Amenorrhea pathophysiology

Amenorrhea Microchapters
Home
Patient Information Primary amenorrhea Secondary amenorrhea
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Amenorrhea from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Criteria
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
X-ray
Echocardiography and Ultrasound
CT scan
MRI
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Amenorrhea pathophysiology On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Amenorrhea pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Amenorrhea pathophysiology
CDC on Amenorrhea pathophysiology
Amenorrhea pathophysiology in the news
Blogs on Amenorrhea pathophysiology
Directions to Hospitals Treating Amenorrhea
Risk calculators and risk factors for Amenorrhea pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].

Pathophysiology

Physiology of normal puberty

Menarche and Menstruation

• After a decrease in menarche age in 1800-1900 in United States and Europe, the mean age of menarche did not change in last 30 years.
• Median age of menstruation onset in girls is 12.43 years in US, 80% of them experience menarche between 11 and 13.75 years of age. Almost all (98%) of the girls experiencing the menarche until age of 15.
• Gonadotropin releasing hormone (GnRH) is the main determinant of puberty onset, which is secreted by neuro-secretory neurons located in hypothalamus into hypophysial portal system. Then, it transferred to anterior pituitary gland, where it stimulates production and secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH). The amplitude and frequency of GnRH pulses are significantly increased during puberty.
• GnRH secretion is also mediated by some neurotransmitters in brain, such as dopamine, endogenous opioids, norepinephrine, gamma amino butyric acid (GABA), and corticotropin releasing hormone (CRH). Each of these neurotransmitters would be defected in specific types of amenorrhea. For example, stress, exercise, and malnutrition are affected CRH, β-endorphin, and dopamine, respectively.
• After initiating puberty, the negative feedback on GnRH will be gone, pulsatile GnRH secretion induce the LH and FSH, that finally lead to ovulation. Without pregnancy, the ovum will become to corpus luteum, proliferate the endometrium through estrogen release. Withdrawal of progesterone from estrogen-mediated proliferated endometrium make it bleeding.

Hypothalamic-pituitary-ovarian (HPO) axis maturation

• After activation of the HPO axis during 2nd trimester of pregnancy, gonadotropins will be in peak from mid to term pregnancy. After removing placental hormones' feedback, FSH and LH increase slightly, mild secondary peak.
• Negative feedback due to adrenal androgens hold the gonadotropins in low plasma level until puberty.
• Right before puberty the sensitivity of hypothalamus to adrenal androgens' negative feedback is decreased and make it possible for GnRH to be raised in magnitude and frequency, therefore increase LH and FSH.
• It takes about 5-7 years from menstruation initiation to HPO axis become completely mature. Generally, during the first two years of menstruation, the cycles are mostly anovulatory.

Pathogenesis

• It is thought that amenorrhea is absence of menstrual cycle, from the beginning of puberty (primary amenorrhea) or after many normal cycles (secondary amenorrhea).
• Distinguishing between primary and secondary amenorrhea is based on history, solely; because upon every cause of secondary amenorrhea can be a cause of primary amenorhea, indeed.
• Mainly the pathophysiology of amenorrhea is described in many categories, include hypothalamic, pituitary, thyroid, adrenal, ovarian, uterine, and vaginal pathogenesis.

Hypothalamic pathogenesis

• The most common cause of amenorrhea in adolescents is hypothalamic pathogenesis, called hypothalamic amenorrhea.
• During 2-3 years after menarche, HPO axis is developing. Therefore, anovulatory cycles may lead to some abnormalities in menstrual cycles.
• The most common causes of amenorrhea, after 2-3 years of puberty, include eating disorders, excessive exercise, medications, and psychosocial stress.
• Leptin plays an important role in energy consumption, body composition, food intake, and their regulations; along with sexual maturation and reproductive improvement. It is assumed that leptin has an important role in hypothalamic amenorrhea. Leptin receptors are in close relationship with hypothalamus and it is revealed that they have some effects on GnRH production and secretion. The main reason of amenorrhea in patients with anorexia nervosa or excessive exercise is down-regulation of leptin receptors, which is elevated by refeeding.
• Leptin level in cachexic patients will increase after gaining appropriate weight in normal people, but will remain low in patients with amenhorrea.
• It is found that leptin levels in amenorrheic athletes are lower than non-athletes women or athletes with regular menses.
• Administration of recombinant leptin for 3 months in women involving in hypothalamic amenorrhea, with excessive exercises or weight loss, increase their LH, FSH, and estradiol and lead to ovulatory cycles.
• Antipsychotic drugs and all the medicines that may have inhibitory effects on dopamine D2 receptor can deteriorate the inhibitory influence of dopamine on prolactin. It means that they increase prolactin. Higher levels of prolactin suppress pulsatile GnRH and also block positive feedback of estradiol on hypothalamus, thus, disturb the HPO axis.
• Stress and strenuous activities as like as any other metabolic or cardiovascular responses are regulated through corticotropin releasing hormone (CRH), secreted by paraventricular nuclei of hypothalamus. CRH induce the release of β-endorphin, an endogenous opioid. Both CRH and β-endorphin suppress GnRH release. On the other hand, glucocorticoids suppress LH production from pituitary and also estrogen/progesterone from ovaries.
• Kallmann syndrome, genetic disorder caused by KAL gene mutation, has disturbance in migration of olfactory nerves along with GnRH neurons. Lack of GnRH in this syndrome encounter the patient with absence of secondary sexual characteristics and also amenorrhea.

Pituitary pathogenesis

• One of the most prevalent anterior pituitary tumors is prolactinoma. Both effect of the mass itself and also secreted prolactin by the mass suppress the GnRH pulsatility, decrease LH and FSH.
• Second prevalent tumor in suprasellar region is craniopharyngioma. The tumor leads to LH and FSH disturbances, which may cause amenorrhea.

Thyroid pathogenesis

• In hypothyroidism, the main mechanism that can lead to amenorrhea is the influence of thyrotropin releasing hormone (TRH) on lactotroph cells, increasing prolactin levels. Since the TRH is increased in hypothyroidism, it leads to functional hyperprolactinemia as well. The concluded increased prolactin can suppress the GnRH pulsatility and lead to amenorrhea.
• In hyperthyroidism, the main mechanism of amenorrhea is not clear. It is assumed that increased level of sex hormone binding globulins (SHBGs) in hyperthyroidism can lead to increase androgens along with estrogen. Conclusively, the LH surge become absent and amenorrhea happens.

Adrenal pathogenesis

• Congenital adrenal hyperplasia (CAH) is a group of genetic enzyme deficiency in adrenal gland. Most of the time the defect is in 21-hydroxylase enzyme, leading to decreasing the main enzymes. To overcome the enzyme deficiency, CRH production is increased by hypothalamus. As mentioned before increased CRH can suppress GnRH and lead to amenorrhea.
• Cushing syndrome has increased level of cortisol, that can directly inhibit HPO axis and cause amenorrhea.

Ovarian pathogenesis

• Polycystic ovary syndrome (PCOS) is mainly due to insulin resistance, that can be lead to androgen over-production (insulin reduces the SHBG circulating in plasma, causes increasing testosterone). In the ovary there will be increased response to GnRH for 17-hydroxy progesterone and also cytochrome P450c17; both lead to increasing androgens biosynthesis. Finally, the pulsatility of GnRH will be disrupted and amenorrhea happens.
• Primary ovarian insufficiency occurs due to several pathologies, all of them lead to ovarian failure and decrease in esterogen. In galactosemia, it is assumed that galactose and its metabolites are toxic to ovarian tissue.

Uterine pathogenesis

• The main pathogenesis of amenorrhea in androgen insensitivity syndrome is absence of uterus. The patient is genotypely male, 46 XY; but has not experienced sexual characteristics due to lack of functional effect of androgen hormones on their receptors.
• One of the acquired conditions that can lead to amenorrhea is Asherman syndrome. The base of this syndrome is any condition that can harm the endometrium, such as scarring from surgical procedure or adhesion from severe infection.
• Mayer-Rokitansky-Kuster-Hauser syndrome is complete agenesis of uterine, blind ended vagina. The lack of uterine and endometrium is the main pathogenesis of amenorrhea. The main reason of uterine agenesis is overactivation of anti-mullerian hormone in embryogenesis period. Cervical agenesis also follow the similar process.
• Imperforated hymen, transverse vaginal septum, and vaginal agenesis are other anatomical disorders of female reproductive system that can lead to amenorrhea.

Genetics

The major genes in amenorrhea

Abbreviations (alphabetic):
CHD7: Chromodomain helicase DNA-binding protein 7 gene, DAX1: DSS-AHC on the X-chromosome 1, EBF2: Early B-cell factor 2 gene, FGF8: Fibroblast growth factor 8 gene, FGFR1: Fibroblast growth factor receptor 1 gene, FSH: Follicle stimulating hormone, GnRH: Gonadotropin releasing hormone, GnRH1: Gonadotropin releasing hormone 1 gene, GnRHR: Gonadotropin releasing hormone receptor gene, GPR54: G protein-coupled receptor-54 gene, HESX-1: Homeobox gene 1, HPG axis: Hypothalamus-pituitary-gonadal axis, HS6ST1: Heparan sulfate 6-O-sulphotransferase 1 gene, KAL1: Kallmann syndrome 1 gene, LEP: Leptin gene, LEPR: Leptin receptor gene, LH: Luteinizing hormone, LHX3: LIM homeobox gene 3, NEC1: Neuroendocrine convertase 1, NELF: Nasal embryonic LH-releasing hormone factor gene, NK3R: Neurokinin 3 receptor gene, NKB: Neurokinin B gene, NR0B: Nuclear receptor 0B, NR5A1: Nuclear receptor 5A1, OMIM: Online Mendelian Inheritance in Man, PC1: Proprotein convertase 1, PROK2 : Prokineticin 2 gene, PROKR2: Prokineticin 2 receptor gene, PROP-1: PROP paired-like homeobox 1, RPX: Rathke pouch homeobox, SF-1: Steroidogenic factor 1, TAC3: Tachykinin 3 gene,TACR3: Tachykinin 3 receptor gene,

Groups	Gene	Other name(s)	OMIM number	Chromosome	Function	Other related disorders
Kallmann syndrome and Isolated hypogonadotropic hypogonadism	KAL1	KAL1, anosmin-1	308700	Xp22.3	Migration of GnRH neurons Olfactory bulb development	Midline facial defects (cleft lip and/or cleft palate) Short metacarpals Renal agenesis Sensorineural hearing loss Bimanual synkinesis Oculomotor abnormalities Cerebellar ataxia
	FGFR1	KAL2	136350	8q12	Embryogenesis Homeostasis Wound healing Olfactory bulb differentiation and development GnRH neurons migration and function	Cleft palate or lip Dental agenesis Bimanual synkinesis
	PROKR2	KAL3	607123	20p13	Neuroendocrine system (arcuate nucleus, olfactory tract, and suprachiasmatic nucleus) Olfactory bulb development Gonadal development GnRH increase	Fibrous dysplasia Sleep disorder Severe obesity Synkinesis Epilepsy
	PROK2	KAL4	607002	3p21.1
	CHD7	KAL5	608892	8q12.1	Olfactory bulb development	CHARGE syndrome: Colobomata Heart anomalies Choanal Atresia Retardation Genital anomalies Ear anomalies
	FGF8	KAL6	600483	10q24	Primary generation of neural tissue Olfactory bulb differentiation and development GnRH neurons migration and function	Cardiac developmental abnormalities Craniofacial developmental abnormalities Forebrain developmental abnormalities Midbrain developmental abnormalities Cerebellar developmental abnormalities
	GPR54	KISS1R	604161	19p13.3	Regulation of GnRH secretion	-
	KISS1	KISS1, kisspeptin1	603286	1q32	Sexual maturation and HPG activation with pulsatile GnRH	-
	HS6ST1	-	604846	2q21	Extracellular sugar modifications FGFR-FGF interactions modulator Anosmin-1 interaction with cell membrane	-
	TAC3	NKB	162330	12q13–q21	HPG axis function Stabilize development during puberty Fetal gonadotropins secretion GnRH secretion regulation	Micropenis Cryptorchidism
	TACR3	NK3R	152332	4q25
	GnRH1	-	152760	8p21–8p11.2	One of the most important elements in HPG axis	Teeth abnormal maturation and biomineralization
	GnRHR	-	138850	4q21.2	Gonadal normal functions	Atrophic gonads along with low LH/FSH and sex hormones Sexual puberty disturbance Inability to conceive Failure to impact from exogenous GnRH
	NELF	-	608137	9q34.3	Modulating neuron migration in developmental process Olfactory axons and also GnRH neurons functions	-
	EBF2	-	609934	8p21.2	Effective role in HPG axis	-
HPG axis development	DAX1	NR0B	300473	Xp21.2	Increased expression during the spermatogenesis and steroidogenesis Both sertoli and leydig cells Peak expression during puberty	Congenital adrenal cortex hypoplasia
	SF-1	NR5A1	184757	9q33.3	Mainly expressed in sertoli and leydig cells Plays an important role in steroidogenesis and spermatogenesis Dominantly expressed by leydig cells in puberty	Male pseudohermaphroditism Denys-Drash syndrome hypospadias
	HESX-1	RPX	601802	3p14.3	pituitary development Midfacial differentiation Mutation may lead to pituitary hypoplasia	Septooptic dysplasia Reduced prosencephalon anophthalmia microphthalmia Defective olfactory development Rathke pouch bifurcations Abnormalities in the corpus callosum, hippocampus, and septum pellucidum
	LHX3	LIM3	600577	9q34.3	Development of pituitary gland and its hormone secretion	Neonatal hypoglycemia Short neck with limited rotation Mild sensorineural hearing loss Skin laxity Skeletal abnormalities
	PROP-1	-	601538	5q35.3	Developing anterior pituitary gland gonadotrophs Tthyrotrophs somatotrophs Lactotrophs Low LH and FSH delay the puberty	thyroid dysfunctions growth retardation libido/lactation problems
Obesity related hypogonadotropic hypogonadism	LEP	OB	164160	7q32.1	Modulation of body weight Beginning the puberty recombinant leptin injection in female mice result in puberty Increased about 50% just before puberty and also during the puberty	hematopoiesis disorders angiogenesis disorders wound healing disorders immune or inflammatory response disorders
	LEPR	OBR	601007	1p31.3
	PC1	NEC1	162150	5q15	Regulates neuroendocrine pathway proopiomelanocortin (POMC) cleavage Processing proinsulin and proglucagon in pancreas.	Extreme childhood obesity Abnormal glucose homeostasis hypocortisolism Elevated plasma proinsulin, and also POMC

Gross Pathology

• On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Pathophysiology

Hypogonadotropic amenorrhoea refers to conditions where there are very low levels of serum FSH and LH. Generally, inadequate levels of these hormones lead to inadequately stimulated ovaries who then fail to produce enough estrogen to stimulate the endometrium (uterine lining), hence amenorrhoea. This is typical for conditions of pubertal delay, hypothalamic or pituitary dysfunction. In general, women with hypogonadotropic amenorrhoea are potentially fertile.

Hypergonadotropic amenorrhoea refers to conditions with high levels of FSH (and LH). FSH levels are typically in the menopausal range. This implies that the ovary or gonad does not respond to pituitary stimulation. Gonadal dysgenesis or premature menopause are possible causes. Chromosome testing is usually indicated in younger individuals with hypergonadotropic amenorrhoea.

In normogonadotropic amenorrhoea, FSH levels are in the normal range. This would suggest that the hypothalamic-pituitary-ovarian axis is functional. Amenorrhoea may be due to outflow obstruction, or abnormal ovarian regulation or excess androgens as seen in polycystic ovary syndrome.

Cushing's Disease/Syndrome can also cause amenorrhoea due to excessive amounts of cortisol in the blood stream.

Primary amenorrhea

In primary amenorrhea there is absence of menarche by the age of 16. Menstruation cycles never begin. There will be a delay of menses one year beyond the family history of first menses.

There is no defining sexual characteristics by age 14. Primary amenorrhea may be caused by developmental problems such as the congenital absence of the uterus, or failure of the ovary to receive or maintain egg cells. Also, delay in pubertal development will lead to primary amenorrhoea.

Secondary amenorrhea

Secondary amenorrhea is defined as absence of menses in a woman who had previously menstruated for at least 3 cycles or 6 months. Secondary amenorrhea is more common than primary amenorrhea.

Secondary amenorrhea is often caused by hormonal disturbances from the hypothalamus and the pituitary gland or from premature menopause, or intrauterine scar formation.

Specific types of amenorrhoea

Exercise amenorrhoea

Female athletes or women who perform considerable amounts of exercise on a regular basis are at risk of developing 'athletic' amenorrhoea. It was thought for many years that low body fat levels and exercise related chemicals (such as beta endorphins and catecholamines) disrupt the interplay of the sex hormones estrogen and progesterone. However recent studies have shown that there are no differences in the body composition, or hormonal levels in amenorrheic athletes. Instead, amenorrhea has been shown to be directly attributable to a low energy availability. Many women who exercise at a high level do not take in enough calories to expend on their exercise as well as to maintain their normal menstrual cycles. [2]

A second serious risk factor of amenorrhea is severe bone loss sometimes resulting in osteoporosis and osteopenia. It is the third component of an increasingly common disease known as female athlete triad syndrome. The other two components of this syndrome are osteoporosis and disordered eating. Awareness and intervention can usually prevent this occurrence in most female athletes.

Drug-induced amenorrhea

Certain medications, particularly contraceptive medications, can induce amenorrhoea in a healthy woman. The lack of menstruation usually begins shortly after beginning the medication and can take up to a year to resume after stopping a medication. Hormonal contraceptives that contain only progestogen like the oral contraceptive Micronor, and especially higher-dose formulations like the injectable Depo Provera commonly induce this side-effect. Recently, an extended cycle combined oral contraceptive pill which aims to purposefully induce amenorrhea (Lybrel), has been approved by the FDA.