A 27-year-old woman comes to the office for evaluation of irregular menses. Menarche was at age 12, and the patient started taking combined oral contraceptives at age 18. She had no menstrual periods while using oral contraceptives and was advised that this was normal. The patient stopped her contraception 6 months ago to conceive with her husband, but she still has not menstruated. BMI is 24 kg/m2. Urine pregnancy testing is negative. TSH, FSH, and prolactin levels are normal. Oral medroxyprogesterone for 10 days is prescribed; a few days after completing the progesterone course, the patient has moderately heavy bleeding with some cramping. Which of the following endometrial processes is most likely responsible for this patient's bleeding?
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Menstruation occurs due to fluctuating estrogen and progesterone levels, which regulate the endometrium. Progesterone is secreted during the luteal phase of the menstrual cycle and transforms the endometrium from proliferative to secretory to promote pregnancy implantation. Endometrial glands become more elaborate, and the spiral arteries, which supply the stratum functionalis, elongate and coil. Exogenous progesterone intake for 10 days similarly matures the endometrium.
When the endometrium is no longer exposed to progesterone (ie, progesterone withdrawal), local prostaglandin production increases. This causes uterine contractions (eg, cramping), leading to compression/constriction of the spiral arteries. In response to decreased blood supply, the cells in the stratum functionalis undergo programmed cell death, or apoptosis. Progesterone withdrawal also causes endometrial stromal cells to secrete metalloproteases, causing degradation of the extracellular matrix. The net effect is degeneration of the stratum functionalis, which sloughs away as menstrual blood flow. The stratum basalis remains intact (as it is supplied by the straight, not spiral, arteries), allowing for regeneration of the stratum functionalis during the next proliferative phase.
(Choice B) Dysplasia is the abnormal growth of cells, tissues, or organs. In epithelial tissues such as the transformation zone of the cervix, dysplasia is an early form of precancer.
(Choice C) Granulation refers to the formation of new connective tissue and capillaries as part of the wound healing process. Intrauterine procedures or infection can result in proliferation of granulation tissue with subsequent endometrial scarring and formation of fibrous adhesions (ie, Asherman syndrome).
(Choice D) Hyperplasia is increased cell number due to increased cell proliferation. Endometrial hyperplasia can cause abnormal (eg, intermenstrual, prolonged) uterine bleeding if the overly proliferative, thickened endometrium outgrows its blood supply. However, the immediate cause of bleeding in this patient is cellular apoptosis triggered by withdrawal of progesterone.
(Choice E) Hypertrophy is the enlargement of tissue due to increased cell size without increased cell proliferation. Patients with adenomyosis have hypertrophy of the surrounding uterine smooth muscle cells, which results in a uniformly enlarged, globular uterus.
(Choice F) Invagination (inward folding) of epithelial cells occurs during embryonic development (gastrulation) to form structures such as the neural tube. It is not associated with menstruation.
Educational objective:
Progesterone is secreted during the luteal phase of the menstrual cycle and transforms the endometrium from proliferative to secretory. Progesterone withdrawal causes endometrial cells in the stratum functionalis to undergo apoptosis, resulting in menstrual bleeding.