Infertility : definition, causes and investigation

Definition

Infertility can be defined as inability of couples to conceive after 1 year or more of trying.

There are few terms under infertility to describe different types of infertility: 1. Resolved infertility - pregnancies that occur after 1 year of trying without medical intervention, 2. Primary infertility - never pregnant, 3. Secondary infertility - failure to conceive after having previously delivered an infant without the use of infertility treatment.

Causes

Causes of infertility can be divided into male and female factors.

Female factors

Causes of female infertility includes disorder of ovulation, tubal disease, uterine/cervical pathology, endometriosis/pelvic adhesion and other pelvic pathology.

Problem with ovulation can be due to several medical conditions, which usually associated with hormonal abnormalities such as PCOS (polycystic ovarian syndrome) , hypothalamic amenorrhea, ovarian failure, hyperprolactinemia (e.g pituitary tumor), hypothyroidism, hyperandrogenism (e.g congenital adrenal hyperplasia, androgen-secreting tumors) and so on. Some medications also can cause anovulation thus affecting fertility. Besides that, problem with ovulation can also occur due to aging and diminished ovarian reserve.

Measurement of mid-luteal progesterone level, urinary luteinizing hormone using home prediction kit, and basal body temperature charting can be used to document whether ovulation occurs or not. If ovulatory dysfunction suspected, measurement of FSH, prolactin, thyroid-stimulating hormone, 17α-hydroxyprogesterone (if hyperandrogenism suspected), and testosterone (if hyperandrogenism suspected) can assist in identification of the etiology. In women older than 35 years old, assessment of ovarian reserve is recommended. The assessment includes: measurement of FSH and estradiol levels on day 3 of the menstrual cycle, clomiphene citrate (Clomid) challenge test, or transvaginal ultrasonography for antral follicle count.

Tubal blockage causing infertility either by preventing fertilization, in which the sperm unable to reach the ovum on time, or, by preventing fertilized ovum to go to uterine cavity for implantation. Uterine/cervical abnormalities also can be associated with infertility such as congenital uterine anomalies, fibroids, and polyps. Transvaginal sonography and hysterosalpingography allow assessment of the tubes, uterus and pelvis. Hysteroscopy might be done if hysterosalpingography reveals intrauterine abnormalities.

Endometriosis, pelvic adhesion and other pelvic pathology should be considered as causes that can lead to infertility and should be investigated after above causes has been rule out. More invasive procedure i.e laparoscopy might be done to diagnose these conditions.

-Male factors-

Causes of male infertility can be divided into: 1. Altered sperm transport, 2.Primary hypogonadism, 3.Secondary hypogonadism, 4.Abnormal spermatogenesis, 5.Idiopathic.

Men with altered/blocked sperm transport commonly presented with low volume of ejaculate or no ejaculate, which can be confirmed by doing a proper sperm analysis (showing low or no volume of semen). This could be due to erection/ejaculation problem or blockage of the sperm transport. Post ejaculatory urinalysis and transrectal ultrasonography may be performed to rule out retrograde ejaculation and ejaculatory duct obstruction respectively. Scrotal ultrasonography also can be helpful in assessing suspected testicular and scrotal abnormalities such as hydrocele and tumor.

Primary hypogonadism (primary testosterone insufficiency) , also referred as testicular failure or dysfunction, can be defined as insufficient production of testosterone due to testicular disorders. Meanwhile, secondary hypogonadism (secondary testosterone insufficiency), also referred as hypothalamic-pituitary dysfunction is defined as insufficient production of testosterone due to disorders of hypothalamus/pituitary gland. Hypogonadism (testosterone insufficiency) is suspected based on abnormal semen analysis (showing severe oligospermia-reduced number of sperm in semen or azoospermia-no sperm in semen). The relationship between serum FSH level , LH and testosterone can help to distinguish between primary and secondary hypogonadism. Measurement of serum prolactin level assists in detecting hyperprolactinemia that also can cause male infertility. Sometimes the level of LH, testosterone and prolactin are normal but only FSH is high or in the upper range of normal. These highly indicate abnormalities in spermatogenesis. However, many men with abnormal spermatogenesis can have a normal FSH level, thus a normal FSH level does not guarantee the presence of intact spermatogenesis.

In such cases where the initial evaluation unable to identify the causes of infertility, further specialized tests such as specialized sperm and semen studies might be recommended if identification of the cause of male infertility will direct the treatment of infertility.

Infertility evaluation

Generally, infertility evaluation should started after 1 year of unprotected intercourse during which pregnancy has not been achieved. Earlier evaluation may be indicated when there is presence of factors suggesting infertility such as history of pelvic inflammatory disease, amenorrhea, tubal surgery and so on. Other indication for earlier evaluation is the female partner is older than 35 years old. This is because fertility rates reduce and spontaneous abortion and chromosomal abnormality increase with advancing maternal age.

Components of infertility evaluation (history, physical examination and investigation)

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Infertility

Dysfunctional uterine bleeding : medical treatment

Once all causes of abnormal uterine bleeding (AUB) have been excluded, medication should be considered as the first line treatment. Medication used in the treatment of dysfunctional uterine bleeding can be divided into hormonal and non-hormonal.

     Combined oral contraceptive pills (estrogen component + progesterone component) have been proven to reduce menstrual blood loss in heavy menstrual bleeding. The progesterone component acts by suppressing ovulation, thus inhibits ovarian production of estrogen and progesterone. This leads to absence of hormonal stimulation for endometrial proliferation and eventually this leads to endometrial atrophy. Meanwhile, the estrogen component of the COCP provides support to the endometrial lining of the endometrium to reduce the occurrence of irregular breakthrough bleeding/spotting. However it is contraindicated in certain conditions including history of thrombosis, stroke, uncontrolled hypertension, migraine with aura, coronary arterial disease, liver disease and history of breast cancer. These contraindications are mainly due to the estrogen component. Adverse effects include hormonal systemic effects such as breast tenderness, mood change and fluids retention. Rarely, it causes venous thromboembolism, stroke and coronary artery disease.

     Progesterone-only therapy includes progesterone-only pills, injected progesterone (DMPA) and LNG-IUS. The action is similar to progesterone component in COCP. However, since there is no estrogen component and no support to the endometrial lining, thus irregular breakthrough bleeding/spotting is more likely to occur. Common systemic  effects of progesterone include breast tenderness, weight gain, acne, water retention and headache .These systemic side effects are more prominent in progesterone-only pills and DMPA. However it is mild in LNG-IUS since this device is inserted into the uterus thus it administers high concentration of progesterone directly to the endometrium with only minimal amount of progesterone escaped into the systemic circulation. Other side effects of progesterone-only therapy,which is breakthrough bleeding as mentioned above, post insertion breakthrough bleeding is also common in LNG-IUS, but it is self limiting and it may be up to 6 months duration before it completely resolves. Other side effects of LNG-IUS are risk of expulsion, perforation and pelvic inflammatory disease. The risks of expulsion and perforation is partially operator dependent. Meanwhile, risk of pelvic inflammatory disease is more likely to occur in severely immuno-compromised patient and women with high risk of sexually transmitted infection.

GnRH agonist and Danazol are both proven to be effective in reducing menstrual blood loss. However, they may be used only as a short-term therapy (short-term usage of GnRH agonist pre-operatively), or for cases in which other medical or surgical therapies has failed or contraindicated (long -term usage of GnRH agonist, or Danazol). GnRH agonist is mainly associated with hypo-estrogenic side effects while Danazol is associated with androgenic effects.   

NSAIDs and tranaxemic acid is effective in reducing menstrual blood loss especially in ovulatory  bleeding. Tranaxemic acid is considered as the 1st line treatment for ovulatory dysfunctional uterine bleeding.

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Dysfunctional uterine bleeding

Dysfunctional uterine bleeding : Investigation

A complete history taking and thorough physical examination usually enable us to establish few possible causes for the abnormal uterine bleeding (AUB) and direct us with further investigations. 

Common lab tests done in the assessment of abnormal uterine bleeding (AUB) include: 1) Full blood count (for heavy or prolonged bleeding), 2) Serum ferritin (to diagnose iron deficiency anemia), 3) Coagulation tests (if there is bleeding tendency or family history of bleeding disorders), 4)Thyroid function tests (if there is signs and symptoms of thyroid problems), and 5) Urine pregnancy test (to rule out pregnancy).

Other than that, investigations include imaging , hysteroscopy and biopsy.

Transvaginal sonography should be considered as the 1^st line imaging modality in the assessment of abnormal uterine bleeding (AUB). It allows detailed assessment of the uterus, cervix, fallopian tubes and ovaries

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Saline infusion sonohysterography is done by introducing 5 – 15 ml of saline into the uterine cavity during the transvaginal sonography. This procedure improves the image features where it allows greater discrimination of location and relationship of intrauterine pathologies to the uterine cavity. 

MRI is rarely indicated but may be useful in some conditions: 1) To map the exact location of fibroids in planned surgery and prior to embolization procedure. 2) To assess the endometrium when transvaginal sonohysterography could not be performed (e.g in case of uterus anomalies).

Hysteroscopy allows direct visualization of the endometrium and intrauterine cavity, and it allows directed biopsy to be done.

Directed biopsy under direct visualization provides more benefit compared to blind biopsy done during dilation and curettage.

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Dysfunctional uterine bleeding

Causes of abnormal uterine bleeding

An international expert consensus from the FIGO Menstrual Disorders Working Group has proposed a standardized classification system for causes of abnormal uterine bleeding (AUB). This classification allows the characterization of more than one etiology in the same patient. There are 9 main categories within the classification system named for the acronym PALM-COEIN. The PALM side refers to structural causes that could be diagnosed and assessed by imaging and/or biopsy. The COEIN side refers to non-structural causes such as underlying medical condition, medication primary endometrial disorder, and others. 

Women with what was called ‘dysfunctional uterine bleeding’ may be has primary endometrial disorder or ovulation dysfunction.

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Dysfunctional Uterine Bleeding

Definition of different terms under Abnormal Uterine Bleeding (AUB)

Definition of different terms under AUB

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Dysfunctional uterine bleeding

Dysfunctional uterine bleeding

Dysfunctional uterine bleeding (DUB) is defined as an abnormal uterine bleeding (AUB) characterized by heavy, prolonged or frequent bleeding that is not due to pregnancy or any recognizable local or systemic disease. It is therefore a diagnosis of exclusion. 

Abnormal uterine bleeding (AUB) can be defined as any variation from the normal menstrual cycle, including changes in regularity and frequency of menses, changes in duration of flow, or changes in amount of blood loss. Abnormal uterine bleeding (AUB) can be further subcategorized into different terms with different definition/description. The terms include: 1) Heavy menstrual bleeding (HMB), 2)Irregular menstrual bleeding, 3)Infrequent uterine bleeding 4) Frequent uterine bleeding 5)Prolonged uterine bleeding 6) Shortened uterine bleeding 7) Inter-menstrual bleeding 8)Post coital bleeding 9)Pre or post menstrual bleeding 10) Post-menopausal uterine bleeding 11)Precocious uterine bleeding 12) Acute abnormal uterine bleeding 13)Chronic abnormal uterine bleeding.

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Definition of different terms under Abnormal uterine bleeding (AUB)

When a patient presented with abnormal uterine bleeding (AUB), a detail history taking and thorough physical examination should be done to look for the causes and complications of the bleeding, and to guide in term of further investigations and management.

Most common presentation of abnormal uterine bleeding is heavy menstrual bleeding (HMB). Features that suggest heavy menstrual bleeding (HMB) from the history include: 1) Need to change pad/tampon frequently (e.g 1 – 3 hourly), 2) Bleeding more than 7 days, 3) Need to use double protection i.e pad + tampon, 4) Need to change at night, 5) Flooding, 6) Clotting >3cm.

From the history, it is important to know whether the bleeding is regular or irregular. Ovulatory bleeding is regular while anovulatory bleeding is usually irregular. By identifying whether the abnormal uterine bleeding (AUB) is ovulatory or anovulatory may help us to narrow down the causes of abnormal uterine bleeding (AUB), besides guide us in term of management since the management is different between ovulatory and anovulatory bleeding.

Ovulatory bleeding usually can be successfully treated with both hormonal and non-hormonal options, while anovulatory bleeding is most effectively treated with hormonal options, by which they regulate menstrual cycle, and protect endometrium from unopposed estrogen and the risk of endometrial hyperplasia or carcinoma. In ovulatory AUB, regular ovulation and menstrual cycle do occur, however, there is excessive bleeding. This can be due to structural abnormalities such as polyp or fibroid which cause increase in endometrial surface area; or, systemic diseases like chronic liver disease, von Willebrand syndrome, or medication that cause coagulation abnormalities. Meanwhile, in anovulatory AUB, there is no ovulation occurs, thus no corpus luteum been produced result in no progesterone production. This leads to prolonged estrogenic stimulation of endometrium causing excessive endometrial proliferation. The existing blood supply is unable to provide sufficient nutritional support to the excessive tissue proliferation, and eventually tissue ischemia and necrosis occur, and lead to erratic bleeding. Examples of conditions that lead to anovulation are Polycystic ovarian syndrome (PCOS), thyroid problems, uncontrolled diabetes mellitus and so on. Some medication also can lead to ovulatory dysfunction.

Presence of associated gynaecological symptoms such as inter-menstrual spotting, post coital bleeding, dyspareunia, pelvic pain / pressure, abnormal vaginal discharge / odor may suggest toward local pelvic causes which could be benign, malignant, or infective in nature. Besides abnormal uterine bleeding, patient may complaint of other systemic symptoms which suggest systemic cause of the abnormal uterine bleeding such as hyperthyroidism, coagulation disorders and polycystic ovarian syndrome (PCOS). Patient with abnormal uterine bleeding also may suffer from complication of chronic blood loss particularly iron deficiency anemia causing them to have symptoms like giddiness, exertional shortness of breath, lethargy, and so on.

Other important information to be elicited from the history includes: 1) Comorbid condition such as tumour, thromboembolic disease or cardiovascular problems that would influence treatment option (e.g these diseases are contraindication for COCP). 2) Medication history including over the counter, herbal remedies that may lead to ovulatory dysfunction or otherwise associated with bleeding tendency. 3) Family history of inherited coagulation disorders, PCOS, endometrial or colon cancer. 4) Sexual and reproductive history including contraception, desire for future pregnancy, infertility, cervical screening and risk of sexual transmitted infection(STI). 4) Impact of the condition on social life.

A complete history taking and thorough physical examination should be able to guide further investigations to be done.

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Abnormal uterine bleeding - investigation

Once all causes of abnormal uterine bleeding (AUB) have been excluded, medication should be considered as the first line treatment. Medication used in the treatment of dysfunctional uterine bleeding can be divided into hormonal and non-hormonal.

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Causes of Abnormal uterine bleeding

Hormonal treatments include COCP, progesterone (progestin only pill, DMPA, LNG-IUS), GnRH agonist and Danazol. These medications treat dysfunctional uterine bleeding by regulating the menstrual cycle, inhibit endometrial proliferation, and promote endometrial atrophy.

Tranexamic acid is one of the non-hormonal treatments for dysfunctional bleeding. It is an antifibrinolytic agent. It reduces the endometrial fibrinolytic enzymes that are increased in dysfunctional uterine bleeding. It is the 1st line treatment for ovulatory dysfunctional uterine bleeding.

Besides tranexamic acids, NSAIDs also useful in the treatment of dysfunctional uterine bleeding. It is known that endometrial prostaglandin level is high in uterus of women with heavy menstrual bleeding. NSAIDs reduce the level of prostaglandin by inhibition of cyclo-oxygenase (enzyme that converts arachidonic acid to prostaglandin), thus reducing total production of prostaglandin.

Iron therapy should be prescribed if iron deficiency anemia is diagnosed.

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Medical treatment  for Abnormal uterine bleeding