Overview of the biological aspects of the fertile period

The fertile period of the human menstrual cycle consists of those days on which sexual intercourse can result in a pregnancy. Its duration is determined by the functional life span of the gametes within the female reproductive tract. Various mechanisms control gamete transport and survival in the reproductive tract of the human female. The ovarian hormones estradiol and progesterone have an important role in regulating these mechanisms. The nature of cervical mucus and its governing influences on sperm transport and survival following coitus are of prime importance in defining the fertile days of the menstrual cycle. Man's early concepts of the fertile period were often based on erroneous theories of the female reproductive cycle. It is only since the late 1920's that a true understanding of ovulation and the menstrual cycle has evolved. Current approaches in natural family planning to recognizing the fertile and infertile days of the menstrual cycle are discussed and evaluated.     

Cervical mucus. Spontaneous or hormone induced quantitative changes

Variations in the quantity of cervical mucus secreted during the menstrual cycle and under estrogenic stimulation were studied in 7 women aged 25-30 years with normal biphasic cycles. Quantities varied during the cycle, gradually increasing during the preovulatory phase and reaching a maximum the day of ovulation. Dry weight of cervical mucus did not vary, however. In women treated with mixtures of conjugated estrogens or with ethinyl estradiol, mucus secretion rapidly reached levels comparable to ovulatory levels, and remained at these levels until treatment was stopped. It is suggested that cervical mucus levels may provide a simple and reliable index of ovarian function and particularly of ovulation.     

Menstrual bleeding, hormones, and the menopausal transition

The perimenopause represents a time of great variability in reproductive hormone dynamics and menstrual cycle characteristics, but age-related changes begin prior to this. These changes include a gradual increase in follicle stimulating hormone (FSH) levels, a gradual shortening of mean cycle length, and a decline in the number of ovarian follicles. The onset of perimenopause is thought to occur with the first break in menstrual cycle regularity. With the onset of cycle irregularities, hormone concentrations exhibit large increases in variability and unpredictability, rather than following a gradual trend with the approach of menopause, the final menstrual period. Abrupt spikes in gonadotropins and considerable fluctuations in estradiol and inhibin levels have been observed. Variability is the norm in the perimenopause, with hormonal fluctuations contributing to the visible signs of menstrual cycle and bleeding irregularities. To date there is no single endocrine indicator to serve as an adequate marker of menopausal status. This paper provides a review of research to date on patterns of reproductive hormones and menstrual bleeding during the menopausal transition. An understanding of such patterns can contribute to a better ability to distinguish "normal" transitional events from more serious pathology.     

Pain in endometriosis: effectiveness of medical and surgical management

PURPOSE OF REVIEW: Endometriosis is a common cause of chronic pelvic pain and has a detrimental effect on the quality of life for women affected with the condition. It is also clear that early diagnosis with prompt effective management does not always occur. This review will discuss the medical and surgical treatment options and support conclusions with randomized double blind placebo-controlled studies where possible. RECENT FINDINGS: Assessment of the pelvic pain associated with endometriosis can be categorized according to its relation to the menstrual cycle. Dysmenorrhoea and ovulatory pain occur with cyclical changes, as compared with chronic non-cyclic pain and deep dyspareunia. Dyskesia and urinary pain may have a relation to the menstrual cycle. The severity of pain symptoms, as well as the effect on the woman's quality of life, should be quantified. The preoperative symptoms can be compared with the operative findings and the stage of endometriosis according to the revised American Fertility Score. SUMMARY: Review of the current literature demonstrates that a combined medical and conservative surgical approach is beneficial for most women with endometriosis associated pelvic pain.     

Effect of prednisone on plasma testosterone levels and on duration of phases of the menstrual cycle in hyperandrogenic women.

A group of 106 women of reproductive age with laboratory and clinical evidence of hyperandrogenism was treated with prednisone. The daily dosage varied between 7.5 and 10 mg. Ovulatory activity was assessed prior to and during therapy by basal body temperature and observation of changes in the cervical os and cervical mucus. Plasma testosterone levels were significantly suppressed by prednisone therapy. This was associated with initiation of ovulatory activity in 5 of 14 (35.7%) amenorrheic patients and 10 of 11 (90.9%) anovulatory patients. In 81 ovulatory patients, prednisone therapy resulted in statistically significant shortening of the follicular phase and lengthening of the luteal phase of the menstrual cycle. The mean length of the menstrual cycle was unchanged. Significant correlations between percentage suppression of plasma testosterone and shortening of the follicular phase or lengthening of the luteal phase were observed. Suppression of plasma testosterone by prednisone was maximal after 2 months of treatment, while the effect on the phases of the menstrual cycle was progressive with duration of treatment. The effects of prednisone at daily dosages of 7.5 or 10 mg were not significantly different. These results suggest that prednisone therapy in hyperandrogenic women exerts an effect on both phases of the menstrual cycle, possibly related to suppression of plasma testosterone levels.     

Adipositas und Kinderwunsch

Obesity is a frequent health disorder in industrialized countries. In this review article the neuroendocrine regulation of food intake, the association of obesity with general inflammation and the occurrence of endocrine and reproductive disorders in women are discussed. It is well established that overweight women have a higher risk of ovulatory disorders and infertility. Furthermore, data from treatment with assisted reproductive techniques (ART) have shown that the likelihood of treatment success is drastically reduced in obese patients. Weight reduction can normalize menstrual cycles and increase the chance of spontaneous or assisted conception. Gradual and sustained weight loss is preferable as crash dieting can negatively impact reproductive function. Overweight patients need an integrated management including advice for physical activity and nutritional advice.     

Cervical mucus peroxidase is a reliable indicator for ovulation in humans

This study was designed to establish whether fluctuation in cervical mucus peroxidase concentration correlates with the cyclic pattern of the menstrual cycle hormones in the human female. Forty healthy, normal-cycling women between the ages of 19 and 29 years were chosen for the study. Blood samples and cervical mucus were collected on days 6, 9 through 15, and 17 through 19 of the menstrual cycle for three consecutive cycles in each volunteer. Blood estrogen, progesterone, follicle-stimulating hormone, and luteinizing hormone levels were quantitated by radioimmunoassay, and cervical mucus peroxidase concentrations were measured spectrophotometrically. The data showed that in the typical menstrual cycle the mucus peroxidase peak was reached immediately prior to the luteinizing hormone/follicle-stimulating hormone surge and coincided with the estrogen peak. Consistent data in three consecutive menstrual cycles in each volunteer led us to postulate that the mucus peroxidase peak during the menstrual cycle precedes the ovulatory period in the normal healthy woman.     

Technique for locating the start of the ovarian cycle in women who have no uterus

A technique was required to identify the start of the ovarian cycle in hysterectomized women. Daily observations of the excretion of pregnanediol relative to creatinine by menstruant women during the course of 15 ovulatory cycles have been used to establish (a) that the centre of the pregnanediol peak can be located from as few as two pregnanediol measurements per week and (b) that this centre precedes the start of menstruation by 7.14 +/- 0.07 days (mean +/- SEM). With this information the onset of menstrual bleeding in an ovulatory cycle can be predicted. Comparison of the prediction with the observation of menstrual onset in 50 cycles gave a mean deviation of 0.276 +/- 0.109 days with a maximum deviation of 1.9 days. In three women observed before and after hysterectomy there was no significant change in the length of the ovarian cycle. It is concluded that this procedure provides a way of identifying the start of a new ovarian cycle in women who have no uterus. The procedure is only applicable to ovulatory cycles.     

In vitro sperm capacitation and transcervical intrauterine insemination for the treatment of refractory infertility: phase I

Fourteen couples with long-standing infertility, associated with cervical mucus insufficiency, male subfertility, or unexplained infertility, participated in a therapeutic trial. The female partners, who were all ovulatory, were given human menopausal gonadotropin from day 2 of the menstrual cycle (controlled ovarian hyperstimulation). When plasma estradiol concentrations reached 1000 to 2000 pg/ml, human chorionic gonadotropin was given. Approximately 32 hours and again 70 hours thereafter, a masturbation specimen of the husband's sperm was capacitated in vitro and inseminated transcervically into the uterine cavity. Five women (35%) conceived following a single cycle of treatment. Four of the pregnancies are currently progressing normally; one ended in a spontaneous miscarriage in the early first trimester. The potential role of in vitro sperm capacitation and transcervical intrauterine insemination in the treatment of refractory infertility unrelated to female organic pelvic disease is discussed.     

Benefits and risks of ovarian function and reproduction for cancer development and prevention

Ovarian function and menstrual cycle disturbances, pregnancy, and reproductive medicine procedures can either increase gynecological cancer risk or prevent cancer development. For ovarian cancer development, there are two hypotheses, which are connected with ovulation and gonadotropin secretion. Most of the ovarian cancers seem to be derived from displaced ovarian surfice epithelial cells. One year of ovulatory cycles increases the ovarian cancer risk by 6%. Ovulation between 22 and 29 years of age causes the highest risk increase per year. In contrast, progesterone or progestins appear to create protection. Lifestyle can affect or modify ovarian cancer risk. Breast cancer risk is very much related to age of menarche and menopause, pregnancy, and breast feeding. All of which are related to ovarian function and progestogenic impact that translates either into breast cancer risk increase or decrease. This is modified by body mass index, physical activity, and lifestyle in general. The risk of endometrial cancer is most closely related to endogenous progesterone during the menstrual cycle and pregnancy or by exogenous progestogens as in oral contraceptives. These effects are progestogen dose and time dependent. Endometrial cancer risk can also be increased by estrogen-producing tumors or long-term estrogen treatment.     

Female obesity in life cycle

Adipose tissue undergoes aging process as other tissues and both of quantity and distribution of body fat vary with an older age. Obesity in which body fat accumulates excessively is also influenced by aging. For evaluation of obesity, Kaup's index was most correlated with the thickness of fat tissues. Waist hip ratio (WHR) increased with an older age. From the view point of menarche, a role of body fat in reproductive function was evaluated. Ratio of body fat to body weight in the menarcheal age was between 22 and 24%. The ratio of non-menarcheal girls was smaller than that of the menarcheal of the same age. A proper amount of body fat seemed to be necessary for onset of ovarian function to menstruate. On obesity in reproductive age, two topics were discussed. One was the mechanism of menstrual disorders in obese women, the other complications of pregnancy. Concerning the central mechanism of menstrual disorders, hypothalamic disorders cause overfeeding to obesity and gonadal dysfunction to menstrual disorders because feeding center and control center of gonadal system are located in hypothalamus. For the peripheral mechanism, accumulation of fat soluble steroid hormones in the fat tissue disturbs cyclic state of endocrine fluctuation, and extraglandular estrogen production from androgen by aromatase in adipose tissue causes hyperestrogenism. Besides, hyperandrogenism in obese women was stressed on for a causing factor of menstrual disorders in obesity. Hyperandrogenism of obese women with menstrual disorders was associated with high level of cortisol and was corrected by weight reduction to regularize menstrual cycle.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of cytokines in polycystic ovarian syndrome

Abstract

Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in women of reproductive age. Inflammation has been implicated in the metabolic disturbances and menstrual irregularities, which characterize this condition. Various inflammatory proteins have been investigated in women with PCOS including C-reactive protein, interleukin-6, interleukin-18 and tumor necrosis factor-alpha. The data is suggestive of the presence of a chronic low-grade inflammatory state, especially in case of obesity, insulin resistance and hyperandrogenism. Targeting this inflammatory process by means of anti-inflammatory agents might be a therapeutic alternative to the current treatment.     

An algorithm for treatment of infertile women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common condition with both a reproductive and metabolic phenotype. Women with PCOS often seek care because of infertility or menstrual cycle irregularities that result from chronic anovulation interspersed with occasional ovulatory cycles. Initially, it is important to delineate a differential diagnosis for oligo- or amenorrhea and to evaluate for disorders that may “masquerade” as PCOS. If fertility is a desired goal, then it is critical to optimize health conditions that impact fertility and gestation. Lifestyle modifications, including nutritional counseling and weight loss, should be a part of all treatment plans. Even minimal (5%) weight loss in obese women with PCOS improves both ovulation and pregnancy rates. The first line of treatment for ovulation induction remains the selective estrogen receptor modulator (SERM) clomiphene citrate. The role of insulin sensitizers, particularly metformin, remains unclear. A recent consensus panel recommended against its routine use in the absence of an elevated glucose or hemoglobin A1c. If a woman fails to achieve pregnancy after a trial of weight loss and six ovulatory cycles induced by clomiphene citrate, then ovulation induction with exogenous gonadotropin, with or without timed intrauterine insemination, or in vitro fertilitization, is a reasonable next step. Women with PCOS are particularly prone to excessive follicle development and are at increased risk for ovarian hyperstimulation syndrome (OHSS). Although limited data exist comparing approaches to ovulation induction or controlled ovarian stimulation in women with PCOS, the American Society for Reproductive Medicine recommends the use of “step-up” or “step-down” protocols in which a low dose of exogenous FSH or combined gonadotropins are employed in an attempt to constrain ovarian responsiveness. In vitro fertilization allows for the transfer of only one embryo or for cryopreservation of all embryos with subsequent transfer of a single embryo in a subsequent cycle without ovarian stimulation. Countless questions regarding pathogenesis and treatment of PCOS create opportunity for basic and clinical research and for refinement of existing therapeutic approaches.     

Ovarian hyperstimulation and follicular aspiration. Effect on ovulatory function.

The return of normal function of the reproductive axis immediately after hyperstimulation and follicular aspiration is of both physiologic and clinical interest. These cycles may be utilized for the replacement of cryopreserved embryos, for repeated ovarian stimulation or for any alternative treatment that relies upon normal ovulatory function. Thirty-five women were randomly assigned to be monitored in the first (n = 11), second (n = 13) or third (n = 11) menstrual cycle after in vitro fertilization (IVF). Five of 35 patients (14.3%) failed to ovulate, 2 in each of the first and second menstrual cycles and 1 in the third cycle after IVF. Six (20%) ovulatory cycles demonstrated luteal phase deficiencies. The defective luteal phases were evenly distributed between cycles immediately after IVF and those more remote in time from the procedure.     

Apoptosis in the human ovary

Programmed cell death or apoptosis is an essential component of human ovarian function and development. During early fetal life approximately 7 x 10(6) oocytes are formed in the human ovary. However, the number of oocytes is dramatically reduced already before birth through apoptotic cell death. In reproductive life, a number of primordial follicles start growing during each menstrual cycle. Usually only one will ovulate and the fate of the rest of the follicles is atresia through the mechanism of apoptosis. Ultimately, only around 400 follicles will ovulate during a woman's reproductive life. After ovulation, the dominant follicle forms the corpus luteum, a novel endocrine gland that is responsible for the production of progesterone and maintenance of endometrium during early pregnancy. If pregnancy does not occur, corpus luteum action must cease so that new follicles can resume growing during the next menstrual cycle. Apoptosis is also responsible for corpus luteum regression in the human ovary. In recent years, new knowledge of the role and regulation of apoptosis in the ovary has been acquired through the use of knockout and transgenic animals. Apoptosis seems to be the mechanism that makes the female biological clock tick. The following review will discuss the role of apoptosis and its regulation of human ovarian function.     

Metabolic effects of obesity on reproduction

Obese women are characterized by similar comorbidities to men, particularly type 2 diabetes mellitus and cardiovascular diseases. Moreover, they also develop some specific problems, including fertility-related disorders and some hormone-dependent forms of cancer. The relationship between excess body fat and reproductive disturbances appears to be stronger for early-onset obesity. Early onset of obesity, particularly during adolescence, favours the development of menses irregularities, chronic oligo-anovulation and infertility in adulthood. Moreover, obesity in women can increase the risk of miscarriage and impair the outcome of assisted reproductive technologies. The main factor implicated in the association between obesity and fertility-related disorders is insulin excess, which accompanies insulin resistance. Hyperinsulinaemia may be directly responsible for the development of androgen excess, through its effects in reducing sex hormone-binding globulin synthesis and circulating concentrations, and in stimulating ovarian androgen production rates. Androgen excess, in turn, represents one of the major factors leading to altered ovarian physiology and associated ovulatory disturbances. Obesity-associated hyperleptinaemia may represent an additional factor involved in anovulation, not only through the induction of insulin resistance, but also through a direct impairment of ovarian function.     

Menstrual dysfunction

Menstrual dysfunction is common, with approximately 9–30% of reproductive-aged women presenting with menstrual irregularities requiring medical evaluation. The causes are diverse and multiple treatment options are available. Appropriate management relies on relevant investigation and accurate diagnosis. This article reviews the most common causes of menstrual dysfunction using case histories for illustration. The conditions covered in this review include menstrual dysfunction around the time of menarche, ovulatory and anovulatory dysfunctional uterine bleeding, polycystic ovarian syndrome, uterine fibroids and dysfunctional bleeding around the perimenopause. Appropriate investigations and current management strategies are also discussed.     

Environmental influence on reproductive health.

A rise in industrialization and the consequent environmental pollution, an increase in the use of synthetic chemicals and repeated exposure to hazardous compounds at the workplace and at home adversely affects reproductive health. Biohazardous compounds, some of which act as endocrine disrupters, are being increasingly implicated in infertility, menstrual irregularities, spontaneous abortions, birth defects, endometriosis and breast cancer. In some cases, women are at a greater risk than men, especially with the rise in environmental estrogens. Only a fraction of these chemicals have been adequately examined for toxicity and for synergistic effects due to multiple exposures. There is a need for a greater awareness and vigilance of the effects of environmental pollution on reproductive health.     

Polymorphisms of anti-Müllerian hormone signaling pathway in healthy Singapore women: population differences,endocrine effects and reproductive outcomes

In order to study the association of genetic polymorphisms of anti-Müllerian hormone (AMH) signaling pathway with endocrine changes and pregnancy outcomes, a total of 213 women of reproductive ages were recruited according to our inclusion and exclusion criteria between November 2011 and September 2014 in Singapore. Genotyping studies were performed using a minor groove binder primer/probe Taqman assay. The allele frequencies of the AMH Ile⁴⁹Ser and AMHR2 ?482A?>?G polymorphisms were analyzed in relation to female reproductive hormone levels, ovarian parameters, menstrual cycle lengths and pregnancy outcomes. AMH Ser allele frequency and AMHR2 G allele frequency of our Singapore population were compared with those of other populations reported in HapMap. The genotype distributions and allele frequencies for the AMH Ile⁴⁹Ser and AMHR2 ?482A?>?G polymorphisms were not associated with estradiol (E2) levels, ovarian parameters, menstrual cycle length, or pregnancy outcomes in our cohort. Our findings suggest that genetic variants in the AMH signal transduction pathway have population differences but do not appear to have significant effects on ovarian, endocrine, metabolic parameters and reproductive outcomes.