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We evaluated bleeding pattern and endometrium following the administration of two of the most common types of progestogens used in hormone replacement therapy, medroxyprogesterone acetate (MPA) and medrogestone acetate. Twenty eight patients in spontaneous menopause were randomly allocated to two groups. Group 1 (n = 14) received 5 mg/day of of MPA and group 2 (n = 14) received 5 mg/day of medrogestone: both the progestogens were sequentially added for the last 12 days of a 21-day period of transdermal estradiol administration (50 micrograms per day). A 7-day treatment-free period completed the cycle. The study treatments were administered for 6 cycles. The endomtria were checked for their thickness by transvaginal ultrasound before starting treatment and at 6th treatment cycle (days 6-10 of the estrogen-only phase and during the period between days 8 and 12 of the progestogen addition). Endometrial biopsies were performed before starting treatment only in the patients with a positive progesterone challenge test and in all the patients at the end of the study during the addition of the progestogen. The bleeding pattern was closely monitored. MPA is accompanied by a thick endometrium with full secretory transformation in all cases. On the contrary, the same dose of medrogestone induced a consistent decrease of estrogen primed endometrium with only 4 cases of full secretory transformation. Four medrogestone-treated patients dropped out due to unscheduled bleeding. A low dose of medrogestone added to transdermal estradiol induced incomplete transformation of endometrium and oligo-amenorrhea more frequently than MPA, but it increased the chances of irregular bleeding. MPA fully transformed the endometrium: periods were thus heavier but regular. None of the patients in either group had endometrial hyperplasia.

Endometrial thickness was evaluated in apparently normal postmenopausal women by transvaginal ultrasonography and the results were compared with the response to the progesterone challenge test (PCT). A positive correlation between amount of withdrawal bleeding after PCT and endometrial thickness was found, also demonstrated by the significative correlation between bleeding length and endometrial thickness. Among women referring withdrawal bleeding, 100 and 22% of cases classified as overt flow and spotting, respectively, were characterized by pathologic histological findings. The combined use of these two procedures is suggested as an effective screening mean in the preventive endometrial management of apparently normal postmenopausal women to select candidates for diagnostic invasive procedures.

We have analysed the distribution and the binding properties of the epidermal growth factor (EGF) receptor in human endometrium during the menstrual cycle to validate the proposal that steroids affect the growth rate of target cells via growth factor-related pathways. The total number of EGF receptors and their affinity for the iodinate exogenous ligand are significantly higher during the proliferative than the secretory phase; the binding kinetics appear to be hyperbolic and sigmoid during the proliferative and the secretory phase, respectively. These results suggest that endogenous sex steroids can regulate the levels and the properties of EGF receptors in vivo, and support the possibility that receptor-coupled events may play a role in estrogen-stimulated growth.

When human endometrial transglutaminase was measured a 10-fold higher activity was detected during the secretive phase. This change was not related to either differences in solubility of the enzyme or to selective contamination by plasma factor XIII and rather appears to depend on the expression of the tissue form of transglutaminase, suggesting that this enzyme is regulated in vivo by progesterone.

In human endometria, a membrane-bound adenylate cyclase is present, which is recovered in high yield in a low-speed particulate fraction. Neither the specific activity of the enzyme nor the response to modifiers that act through the regulatory subunit of the complex, are modified during the proliferative or secretory phase of the cycle. Surprisingly, we found that in vitro treatment of secretory endometrial membranes with 17 beta-estradiol stimulates 3- to 4-fold the activity of adenylate cyclase. However this response does not occur on proliferative membranes. The activation by estradiol is independent of the presence of guanylylimidodiphosphate and is additive to that of the nucleotide. Possibly, as the consequence of the phenomenon, the concentration of cyclic AMP is significantly higher in curretage samples obtained from patients during the secretory rather than in the proliferative phase of the cycle. To our knowledge this is the first evidence of a target-cell membrane-directed effect of sex steroids in humans.

The measurement of the tissue concentrations of cyclic adenosine monophosphate (cAMP) in human endometrium shows that the levels of the nucleotide vary during the menstrual cycle, being 11.4 +/- (SE) 2.5 and 37.7 +/- (SE) 10.1 pmol/mg protein in the proliferative and secretory phase, respectively. The individual determinations of cAMP are significantly correlated to the estradiol/progesterone blood concentration ratio: by this means we obtained a superimposable distribution with the results of histologic examination suggesting that the hormones have a direct action in determining the cAMP levels in this tissue. The relevance of these observations for the physiology of the endometrium is discussed.