Defining ovarian reserve to better understand ovarian aging

Though a widely utilized term and clinical concept, ovarian reserve (OR) has been only inadequately defined. Based on Medline and PubMed searches we here define OR in its various components, review genetic control of OR, with special emphasis on the FMR1 gene, and discuss whether diminished OR (DOR) is treatable. What is generally referred to as OR reflects only a small portion of total OR (TOR), a pool of growing (recruited) follicles (GFs) at different stages of maturation. Functional OR (FOR) depends on size of the follicle pool at menarche and the follicle recruitment rate. Both vary between individuals and, at least partially, are under genetic control. The FMR1 gene plays a role in defining FOR at all ages. Infertility treatments have in the past almost exclusively only centered on the last two weeks of folliculogenesis, the gonadotropin-sensitive phase. Expansions of treatments into earlier stages of maturation will offer opportunity to significantly improve ovarian stimulation protocols, especially in women with DOR. Dehydroepiandrosterone (DHEA) may represent a first such intervention. Data generated in DHEA-supplemented women, indeed, suggest a new ovarian aging concept, based on aging of ovarian environments and not, as currently is believed, aging oocytes.     

Current understanding of ovarian aging

The reproductive system of human female exhibits a much faster rate of aging than other body systems. Ovarian aging is thought to be dominated by a gradual decreasing numbers of follicles, coinciding with diminished quality of oocytes. Menopause is the final step in the process of ovarian aging. This review focuses on the mechanisms underlying the ovarian aging involving a poor complement of follicles at birth and a high rate of attrition each month, as well as the alternated endocrine factors. We also discuss the possible causative factors that contribute to ovarian aging, e.g., genetic factors, accumulation of irreparable damage of microenvironment, pathological effect and other factors. The appropriate and reliable methods to assess ovarian aging, such as quantification of follicles, endocrine measurement and genetic testing have also been discussed. Increased knowledge of the ovarian aging mechanisms may improve the prevention of premature ovarian failure.     

Neuroendocrinology of Teleosts

The nucleus preopticus has been shown to receive afferent inputfrom certain cranial nerves and the spinal cord. In addition,the nucleus preopticus and its tracts can synthesize and transporthormones about as rapidly as a mammal can. The nucleus preopticusis functionally involved in the spawning reflex behavior. The hypothalamic control of each of the adenohypophysial hormonesis discussed. There is conflicting and incomplete evidence forthe control of melanocyte-stimulating hormone (MSH), prolactin,and somatotropin. Secretion of prolactin and MSH may each becontrolled by an inhibitory factor. Corticotropin secretionhas been shown to be controlled by corticotropin releasing factor(CRF). There is a negative fedback effect by cortisol on thepituitary to suppress corticotropin secretion. Gonadotropinsecretion is controlled by gonadotropin releasing factor (GRF).A part of the nucleus lateralis tuberis is involved in the controlof gonadotropin secretion. A great deal of indirect evidenceindicates that a thyrotropin inhibitory factor (TIF) controlsthyrotropin secretion. There is a negative feedback effect bythyroxine on the pituitary to suppress thyrotropin secretionand a positive feedback effect on the hypothalamus to stimulateTIF secretion. The above findings are restricted to only one or two speciesin each instance. It is not known how general the above mechanismsof control are found throughout the teleosts.     

Neuroendocrinology of the thymus

The neuropeptides oxytocin (OT) and vasopressin (VP) are synthesized in the human thymus in a similar way as in the hypothalamo-neurophypophyseal system. Immunocytochemistry with polyclonal and monoclonal antibodies revealed that immunoreactive OT- and VP-producing cells are localized in the subcapsular cortex and medulla of human and murine thymuses. The epithelial nature of the neuroendocrine thymic cells is demonstrated by their immunostaining with a monoclonal antibody against cytokeratin. An original example of a neuroendocrine-immune microenvironment is given by the thymic nurse cells which are composed of a large neuroendocrine epithelial cell enclosing numerous mitotic immature thymocytes. These observations and the previously reported mitogenic and immunomodulatory properties of VP and OT upon mature T cells and thymocytes strongly support the existence of a neuroendocrine thymo-lymphoid axis and an active role of thymic VP and OT in T cell differentiation and activation.     

Neuroendocrinology of Osmoregulation in Decapod Crustacea

Experimental evidences for neuroendocrine control of osmoreregulationin decapod crustaceans are mounting. The eyestalk system, brainand thoracic ganglionic centers, and the pericardial organ appearto be involved in this control. Evidences based on experimentationwith eyestalk removal and the injection of extracts of neuroendocrinecenters are presented. Neuroendocrine extracts affect the movementsof salts and water in the gills, stomach, intestine and antennalglands. The pericardial organ material may affect osmoregulationby increasing rate of circulation and influencing salt movement. Three factors have been partially separated from CNS tissues.A factor of the freshwater crayfish, and other freshwater decapods,increases the influx of salt. Two factors from an estuarinecrab influence the movement of water, an acetone-soluble factorincreasing its influx and a water-soluble factor decreasinginflux and increasing efflux. The factors may be involved inthe adaptation of the animals to their osmotic environments. None of the factors have yet been identified in circulationnor in effector tissues. Future research must place specialemphasis on the identification of the CNS factors in circulationas well as in secretory cells and effector tissues to establishtheir true hormonal nature.     

Bovine model of reproductive aging: response to ovarian synchronization and superstimulation

The responsiveness of the hypothalamo-pituitary axis to steroid treatments for ovarian synchronization and the ovarian superstimulatory response to exogenous FSH was compared in 13-14 year old cows and their 1-4 year old young daughters. We tested the hypotheses that aging in cattle is associated with: (1) decreased follicular wave synchrony after estradiol and progesterone treatment; (2) delayed LH surge and ovulation in response to exogenous preovulatory estradiol treatment; (3) reduced superstimulatory response to exogenous FSH. Higher plasma FSH concentrations (P<0.01), and a tendency (P=0.07) for fewer 4-5 mm follicles at wave emergence were observed in old cows (n=10) than in young cows (n=9). The suppressive effect of estradiol/progesterone treatment on FSH was similar between old and young cows. Although the preovulatory LH surge in response to estradiol treatment was delayed in old than young cows (P=0.01), detected ovulation times were not different. No difference in ovarian superstimulatory response was detected between age groups, but old cows (n=8) tended (P=0.10) to have fewer large follicles (>or=9 mm) 12 h after last FSH treatment than in young cows (n=7). We concluded that pituitary and ovarian responsiveness to estradiol/progesterone synchronization treatment was similar between old and young cows, but aging was associated with a delayed preovulatory LH surge subsequent to estradiol treatment. Old cows tended to have fewer large follicles after superstimulatory treatment than young cows.     

Differences in ovarian aging patterns between races are associated with ovarian genotypes and sub-genotypes of the FMR1 gene

ABSTRACT: BACKGROUND: Ovarian aging patterns differ between races, and appear to affect fertility treatment outcomes. What causes these differences is, however, unknown. Variations in ovarian aging patterns have recently been associated with specific ovarian genotypes and sub-genotypes of the FMR1 gene. We, therefore, attempted to determine differences in how functional ovarian reserve (FOR) changes with advancing age between races, and whether changes are associated with differences in distribution of ovarian genotypes and sub-genotypes of the FMR1 gene. METHODS: We determined in association with in vitro fertilization (IVF) FOR in 62 young Caucasian, African and Asian oocyte donors and 536 older infertility patients of all three races, based on follicle stimulating hormone (FSH), anti-Mullerian hormone (AMH) and oocyte yields, and investigated whether differences between races are associated with differences in distribution of FMR1 genotypes and sub-genotypes. RESULTS: Changes in distribution of mean FSH, AMH and oocyte yields between young donors and older infertility patients were significant (all P < 0.001). Donors did not demonstrate significant differences between races in AMH and FSH but demonstrated significant differences in oocyte yields [F(2,59) = 4.22, P = 0.019]: Specifically, African donors demonstrated larger oocyte yields than Caucasians (P = 0.008) and Asians (P = 0.022). In patients, AMH levels differed significantly between races [F (2,533) = 4.25, P = 0.015]. Holm-Sidak post-hoc comparisons demonstrated that Caucasians demonstrated lower AMH in comparison to Asians (P = 0.007). Percentages of FMR1 genotypes and sub-genotypes in patients varied significantly between races, with Asians demonstrating fewer het-norm/low sub-genotypes than Caucasians and Africans (P = 0.012). CONCLUSION: FOR changes in different races at different rates, and appears to parallel ovarian FMR1 genotypes and sub-genotype distributions. Differences in ovarian aging between races may, therefore, be FMR1-associated.