Last updated date: 15-May-2023
Originally Written in English
Ovarian continuity may be thought of as a process that happens throughout a woman's life and begins with fertilization during intrauterine life. Women begin their reproductive years with roughly 500,000 follicles holding oocytes, of which only about 500 will be released during ovulation. Ovulation has long been regarded as a reproductive event; nevertheless, new data supports the relevance of ovulation as a health indicator.
The use of biomarkers that assist women in recognizing ovulation allows them to determine their health state. This information assists medical healthcare practitioners in the prevention, diagnosis, and treatment of endocrine problems, gynecological abnormalities, autoimmune, genetic, and neoplastic illnesses, as well as pregnancy-related difficulties.
Understanding the ovarian continuum and using biomarkers to detect ovulation should be seen as a strong tool for both women and medical professionals.
Endocrine Regulation of the Ovulatory Cycle
Positive and negative feedback mechanisms govern the ovulatory cycle. The ovary's steroid sex hormones influence the secretion pattern of kisspeptin, gonadotrophin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), which in turn modifies the release of ovarian hormones.
A rise in FSH levels at the start of each cycle stimulates follicular recruitment and development, followed by an increase in estradiol levels. Endometrial proliferation, a change in the size of the cervical os, and a rise in the quantity of cervical mucus with changes in its rheological and physicochemical qualities are all caused by rising estradiol levels released by developing follicles.
During the follicular phase of the cycle, estradiol and inhibin exert a negative feedback mechanism on the hypothalamic-hypophyseal-gonadal (HHG) axis, resulting in a drop in FSH levels. During this time, estrogen also suppresses kisspeptin expression in the hypothalamic arcuate nucleus.
Later, when a follicle becomes the dominant follicle, it generates increasingly high quantities of estradiol, which stimulates kisspeptinergic neurons in the hypothalamic anteroventral periventricular nucleus, shifting the negative feedback process to a positive one.
Ovulatory Dysfunction and Underlying Health Disorders
Hormonal imbalances are the most common cause of menstrual irregularities linked with ovulatory dysfunctions. Hypothalamic, pituitary, thyroid, adrenal, ovarian, and metabolic problems are examples.
Hypothalamic diseases are distinguished by a deviation from the typical pattern of GnRH production, which delays the rise of FSH levels over the threshold. Excessive activity, dietary imbalances, stress, or mental problems such as anorexia can all lead to hypothalamic abnormalities. Low levels of leptin, a hormone released by adipocytes that increases the production of kisspeptin, are caused by nutritional deficiencies and/or low body fat.
Kisspeptin levels are influenced by GnRH release and hence ovulation. Furthermore, an increase in adipose tissue may result in a rise in leptin levels, which causes leptin resistance and consequently affects kisspeptin release. Hypercortisolemia can also cause hypothalamic problems. Cortisol levels that are too high inhibit both GnRH release and gonadotrophin action. As a result, these illnesses can cause hypoestrogenic cycles, anovulation, and amenorrhea.
Prolactinomas are the most frequent pituitary tumors, and they are often linked with hyperprolactinemia. Prolactin production may be increased as a result of stress and/or the usage of antidepressant medications. GnRH is inhibited by high prolactin levels via negative regulation of kisseptinergic neurons and activation of dopaminergic neurons in the hypothalamus. High circulating prolactin levels also stimulate adrenal androgen release and inhibit ovarian androgen aromatization, resulting in greater androgen and lower estrogen levels.
Menstrual abnormalities (occasionally amenorrhea), short luteal phases, reduced libido, dyspareunia, and galactorrhea are symptoms of hyperprolactinemia in women. In our experience, these ladies commonly arrive with allergies, warts, and increased susceptibility to infections. Several autoimmune illnesses, including systemic lupus erythematosus, rheumatoid arthritis, Hashimoto's thyroiditis, and multiple sclerosis, have elevated prolactin levels.
Furthermore, prolactin reduces the negative selection of autoreactive B cells while increasing the proliferative response to antigens and mitogens and the generation of autoantibodies. As a result, this hormone stimulates the immune system, inducing autoimmunity. In this sense, ovulatory dysfunctions can serve as an early warning indication of more significant underlying health problems.
Thyroid hormones control ovulation via influencing ovarian folliculogenesis and steroidogenesis, as well as sex hormone-binding globulin (SHBG) and GnRH production. Menstrual irregularities such as hypomenorrhea, hypermenorrhea, menorrhagia, polymenorrhea, intermenstrual hemorrhage, oligomenorrhea, or amenorrhea can occur in women with thyroid issues.
Menorrhagia is a typical symptom of hypothyroidism caused by low SHBG levels, which increase free estradiol, and stimulates endometrial development. Furthermore, greater levels of thyrotropin-releasing hormone (TRH) in primary hypothyroidism promote the release of prolactin and dopamine, which suppresses GnRH, resulting in ovulatory failure.
In individuals with hyperthyroidism, on the other hand, SHBG levels rise, lowering free estradiol levels. Ovarian and hypophyseal hormones may be elevated as well, leading to ovulatory failure.
Ovulatory dysfunction is usually connected with adrenal and/or ovarian problems. The most prevalent endocrine condition in women is polycystic ovary syndrome (PCOS). These people have hyperandrogenemia, which can cause acne, hirsutism, alopecia, increased body weight, and mood swings. However, the most prevalent symptom reported by these individuals is irregular menstrual periods and an abnormal pattern of cervical mucus, both of which are linked with ovulatory dysfunction.
Obesity, insulin resistance, and subsequent hyperinsulinemia are common co-morbidities of PCOS that might interfere with ovulation. Elevated insulin levels are found in approximately half of these individuals and are associated to BMI, however not all PCOS patients are insulin resistant. High insulin levels enhance androgen production even further by activating ovarian theca cells to create more androgens, resulting in early follicular atresia and potentially anovulation.
Increased testosterone production inhibits granulosa cell aromatase, resulting in decreased estradiol synthesis. High amounts of testosterone and insulin reduce SHBG, resulting in an increase in the free estradiol fraction. This, together with an increase in peripheral estrogen synthesis by adipose tissue, may block the kisspeptinergic system, lowering GnRH and gonadotrophins. PCOS is also linked to an increased risk of developing type 2 diabetes, metabolic syndrome, cardiovascular disease, and endometrial, ovarian, and/or breast cancer.
Congenital adrenal hyperplasia (CAH) is a group of illnesses caused by gene abnormalities that code for enzymes involved in one of the several phases of adrenal steroid manufacture. In certain of these illnesses, cortisol synthesis is defective, causing the adenohypophysis to release excessive amounts of adrenocorticotrophic hormone (ACTH), resulting in hyperandrogenemia owing to adrenal overstimulation.
This causes gonadal dysfunction, premature puberty, menarche delay, menstrual problems, anovulation, and infertility. Addison's disease, also known as premature adrenal insufficiency, is characterized by a lack of cortisol, aldosterone, and adrenal androgen hormone precursors, and is linked to early ovarian failure in certain women.
Premature ovarian senescence affects roughly 10% of all women, with primary occult ovarian insufficiency being the most frequent ailment in this group. Autoimmune, hereditary, and iatrogenic disorders are the three main reasons. These women produce little estrogen and androgen. A dry mucus pattern will indicate an early estrogen insufficiency. In these women, estrogen and/or androgen replacement will enhance mood and reduce the risk of cardiovascular disease, osteoporosis, and other problems.
Vitamin D has also been linked to normal ovarian function, as well as boosting steroidogenesis and follicular growth. By decreasing the aromatase activity of granulosa cells, hypovitaminosis D increases androgen and decreases estrogen levels. Obese people will have low vitamin D levels as a result of adipose tissue sequestering.
Women who have hereditary disorders such as Turner's syndrome will also have ovulatory disruption. Because of poor growth and development, this ailment is normally discovered early in life; but, in some cases, it goes untreated until puberty. There will be amenorrhea along with elevated FSH levels and a hypoestrogenic condition. Karyotyping is required to confirm the diagnosis and rule out the presence of a Y component, as in mosaicism.
Abnormal uterine bleeding can be caused by gynecological illnesses such as anatomical defects, neoplasia, and inflammatory diseases (AUB). Leukemia and anomalies in blood clotting factors must be checked out in women with AUB. AUB may be caused by iatrogenic factors such as hormonal contraception, anabolics, and selective estrogen receptor modulators (SERMs)
Cycle duration varies following contraceptive withdrawal, most likely because the HHG axis is re-establishing itself after being repressed during contraceptive usage, and the quality of cervical mucus is reduced for at least the first six menstrual cycles. In cases of AUB, traumatic occurrences in the pelvic area, pregnancy-related diseases such as spontaneous abortion, and ectopic pregnancies must all be checked out.
Diagnosis of Ovulatory Dysfunction
- Menstrual history
- Sometimes basal body temperature monitoring
- Measurement of urinary or serum hormones or ultrasonography
Based on the menstrual history, anovulation is frequently visible. Measuring your morning body temperature on a regular basis can help you establish whether or not you are ovulating. This strategy, however, is frequently wrong.
More accurate methods include:
- Home testing kits that detect an increase in urine luteinizing hormone (LH) excretion 24 to 36 hours before ovulation are available (requiring daily testing for several days around midcycle, usually beginning about or after cycle day 9)
- Pelvic ultrasonography is used to evaluate ovarian follicle diameter increases and follicle collapse (monitoring should begin in the late follicular phase)
- Measurement of serum progesterone and urinary pregnanediol glucuronide (a urinary metabolite of progesterone)
Ovulation is indicated by serum progesterone levels of 3 ng/mL (9.75 nmol/L) or increased levels of pregnanediol glucuronide in urine (measured, if feasible, 1 week before the commencement of the next menstrual period). Intermittent or missing ovulation should elicit a check for pituitary, hypothalamic, or ovarian problems (especially PCOS).
Treatment of Ovulatory Dysfunction
- Clomiphene or letrozole
- Possibly metformin if body mass index is ≥ 35
- Gonadotropins if clomiphene is ineffective
Ovulation can usually be induced with drugs.
Chronic anovulation that is not caused by hyperprolactinemia is commonly treated with the antiestrogen clomiphene citrate at first.
When the reason is polycystic ovarian syndrome, clomiphene is most helpful (PCOS). Clomiphene 50 mg orally once a day is taken between the third and fifth day after bleeding begins; bleeding can be spontaneous or provoked (eg, by progestin withdrawal). Clomiphene is taken every day for 5 days. Ovulation typically happens 5 to 10 days (on average 7 days) following the final day of clomiphene; if ovulation occurs, menstruation comes within 35 days of the induced bleeding episode.
If menstruation does not occur, a pregnancy test is performed. The treatment cycle is repeated if the lady is not pregnant. To stimulate ovulation, the daily dose can be raised by up to 50 mg per cycle, up to a maximum of 200 mg/day. Treatment is maintained for up to four ovulatory cycles as needed. The majority of women who become pregnant do so by the fourth cycle of ovulation. Ovulation occurs in 75 to 80 percent of clomiphene-treated women, while pregnancy occurs in just 40 to 50 percent.
Clomiphene side effects include vasomotor flushes (10%), stomach distention (6%), breast tenderness (2%), nausea (3%), visual problems (1 to 2%), and headaches (1 to 2 % ). Multifetal pregnancy (mainly twins) occurs in around 5% of cases, while ovarian hyperstimulation syndrome occurs in 1% of cases. Ovarian cysts are rather frequent. A previously proposed link between clomiphene use for more than 12 cycles and ovarian cancer has not been proven.
Clomiphene should not be given to women who are pregnant because, theoretically, it may cause genital birth defects.
Letrozole (an aromatase inhibitor) appears to be more likely than clomiphene to induce ovulation in obese women with PCOS. According to new research, this impact may also occur in skinny women with PCOS. There is no evidence that letrozole is more successful than clomiphene for anovulation caused by conditions other than PCOS. Letrozole's half-life is significantly shorter than that of clomiphene.
Letrozole, like clomiphene, is started between the third and fifth day following the onset of bleeding. For the first five days, women are given 2.5 mg orally once a day. If ovulation fails, the dose can be raised by 2.5 mg per cycle up to a maximum of 7.5 mg/dose.
The most common adverse effects of letrozole are fatigue and dizziness.
Letrozole should not be administered to pregnant women since it has the potential to cause genital birth abnormalities.
Metformin (750 to 1000 mg orally twice a day) may be a valuable adjuvant in promoting ovulation in women with PCOS, especially if the patient is insulin-resistant, as many PCOS patients are. Clomiphene alone, on the other hand, is more effective than metformin alone and is just as effective as metformin and clomiphene together. Metformin is not recommended as first-line medication for women with PCOS who desire to become pregnant.
Metformin may be beneficial for women with BMIs more than 35, and it should be evaluated for women with PCOS and glucose intolerance.
Human gonadotropins (preparations containing pure or recombinant follicle-stimulating hormone [FSH] and various levels of luteinizing hormone [LH]) can be used to treat all women with ovulatory dysfunction who do not react to clomiphene (or letrozole, when taken). There are other IM and subcutaneous formulations with comparable potency; they generally comprise 75 IU of FSH activity with or without LH activity. They are normally administered once a day, starting on the third to fifth day following induced or spontaneous bleeding; ideally, they encourage maturity of 1 to 3 follicles within 7 to 14 days, as assessed ultrasonographically.
Ovulation is commonly initiated by 5,000 to 10,000 IU IM human chorionic gonadotropin (hCG) following follicle maturation; requirements for employing hCG vary, but at least one follicle should be > 16 mm in diameter. A gonadotropin-releasing hormone (GnRH) agonist can also be used to induce ovulation, particularly in women at high risk of ovarian hyperstimulation syndrome.
Although using a GnRH agonist to initiate ovulation reduces the risk of ovarian hyperstimulation syndrome in women at high risk, it is safest not to trigger ovulation if women are at high risk of ovarian hyperstimulation syndrome or multifetal pregnancy. These are some of the risk factors for these issues.
- Presence of > 3 follicles > 16 mm in diameter
- Preovulatory serum estradiol levels > 1500 pg/mL (or possibly > 1000 pg/mL) in women with several small ovarian follicles
When exogenous gonadotropins are utilized correctly, more than 95% of women treated with them ovulate, yet the pregnancy rate is just 50 to 75%. Following gonadotropin medication, 10 to 30% of successful pregnancies are multiple.
Ovarian hyperstimulation syndrome affects 10 to 20% of individuals; the ovaries can become grossly enlarged, and intravascular fluid content moves into the peritoneal cavity, resulting in potentially fatal ascites and hypovolemia.
Treatment of the underlying disorder
If functional hypothalamic amenorrhea is the reason, gonadorelin acetate, a synthetic GnRH agonist administered as a pulsatile IV infusion, can stimulate ovulation. The most effective dosages are 2.5- to 5.0-mcg boluses (pulse doses) given every 60 to 90 minutes. It is improbable that gonadorelin acetate will result in multiple fetal pregnancies.
Because gonadorelin is no longer accessible in the United States, clomiphene citrate is the primary medicine used to treat functional hypothalamic amenorrhea, followed by exogenous gonadotropins if clomiphene induction fails.
Infertility can be caused by disruptions in the formation of an egg (also known as an oocyte or ovum). Home monitoring can be used to detect the commencement of ovulation in the middle of a woman's menstrual cycle by measuring an increase in luteinizing hormone (LH) in her urine using an over-the-counter ovulation prediction kit and/or tracking a substantial rise in her basal body temperature (BBT). Although these monitoring approaches may not establish ovulation, they do give important information.
Oral and injectable medicines can be used to treat ovulatory disorders (commonly referred to as fertility drugs). These drugs cause the ovaries to create and release eggs (also known as ovulation induction). While most patients will respond to oral drugs that require minimum monitoring, certain patients will require injectable treatments that require close monitoring by ultrasounds and estradiol levels, which should only be administered by clinicians with proper training and expertise.
Ovulation induction can be combined with intrauterine insemination (IUI), which can be done with either the husband or donor sperm. IUI is a type of artificial insemination in which sperm that has been specifically prepared and concentrated is put into the woman's uterus via a tiny catheter during the time of ovulation. This sperm preparation is carried out in our accredited andrology laboratory by highly qualified and experienced personnel.