The functional layer of the endometrium of the uterus undergoes repeated cycles of proliferation and differentiation and, if no implantation occurs, breakdown and sloughing of tissue. These processes are under the control of the ovarian steroid hormones which define three distinct hormonal environments: estrogen dominance during the proliferative phase; progesterone dominance during the secretory phase; and progesterone withdrawal in the breakdown phase. The window of implantation occurs during the midsecretory phase, six to ten days following the LH surge.

Estradiol (E2) is required for the changes in the endometrium during the proliferative phase and for preparing it to respond to progesterone during the secretory phase. E2 governs uterine responsitivity to itself and to progesterone by increasing the transcription of the mRNA for both ERα and PR.

The effects of E2 during the proliferative phase are mediated primarily by ERα, the expression of which in the endometrium is greatest during the proliferative phase. ERα expression declines following ovulation due to the suppressive effects of progesterone on transcription of its mRNA. During the proliferative phase, E2 interacts with ERα in stromal cells of the endometrium which respond by producing growth factors and cytokines. Among these are insulin-like growth factor 1 (IGF-1), transforming growth factor β (TGF-β), and epidermal growth factor (EGF) (see Chapter 17 for further discussion of these and other growth factors). These growth factors and cytokines exert paracrine effects on the epithelial cells of the endometrial glands, increasing mitosis and growth.

The signaling pathways that E2 stimulates in the stromal cells also operate in the endothelial cells of the blood vessels to promote angiogenesis. Currently the best candidate for a role in the increased blood vessel growth and differentiation seen during each menstrual cycle is vascular endothelial growth factor, VEGF, although many other signaling molecules are also likely to be involved.

Progesterone levels begin to rise just prior to ovulation and peak in the midsecretory phase of the uterine cycle, during the window of implantation. Progesterone is required for ovulation, for fertilization, and for the differentiation of the endocrine cells of the endometrial glands for their secretory functions. These secretions include glycogen, mucus, chemokines, cytokines, and other substances required for successful implantation.

Progesterone limits the effectiveness of E2 on the growth of the endometrium during the secretory phase of the menstrual cycle through three mechanisms. It blocks the transcription of the mRNA for ERα. It stimulates the transcription of mRNA for and therefore the activity of 17βHSD2 (same activity as 17βHSD1), thereby increasing the conversion of active E2 to relatively inactive estrone. And it increases the levels of estradiol sulfotransferase, an enzyme that catalyzes the incorporation of sulfate at C-3 to inactivate the molecule. The importance of the role of progesterone in limiting the stimulatory activity of E2 is apparent from the observation that absence of PRB is associated with endometrial hyperplasia in mice and in the condition of endometriosis in the human. In the latter case, endometrial tissue outside the uterus under goes estradiol stimulated hyperplasia unopposed by progesterone. This tissue contains PRA but not PRB, suggesting that PRB is responsible for the progesterone restraint on estrogen stimulation of endometrial growth.

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مواضيع ذات صلة

Menopause

Chemistry and Metabolism of Female Steroid Hormones: Feedback Effects on the Hypothalamus and Pituitary

Control of the Ovary by the Hypothalamus and Pituitary

Synthesis of Progesterone and Estrogens

Female Steroid Hormones

The Androgen Receptor

Hypothalamic-Pituitary-Testis Axis: Feedback Control

Causes of Destructive (Low RAIU) Thyrotoxicosis

Causes of Hyperthyroidism

Hypothalamic-Pituitary-Testes Axis: Hormonal Control of the Testis

Sex Hormone-binding Globulin

Modification of Testosterone in Target Tissues