The role of the brain in female reproductive aging

Abstract

In middle-aged women, follicular depletion is a critical factor mediating the menopausal transition; however, all levels of the hypothalamic-pituitary-gonadal (HPG) axis contribute to the age-related decline in reproductive function. To help elucidate the complex interactions between the ovary and brain during middle-age that lead to the onset of the menopause, we utilize animal models which share striking similarities in reproductive physiology. Our results show that during middle-age, prior to any overt irregularities in estrous cyclicity, the ability of 17β-estradiol (E 2 ) to modulate the cascade of neurochemical events required for preovulatory gonadotropin-releasing hormone (GnRH) release and a luteinizing hormone (LH) surge is diminished. Middle-aged female rats experience a delay in and an attenuation of LH release in response to E 2 . Additionally, although we do not observe a decrease in GnRH neuron number until a very advanced age, E 2 -mediated GnRH neuronal activation declines during the earliest stages of age-related reproductive decline. Numerous hypothalamic neuropeptides and neurochemical stimulatory inputs (i.e., glutamate, norepinephrine (NE), and vasoactive intestinal peptide (VIP) that drive the E 2 -mediated GnRH/LH surge appear to dampen with age or lack the precise temporal coordination required for a specific pattern of GnRH secretion, while inhibitory signals such as gamma aminobutyric acid (GABA) and opioid peptides remain unchanged or elevated during the afternoon of proestrus. These changes, occurring at the level of the hypothalamus, lead to irregular estrous cycles and, ultimately, the cessation of reproductive function. Taken together, our studies indicate that the hypothalamus is an important contributor to age-related female reproductive decline.

Pituitary Hormone-producing Cells After Estradiol Application in Rat Models of Menopause

“…Ključne reči: ženke pacova, srednje doba, hipofi zne će-lije, estradiol decrease in circulating estradiol, is a critical factor triggering the menopausal transition (6), along with the distinctive changes at the level of the hypothalamus and anterior pituitary hormone-producing cells in the same individuals (7)(8).…”

Prevention of Breast Cancer Could Be a Consequence of Pregnancy: A Review

“…The ovaries work under the control of the hypothalamicpituitary-gonadal (HPG) axis [16,17], which synchronizes the ovarian secretions with those of pituitary and placental hormones for stimulating breast development in preparation for milk production [17,18]. Primiparous women younger than 25 years of age who have elevated serum levels of hCG during their first trimester have 33% decreased risk of a breast cancer diagnosis after age 50, whereas estrogen concentrations have been positively associated with risk of breast cancer before age 40, supporting the role of this or other pregnancy hormones in the development of breast cancer [19][20][21][22][23].…”

“…During these periods the maturation of the hypothalamic gonadal (HPG) axis [16,17,33] and endogenous hormone secretions play essential roles on the development of the breast at puberty, which is driven by the initiation of ovulation and the establishment of regular menstrual cycles [34]. The architecture of the breast of normally cycling women has been widely described as composed of three main lobular structures that are classified on the basis of their degree of development into lobules type 1 (Lob 1), lobules type 2 (Lob 2) and lobules type 3 (Lob 3) [22,35,36].…”

Somatostatin in the Periventricular Nucleus of the Female Rat: Age Specific Effects of Estrogen and Onset of Reproductive Aging

“…Taken together, this suggests that the input onto GnRH neurons may change with age, resulting in less activated GnRH neurons and reduced GnRH release that together with a reduction in endogenous GnRH priming could indeed lead to an attenuated LH surge. Previous studies have proposed a contribution of the suprachiasmatic nucleus (SCN) in the attenuation of the LH release surge (Wise et al, 2002;Downs and Wise 2009). Yet, we did not find any significant changes in timing of the LH surge (i.e.…”

“…The latter is strongly associated with the age at which rats become acyclic (Nass et al, 1984). Previous research suggested that changes in ovarian hormone release (DePaolo et al, 1986;Lu et al, 1985), pituitary hormone storage and/or responsiveness to ovarian or hypothalamic signaling (Brito et al, 1994;Keizer et al, 2001;Matt et al, 1998), or changes in hypothalamic signaling (Rubin et al, 2000;Downs and Wise, 2009;Wise et al, 2002) may underlie the age-related attenuation of the pituitary LH surge. Evidence suggests that exposure to chronically elevated levels of circulating E 2 during life advances the decline in fertility with age (Lu et al, 1981;Rodrigues et al, 1993).…”