Leydig cell hypoplasia (or aplasia) (LCH), also known as Leydig cell agenesis, is a rare
autosomal recessive genetic and
endocrine
The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the ...
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
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 (Gn ...
(LH), a
gonadotropin
Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chori ...
which is normally responsible for signaling
Leydig cells of the
testicles to produce
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteris ...
and other
androgen
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
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 ...
s. The condition manifests itself as
pseudohermaphroditism (partially or fully underdeveloped
genitalia
A sex organ (or reproductive organ) is any part of an animal or plant that is involved in sexual reproduction. The reproductive organs together constitute the reproductive system. In animals, the testis in the male, and the ovary in the female, ...
),
hypergonadotropic hypogonadism (decreased or lack of production of
sex steroids by the
gonad
A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces ...
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 girl, the testes in a b ...
(lack of development of
secondary sexual characteristics, resulting in
sexual infantilism if left untreated), and
infertility
Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal st ...
.
Leydig cell hypoplasia does not occur in biological females as they do not have either Leydig cells or testicles. However, the cause of the condition in males, luteinizing hormone insensitivity, does affect females, and because LH plays a role in the female
reproductive system, it can result in
primary amenorrhea or
oligomenorrhea (absent or reduced
menstruation
Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and mucosal tissue from the inner lining of the uterus through the vagina. The menstrual cycle is characterized by the rise and fall of ...
), infertility due to
anovulation, and
ovarian cysts.
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 females and merely problems with fertility in males). Despite their similar causes, FSH insensitivity is considerably less common in comparison to LH insensitivity.
Symptoms and signs
The
symptom
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...
s of Leydig cell hypoplasia include pseudohermaphroditism, i.e.,
feminized,
ambiguous, or relatively mildly underdeveloped (e.g.,
micropenis, severe
hypospadias
Hypospadias is a common variation in fetal development of the penis in which the urethra does not open from its usual location in the head of the penis. It is the second-most common birth abnormality of the male reproductive system, affecting abo ...
,
and/or
cryptorchidism 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 ...
or
gender variance
Gender variance or gender nonconformity is behavior or gender expression by an individual that does not match masculine or feminine gender norms. A gender-nonconforming person may be variant in their gender identity, being transgender or non-bina ...
,
hypergonadotropic hypogonadism (
hypogonadism
Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low est ...
despite high levels of gonadotropins), delayed, impaired, or fully 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 girl, the testes in a b ...
with an associated reduction in or complete lack of development of secondary sexual characteristics (
sexual infantilism), impaired
fertility
Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Ferti ...
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 2n ...
oid
skeletal
A skeleton is the structural frame that supports the body of an animal. There are several types of skeletons, including the exoskeleton, which is the stable outer shell of an organism, the endoskeleton, which forms the support structure inside ...
proportions, delayed or absent
bone maturation, and
osteoporosis.
Cause
Leydig cell hypoplasia is caused by
genetic mutations in ''LHCGR'', a
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
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 (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, 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
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 girl, the testes in a b ...
.
Diagnosis
Since the
Sertoli cells are not affected by Leydig cell hypoplasia,
anti-Müllerian hormone is secreted normally and so there are no
Müllerian structures.
Wolffian structures
The mesonephric duct (also known as the Wolffian duct, archinephric duct, Leydig's duct or nephric duct) is a paired organ that forms during the embryonic development of humans and other mammals and gives rise to male reproductive organs.
Struc ...
, 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
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteris ...
and
dihydrotestosterone. 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. 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 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. These symptoms can include hot flashes, vaginal ...
(i.e., with androgens), which will result in normal
sexual development and the resolution of most symptoms. In the case of 46,XY (genetically "male") individuals who are phenotypically female and/or identify as the female gender, estrogens should be given instead. Surgical correction of the genitals in 46,XY males may be required, and, if necessary, an
orchidopexy
Orchiopexy (or orchidopexy) is a surgery to move and/or permanently fix a testicle into the scrotum. While orchiopexy typically describes the operation to surgically correct an undescended testicle, it is also used to resolve testicular torsion.
...
(relocation of the undescended testes to the scrotum) may be performed as well.
See also
*
Disorders of sex development
Disorders of sex development (DSDs), also known as differences in sex development, diverse sex development and variations in sex characteristics (VSC), are congenital conditions affecting the reproductive system, in which development of chromos ...
*
Intersex
Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical b ...
uality,
pseudohermaphroditism, and
ambiguous genitalia
*
Hypogonadism
Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low est ...
and
hypogonadotropic hypogonadism
*
Familial male-limited precocious puberty (or LH oversensitivity)
*
Follicle-stimulating hormone insensitivity
*
Gonadotropin-releasing hormone insensitivity
*
Inborn errors of steroid metabolism
*
Isolated 17,20-lyase deficiency
*
Combined 17α-hydroxylase/17,20-lyase deficiency
*
17β-Hydroxysteroid dehydrogenase III deficiency
*
Androgen insensitivity syndrome
Androgen insensitivity syndrome (AIS) is a difference in sex development involving hormonal resistance due to androgen receptor dysfunction.
It affects 1 in 20,000 to 64,000 XY (karyotype, karyotypically male) births. The condition results in the ...
References
External links
{{Receptor deficiencies
Autosomal recessive disorders
Endocrine gonad disorders
Gonadotropin-releasing hormone and gonadotropins
Rare diseases
Syndromes
Intersex variations