The normal breast tissue undergoes changes which correspond to the different phases of the menstrual cycle. These changes can be seen in the structure of the breast cells, their interaction with each other and their protein expression. However, in women suffering from breast cancer, these physiological, cyclical changes are altered. This is because the cancer cells do not respond in a normal fashion to the difference in hormonal levels during the various phases of the menstrual cycle, a phenomenon called as “global dysregulation of response to hormonal influences”. It is important to study the changes in the breast morphology, as a response to the changing hormonal environment, during the different phases of menstrual cycle because of two reasons. First, you can match patients on the basis of these changes for the different epidemiological studies relating to breast cancer. And secondly, there are studies which suggest that breast cancer surgeries, when performed in the late luteal phase of the menstrual cycle, have a better prognosis.
Classification of Menstrual Cycle on the Basis of Cellular Morphology
On the basis of the level of sex hormones namely, estrogen, progesterone, luteal hormone and the follicular stimulating hormone, the menstrual cycle has been divided into four phases:
Early follicular phase which lasts from Day 0 to Day 5 of the menstrual cycle.
Late follicular phase which lasts from Day 6 to Day 15 of the menstrual cycle.
Early luteal phase which lasts from Day 16 to Day 24 of the menstrual cycle.
Late luteal phase which lasts from Day 25 to Day 28 of the menstrual cycle.
Classification of Cyclic Breast Changes Corresponding with Menstrual Cycle
Although the cyclic changes in the endometrium associated with the different phases of the menstrual cycle have been well studied, similar changes occurring in the breast tissue have been studied only recently. According to Geschickter, there are two cyclical phases of the breast tissue which correspond with the menstrual cycle. They are:
Regressive phase lasting from Day 1 to Day 8 of the menstrual cycle. The characteristic changes found in this phase are atrophy of the epithelium, closing of the alveolar lumina, condensation of the intralobular stroma, and an inflammatory infiltrate.
Progressive phase which corresponds to the later part of the menstrual cycle and is characterized by alveolar budding, secretions, and stromal edema.
There is another method of classifying the breast changes according to the different phases of menstrual cycle. According to it, the breast changes are classified into:
- Proliferative phase
- Follicular phase of differentiation
- Luteal phase of differentiation
- Secretory phase
- Menstrual phase
Morphological Changes in Breast Tissue with Menstrual Cycle
A study led by Rathi Ramakrishnan et al., studied the morphological changes in breast tissue with menstrual cycle. The important findings of the study are mentioned below:
Changes seen in Early Follicular phase: The difference between the epithelial and the myoepithelial layers of the acini is not very clear. The cells have round nuclei and there is little infiltrate in the intralobular stroma. Vacuolation, apoptosis and mitosis were not the conspicuous features of this phase.
Changes seen in Late Follicular phase: The distinction between the epithelial and the myoepithelial layers is clearer. The acini are well formed within the lobules and show an increasing tendency of vacuolation. Stromal infiltrate as well as mitotic and apoptotic bodies are absent.
Changes seen in Early Luteal phase: Larger lobules with increased numbers of terminal duct units are seen. There is marked vacuolation with a central or atypically placed nucleus. There is mixed inflammatory infiltrate in the intralobular stroma. A few mitotic and apoptotic bodies are seen occasionally.
Changes seen in Late Luteal phase: There is extensive vacuolation in the lobules. The epithelial cells have prominent nuclei and mitotic figures are frequently encountered. There is an increase in the number of apoptotic bodies seen. There is widespread intrastromal edema with the presence of a large number of inflammatory cells.
Amongst these stages, it is the late luteal phase which appears to be of the most interest to the scientists studying the relationship of breast cancer with menstrual cycle. During the luteal phase, there is a cumulative effect of both estrogen and progesterone which leads to a rapid proliferation of breast epithelial cells. There is an increased mitotic activity in the breast lobules and we get to see many apoptotic figures towards the late luteal phase of the menstrual cycle.
Effect of Menstrual History on a Woman’s Chances of Developing Breast Cancer
The age of the woman at the time of commencement of her menstrual periods and at the time she attains menopause is likely to affect her chances of developing breast cancer. Similarly, in many epidemiological studies, the age of the woman when she first borne a child, has also been demonstrated as an important risk factor in the development of breast cancer. It is a known fact that the endocrine environment inside a woman’s body is significantly altered during all the three phases of her reproductive life, which have been mentioned above. Our knowledge about the pathogenesis of breast cancer will improve considerably once we are able to fully understand the mechanism by which these endocrine events alter the risk of breast cancer.
Menstruation is a result of an orderly cyclical pattern of follicular maturation, development of corpus luteum, and its regression associated with specific changes in the levels of different sex hormones. It has been seen that women frequently observe irregular periods just after menarche and in the years prior to menopause. This is a result of an improper follicular maturation and can lead to insufficient progesterone production by the impaired corpus luteum. The hormonal environment thus produced, is deficient in progesterone but rich in estrogen. Women who experience early menarche and a late menopause are more exposed to these phases of irregular periods and as a result, more exposed to a relative estrogen excess. Similarly, late age for conceiving the first child is a result of involuntary infertility. This too, is associated with inadequate production of progesterone in the luteal phase and thereby, an increased exposure to estrogen. In the light of this knowledge, it can be inferred that exposure to excess estrogen resulting from an altered menstrual cycle in women with early menarche, late menopause and increased age of first parity can lead to the pathogenesis of hormone responsive breast cancers. Moreover, even if women with an early menarche and a late menopause, even if they have regular cycles, have more number of menstrual cycles in their reproductive age and are therefore exposed to a greater cumulative exposure to estrogen. Therefore an early menarche and a late menopause can be a risk factor in the development of breast cancer.
Another important finding worth noting is that there is an increase of about 0.30 C in the basal temperature of the body during the second half of the menstrual cycle. This increase in basal temperature is often absent during the irregular cycles of postmenarchal and premenopausal women. This absence in the fluctuation of the basal body temperature is associated with inadequate production of progesterone from the corpus luteum, as has been revealed by radioimmunoassay of the pituitary and ovarian hormones. Inadequate function of the corpus luteum has also been reported in women suffering from infertility and in women with polycystic ovarian syndrome. The latter condition causes infertility and is a known risk factor for the development of breast cancer.
Relationship between Timing of Surgery for Breast Cancer and the Menstrual Cycle
Hrushesky et al. were responsible to find an association between the prognosis of a woman following breast cancer surgery and the timing of the surgery with regards to her menstrual cycle. They conducted a retrospective study of 44 premenopausal women who had undergone surgery as a part of their breast cancer treatment and derived the conclusion that chances of survival were better if the surgery was performed mid-cycle (Days 7 to 20) rather than when it was performed in the perimenstrual period (Days 0 to 6 and Days 21 to the end of the cycle). However subsequent studies did not support this view. Many other scientists believe that the ideal time for a breast cancer surgery is during the late luteal phase of the menstrual cycle. According to them, a surgery performed in this phase of menstrual cycle offers better chances of survival and less chances of developing a recurrent tumor.
Another prospective study, led by the North Central Cancer Treatment Group (NCCTG) in collaboration with the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the International Breast Cancer Study Group (IBCSG), studied the incidence of recurrence and death in 834 premenstrual women with early stage breast cancer. They reached to the conclusion that the time of menstrual cycle when the patient was operated upon, does not bear any relationship, with either recurrence of breast cancer or death, following the surgery.
This controversy, regarding a possible link between menstrual cycle phase at surgery for breast cancer and outcome has existed for almost 20 years. This may be due to misclassification of a large segment of a study population which leads to discrepancies in findings. The misclassification is largely because of the absence of any standard method for determining the menstrual cycle phase on the basis of last menstrual period (LMP).
Another recent study conducted by Love and Young et al. found that adjuvant surgical oophorectomy during the luteal phase of the menstrual cycle resulted in reduced risk of recurrence of the breast cancer as compared to removal of ovaries in the follicular phase during the first 5.5 years of follow up. However, the benefits of a luteal phase surgery on the chances of recurrence of breast cancer seem to diminish after 6 years of surgery.
It is important to stress that the results obtained from the various studies are not conclusive. There is a lot of contradiction between the results of different studies and a rigorous evaluation of these clinical trials is still required. It is true that the different phases of menstrual cycle affect the development of breast cancer because of the altered hormonal environment in each phase. However, the practical and biological implications of these facts need to be studied in greater detail.
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