Follicle-stimulating hormone insensitivity

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Follicle-stimulating hormone insensitivity
Other namesOvarian 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). [1] [2]

Contents

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. [1]

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. [1] [2] [3]

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. [4] [5] 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). [6] 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.[ citation needed ]

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). [1] [2]

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. [1] [2]

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.[ citation needed ]

See also

Related Research Articles

<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">Corpus luteum</span> Temporary endocrine structure in ovaries

The corpus luteum is a temporary endocrine structure in female ovaries involved in the production of relatively high levels of progesterone, and moderate levels of estradiol, and inhibin A. It is the remains of the ovarian follicle that has released a mature ovum during a previous ovulation.

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 anovulation is a common cause of infertility.

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/chorionic gonadotropins, human chorionic gonadotropin (hCG) and equine chorionic gonadotropin (eCG), as well as at least two forms of fish gonadotropins. These hormones are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. LH and FSH are secreted by the anterior pituitary gland, while hCG and eCG are secreted by the placenta in pregnant humans and mares, respectively. The gonadotropins act on the gonads, controlling gamete and sex hormone production.

Hypogonadism means diminished functional activity of the gonads—the testicles or the ovaries—that may result in diminished production of sex hormones. Low androgen levels are referred to as hypoandrogenism and low estrogen as hypoestrogenism. These are responsible for the observed signs and symptoms in both males and females.

<span class="mw-page-title-main">Folliculogenesis</span> Process of maturation of primordial follicles

In biology, folliculogenesis is the maturation of the ovarian follicle, a densely packed shell of somatic cells that contains an immature oocyte. Folliculogenesis describes the progression of a number of small primordial follicles into large preovulatory follicles that occurs in part during the menstrual cycle.

<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.

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 cardiovascular disease, and has been linked to diseases like urinary tract infections and osteoporosis.

<span class="mw-page-title-main">Follicular phase</span> Phase of the estrous or menstrual cycle

The follicular phase, also known as the preovulatory phase or proliferative phase, is the phase of the estrous cycle during which follicles in the ovary mature from primary follicle to a fully mature graafian follicle. It ends with ovulation. The main hormones controlling this stage are secretion of gonadotropin-releasing hormones, which are follicle-stimulating hormones and luteinising hormones. They are released by pulsatile secretion. The duration of the follicular phase can differ depending on the length of the menstrual cycle, while the luteal phase is usually stable, does not really change and lasts 14 days.

<span class="mw-page-title-main">Follicular atresia</span>

Follicular atresia refers to the process in which a follicle fails to develop, thus preventing it from ovulating and releasing an egg. It is a normal, naturally occurring progression that occurs as mammalian ovaries age. Approximately 1% of mammalian follicles in ovaries undergo ovulation and the remaining 99% of follicles go through follicular atresia as they cycle through the growth phases. In summary, follicular atresia is a process that leads to the follicular loss and loss of oocytes, and any disturbance or loss of functionality of this process can lead to many other conditions.

<span class="mw-page-title-main">Estrogen insensitivity syndrome</span> Medical condition

Estrogen insensitivity syndrome (EIS), or estrogen resistance, is a form of congenital estrogen deficiency or hypoestrogenism which is caused by a defective estrogen receptor (ER) – specifically, the estrogen receptor alpha (ERα) – that results in an inability of estrogen to mediate its biological effects in the body. Congenital estrogen deficiency can alternatively be caused by a defect in aromatase, the enzyme responsible for the biosynthesis of estrogens, a condition which is referred to as aromatase deficiency and is similar in symptomatology to EIS.

The theca folliculi comprise a layer of the ovarian follicles. They appear as the follicles become secondary follicles.

<span class="mw-page-title-main">Aromatase deficiency</span> Medical condition

Aromatase deficiency is a rare condition characterized by extremely low levels or complete absence of the enzyme aromatase activity in the body. It is an autosomal recessive disease resulting from various mutations of gene CYP19 (P450arom) which can lead to ambiguous genitalia and delayed puberty in females, continued linear growth into adulthood and osteoporosis in males and virilization in pregnant mothers. As of 2020, fewer than 15 cases have been identified in genetically male individuals and at least 30 cases in genetically female individuals.

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.

<span class="mw-page-title-main">Isolated 17,20-lyase deficiency</span> Medical condition

Isolated 17,20-lyase deficiency (ILD), also called isolated 17,20-desmolase deficiency, is a rare endocrine and autosomal recessive genetic disorder which is characterized by a complete or partial loss of 17,20-lyase activity and, in turn, impaired production of the androgen and estrogen sex steroids. The condition manifests itself as pseudohermaphroditism in males, in whom it is considered to be a form of intersex, and, in both sexes, as a reduced or absent puberty/lack of development of secondary sexual characteristics, resulting in a somewhat childlike appearance in adulthood.

<span class="mw-page-title-main">Leydig cell hypoplasia</span> Medical condition

Leydig cell hypoplasia (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive genetic and endocrine 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 (LH), a gonadotropin which is normally responsible for signaling Leydig cells of the testicles to produce testosterone and other androgen sex hormones. The condition manifests itself as pseudohermaphroditism, hypergonadotropic hypogonadism, reduced or absent puberty, and infertility.

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.

Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian hormone produced by the granulosa cells of small antral ovarian follicles in females. GnSAF is involved in regulating the secretion of luteinizing hormone (LH) from the anterior pituitary and the ovarian cycle. During the early to mid-follicular phase of the ovarian cycle, GnSAF acts on the anterior pituitary to attenuate LH release, limiting the secretion of LH to only basal levels. At the transition between follicular and luteal phase, GnSAF bioactivity declines sufficiently to permit LH secretion above basal levels, resulting in the mid-cycle LH surge that initiates ovulation. In normally ovulating women, the LH surge only occurs when the oocyte is mature and ready for extrusion. GnSAF bioactivity is responsible for the synchronised, biphasic nature of LH secretion.

References

  1. 1 2 3 4 5 Mark A. Sperling (25 April 2008). Pediatric Endocrinology E-Book. Elsevier Health Sciences. p. 35. ISBN   978-1-4377-1109-7 . Retrieved 10 June 2012.
  2. 1 2 3 4 Eberhard Nieschlag; Hermann M. Behre; Susan Nieschlag (3 December 2009). Andrology: Male Reproductive Health and Dysfunction. Springer. p. 225. ISBN   978-3-540-78354-1 . Retrieved 10 June 2012.
  3. ↑ Allen M. Spiegel (23 January 1998). G Proteins, Receptors, and Disease. Humana Press. p. 159. ISBN   978-0-89603-430-3 . Retrieved 10 June 2012.[ permanent dead link ]
  4. ↑ Barnes RB, Rosenfield RL, Namnoum A, Layman LC (October 2000). "Effect of follicle-stimulating hormone on ovarian androgen production in a woman with isolated follicle-stimulating hormone deficiency". The New England Journal of Medicine. 343 (16): 1197–8. doi: 10.1056/NEJM200010193431614 . PMID   11041762.
  5. ↑ Wachs DS, Coffler MS, Malcom PJ, Shimasaki S, Chang RJ (May 2008). "Increased androgen response to follicle-stimulating hormone administration in women with polycystic ovary syndrome". The Journal of Clinical Endocrinology and Metabolism. 93 (5): 1827–33. doi:10.1210/jc.2007-2664. PMC   2386684 . PMID   18285408.[ permanent dead link ]
  6. ↑ Richard Evan Jones; Kristin H. López (17 March 2006). Human Reproductive Biology . Academic Press. pp.  38–39. ISBN   978-0-12-088465-0 . Retrieved 11 June 2012.
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