Fecundability is the ability to conceive. Successful pregnancy requires a complex sequence that includes ovulation, ovum pick-up by a fallopian tube, fertilization, transport of a fertilized ovum into the uterus, and implantation into a receptive uterine cavity. Various studies show a monthly probability of conceiving up to 20–25%.

The female genital system is made up of dynamic organs that change during the woman’s life cycle.

Schematically, during the period between two menses, it can be divided into:

  • Ovarian Cycle: It consists of the growth and development of the ovarian follicle, its bursting, and transformation into the corpus luteum with relative production of estrogens and progesterone.

  • Menstrual Cycle: It consists of the modifications of the endometrium, affected by ovarian hormones, that has to be prepared to accommodate the fertilized egg.

The normal menstrual cycle is the result of the integration of the primary neuroendocrine complex (the hypothalamus–pituitary–ovarian axis) into a control system regulated by a series of peripheral mechanisms of feedback and nerve signals that result in the release of a single mature oocyte from a pool of hundreds of thousands of primordial oocytes [1, 2].

16.1 Hypothalamic–Pituitary Axis [3,4,5]

The hypothalamus is made up of a series of nuclei located at the base of the brain, whose neurons contract synapses throughout the central nervous system. It is linked with the anterior pituitary gland by the portal system of blood supply. The posterior pituitary gland or neurohypophysis is like a “repository” for the hypothalamic hormones ADH and oxytocin. In fact, it contains the axonal terminals of neurons arising in the supraoptic (SO) nucleus that produces ADH and paraventricular nucleus (PVN) that produces oxytocin of the hypothalamus.

The hypothalamus produces GnRh, a decapeptide which stimulates gonadotropins biosynthesis and secretion: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Pulsatile GnRh input is required for activation and maintenance of GnRh receptors; changes in GnRh pulse frequency affect the absolute levels and the ratio of LH and FSH release.

The anterior pituitary gland contains five hormone-producing cell types: gonadotrophs (LH and FSH), lactotrophs (PRL), somatotrophs (GH), thyrotrophs (TSH), and adrenocorticotrophs (ACTH). All the pituitary hormones are stimulated by hypothalamic neuroendocrine secretion, while PRL is under tonic inhibition and its expression is primarily under inhibitory regulation by dopamine. In fact, the gonadotropins (LH and FSH) are regulated by GnRH. The biosynthesis of ACTH is stimulated by the corticotropin-releasing hormone. The secretion of TSH is induced by the Thyrotropin-releasing hormone.

By convention, the first day of menses represents the first day of the cycle (day 1). The cycle is then divided into two phases: follicular and luteal.

  • The follicular phase begins with the onset of menses and ends on the day before the LH surge.

  • The luteal phase begins on the day of the LH surge and ends at the onset of the next menses.

An average menstrual cycle lasts from 28 to 35 days, with approximately 14 to 21 days in the follicular phase and 14 days in the luteal phase [1, 2]. Changes in the intermenstrual interval are primarily due to changes in the follicular phase; in comparison, the luteal phase remains relatively constant.

16.2 Early Follicular Phase

In the early follicular phase, the ovary is least hormonally active, resulting in low serum estradiol and progesterone concentrations. Influenced from the negative feedback effects of estradiol, progesterone and probably inhibin, there is an increase in gonadotropin-releasing hormone (GnRH) pulse frequency and a subsequent increase in serum follicle-stimulating hormone (FSH) concentrations of approximately 30% [6]. This small increase in FSH secretion appears to be required for the recruitment of the next cohort of developing follicles, one of which will become the dominant and then ovulatory follicle during that cycle [7,8,9]. There is also a rapid increase in LH pulse frequency at this time, from one pulse every four hours in the late luteal phase to one pulse every 90 min in the early follicular phase [10]. Serum anti-Müllerian hormone (AMH) has been used as a potential marker of ovarian health and aging. It is secreted by small antral follicles and correlates with the total number of ovarian antral follicles. The variability of serum AMH across the menstrual cycle appears to be minimal [11].

16.2.1 Ovaries and Endometrium

The ovary is quiescent in the early follicular phase, except for the occasionally visible resolving corpus luteum from the previous cycle. It is possible to see small follicles of 3 to 8 mm in diameter at this time. The endometrium is relatively indistinct during menses becoming a thin line once menses are completed.

16.3 Mid-Follicular Phase

The moderate rise in follicle-stimulating hormone (FSH) secretion progressively stimulates folliculogenesis and estradiol production, leading to progressive growth of the cohort of follicles selected. When several follicles initially grow to the antral stage, their granulosa cells increase in the size and divide, producing increasing serum concentrations of estradiol via FSH stimulation of aromatase and then inhibin A from the granulosa cells in the ovaries. The increase in estradiol production negatively affects the hypothalamus–pituitary axis, suppressing the FSH and LH concentrations as well as the LH pulse amplitude. At the same time, the gonadotropin-releasing hormone (GnRH) pulse generator accelerates slightly to a mean LH pulse frequency of approximately one per hour (versus one per 90 min in the early follicular phase). This GnRH stimulation is probably due to the negative feedback effects of progesterone from the previous luteal phase.

16.3.1 Ovarian and Endometrial Changes

Several antral follicles of 9–10 mm are visible on ovarian ultrasonography. There is a proliferation of the uterine endometrium that becomes thicker with an increase in the number of glands and the typical aspect of a “triple stripe” due to the increased concentrations of estradiol [12].

16.4 Late Follicular Phase

During the week before ovulation, the growing follicle induces the increase of estradiol and inhibin A. This increase of the estradiol is responsible for reducing the concentrations of FSH and luteinizing hormone LH due to negative feedback effects. Once the dominant follicle has been selected, FSH induces LH receptors in the ovary and increases ovarian secretion of intrauterine growth factors.

16.4.1 Ovarian, Endometrial, and Cervical Mucus Changes

A single dominant follicle has been selected. It increases in size 2 mm per day until a mature size of 20 to 26 mm is reached. The rest of the growing cohort of follicles gradually stop developing and undergo atresia. There is a gradual thickening of the uterine endometrium due to the rising of estradiol concentrations and changes of the cervical mucus; in particular, there is an increase in the amount and “stringiness”.

16.5 Midcycle Surge and Ovulation

One day before the ovulation, an important neuroendocrine phenomenon occurs: the midcycle surge [10, 13]. It consists of a switch from negative feedback control of LH secretion by ovarian hormones (such as estradiol and progesterone) to a sudden positive feedback effect, resulting in an increase in serum LH concentrations and a smaller rise in FSH concentrations. This is probably due to an increase in the number of pituitary gonadotropin-releasing hormone (GnRH) receptors, but there is probably no change in GnRH input to the pituitary gland [14]. At this time, the amplitude of the LH pulses increases drastically even if the frequency of LH pulses continues to be approximately one per hour [15].

16.5.1 Ovarian Changes

The LH surge is responsible for important changes in the ovary. The oocyte in the dominant follicle completes its first meiotic division, then it is released from the follicle at the surface of the ovary approximately 36 h after the LH surge. It then travels down the fallopian tube to the uterine cavity. At the same time, there is an increase of secretion of plasminogen activator and other cytokines required for the process of ovulation [16, 17]. Before the oocyte is released, the granulosa cells begin to luteinize and produce progesterone. Progesterone is responsible for reducing LH pulse that becomes less frequent by the termination of the surge. There is a close relation of follicular rupture and oocyte release to the LH surge; as a result, measurements of serum or urine LH can be used to estimate the time of ovulation in women.

16.5.2 Endometrium

The endometrium becomes more uniformly bright, the “triple stripe” image is lost. This is due to the impact of progesterone increase that it is responsible for cessation of mitoses and “organization” of the glands [12, 18].

16.6 Luteal Phase

The corpus luteum induces the rising of progesterone concentrations in the middle and late luteal phase [19]. This increase causes the progressive slowing of LH pulses down to one pulse every four hours. A decrease in LH secretions results in a gradual fall in progesterone and estradiol production by the corpus luteum in the absence of a fertilized oocyte [20]. However, if the oocyte becomes fertilized, several days after ovulation starts its implantation in endometrium. The early embryo begins to make chorionic gonadotropin, which maintains the corpus luteum and progesterone production. Inhibin A is also produced by the corpus luteum, and serum concentrations of inhibin A reach peak in the mid-luteal phase. Inhibin B secretion is virtually absent during the luteal phase.

16.6.1 Endometrial Changes

In response to estradiol and progesterone decline due to the resolving of corpus luteum, the endometrium lose the blood supply. Menstruation is the cyclic, orderly sloughing of the uterine lining approximately 14 days after the LH surge [6]. Simultaneously, the hypothalamic–pituitary axis induces the LH rise and a new cycle starts.

16.7 Puberty

After birth, the gonads are quiescent until they are activated by gonadotropins from the pituitary gland to bring about the final maturation of the reproductive system (gonadarche). This period of transition to final sexual maturation is known as puberty. The age at the time of puberty is variable, generally occurring between the ages of 8 and 13 in girls depending on race/ethnic background and weight status. Between 5 and 12% of girls have menarche younger than 11 years of age [21]. The main physiological events in puberty are:

  • Gonadarche: the activation of the gonads by gonadotropins from the pituitary gland. In details, the follicle-stimulating hormone (FSH) stimulates the growth of ovarian follicles and LH stimulates production of estradiol by the ovaries. At the onset of puberty, estradiol induces breast development and growth of the skeleton, leading to pubertal growth acceleration. Later in puberty, the interaction between pituitary secretions of gonadotropins and the secretion of estradiol by ovarian follicles leads to ovulation and menstrual cycles [22].

  • Adrenarche: An increase in the secretion of adrenal androgens by the adrenal cortex. Typically happens in females before the onset of puberty occurring at age of 8–10 years. It is probably due to a rise in a 17α-hydroxylase activity. There is a gradual decline in this activity as plasma adrenal androgen secretion declines to low levels in old age.

Most adolescents have a predictable path for pubertal maturation, although there is some variability between individuals in terms of timing and sequence.

The first event of puberty is thelarche, the development of breasts. The breasts develop under the influence of the ovarian hormones, estradiol and progesterone, with estradiol primarily responsible for the growth of ducts and progesterone primarily responsible for the growth of lobules and alveoli.

Thelarche is then followed by pubarche, the development of axillary and pubic hair. The adrenal androgens significantly contribute to the growth of axillary and pubic hair.

Finally, there is menarche, the first menstrual period. The initial periods are generally anovulatory and occurs up to 2–2.5 years after the onset of puberty. A physiologic leukorrhea which is a thin, white, non-foul-smelling vaginal discharge occurs up 6 to 12 months before menarche for the estrogen stimulation of the vaginal mucosa [23,24,25,26].

The initial manifestation and the earlier onset of puberty has a lot of clinical implications. Earlier menarche (before 12 years of age) is associated with higher BMI during adulthood as compared with later menarche [27]. The earlier onset of puberty has important implications for the diagnosis of precocious puberty that has been defined as breast development prior to eight years of age in girls. Earlier puberty is associated with increased risk of adult pathological conditions. Multiple studies have reported the association of earlier age at menarche with breast cancer, with a 7% decreased risk for premenopausal breast cancer and 3% decreased risk for postmenopausal breast cancer for every year menarche is delayed [28]. Earlier puberty is also associated with increased risk for other reproductive cancers: endometrial and ovarian cancer in women and prostate cancer in men [29]. The relationship of pubertal timing and cardiovascular disease is more complex; in women, both earlier and later age at menarche are associated with increased risk of coronary heart and cerebrovascular diseases [30]. Additionally, earlier age at menarche is associated with increased risk for type 2 diabetes and impaired glucose tolerance; part of this association is mediated by increased adiposity and part is independent from adiposity [31]. Later puberty onset includes lower bone mineral density, increased fracture risk, and in men, increased risk for depression and anxiety. The pathophysiological processes for these associations are not known [32, 33].

16.8 Menopause

Natural menopause is the permanent cessation of menstrual periods, determined retrospectively after a woman has experienced 12 months of amenorrhea without any other obvious pathologic or physiologic cause. It is a reflection of complete, or near complete, ovarian follicular depletion, with resulting hypoestrogenemia and high FSH concentrations. Perimenopause is characterized by irregular menstrual cycles, endocrinological changes, and many symptoms. Early menopause begins between the ages of 40 and 45 years and late menopause after age of 55 years.

16.8.1 Clinic

Perimenopause starts about several years before the final menstrual cycle and results in various physiological changes that may affect woman’s quality of life. It is characterized by irregular menstrual cycles and hormonal fluctuations.

Some of the symptoms are:

  • Neurovegetative symptoms (the most frequent clinical manifestation of menopause are hot flushes (80%)) [34]. Palpitations and insomnia also occur.

  • Sleep disorders.

  • Atrophy of the urogenital system.

  • Mood fluctuations.

  • Emotional instability, nervousness, decreased libido, concentration difficulties, memory loss.

  • Atrophy, dryness, and itching of skin and mucous membranes.

  • Higher cardiovascular risk [35].

  • Osteoporosis [36].

  • Body composition (in the early postmenopausal years women usually gain fat mass and lose lean mass with a central fat distribution) [37].

16.8.2 Menopausal Endocrinology

During menopause, there is a gradual decrease in estradiol and inhibin and an increase in gonadotropins (more FSH than LH) as there is no negative feedback of ovarian steroid hormones [38]. The main source of estrogens will be the peripheral conversion of adrenal androgens to estrogens; estrone is the most important estrogen in menopause.

Other endocrine changes through the menopausal transition include a progressive decrease in serum inhibin B and AMH. Also, ovarian antral follicle count (AFC) declines steadily across the reproductive years until postmenopause.

16.8.3 Diagnosis

Generally, it is clinical: amenorrhea for 1 year accompanied by climacteric symptoms. Hormonal determinations also can be carried out: FSH >40 mU/mL, estradiol <20 pg/mL, and AMH < 10 pg/mL [39]. However, hormonal concentrations are less predictive of menopausal stage than clinical criteria, so they should not be used alone [40].

16.8.4 Treatment

Postmenopausal women experience vulvovaginal symptoms including dyspareunia and atrophy, which can be treated by local administration of estrogen. Osteoporosis is treated with calcium-rich diets, moderate exercise, calcitonin, and/or bisphosphonates. Coffee, tobacco, and alcohol should be avoided. Hormone replacement therapy is indicated for the management of menopausal symptoms, but not to prevent chronic disease such as cardiovascular disease, osteoporosis, or dementia [41, 42]. Indications are: symptomatic menopause (systemic estrogens are the most effective treatment available for relief of hot flashes) and early menopause (surgical or nonsurgical). Absolute contraindications are:

  • Hormone-dependent gynecological carcinomas (breast, endometrial).

  • Thrombophilia.

  • History of coronary or cerebrovascular disease.

  • Ongoing severe hepatopathy or liver tumors.

  • Abnormal uterine bleeding of unknown cause.

There are two categories of menopausal hormone therapy: combined estrogen-progestin therapy and estrogen-alone therapy. The protective and side effects of both therapies have been investigated [41].

16.9 Amenorrhea

Approximately 2.5% of the population is affected by primary amenorrhea, defined as the absence of menses by age of 13 years in the absence of normal growth or secondary sexual development, or the absence of menses by age of 15 years in the setting of normal growth and secondary sexual development.

Secondary amenorrhea is defined as the absence of menses, in a previously menstruating woman, for more than three cycle intervals, or six consecutive months.

Regular and spontaneous menstruation requires:

  • Functional hypothalamic–pituitary–ovarian endocrine axis.

  • An endometrium able to respond to steroid hormone stimulation.

  • An intact outflow tract from internal to external genitalia.

16.9.1 Causes of Amenorrhea


  • Pregnancy.

  • Hypothalamic amenorrhea.

  • Galactorrhea-amenorrhea syndrome.

  • Polycystic ovarian syndrome.

  • Pituitary amenorrhea.

Less frequent:

  • Premature ovarian failure (POF).

  • Asherman’s syndrome.

  • Sheehan’s syndrome.

  • Drug-induced amenorrhea.


  • Diabetes.

  • Hyperthyroidism or hypothyroidism.

  • Cushing’s syndrome.

  • Addison’s disease.

  • Cirrhosis.

  • Infection (tuberculosis, syphilis, encephalitis/meningitis, sarcoidosis).

  • Chronic renal failure.

  • Malnutrition.

  • Irradiation or chemotherapy.

  • Hemosiderosis.

  • Surgery.

16.9.2 Causes of Primary Amenorrhea

Primary amenorrhea is mainly due to genetic and anatomical disorders. The most common etiologies are Gonadal dysgenesis, Mullerian agenesis, Polycystic ovary syndrome (PCOS), and isolated GnRH deficiency.

Ovarian dysgenesis is caused primary by chromosomal abnormalities of the X. Most of the patients have Turner syndrome (45, XO or 45, XO/XX mosaics) and present with primary amenorrhea. Women with Turner syndrome are missing an X chromosome. The oocytes and follicles go into apoptosis even before the fetus is born. The ovaries are replaced by steak gonads, and in the absence of follicles, there is no secretion of ovarian estrogen, resulting in primary amenorrhea. However, the external female genitalia, uterus, and fallopian tubes develop normally until puberty, when estrogen-induced development does not occur. However, some patients with mosaic abnormalities may experiment secondary amenorrhea [43].

Müllerian dysgenesis: It results from agenesis or hypoplasia of the Müllerian duct system, with different degrees of severity according to the absent anatomical components. All or part of the vagina will be absent while the other female sexual characteristics are normal.

Other anatomic defects include imperforate hymen, transverse vaginal septum, and isolated absence of the vagina or cervix. These conditions present with cyclic pain and an accumulation of blood behind the obstruction, which can lead to endometriosis and pelvic adhesions [44].

Polycystic ovary syndrome: It is the most common reproductive disorder in women, accounts for approximately 20% of cases of secondary amenorrhea, but may account for approximately 50% of cases of oligomenorrhea [48]. It is a rare cause of primary amenorrhea. After exclusion of other etiologies, the diagnosis is based on the presence of at least two of the following criteria: (1) oligo- or anovulation, (2) clinical and/ or biochemical signs of hyperandrogenism, and (3) polycystic ovaries on ultrasound [45]. Even if the exact mechanics are not clear, it appears that insulin resistance and hyperinsulinemia are involved [46].

Isolated GnRH deficiency is rare and is called idiopathic hypogonadotropic hypogonadism or Kallmann syndrome if it is associated with anosmia [47].

Steroid Enzyme Defects alter ovary steroidogenesis in the different steps leading to testosterone and estradiol synthesis. The resulting clinical picture is different depending on the involved enzyme. They are a rare cause of primary amenorrhea.

16.9.3 Causes of Secondary Amenorrhea

The most common causes of secondary amenorrhea are, in order of frequency, pregnancy, functional hypothalamic amenorrhea, pituitary defects, polycystic ovary syndrome, premature ovarian insufficiency, and intrauterine adhesions.

Functional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea and excludes pathologic disease. Several factors can lead to this condition, including a significant weight loss or restricted diet, intense exercise, and stress.

Pituitary Defects: acquired pituitary dysfunction can follow local radiation or surgery or Sheehan’s syndrome, characterized by postpartum amenorrhea, in women with significant postpartum blood loss. This may result in ischemic necrosis of the pituitary gland and hypopituitarism [48]. Hyperprolactinemia is the most common pituitary cause of secondary amenorrhea. Prolactin-secreting adenomas are the most common subtype of secretory pituitary adenoma. These tumors are usually benign, and prolactin levels typically correlate with tumor size. Elevated prolactin levels lead to amenorrhea, but the mechanisms underlying are unclear [47]. Isolated hyperprolactinemia is an infrequent cause of primary amenorrhea. The diagnosis is suggested by a history of galactorrhea and elevated serum prolactin level. Medications such as antipsychotic, antidepressant, and prokinetics can increase serum prolactin levels and lead to amenorrhea. TRH also induces prolactin secretion, so primary hypothyroidism will result in elevated TRH, hyperprolactinemia, and galactorrhea-amenorrhea syndrome [49].

Premature Ovarian Failure (POF): If menopause occurs before age 40 year, it is marked by amenorrhea, increased gonadotropin levels, and estrogen deficiency. Causes of premature ovarian failure may be different: Turner syndrome, fragile X premutation, autoimmune ovarian destruction, radiation therapy, or chemotherapy with alkylating agents or unknown [50].

Intrauterine synechiae are often caused by a complicated dilatation and curettage (Asherman’s syndrome).

16.9.4 Differential Diagnosis Diagnosis of Primary Amenorrhea

A pelvic examination and an ultrasound scan can be used to define the presence of uterus, vagina, and no outflow obstruction that may cause the absence of menses.

Moreover, FSH serum level should be measured too. If hypergonadotropic hypogonadism is present, the probable diagnosis is gonadal dysgenesis, and a karyotype should be done.

In case of Mullerian agenesis, serum gonadotropins are in the range and the uterus is absent.

In case of obstructed outflow, FSH is normal, uterus is present, but instrumental examination reveals accumulation of blood in the uterus or vagina. A story of pelvic pain will be attended.

If the FSH is low, the uterus is present and there’s no evidence of breast development, most likely the patient has a hypothalamic-pituitary disorder. Distinction of hypothalamic from pituitary disorders can be obtained by the injection of GnRH, but pituitary causes are rare and can often be diagnosed by history alone. Diagnosis of Secondary Amenorrhea

The first cause of secondary amenorrhea is pregnancy, so measurement of beta-hCG is recommended.

History of weight loss, extreme exercise, diet, or illness should be indagated to discover a functional hypothalamic amenorrhea. If there are clinical evidences of hyperandrogenism, an ultrasound should be done to study the ovaries and serum total testosterone should be measured. If a patient has no history of dilatation and curettage, we can almost certainly exclude Asherman’s syndrome. Karyotype genetic test is indicated for all women who present with primary ovarian failure. Serum PRL, FSH, and TSH should be tested. If PRL is initially higher than 50–200 ng/mL, the patient must be studied to discover a prolactinoma. If prolactin level is in the range of 20–50 ng/mL, TSH levels should be measured. If TSH levels are high, hypothyroidism must be corrected and prolactin must be measured again. Estrogen status can be assessed with a progestin challenge. Withdrawal bleeding after progestin discontinuation indirectly determines that endometrium has been prepared with ovarian estrogen. Absence of bleeding can be due to hypoestrogenism or an outflow obstruction.

16.9.5 Amenorrhea Complications

Many are the complications of amenorrhea, including infertility and psychosocial disorders. Hypoestrogenism can lead to the development of severe osteoporosis [36]. In patients responding to progesterone challenge, hyperestrogenism not counterbalanced by progestin is a risk factor for endometrial hyperplasia and cancer.

16.9.6 Treatment Ovulation Induction in Patient Desiring Pregnancy

Dopamine agonist drugs remain the first-line therapy in patients with both micro and macroadenomas. These drugs can decrease prolactin secretion and tumor size. Thyroid replacement therapy should be used in patient with hypothyroidism. In patients with a negative progestin-challenge, estrogen levels are low, and the pituitary does not produce high quantities of LH and FSH, so exogenous gonadotropins are the first-line therapy. Patients with a positive progestin challenge would probably respond to clomiphene citrate, which has important antiestrogenic activity on the hypothalamus and pituitary, preventing negative feedback on GnRH release and leading an increase in endogenous FSH.

Most of the premature ovarian failures are idiopathic and cannot be treated. Patient Not Desiring Pregnancy Can Be Divided into Two Categories

Hypoestrogenic patients must be treated with both estrogen and progestin to prevent complications due to the absence of these two hormones. Oral contraceptives can be used. Patients who respond to the progestin challenge require sporadic progestin delivery to prevent endometrial hyperplasia and carcinoma. In patients with hyperprolactinemia, prolactin should be measured periodically, and they must be studied for the development of macroadenomas.

16.10 Infertility

16.10.1 Definition

  • Infertility is defined as the inability of a couple to conceive within 1 year of regular, unprotected sexual intercourse.

  • Primary infertility applies to those who have never conceived.

  • Secondary infertility designates those who have conceived in the past.

  • Sterility implies an intrinsic inability to achieve pregnancy.

  • Fecundability is the probability of being pregnant in a single menstrual cycle.

  • Fecundity is the probability of achieving a live birth within a single cycle.

The prevalence of women diagnosed with infertility is approximately 13%, with a range from 7 to 28%, depending on the age of the woman [51]. The incidence of primary infertility has increased, with a concurrent decrease in secondary infertility, most likely because of social changes such as delayed childbearing. In normal fertile couples having frequent intercourse, the fecundability is estimated to be approximately 20–25%. Approximately 85–90% of couples with unprotected intercourse will conceive within 1 year.

16.10.2 Timing of Infertility Evaluation

Infertility evaluation should be undertaken for couples who have not been able to conceive after 12 months of unprotected and frequent intercourse, but earlier evaluation should be undertaken based on medical history and physical findings, and in women over 35 years of age [52].

An inverse relationship exists between fecundity and the age of the woman. This decline in fertility is multifactorial. Females are born with a fixed number of oocytes, which decreases with age. The quality of oocytes also falls with age because meiotic errors occur more frequently with increasing age [53]. During the menstrual cycle, the process to select a dominant follicle for ovulation does not exclude genetically abnormal oocytes. In addition to the endogenous accumulation of genetic errors in the oocyte pool, other factors such as smoking, other environmental exposures, and certain medical and surgical treatments can compromise oocyte quality, ovarian reserve, and chance for a healthy outcome for pregnancy [54].

16.10.3 Most Common Female Factors of Infertility

Female factor infertility was reported in 37% of infertile couples in developed countries. The most common identifiable female factors, which accounted for 81% of female infertility, were:

  • Ovulatory disorders (25%).

  • Tubal abnormalities (20%).

  • Endometriosis (15%).

  • Pelvic adhesions (12%).

  • Hyperprolactinemia (7%). Ovulatory Disorders

An ovulatory dysfunction is responsible for approximately 20–25% of infertility cases. The history, including the onset of menarche, menstrual cycle length, and presence or absence of premenstrual symptoms, should be investigated. Signs and symptoms of systemic disease, especially of hypothyroidism, and physical signs of endocrine disease (i.e., hirsutism, galactorrhea, and obesity) should be focused on. The degree and intensity of exercise and a history of weight loss and of hot flushes are clinical clues of possible endocrine or ovulatory dysfunction. Progesterone serum levels of 3 ng/mL or greater in the mid-luteal phase are coherent with ovulation, which can be supported by pelvic ultrasonography. In the follicular phase, the developing follicle can be monitored until maturation and subsequent rupture. The disappearance of the follicle and appearance of free fluid can document ovulation. A secretory endometrium confirms ovulation. To detect the LH surge, the patient can use urinary LH kits or serum LH assay. Ovulation occurs 24–36 hours after the onset of the LH surge and 10–12 hours after the peak of the LH.

Ovarian reserve is the functional capacity of the ovary and it is determined by the number and the quality of oocytes at a certain time. It depends on age, exposure to toxic factors (i.e., smoking, surgery, gonadotropic therapies), and individual follicular wealth.

Initially, the basal FSH level in the early follicular phase was used as a test of ovarian reserve. However, FSH has considerable intra- and inter-cycle variability, and this greatly limits its reliability [55].

The most appropriate quantitative tests are the AMH assay [54] and the transvaginal ultrasound count of pre-antral follicles (AFC), which are used as predictors of the potential success of fertility treatments.

AMH is secreted exclusively by the granulosa cells of the pre-antral pool and small FSH-independent antral follicles, so it can be assayed at any stage of the cycle.

The antral follicle count (AFC) is calculated by adding up the number of follicles between 2 and 10 mm in size in both ovaries. Ninety nine percent of the follicles in the ovary are primordial follicles, plus a proportion of follicles in the early growth phase that are too small to be seen by ultrasound. However, a proportion of these follicles mature into antral follicles with a diameter of more than 2 mm, forming the recruitable pool responsive to FSH. These follicles can be detected by transvaginal ultrasound. Pelvic Factor

The pelvic factor includes abnormalities of the uterus, fallopian tubes, ovaries, and adjacent pelvic structures. A history of pelvic infection, the use of intrauterine devices, endometritis, and septic abortion are suggestive for diagnosis.

Endometriosis may be suggested by worsening dysmenorrhea, dyspareunia, or previous surgical reports. Endometriosis decreases fertility due to anatomic distortion from pelvic adhesions, damage to ovarian tissue by endometrioma formation and surgical resection, and the production of substances such as cytokines and growth factors which impair the normal processes of ovulation, fertilization, and implantation [56].

Uterus: An impaired implantation, due to mechanical factors or reduced endometrial receptivity, is the uterine cause of infertility.

Uterine fibroids are common benign smooth muscle monoclonal tumors. Apparently, fibroids with a submucosal or intracavitary component can reduce implantation rates [57].

Uterine abnormalities, like Müllerian anomalies, are a significant cause of recurrent pregnancy loss. The septate uterus is associated with the poorest reproductive outcome [58, 59].

Any history of ectopic pregnancy, adnexal surgery, leiomyomas, or exposure to diethylstilbestrol (DES) in utero should be noted as possibly contributory to the diagnosis of a pelvic factor.

A pelvic examination can give many information (a fixed uterus is suggestive of adhesions, leiomyomas, or adnexal masses).

A transvaginal ultrasound examination can add information (hydrosalpinx, leiomyoma, ovarian cysts, including endometriomas, can often be observed). Tubal Disease

The main cause of tubal factor infertility is pelvic inflammatory disease caused by pathogens such as Gonorrhea, Chlamydia trachomatis, or Mycoplasma genitalium [60]. Other conditions that may interfere with tubal transport include severe endometriosis, adhesions from previous surgery or non-tubal infection (i.e., appendicitis, inflammatory bowel disease), pelvic tuberculosis, and salpingitis isthmica nodosa (i.e., diverticulosis of the fallopian tube). Cervical Factors

Congenital malformations and trauma to the cervix may result in stenosis and inability of the cervix to produce normal mucus, which usually facilitates the transport of sperm.

Cervix abnormalities may be indicated by a history of abnormal Pap-test, postcoital bleeding, or surgery. The best evaluation of the cervix is performed with speculum examination, which can reveal evidence of cervicitis or cervical stenosis, especially in a patient with prior history of surgery (i.e., conization or cryotherapy). Genetic Causes

Infertile couples have a higher prevalence of karyotype abnormalities than the general population. The most common aneuploidies associated with infertility are 45, X (Turner syndrome) in women and 47, XXY (Klinefelter syndrome) in men [61]. Unexplained Infertility

Diagnosis of unexplained infertility generally implies normal uterine cavity, bilateral patent tubes, normal semen analysis, and evidence of ovulation.

16.10.4 Essentials of Infertility Diagnosis

  • History

In presence of oligomenorrhea, amenorrhea, short or very irregular menstrual cycles, or when ovulation is not confirmed, evaluation of the hypothalamic–pituitary–ovarian axis is advised. A usual initial assessment includes the serum concentrations of FSH, estradiol, prolactin, and TSH.

  • Ovarian Factor.

    • Ovarian reserve.

    • Day 3 serum follicle-stimulating hormone and estradiol levels.

    • AMH.

    • Antral follicle count.

  • Confirmation of Ovulation.

    • History.

    • Serum progesterone assay.

    • Pelvic ultrasonography.

    • Changes in cervical mucus.

    • Luteal phase defect.

  • Pelvic Factor.

    • Physical exam.

    • Ultrasound examination.

    • Hysterosalpingogram to evaluate uterine cavity and fallopian tubes.

    • Possible saline sonogram to evaluate uterine cavity.

    • Laparoscopy to assess endometriosis when indicated.

  • Cervical Factor.

    • History.

    • PAP test.

    • Speculum examination.

  • Metabolic Disease.

    • Thyroid assessment.