Catholic Medical Quarterly Volume 66(3) Aug 2016

Signs of Reproductive Health in Women

Vigil, P.(1,2,*), Alvarado, J.L.(2), Flores, B.(2)
(1) Reproductive Health Research Institute,
(2) Pontificia Universidad Catolica De Chile
(*) Corresponding Author. e-mail: (p. vigil)


Reproductive health in women is increasingly compromised by lifestyles, the rhythm of life, and several environmental conditions such as the presence of pollutants and exposure to infectious agents. Critical manifestations of women’s reproductive health, such as the presence and regularity of menses and ovulation, are poorly understood and, when subjected to treatment, have been managed pharmacologically in order to control signs and symptoms that may not correct the underlying causes. Women’s health is complex to understand due to interac­tions between variable hormonal levels, which make understanding and management difficult, and require integration across health management specialties. Finally, some conditions do not present themselves with recognizable signs and symptoms and are therefore underdiagnosed and untreated.

Endocrine control of reproductive processes

Reproductive processes in women are regulated from puberty onwards by changes in the hormones produced by the hypothalamus and the adenohypophysis (anterior pituitary), as well as by the ovaries, which constitute a system known as the hypothalamic-hypophyseal-gonadal axis (1-3).

Often, the first sign of an underlying reproductive health problem is the presence of irregular cycles, which can be caused by an abnormality in ovulation. When pregnancy, lactation or menopause are not the cause, persistent irregularities in the ovulatory cycle can be associated with endocrine, gynecological, nutritional or iatrogenic disorders (4). However, while regular menstrual cycles are generally considered a sufficient indicator of ovulation, recent evidence shows that they can also be anovulatory (5, 6) and therefore, the presence of regular menstruation is not sufficient to monitor women’s health. Ovulation should be taken as the critical sign to identify and treat abnormalities and reproductive health related conditions.

For ovulation to occur, a series of highly synchronized sequential events are required. At the beginning of each cycle, an increase in FSH levels causes follicular recruitment and development with the subsequent elevation of estradiol levels (7, 8). Increasing estradiol levels, secreted by maturing follicles, produce endometrial proliferation, a change in the size of the cervical os and an increase in the amount of cervical mucus with modifica­tions in its rheological and physicochemical properties (2, 9, 10). Estradiol then exerts a negative feedback effect on the hypothalamic-hypophyseal-gonadal axis, decreasing FSH levels (11-13). However, the high levels of estradiol produced during follicular dominance, change the feedback mechanism from negative to positive (14). This feedback induces a change in GnRH secretion through the kisspeptinergic neurons and produces the pre-ovula­tory LH peak, which initiates follicle luteinization leading to the formation of the corpus luteum. LH triggers follicular wall degradation by prostaglandins and other compounds, resulting in ovulation or release of the oocyte which normally survives 12 to 24 hours (11). Follicle luteinization causes a rise in progesterone secreted by follicular cells that, among other things, modifies the endometrial lining from proliferative to secretory type and changes the cervical mucus from estrogenic to progesta­tional (9, 15). About 8 days later, in the absence of fertiliza­tion, the corpus luteum begins to regress and lasts for a total of approximately 11 to 17 days, with an average lifes­pan of 14 days. As a consequence, estrogen and progesterone concentrations return to the levels observed in the early follicular phase about two weeks after the initial formation of the corpus luteum (2, 8). This eliminates the suppression exerted on FSH and LH and causes the beginning of a new cycle. The hypothalamus maintains the production of GnRH pulsatility throughout the cycle, changing its pattern according to the feedback mechanism exerted by ovarian steroids to hypothalamic kisspeptinergic neurons (16).


There are several observable changes in the body (bio­markers) that can help a woman to identify ovulation. The most important are the changes observed in the cervical mucus, the basal body temperature and the cervical os.

The cervical mucus is a hydrogel formed by several low molecular mass compounds, such as inorganic salts, fructose, glucose, and glycoproteins such as mucins. These glycoproteins are produced and secreted by specialized cells present in the epithelium that line the cervical crypts (17). Gel-forming mucins associate with each other to create macromolecular groups responsible for the so-called rheological properties of the cervical mucus. It has been proposed that the characteristic structure of the mucus emerges when these glycoproteins generate a network of interconnected molecules (17).

PregnacyDuring the menstrual cycle the amount and properties of the cervical mucus change as a result of hormonal changes. The rising levels of estrogen induce an increase in the production of mucus in the cervix. During the follicular phase, as estrogen levels rise, the cervical mucus becomes aqueous, transparent, fluid and crystalline, and women feel the sensation of wetness and lubrication at the vulva. The last day of this sensation at the vulva is termed peak day, which coincides closely with the day of ovulation in the woman’s menstrual cycle. It has been shown that ovulation occurs within 3 days on either side of peak day in 98% of cycles (18-20). During the luteal phase, progesterone has the opposite effect, decreasing the degree of hydration and making the mucus opaque and less fluid. This mucus forms a barrier in the cervix against sperm and bacteria and is generally experienced as a dry sensation or as thick mucus (15, 21).

Basal body temperature is considered another useful biomarker for ovulation. It rises around 0.5°F or 0.3°C after the LH peak and coincides with elevated blood progesterone concentrations. The explanation proposed for this is that progesterone stimulates the release of the neurotransmitter noradrenaline, which acts on the hypothalamus, the thermoregulatory center of the central nervous system (22).

Structural changes in the cervix are also generated by estrogen. At the beginning of the menstrual cycle, the cervix is positioned low in the vaginal canal, has a hard consistency and is almost fully closed. As estrogen levels progressively increase in the follicular phase, the cervix rises, softens and starts to open. After ovulation, its position, consistency and opening gradually return to the initial characteristics. Some women can easily feel these changes, while others have a tougher time (23).

Ovulatory dysfunction and underlying health disorders

Menstrual disorders and abnormal mucus patterns may have endocrine, gynecological, nutritional or iatrogenic origins. Gynecological disorders include anatomical abnormalities, neoplasia and inflammatory diseases. Inflammation is usually secondary to genital tract infec­tions caused by sexually transmitted infections (STI), such as chlamydia, human papilloma virus, syphilis, gonorrhea and human immunodeficiency virus (24, 25). STI pathogens can degrade mucins in cervical mucus, causing a change in its properties (26).

Endocrine disorders that underlie ovulatory dysfunction are predominantly associated with irregular menstrual cycles and can impact quality of life as well as being the most common cause of infertility (27). There are several types of endocrine dysfunctions that can affect the ovulatory cycle, including hypothalamic, pituitary, thyroid, adrenal, and ovarian disturbances (4, 28).

In hypothalamic disorders there is a change in the normal pattern of secretion of GnRH, delaying the increment of FSH levels above threshold. Hypothalamic disorders can be caused by excessive exercise, nutritional deficits, stress or psychiatric disorders, such as anorexia (28).

Deficits in nutrition can result in low levels of leptin, a hormone that is secreted by adipocytes and promotes the secretion of kisspeptin, a hormone affecting GnRH release (14). On the other hand, high blood concentrations of cortisol (hypercortisolemia) block both the secretion of GnRH from the hypothalamus and the action of gonadotropins on the ovaries. Therefore, these disorders may result in hypoestrogenic cycles, “dry” days (no mucus) due to the lack of estrogen, anovulation and amenorrhea

Increased levels of prolactin (hyperprolactinemia) can be caused by prolactinomas (a type of pituitary tumor),certain drugs, or conditions such as high levels of stress (30). This condition inhibits GnRH and gonadotropin secretion, thus impairing ovulation. Symptoms include menstrual irregularities, galactorrhea, infertile cycles, decreased libido and dyspareunia. Moreover, amenorrhea or short luteal phases can be present (28), which can be explained, at least in part, by an impairment in steroido­genic activity (31). In addition, women suffering from hyperprolactinemia frequently present allergies and warts, and a higher tendency to suffer from infections because prolactin has an immunostimulatory effect, promoting autoimmunity (32).

Thyroid hormones influence ovulation both directly by impacting the ovaries and indirectly by affecting sex hormone-binding globulin (SHBG) and GnRH secretion (33). Women with thyroid disorders can suffer from a number of menstrual abnormalities, including hypomen­orrhea, hypermenorrhea, menorrhagia, polymenorrhea, oligomenorrhea or amenorrhea (34, 35). Moreover, the higher levels of thyrotropin-releasing hormone (TRH) stimulate the secretion of prolactin, which can lead to anovulation as previously mentioned. Treatment of the underlying dysfunction can correct ovulatory irregularities and improve fertility (33).

Adrenal and/or ovarian disorders are frequently associated with ovulatory dysfunction. Polycystic ovary syndrome (PCOS) is the cause of 75% of cases of anovulatory infertility and the most common endocrine disorder in reproductive-aged women (36, 37). They may exhibit acne, hirsutism, alopecia, increased body weight and mood changes. Obesity, insulin resistance and consequent hyper­insulinemia are highly prevalent co-morbidities of PCOS and can impair ovulation and fertility (38, 39) by causing ovarian theca cells to produce excessive androgens (hyper­androgenemia), which leads to premature follicular atresia and even anovulation(40). PCOS is also often accompanied by increased risk of Type 2 diabetes, cardiovascular disease and endometrial, ovarian, and/or breast cancer (36, 41). The cycle pattern of women with PCOS can be marked by continuous presence of fertile mucus or by fertile mucus patches in different days of the cycle (4, 10).

Vitamin D has also been associated with ovarian function. It is a steroid hormone synthesized mainly by the skin through ultraviolet light exposure, with less than 10%-20% coming from diet (42). Besides its key role in maintaining calcium and phosphorus homeostasis and promoting bone mineralization, vitamin D stimulates steroidogenesis and follicular development. Today it is common to find low levels of Vitamin D and associated ovulatory disorders in women because of frequent use of sun blockers and little exposure to sunlight

Iatrogenic causes of ovarian dysfunction include the use of steroids, such as hormonal contraceptives, anabolics and selective estrogen receptor modulators (SERMs). The cycles of women who have discontinued contraceptives are often longer and variable in length, likely because the hy­pothalamic-hypophyseal-gonadal axis is normalizing itself after it has been suppressed during contraceptive use. Moreover, the quality of cervical mucus is diminished for at least the first six menstrual cycles after discontinuation of the pill


Ovulation as a marker of endocrine homeostasis and health status

Monitoring cycles may allow women to understand, maintain, and improve their health. In addition to monitoring the duration of the menstrual cycle, women should understand the significance of the duration and flow of menstruation, cervical mucus quality and duration of the luteal phase, as well as changes across menstrual cycles. Woman can identify irregularities that should be addressed by noting three or more cycles in a year with altered ovulation, such as anovulation, short luteal phases or varied cycle lengths of less than 24 days or more than 36 days. Health education and monitoring is important because the first sign of many underlying health problems is often ovulatory dysfunction followed by irregular cycles (4). It has also been shown that varying, short or long cycle lengths are associated with decreased fecundity, and that menstrual cycle patterns may help predict the outcome of pregnancy (46)

It should be emphasized that menstrual cycles with normal length are not an indicator of proper ovarian function, due to the existence of normal length anovulatory cycles (10). Therefore, it is regular ovulation and not regular menstruation which is evidence of reproductive health.

Tracking ovulation biomarkers is a reliable method for managing health and fertility as well as identifying abnormal patterns that point to disorders needing treatment. Since ovulation is a sign of both endocrine homeostasis and health, understanding these changing hormonal fluctuations through biomarker observation allows women to be aware of their long-term health.


  1. Brown JB. Types of ovarian activity in women and their signifi cance: the continuum (a reinterpretation of early findings). Hum Reprod Update. 2011 Mar-Apr;17(2):141-58.
  2. Hawkins SM, Matzuk MM. The menstrual cycle: basic biology. Ann N Y Acad Sci. 2008;1135:10-8.
  3. Sigel EJ. Adolescent Growth and Development. In: Greydanus DE, Patel DR, Pratt HD, editors. Essential Adolescent Medicine. New York: McGraw Hill Professional; 2005. p. 3-15.
  4. Vigil P, Ceric F, Cortes ME, Klaus H. Usefulness of monitoring fertility from menarche. J Pediatr Adolesc Gynecol. 2006 Jun;19(3):173-9.
  5. Malcolm CE, Cumming DC. Does anovulation exist in eumenor rheic women? Obstet Gynecol. 2003 Aug;102(2):317-8.
  6. Prior JC, Naess M, Langhammer A, Forsmo S. Ovulation Preva lence in Women with Spontaneous Normal-Length Menstrual Cycles - A Population-Based Cohort from HUNT3, Norway. PLoS One. 2015;10(8):e0134473.
  7. Blackwell LF, Brown JB, Vigil P, Gross B, Sufi S, d'Arcangues C. Hormonal monitoring of ovarian activity using the Ovarian Mon itor, part I. Validation of home and laboratory results obtained during ovulatory cycles by comparison with radioimmunoassay. Steroids. 2003 May;68(5):465-76.
  8. Miro F, Aspinall LJ. The onset of the initial rise in follicle-stimu lating hormone during the human menstrual cycle. Hum Reprod. 2005 Jan;20(1):96-100.
  9. Morales P, Roco M, Vigil P. Human cervical mucus: relationship between biochemical characteristics and ability to allow migration of spermatozoa. Hum Reprod. 1993 Jan;8(1):78-83.
  10. Vigil P, Cortes ME, Zuniga A, Riquelme J, Ceric F. Scanning electron and light microscopy study of the cervical mucus in women with polycystic ovary syndrome. J Electron Microsc (Tokyo). 2009 Jan;58(1):21-7.
  11. Ferin M, Van Vugt D, Wardlaw S. The hypothalamic control of the menstrual cycle and the role of endogenous opioid peptides. Recent Prog Horm Res. 1984;40:441-85.
  12. Hoff JD, Quigley ME, Yen SS. Hormonal dynamics at midcycle: a reevaluation. J Clin Endocrinol Metab. 1983 Oct;57(4):792-6.
  13. Laven JS, Fauser BC. Inhibins and adult ovarian function. Mol Cell Endocrinol. 2004 Oct 15;225(1-2):37-44.
  14. Cortés ME, Carrera B, Rioseco H, del Río JP, Vigil P. The role of kisspeptin on the onset of puberty and on the ovulatory mechanism: A minireview. J Pediatr Adolesc Gynecol. 2014.
  15. Odeblad E, Ingelman-Sundberg A, Hallström L, Hoglund A, Leppanen U, Lisspers K, et al. The biophysical properties of the cervical-vaginal secretions. Int Rev Nat Fam Plann. 1983;7(1):1-56.
  16. Lincoln DW, Fraser HM, Lincoln GA, Martin GB, McNeilly AS. Hypothalamic pulse generators. Recent Prog Horm Res. 1985;41:369-419.
  17. Verdugo P. Goblet cells secretion and mucogenesis. Annu Rev Physiol. 1990;52:157-76.
  18. Billings EL, Brown JB, Billings JJ, Burger HG. Symptoms and hormonal changes accompanying ovulation. Lancet. 1972 Feb 5;1(7745):282-4.
  19. Fehring RJ. Accuracy of the peak day of cervical mucus as a bio logical marker of fertility. Contraception. 2002 Oct;66(4):231-5.
  20. Hilgers TW, Abraham GE, Cavanagh D. Natural family plan ning. I. The peak symptom and estimated time of ovulation. Obstet Gynecol. 1978 Nov;52(5):575-82.
  21. Gipson IK. Mucins of the human endocervix. Front Biosci. 2001 Oct 1;6:D1245-55.
  22. Zuspan FP, Rao P. Thermogenic alterations in the woman. I. Interaction of amines, ovulation, and basal body temperature. Am J Obstet Gynecol. 1974 Mar 1;118(5):671-8.
  23. Vigil P. La Fertilidad de la Pareja Humana. 4 ed. Santiago, Chile: Ediciones Universidad Católica de Chile; 2013.
  24. Hay P, Ugwumadu A. Detecting and treating common sexually transmitted diseases. Best Pract Res Clin Obstet Gynaecol. 2009 Oct;23(5):647-60.
  25. Pellati D, Mylonakis I, Bertoloni G, Fiore C, Andrisani A, Am brosini G, et al. Genital tract infections and infertility. Eur J Obstet Gynecol Reprod Biol. 2008 Sep;140(1):3-11.
  26. Howe L, Wiggins R, Soothill PW, Millar MR, Horner PJ, Corfield AP. Mucinase and sialidase activity of the vaginal microflora: implications for the pathogenesis of preterm labour. Int J STD AIDS. 1999 Jul;10(7):442-7.
  27. Vigil P, Rodríguez-Rigau L, Palacios X, Kauak S, Morales P. Diagnosis of menstrual disorders in adolescence. In: Frajese G, Steinberger E, Rodríguez-Rigau LJ, editors. Reproductive Medicine. New York: Raven Press; 1993. p. 149-54.
  28. Unuane D, Tournaye H, Velkeniers B, Poppe K. Endocrine disorders & female infertility. Best Pract Res Clin Endocrinol Metab. 2011 Dec;25(6):861-73.
  29. Saketos M, Sharma N, Santoro NF. Suppression of the hypothal amic-pituitary-ovarian axis in normal women by glucocorticoids. Biol Reprod. 1993 Dec;49(6):1270-6.
  30. Johansson GG, Karonen SL, Laakso ML. Reversal of an elevated plasma level of prolactin during prolonged psychological stress. Acta Physiol Scand. 1983 Dec;119(4):463-4.
  31. Barron ML. Proactive management of menstrual cycle abnormal ities in young women. J Perinat Neonatal Nurs. 2004 Apr-Jun;18(2):81-92.
  32. Orbach H, Shoenfeld Y. Hyperprolactinemia and autoimmune diseases. Autoimmun Rev. 2007 Sep;6(8):537-42.
  33. Poppe K, Velkeniers B, Glinoer D. Thyroid disease and female re production. Clin Endocrinol (Oxf). 2007 Mar;66(3):309-21.
  34. Krassas GE, Pontikides N, Kaltsas T, Papadopoulou P, Batrinos M. Menstrual disturbances in thyrotoxicosis. Clin Endocrinol (Oxf). 1994 May;40(5):641-4.
  35. Krassas GE, Pontikides N, Kaltsas T, Papadopoulou P, Paunkovic J, Paunkovic N, et al. Disturbances of menstruation in hypothyroidism. Clin Endocrinol (Oxf). 1999 May;50(5):655-9.
  36. Consensus on women's health aspects of polycystic ovary syndrome (PCOS). Hum Reprod. 2011 Jan;27(1):14-24.
  37. Amer SAK. Polycystic ovarian syndrome: diagnosis and manage ment of related infertility. Obstetrics, Gynaecology & Reprod Med. 2009;19(10):263-70.
  38. Pauli JM, Raja-Khan N, Wu X, Legro RS. Current perspectives of insulin resistance and polycystic ovary syndrome. Diabet Med. 2011 Dec;28(12):1445-54.
  39. Vigil P, Contreras P, Alvarado JL, Godoy A, Salgado AM, Cortes ME. Evidence of subpopulations with different levels of insulin resistance in women with polycystic ovary syndrome. Hum Reprod. 2007 Nov;22(11):2974-80.
  40. Diamanti-Kandarakis E. Insulin resistance in PCOS. Endocrine. 2006 Aug;30(1):13-7.
  41. Solomon CG, Hu FB, Dunaif A, Rich-Edwards JE, Stampfer MJ, Willett WC, et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab. 2002 May;87(5):2013-7.
  42. Bouillon R, Carmeliet G, Daci E, Segaert S, Verstuyf A. Vitamin D metabolism and action. Osteoporos Int. 1998;8 Suppl 2:S13-9.
  43. Irani M, Merhi Z. Role of vitamin D in ovarian physiology and its implication in reproduction: a systematic review. Fertil Steril. 2014 Aug;102(2):460-8 e3.
  44. Lerchbaum E, Obermayer-Pietsch B. Vitamin D and fertility: a systematic review. Eur J Endocrinol. 2012 May;166(5):765-78.
  45. Nassaralla CL, Stanford JB, Daly KD, Schneider M, Schliep KC, Fehring RJ. Characteristics of the menstrual cycle after discon tinuation of oral contraceptives. J Womens Health (Larchmt). 2011 Feb;20(2):169-77.
  46. Kolstad HA, Bonde JP, Hjollund NH, Jensen TK, Henriksen TB, Ernst E, et al. Menstrual cycle pattern and fertility: a prospective follow-up study of pregnancy and early embryonal loss in 295 couples who were planning their first pregnancy. Fertil Steril. 1999 Mar;71(3):490-6.