The effect of leukemia inhibitory factor (LIF) on trophoblast differentiation: a potential role in human implantation.

Leukemia inhibitory factor (LIF) is a multifunctional glycoprotein strongly associated with normal implantation in the mouse. We have recently determined that LIF is expressed in the human endometrium in a menstrual cycle dependent manner. Maximal expression is observed between days 19 and 25 of the menstrual cycle, coinciding with the time of human implantation. In this study we have utilized purified cultures of human cytotrophoblasts to examine the effects of LIF on several morphologic and biochemical markers of the trophoblastic differentiation. We purified human cytotrophoblasts from term placentae and cultured them with and without LIF (10 ng/mL). The secretion of human CG, oncofetal fibronectin, and progesterone were measured at 24, 48, 72, and 96 h. Northern blot analysis was used to assess messenger RNA (mRNA) expression of beta hCG and oncofetal fibronectin. We found that LIF markedly decreased trophoblast production of hCG protein at 72 and 96 h, as well as expression of beta hCG mRNA. LIF also significantly increased the expression of oncofetal fibronectin mRNA and secretion of the protein. LIF did not affect steroidogenic activity of cultured trophoblasts, as determined by progesterone production. These biochemical changes are characteristic of cytotrophoblast differentiation toward an anchoring extravillous phenotype. Thus, LIF appears to be an important regulator of human embryonic implantation by directly modulating trophoblast differentiation.

Hormone replacement therapy.

Although hormone replacement therapy (HRT) has been available for almost 100 years, conflicting opinions still exist about its efficacy and safety. There is uniform agreement that vasomotor instability and vaginal atrophy are totally reversible with HRT. Effective treatment of bone loss with HRT depends on the number of years of estrogen deprivation, peak bone mass, and rapidity of bone loss. Oral, transdermal, and pellet estrogens are equality effective. Mortality from coronary heart disease decreased 20% to 40% in women on HRT, yet the mechanism has not yet been ascertained. The increased risk of endometrial cancer has been confirmed, but better diagnostic techniques for detection in the precancerous state have been developed. The relationship of breast cancer to estrogen use has not been conclusive. Meta-analysis of 13 studies results in a relative risk of 1.06, whereas a large case-control study reveals a relative risk of 0.9. However, it is clear that in the average, healthy woman, low-dose estrogen replacement for less than 10 years does not increase the risk of breast cancer. Physicians are encouraged to help patients weigh the risks and benefits of HRT.

Incidence of breast cancer in a 22-year study of women receiving estrogen-progestin replacement therapy.

OBJECTIVE: To review the incidence of breast cancer in a continuous 22-year study of conjugated estrogen-medroxyprogesterone acetate hormone replacement therapy. METHODS: Eighty-four pairs of continuously hospitalized postmenopausal women who were matched for age, smoking history, and medical diagnosis were treated with estrogen-progestin hormone replacement therapy or placebo in a prospective and double-blind manner for 10 years. In the subsequent 12 years, the women were offered the choice of starting, stopping, or continuing hormone replacement therapy. RESULTS: After the initial 10 years, the incidence of breast cancer in the placebo group was 4.8%, whereas no cancers were found in the hormone replacement therapy group (P = .12). After an additional 12 years of follow-up, the overall incidence of breast cancer in the women who had never taken hormone replacement therapy was 11.5%, whereas no breast cancers had developed in the women who had ever taken hormone replacement therapy (P < .01). CONCLUSIONS: These data suggest that the 22-year administration of estrogen-progestin hormone replacement therapy did not increase the incidence of breast cancer in a small group of continuously hospitalized postmenopausal women.

Estrogen regulation of agonistic and proceptive responses in the golden hamster.

The role of estrogen in modulation of agonistic (attack-chase) and proceptive (vaginal-marking) responses of the female hamster toward a male was examined in relation to time course of induction and duration of response. In addition, the sex-specific nature of the vaginal-marking response was examined. Cycling females showed a significantly higher frequency of attack-chase when endogenous estrogen levels were minimal in comparison to that at peak estrogen levels during the estrous cycle. Removal of estrogen (ovariectomy) resulted in a significant increase in attack-chase scores compared to high endogenous estrogen. Addition of exogenous estrogen (Silastic capsule) resulted in a significant decrease in attack-chase scores compared to ovariectomized animals. The inverse effect was found for vaginal marking with the lowest frequency of vaginal marking at low endogenous estrogen levels or following ovariectomy. During high endogenous estrogen levels or following treatment with exogenous estrogen vaginal-marking scores were maximal. Maximal induction of vaginal-marking responses and reduction of attack-chase were found between 6 and 48 hr of estrogen treatment. Both behaviors then returned to the prehormonal treatment level. Failure to detect effects beyond 48 hr was not due to repeated testing, as animals lacking hormone, or animals first tested at 96 hr of estrogen exposure, showed no effect of the treatment. Males gonadectomized as adults never showed vaginal marking, whereas males gonadectomized neonatally showed a low level of vaginal marking which was increased significantly following estrogen treatment. Thus both attack-chase and vaginal marking in the presence of a male are modulated by estrogen. Further, since vaginal marking is estrogen sensitive in the neonatally gonadectomized male, expression of vaginal marking is determined by the hormonal environment during the neonatal period. However, peripheral feedback may be important for frequency of occurrence.