Menstrual irregularities in adolescents: hormonal pattern and ovarian morphology

The endocrine pattern and ovarian characteristics of 110 healthy adolescents with menstrual irregularities were investigated during the early follicular and premenstrual phases and were compared to those of 14 adolescents with regular menstrual cycles and 20 adults. Over a period of six gynecological years a low ovulation rate (49%) was found in the group of subjects with irregular cycles and regular ovulation was noted in only a few subjects. Slight differences in endocrine pattern and ovarian morphology were observed between the group of adolescents with regular cycles and the group of adults. In contrast, adolescents with irregular menses had higher mean values of luteinizing hormone (LH), testosterone (T), and androstenedione (A) in comparison with the other two groups both in follicular and premenstrual phases. Nearly 35% of the subjects with irregular cycles had levels of T, A and LH which were higher than the upper limit of the adult normal range. Lower progesterone (P), 17P and oestradiol values were observed in the premenstrual phase. Within the group of subjects with irregular menses, LH levels were higher in anovulatory than in ovulatory cycles, in both phases of the cycle, while T and A levels were higher and prolactin levels were lower in the premenstrual phase of anovulatory cycles. Unlike irregular anovulatory cycles, irregular ovulatory cycles showed a hormonal pattern similar to that found in the adult group. By ultrasound evaluation, a high percentage of subjects with irregular menses had multicystic ovaries (57.9%) and the mean (+/- SEM) ovarian volume was higher (10.6 +/- 0.5 cm3) than that found in adolescents with regular menses (6.7 +/- 0.8 cm3) and in the adult group (7.7 +/- 0.3 cm3). With the increase in frequency and continuity of ovulation an improvement in the direction of adult volume and ovarian structure was observed. Besides the endocrine similarity the data emphasize the striking similarity, already documented by histological studies, between pubertal ovaries and those seen in micropolycystic ovary syndrome. These endocrine and ovarian characteristics are typical of a large number of adolescents with irregular menstrual cycles: these features may be representative of a developmental step toward adult normality, although the possibility of a pathological evolution for some subjects cannot be excluded.     

Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism.

Polycystic ovaries were defined with ultrasound imaging in a series of 173 women who presented to a gynaecological endocrine clinic with anovulation or hirsutism. Polycystic ovaries were found in 26% of women with amenorrhoea, 87% with oligomenorrhoea, and 92% with idiopathic hirsutism--that is, hirsutism but with regular menstrual cycles. Fewer than half the anovulatory patients with polycystic ovaries were hirsute, but in 93% of cases there was at least one endocrine abnormality to support the diagnosis of polycystic ovaries--that is, raised serum concentrations of luteinising hormone, raised luteinising hormone: follicle stimulating hormone ratio, or raised serum concentrations of testosterone or androstenedione. This study shows that polycystic ovaries, as defined by pelvic ultrasound, are very common in anovulatory women (57% of cases) and are not necessarily associated with hirsutism or a raised serum luteinising hormone concentration. Most women with hirsutism and regular menses have polycystic ovaries so that the term "idiopathic" hirsutism no longer seems appropriate.     

Menstrual disorders associated with hyperprolactinemia

In hyperprolactinemia, menstrual disorders ranging from irregular bleeding, insufficient luteal phase, spanio-amenorrhea, to anovulatory cycles and amenorrhea, are frequent. Multiple mechanisms are involved in these disorders: hyperprolactinemia could act at the hypothalamic level on LHRH secretion and directly on LH and sex steroids secretion. Hyperprolactinemia could also act by impairing fertilization or implantation at the endometrial level.     

The enigma of "shock".

The hormonal contraceptives seem to have no direct effect on cervical carcinoma or dysplasia, but they are responsible for the appearance of glandular adenomatous hyperplasia of the endocervix.The long-term use of progestins is responsible for the inactive appearance of the ovaries, with thickening of the tunica albuginea, rare follicle growth, occasional fibrosis of the stroma and a decreased DNA formation.After stopping oral and injectable hormonal contraceptives the first cycle is usually long and cases of amenorrhea have been reported. The causes of secondary amenorrhea probably lie in the hypothalamus and/or the ovaries.The time lapse between cessation of oral contraception and conception is between 5.8 and 6.5 months. No increase in abortion has been noted, but abortuses and ova have an increased polyploid tendency and incidence of chromosome breaks. Further investigations of larger series are necessary to provide definite proof. Meanwhile it would seem advisable that after cessation of hormonal contraception there should be a time lapse of six to eight months before a patient becomes pregnant.     

Shifts in gonadotropin and steroid levels that precede anestrus in female golden hamsters exposed to a short photoperiod

Female golden hamsters exposed to short photoperiods become anestrous and exhibit daily surges of gonadotropins and progesterone. Since little is known about the transition between the cycling and anovulatory states, the following experiments were done to determine whether there are hormonal changes that precede cessation of estrous cyclicity. Females killed on the morning of estrus, up to the tenth estrous cycle in short days, showed no hormonal or ovarian morphologic evidence of changes in reproductive function. When assessed on the afternoon of estrus, however, serum levels of luteinizing hormone and progesterone increased significantly before vaginal and ovarian cyclicity ceased. Females sampled in both the morning and afternoon at increasing durations since their last vaginal estrus revealed that maximal daily surges of both gonadotropins and progesterone were not consistently manifested until the vaginal cycle had been absent for 2 weeks. By then, estrogen levels and uterine weights were low and ovaries showed hypertrophied interstitia and arrested follicular growth. We have demonstrated that there are hormonal changes in females before the loss of the vaginal cycle and onset of major daily hormonal surges. Our results suggest that alterations in feedback relationships between steroid hormones and gonadotropins may precede photoperiod-induced anestrus.     

Menstrual variation in salivary testosterone among regularly cycling women.

To determine menstrual variation in salivary testosterone daily saliva samples were collected from 20 regularly cycling women. Results indicate that the menstrual profile of salivary testosterone for both ovulatory and anovulatory cycles exhibits local peaks during the follicular phase and at midcycle, as well as a luteal trough. However, the testosterone profile for anovulatory cycles exhibited a later midcycle peak than that for ovulatory cycles, as well as significantly higher average testosterone levels. These results extend the observation of a midcycle peak in serum testosterone to saliva and suggest the existence of a follicular peak in unbound testosterone coincident with the early androgen production of a cohort of developing follicles.     

Correlation of perineal detumescence and ovulation in the pigtail macaque (Macaca nemestrina).

A study was made of the relationship between ovulation and perineal detumescence in the pigtail macaque (Macaca nemestrina). Daily laparoscopic examation of both ovaries was made beginning on the 9th day of the menstrual cycle. The appearance of the ovaries was recorded and photographs were taken of the perineum and ovaries. This procedure was repeated daily until the 5th day after ovulation or until the 20th day of the menstrual cycle for presumed anovulatory cycles. The time at which ovulation occurred was correlated with first signs of detumescence, both events occurring within a 24-hour period.     

Pure gonadal dysgenesis. Case report with unusual anatomical and endocrine findings

The syndrome of pure gonadal dysgenesis (PGD) cannot always easily be distinguished from other disorders of gonadal development. Relations are evident with Turner's syndrome, females with hypoplastic ovaries, male pseudohermaphroditism, mixed gonadal dysgenesis and the vanishing testes syndrome. The case is reported of a 40 year old female with primary amenorrhea, alopecia, eunuchoid features, XY karyotype with normal breast development and sexual hair after estrogen therapy. On laparotomy streak ovaries were found at ovarian site. Pathohistological examination revealed on the left side wolffian duct remnants such as ductuli deferentes and epididymis besides sparse Leydig-(hilus-)cells and on the right side only a rudimentary fallopian tube with subendothelial accumulation of hyperplastic Leydig-(hilus-)cells. Serum-testosterone elevation above the normal female range (630 ng/dl) persisted following gonadectomy (151 ng/dl). Ectopic Leydig-(hilus-)cells were regarded responsible for the continuing testosterone production. The present case lies on borderline between PGD and mixed gonadal dysgenesis because remnants of wolffian duct derivatives suggest unilateral fetal testicular activity; classification as PGD however was justified in purely female body features and lacking evidence of testicular tissue.     

Precocious puberty with congenital hypothyroidism

Precocious puberty associated with profound hypothyroidism is a rare condition. It is usually characterized by breast development, vaginal bleeding, lack of pubic hair and delayed bone age. Multicystic ovaries in profound hypothyroid patients with precocious puberty have been rarely described. Vaginal bleeding in adolescent girls should be considered as a clinical significance particularly when it is prolonged or heavy, whereas vaginal bleeding in younger girls, regardless of its duration and quantity is always of clinical importance. Bleeding in such patients could be caused by local causes such as vulvar or vaginal lesions, or it could be from the endometrium, which is usually a sign of systemic hormonal disturbance [1]. In this report a rare case of vaginal bleeding, large, multicystic ovaries, precocious puberty and delayed bone age in a 7 years old girl with profound hypothyroidism is described.     

Regulation of testicular function in men: implications for male hormonal contraceptive development

In the adult male, the testes produce both sperm and testosterone. The function of the testicles is directed by the central nervous system and pituitary gland. Precise regulation of testicular function is conferred by an elegant feedback loop in which the secretion of pituitary gonadotropins is stimulated by gonadotropin hormone-releasing hormone (GnRH) from the hypothalamus and modulated by testicular hormones. Testosterone and its metabolites estradiol and dihydrotestosterone (DHT) as well as inhibin B inhibit the secretion of the gonadotropins both directly at the pituitary and centrally at the level of the hypothalamus. In the testes, LH stimulates testosterone synthesis and FSH promotes spermatogenesis, but the exact details of gonadotropin action are incompletely understood. A primary goal of research into understanding the hormonal regulation of testicular function is the development of reversible, safe and effective male hormonal contraceptives. The administration of exogenous testosterone suppresses pituitary gonadotropins and hence spermatogenesis in most, but not all, men. The addition of a second agent such as a progestin or a GnRH antagonist yields more complete gonadotropin suppression; such combination regimens effectively suppress spermatogenesis in almost all men and may soon bring the promise of hormonal male contraception to fruition.     

Changes in ovarian follicles following acute infection with bovine viral diarrhea virus

Bovine viral diarrhea virus (BVDV) has been associated with several reproductive problems in cattle, including poor fertility, early embryonic deaths, abortion and congenital anomalies. Little is known about the cause of poor fertility in cows acutely infected with BVDV. The purpose of this study was to identify changes in ovarian function following acute infection with noncytopathic BVDV. The ovaries of 5 BVDV sero-negative and virus-negative pubertal heifers were monitored daily for 4 consecutive estrous cycles. The position and diameter of all follicles (> 5 mm) and luteal structures were recorded. Daily plasma samples were collected to measure peripheral progesterone and estradiol levels. Each heifer was infected intranasally with noncytopathic BVDV following ovulation of the second estrous cycle. The maximum diameter and growth rate of dominant anovulatory and ovulatory follicles were significantly reduced following acute BVDV infection. Similarly, the number of subordinate follicles associated with both the anovulatory and ovulatory follicle was reduced following infection. There were no significant differences in other follicle or luteal dynamic parameters or in peripheral progesterone or estradiol levels. Ovarian follicular growth was different during the first 2 estrous cycles following acute infection with BVDV when compared with the 2 estrous cycles preceding infection. These differences may be important in explaining reduced fertility in herds with acute BVDV infection.     

Impact of electro-acupuncture and physical exercise on hyperandrogenism and oligo/amenorrhea in women with polycystic ovary syndrome: a randomized controlled trial

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenism, oligo/amenorrhea, and polycystic ovaries. We aimed to determine whether low-frequency electro-acupuncture (EA) would decrease hyperandrogenism and improve oligo/amenorrhea more effectively than physical exercise or no intervention. We randomized 84 women with PCOS, aged 18-37 yr, to 16 wk of low-frequency EA, physical exercise, or no intervention. The primary outcome measure changes in the concentration of total testosterone (T) at week 16 determined by gas and liquid chromatography-mass spectrometry was analyzed by intention to treat. Secondary outcome measures were changes in menstrual frequency; concentrations of androgens, estrogens, androgen precursors, and glucuronidated androgen metabolites; and acne and hirsutism. Outcomes were assessed at baseline, after 16 wk of intervention, and after a 16-wk follow-up. After 16 wk of intervention, circulating T decreased by -25%, androsterone glucuronide by -30%, and androstane-3α,17β-diol-3-glucuronide by -28% in the EA group (P = 0.038, 0.030, and 0.047, respectively vs. exercise); menstrual frequency increased to 0.69/month from 0.28 at baseline in the EA group (P = 0.018 vs. exercise). After the 16-wk follow-up, the acne score decreased by -32% in the EA group (P = 0.006 vs. exercise). Both EA and exercise improved menstrual frequency and decreased the levels of several sex steroids at week 16 and at the 16-wk follow-up compared with no intervention. Low-frequency EA and physical exercise improved hyperandrogenism and menstrual frequency more effectively than no intervention in women with PCOS. Low-frequency EA was superior to physical exercise and may be useful for treating hyperandrogenism and oligo/amenorrhea.     

Association of uterine edema with follicle waves around the onset of the breeding season in pony mares

During spring transition, when estrus may be exhibited for prolonged periods, it is important for veterinarians and stud farm personnel to be able to predict whether a large follicle will ovulate or regress. It is thought that the presence of ultrasonically detectable uterine edema indicates that a follicle will ovulate, however, there is little evidence to support this. In the present study, 16 mares were regularly examined by transrectal ultrasonography to follow growth and regression of follicles from seasonal anestrus in February until second ovulation. Blood samples were collected daily for measurement of estradiol concentrations when a large ovarian follicle was present. Estrous-like uterine edema was detected during 7 of 11 (64%) anovulatory follicle waves, in 12 of 14 (86%) mares before their first ovulation, and in 100% of mares before their second ovulation. Uterine edema was first detected 43+/-6.7 days before first ovulation. Large anovulatory follicles tended to be present for longer periods of time than ovulatory follicles. Uterine edema was present for a significantly greater proportion of time in the presence of a large follicle at second ovulation than at first ovulation (P<0.05) or for anovulatory follicles (P<0.01). Peak plasma estradiol concentrations and mean plasma estradiol concentrations were significantly higher (P<0.001) when a dominant preovulatory follicle was present compared with a dominant anovulatory follicle, but there was no difference in estradiol concentrations between first and second ovulations. It was apparent, therefore, that uterine edema was not a reliable indicator of follicular steroidogenic competence, or of whether the follicle would ovulate.     

Relationship between the release of hypophyseal LH under the influence of LRH and the plasma testosterone level in women]

There is a direct significant correlation (r = 0,49, p less than 0,01) between cumulative LH response to i.v. injection of 25 mug LRH and testosterone blood level in 17 women with an excess of endogenous androgens (plasmatic testosterone and/or urinary androsterone and etiocholanolone). The relation also exists if the patients are divided in two groups according to the origin of the dysfunction: polycystic ovaries (n = 9, r = 0,62, p less than 0.05) or hypercorticism (n = 8, r = 0,53, p less than 0.1). In the same patients there is no correlation between LH release and the sum of androsterone and etiocholanolone 24 hours urinary excretion (r = 0,21, p: NS); there is no correlation between basal testosterone blood levels and urinary metabolites (r = 0,19, p: NS). Our data suggest that testosterone (or a closely related metabolite) acts at the hypophyseal level to inhibit the spontaneous LH discharge hence increasing the pituitary hormonal stores. This action could be responsible for menstrual abnormalities often found in hirsut women.     

Developmental programming: deficits in reproductive hormone dynamics and ovulatory outcomes in prenatal, testosterone-treated sheep

Prenatal testosterone excess leads to neuroendocrine, ovarian, and metabolic disruptions, culminating in reproductive phenotypes mimicking that of women with polycystic ovary syndrome (PCOS). The objective of this study was to determine the consequences of prenatal testosterone treatment on periovulatory hormonal dynamics and ovulatory outcomes. To generate prenatal testosterone-treated females, pregnant sheep were injected intramuscularly (days 30-90 of gestation, term=147 days) with 100 mg of testosterone-propionate in cottonseed oil semi-weekly. Female offspring born to untreated control females and prenatal testosterone-treated females were then studied during their first two breeding seasons. Sheep were given two injections of prostaglandin F2alpha 11 days apart, and blood samples were collected at 2-h intervals for 120 h, 10-min intervals for 8 h during the luteal phase (first breeding season only), and daily for an additional 15 days to characterize changes in reproductive hormonal dynamics. During the first breeding season, prenatal testosterone-treated females manifested disruptions in the timing and magnitude of primary gonadotropin surges, luteal defects, and reduced responsiveness to progesterone negative feedback. Disruptions in the periovulatory sequence of events during the second breeding season included: 1) delayed but increased preovulatory estradiol rise, 2) delayed and severely reduced primary gonadotropin surge in prenatal testosterone-treated females having an LH surge, 3) tendency for an amplified secondary FSH surge and a shift in the relative balance of FSH regulatory proteins, and 4) luteal responses that ranged from normal to anovulatory. These outcomes are likely to be of relevance to developmental origin of infertility disorders and suggest that differences in fetal exposure or fetal susceptibility to testosterone may account for the variability in reproductive phenotypes.     

Seasonal changes in ovarian activity: lessons learnt from the horse

The annual reproductive cycle in the horse involves a reduction in ovarian activity during short days. The absence of ovulatory activity during winter has important consequences for an equine industry eager to breed mares early during the year. The anovulatory season results from a reduction in the secretion of pituitary gonadotropin that is in turn triggered by the inhibitory effects of short photoperiod on the hypothalamus–pituitary axis. Recent studies have provided evidence that the response of the ovaries to endocrine stimuli during the anovulatory season is affected not only by circulating concentrations of trophic hormones but also by locally produced growth factors that are putative modulators of follicular responses to gonadotropins. The present review summarises current knowledge on ovarian dynamics during the equine anovulatory season and the regulatory mechanisms involved at both systemic and local levels.     

Role of Thy-1+ and Ia+ cells in ovarian function

Cryostat sections of anovulatory ovaries from persistent estrous rats following a single postnatal dose of testosterone and from persistent diestrous rats following long-term postnatal estradiol treatment were investigated. The indirect immunoperoxidase technique was used to localize ovarian Thy-1 and Ia glycoproteins, as well as several other cell surface markers, and the results were compared with those obtained in normal ovaries of cycling females. Folliculogenesis in persistent estrous rats proceeded up to cystic antral follicles and was associated with the occurrence of Thy-1+ stromal cells under follicular basal lamina. In contrast to normal ovaries, Thy-1+ material did not invade the basal layers of granulosa cells. There was also no association of Ia+ cells with follicular basal lamina, but Ia+ cells were usually found associated with some thecal vessels. In persistent diestrous rats folliculogenesis was significantly retarded in both advanced antrum formation and thecal development. Thy-1+ cells were usually present in theca. No Thy-1+ material was found among basal layers of granulosa cells and the depletion of thecal Ia+ cells was almost complete. We suggest that normal follicular development may be dependent on the correct effects of Thy-1+ and Ia+ cells in addition to appropriate gonadotropin and steroid stimulation. On the other hand, anovulatory syndromes following postnatal androgen or estrogen treatment might be induced by temporary direct ovarian effects disturbing the establishment of the normal relationship between follicular structures and the immune system.     

The role of aberrant hypothalamic opiatergic function in generating polycystic ovaries in the rat

Treatment of adult female rats with estradiol valerate produces an intractable hypothalamic impairment that ultimately results in anovulatory acyclicity and polycystic ovaries. Evidence from our laboratory suggests that the hypothalamic impairment compromises regulation of the endogenous opioid system engendering a persistent opiatergic suppression of gonadotropin-releasing hormone secretion, which is subsequently reflected in a chronically low pituitary content of gonadotropin-releasing hormone receptors. If such is the case, inhibition of opiatergic transmission should improve the gonadotropin-releasing hormone pattern resulting in an improvement in the pituitary content of gonadotropin-releasing hormone receptors, and in an amelioration of the polycystic condition. We, therefore, treated rats with the polycystic ovarian condition, with daily injections of naltrexone. Within 1 week, there was a significant increase in the pituitary content of gonadotropin-releasing hormone receptors and a marked improvement in ovarian morphology, indicating that the hypothalamic opiatergic system is chronically active, and contributes significantly to the polycystic ovarian condition.     

Wild fulvous fruit bats (Rousettus leschenaulti) exhibit human-like menstrual cycle

We investigated the menstrual cycle of wild fulvous fruit bats (Rousettus leschenaulti), focusing on changes in the endometrial and ovarian structure and pituitary and steroid hormones. The menstrual cycle lasts for 33 days in bats studied in their natural habitat and in captivity. Vaginal bleeding was restricted to a single day (Day 1). A preovulatory follicle was found in the ovary on Day 18 when the levels of LH and FSH reached their maxima, accompanied by a thickened endometrium. On Day 24, serum levels of progesterone and estradiol-17 were also maximal, and uterine glands increased in size. After that, the levels of progesterone dropped precipitously, leading to menstrual bleeding. Both the morphologic and hormonal changes observed in fulvous fruit bats during the menstrual cycle resemble similar changes in humans. Fulvous fruit bats may be useful nonprimate laboratory models to study menstruation and menstrual dysfunction.