The female genital system is made up of dynamic organs that change during the woman’s life cycle. Ovarian cycle 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.
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. Alterations of these mechanisms can lead to pathological conditions and affect fertility of patients.
- Ovarian cycle
- Menstrual cycle
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% . 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 . 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 .
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 .
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 . 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 .
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.
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 . 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 . 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 . Simultaneously, the hypothalamic–pituitary axis induces the LH rise and a new cycle starts.
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 . 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 .
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 . 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 . Earlier puberty is also associated with increased risk for other reproductive cancers: endometrial and ovarian cancer in women and prostate cancer in men . 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 . 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 . 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].
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.
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%)) . Palpitations and insomnia also occur.
Atrophy of the urogenital system.
Emotional instability, nervousness, decreased libido, concentration difficulties, memory loss.
Atrophy, dryness, and itching of skin and mucous membranes.
Higher cardiovascular risk .
Body composition (in the early postmenopausal years women usually gain fat mass and lose lean mass with a central fat distribution) .
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 . 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.
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 . However, hormonal concentrations are less predictive of menopausal stage than clinical criteria, so they should not be used alone .
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).
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 .
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
Polycystic ovarian syndrome.
Premature ovarian failure (POF).
Hyperthyroidism or hypothyroidism.
Infection (tuberculosis, syphilis, encephalitis/meningitis, sarcoidosis).
Chronic renal failure.
Irradiation or chemotherapy.
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 .
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 .
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 . 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 . Even if the exact mechanics are not clear, it appears that insulin resistance and hyperinsulinemia are involved .
Isolated GnRH deficiency is rare and is called idiopathic hypogonadotropic hypogonadism or Kallmann syndrome if it is associated with anosmia .
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 . 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 . 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 .
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 .
Intrauterine synechiae are often caused by a complicated dilatation and curettage (Asherman’s syndrome).
16.9.4 Differential Diagnosis
184.108.40.206 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.
220.127.116.11 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 . In patients responding to progesterone challenge, hyperestrogenism not counterbalanced by progestin is a risk factor for endometrial hyperplasia and cancer.
18.104.22.168 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.
22.214.171.124 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.
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 . 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 .
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 . 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 .
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%).
Pelvic adhesions (12%).
126.96.36.199 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 .
The most appropriate quantitative tests are the AMH assay  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.
188.8.131.52 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 .
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 .
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).
184.108.40.206 Tubal Disease
The main cause of tubal factor infertility is pelvic inflammatory disease caused by pathogens such as Gonorrhea, Chlamydia trachomatis, or Mycoplasma genitalium . 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).
220.127.116.11 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).
18.104.22.168 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 .
22.214.171.124 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
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.
Day 3 serum follicle-stimulating hormone and estradiol levels.
Antral follicle count.
Confirmation of Ovulation.
Serum progesterone assay.
Changes in cervical mucus.
Luteal phase defect.
Hysterosalpingogram to evaluate uterine cavity and fallopian tubes.
Possible saline sonogram to evaluate uterine cavity.
Laparoscopy to assess endometriosis when indicated.
Treloar AE, Boynton RE, Behn BG, Brown BW. Variation of the human menstrual cycle through reproductive life. Int J Fertil. 1967;12:77.
Sherman BM, Korenman SG. Hormonal characteristics of the human menstrual cycle throughout reproductive life. J Clin Invest. 1975;55:699.
Mahendro MS, Cunningham FG. Parturition. In: Cunningham FG, Leveno KJ, Bloom SL, et al., editors. Williams obstetrics. 23th ed. New York: McGraw-Hill; 2010a. p. 159.
Mahendro MS, Cunningham FG. Implantation and placental development. In: Cunningham FG, Leveno KJ, Bloom SL, et al., editors. Williams obstetrics. 25th ed. New York: McGraw-Hill; 2018a. p. 81.
Mahendro MS, Cunningham FG. Parturition. In: Cunningham FG, Leveno KJ, Bloom SL, et al., editors. Williams obstetrics. 25th ed. New York: McGraw-Hill; 2018b. p. 406.
Hall JE, Schoenfeld DA, Martin KA, Crowley WF Jr. Hypothalamic gonadotropin-releasing hormone secretion and follicle-stimulating hormone dynamics during the luteal-follicular transition. J Clin Endocrinol Metab. 1992;74:600.
Gougeon A. Dynamics of follicular growth in the human: a model from preliminary results. Hum Reprod. 1986;1:81.
Welt CK, Martin KA, Taylor AE, et al. Frequency modulation of follicle-stimulating hormone (FSH) during the luteal-follicular transition: evidence for FSH control of inhibin B in normal women. J Clin Endocrinol Metab. 1997;82:2645.
Welt CK, McNicholl DJ, Taylor AE, Hall JE. Female reproductive aging is marked by decreased secretion of dimeric inhibin. J Clin Endocrinol Metab. 1999;84:105.
Filicori M, Santoro N, Merriam GR, Crowley WF Jr. Characterization of the physiological pattern of episodic gonadotropin secretion throughout the human menstrual cycle. J Clin Endocrinol Metab. 1986;62:1136.
Kissell KA, Danaher MR, Schisterman EF, et al. Biological variability in serum anti- Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women. Hum Reprod. 2014;29:1764.
Fleischer AC, Kalemeris GC, Entman SS. Sonographic depiction of the endometrium during normal cycles. Ultrasound Med Biol. 1986;12:271.
Adams JM, Taylor AE, Schoenfeld DA, et al. The midcycle gonadotropin surge in normal women occurs in the face of an unchanging gonadotropin-releasing hormone pulse frequency. J Clin Endocrinol Metab. 1994;79:858.
Taylor AE, Whitney H, Hall JE, et al. Midcycle levels of sex steroids are sufficient to recreate the follicle-stimulating hormone but not the luteinizing hormone midcycle surge: evidence for the contribution of other ovarian factors to the surge in normal women. J Clin Endocrinol Metab. 1995;80:1541.
Martin KA, Welt CK, Taylor AE, et al. Is GnRH reduced at the midcycle surge in the human? Evidence from a GnRH-deficient model. Neuroendocrinology. 1998;67:363.
Richards JS. Hormonal control of gene expression in the ovary. Endocr Rev. 1994;15:725.
Tsafriri A, Chun SY, Reich R. Follicular rupture and ovulation. In: The ovary, Adashi EY, Leu ng PCK (Eds), Raven Press, New York 1993. 227.
Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Fertil Steril. 1950;1:3.
Stocco C, Telleria C, Gibori G. The molecular control of corpus luteum formation, function, and regression. Endocr Rev. 2007;28:117.
Filicori M, Butler JP, Crowley WF Jr. Neuroendocrine regulation of the corpus luteum in the human. Evidence for pulsatile progesterone secretion. J Clin Invest. 1984;73:1638.
Dunger DB, Ahmed ML, Ong KK. Early and late weight gain and the timing of puberty. Mol Cell Endocrinol. 2006;254–255:140.
Wu FC, Butler GE, Kelnar CJ, Sellar RE. Patterns of pulsatile luteinizing hormone secretion before and during the onset of puberty in boys: a study using an immunoradiometric assay. J Clin Endocrinol Metab. 1990;70:629.
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969;44:291.
Biro FM, Huang B, Crawford PB, et al. Pubertal correlates in black and white girls. J Pediatr. 2006;148:234.
Taranger J, Engström I, Lichtenstein H, Svennberg- RI. VI. Somatic pubertal development. Acta Paediatr Scand Suppl. 1976;258:121–35.
Susman EJ, Houts RM, Steinberg L, et al. Longitudinal development of secondary sexual characteristics in girls and boys between ages 91/2 and 151/2 years. Arch Pediatr Adolesc Med. 2010;164:166.
Yang L, Li L, Millwood IY, et al. Adiposity in relation to age at menarche and other reproductive factors among 300 000 Chinese women: findings from China Kadoorie biobank study. Int J Epidemiol. 2017;46:502.
Clavel-Chapelon F, E3N-EPIC Group. Differential effects of reproductive factors on the risk of pre- and postmenopausal breast cancer. Results from a large cohort of French women. Br J Cancer. 2002;86:723–7.
Day FR, Thompson DJ, Helgason H, et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat Genet. 2017;49:834.
Canoy D, Beral V, Balkwill A, et al. Age at menarche and risks of coronary heart and other vascular diseases in a large UK cohort. Circulation. 2015;131:237.
Cheng TS, Day FR, Lakshman R, Ong KK. Association of puberty timing with type 2 diabetes: a systematic review and meta-analysis. PLoS Med. 2020;17:e1003017.
Day FR, Elks CE, Murray A, et al. Puberty timing associated with diabetes, cardiovascular disease and also diverse health outcomes in men and women: the UK biobank study. Sci Rep. 2015;5:11208.
Chan YM, Feld A, Jonsdottir-Lewis E. Effects of the timing of sex-steroid exposure in adolescence on adult health outcomes. J Clin Endocrinol Metab. 2019;104:4578.
Woods NF, Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women’s lives. Am J Med. 2005;118:14–24.
Derby CA, Crawford SL, Pasternak RC, Sowers M, Sternfeld B, Matthews KA. Lipid changes during the menopause transition in relation to age and weight: the Study of Women’s Health Across the Nation. Am J Epidemiol. 2009;169(11):1352–61.
Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25(10):2359–81.
Sternfeld B, Wang H, Quesenberry CP, Abrams B, Everson-Rose SA, Greendale GA, et al. Physical activity and changes in weight and waist circumference in midlife women: findings from the Study of Women’s Health Across the Nation. Am J Epidemiol. 2004;160(9):912–22.
Hall JE. Neuroendocrine physiology of the early and late menopause. Endocrinol Metab Clin North Am. 2004;33(4):637–59.
Finkelstein JS, Lee H, Karlamangla A, Neer RM, Sluss PM, Burnett-Bowie S-AM, et al. Antimullerian Hormone and Impending Menopause in Late Reproductive Age: The Study of Women’s Health Across the Nation. J Clin Endocrinol Metab. 2020;105(4):e1862–71.
Randolph JF, Crawford S, Dennerstein L, Cain K, Harlow SD, Little R, et al. The value of follicle-stimulating hormone concentration and clinical findings as markers of the late menopausal transition. J Clin Endocrinol Metab. 2006;91(8):3034–40.
Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–68.
ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol. 2014;123(1):202–16.
Fourman LT, Fazeli PK. Neuroendocrine causes of amenorrhea—an update. J Clin Endocrinol Metab. 2015;100(3):812–24.
Practice Committee of the American Society for reproductive medicine. Current evaluation of amenorrhea. Fertil Steril. 2006;86(5 Suppl 1):S148–55.
The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41–7.
Diamanti-Kandarakis E. Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications. Expert Rev Mol Med. 2008;10:e3.
Turner’s syndrome. West J Med. 1982;137(1):32–44.
Zargar AH, Singh B, Laway BA, Masoodi SR, Wani AI, Bashir MI. Epidemiologic aspects of postpartum pituitary hypofunction (Sheehan’s syndrome). Fertil Steril. 2005;84(2):523–8.
Kakuno Y, Amino N, Kanoh M, Kawai M, Fujiwara M, Kimura M, et al. Menstrual disturbances in various thyroid diseases. Endocr J. 2010;57(12):1017–22.
Rebar RW. Premature Ovarian Failure. Obstet Gynecol. 2009;113(6):1355–63.
Chandra A, Copen CE, Stephen EH. Infertility and impaired fecundity in the United States, 1982–2010: data from the National Survey of Family Growth. Natl Health Stat Report. 2013;67:1–18.
Practice Committee of the American Society for Reproductive Medicine. Optimal evaluation of the infertile female. Fertil Steril. 2006;86(5):S264–7.
Jones KT. Meiosis in oocytes: predisposition to aneuploidy and its increased incidence with age. Hum Reprod Update. 2008;14(2):143–58.
Nappi L, Angioni S, Sorrentino F, Cinnella G, Lombardi M, Greco P. Anti-Mullerian hormone trend evaluation after laparoscopic surgery of monolateral endometrioma using a new dual wavelengths laser system (DWLS) for hemostasis. Gynecol Endocrinol. 2016;32(1):34–7. https://doi.org/10.3109/09513590.2015.1068754.
Parry JP, Koch CA. Ovarian reserve testing. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext. South Dartmouth (MA), MDText.com, Inc.; 2019.
Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–99.
Practice Committee of the American Society for reproductive medicine. Electronic address: ASRM@asrm.org, practice Committee of the American Society for reproductive medicine. Removal of myomas in asymptomatic patients to improve fertility and/or reduce miscarriage rate: a guideline. Fertil Steril. 2017;108(3):416–25.
Nappi L, Pontis A, Sorrentino F, Greco P, Angioni S. Hysteroscopic metroplasty for the septate uterus with diode laser: a pilot study. Eur J Obstet Gynecol Reprod Biol. 2016;206:32–5. https://doi.org/10.1016/j.ejogrb.2016.08.035.
Nappi L, Falagario M, Angioni S, et al. The use of hysteroscopic metroplasty with diode laser to increase endometrial volume in women with septate uterus: preliminary results. Gynecol Surg. 2021;18:11. https://doi.org/10.1186/s10397-021-01093-8.
Soper DE. Pelvic inflammatory disease. Obstet Gynecol. 2010;116(2 Pt 1):419–28.
Clementini E, Palka C, Iezzi I, Stuppia L, Guanciali-Franchi P, Tiboni GM. Prevalence of chromosomal abnormalities in 2078 infertile couples referred for assisted reproductive techniques. Hum Reprod. 2005;20(2):437–42.
Editors and Affiliations
Rights and permissions
Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.
The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
© 2023 The Author(s)
About this chapter
Cite this chapter
Nappi, L., Sorrentino, F., Greco, F., Vona, L., Zullo, F.M., Bettocchi, S. (2023). Pathophysiology of Female Reproduction and Clinical Management. In: Bettocchi, C., Busetto, G.M., Carrieri, G., Cormio, L. (eds) Practical Clinical Andrology. Springer, Cham. https://doi.org/10.1007/978-3-031-11701-5_16
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-11700-8
Online ISBN: 978-3-031-11701-5
eBook Packages: MedicineMedicine (R0)