Hypergonadotropic hypogonadism

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Hypergonadotropic hypogonadism
Other namesPeripheral/gonadal hypogonadism
Specialty Endocrinology

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. [1] 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. [1] HH may present as either congenital or acquired, but the majority of cases are of the former nature. [2] [3] HH can be treated with hormone replacement therapy. [4]

Contents

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, complex genital anomaly, or normal female phenotype. [5] Children often have small or non-palpable testes and this can present with or without genital anomaly. [5] As individuals progress onto adolescence, they may experience absent or delayed puberty or puberty that starts but fails to progress. [5] 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) or no (azoospermia) sperm count, loss of body hair, loss of muscle mass, hot flashes, psychological disturbances and poor sleep pattern. [4] [5]

Females

Females may present with low levels of estrogen and abnormal menstruation. [4] Individuals with Turner syndrome may have short stature, dysmorphic features, gonadal dysgenesis, and delayed puberty. [5] 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. [5]

Other complications that can arise include anxiety and depression, osteoporosis and relationship problems. [4]

Causes

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

Congenital causes include the following

Sources: [2] [6] [5]

Acquired causes

(due to damage to or dysfunction of the gonads) include testicular torsion, [5] ovarian torsion, vanishing/anorchia, orchitis, premature ovarian failure, ovarian resistance syndrome, trauma, surgery, autoimmunity, chemotherapy, radiation, infections (e.g., sexually-transmitted diseases), toxins (e.g., endocrine disruptors), infection, kidney disease, liver disease, iron overload, and drugs (e.g., antiandrogens, opioids, alcohol). [2] [6] [5] [7]

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. [10] [8] 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. [11]

Examination

Individuals will be examined for height, weight, and any abnormal body features. [10] Breast and genitalia examinations in presence of a chaperone may also be needed. [10] 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 (PCOS). [9] [10]

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. [12] 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. [10] Karyotyping and molecular genetic testing can also be done to evaluate for any chromosomal abnormalities. [7] [9] 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.

Treatment

Treatment of HH is usually with hormone replacement therapy, consisting of androgen and estrogen administration in males and females, respectively. [6] Therapies should be individualized based on individuals needs to help develop and maintain secondary sexual characteristics. [7] 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. [13] There are many infertility treatment options available for individuals with HH, such as selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and gonadotropins. [9] Testicular sperm extraction, intracytoplasmic sperm injections, semen/embryo cryopreservation are also possible treatment options . [10]

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. [10] Estrogen therapy, commonly using ethinylestradiol, should start at low doses and are gradually increased according to the body responses. [14] 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. [8] 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. [10]

Testosterone Replacement

In males with HH, most of the studies have focused on Klinefelter's syndrome 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. [14] However, for children, testosterone should be avoided due to the possible adverse effects of rapid bone aging and growth acceleration. [10] There are various formulation of testosterone including oral, intramuscular, and transdermal such as patches and gels. [8] Testosterone therapy should be avoided in individuals with breast and/or prostate cancer. [15]

See also

Related Research Articles

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

<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.

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.

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.

Gonadarche refers to the earliest gonadal changes of puberty. In response to pituitary gonadotropins, the ovaries in females and the testes in males begin to grow and increase the production of the sex steroids, especially estradiol and testosterone. The ovary and testis have receptors, follicle cells and leydig cells, respectively, where gonadotropins bind to stimulate the maturation of the gonads and secretion of estrogen and testosterone. Certain disorders can result in changes to timing or nature of these processes.

Kallmann syndrome (KS) is a genetic disorder that prevents a person from starting or fully completing puberty. Kallmann syndrome is a form of a group of conditions termed hypogonadotropic hypogonadism. To distinguish it from other forms of hypogonadotropic hypogonadism, Kallmann syndrome has the additional symptom of a total lack of sense of smell (anosmia) or a reduced sense of smell. If left untreated, people will have poorly defined secondary sexual characteristics, show signs of hypogonadism, almost invariably are infertile and are at increased risk of developing osteoporosis. A range of other physical symptoms affecting the face, hands and skeletal system can also occur.

<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.

Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD), is a condition which results in a small subset of cases of hypogonadotropic hypogonadism (HH) due to deficiency in or insensitivity to gonadotropin-releasing hormone (GnRH) where the function and anatomy of the anterior pituitary is otherwise normal and secondary causes of HH are not present.

<span class="mw-page-title-main">Gonadotropin-releasing hormone agonist</span> Drug class affecting sex hormones

A gonadotropin-releasing hormone agonist is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth among other uses. It is also used in the suppression of spontaneous ovulation as part of controlled ovarian hyperstimulation, an essential component in IVF. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.

<span class="mw-page-title-main">Gonadal dysgenesis</span> Congenital disorder of the reproductive system

Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system in humans. It is atypical development of gonads in an embryo. One type of gonadal dysgenesis is the development of functionless, fibrous tissue, termed streak gonads, instead of reproductive tissue. Streak gonads are a form of aplasia, resulting in hormonal failure that manifests as sexual infantism and infertility, with no initiation of puberty and secondary sex characteristics.

<span class="mw-page-title-main">Micropenis</span> Unusually small penis

A micropenis is an unusually small penis. A common criterion is a dorsal penile length of at least 2.5 standard deviations smaller than the mean human penis size. A micropenis is stretched penile length less than 2.5 cm in term infants, 2.6 cm in one-year-old, 3.5 cm in five year old, 3.8 cm in ten year old, and 9.3 cm in adults. The condition is usually recognized shortly after birth. The term is most often used medically when the rest of the penis, scrotum, and perineum are without ambiguity, such as hypospadias. A microphallus describes a medical term where other sections of genitallia are different, such as hypospadias or cryptorchidism. Micropenis incidence is about 1.5 in 10,000 male newborns in North America.

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

Aromatase deficiency is a rare condition characterized by extremely low levels or complete absence of the enzyme aromatase activity in the body. It is an autosomal recessive disease resulting from various mutations of gene CYP19 (P450arom) which can lead to ambiguous genitalia and delayed puberty in females, continued linear growth into adulthood and osteoporosis in males and virilization in pregnant mothers. As of 2020, fewer than 15 cases have been identified in genetically male individuals and at least 30 cases in genetically female individuals.

Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testicles in a male. In response to the signals, the gonads produce hormones that stimulate libido and the growth, function, and transformation of the brain, bones, muscle, blood, skin, hair, breasts, and sex organs. Physical growth—height and weight—accelerates in the first half of puberty and is completed when an adult body has been developed. Before puberty, the external sex organs, known as primary sexual characteristics, are sex characteristics that distinguish males and females. Puberty leads to sexual dimorphism through the development of the secondary sex characteristics, which further distinguish the sexes.

Hyperestrogenism, hyperestrogenic state, or estrogen excess, is a medical condition characterized by an excessive amount of estrogenic activity in the body.

<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.

Hypergonadotropic hypergonadism is an endocrine situation and subtype of hypergonadism in which both gonadotropin levels and gonadal function, such as sex hormone production, are abnormally high. It can be associated with hyperandrogenism and hyperestrogenism and with gonadal cysts and tumors. It can be caused by medications such as gonadotropins, gonadotropin-releasing hormone agonists, nonsteroidal antiandrogens, and selective estrogen receptor modulators, as well as conditions like human chorionic gonadotropin-secreting tumors, complete androgen insensitivity syndrome, and estrogen insensitivity syndrome.

References

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  3. ↑ Piñón R (2002). Biology of Human Reproduction. University Science Books. p. 363. ISBN   978-1-891389-12-2 . Retrieved 10 June 2012.
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  11. ↑ Vogiatzi MG (2022-01-24). Windle ML, Bercu BB, Griffing GT (eds.). "Hypogonadism Differential Diagnoses". Medscape.
  12. ↑ Dye AM, Nelson GB, Diaz-Thomas A (January 2018). "Delayed Puberty". Pediatric Annals. 47 (1): e16–e22. doi:10.3928/19382359-20171215-01. PMID   29323692.
  13. ↑ Hayes F, Dwyer A, Pitteloud N (2000). "Hypogonadotropic Hypogonadism (HH) and Gonadotropin Therapy". In Feingold KR, Anawalt B, Boyce A, Chrousos G (eds.). Endotext. South Dartmouth (MA): MDText.com, Inc. PMID   25905304 . Retrieved 2022-07-28.
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  15. ↑ Papadakis MA, McPhee SJ, Bernstein J, eds. (2022). "Hypogonadism, Male". Quick Medical Diagnosis & Treatment. McGraw Hill.
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