Macroorchidism

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Macroorchidism
Specialty Urology

Macroorchidism is a disorder found in males, specifically in children, where a subject has abnormally large testes. The condition is commonly inherited in connection with fragile X syndrome (FXS), which is also the second most common genetic cause of intellectual disability. [1] The condition is also a rare sign of the McCune-Albright syndrome. [2] The opposite of macroorchidism is called microorchidism, which is the condition of abnormally small testes.

Contents

Macroorchidism is related to IGFS1 deficiency which causes an increase in the secretion of follicle stimulating hormone (FSH). There are other causes for macroorchidism such as hypothyroidism, local tumors, and aromatase deficiency. [3] Macroorchidism can be diagnosed by measuring the testicular volume using a prader orchidometer. [4] There is no cure for macroorchidism, however, medications are currently being tested and used to control the disorder to promote quality living. [5]

Signs and symptoms

The most distinguishing physical symptom of macroorchidism in patients is the increased testicular size. To determine enlargement of the testes (i.e. macroorchidism), the testes must be greater than the 95th percentile of the confidence interval in males after puberty. The 95th percentile means that the child's testicular size exceeds 95% of children similar in age. This rules out males with early puberty. Another symptom of macroorchidism is if there is an increase in testicular volume that is at least twice the normal testicular volume for the age. [4]

Macroorchidism is mostly found in prepubescent boys with fragile X syndrome. However, true macroorchidism does not start until the testicular size is greater than 4 cm, which can only occur later in the prepubertal period. [2] Because macroorchidism is associated with fragile X syndrome patients, the signs in patients with FXS is similar in patients with macroorchidism. These signs include protruding ears, long face, bulging jaw and forehead, macrocephaly, mid-facial hypoplasia, and a high arched palate. [6]

Even though FXS affects both males and females, the prevalence in males is approximately 1 in 4000 males. [1]

Cause

The cause of macroorchidism is still unclear. [7] However, there are studies that show a connection between macroorchidism and other disorders related to hormones that reveal their possible role with the abnormal enlargement of the testes. [4] An excessive increase in the interstitial volume and the connective tissue of the testes can lead to macroorchidism. [2]

There are other causes of macroorchidism such as long-standing primary hypothyroidism, adrenal tissue remains in congenital adrenal hyperplasia (CAH), follicle stimulating hormone (FSH) secreting pituitary macroadenomas, local tumors, lymphomas, and aromatase deficiency. [3]

Pathophysiology or mechanism

Macroorchidism result from an increased secretion of the follicle stimulating hormone. The follicle stimulating hormone is secreted without being affected by an increase in the secretion of the luteinizing hormone (LH) or a luteinizing hormone response to Gonadotropin-releasing hormone (GnRH). [2]

Macroorchidism is related to a genetic defect in the Immunoglobulin Superfamily 1 (IGSF1) gene. However, not all patients with a failing IGSF1 gene present with macroorchidism. In gonadotropes, there is activin A. Gonadotropes are endocrine cells in the anterior pituitary that control and regulate reproduction. These cells release the FSH and LH hormones and play an important role in puberty. Activin A is a dimeric glycoprotein that is a member of the transforming growth factor-β (TGF-β) family. Activin A is responsible for hormonal homeostasis, gonadal functions, muscle growth, immunity, inflammation, and bone remodeling. [8] Activin A binds to activin receptors (ActRs) in the gonadotropes and stimulates the Smad2 or Smad3 pathway to increase follicle-stimulating hormone beta subunit (FSHB). The follicle stimulating hormone (FSH) then stimulates the follicle-stimulating hormone receptor (FSHR) of the sertoli cells, therefore producing inhibin B which brings into play a negative feedback over the pituitary FSHB expression. The IGSF1 gene inhibits the activin A pathway which decreases the rate of FSHB expression. IGSF1 gene deficiency leads to over-secretion of pituitary FSH causing an early and rapid increase in the testicular sertoli cell mass (i.e. macroorchidism) in children and adults with FSH-secreting pituitary adenomas. [9]

An Orchidometer Orchidometr.png
An Orchidometer

Diagnosis

Macroorchidism is usually found in prepubertal boys with long-standing primary hypothyroidism, [2] boys with Van Wyk Grumbach Syndrome (VWGS), [7] and boys with fragile X syndrome (FXS). [3]

When macroorchidism is considered, the testicular volume is measured using a prader orchidometer. [4] The prader orchidometer is used to quickly and accurately measure the testicular volume to evaluate male growth and development. [10] The prader orchidometer is the most widely used orchidometer since 1966 and is calculated using the formula: Length*Width*Height*0.71. [4] The correct final value from the calculation is compared with an age percentile table that shows how much the child exceeds the percentage of children their age for testicular volume. [4]

The testicular volume changes throughout a males life and is as follows: [11]

People with macroorchidism have testicular volume larger than 4 ml before puberty. [11]

Treatment or management

Treatment of macroorchidism depends on pathogenesis.

Surgical removal of the tumor is the most important and advised option for treating macroorchidism caused by non-functioning pituitary macroadenoma. [12] A non-functioning pituitary adenoma is a kind of benign tumor that does not secrete active hormones, and is from the pituitary gland. [13]

Macroorchidism caused from congenital adrenal hyperplasia (CAH) is treated using glucocorticoid. Using glucocorticoid at the beginning of macroorchidism can help reduce the abnormal testicular size. [4] Glucocorticoid treatment is a dosage treatment in which glucocorticoids such as hydrocortisone, prednisolone, and dexamethasone are taken at various amounts and times of the day. Glucocorticoid treatment can help restore male fertility prohibited by macroorchidism. [14] However, overusing glucocorticoid for long periods of time can lead to low semen quality. [4]

Metformin is considered a long-term treatment of macroorchidism due to its relationship with FXS. Metformin lowers the excessive production of the proteins that cause abnormal testicular growth in people with FXS. [11]

Prognosis

Macroorchidism becomes more clear after puberty. [5] Testicular size starts to increase normally from 8 to 9 years of age in boys. However, in patients with macroorchidism, around this time is when the testicles become abnormally and noticeably enlarged. [11] Also, because macroorchidism is usually associated with intellectual disability, the brainpower typically declines with age. [5]

The life expectancy of patients with macroorchidism is normal. [5] There is no cure for macroorchidism; however, there are medications tested in clinical trails identified to bring positive results. [5]

Epidemiology

Macroorchidism only affects males. The prevalence of macroorchidism is approximately 1 in 4000 males. [1] Macroorchidism is present in more than 80 - 90% of postpubertal males with fragile X syndrome. [11]

Research direction

A research study was done in 2014 to learn if there is a relationship between macroorchidism and intellectual disability associated with decreased levels of Fragile X Mental Retardation 1 gene protein (FMRP), but in the pre-mutation or carrier state. FMRP is made from FMR1 gene, and is mainly in the brain and testis. They used the analysis of covariance (ANCOVA) to compare the IQs of the macroorchidism patients with and without pre-mutation carriers. The results showed that there is a relationship between macroorchidism and intellectual disability in FMR1 pre-mutation carrier males. Further studies need to be done to determine if the correlation is due to higher or lower levels of FMR1 mRNA and FMRP respectively. [1]

Another study done in 2018 researched the role of Immunoglobulin Superfamily 1 (IGSF1) serves in hypothyroidism and macroorchidism as a regulator of pituitary hormone secretion. A defect in the IGSF1 gene is one of the causes of macroorchidism. The results showed that IGSF1 is important for pituitary hormone regulation, and that there are two important mechanisms of macroorchidism related to IGSF1 deficiency. [9]

Related Research Articles

<span class="mw-page-title-main">Fragile X syndrome</span> X-linked dominant genetic disorder

Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles. About a third of those affected have features of autism such as problems with social interactions and delayed speech. Hyperactivity is common, and seizures occur in about 10%. Males are usually more affected than females.

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.

<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.

<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">Pituitary adenoma</span> Human disease

Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas. Pituitary adenomas represent from 10% to 25% of all intracranial neoplasms and the estimated prevalence rate in the general population is approximately 17%.

<span class="mw-page-title-main">Endocrine gland</span> Glands of the endocrine system that secrete hormones to blood

Endocrine glands are ductless glands of the endocrine system that secrete their products, hormones, directly into the blood. The major glands of the endocrine system include the pineal gland, pituitary gland, pancreas, ovaries, testicles, thyroid gland, parathyroid gland, hypothalamus and adrenal glands. The hypothalamus and pituitary glands are neuroendocrine organs.

<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.

Nelson's syndrome is a disorder that occurs in about one in four patients who have had both adrenal glands removed to treat Cushing's disease. In patients with pre-existing adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, loss of adrenal feedback following bilateral adrenalectomy can trigger the rapid growth of the tumor, leading to visual symptoms and hyperpigmentation. The severity of the disease is dependent upon the effect of ACTH release on the skin, pituitary hormone loss from mass compression, as well as invasion into surrounding structures around the pituitary gland.

The gonadotropin-releasing hormone receptor (GnRHR), also known as the luteinizing hormone releasing hormone receptor (LHRHR), is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is the receptor of gonadotropin-releasing hormone (GnRH). The GnRHR is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate.

<span class="mw-page-title-main">Histrelin</span> Chemical compound

Histrelin acetate, sold under the brand names Vantas and Supprelin LA among others, is a nonapeptide analogue of gonadotropin-releasing hormone (GnRH) with added potency. When present in the bloodstream, it acts on particular cells of the pituitary gland called gonadotropes. Histrelin stimulates these cells to release luteinizing hormone and follicle-stimulating hormone. Thus it is considered a gonadotropin-releasing hormone agonist or GnRH agonist.

<span class="mw-page-title-main">FSHB</span> Protein-coding gene in the species Homo sapiens

Follitropin subunit beta also known as follicle-stimulating hormone beta subunit (FSH-B) is a protein that in humans is encoded by the FSHB gene. Alternative splicing results in two transcript variants encoding the same protein.

<span class="mw-page-title-main">IGSF1</span> Protein-coding gene in the species Homo sapiens

Immunoglobulin superfamily, member 1 is a plasma membrane glycoprotein encoded by the IGSF1 gene, which maps to the X chromosome in humans and other mammalian species.

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.

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.

References

  1. 1 2 3 4 Lozano, Reymundo; Summers, Scott; Lozano, Cristina; Mu, Yi; Hessl, David; Nguyen, Danh; Tassone, Flora; Hagerman, Randi (September 2014). "Association between macroorchidism and intelligence in FMR1 premutation carriers". American Journal of Medical Genetics Part A. 164 (9): 2206–2211. doi:10.1002/ajmg.a.36624. PMC   4332881 . PMID   24903624.
  2. 1 2 3 4 5 Styne, Dennis M. (2019). "Physiology and Disorders of Puberty". Williams Textbook of Endocrinology. 26: 1023–1164.e25.
  3. 1 2 3 Maheshwari, R.; Bharath, R.; Karthik, T. Sriram; Prasad, N. Rajendra; Rani, P. Radha; Reddy, P. Amaresh (2013-04-01). "Macroorchidism as presenting feature of Fragile X Syndrome". Journal of Clinical and Scientific Research. 2 (2): 108. doi: 10.4103/2277-5706.241247 . ISSN   2277-5706.
  4. 1 2 3 4 5 6 7 8 De Sanctis, Vincenzo; Marsella, Maria; Soliman, Ashraf; Yassin, Mohamed (February 2014). "Macroorchidism in childhood and adolescence: an update". Pediatric Endocrinology Reviews: PER. 11 (Suppl 2): 263–273. ISSN   1565-4753. PMID   24683950.
  5. 1 2 3 4 5 Jones, Kenneth Lyons (June 18, 2021). Smith's Recognizable Patterns of Human Malformation (8th ed.). Elsevier. pp. 198–225. ISBN   978-0323638821.
  6. ↑ Hoffmann, Anne; Berry-Kravis, Elizabeth (2016-01-01), Sala, Carlo; Verpelli, Chiara (eds.), "Chapter 20 - Fragile X Syndrome", Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability, San Diego: Academic Press, pp. 325–346, ISBN   978-0-12-800109-7 , retrieved 2022-10-18
  7. 1 2 Philip, Rajeev; Saran, Sanjay; Gutch, Manish; Gupta, Kumar K. (2013-01-01). "An unusual case of precocious puberty and macroorchidism". Thyroid Research and Practice. 10 (1): 29. doi: 10.4103/0973-0354.105845 . ISSN   0973-0354. S2CID   72752892.
  8. ↑ Terpos, Evangelos; Gavriatopoulou, Maria (2019-01-01), "Multiple Myeloma Bone Disease", in Huhtaniemi, Ilpo; Martini, Luciano (eds.), Encyclopedia of Endocrine Diseases (Second Edition), Oxford: Academic Press, pp. 329–340, ISBN   978-0-12-812200-6 , retrieved 2022-11-06
  9. 1 2 García, Marta; Barrio, Raquel; García-Lavandeira, Montserrat; Garcia-Rendueles, Angela R.; Escudero, Adela; Díaz-Rodríguez, Esther; Gorbenko Del Blanco, Darya; Fernández, Ana; de Rijke, Yolanda B.; Vallespín, Elena; Nevado, Julián; Lapunzina, Pablo; Matre, Vilborg; Hinkle, Patricia M.; Hokken-Koelega, Anita C. S. (March 2017). "The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFβ and Activin pathways". Scientific Reports. 7 (1): 42937. Bibcode:2017NatSR...742937G. doi: 10.1038/srep42937 . ISSN   2045-2322. PMC   5338029 . PMID   28262687.
  10. ↑ Anyanwu, Lofty-John C.; Sowande, Oludayo A.; Asaleye, Christianah M.; Saleh, Mohammed K.; Mohammad, Aminu M.; Onuwaje, Mayomi; Olajide, Timothy A.; Talabi, Ademola O.; Elusiyan, Jerome B. E.; Adejuyigbe, Olusanya (2020-03-02). "Testicular volume: correlation of ultrasonography, orchidometer and caliper measurements in children". African Journal of Urology. 26 (1): 6. doi: 10.1186/s12301-020-0016-z . ISSN   1961-9987. S2CID   211574291.
  11. 1 2 3 4 5 Protic, D.; Kaluzhny, Petrina; Tassone, F.; Hagerman, R. (2019). "Prepubertal Metformin Treatment in Fragile X Syndrome Alleviated Macroorchidism: A Case Study". Advances in Clinical and Translational Research. S2CID   195411698.
  12. ↑ Wass, John A. H.; Karavitaki, Niki (2017-01-01), Melmed, Shlomo (ed.), "Chapter 19 - Nonfunctioning and Gonadotrophin-Secreting Adenomas", The Pituitary (Fourth Edition), Academic Press, pp. 589–603, ISBN   978-0-12-804169-7 , retrieved 2022-11-04
  13. ↑ Drummond, Juliana Beaudette; Ribeiro-Oliveira, Antônio; Soares, Beatriz Santana (2000), Feingold, Kenneth R.; Anawalt, Bradley; Boyce, Alison; Chrousos, George (eds.), "Non-Functioning Pituitary Adenomas", Endotext, South Dartmouth (MA): MDText.com, Inc., PMID   30521182 , retrieved 2022-11-23
  14. ↑ Whittle, Emma; Falhammar, Henrik (2019-04-18). "Glucocorticoid Regimens in the Treatment of Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis". Journal of the Endocrine Society. 3 (6): 1227–1245. doi:10.1210/js.2019-00136. ISSN   2472-1972. PMC   6546346 . PMID   31187081.

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