D. Marchesoni, M. Gangemi, B. Mozzanega, G.B. Nardelli,T. Maggino, and M. Velasco

Department of Obstetrics and Gynecology, University of Padua, 35100 Padova, Italy.

Introduction

The hormone-responsiveness of breast tissue and the hormone-dependence of its morphostructural modifications and functional potentialities are generally acknowledged. A chronologically and quantitatively precise ratio between the two hormones that condition its development, estradiol and progesterone, is necessary to assure breast eutrophy. Estradiol-induced cell proliferation in galactophorous ducts and edema formation in periductal stroma are followed by progesterone-induced growth inhibition and acinar differentiation toward secretion.

When the equilibrium found in normal menstrual cycles is broken, with an even partial loss of progesterone modulation, structural changes may occur in breast tissue. These changes are clinically grouped in the mastosis syndrome: their origin is neither phlogistic nor neoplastic, but, much more likely, seems dysendocrinic.

This etiopathogenetic hypothesis is supported by epidemiological observations indicating that the disease is more frequent in women in the reproductive age who are nulliparous, or never breast-fed, or show evidence of neurovegetative lability, or are obese, or who experienced anovulatory cycles. Physiological menopause is often associated with a disappearance of symptoms. Also, low progesterone levels have been noted in the luteal phase of women who, though ovulating, were affected with this syndrome.

This chapter investigates estradiol and progesterone plasma levels in normally menstruating women affected with mastosis, and offers a rationale for endocrine therapy of this disease.

Materials and methods

Of 22 normally menstruating outpatients studied 10 were breast disease-free controls, and 12 complained of mastodynia, mostly affecting their premenstrual phase. A mono- or bilateral breast micronodularity was also present in the affected patients, which was clinically evident and diagnostically confirmed by the use of plate thermography, transillumination, echography, and, when necessary, mammography. The affected patients’ mean age was 27 ± 7 years; the average length of their menstrual cycles was 29 ± 4 days; their basal body temperature curves were biphasic; and none had galactorrhea.

All patients underwent blood drawings from the cubital vein taken between 8 and 10 a.m. on the third, sixth, and ninth days of the thermal plateau, for radioimmunoassay (RIA) of plasma estradiol and progesterone levels (Serono-Biodata Kit, sensitivity =10 pg/tube and 15 ng/ml, respectively).

Results

The significance of the differences between the averages of the two hormones was calculated in the two groups by the Student’s r-test. The luteal phase ratio P/E2 was then calculated in both groups, according to the formula (6):

Table 1 illustrates the average levels of estradiol and progesterone in both groups, and the results of the statistical analysis. The PEL ratio was 0.52 in the affected patients and 1.13 in the controls.

Table 1. Estradiol and progesterone levels in the luteal phase of the affected and control patients

Discussion

The results of our research clearly point out that progesterone plasma levels are diminished in the luteal phase of patients affected with benign breast disease compared with controls.

Our data agree with the almost (3) unanimous (2,4—6,8,9) findings in the literature that benign breast disease, associated or not with mastodynia, can be due to a luteal deficit as occurs in the short or inadequate luteal phase. The presence in the affected patients of luteal estradiol levels that are the same as in the controls makes the hormonal balance shift toward hyperestrinism, which is the common base of the different ways through which mastosis can arise.

The prevalence in target tissues of estrogen stimulation can be associated with anovulatory syndromes (obesity, ovarian polycystosis) in which estradiol secretion and action are unopposed; or with the missed occurrence of physiological conditions (pregnancy, breast feeding) which protect the target tissues from estrogen-dependent risks; or with other situations that cannot be clinically diagnosed unless we resort to plasma progesterone radioimmunoassay (short or inadequate luteal phase).

In any of these cases, the antiestrogenic action of progesterone is inadequate; progesterone induces in target tissues a drop in the levels of E₂-receptors and an increased synthesis of 17-beta-dehydrogenase which converts estradiol to estrone. Its absence renders estradiol stimulation persistent, with edema induction in periductal stroma, causing mastodynia, fibrosis, and, eventually increased cellularity in galactophorous ducts. Therefore, the succession hyperplasia-dysplasia-cancer can be hypothesized (1).

A critical examination of our cases points out the impossibility of achieving an etiological diagnosis of mastodynia based solely on clinical findings. All our patients menstruated normally and their basal body temperature followed biphasic curves. However, the normal occurrence of ovulation does not mean their luteal function was satisfactory, both in intensity and in length. Only progesterone RIA can rule out a corpus luteum dysfunction.

Progesterone values in the affected patients were statistically lower than in the controls (10.9 ± 0.7 SEng/ml and 23.4 ± 1.5 SB ng/ml, respectively;p < 0.01). If we consider that progesterone levels of 3 ng/ml are the minimum required to raise the thermal curve, this physical index appears unsuitable for a correct monitoring of the luteal function (8), even if, after progesterone RIA, a careful examination of the thermal curve may help in distinguishing between the luteal pathologies. As our patients’ thermal plateaus were never shortened, we can diagnose an inadequate luteal phase.

Finally, the affected patients’ progesterone levels were the same as levels believed critical to allow mastodynia to appear clinically.

The assay of progesterone plasma levels, then, seems to be important for proper therapy. Progesterone supply in the luteal phase, besides reducing or suppressing mastodynia, might induce a regression in breast objectivity, as recently reported in breast micronodularity (7).

A further investigation of the connection between dysplasia and cancer might suggest for progesterone luteal supply yet another effect: the possible prophylaxis toward breast malignancies.

References

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