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Follicle-stimulating hormone insensitivity

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Follicle-stimulating hormone insensitivity

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Follicle-stimulating hormone insensitivity
Other names	Ovarian insensitivity to FSH, Granulosa cell hypoplasia

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 (decreased or lack of production of sex steroids by the gonads despite high circulating levels of gonadotropins), reduced or absent puberty (lack of development of secondary sexual characteristics, resulting in sexual infantilism if left untreated), amenorrhea (lack of menstruation), and infertility 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); however, males also present with feminized or ambiguous genitalia (also known as pseudohermaphroditism), 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 levels, and reduced inhibin B levels.

Due in part to elevated LH levels, which stimulate androgen production by theca cells in the ovaries, and due in part to FSH insensitivity, resulting in a lack of aromatase 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 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, 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). 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) hypergonadotropic hypogonadism or hypoestrogenism, resulting in a delayed, reduced, or fully absent puberty and associated sexual infantilism (if left untreated), reduced uterine volume, and osteoporosis; and 2) ovarian dysgenesis or failure, resulting in primary or secondary amenorrhea, infertility, and normal sized to slightly enlarged ovaries. Males on the other hand are significantly less affected, presenting merely with partial or complete infertility, reduced testicular volume, and oligozoospermia (reduced spermatogenesis).

Cause

FSH insensitivity is caused by inactivating mutations of the follicle-stimulating hormone receptor (FSHR) and thus an insensitivity of the receptor to FSH. This results in an inability of the granulosa cells in ovarian follicles to respond to FSH in females, in turn resulting in diminished estrogen production by the ovaries and loss of menstrual cycles, and an inability of Sertoli cells in the seminiferous tubules of the testicles to respond to FSH in males, which in turn results in impaired spermatogenesis.

Diagnosis

Treatment

Hormone replacement therapy 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.

Anterior	Kallmann syndrome Growth hormone deficiency Hypoprolactinemia ACTH deficiency/Secondary adrenal insufficiency GnRH insensitivity FSH insensitivity LH/hCG insensitivity
Posterior	Neurogenic diabetes insipidus
General	Empty sella syndrome Pituitary apoplexy Sheehan's syndrome Lymphocytic hypophysitis Pituitary adenoma

Genetic disorders relating to deficiencies of transcription factor or coregulators

(1) Basic domains

1.2	Feingold syndrome Saethre–Chotzen syndrome
1.3	Tietz syndrome

(2) Zinc finger
DNA-binding domains

2.1	(Intracellular receptor): Thyroid hormone resistance Androgen insensitivity syndrome PAIS MAIS CAIS Kennedy's disease PHA1AD pseudohypoaldosteronism Estrogen insensitivity syndrome X-linked adrenal hypoplasia congenita MODY 1 Familial partial lipodystrophy 3 SF1 XY gonadal dysgenesis
2.2	Barakat syndrome Tricho–rhino–phalangeal syndrome
2.3	Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome Denys–Drash syndrome Duane-radial ray syndrome MODY 7 MRX 89 Townes–Brocks syndrome Acrocallosal syndrome Myotonic dystrophy 2
2.5	Autoimmune polyendocrine syndrome type 1

(3) Helix-turn-helix domains

3.1	ARX Ohtahara syndrome Lissencephaly X2 MNX1 Currarino syndrome HOXD13 SPD1 synpolydactyly PDX1 MODY 4 LMX1B Nail–patella syndrome MSX1 Tooth and nail syndrome OFC5 PITX2 Axenfeld syndrome 1 POU4F3 DFNA15 POU3F4 DFNX2 ZEB1 Posterior polymorphous corneal dystrophy Fuchs' dystrophy 3 ZEB2 Mowat–Wilson syndrome
3.2	PAX2 Papillorenal syndrome PAX3 Waardenburg syndrome 1&3 PAX4 MODY 9 PAX6 Gillespie syndrome Coloboma of optic nerve PAX8 Congenital hypothyroidism 2 PAX9 STHAG3
3.3	FOXC1 Axenfeld syndrome 3 Iridogoniodysgenesis, dominant type FOXC2 Lymphedema–distichiasis syndrome FOXE1 Bamforth–Lazarus syndrome FOXE3 Anterior segment mesenchymal dysgenesis FOXF1 ACD/MPV FOXI1 Enlarged vestibular aqueduct FOXL2 Premature ovarian failure 3 FOXP3 IPEX
3.5	IRF6 Van der Woude syndrome Popliteal pterygium syndrome

(4) β-Scaffold factors
with minor groove contacts

4.2	Hyperimmunoglobulin E syndrome
4.3	Holt–Oram syndrome Li–Fraumeni syndrome Ulnar–mammary syndrome
4.7	Campomelic dysplasia MODY 3 MODY 5 SF1 SRY XY gonadal dysgenesis Premature ovarian failure 7 SOX10 Waardenburg syndrome 4c Yemenite deaf-blind hypopigmentation syndrome
4.11	Cleidocranial dysostosis

(0) Other transcription factors

0.6	Kabuki syndrome

Ungrouped

Transcription coregulators

Coactivator:	CREBBP Rubinstein–Taybi syndrome
Corepressor:	HR (Atrichia with papular lesions)

Inborn errors of steroid metabolism

Mevalonate
pathway

HMG-CoA lyase deficiency

Hyper-IgD syndrome
Mevalonate kinase deficiency

To cholesterol

desmosterol path: Desmosterolosis

Steroids

Corticosteroid
(including CAH)

aldosterone: Glucocorticoid remediable aldosteronism

Sex steroid

To androgens	17α-Hydroxylase deficiency 17,20-Lyase deficiency Cytochrome b₅ deficiency 3β-Hydroxysteroid dehydrogenase deficiency 17β-Hydroxysteroid dehydrogenase deficiency 5α-Reductase 2 deficiency Pseudovaginal perineoscrotal hypospadias
To estrogens	Aromatase deficiency Aromatase excess syndrome

Other

Cell surface receptor deficiencies

G protein-coupled receptor
(including hormone)

Class A	TSHR (Congenital hypothyroidism 1) LHCGR (Luteinizing hormone insensitivity, Leydig cell hypoplasia, Male-limited precocious puberty) FSHR (Follicle-stimulating hormone insensitivity, XX gonadal dysgenesis) GnRHR (Gonadotropin-releasing hormone insensitivity) EDNRB (ABCD syndrome, Waardenburg syndrome 4a, Hirschsprung's disease 2) AVPR2 (Nephrogenic diabetes insipidus 1) PTGER2 (Aspirin-exacerbated respiratory disease)
Class B	PTH1R (Jansen's metaphyseal chondrodysplasia)
Class C	CASR (Familial hypocalciuric hypercalcemia)
Class F	FZD4 (Familial exudative vitreoretinopathy 1)

Enzyme-linked receptor
(including
growth factor)

RTK	ROR2 (Robinow syndrome) FGFR1 (Pfeiffer syndrome, KAL2 Kallmann syndrome) FGFR2 (Apert syndrome, Antley–Bixler syndrome, Pfeiffer syndrome, Crouzon syndrome, Jackson–Weiss syndrome) FGFR3 (Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, Muenke syndrome) INSR (Donohue syndrome Rabson–Mendenhall syndrome) NTRK1 (Congenital insensitivity to pain with anhidrosis) KIT (KIT Piebaldism, Gastrointestinal stromal tumor)
STPK	AMHR2 (Persistent Müllerian duct syndrome II) TGF beta receptors: Endoglin/Alk-1/SMAD4 (Hereditary hemorrhagic telangiectasia) TGFBR1/TGFBR2 (Loeys–Dietz syndrome)
GC	GUCY2D (Leber's congenital amaurosis 1)