Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by

hypogonadism Hypogonadism means diminished functional activity of the human gonad, gonads—the testicles or the ovary, ovaries—that may result in diminished biosynthesis, production of sex hormones. Low androgen (e.g., testosterone) levels are referred t ...

which is due to an impaired response of the

gonad A gonad, sex gland, or reproductive gland is a Heterocrine gland, mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gon ...

s to the

gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. They are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. T ...

follicle-stimulating hormone 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, puberty, pubertal maturat ...

(FSH) and

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (G ...

(LH), and in turn a lack of

sex steroid Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...

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 (of the hypothalamic-pituitary-gonadal (HPA) axis) 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 Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. Effects of menopause can include symptoms such ...

Signs and symptoms

Symptoms can vary greatly depending on the stage of life, biological sex, and etiology.

Males

During birth and early infancy, HH in males can present as normal male phenotype with or without

cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is . It is the most common birth defect of the male genital tract. About 3% of full-term and 30% of premature infant boy ...

, complex genital anomaly, or normal female phenotype. Children often have small or non-palpable testes and this can present with or without genital anomaly. As individuals progress onto adolescence, they may experience absent or delayed puberty or puberty that starts but fails to progress. Adult males with HH may exhibit gynecomastia, erectile dysfunction, reduced testicular volume (absence of testicular enlargement during puberty), abnormal testicular texture and consistency, small stature, decreased libido and sexual activity, infertility due to low (

oligospermia Terms oligospermia, oligozoospermia, and low sperm count refer to semen with a low concentration of sperm and is a common finding in male infertility. Often, semen with a decreased sperm concentration may also show significant abnormalities in sper ...

) or no (

azoospermia Azoospermia is the medical condition of a man whose semen contains no sperm. It is associated with male infertility, but many forms are amenable to medical treatment. In humans, azoospermia affects about 1% of the male population and may be see ...

) sperm count, loss of body hair, loss of muscle mass, hot flashes, psychological disturbances and poor sleep pattern.

Females

Females may present with low levels of estrogen and abnormal menstruation. Individuals with Turner syndrome may have short stature, dysmorphic features, gonadal dysgenesis, and delayed puberty. Other signs and symptoms associated with HH consist of intellectual disability or learning difficulties and delayed puberty including amenorrhea and absent breast and pubic hair development. Other complications that can arise include anxiety and depression, osteoporosis and relationship problems.

Causes

There are a multitude of etiologies for HH and it can include congenital or acquired causes.

Congenital causes include the following

Sources: * Disorders of Sex Development (DSD) –

Turner's syndrome Turner syndrome (TS), commonly known as 45,X, or 45,X0,Also written as 45,XO. is a chromosomal disorder in which cells of females have only one X chromosome instead of two, or are partially missing an X chromosome (sex chromosome monosomy) lead ...

Klinefelter's syndrome Klinefelter syndrome (KS), also known as 47,XXY, is a chromosome anomaly where a male has an extra X chromosome. These complications commonly include infertility and small, poorly functioning testicles (if present). These symptoms are often not ...

, Swyer's syndrome,

XX gonadal dysgenesis XX gonadal dysgenesis is a type of female hypogonadism in which the ovaries do not function to induce puberty in a person assigned female at birth, whose karyotype is 46,XX. Individuals with XX gonadal dysgenesis have normal-appearing external geni ...

mosaicism Mosaicism or genetic mosaicism is a condition in which a multicellular organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized egg. Mosaicism is o ...

, partial androgen insensitivity,

complete androgen insensitivity syndrome Complete androgen insensitivity syndrome (CAIS) is an AIS condition that results in the complete inability of the cell to respond to androgens. As such, the insensitivity to androgens is only clinically significant when it occurs in individual ...

congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of Genetic disorder#Autosomal recessive, autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the Biosy ...

galactosemia Galactosemia (British galactosaemia, from Greek γαλακτόζη + αίμα, meaning galactose + blood, accumulation of galactose in blood) is a rare genetics, genetic Metabolism, metabolic Disease, disorder that affects an individual's ability t ...

, and testicular regression sequence. * Gonadotropin resistance (e.g., due to inactivating mutations in the

gonadotropin receptor The gonadotropin receptors are a group of receptors that bind a group of pituitary hormones called gonadotropins. They include the: * Follicle-stimulating hormone receptor (FSHR) - binds follicle-stimulating hormone (FSH) * Luteinizing hormone rec ...

s) – carbohydrate-deficient glycoprotein syndrome,

Leydig cell hypoplasia Leydig cell hypoplasia (or aplasia) (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive genetic and endocrine syndrome affecting an estimated 1 in 1,000,000 individuals with XY chromosomes. It is characterized by an inability ...

(or insensitivity to LH) in males, FSH insensitivity in females, and LH and FSH resistance due to mutations in the '' GNAS''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

(termed

pseudohypoparathyroidism Pseudohypoparathyroidism is a rare autosomal dominant genetic condition associated primarily with resistance to the parathyroid hormone. Those with the condition have a low serum calcium and high phosphate, but the parathyroid hormone level (PTH) ...

type 1A) *

Myotonic Dystrophy Myotonic dystrophy (DM) is a type of muscular dystrophy, a group of genetic disorders that cause progressive muscle loss and weakness. In DM, muscles are often myotonia, unable to relax after contraction. Other manifestations may include catarac ...

Acquired causes

(due to damage to or dysfunction of the

s) include testicular torsion,

ovarian torsion Ovarian torsion (OT) or adnexal torsion is an abnormal condition where an ovary twists on its attachment to other structures, such that blood flow is decreased. Symptoms typically include pelvic pain on one side. While classically the pain is su ...

, vanishing/

anorchia Gonadal agenesis is a rare condition where an individual lacks both gonads. If the karyotype is 46,XY and the individual otherwise has a male phenotype, it is called anorchia; this occurs in one of 20,000 male births. The corresponding condition ...

orchitis Orchitis is inflammation of the testicles. It can also involve swelling, pains, and frequent infection, particularly of the epididymis, as in epididymitis. The term is from the Ancient Greek ὄρχις meaning "testicle"; same root as ''orchid ...

premature ovarian failure Primary ovarian insufficiency (POI), also called premature ovarian insufficiency and premature ovarian failure, is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of follicular ( egg produc ...

, ovarian resistance syndrome,

trauma Trauma most often refers to: *Psychological trauma, in psychology and psychiatric medicine, refers to severe mental and emotional injury caused by distressing events *Traumatic injury, sudden physical injury caused by an external force, which doe ...

surgery Surgery is a medical specialty that uses manual and instrumental techniques to diagnose or treat pathological conditions (e.g., trauma, disease, injury, malignancy), to alter bodily functions (e.g., malabsorption created by bariatric surgery s ...

autoimmunity In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease ...

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

radiation In physics, radiation is the emission or transmission of energy in the form of waves or particles through space or a material medium. This includes: * ''electromagnetic radiation'' consisting of photons, such as radio waves, microwaves, infr ...

infection An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...

s (e.g.,

sexually-transmitted disease A sexually transmitted infection (STI), also referred to as a sexually transmitted disease (STD) and the older term venereal disease (VD), is an infection that is spread by sexual activity, especially vaginal intercourse, anal sex, oral ...

s),

toxin A toxin is a naturally occurring poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919), derived ...

s (e.g.,

endocrine disruptor Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine (or hormonal) systems. These disruptions can cause ...

s), infection, kidney disease, liver disease, iron overload, and

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

s (e.g.,

antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking t ...

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

Diagnosis

A diagnosis can be made from the following:

History

Family history including age, healthy pubertal development of family members, and possibility of genetic disease will be evaluated. Prenatal history, such as maternal medication use, birthweight of the affected individual, childhood surgical interventions, and overall general health will also play a significant role during diagnosis. In children with delayed puberty, hypogonadism can be distinguished from constitutional delay through family history, with constitutional delay being closely associated with positive family history.

Examination

Individuals will be examined for height, weight, and any abnormal body features. Breast and genitalia examinations in presence of a chaperone may also be needed. Diagnostic imaging such ultrasound, computerized tomography (CT), and magnetic resonance imaging (MRI) can be done to evaluate for any abnormalities of the internal genitalia, tumors in the pituitary gland or in the brain, and ovarian cysts for possibilities of

polycystic ovarian syndrome Polycystic ovary syndrome, or polycystic ovarian syndrome, (PCOS) is the most common endocrine disorder in women of reproductive age. The name is a misnomer, as not all women with this condition develop cysts on their ovaries. The name origi ...

(PCOS).

Further Testing

Individuals with hypergonadotropic hypogonadism also exhibit gonadotropin levels (FSH and LH) that are above normal range and gonadal hormone levels (estrogen in females and testosterone in males) that are below normal range, so these biochemical parameters will be measured via a blood test. However for young males before adolescence, anti-Müllerian hormone (AMH) levels may be more indicative of HH since only small amounts of testosterone will be produced prior to the reactivation of the HPG axis during adolescence. Karyotyping and molecular

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

can also be done to evaluate for any chromosomal abnormalities. Blood tests to check levels of prolactin, iron and thyroid hormones can be done to diagnose HH. Semen analysis can be another way to measure the sperm count to help diagnose individuals with HH.

Etiology

Hypergonadotropic hypogonadism can be caused by a variety of genetic and acquired factors. Common genetic causes include Turner syndrome and Klinefelter syndrome, while acquired causes may involve infections, trauma, radiation, or chemotherapy affecting the gonads.

Treatment

Treatment of HH is usually with

, consisting of

androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

and

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

administration in males and females, respectively. Therapies should be individualized based on individuals needs to help develop and maintain secondary sexual characteristics. In males, androgen therapy is usually either done by induction of endogenous testosterone production by hCG or by exogenous testosterone replacement therapy. However, it is important to note that testosterone treatment does not restore fertility in men. There are many infertility treatment options available for individuals with HH, such as selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and gonadotropins. Testicular sperm extraction, intracytoplasmic sperm injections, semen/embryo cryopreservation are also possible treatment options .

Estrogen Replacement

In females with HH, estrogen therapy is done initially for breast development and pubertal induction. Pubertal induction should start no later than the age of 12 to maximize height growth and for benefits to outweigh adverse effects. Estrogen therapy, commonly using ethinylestradiol, should start at low doses and are gradually increased according to the body responses. Most of the studies regarding estrogen therapy have focused on girls with Turner Syndrome. There are many formulations for estrogen therapy that include oral estradiol, oral conjugated estrogen, transdermal estrogen patches, and estrogen gel. The therapy is individualized and is initiated based on many factors including age, bone age, absolute height, and psychosocial issues. Progesterone therapy for a week per month in addition to estrogen allows for adequate uterine and breast development. Routine follow-ups for during and after pubertal inductions can include checkups for height, weight, body-mass index (BMI), and blood pressure three times a year and FSH/LH measurements every year.

Testosterone Replacement

In males with HH, most of the studies have focused on

and constitutional delay of growth and puberty (CDGP). The therapy is initiated as 15 to 25% of that of adults doses, then it gradually increased over 4 to 6 months. 50 to 100mg of testosterone ester is given intramuscularly every 2 to 4 weeks. Therapy is lifelong in boys who have permanent hypogonadism. Neonatal testosterone therapy can be given to infants with HH. However, for children, testosterone should be avoided due to the possible adverse effects of rapid bone aging and growth acceleration. There are various formulation of testosterone including oral, intramuscular, and transdermal such as patches and gels. Testosterone therapy should be avoided in individuals with breast and/or prostate cancer.

References

{{Gonadal disorder Endocrine gonad disorders Gynaecological endocrinology Gonadotropin-releasing hormone and gonadotropins

Signs and symptoms

Males

Females

Causes

Congenital causes include the following

Acquired causes

Diagnosis

History

Examination

Further Testing

Etiology

Treatment

Estrogen Replacement

Testosterone Replacement

See also

References