Amenorrhea

Last updated
Amenorrhea
Other namesAmenorrhea, amenorrhœa
Specialty Gynecology

Amenorrhea is the absence of a menstrual period in a female who has reached reproductive age. [1] Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). [1] Outside the reproductive years, there is absence of menses during childhood and after menopause. [1]

Contents

Amenorrhoea is a symptom with many potential causes. [2] Primary amenorrhea is defined as an absence of secondary sexual characteristics by age 13 with no menarche or normal secondary sexual characteristics but no menarche by 15 years of age. [3] It may be caused by developmental problems, such as the congenital absence of the uterus, failure of the ovary to receive or maintain egg cells, or delay in pubertal development. [4] Secondary amenorrhoea, ceasing of menstrual cycles after menarche, is defined as the absence of menses for three months in a woman with previously normal menstruation, or six months for women with a history of oligomenorrhoea. [3] It is often caused by hormonal disturbances from the hypothalamus and the pituitary gland, premature menopause, intrauterine scar formation, or eating disorders. [5] [6] [7]

Pathophysiology

Although amenorrhea has multiple potential causes, ultimately, it is the result of hormonal imbalance or an anatomical abnormality. [8]

Physiologically, menstruation is controlled by the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. [8] GnRH acts on the pituitary to stimulate the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH). [8] FSH and LH then act on the ovaries to stimulate the production of estrogen and progesterone which, respectively, control the proliferative and secretary phases of the menstrual cycle. [8] Prolactin also influences the menstrual cycle as it suppresses the release of LH and FSH from the pituitary. [9] Similarly, thyroid hormone also affects the menstrual cycle. [9] Low levels of thyroid hormone stimulate the release of TRH from the hypothalamus, which in turn increases both TSH and prolactin release. [9] This increase in prolactin suppresses the release of LH and FSH through a negative feedback mechanism. [9] Amenorrhea can be caused by any mechanism that disrupts this hypothalamic-pituitary-ovarian axis, whether that it be by hormonal imbalance or by disruption of feedback mechanisms.

Classification

Amenorrhea is classified as either primary or secondary. [10]

Primary amenorrhea

Primary amenorrhoea is the absence of menstruation in a woman by the age of 16. [11] Females who have not reached menarche at 14 and who have no signs of secondary sexual characteristics (thelarche or pubarche) are also considered to have primary amenorrhea. [12] Examples of amenorrhea include constitutional delay of puberty, Turner syndrome, and Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome. [13] [14]

It produces the appearance of secondary sexual characteristics, which are the sprouting of pubic and armpit hair, development of the breasts or breasts, and a lack of definition in the female body structure, such as the waist and hips.

Secondary amenorrhea

Secondary amenorrhoea is defined as the absence of menstruation for three months in a woman with a history of regular cyclic bleeding or six months in a woman with a history of irregular menstrual periods. [15] Examples of secondary amenorrhea include hypothyroidism, hyperthyroidism, hyperprolactinemia, polycystic ovarian syndrome, primary ovarian insufficiency, and functional hypothalamic amenorrhea. [16] [17]

Causes

Primary amenorrhea

Turner syndrome

Turner syndrome, monosomy 45XO, is a genetic disorder characterized by a missing, or partially missing, X chromosome. [18] Turner syndrome is associated with a wide spectrum of features that vary with each case. [18] However, one common feature of this syndrome is ovarian insufficiency due to gonadal dysgenesis. [18] [19] Most people with Turner syndrome experience ovarian insufficiency within the first few years of life, prior to menarche. [18] Therefore, most patients with Turner syndrome will have primary amenorrhea. [18] However, the incidence of spontaneous puberty varies between 8–40% depending on whether or not there is a complete or partial absence of the X chromosome. [18]

MRKH

MRKH (Mayer–Rokitansky–Küster–Hauser) syndrome is the second-most common cause of primary amenorrhoea. [20] The syndrome is characterized by Müllerian agenesis. [21] In MRKH Syndrome, the Müllerian ducts develop abnormally and result in the absence of a uterus and cervix. [21] Even though patient's with MRKH have functioning ovaries, and therefore have secondary sexual characteristics, they experience primary amenorrhea since there is no functioning uterus. [21]

Intersex conditions

Individuals with a female phenotype can present with primary amenorrhea due to complete androgen insensitivity syndrome (CAIS), 5-alpha-reductase 2 deficiency, pure gonadal dysgenesis, 17β-hydroxysteroid dehydrogenase deficiency, and mixed gonadal dysgenesis. [22] [23]

Constitutional delay of puberty

Constitutional delay of puberty is a diagnosis of exclusion that is made when the workup for primary amenorrhea does not reveal another cause. [24] Constitutional delay of puberty is not due to a pathologic cause. It is considered a variant of the timeline of puberty. [24] Although more common in boys, girls with delayed puberty present with onset of secondary sexual characteristics after the age of 14, as well as menarche after the age of 16. [25] This may be due to genetics, as some cases of constitutional delay of puberty are familial. [25]

Secondary amenorrhea

Breastfeeding

Physiologic amenorrhea is present before menarche, during pregnancy and breastfeeding, and after menopause. [3]

Breastfeeding or lactational amenorrhea is also a common cause of secondary amenorrhoea. [26] Lactational amenorrhea is due to the presence of elevated prolactin and low levels of LH, which suppress ovarian hormone secretion. [27] Breastfeeding typically prolongs postpartum lactational amenorrhoea, and the duration of amenorrhoea varies depending on how often a woman breastfeeds. [28] Due to this reason, breastfeeding has been advocated as a method of family planning, especially in developing countries where access to other methods of contraception may be limited. [27]

Diseases of the thyroid

Disturbances in thyroid hormone regulation has been a known cause of menstrual irregularities, including secondary amenorrhea. [29] [30]

Patients with hypothyroidism frequently present with changes in their menstrual cycle. [29] It is hypothesized that this is due to increased TRH, which goes on to stimulate the release of both TSH and prolactin. [29] Increased prolactin inhibits the release of LH and FSH which are needed for ovulation to occur. [29]

Patients with hyperthyroidism may also present with oligomenorrhea or amenorrhea. [29] Sex hormone binding globulin is increased in hyperthyroid states. [29] This, in turn, increases the total levels of testosterone and estradiol. [29] Increased levels of LH and FSH have also been reported in patients with hyperthyroidism. [29]

Hypothalamic and pituitary causes

Changes in the hypothalamic-pituitary axis is a common cause of secondary amenorrhea. [3] GnRH is released from the hypothalamus and stimulates the anterior pituitary to release FSH and LH, which in turn stimulate the ovaries to release estrogen and progesterone. [3] Any pathology in the hypothalamus or pituitary can alter the way this feedback mechanism works and can cause secondary amenorrhea. [3]

Pituitary adenomas are a common cause of amenorrhea. [31] Prolactin secreting pituitary adenomas cause amenorrhea due to the hyper-secretion of prolactin which inhibits FSH and LH release. [31] Other space occupying pituitary lesions can also cause amenorrhea due to the inhibition of dopamine, an inhibitor of prolactin, due to compression of the pituitary gland. [32]

Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 4–8% of women worldwide. [33] It is characterized by multiple cysts on the ovary, amenorrhea or oligomenorrhea, and increased androgens. [33] Although the exact cause remains unknown, it is hypothesized that increased levels of circulating androgens is what results in secondary amenorrhea. [34] PCOS may also be a cause of primary amenorrhea if androgen access is present prior to menarche. [34] Although multiple cysts on the ovary are characteristic of the syndrome, this has not been noted to be a cause of the disease. [34]

Low body weight

Women who perform extraneous exercise on a regular basis or lose a significant amount of weight are at risk of developing hypothalamic amenorrhoea. [35] Functional hypothalamic amenorrhoea (FHA) can be caused by stress, weight loss, or excessive exercise. [35] Many women who diet or who exercise at a high level do not take in enough calories to maintain their normal menstrual cycles. [35] The threshold of developing amenorrhoea appears to be dependent on low energy availability rather than absolute weight because a critical minimum amount of stored, easily mobilized energy is necessary to maintain regular menstrual cycles. [36] Amenorrhoea is often associated with anorexia nervosa and other eating disorders. [37] Relative energy deficiency in sport, also known as the female athlete triad, is when a woman experiences amenorrhoea, disordered eating, and osteoporosis. [37]

Energy imbalance and weight loss can disrupt menstrual cycles through several hormonal mechanisms. [38] Weight loss can cause elevations in the hormone ghrelin which inhibits the hypothalamic-pituitary-ovarial axis. [38] Elevated concentrations of ghrelin alter the amplitude of GnRH pulses, which causes diminished pituitary release of LH and follicle-stimulating hormone (FSH). [39] Low levels of the hormone leptin are also seen in females with low body weight. [40] Like ghrelin, leptin signals energy balance and fat stores to the reproductive axis. [3] Decreased levels of leptin are closely related to low levels of body fat, and correlate with a slowing of GnRH pulsing. [3]

Drug-induced

Certain medications, particularly contraceptive medications, can induce amenorrhoea in a healthy woman. [41] The lack of menstruation usually begins shortly after beginning the medication and can take up to a year to resume after stopping its use. [41] Hormonal contraceptives that contain only progestogen, like the oral contraceptive Micronor, and especially higher-dose formulations, such as the injectable Depo-Provera, commonly induce this side effect. [42] [43] Extended cycle use of combined hormonal contraceptives also allow suppression of menstruation. Patients who stop using combined oral contraceptive pills (COCP) may experience secondary amenorrhoea as a withdrawal symptom. [43] The link is not well understood, as studies have found no difference in hormone levels between women who develop amenorrhoea as a withdrawal symptom following the cessation of COCP use and women who experience secondary amenorrhoea because of other reasons. [41] New contraceptive pills which do not have the normal seven days of placebo pills in each cycle, have been shown to increase rates of amenorrhoea in women. [42] Studies show that women are most likely to experience amenorrhoea after one year of treatment with continuous OCP use. [42]

The use of opiates (such as heroin) on a regular basis has also been known to cause amenorrhoea in longer term users. [44] [45]

Anti-psychotic drugs, which are commonly used to treat schizophrenia, have been known to cause amenorrhoea as well. [46] Research suggests that anti-psychotic medications affect levels of prolactin, insulin, FSH, LH, and testosterone. [46] Recent research suggests that adding a dosage of Metformin to an anti-psychotic drug regimen can restore menstruation. [46] Metformin has been shown to decrease resistance to the hormone insulin, as well as levels of prolactin, testosterone, and luteinizing hormone (LH). [46]

Primary ovarian insufficiency

Primary ovarian insufficiency (POI) affects 1% of females and is defined as the loss of ovarian function before the age of 40. [47] Although the cause of POI can vary, it has been linked to chromosomal abnormalities, chemotherapy, and autoimmune conditions. [16] Hormone levels in POI are similar to menopause and are categorized by low estradiol and high levels of gonadotropins. [15] Since the pathogenesis of POI involves the depletion of ovarian reserve, restoration of menstrual cycles typically does not occur in this form of secondary amenorrhea. [15]

Diagnosis

Primary amenorrhoea

Primary amenorrhoea can be diagnosed in female children by age 14 if no secondary sex characteristics, such as enlarged breasts and body hair, are present. [15] In the absence of secondary sex characteristics, the most common cause of amenorrhoea is low levels of FSH and LH caused by a delay in puberty. [13] Gonadal dysgenesis, often associated with Turner syndrome, or premature ovarian failure may also be to blame. [17] If secondary sex characteristics are present, but menstruation is not, primary amenorrhoea can be diagnosed by age 16. [17]

Evaluation of primary amenorrhea begins with a pregnancy test, prolactin, FSH, LH, and TSH levels. [13] Abnormal TSH levels prompt evaluation for hyper- and hypo-thyroidism with additional thyroid function tests. [13] Elevated prolactin levels prompt evaluation of the pituitary with an MRI to assess for any masses or malignancies. [13] A pelvic ultrasound can also be obtained in the initial evaluation. [13] If a uterus is not present on ultrasound, karyotype analysis and testosterone levels are obtained to assess for MRKH or androgen insensitivity syndrome. [48] If a uterus is present, LH and FSH levels are used to make a diagnosis. [13] Low levels of LH and FSH suggest delayed puberty or functional hypothalamic amenorrhea. [13] Elevated levels of FSH and LH suggest primary ovarian insufficiency, typically due to Turner syndrome. [13] Normal levels of FSH and LH can suggest an anatomical outflow obstruction. [13] [48] [49]

Secondary amenorrhea

Secondary amenorrhea's most common and most easily diagnosable causes are pregnancy, thyroid disease, and hyperprolactinemia. [50] A pregnancy test is a common first step for diagnosis. [50]

Similar to primary amenorrhea, evaluation of secondary amenorrhea also begins with a pregnancy test, prolactin, FSH, LH, and TSH levels. [13] A pelvic ultrasound is also obtained. [13] Abnormal TSH should prompt a thyroid workup with a full thyroid function test panel. [13] Elevated prolactin should be followed with an MRI to look for masses. [51] [13] If LH and FSH are elevated, menopause or primary ovarian insufficiency should be considered. [13] Normal or low levels of FSH and LH prompts further evaluation with patient history and the physical exam. [13] Testosterone, DHEA-S, and 17-hydroxyprogesterone levels should be obtained if there is evidence of excess androgens, such as hirsutism or acne. [13] 17-hydroxyprogesterone is elevated in congenital adrenal hyperplasia. [13] Elevated testosterone and amenorrhea can suggest PCOS. [13] [34] Elevated androgens can also be present in ovarian or adrenal tumors, so additional imaging may also be needed. [13] History of disordered eating or excessive exercise should raise concern for hypothalamic amenorrhea. [52] Headache, vomiting, and vision changes can be signs of a tumor and needs evaluation with MRI. [13] Finally, a history of gynecologic procedures should lead to evaluation of Asherman syndrome with a hysteroscopy or progesterone withdrawal bleeding test. [13] [49]

Treatment

Treatment for amenorrhea varies based on the underlying condition. [53] Treatment not only focuses on restoring menstruation, if possible, but also preventing additional complications associated with the underlying cause of amenorrhea. [3]

Primary amenorrhea

In primary amenorrhea, the goal is to continue pubertal development, if possible. [3] For example, most patients with Turner syndrome will be infertile due to gonadal dysgenesis. [54] However, patients are frequently prescribed growth hormone therapy and estrogen supplementation to achieve taller stature and prevent osteoporosis. [54] In other cases, such as MRKH, hormones do not need to be prescribed since the ovaries are able to function normally. [55] Patients with constitutional delay of puberty may be monitored by an endocrinologist, but definitive treatment may not be needed as there will eventually be progression to normal puberty. [56]

Secondary amenorrhea

Treatment for secondary amenorrhea varies greatly based on the root cause. Functional hypothalamic amenorrhoea is typically treated by weight gain through increased calorie intake and decreased expenditure. [7] Multidisciplinary treatment with monitoring from a physician, dietitian, and mental health counselor is recommended, along with support from family, friends, and coaches. [7] Although oral contraceptives can cause menses to return, oral contraceptives should not be the initial treatment as they can mask the underlying problem and allow other effects of the eating disorder, like osteoporosis, continue to develop. [7]

Patients with hyperprolactinemia are often treated with dopamine agonists to reduce the levels of prolactin and restore menstruation. [51] Surgery and radiation may also be considered if dopamine agonists, such as cabergoline and bromocriptine are ineffective. [51] Once prolactin levels are lowered, the resulting secondary amenorrhea is typically resolved. [51] Similarly, treatment of thyroid abnormalities often resolves the associated amenorrhea. [57] For example, administration of thyroxine in patients with low thyroid levels restored normal menstruation in a majority of patients. [57]

Although there is currently no definitive treatment for PCOS, various interventions are used to restore more frequent ovulation in patients. [34] Weight loss and exercise have been associated with a return of ovulation in patients with PCOS due to normalization of androgen levels. [34] Metformin has also been recently studied to regularize menstrual cycles in patients with PCOS. [34] Although the exact mechanism still remains unknown, it is hypothesized that this is due to metformin's ability to increase the body's sensitivity to insulin. [34] Anti-androgen medications, such as spironolactone, can also be used to lower body androgen levels and restore menstruation. [34] Oral contraceptive pills are also often prescribed to patients with secondary amenorrhea due to PCOS in order to regularize the menstrual cycle, although this is due to the suppression of ovulation. [34]

Related Research Articles

<span class="mw-page-title-main">Menstrual cycle</span> Natural changes in the human female reproductive system

The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of eggs and the cyclic release of estrogen and progesterone. The uterine cycle governs the preparation and maintenance of the lining of the uterus (womb) to receive an embryo. These cycles are concurrent and coordinated, normally last between 21 and 35 days, with a median length of 28 days, and continue for about 30–45 years.

<span class="mw-page-title-main">Luteinizing hormone</span> Gonadotropin secreted by the adenohypophysis

Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. In females, an acute rise of LH known as an LH surge, triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH), it stimulates Leydig cell production of testosterone. It acts synergistically with follicle-stimulating hormone (FSH).

<span class="mw-page-title-main">Follicle-stimulating hormone</span> Gonadotropin that regulates the development of reproductive processes

Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) work together in the reproductive system.

<span class="mw-page-title-main">Anterior pituitary</span> Anterior lobe of the pituitary gland

A major organ of the endocrine system, the anterior pituitary is the glandular, anterior lobe that together with the posterior lobe makes up the pituitary gland (hypophysis) which, in humans, is located at the base of the brain, protruding off the bottom of the hypothalamus.

Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormonal signs that puberty has begun. In the United States, girls are considered to have delayed puberty if they lack breast development by age 13 or have not started menstruating by age 15. Boys are considered to have delayed puberty if they lack enlargement of the testicles by age 14. Delayed puberty affects about 2% of adolescents.

Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.

Hypogonadism means diminished functional activity of the gonads—the testicles or the ovaries—that may result in diminished production of sex hormones. Low androgen levels are referred to as hypoandrogenism and low estrogen as hypoestrogenism. These are responsible for the observed signs and symptoms in both males and females.

<span class="mw-page-title-main">Hypopituitarism</span> Medical condition

Hypopituitarism is the decreased (hypo) secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is known as selective hypopituitarism. If there is decreased secretion of most or all pituitary hormones, the term panhypopituitarism is used.

<span class="mw-page-title-main">Hyperandrogenism</span> Medical condition

Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea, hair loss on the scalp, increased body or facial hair, and infrequent or absent menstruation. Complications may include high blood cholesterol and diabetes. It occurs in approximately 5% of women of reproductive age.

<span class="mw-page-title-main">Hypothalamic–pituitary–gonadal axis</span> Concept of regarding the hypothalamus, pituitary gland and gonadal glands as a single entity

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

Hypoestrogenism, or estrogen deficiency, refers to a lower than normal level of estrogen. It is an umbrella term used to describe estrogen deficiency in various conditions. Estrogen deficiency is also associated with an increased risk of cardiovascular disease, and has been linked to diseases like urinary tract infections and osteoporosis.

<span class="mw-page-title-main">Menstrual disorder</span> Medical condition affecting menstrual cycle

A menstrual disorder is characterized as any abnormal condition with regards to a woman's menstrual cycle. There are many different types of menstrual disorders that vary with signs and symptoms, including pain during menstruation, heavy bleeding, or absence of menstruation. Normal variations can occur in menstrual patterns but generally menstrual disorders can also include periods that come sooner than 21 days apart, more than 3 months apart, or last more than 10 days in duration. Variations of the menstrual cycle are mainly caused by the immaturity of the hypothalamic-pituitary-ovarian (HPO) axis, and early detection and management is required in order to minimize the possibility of complications regarding future reproductive ability.

Primary ovarian insufficiency (POI), also called premature ovarian insufficiency, premature menopause, and premature ovarian failure, is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of follicular dysfunction or early loss of eggs. POI can be seen as part of a continuum of changes leading to menopause that differ from age-appropriate menopause in the age of onset, degree of symptoms, and sporadic return to normal ovarian function. POI affects approximately 1 in 10,000 women under age 20, 1 in 1,000 women under age 30, and 1 in 100 of those under age 40. A medical triad for the diagnosis is amenorrhea, hypergonadotropism, and hypoestrogenism.

Functional hypothalamic amenorrhea (FHA) is a form of amenorrhea and chronic anovulation and is one of the most common types of secondary amenorrhea. It is classified as hypogonadotropic hypogonadism. It was previously known as "juvenile hypothalamosis syndrome," prior to the discovery that sexually mature females are equally affected. FHA has multiple risk factors, with links to stress-related, weight-related, and exercise-related factors. FHA is caused by stress-induced suppression of the hypothalamic-pituitary-ovarian (HPO) axis, which results in inhibition of gonadotropin-releasing hormone (GnRH) secretion, and gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Severe and potentially prolonged hypoestrogenism is perhaps the most dangerous hormonal pathology associated with the disease, because consequences of this disturbance can influence bone health, cardiovascular health, mental health, and metabolic functioning in both the short and long-term. Because many of the symptoms overlap with those of organic hypothalamic, pituitary, or gonadal disease and therefore must be ruled out, FHA is a diagnosis of exclusion; "functional" is used to indicate a behavioral cause, in which no anatomical or organic disease is identified, and is reversible with correction of the underlying cause. Diagnostic workup includes a detailed history and physical, laboratory studies, such as a pregnancy test, and serum levels of FSH and LH, prolactin, and thyroid-stimulating hormone (TSH), and imaging. Additional tests may be indicated in order to distinguish FHA from organic hypothalamic or pituitary disorders. Patients present with a broad range of symptoms related to severe hypoestrogenism as well as hypercortisolemia, low serum insulin levels, low serum insulin-like growth factor 1 (IGF-1), and low total triiodothyronine (T3). Treatment is primarily managing the primary cause of the FHA with behavioral modifications. While hormonal-based therapies are potential treatment to restore menses, weight gain and behavioral modifications can have an even more potent impact on reversing neuroendocrine abnormalities, preventing further bone loss, and re-establishing menses, making this the recommended line of treatment. If this fails to work, secondary treatment is aimed at treating the effects of hypoestrogenism, hypercortisolism, and hypothyroidism.

Hypomenorrhea or hypomenorrhoea, also known as short or scanty periods, is extremely light menstrual blood flow. It is the opposite of heavy periods or hypermenorrhea which is more properly called menorrhagia.

Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production. As compensation and the lack of negative feedback, gonadotropin levels are elevated. Individuals with HH have an intact and functioning hypothalamus and pituitary glands so they are still able to produce FSH and LH. HH may present as either congenital or acquired, but the majority of cases are of the former nature. HH can be treated with hormone replacement therapy.

<span class="mw-page-title-main">Leydig cell hypoplasia</span> Medical condition

Leydig cell hypoplasia (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive genetic and endocrine syndrome affecting an estimated 1 in 1,000,000 genetic males. It is characterized by an inability of the body to respond to luteinizing hormone (LH), a gonadotropin which is normally responsible for signaling Leydig cells of the testicles to produce testosterone and other androgen sex hormones. The condition manifests itself as pseudohermaphroditism, hypergonadotropic hypogonadism, reduced or absent puberty, and infertility.

Gonadotropin-releasing hormone (GnRH) insensitivity also known as Isolated gonadotropin-releasing hormone (GnRH)deficiency (IGD) is a rare autosomal recessive genetic and endocrine syndrome which is characterized by inactivating mutations of the gonadotropin-releasing hormone receptor (GnRHR) and thus an insensitivity of the receptor to gonadotropin-releasing hormone (GnRH), resulting in a partial or complete loss of the ability of the gonads to synthesize the sex hormones. The condition manifests itself as isolated hypogonadotropic hypogonadism (IHH), presenting with symptoms such as delayed, reduced, or absent puberty, low or complete lack of libido, and infertility, and is the predominant cause of IHH when it does not present alongside anosmia.

Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis. Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.

Follicle-stimulating hormone (FSH) insensitivity, or ovarian insensitivity to FSH in females, also referable to as ovarian follicle hypoplasia or granulosa cell hypoplasia in females, is a rare autosomal recessive genetic and endocrine syndrome affecting both females and males, with the former presenting with much greater severity of symptomatology. It is characterized by a resistance or complete insensitivity to the effects of follicle-stimulating hormone (FSH), a gonadotropin which is normally responsible for the stimulation of estrogen production by the ovaries in females and maintenance of fertility in both sexes. The condition manifests itself as hypergonadotropic hypogonadism, reduced or absent puberty, amenorrhea, and infertility in females, whereas males present merely with varying degrees of infertility and associated symptoms.

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