The delay in childbearing is an important societal change contributing to an increasing incidence of subfertility. The prevailing concept of female reproductive ageing assumes that the decline of both quantity and quality of the oocyte/follicle pool determines an age-dependent loss of female fertility. There is an apparent discrepancy between the ability to maintain a regular ovulatory cycle pattern and the several years earlier cessation of female fertility. This latter is largely explained by an age-related increase of meiotic non-disjunction leading to chromosomal aneuploidy and early pregnancy loss, such that most embryos from women > or =40 years old are chromosomally abnormal and rarely develop further. The final stage of reproductive ageing-the occurrence of menopause-shows a huge variation between women. Age at last birth in natural fertility populations, which marks the end of female fertility, shows an identically wide variation as age at menopause, but occurs on average 10 years earlier. Given the high heritability for age at menopause, the variation in both age of menopause and last birth are probably under genetic control by the same set of genes. Some of those genes must carry heritable variants which modulate the rate of ovarian ageing and give rise to the wide age variations for the various phases of reproductive ageing.

The variability of female reproductive ageing

The concept that hormones can cause, i.e., increase the incidence of, neoplasia was first developed by Bittner et al. (1), based on experimental studies of estrogens and mammary can cer in mice. We have refined that concept into a hypothesis for a major role of estrogen and other hormones in the etiology of several human cancers (2). A key element of this hypothesis is that neoplasia is the consequence of excessive hormonal stim ulation of a particular target organ, the normal growth and function of which are under hormonal control. The response of this end organ (e.g., endometrium, breast) to the proliferative effects of the hormone is a progression from normal growth to hyperplasia to neoplasia. In this model, hormones increase the incidence of neoplasia in the absence of outside initiators such as chemicals or ionizing radiation. We have hypothesized three specific circumstances in which estrogen plays a role in this model of hormone-induced neopla sia. In the first two circumstances, which relate to the breast and the endometrium, estrogens themselves act as the stimu latory hormones, increasing the frequency of mitotic activity in the target organ. As rare consequences of this estrogen-induced proliferation, malignant phenotypes develop due to errors in the mechanics of cell division (e.g., DNA copying errors, chro mosomal translocations, etc.) (Fig. 1). We believe that breast cancer risk is determined primarily by the total cumulative exposure of breast tissue to bioavailable estrogens and the associated cumulative mitotic activity. Al though a related mechanism applies to endometrial cancer, the critical exposure in the endometrium is not estrogen per se but that fraction of estrogen which is unopposed by the modifying influences of progesterone. The primary prevention of these two estrogen-induced neoplasms probably will come not from control of exposure to classical exogenous initiators but from modification of factors which directly affect the secretion, tissue binding, and availability of estrogen itself over a woman's entire

https://cancerres.aacrjournals.org/content/canres/48/2/246.full.pdf

Estrogens as a Cause of Human Cancer: The Richard and Hinda Rosenthal Foundation Award Lecture

The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer

The contribution of prolactin (PRL) to the pathogenesis and progression of human breast cancer at the cellular, transgenic, and epidemiological levels is increasingly appreciated. Acting at the endocrine and autocrine/paracrine levels, PRL functions to stimulate the growth and motility of human breast cancer cells. The actions of this ligand are mediated by at least six recognized PRL receptor isoforms found on, or secreted by, human breast epithelium. The PRL/PRL receptor complex associates with and activates several signaling networks that are shared with other members of the cytokine receptor superfamily. Coupled with the recently identified intranuclear function of PRL, these networks are integrated into the in vitro and in vivo actions induced by ligand. These findings indicate that antagonists of PRL/PRL receptor interaction or PRL receptor-associated signal transduction may be of considerable utility in the treatment of human breast cancer.

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The Role of Prolactin in Mammary Carcinoma

Uterine fibroids are the most common benign tumour of the female genital tract. However, their true prevalence is probably under-estimated, as the incidence at histology is more than double the clinical incidence. Recent longitudinal studies have estimated that the lifetime risk of fibroids in a woman over the age of 45 years is more than 60%, with incidence higher in blacks than in whites. The cause of fibroids remains unclear and their biology poorly understood. No single candidate gene has been detected for commonly occurring uterine fibroids. However, the occurrence of rare uterine fibroid syndromes, such as multiple cutaneous and uterine leiomyomatosis, has been traced to the gene that codes for the mitochondrial enzyme, fumarate hydratase. Cytogenetic abnormalities, particularly deletions of chromosome 7, which are found in up to 50% of fibroid specimens, seem to be secondary rather than primary events, and investigations into the role of tumour suppressor genes have yielded conflicting results. The key regulators of fibroid growth are ovarian steroids, both oestrogen and progestogen, growth factors and angiogenesis, and the process of apoptosis. Black race, heredity, nulliparity, obesity, polycystic ovary syndrome, diabetes and hypertension are associated with increased risk of fibroids, and there is emerging evidence that familial predisposition to fibroids is associated with a distinct pattern of clinical and molecular features compared with fibroids in families without this prevalence.

Incidence, aetiology and epidemiology of uterine fibroids.

An early first pregnancy is known to protect against subsequent breast cancer. We speculated that this effect may be mediated by a long-term depression of prolactin secretion after pregnancy. We therefore measured basal and post-stimulation serum levels of prolactin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in two groups--15 women 18 to 23 years of age and 9 women 29 to 40--before and after a first full-term pregnancy, and in 40 appropriate nulliparous controls. We observed no significant change in basal levels of serum LH or FSH or in the levels stimulated by gonadotropin-releasing hormone in any group. A significant decrease was seen, however, in basal and perphenazine-stimulated levels of prolactin after pregnancy in both the younger and older first-pregnancy groups but not in the controls. In a separate cross-sectional study, we compared basal serum prolactin levels in 29 parous and 19 nulliparous women of similar age. The serum prolactin levels were significantly lower in the parous group but were not related to the number of pregnancies (one to three) or the time elapsed (12 to 150 months) since the last delivery. We conclude that a first pregnancy leads to a long-term decrease in serum prolactin secretion, lasting at least 12 to 13 years.

D. Martino-Saltzman

Papers

Long-term effect of a first pregnancy on the secretion of prolactin

Age-related changes in the female hormonal environment during reproductive life