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 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 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 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), 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 the stimulation of

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 ...

production by the

ovaries The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are endocr ...

in females and maintenance of

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 ...

in both sexes. The condition manifests itself as

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 (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),

amenorrhea Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...

(lack of

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 ...

), 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 ...

in females, whereas males present merely with varying degrees of infertility and associated symptoms (e.g., decreased sperm production). A related condition is luteinizing hormone (LH) insensitivity (termed Leydig cell hypoplasia when it occurs in males), which presents with similar symptoms to those of FSH insensitivity but with the symptoms in the respective sexes reversed (i.e., hypogonadism and sexual infantilism in males and merely problems with fertility in females). For individuals with XY feminized or ambiguous genitalia are common, whereas ambiguous genitalia does not occur in females with FSH insensitivity. Despite their similar causes, LH insensitivity is considerably more common in comparison to FSH insensitivity.

Signs and symptoms

In females, FSH insensitivity results in diminished development of ovarian follicles and granulosa cells and low to normal estrogen levels, elevated to very elevated gonadotropin levels, and low inhibin B levels, whereas males present with diminished Sertoli cell proliferation and moderately elevated FSH levels, normal to slightly elevated LH levels, normal

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 ...

levels, and reduced inhibin B levels. Due in part to elevated LH levels, which stimulate androgen production by

theca cell The theca folliculi comprise a layer of the ovarian follicles. They appear as the follicles become secondary follicles. The theca are divided into two layers, the theca interna and the theca externa. Theca cells are a group of endocrine cel ...

s in the

, and due in part to FSH insensitivity, resulting in a lack of

aromatase Aromatase (), also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily, which are monooxygenases that catalyze man ...

in nearby granulosa cells that normally convert androgens into estrogens, it could be expected that females with FSH insensitivity might present with symptoms of

hyperandrogenism Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea, hair loss on the scalp, increased body or facial hair, and infre ...

at puberty. However, this has not been found to be the case. This may be in part because FSH, via stimulation of granulosa cells and the resultant secretion of yet-unidentified paracrine factors (but possibly including inhibin B), has been shown to significantly enhance the LH-mediated stimulation of androgen production by theca cells. In addition, theca cells predominantly secrete the relatively weak androgen

androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroe ...

, whereas granulosa cells, signaled to do so by FSH under normal circumstances, convert androstenedione into its more potent relative testosterone (which is subsequently converted into

estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...

). Hence, in females, FSH insensitivity may not only result in deficiencies in estrogen production by granulosa cells, but in diminished androgen synthesis by both theca and granulosa cells as well, which could potentially explain why hyperandrogenism does not occur. FSH insensitivity presents itself in females as two clusters of symptoms: 1)

hypoestrogenism Hypoestrogenism, or estrogen deficiency, refers to a lower than normal level of estrogen. It is an umbrella term used to describe estrogen deficiency in various conditions. Estrogen deficiency is also associated with an increased risk of cardiov ...

, resulting in a delayed, reduced, or fully absent puberty and associated sexual infantilism (if left untreated), reduced uterine volume, 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 ...

; and 2) ovarian dysgenesis or

failure Failure is the social concept of not meeting a desirable or intended objective, and is usually viewed as the opposite of success. The criteria for failure depends on context, and may be relative to a particular observer or belief system. On ...

, resulting in primary or secondary

, and normal sized to slightly enlarged

. Males on the other hand are significantly less affected, presenting merely with partial or complete

, reduced testicular volume, and

oligozoospermia 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 ...

(reduced

spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testicle. This process starts with the Mitosis, mitotic division of the stem cells located close to the basement membrane of ...

Cause

FSH insensitivity is caused by inactivating

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, ...

s of the

follicle-stimulating hormone receptor The follicle-stimulating hormone receptor or FSH receptor (FSHR) is a transmembrane receptor that interacts with the follicle-stimulating hormone (FSH) and represents a G protein-coupled receptor (GPCR). Its activation is necessary for the horm ...

(FSHR) and thus an insensitivity of the receptor to FSH. This results in an inability of the

granulosa cell A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete (called an oocyte or egg) in the ovary of mammals. Structure and function In the Folliculogenesis#Primordial, primo ...

s in

ovarian follicle An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. In humans, women have approximately 200,000 to 300,000 follicles at the time of puberty, ea ...

s to respond to FSH in females, in turn resulting in diminished estrogen production by the ovaries and loss of

menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of eg ...

s, and an inability of

Sertoli cell 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 ...

s in the

seminiferous tubule Seminiferous tubules are located within the testicles, and are the specific location of meiosis, and the subsequent creation of male gametes, namely spermatozoa. Structure The epithelium of the tubule consists of a type of sustentacular cells k ...

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 respond to FSH in males, which in turn results in impaired

Diagnosis

Treatment

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 ...

with estrogen may be used to treat symptoms of hypoestrogenism in females with the condition. There are currently no known treatments for the infertility caused by the condition in either sex.

References

{{Receptor deficiencies Autosomal recessive disorders Endocrine gonad disorders Gonadotropin-releasing hormone and gonadotropins Rare diseases Syndromes Human female endocrine system

Signs and symptoms

Cause

Diagnosis

Treatment

See also

References