Genetic Regulation of Physiological Reproductive Lifespan and Female Fertility.

There is substantial genetic variation for common traits associated with reproductive lifespan and for common diseases influencing female fertility. Progress in high-throughput sequencing and genome-wide association studies (GWAS) have transformed our understanding of common genetic risk factors for complex traits and diseases influencing reproductive lifespan and fertility. The data emerging from GWAS demonstrate the utility of genetics to explain epidemiological observations, revealing shared biological pathways linking puberty timing, fertility, reproductive ageing and health outcomes. The observations also identify unique genetic risk factors specific to different reproductive diseases impacting on female fertility. Sequencing in patients with primary ovarian insufficiency (POI) have identified mutations in a large number of genes while GWAS have revealed shared genetic risk factors for POI and ovarian ageing. Studies on age at menopause implicate DNA damage/repair genes with implications for follicle health and ageing. In addition to the discovery of individual genes and pathways, the increasingly powerful studies on common genetic risk factors help interpret the underlying relationships and direction of causation in the regulation of reproductive lifespan, fertility and related traits.

Prospects for FSH Treatment of Male Infertility.

CONTEXT: Despite the new opportunities provided by assisted reproductive technology (ART), male infertility treatment is far from being optimized. One possibility, based on pathophysiological evidence, is to stimulate spermatogenesis with gonadotropins. EVIDENCE ACQUISITION: We conducted a comprehensive systematic PubMed literature review, up to January 2020, of studies evaluating the genetic basis of follicle-stimulating hormone (FSH) action, the role of FSH in spermatogenesis, and the effects of its administration in male infertility. Manuscripts evaluating the role of genetic polymorphisms and FSH administration in women undergoing ART were considered whenever relevant. EVIDENCE SYNTHESIS: FSH treatment has been successfully used in hypogonadotropic hypogonadism, but with questionable results in idiopathic male infertility. A limitation of this approach is that treatment plans for male infertility have been borrowed from hypogonadism, without daring to overstimulate, as is done in women undergoing ART. FSH effectiveness depends not only on its serum levels, but also on individual genetic variants able to determine hormonal levels, activity, and receptor response. Single-nucleotide polymorphisms in the follicle-stimulating hormone subunit beta (FSHB) and follicle-stimulating hormone receptor (FSHR) genes have been described, with some of them affecting testicular volume and sperm output. The FSHR p.N680S and the FSHB -211G>T variants could be genetic markers to predict FSH response. CONCLUSIONS: FSH may be helpful to increase sperm production in infertile men, even if the evidence to recommend the use of FSH in this setting is weak. Placebo-controlled clinical trials, considering the FSHB-FSHR haplotype, are needed to define the most effective dosage, the best treatment length, and the criteria to select candidate responder patients.

Subfertility in androgen-insensitive female mice is rescued by transgenic FSH.

Androgens synergise with FSH in female reproduction but the nature of their interaction in ovarian function and fertility is not clear. In the present study, we investigated this interaction, notably whether higher endogenous FSH can overcome defective androgen actions in androgen receptor (AR)-knockout (ARKO) mice. We generated and investigated the reproductive function of mutant mice exhibiting AR resistance with or without expression of human transgenic FSH (Tg-FSH). On the background of inactivated AR signalling, which alone resulted in irregular oestrous cycles and reduced pups per litter, ovulation rates and antral follicle health, Tg-FSH expression restored follicle health, ovulation rates and litter size to wild-type levels. However, Tg-FSH was only able to partially rectify the abnormal oestrous cycles observed in ARKO females. Hence, elevated endogenous FSH rescued the intraovarian defects, and partially rescued the extraovarian defects due to androgen insensitivity. In addition, the observed increase in litter size in Tg-FSH females was not observed in the presence of AR signalling inactivation. In summary, the findings of the present study reveal that FSH can rescue impaired female fertility and ovarian function due to androgen insensitivity in female ARKO mice by maintaining follicle health and ovulation rates, and thereby optimal female fertility.

Unifying theory of adult resting follicle recruitment and fetal oocyte arrest.

One of the biggest mysteries of ovarian physiology is what controls the emergence of adult primordial follicles from the resting stage, and their steady depletion over the woman's lifetime. A related mystery is why do early oogonia begin meiosis in the fetus and then suddenly arrest for most of fetal and adult life. If fetal oocyte arrest did not occur after meiotic activation, there would be no oocytes left in the female baby by the time she is born. Similarly, without a steady controlled release in the adult ovary of resting follicles, the adult woman would run out of her eggs prematurely and have an early menopause. Could there be a similarity between what causes fetal oocyte arrest and what causes adult oocyte recruitment? The answer begins with the observation of a sudden massive recruitment of primordial follicles after human ovarian transplantation, and the embryologic discoveries about oocyte activation and the time of differentiation of cortex and medulla. The unifying theory is that ovarian cortical tissue pressure controls both fetal oocyte arrest and adult oocyte recruitment.

Menstruation, perimenopause, and chaos theory.

This article argues that menstruation, including the transition to menopause, results from a specific kind of complex system, namely, one that is nonlinear, dynamical, and chaotic. A complexity-based perspective changes how we think about and research menstruation-related health problems and positive health. Chaotic systems are deterministic but not predictable, characterized by sensitivity to initial conditions and strange attractors. Chaos theory provides a coherent framework that qualitatively accounts for puzzling results from perimenopause research. It directs attention to variability within and between women, adaptation, lifespan development, and the need for complex explanations of disease. Whether the menstrual cycle is chaotic can be empirically tested, and a summary of our research on 20- to 40-year-old women is provided.

Maturation and fertilization of nonhuman primate oocytes are compromised by oral administration of a cyclooxygenase-2 inhibitor.

OBJECTIVE: To determine if oral administration of a cyclooxygenase-2 (COX2) inhibitor affects oocyte nuclear maturation and fertilization in nonhuman primates. DESIGN: Laboratory research study. SETTING: Medical school. ANIMAL(S): Adult female cynomolgus monkeys (Macaca fascicularis). INTERVENTION(S): Monkeys received gonadotropins to stimulate multiple follicular development. An ovulatory dose of hCG was administered either alone or with oral celecoxib, a COX2 inhibitor. Oocytes were retrieved 36 hours later and exposed to sperm in vitro. MAIN OUTCOME MEASURE(S): Oocytes were assessed for nuclear status at retrieval, resumption of meiosis in vitro, and success of in vitro fertilization. RESULT(S): Treatment with hCG alone yielded oocytes that were primarily (72.9%) at the meiosis II (MII) stage of nuclear maturation; few oocytes were obtained at the germinal vesicle and germinal vesicle breakdown stages. Treatment with hCG and celecoxib yielded fewer mature (MII) oocytes (35.6%) and more oocytes at less mature stages compared with oocytes from monkeys treated with hCG alone. The majority (68.3 ± 15.9%) of MII oocytes from monkeys treated with hCG alone fertilized in vitro, compared with only 11.0 ± 5.9% of MII oocytes from monkeys treated with hCG and celecoxib. CONCLUSION(S): Oral administration of a COX2 inhibitor reduced the rate of oocyte nuclear maturation and the success of in vitro fertilization. Drugs of this class may block multiple essential steps in female reproduction and be effective contraceptives for women.

Luteotrophic effects of relaxin, chorionic gonadotrophin and FSH in common marmoset monkeys (Callithrix jacchus).

In early pregnant primates, relaxin (RLX) is highly upregulated within the corpus luteum (CL), suggesting that RLX may have an important role in the implantation of the blastocyst. Therefore, the aim of the present study was to investigate the local effects of RLX and gonadotrophins on the maintenance of the CL using an in vitro microdialysis system. CLs of common marmoset monkeys were collected by luteectomy during different stages of the luteal phase and early pregnancy. Each CL was perfused with either Ringer's solution alone or Ringer's solution supplemented with either porcine RLX (250, 500 and 1000 ng/ml) or gonadotrophins (50 IU/ml). Application of RLX provoked a significant luteal response of progesterone (P(4)) and oestradiol (E(2)) secretions during the mid-luteal phase (500 ng/ml: P(4) 54+/-42%, E(2) 24+/-11%; 1000 ng/ml: E(2) 16+/-13%), and especially during the late luteal phase (250 ng/ml: P(4) 53+/-10%; 500 ng/ml: P(4) 44+/-15%; 1000 ng/ml: P(4) 62+/-15%, E(2) 18+/-7%). The effects of RLX on steroid secretion were irrespective of the RLX dosages. While treatment with human chorionic gonadotrophin did not affect luteal steroid or RLX secretion, the application of FSH resulted in a significant increase in the secretion of both P(4) (20+/-8%) and E(2) (37+/-28%), and a prominent rise in RLX during early pregnancy. In conclusion, our results demonstrate that RLX and FSH have a luteotrophic function in the marmoset monkeys; moreover, FSH has a function beyond its traditional role just as a follicle-stimulating hormone.

An in vitro comparative study of follicle stimulating hormone (FSH) and activin A effects on the maturation of preantral follicle-enclosed oocytes from immature Syrian mice.

OBJECTIVES: It was aimed to investigate the effects of different doses of follicle stimulating hormone (FSH) and activin A on the growth and maturation of preantral mouse follicles during the in vitro culture. METHODS: Preantral follicles (90-100 microm in diameter) were harvested from 6-8 week-old Syrian mice and cultured in TCM199 culture medium for 6 days to see the effect of FSH and Activin A. Activin A concentrations in the range of 10-200 ng/ml were used, while 10, 50, 100, 150 and 200 mIU/ml FSH were used in the experiment. RESULTS: Activin A concentration of 100 ng/ml resulted in a significant increase in follicle diameter (170 microm) with the survival rate of 73% as compared to the control (100 microm and 25%, P<0.05). The number of oocytes matured and the percentage of germinal vesicle breakdown (GVBD) was 61 and 70%, respectively as compared to the control (20 and 29%, P<0.05). Follicle diameter (190 microm) and survival rate (85%) increased significantly in the presence of 100 mIU/ml of FSH as compared to the control (P<0.05). But, the administration of activin A+FSH increased the effect of both factors on follicular diameter (205 microm as compared to 100 microm in control, P<0.01). Follicle survival, oocyte maturation and GVBD rates were 91, 81 and 89%, respectively (P<0.01). CONCLUSION: These results have suggested that exposure to FSH and activin A before the formation of antral cavity had positive effect on follicle survival and oocyte robustness.

Relationships among self-rated tanner staging, hormones, and psychosocial factors in healthy female adolescents.

STUDY OBJECTIVE: Females are more likely than males to suffer from various mood and pain disorders. However, this female predominance does not appear to develop until puberty. The purpose of the present study was to examine the associations among hormone concentrations, self-rated Tanner staging and dysmenorrhea, and to determine whether various psychosocial factors modulate these relationships. DESIGN: As part of a larger prospective study of the influence of puberty on laboratory pain response, Tanner ratings, estradiol and follicle stimulating hormone concentrations, dysmenorrhea and psychosocial parameters including depression, anxiety, somatization, and socioeconomic status were observed. PARTICIPANTS: 124 healthy girls ages 8 to 18 were evaluated. MAIN OUTCOME MEASURE: There were significant correlations between pubertal status utilizing self-rated diagrams of Tanner stage and hormonal markers of pubertal development, specifically estradiol and FSH. Tanner stage but not estradiol was correlated with presence of dysmenorrhea. There was no effect of body mass index (BMI), socioeconomic status (SES), anxiety, depression, or somatization on presence or absence of painful menses. There was no correlation between BMI or SES and age of menarche. However, Tanner stage was correlated with BMI but not with SES. RESULTS AND CONCLUSIONS: Tanner self-staging is at least as accurate as estradiol and FSH measurements alone in evaluating healthy female adolescents' physical changes and menstrual pain. Tanner self-ratings are thus particularly useful in large, epidemiologic, or cross cultural studies where physical examination and blood sampling may not be feasible due to cost, access, or psychosocial barriers.

GnRHa flare and IVF pregnancy rates.

OBJECTIVES: GnRH agonist administered early in the menstrual cycle (flare) causes an endogenous discharge of FSH and LH. Flare has been used in conjunction with gonadotropin ovarian stimulation for IVF 'poor responders'. There is an ongoing controversy regarding whether flare protocols improve pregnancy rates in 'poor responders'. The current study was designed to compare a GnRHa flare protocol with long suppression GnRHa IVF in 'poor responders'. METHODS: Seventy-three newly diagnosed poor responders who failed long GnRHa suppression IVF attempts were compared retrospectively with 128 age-matched IVF patients previously known poor ovarian responders treated with a long GnRHa suppression protocol. 'Poor responders' consisted of patients with peak E(2) less than 1000 pg/ml and/or less than five mature follicles with diameter >15 mm on the day of hCG administration. Student's t-test was used to analyze the data and the chi-squared test was used to compare fertilization and pregnancy rates. RESULTS: The flare protocol produced higher peak E(2) levels (1647+/-747 vs. 720+/-258 mIU/ml, P<0.05) and a larger number of mature follicles (5.8+/-2.2 vs. 4.0+/-1.0 P<0.05) in the study vs. the control group. A 30% pregnancy rate was achieved during this second IVF attempt using GnRHa flare protocol in the study group vs. 37 in the control group (P>0.05, NS). CONCLUSIONS: A comparison between the flare protocol group and the age-matched control group of poor ovarian responders subject to down regulation protocol, revealed higher peak E(2) levels and more mature follicles, respectively. However, both groups yielded comparable pregnancy rates. The use of high dose gonadotropin treatment in our study groups seems to be the only explanation for their subsequent successful outcome. We concluded that GnRH agonist flare protocol does not result in better IVF outcome compared with long GnRH agonist suppression protocol in IVF poor responders.

Ovarian reserve, female age and the chance for successful pregnancy.

Both quantitative and qualitative factors regarding egg production are strong influences on IVF outcome. Markers of ovarian reserve such as basal FSH, clomiphene citrate challenge test (CCCT), and antral follicle counts are good predictors of the quantity of eggs which can be induced to grow. However, the quality of those eggs seems better predicted by the age of the women. In women past age 40, current success rates are low overall, even in those who good ovarian reserve who make many eggs; at this age, quantity does not make up for quality. By contrast, young women with limited ovarian reserve can have good success rates despite their limited cohort of eggs, because the eggs themselves are of high potential; here quality matters more than quantity. The ramifications of these observations include the following: diminished ovarian reserve should not be used as an exclusionary criterion in young women, because overall they still have satisfactory pregnancy rates, though their risk of cancellation is increased. In women past age 40, normal ovarian reserve testing is not reassuring because even reduced egg quality is likely to limit the opportunity for successful pregnancy no matter how many eggs are available.