Leydig cell hypoplasia (or aplasia) (LCH), also known as Leydig cell agenesis, is a rare

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

genetic and

endocrine The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...

syndrome A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek language, Greek σύνδρομον, meaning "concurrence". When a sy ...

affecting an estimated 1 in 1,000,000 individuals with XY chromosomes. It is characterized by an inability of the body to respond to

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), a

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 ...

which is normally responsible for signaling

Leydig cell Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedral ...

s of the

testicle A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is Homology (biology), homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of Androgen, androgens, p ...

s to produce

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

and other

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 ...

sex hormone 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 ...

s. The condition manifests itself as

pseudohermaphroditism Pseudohermaphroditism is an outdated term for when an individual's gonads were mismatched with their internal reproductive system and/or external genitalia. The term was contrasted with "true hermaphroditism" (now known as ovotesticular syndrome), ...

(partially or fully underdeveloped

genitalia A sex organ, also known as a reproductive organ, is a part of an organism that is involved in sexual reproduction. Sex organs constitute the primary sex characteristics of an organism. Sex organs are responsible for producing and transporting ...

hypergonadotropic hypogonadism 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 ...

(decreased or lack of production 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 ...

s by 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 despite high circulating levels of gonadotropins), reduced or absent

puberty 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 i ...

(lack of development of

secondary sexual characteristic A secondary sex characteristic is a physical characteristic of an organism that is related to or derived from its sex, but not directly part of its reproductive system. In humans, these characteristics typically start to appear during puberty ...

s, resulting in sexual infantilism if left untreated), and

infertility In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...

. Leydig cell hypoplasia does not occur in people with XX chromosomes as they do not have either Leydig cells or testicles. However, the cause of the condition in people with XY chromosomes, luteinizing hormone insensitivity, does affect people with XX chromosomes, and because LH plays a role in the female

reproductive system The reproductive system of an organism, also known as the genital system, is the biological system made up of all the anatomical organs involved in sexual reproduction. Many non-living substances such as fluids, hormones, and pheromones are al ...

, it can result in primary amenorrhea or

oligomenorrhea Oligomenorrhea is characterised by infrequent menstrual periods. Generally, the menstrual periods occur at intervals of greater than 35 days, with fewer than 9 periods in a year, where previously there had been a regularly established pattern. Th ...

(absent or reduced

menstruation Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and Mucous membrane, mucosal tissue from the endometrium, inner lining of the uterus through the vagina. The menstrual cycle is characterized ...

), infertility due to

anovulation 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 anovulat ...

, and

ovarian cyst An ovarian cyst is a fluid-filled sac within the ovary. They usually cause no symptoms, but occasionally they may produce bloating, lower abdominal pain, or lower back pain. The majority of cysts are harmless. If the cyst either #Cyst rupture, br ...

s. A related condition is follicle-stimulating hormone (FSH) insensitivity, which presents with similar symptoms to those of Leydig cell hypoplasia but with the symptoms in the respective sexes reversed (i.e., hypogonadism and sexual infantilism in XX individuals and difficulties with fertility in XY individuals). Despite their similar causes, FSH insensitivity is considerably less common in comparison to LH insensitivity.

Symptoms and signs

The

symptom Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...

s of Leydig cell hypoplasia include pseudohermaphroditism, i.e., feminized,

ambiguous Ambiguity is the type of meaning in which a phrase, statement, or resolution is not explicitly defined, making for several interpretations; others describe it as a concept or statement that has no real reference. A common aspect of ambiguit ...

, or relatively mildly underdeveloped (e.g.,

micropenis A micropenis or microphallus is an unusually small Human penis, penis. A common criterion is a dorsal (measured on top) Human penis size, penile length of at least 2.5 standard deviations smaller than the mean human penis size for age. A micr ...

, severe

hypospadias Hypospadias is a common malformation in fetal development of the penis in which the urethra does not open from its usual location on the head of the penis. It is the second-most common birth defect of the male reproductive system, affecting about ...

, and/or

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 ...

ndescended testes external genitalia, a female

gender identity Gender identity is the personal sense of one's own gender. Gender identity can correlate with a person's assigned sex or can differ from it. In most individuals, the various biological determinants of sex are congruent and consistent with the in ...

gender variance Gender nonconformity or gender variance is gender expression by an individual whose behavior, mannerisms, and/or appearance does not match masculine or feminine gender norms. A person can be gender-nonconforming regardless of their gender identity ...

(

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 ...

despite high levels of gonadotropins), delayed, impaired, or fully absent

with an associated reduction in or complete lack of development of secondary sexual characteristics ( sexual infantilism), impaired

fertility Fertility in colloquial terms refers the ability to have offspring. In demographic contexts, fertility refers to the actual production of offspring, rather than the physical capability to reproduce, which is termed fecundity. The fertility rate ...

or complete sterility, tall stature (due to delayed epiphyseal closure),

eunuch A eunuch ( , ) is a male who has been castration, castrated. Throughout history, castration often served a specific social function. The earliest records for intentional castration to produce eunuchs are from the Sumerian city of Lagash in the 2 ...

oid

skeletal A skeleton is the structural frame that supports the body of most animals. There are several types of skeletons, including the exoskeleton, which is a rigid outer shell that holds up an organism's shape; the endoskeleton, a rigid internal fram ...

proportions, delayed or absent bone maturation, and

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...

Cause

Leydig cell hypoplasia is caused by

genetic mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis ...

s in ''LHCGR'', a

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 ...

which encodes the LH/hCG receptor. LH normally acts through the LH/hCG receptor to stimulate the growth of Leydig cells in the testicles and the production of androgens such as testosterone and

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production o ...

(DHT) by these cells. In Leydig cell hypoplasia however, there is a reduced capacity for the LH/hCG receptor to respond to LH. This results in hypoplasia or absence of Leydig cells,

testicular atrophy Testicular atrophy is a medical condition in which one or both testicles (or "testes") diminish in size and may be accompanied by reduced testicular function. Testicular atrophy is not related to the temporary shrinkage of the surrounding scrotum, ...

, and lower than normal androgen levels. In the most severe form of the condition in which there is a complete lack of response of the Leydig cells to LH, androgen production by the testicles is virtually negligible and secondary sexual characteristics entirely fail to develop at

Diagnosis

Since the

Sertoli cells Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis (the production of sperm) as a structural component of the seminiferous tubules. They are activated by follicle-sti ...

are not affected by Leydig cell hypoplasia,

anti-Müllerian hormone Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to Activin and inhibin, inhibin and activin from the transforming growth factor beta superfamily, whose key roles a ...

is secreted normally and so there are no Müllerian structures. Wolffian structures, such as the prostate, vasa deferentia, and epidydimides are present. In type I, abdominal testes are revealed on ultrasound; in type II testes may be descended or undescended. People with Leydig cell hypoplasia type I display no response to the hCG stimulation test; there is no increase in serum levels of

and

. Leydig cell hypoplasia type II can display either a pronounced rise of testosterone levels or no rise. In any case, the diagnosis is confirmed on biopsy of the testes, revealing either absent or hypoplastic

Leydig cells Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedral ...

. The inside of the testis will be grayish and mucous, displaying arrested spermatogenesis and the presence of Sertoli cells. The diagnosis can also be confirmed by looking for mutations in the gene for the LH receptor. A diagnosis of Leydig cell hypoplasia is usually made in the neonatal period, following the discovery of ambiguous genitalia, or at puberty, when

secondary sex characteristics A secondary sex characteristic is a physical characteristic of an organism that is related to or derived from its sex, but not directly part of its reproductive system. In humans, these characteristics typically start to appear during puberty ...

fail to develop. Puberty is the most common time for Leydig cell hypoplasia to be diagnosed.

Treatment

Patients with Leydig cell hypoplasia may 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 ...

(i.e., with androgens), which will result in normal

sexual development Puberty is the process of physical changes through which a child's Human body, body matures into an adult body capable of sexual reproduction. It is initiated by hormone, hormonal signals from the Human brain, brain to the gonads: the ovary ...

and the resolution of most symptoms. In the case of 46,XY (genetically "male") individuals who are phenotypically female and/or have a female gender identity, estrogens are recommended instead. Surgical correction of the genitals in individuals with male gender identity may be required, and, if necessary, an orchidopexy (relocation of the undescended testes to the scrotum) may be performed as well.

References

External links