 vs. 2 and 3). Obese Tanner 1-2 girls had lower 12-h LH frequency and LH amplitude (P < 0.05 for both), with no overnight changes of LH pulse parameters. Compared to normal, LH frequency was elevated in Tanner 3-5 obese girls (P < 0.01 in all blocks), whereas LH amplitude was low (P < 0.05 in all blocks). Overnight increases of LH amplitude were observed in nonobese Tanner 3-5 girls (P < 0.0001), but not in obese Tanner 3-5 girls. CONCLUSIONS Obesity in prepubertal and early pubertal girls is associated with reduced LH secretion and reduced nocturnal changes of LH. In later pubertal girls, obesity is linked with reduced LH amplitude, but elevated LH frequency; the latter may reflect effects of hyperandrogenemia.

Modulation of Gonadotropin-Releasing Hormone Pulse Generator Sensitivity to Progesterone Inhibition in Hyperandrogenic Adolescent Girls—Implications for Regulation of Pubertal Maturation

CONTEXT Adult women with polycystic ovary syndrome (PCOS) have decreased GnRH pulse generator sensitivity to progesterone (P)-mediated slowing. This defect is androgen mediated because it is reversed with androgen receptor blockade. Adolescent hyperandrogenism often precedes PCOS. OBJECTIVE The aim of the study was to evaluate GnRH pulse generator sensitivity to P-mediated slowing in normal and hyperandrogenic girls. DESIGN We conducted a controlled interventional study. SETTING The study was conducted in a general clinical research center. PARTICIPANTS A total of 26 normal control (NC) and 26 hyperandrogenic (HA) girls were studied. INTERVENTION Frequent blood sampling was performed for 11 h to assess LH pulse frequency before and after 7 d of oral estradiol and P. MAIN OUTCOME MEASURE We measured the slope of the percentage reduction in LH pulse frequency as a function of d 7 P (slope). RESULTS Overall, Tanner 3-5 HA subjects were less sensitive to P-mediated slowing than Tanner 3-5 NC (slope, 4.7 +/- 3.4 vs. 10.3 +/- 7.7; P = 0.006). However, there was variability in the responses of HA subjects; 15 had P sensitivities within the range seen in NC, whereas nine were relatively P insensitive. The two groups had similar testosterone levels. Fasting insulin levels were higher in P-insensitive HA girls (39.6 +/- 30.6 vs. 22.2 +/- 13.9 microIU/ml; P = 0.02), and there was an inverse relationship between fasting insulin and P sensitivity in HA girls (P = 0.02). Tanner 1-2 NC had lower testosterone levels and were more P sensitive than Tanner 3-5 NC (slope, 19.3 +/- 5.8; P = 0.04). CONCLUSIONS Hyperandrogenism is variably associated with reduced GnRH pulse generator sensitivity to P-mediated slowing during adolescence. In addition to androgen levels, insulin resistance may modulate P sensitivity.

Polycystic Ovary Syndrome in Adolescence

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive‐aged women and is characterized by hyperandrogenemia, menstrual dysfunction, and polycystic ovarian morphology. The hormonal abnormalities inherent in PCOS often begin in adolescence and include hyperinsulinemia and rapid luteinizing hormone (LH) pulse frequency, both of which mediate ovarian and adrenal overproduction of androgens. Although differences exist regarding the diagnostic criteria for PCOS, we believe that hyperandrogenemia is the final common pathway for the development of adolescent PCOS, and we propose a hypothesis to illustrate such. Recognizing and reducing androgen levels in adolescence is critical given their association with the metabolic syndrome (MBS), diabetes, and infertility in adulthood.

Hyperandrogenemia in adolescent girls: origins of abnormal GnRH secretion

Polycystic ovarian syndrome is a common disorder characterized by ovulatory dysfunction and hyperandrogenemia (HA). Its origins begin peripubertally, as adolescent HA commonly leads to adult HA and decreased fertility. HA reduces inhibition of gonadotropin releasing hormone pulse frequency by progesterone, causing rapid LH pulse secretion and further increasing ovarian androgen production. Obese girls are at risk for HA and develop increased LH pulse frequency with elevated mean LH by late puberty. Many girls with HA do not exhibit normal LH pulse sensitivity to progesterone inhibition. Thus, HA may adversely affect LH pulse regulation during pubertal maturation leading to persistent HA.

Role of androgen receptor CAG repeat polymorphism length in hypothalamic progesterone sensitivity in hyperandrogenic adolescent girls.

Polycystic ovary syndrome (PCOS) is characterized by oligo/anovulation, hyperandrogenism, and in many cases, polycystic ovaries. Women with PCOS often exhibit persistently increased gonadotropin-releasing hormone (GnRH) pulse frequency compared to normal cycling women, contributing to enhanced luteinizing hormone (LH) secretion and increased androgen production [1]. Administration of progesterone (P) decreases GnRH pulse frequency in normal women, but the GnRH pulse generator in women with PCOS is relatively insensitive to P negative feedback [2]. Treatment with the androgen-receptor antagonist flutamide restores GnRH pulse generator sensitivity to P inhibition in women with PCOS [3]. Hyperandrogenemia in adolescence can represent a forerunner of adult PCOS, though the etiology of PCOS remains unclear. As a group, adolescent girls with HA display impaired GnRH pulse generator sensitivity to progesterone inhibition (i.e., reduced P-sensitivity). However, P-sensitivity is varied in HA girls, despite comparable levels of plasma free testosterone (T) [4] . The androgen receptor (AR) gene contains a polymorphic trinucleotide (CAG) repeat sequence located in the N-terminal transactivation domain of the AR [5] , and the number of CAG repeats influences AR activity. In vitro, expression of AR alleles with shorter CAG repeat lengths is associated with increased AR activity [6]. We measured AR CAG repeat length in a subgroup of subjects previously shown to have varied GnRH pulse generator sensitivity to P-mediated slowing [4] , hypothesizing that shorter AR CAG repeat length would be associated with reduced P-sensitivity in HA girls.

Hyperandrogenaemia in adolescent girls: origins of abnormal gonadotropin-releasing hormone secretion: Abnormal GnRH secretion in hyperandrogenaemic girls

Polycystic ovarian syndrome is a common disorder characterized by ovulatory dysfunction and hyperandrogenemia (HA). Its origins begin peripubertally, as adolescent HA commonly leads to adult HA and decreased fertility. HA reduces inhibition of gonadotropin releasing hormone pulse frequency by progesterone, causing rapid LH pulse secretion and further increasing ovarian androgen production. Obese girls are at risk for HA and develop increased LH pulse frequency with elevated mean LH by late puberty. Many girls with HA do not exhibit normal LH pulse sensitivity to progesterone inhibition. Thus, HA may adversely affect LH pulse regulation during pubertal maturation leading to persistent HA.

Pubertal Precursors of the Polycystic Ovarian Syndrome

Polycystic ovarian syndrome (PCOS) is a disorder characterized by ovulatory dysfunction and hyperandrogenemia. In the majority of women with PCOS, luteinizing hormone (LH) [gonadotropin-releasing hormone (GnRH)] pulse frequency is persistently rapid, which favors synthesis of LH and elevated plasma LH that in turn stimulates increased androgen production. Rapid GnRH frequencies are not optimal for FSH synthesis and secretion, contributing to impaired follicular maturation. In normal women, luteal phase concentrations of progesterone markedly slow GnRH pulse frequency (to one pulse every 3–4 h), but in anovulatory women with PCOS, this does not occur. In part, this reflects the low levels of circulating progesterone, but studies have also demonstrated reduced hypothalamic sensitivity to progesterone inhibition of GnRH secretion. The reduced sensitivity to progesterone appears to be the result of elevated androgens, as sensitivity is restored following treatment with the anti-androgen, flutamide. In the etiology of the disorder PCOS, ovulatory and hormonal abnormalities are commonly observed during puberty, with plasma measurements revealing hyperandrogenemia. In some girls, impaired hypothalamic progesterone sensitivity is present, similar to that in adult women, though not all hyperandrogenemic adolescents are affected. We propose that the pre- and early-pubertal hyperandrogenemia interferes with normal ovarian hypothalamic regulation of GnRH pulse frequency, leading to a persistently rapid frequency of GnRH pulse secretion. This in turn favors LH synthesis and secretion, further stimulating ovarian testosterone secretion and impairing normal regulation of ovulatory function.