Fig. 1.1
Chronology of folliculogenesis in human ovaries. Preantral period: It takes 300 days for a recruited primordial to grow and develop to the class 2/3 (0.4 mm) or cavitation (early antrum) stage. Antral period: A class 4 (1–2 mm) follicle, if selected, requires about 50 days to grow and develop to the preovulatory stage. The dominant follicle of the cycle appears to be selected from a cohort of class five follicles, and it requires about 20 days to develop to the ovulatory stage. gc number of granulosa cells, d days (From Gougeon et al. [1]. Image courtesy of Alain Gougeon)
1.2.2 Oogenesis
Process of oogenesis starts with the migration of germ cells from yolk sac to gonadal ridge during intra-uterine life. By birth, all germ cells have initiated their first meiotic division (now called primary oocyte) and remain arrested in prophase stage of meiosis 1 till puberty. After puberty, each month few primary oocytes under the effect of pre-ovulatory surge of FSH and LH resume and complete their first meiotic division and result in formation of secondary oocyte and a polar body. The dominant secondary oocyte enters second meiotic division, gets arrested at second meiotic metaphase and subsequently ovulates. Fertilization triggers the resumption and completion of meiosis resulting in the formation of second polar body.
1.2.3 Physiology of Ovulation
In the luteal phase, corpus luteum is the site of estradiol and progesterone production. Corpus luteum possesses considerable capacity of self-regulation and maintains its function active for 14 days. With the demise of corpus luteum towards late luteal phase, the decreasing estradiol levels trigger rise in plasma FSH levels. This rise in FSH level recruits a cohort of class 5 follicles towards the end of luteal phase and facilitates its growth. One follicle in the recruited cohort of follicles is able to concentrate high levels of FSH in its follicular fluid and show rapid mitosis of granulosa cells to become the dominant follicle. This dominant follicle has most FSH receptors, is most sensitive to FSH and produces maximum oestrogen by FSH-mediated activation of aromatase enzyme. High concentrations of FSH in the micro-environment of dominant follicle, through gap channels between granulosa cells and oocyte, keep the concentration of cAMP and oocyte maturation inhibitor (OMI) high, which in turn keep the oocyte in immature stage. The rising oestrogen level in turn by negative feedback mechanism lowers the plasma FSH level towards the end of the first week in follicular phase of menstrual cycle. This lowering FSH concentration is unable to sustain growth of rest of the follicles of the recruited cohort, which subsequently undergo atresia. The dominant follicle on the other hand by this time becomes less responsive to declining FSH levels and continues to grow. Moreover, the FSH-mediated induction of LH receptors on dominant follicle enables LH to take part in the growth and development of dominant follicle during later follicular phase and also in preparation of dominant follicle for upcoming LH surge. When the rising oestrogen level crosses a critical level, its negative feedback at hypothalamic-pituitary axis turns into a positive feedback giving rise to LH surge. LH surge lasts for 36–48 h. LH surge by dismantling the gap junctions between granulosa cells and oocyte inhibits the flow of maturation-inhibitory factors into ooplasm and causes drop in concentration of cAMP. Decreased concentration of cAMP in turn increases concentration of Ca and maturation-promoting factor (MPF), which are essential for the resumption of meiosis in oocyte and disruption of oocyte-cumulus complex triggering follicular rupture and ovulation about 36 h the LH surge. What enables one follicle of the cohort to concentrate FSH in its micro-environment in preference to others is still not clearly understood, but this selection leads to a single ovum being released by ovaries in each menstrual cycle [2, 3].
1.2.4 Recent Research
Recent research work has indicated the possibility of presence of renewable oogonia in the lining of female ovaries of humans, primates and mice. These studies have discovered that some mitotically active germ cells may migrate to ovaries from bone marrow and act as extra genial source of stem cells. Researchers have discovered these renewable germ cells as these were identified positive for several essential oocyte markers. If further studies support these findings, it could revolutionise treatment of infertility [4–6].
1.3 Aetiology of Anovulation
Ovulation is the result of complex and finely tuned interactions between hypothalamus, pituitary and ovary (Fig. 1.2). Any aetiology leading to the disruption of this fine tuning can cause anovulation. These can be broadly categorized as
Fig. 1.2
Hormonal regulation of ovulation. Solid arrows: positive feedback. Dotted arrows: negative feedback
1.3.1 Hypothalamic Factors
Hypothalamic hormones particularly gonadotrophin-releasing hormone (GnRH) are an important factor responsible for functional hypothalamo-pituitary-ovarian axis. GnRH hormone is a decapeptide which is synthesised and released by specialised neuronal endings of nucleus arcuate of hypothalamus. Any factor hindering pulsatile release of GnRH hormone leads to anovulation.
1.3.1.1 Functional Hypothalamic Dysfunction
Excessive strenuous exercise, stress, anxiety, under-nutition, eating disorders like anorexia nervosa by inhibiting normal GnRH pulsatility due to excessive release of corticotrophin-releasing hormone and stimulation of beta-endorphins can lead to amenorrhoea and anovulation. Drug abuse (cocaine, marijuana) and psychiatric disorders (schizophrenia) can also cause anovulation by suppression of GnRH.
1.3.1.2 Structural Hypothalamic Dysfunction
Infiltrative disorders of the hypothalamus (e.g. Langerhans cell granulomatosis, lymphoma, sarcoidosis, TB), tumours of hypothalamus, irradiation to the hypothalamus, chemo-toxic agents and traumatic brain injury by destruction of arcuate nucleus or distortion of hypothalamic-pituitary axis can lead to anovulation.
1.3.1.3 Genetic Disorders
Less commonly, genetic disorders like Kallmaan syndrome (defective migration of GnRH neurons), Prader-Willi syndrome and GnRH receptor gene mutation can be a cause of anovulation and infertility [7].
1.3.2 Pituitary Factors
GnRH from hypothalamus via portal circulation is transported to anterior pituitary where it leads to the release of gonadotrophins (LH and FSH). The amplitude and frequency of GnRH pulse determines the release of FSH or LH.
1.3.2.1 Structural Pituitary Dysfunction
Infiltrative conditions of pituitary (TB, sarcoidosis, hemochromatosis), space-occupying lesions of pituitary (microadenomas, macroadenomas, aneurysms), tumours of brain (meningioma, gliomas, craniopharngiomas), trauma to brain, irradiation to brain or postpartum pituitary necrosis by causing destruction of pituitary leads to anovulation.
1.3.2.2 Genetic Disorders
Idiopathic hypogonadotrophic gonadism, isolated gonadotrophin deficiency and gene mutation of beta subunit of FSH and LH are genetic disorders which can result in anovulation and infertility.
1.3.3 Ovarian Factors
The site of the final step in the process of ovulation is ovaries.
1.3.3.1 Iatrogenic Causes
Irradiation to pelvis, chemotherapy and surgical removal of ovaries are some of the iatrogenic factors that can lead to anovulation and infertility.
1.3.3.2 Genetic Factors
Chromosomal abnormalities like Turner syndrome, fragile X syndrome, idiopathic accelerated ovarian follicular atresia and gonadal dysgenesis are genetic causes of absent ovulation.
1.3.3.3 Ovarian Failure
Premature ovarian failure and resistant ovarian syndrome are other causes of anovulation [8].
1.3.4 Endocrine Causes
1.3.4.1 Polycystic Ovarian Syndrome
Polycystic ovarian syndrome is a heterogeneous group of disorders with a prevalence of 5–10 % in reproductive age-group [9]. Hyper-androgenism, oligo-ovulation or anovulation, oligo- or amenorrhoea, insulin resistance and obesity are the common clinical presentation of this syndrome complex. Abnormal endocrine environment with unopposed oestrogen and excess of LH leads to suppression of FSH release and hits the process of ovulation at the stage of follicular recruitment [10].
1.3.4.2 Hyperprolactinemia
Hyperprolactinemia of any cause can lead to anovulation by affecting the hypothalamo-pituitary axis at multiple sites. The important ones are impaired pulsatility of GnRH release and interference with the positive feedback effect of oestrogen on LH surge [7].
1.3.4.3 Hyper-androgenism
Other causes of hyper-androgenism like congenital adrenal hyperplasia, Cushing syndrome, androgen-secreting tumours and drug-induced virilization can lead to anovulatory infertility.
1.3.4.4 Thyroid Dysfunction
Severe untreated thyroid dysfunction, both hyper- or hypothyroidism, can cause menstrual irregularities and anovulatory infertility. The anovulatory effect of severe hypothyroidism is partly mediated by hyper-prolactinemia because of the fact that elevated TSH acts as a release factor for prolactin.
1.3.5 Systemic Causes
1.3.5.1 Renal Disease
Chronic and end-stage renal disease causes hypothalamic anovulation and menstrual acyclicity probably due to absence of positive feedback effect of oestrogen on hypothalamus and thus absence of LH surge. Women with uremia usually show high LH and high prolactin level [11].
1.3.5.2 Liver Disorders
Anovulatory infertility is common in women with end-stage liver disease. These women usually show decreased levels of gonadotrophins and oestrogen. These patients usually do not respond to GnRH stimulation or clomiphene, but successful liver transplant can result in restoration of ovulation.
Testicular feminising syndrome and other intersex conditions are unrelated conditions which can present with anovulatory infertility.
Anovulatory infertility accounts for 21 % of female infertility [12]. The World Health Organization classifies ovulation disorders into three groups (Table. 1.1) [13].
Table 1.1
World Health Organization Classification of ovulation disorders
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