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J Pediatr Adolesc Gynecol (2006) 19:173–179 Usefulness of Monitoring Fertility from Menarche Pilar Vigil, MD, PhDFrancisco Ceric, Manuel E. Corte´sand Hanna Klaus, 1Unit of Reproduction and Development, Faculty of Biological Sciences, Pontifical Catholic University of Chile, Santiago, Chile;2Fundacio´n Me´dica San Cristo´bal, Santiago, Chile; 3School of Psychology, Faculty of Social Sciences, Pontifical Catholic Universityof Chile, Av. Vicun˜a Mackenna 4860, Santiago, Chile; 4TeenSTAR Program, Natural Family Planning Center of Washington, D.C.
8514 Bradmoor Drive, Bethesda, MD 20817-3810, USA The concept of the ovarian cycle as a contin- environmental conditions in order to ensure the health uum considers that all types of ovarian activity encountered of the mother and child. The ovarian continuum be- during the reproductive life are responses to different envi- gins at fertilization, when the zygote starts its devel- ronmental conditions in order to ensure the health of the opment. Approximately 2 months after fertilization woman. During the normal ovulatory cycle, a series of se- occurs, the future oogonia, called primordial germ quential events have to occur in a highly synchronized man- cells at this moment, leave the embryo and migrate ner. Fertility awareness is useful in helping women toidentify the different stages of their reproductive life cycle.
to the vitelline sac in order to escape the process of Fertility awareness is also a valuable tool in helping women cell differentiation. Some four weeks later these cells to identify gynecological disorders. Persistence of irregular- migrate to the region of the future ovary, the gonadal ities within the mucus patterns and the menstrual cycle crest, and start their process of differentiation, form- should be of concern to women presenting with these prob- ing millions of primordial follicles. At this time some lems. These irregularities may be due to obstetrical, endo- 7 million primordial follicles are formed, most of crine, gynecological or iatrogenic disorders. Insight into which will undergo atresia. When the girl is born, 1 early pregnancy complications, ovulatory dysfunction and to 2 million follicles containing the oocytes remain.
pelvic inflammatory disease can be ascertained from abnor- Of these, about 475 will complete folliculogenesis malities within the menstrual cycle and mucus pattern.
Thus, fertility awareness will also enable the recognition Puberty, viewed from the perspective of reproduc- and early treatment of several metabolic, endocrine and tion, could be considered as the process by which hor- monal changes take place in order to permit theexpulsion from the ovary of mature oocytes, thus al- lowing fertilization to take place. The luteinizing hor- mone (LH) peak must follow the estrogen peak for ovulation to occur,but there are a series of sequentialevents that must occur in a highly synchronized man-ner. During the first 2 years after menarche, occa- sional anovulatory cycles may occur. However,subsequently, a healthy ovary will exhibit regular Fertility is a transient biological state that depends on monthly ovulations, characterized by a 25 to 36 day the fertility potential of the couple. During a woman’s cyclThe ovulatory cycles are normally only inter- lifetime, the ovary will go through different states of rupted by pregnancies and breastfeeding. Normal ovu- hormonal secretion and ovulation. The concept of latory activity and fertility are restored following the ovarian cycle as a continuum considers that all pregnancy and lactation; however, stress or excessive types of ovarian activity encountered during the re- exercise may result in chronic ovulatory dysfunction productive life are normal responses to different which requires therapy. Abnormality in cycles suchas anovulation or short luteal phases frequently occursas menopause approaches. This is an expected part of Address correspondence to: Pilar Vigil, MD, PhD, Unit of Repro- a woman’s reproductive life cycle.
duction and Development, Faculty of Biological Sciences, Ponti-fical Catholic University of Chile, Av. Alameda O’Higgins 340, With the use of instruments such as the ovarian monitor, which measures the urinary excretion of Ó 2006 North American Society for Pediatric and Adolescent Gynecology Vigil et al: Usefulness of Monitoring Fertility from Menarche estrone glucuronide (E1G) and pregnanediol glucuro- (14) Throughout the cycle the hypothalamus con- nide (PdG), important metabolites of the two ovarian tinues to produce gonadotropin-releasing hor- hormones, estradiol and progesterone, it has been pos- mone (GnRH) and secretes it continuously in sible to identify hormonal variations during different periods of a woman’s life and to correlate these Throughout life, the ovarian continuum may present different phases as documented by studies carriedout with the ovarian monitor (1) Rising follicle-stimulating hormone (FSH) levels that cause follicular recruitment.
Throughout a woman’s life, the ovarian continuum (2) Follicular development that causes an increase may present different phases or patterns depending on the presence or absence of ovulation. One pattern (3) Increasing estradiol levels, secreted by matur- is characterized by an anovulatory ovarian activity; ing follicles, cause endometrium proliferation this type can be observed in two situations. The first and an increase in the amount of mucus se- type of anovulatory ovarian activity occurs when the creted by the cervical epithelium as well as FSH levels pass the threshold and stimulate a follicle change in the type of the mucus and the degree to develop, but sufficient LH is not released or the re- sulting ovulatory mechanism does not operate. This is an important cause of long cycles. A second type is (5) Estrogen together with inhibin shuts off FSH when the FSH levels rise above threshold, but not suf- ficiently to boost one follicle into dominance. A chronic situation develops in which follicles continue (6) Estrogen secreted by the dominant follicle to grow and regress causing the estrogen levels to pla- feeds back negatively on the hypothalamo- pi- teau. The effect of the raised but constant estrogen production is to develop an unstable endometrium that (7) The pituitary LH rises to LH peak and luteini- zation of the follicle is initiated. The ovum is Another different pattern of the continuum occurs released from the follicle (the ovum has a lim- when the estrogen levels rise to a peak resembling a preovulatory peak. LH is released but not in suffi- (8) With the initiation of follicular luteinization, cient amounts to cause the follicle to rupture and ovu- secretion of progesterone commences in the late. However, it is sufficient to cause a small amount follicle. This initial rise in progesterone main- of luteinization of the follicle with resultant low level (9) This pattern of LH secretion aids the formation The ovarian continuum may also present as a defi- of a normal corpus luteum and an adequate cient luteal phase. A cycle that presents a deficient lu- luteal phase of the menstrual cycle.
teal phase is one in which ovulation occurs, but the (10) The corpus luteum produces progesterone and conditions during the luteal phase do not support an ongoing pregnancy. Thus, any cycle in which the pro- (11) Progesterone changes the endometrium to the gesterone levels fail to reach 10 mmole PdG/24 hours secretory type. It also affects the cervical mu- 7 days after ovulation has occurred or any cycle with cus, converting it from estrogenic to progesta- a luteal phase length of 10 days or less could be tional type, which is not suitable for sperm regarded as ‘‘deficient.’Ovulation is always transport through the cervix. If fertilization has not occurred, the corpus luteum begins to endometrium capable of responding to the hormones is present and there is no human chorionic gonadotro- (12) Estrogen and progesterone levels return to early follicular phase levels approximately 14 Even in fertile ovulatory cycles the potential for days after the initial formation of the corpus conception varies with the timing of insemination, the groups of women studied, and the fertility poten- (13) This drop in sex hormone levels releases the tial of the male partner. Age also is an important fac- suppression of FSH and LH and a new cycle tor to consider when analyzing fertility potential, as Vigil et al: Usefulness of Monitoring Fertility from Menarche Cervical Mucus as a Determinant for Fertility ‘‘peak day.’The woman who understands herown mucus pattern should be able to recognize It has been shown that mucus quality is a better predic- changes in the normal ovulatory pattern and detect tor of the possibility for conception than ovulation.
changes which may indicate a number of gynecolog- Mucins are the main components of To date a total of 20 distinct mucin genes have been identi- Questions arise as to when irregularities within the Mucins are categorized into 3 groups on the mucus patterns and the menstrual cycle should be basis of their structural properties such as transmem- considered abnormal and when the woman should brane mucin (MUCs 1, 2, 3, 4, 12, 13, 15, 16, 17), be sufficiently concerned to consult a physician. Per- gel-forming mucin (MUCs 2, 5AC, 5B, 6) and soluble sistence of abnormal mucus patterns may herald re- mucin (MUCs 7, 9, 11, 14) and others that have not yet productive system disorders. These may be due to been categorized (MUCs 8, 10, 18, 19, and The serious metabolic or endocrine abnormalities or to four large gel-forming mucin genes are located on other diseases, all of which need to be recognized.
Menstrual disorders and alteration in the mucus pat- forming mucin expressed by the endocervical epithe- tern can be caused by obstetrical, endocrine, gyneco- lium and its expression peaks at mid-cycle.There is evidence of other mucins as well, such as MUC4, Early pregnancy complications such as bleeding or which are expressed in the ovulatory phase.
vaginal spotting can alert the woman who has recog- Two main types of cervical mucus have been de- nized a previous fertile phase with a peak day, and can scribed: estrogenic and progestational. According to be identified or ruled out with the use of ultrasensitive Odeblad’s model, the estrogenic type can be subdi- pregnancy tests and pelvic ultrasound. Numerous vided into L, S, and P subtypes.The L subtype studies have shown that 10–15% of couples suffer is the most abundant type of mucus during the perio- from a fertility disorder. These are mainly due to: vulatory period and the P subtype appears close to (a) ovulatory dysfunction generally caused by hor- monal disorders, and (b) inflammatory processes usu- as progesterone levels increase in the blood.During ally secondary to genital tract infections (GTI), the luteal phase the progestational type (G) of mucus mainly sexually transmitted diseases (STD). Ovulatory dysfunction is the most common disorder diagnosed in It has been demonstrated that fertility awareness infertile couples (37%) and is predominantly associ- can help women to identify the different stages of ated with irregular menstrual cycles. Irregular cycles their reproductive life cycle.Understanding the are present in 10% of women, but having an irregular signs of fertility and infertility is important knowledge cycle does not necessarily mean having an ovulatory which should be available to every woman. Briefly, dysfunction. We have been able to show according to fertility awareness involves self detection of mucus cycle charting that 43% of women with irregular cycles at the vulva primarily by noting the progression from present an ovulatory dysfunction, which can be charac- the basic infertile pattern of post-menstrual dryness to terized by the absence of ovulation or abnormal ovula- stickiness, wetness, and ultimate lubrication, the tory activity, as seen in cycles with short or abnormal Fig. 1. Scanning electron-micrograph of cervical mucus types. Network-shaped mesh of estrogenic cervical mucus (type S)with spermatozoa migrating through it (A). In the estrogenic period type P mucus (B) appears close to ovulation. In the pro-gestational period (C) the mucus is compact and impenetrable (type G). Bar 5 10 mm.
Vigil et al: Usefulness of Monitoring Fertility from Menarche luteal phases, while some of the rest have prolonged are characterized by a hyperestrogenic state where early infertile phases followed by a late, but normal a continuous fertile type of mucus pattern (slippery, ovulation. On the other hand, a young nulliparous stringy, clear, mucus) is identified, or mucus patches woman with regular cycles, (i.e., cycle length between (days of sticky or slippery mucus forming no progres- 25 and 36 days) may also present an ovulatory dysfunc- sive pattern to ‘‘peak’’) are present. Cycles can be tion identified by her understanding of the fertility pat- ovulatory, with a long follicular phase, or anovulatory.
When a young woman complains of menstrual abnor- Endocrine disorders are the most common cause of malities, teaching her to observe her fertility signs can be the first step to enable the clinician to rule out met- pothalamic, pituitary, or adrenal and/or ovarian, or abolic conditions such as hyperinsulinemia. Our stud- ies have shown that in 82% of women who present Hypothalamic disorders (e.g., anorexia nervosa) with menstrual irregularities, an endocrine abnormal- are characterized by long hypo-estrogenic cycles with ity is present of which hyperandrogenemia is the most the persistence of ‘‘dry’’ days (days with no mucus).
common (46% of It is important to note that Amenorrhea may be present. This condition is caused an impaired insulin response to the oral glucose toler- by a delay of the FSH levels to rise above threshold ance test is a commonly (50–80%) associated condi- and thus initiate a new cycle. Unless the woman has tion in these women. This requires treatment to permanent ovarian failure, such as having reached prevent progression to type II diabetes mellitus.
menopause, the situation eventually corrects itself.
Proper care, including diet, exercise, and medical This condition is associated with long ovulatory or treatment will restore normal cyclical ovarian activity.
Women who know how to recognize their mucus Long, anovulatory cycles are seen in athletes, and symptoms will be able to follow the improvement in this case they could be considered as a part of the continuum. These women frequently return to reg- Hypothyroidism is a less frequent (about ular ovarian cyclic activity observed within 3 months cause of ovarian dysfunction but it has to be consid- of less strenuous physical exercHowever, some ered along with hyperthyroidism. Different types of of the young women in this category may further de- ovarian dysfunction can be observed in patients with velop an anorectic state and despite discontinuation of thyroid disorders. Menorrhagiais frequently associ- strenuous physical activity will not return to normal ated with hypothyroidism. Although there is no spe- cific pattern of ovarian activity associated with these Pituitary disorders (e.g. hyperprolactinemia) ac- endocrine abnormalities they should always be kept count for about 10% of ovarian dysfunction and are in mind and eliminated as a possible cause.
characterized either by amenorrhea or short cycles Women with ovulatory dysfunctions associated in which a short or abnormal luteal phase with pre- with irregular cycles and abnormal mucus patterns menstrual spotting can be observed. In vitro studies will not usually resume normal cycling spontaneously have shown impairment in steroidogenic activity of without appropriate treatment. Follow-up studies have follicular cells under the influence of prolactin, which shown that in the absence of treatment these condi- could explain, at least in part, the abnormal luteal phases commonly observed in the charts of women Other conditions, such as premature ovarian fail- with hyperprolactinemia.Galactorrhea may be also ure, may also be a cause of fertility disorders present- present. In women with hyperprolactinemia the inter- ing with irregular mucus patterns in response to action between neurological, endocrine, and immune fluctuating estrogen levels. These conditions are also observed in the perimenopausal period, where some women may also present some immunologic alter- cycles show an ovulatory pattern. As the condition ations such as allergies. Stress may be an important worsens, anovulatory cycles will predominate.
factor associated with increased prolactin le In fertile women, naturally occurring midcycle cer- Adrenal and ovarian abnormalities are the most vical mucus studied with scanning electron micros- frequent cause of ovarian dysfunction. The most com- copy shows an arrangement of parallel fibers mon is the polycystic ovary syndrome (PCOS): an oriented along the main axis of the mucus sample, ovulatory dysfunction caused by hyperandrogene- mia.In these women, irregular cycles are usually transport may be facilitated by this normally occur- ring condition. At mid-cycle, cervical mucus is when present at 15 years of age has recently been greater in quantity, has more mucin and less protein, shown to be the best predictor for These girls and has higher water content than in the luteal may present with acne and/or hirsutism as well as in- This increase in the amount of mucin in the creased body weight and mood changes. Their cycles cervical canal, because of its hydrophilic character, Vigil et al: Usefulness of Monitoring Fertility from Menarche probably functions to retain or hold water in place at Trichomonas vaginalis, and Gardnerella vaginalis the cell surface, keeping the cervical canal patent for among others, must also be considered when unusual sperm migration. The increase in water content of the mucus patterns or menstrual irregularities occur. In mucin may protect the cervix. Pathogens or other this situation, both members of the couple should be toxins may be trapped by the mucin, thus preventing treated in order to restore the healthy condition.
their entry into the uterus and Fallopian Fu- Fertility disorders may also be iatrogenic, caused ture research is needed to establish the ultrastructure by contraceptive pills or by hormonal therapy. Women and biochemical properties of mucus in different discontinuing steroidal contraception may present cy- endocrine abnormalities. Also, the function of the cles with short luteal phases, absence of a well- specific mucins and mucus types remains to be defined mucus pattern indicating anovulation, poor determined as well as their possible alterations.
mucus response due to damaged cervical epithelium Menstrual disorders and alteration in the mucus and/or a poor menstrual flow due to alterations of pattern can also be caused by gynecologic disorders such as anatomical abnormalities, neoplasia, or in- for up to seven cycles (cycle length O 35 days or lu- flammatory diseases. The second most frequent cause teal phase ! 10 days, monophasic basal body temper- of fertility disorders are inflammatory processes, usu- ature or anovulatory cycles) occur in women after ally secondary to GTI, which predominantly have discontinuation of oral contraception. They also have their origin in STD. Microbial mucin degrading en- lower monthly conception rates during the first 3 zymes are associated with sexually transmitted infec- months off the pill, and a somewhat lower percentage tions and are produced by the offending micro from the fourth to the tenth month after discontinua- organisms. These enzymes will alter the mutually beneficial cohabitation that normally exists between In conclusion, although usually used for fertility commensals such as Lactobacillus, which use glyco- awareness, cycle charting provides women with infor- gen as an energy source and contribute to normal mu- mation about their cycle pattern and ovarian function.
cin turnover by the production of mucin degrading Klaus and Martinshowed that ethnically and socio- enzymes such as sialidase. Mucin molecules would economically diverse perimenarchal girls can be be partly or completely degraded by the microbial en- taught to recognize their cervical mucus patterns zymes. These molecules dictate the rheological prop- and distinguish anovulatory from ovulatory c erties which determine the amount and viscosity of Menstrual irregularities and/or ovarian dysfunction the mucus, so these properties will change in response may reflect several systemic or reproductive disor- to enzymes produced by microbial organisms in the ders. Recent studies have shown that the menstrual cycle pattern during the first years after menarche is A woman who knows her own mucus pattern in a better predictor for ovulatory dysfunction in adult- times of health will be able to recognize a GTI early.
These will usually cause a continuous discharge and other previously conducted studies support the whose characteristics will depend upon the etiologic evidence that conditions such as hyperandrogenic agent causing the infection. In general, an ovulatory ovulatory dysfunction in the adult female have their pattern is identifiable alongside the continuous dis- origin in adolescence. Most of these conditions are charge. Symptomatic infections (itching and a charac- not self-limited disorders and will worsen during teristic discharge) are usually caused by fungi, bacteria, or parasites. Chlamydia trachomatis infec- women were taught how to chart their cycles they tions, with an incidence of 13% in infertile couples could be able to detect menstrual irregularities and and often associated with tubal pathology, may be ovarian dysfunction early in life. This finding could asymptomatic or present with continuous vulvar alert women to seek medical advice early which could moistness and variable degrees of pelvic pain.This be crucial for the prevention of disorders such as type infection may also show a mucopurulent discharge as- sociated with the mucus discharge. The recognition of Furthermore, sex education programs that include this infection and timely treatment may prevent fertil- training in fertility awareness have an impact in pre- ity disorders. It has been shown that these infections vention of unintended adolescent pregnancyThese provoke pelvic inflammatory processes and are asso- programs have shown retardation of sexual initiation ciated with spontaneous abortions. Recent studies and discontinuation of sexual activity among sexually have shown that the mesh spacing between mucin fi- active adolescents, which is important for prevention bers is large enough for small viruses such as human papilloma virus, associated with cervical neoplasia, Teaching fertility awareness to young women in- volves an effort that may be useful for every women Vigil et al: Usefulness of Monitoring Fertility from Menarche ovulatory cycles by comparison with radioimmunoassay.
Steroids 2003; 68:465 Knowledge about fertility awareness acquired by self 10. Noyes RW, Hertig AT, Rock J: Dating the endometrial observation of cervical mucus patterns at the vulva is an invaluable tool for women desiring to achieve and 11. Johannisson E, Oberholzer M, Swahn ML, et al: Vascular changes in the human endometrium following the admin- maintain a healthy reproductive system. The identifi- istration of the progesterone antagonist RU 486. Contra- cation of medical and environmental causes of abnor- mal menstrual cycle patterns may provide clues to the 12. Barros C, Arguello B, Jedlicki A, et al: Scanning electron causes of the most frequent fertility disorders. Early microscopy study of human cervical mucus. Gam Res diagnosis of these alterations, as can be achieved through fertility awareness, will not only improve fer- 13. Morales P, Rocco M, Vigil P: Human cervical mucus: tility disorders, but may help in the diagnosis and relationship between biochemical characteristics and ability treatment of other pathologies such as metabolic to allow migration of spermatozoa. Hum Reprod 1993; 8:78 and endocrine disorders, anatomical alterations, pel- 14. Vigil P, Pe´rez A, Neira J, et al: Post-partum cervical mu- vic inflammatory diseases or even neoplasia. Mucus cus: biological and rheological properties. Hum Reprod as well as the menstrual cycle patterns are important 15. Armstrong DG, Webb R: Ovarian follicular dominance: components of the clinical decision-making process.
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C1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option H. J. Longhurst,* S. Carr† and K. Khair‡ *Barts and The London NHS Trust, Department Economic and political factors have led to the increased use of home therapy of Immunopathology, London, UK, †Barts and The London NHS Trust, Department of programmes for patients who have tradi

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