The central thesis regarding the human ovaries is that, although primordial germ cells in embryonal ovaries are of extraovarian origin, those generated during the fetal period and in postnatal life are derived from the ovarian surface epithelium (OSE) bipotent cells. With the assistance of immune system-related cells, secondary germ cells and primitive granulosa cells originate from OSE stem cells in the fetal and adult human gonads. Fetal primary follicles are formed during the second trimester of intrauterine life, prior to the end of immune adaptation, possibly to be recognized as self-structures and renewed later. With the onset of menarche, a periodical oocyte and follicular renewal emerges to replace aging primary follicles and ensure that fresh eggs for healthy babies are always available during the prime reproductive period. The periodical follicular renewal ceases between 35 and 40 yr of age, and the remaining primary follicles are utilized during the premenopausal period until exhausted. However, the persisting oocytes accumulate genetic alterations and may become unsuitable for ovulation and fertilization. The human OSE stem cells preserve the character of embryonic stem cells, and they may produce distinct cell types, including new eggs in vitro, particularly when derived from patients with premature ovarian failure or aging and postmenopausal ovaries. Our observations also indicate that there are substantial differences in follicular renewal between adult human and rat ovaries. As part of this chapter, we present in detail protocols utilized to analyze oogenesis in humans and to study interspecies differences when compared to the ovaries of rat females.

The origin of oocytes and primary follicles in ovaries of adult mammalian females has been a matter of dispute for over 100 yr. The prevailing belief that all oocytes in adult mammalian females must persist from the fetal period of life seems to be a uniquely retrogressive reproductive mechanism requiring humans to preserve their gametes from the fetal period for several decades. The utilization of modern techniques during last 10 yr clearly demonstrates that mammalian primordial germ cells originate from somatic cell precursors. This indicates that if somatic cells are precursors of germ cells, then somatic mutations can be passed on to progeny. Mitotically active germline stem cells have been described earlier in ovaries of adult prosimian primates and recently have been reported to also be present in the ovaries of adult mice. We have earlier shown that in adult human females, mesenchymal cells in the ovarian tunica albuginea undergo a mesenchymal-epithelial transition into ovarian surface epithelium cells, which differentiate sequentially into primitive granulosa and germ cells. Recently, we have reported that these structures assemble in the deeper ovarian cortex and form new follicles to replace earlier primary follicles undergoing atresia (follicular renewal). Our current observations also indicate that follicular renewal exists in rat ovaries, and human oocytes can differentiate from ovarian surface epithelium in fetal ovaries in vivo and from adult ovaries in vitro. These reports challenge the established dogma regarding the fetal origin of eggs and primary follicles in adult mammalian ovaries. Our data indicate that the pool of primary follicles in adult human ovaries does not represent a static but a dynamic population of differentiating and regressing structures. Yet, the follicular renewal may cease at a certain age, and this may predetermine the onset of the natural menopause or premature ovarian failure. A lack of follicular renewal in aging ovaries may cause an accumulation of spontaneously arising or environmentally induced genetic alterations of oocytes, and that may be why aging females have a much higher chance of having oocytes with more mutations in persisting primary follicles.

Post-traumatic stress disorder (PTSD) overlaps major depression (MD) clinically, but differs with respect to treatment response and some biological markers. Sleep disturbances represent core features of PTSD and are also common in MD. Rapid eye movement sleep (REM) has been postulated to be involved in the pathophysiology of PTSD, and REM abnormalities occur in MD. Twenty-five patients with combat-related PTSD, 16 men with a principal diagnosis of MD, and 10 asymptomatic male controls were compared by polysomnography (PSG) under medication and substance-free conditions. Data were obtained from recordings made after an accommodation night. One subject from each group was excluded for significant apnea or limb movements. Sleep efficiency was decreased in the PTSD group compared to the MD and control groups. REM density was comparably increased in PTSD and MD groups, while the amount of REM sleep was reduced in PTSD compared to MD groups. These sleep measures were not significantly associated with co-morbid depression, substance-use disorder histories, or subclinical sleep apnea or limb movements within the PTSD group. These findings support sleep maintenance being impaired in chronic PTSD patients. Increased REM density in PTSD patients was replicated and was comparable to increases in the MD group. Divergence of REM time between these clinical groups suggests the possibility of different underlying mechanisms.

Oocyte generation in adult mouse ovaries by putative germ cells (PGCs) in bone marrow and peripheral blood has recently been proposed. It, however, remains unclear whether in laboratory rodents the PGCs reside in BM or the BM cells stimulate oogenesis from ovarian stem cells. We utilized immunoperoxidase staining to localize PGCs, oocytes, and BM derived cells in ovaries of adult (age 45-60 days) control and neonatally estrogenized rat females. In controls, BM derived cells accompanied emergence of PGCs from the ovarian surface epithelium (OSE) cells. The PGCs divided symmetrically, separated, and formed primordial follicles. A proportion (50%) of adult neonatally estrogenized rats lacked OSE. They exhibited occurrence of numerous BM derived cells and appearance of PGC precursors in the medulla. In juxtaposed deep ovarian cortex the emerging PGCs exhibited distinct pseudopodia and apparently migrated toward the mid cortex, where numerous primordial follicles were found. These observations indicate that BM derived cells accompany origination of PGCs from the OSE stem cells in normal adult rat females and from the medullary precursors in the adult neonatally estrogenized rats lacking OSE. An alternative origin of PGCs from the medullary region may explain why ovaries with destructed OSE are still capable of forming new primordial follicles.

The present study tested the hypothesis that if polycystic ovary syndrome (PCOS) results from activating the noradrenergic outflow to the ovary, unilaterally sectioning the superior ovarian nerve (SON) will result in ovulation by the denervated ovary, and the restoration of progesterone (P4), testosterone (T) and estradiol (E2) normal serum level. A single 2 mg dose of estradiol valerate (EV) to adult rats results in the development of a syndrome similar to the human PCOS. Ten-day old rats were injected with EV or vehicle solution (Vh) and were submitted to sham surgery, unilateral or bilateral sectioning of the SON at 24-days of age. The animals were sacrificed at 90 to 92 days of age, when they presented vaginal estrus preceded by a pro-estrus smear. In EV-treated animals, unilateral sectioning of the SON restored ovulation by the innervated ovary and unilateral or bilateral sectioning of the SON normalized testosterone and estradiol levels. These results suggest that aside from an increase in ovarian noradrenergic tone in the ovaries, in the pathogenesis of the PCOS participate other neural influences arriving to the ovaries via the SON, regulating spontaneous ovulation. Changes in P4, T and E2 serum levels induced by EV treatment seem to be controlled by neural signals arising from the abdominal wall and other signals arriving to the ovaries through the SON, and presents asymmetry.

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The ovaries' innervation arrives via the superior ovarian nerve, which originates from the celiac ganglion. Using True Blue as an antidromic marker, the present study analyzed the changes in the anatomical relation between each ovary and the prevertebral celiac-superior mesenteric ganglia during the estrous cycle. The number of labeled neurons increased from the day of diestrus 1 to the day of proestrus. The largest number of labeled cells was observed when tracer was injected into the left ovary on proestrus. The number of labeled cells was significantly higher when the tracer was injected into the left ovary on proestrus than when it was done in the right one. When tracer was injected into the left ovary, the average labeled area of cells increased significantly from diestrus 1 to proestrus, and declined at estrus. In contrast, when True Blue was injected into the right ovary, the average labeled area was similar in diestrus 1 and diestrus 2, and the values increased in proestrus and estrus. The results indicate an apparent asymmetry in the activity of neural connections between ovaries and the prevertebral celiac-superior mesenteric ganglia, and that the number of active neurons of these connections varies during the estrous cycle.

(2008) Mammalian neo-oogenesis and expression of meiosis-specific protein SCP3 in adult human and monkey ovaries, Cell Cycle, 7:5, 683-686,