Effect of Race on Gonadotropin Responses
Condition: Premenopause; Healthy
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The purpose of this study is to attempt to determine why estrogen levels are increased in
      African-American women as compared to Caucasian women by evaluating estrogen feedback on the
      brain. African-American women have increased bone mineral density, higher rates of twins,
      greater incidence of fibroids, and increased incidence of breast cancer below 40 years of age
      as compared to Caucasian women. These traits or illnesses are all believed to be
      estrogen-dependent. In fact, previous research has demonstrated increased estrogen levels in
      African-American women as compared to Caucasian women. However, the reason for these
      differences in estrogen levels has not been studied in humans. One possibility is that
      estrogen feedback on the brain differs between African-American and Caucasian women. Two
      small glands in the brain (hypothalamus and pituitary) respond to estrogen. The hypothalamus
      secretes GnRH (Gonadotropin-Releasing Hormone) that signals the pituitary to secrete the
      reproductive hormones, LH (Luteinizing Hormone) and FSH (Follicle Stimulating Hormone). These
      hormones act on the ovaries and signal the ovaries to produce estrogen and progesterone.
      Estrogen in the bloodstream then acts on the brain to stop this system when the blood has
      enough estrogen levels. This is called estrogen feedback. This study will determine whether
      there are differences in estrogen feedback between African-American and Caucasian women.
    

Detailed description: 
      Several independent lines of evidence have suggested that reproductive endocrine dynamics may
      differ between African-American (AAW) and Caucasian (CW) women. There is an increased
      incidence of dizygotic twinning in African-American women and a further increase in the
      incidence reported in African women compared to Caucasian, Hispanic and Asian populations.
      While the etiology of dizygotic twinning is not well understood, an increase in its incidence
      may imply an alteration in the integrated control of the reproductive axis which usually
      favors development of a single ovulatory follicle. It is widely appreciated that the
      incidence of leiomyomas is increased in African-American women. Growth factors are likely to
      play a role in their control, but there is also ample evidence that leiomyomas are responsive
      to gonadal steroids, decreasing in size following the menopause and in response to
      hypoestrogenism caused by gonadotropin downregulation. African-American women under 40 years
      of age have a higher risk of breast cancer than women of all other ethnicities in that age
      group, again raising the question of whether there are also differences in reproductive
      hormone dynamics. Finally, bone density is increased in African-American women. In a
      cross-sectional study of 54 African-American and 39 Caucasian women between the ages of 20
      and 90, Perry et al found that the increase in bone density in AAW was associated with
      increased serum levels of both estradiol and testosterone. Woods et al also described
      increased levels of estradiol, estrone and androstenedione levels in AAW compared with
      control women on a controlled low-fat, high-fiber diet. In contrast, a recent longitudinal
      cohort study has suggested that AAW have lower levels of estradiol with increasing age and
      BMI in comparison with CW. We have compared reproductive hormone levels in AAW and CW < 35
      years old with a history of regular ovulatory cycles. Our preliminary data indicate that in
      comparison to age and BMI matched CW, estradiol levels are consistently elevated across the
      cycle in AAW in the absence of changes in LH, FSH, progesterone, inhibin A or inhibin B.
      These relationships suggest both altered negative and forward feedback interrelationships
      between FSH and LH and estradiol in the setting of normal inhibin levels. In the current
      protocol we will seek to understand the mechanisms underlying these feedback differences,
      which have never been addressed in these populations.

      A graded infusion of estradiol and progesterone can be used to assess differences in negative
      and positive feedback of gonadal steroids on LH and FSH. We have hypothesized that
      differences exist in feedback regulation of the hypothalamus and pituitary as a function of
      African-American or Caucasian race in reproductive aged women.
    

Intervention name(s): Estradiol steroid infusion; Progesterone steroid infusion
Intervention type(s): Drug; Drug
Intervention description(s): Estradiol infusion of 0.1 mcg/kg/hr for 12 hr, 0.135 mcg/kg/hr for 12 hr, 0.165 mcg/kg/hr for 12 hr and 0.2 mcg/kg/hr for 60 hr; Progesterone infusion of 4.77 nmol/kg/hr (1.5 mcg/kg/hr) for 24 hr and 6.36 nmol/kg/hr (2 mcg/kg/hr) for the final 24 hr
Other intervention name(s): E2; P
Intervention MeSH terms: Estradiol; Progesterone
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Comparisons will be made between response to estradiol and progesterone infusion in young African-American and Caucasian women.
Masking: None (Open Label)
Primary purpose: Other
Keywords: estrogen; progesterone; African-American; Caucasian; infusion; gonadotropins; healthy