Effect of Race on Gonadotropin Responses

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.

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.

• Premenopause
• Healthy

• Drug: Estradiol steroid infusion
  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
• Drug: Progesterone steroid infusion
  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

• 1
  Healthy African-American women 18-35 years old
  Interventions:

  • Drug: Estradiol steroid infusion
  • Drug: Progesterone steroid infusion
• 2
  Healthy Caucasian women 18-35 years old
  Interventions:

  • Drug: Estradiol steroid infusion
  • Drug: Progesterone steroid infusion
• 3
  Healthy Caucasian women 36-45 years old
  Interventions:

  • Drug: Estradiol steroid infusion
  • Drug: Progesterone steroid infusion

Premenopausal Women

• Will be non-smokers or smoke less than 10 cigarettes/day
• African-American women aged 18 to 35 years and Caucasian women aged 18 to 45 years
• BMI <30
• In good general health with normal TSH, prolactin and hemoglobin
• Normal BUN and Creatinine (< 2 times the upper limit of normal)
• On no medications for > 2 months before the study
• Regular menstrual cycles every 25 to 35 days and ovulation documented by a luteal phase progesterone > 3 ng/ml
• With no evidence of androgen excess.
• Subjects must have no known sensitivity to any medications used in the relevant protocol and be willing to use abstinence or barrier methods of contraception for the duration of the study.

Subjects will be asked to volunteer information on ethnicity (self classification). Only African-American and Caucasian subjects will be included in this aim to address the specific hypotheses.