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 The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...

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.

Background

Ovaries The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...

are the site of development and breakdown of

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

which secrete

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

s and oocytes. Oocytes are immature eggs and are surrounded by

granulosa cells 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 primordial ovarian follicle, and ...

and internal and external

theca In biology, a theca (plural thecae) is a sheath or a covering. Botany In botany, the theca is related to plant's flower anatomy. The theca of an angiosperm consists of a pair of microsporangia that are adjacent to each other and share a comm ...

cells. Oocytes are then able to mature within the follicle through meiosis. In humans with ovaries, this process occurs continuously, as they are born with a finite number of follicles (between 500,000-1,000,000 follicles), and about 99% of follicles undergo atresia. Only one follicle will be mature enough to release an egg and may be fertilized. Typically around 20 follicles mature each month but only a single follicle is ovulated; the follicle from which the oocyte was released becomes the

corpus luteum The corpus luteum (Latin for "yellow body"; plural corpora lutea) 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 t ...

. The corpus luteum is the last stage of the ovarian follicles' lifecycle. It has an important role in secreting estrogen and progesterone to prepare the body for conception. If conception does not occur, then it will be shed and is known as the corpus albicans. It has been observed that this mechanism is important in regulating and maintaining a healthy reproductive system in mammals.

Menopause

Follicular atresia occurs throughout all stages of follicular development, until the follicular reserve is completely exhausted. Exhaustion of the follicular reserve occurs at

menopause Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...

, which is typically around the age of 51 in humans with ovaries. The dramatic decrease in

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...

and

progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the majo ...

levels that is characteristic of

is caused by follicular atresia. Breakdown of the follicles prevent them from releasing hormones such as

Progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the majo ...

levels also decrease during

because without any follicles, there is no development of the

, which is the major source of circulating progesterone levels in humans.

Mechanism

Atresia is a complex,

hormonally A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required fo ...

controlled

apoptotic Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes incl ...

process that depends dominantly on granulosa cell apoptosis. Follicular atresia is inhibited by

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, pubertal maturation, ...

(FSH), which promotes follicle development. Once the follicle has developed, it secretes

, which in high levels decreases secretions of FSH. Granulosa cell

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

is considered the underlying mechanism of follicular atresia, and has been associated with five ligand-receptor systems involved in cell death: *

tumor necrosis factor alpha Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolo ...

(TNF alpha) and

receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...

* Fas ligand and receptors * TNF-related

-inducing ligand (TRAIL; also called APO-2) and receptors * APO-3 ligand and receptors * PFG-5 ligand and receptors Granulosa cell apoptosis is promoted by

tumor necrosis factor-alpha Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

(TNFα), although the mechanism of how it occurs is unclear. Fas antigen, a

cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...

protein, that is expressed on granulosa cells, mediates signals that induce apoptosis by binding Fas ligand and therefore plays an important role in follicular atresia. Lack of a functional Fas ligand /

Fas receptor The Fas receptor, also known as Fas, FasR, apoptosis antigen 1 (APO-1 or APT), cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a protein that in humans is encoded by the ''FAS'' gene. Fas ...

system has been linked to abnormal follicle development, and increased numbers of secondary follicles as a result of the inability to induce apoptosis. TNF-related apoptosis-inducing ligand (

TRAIL A trail, also known as a path or track, is an unpaved lane or small road usually passing through a natural area. In the United Kingdom and the Republic of Ireland, a path or footpath is the preferred term for a pedestrian or hiking trail. ...

) activates

caspase 3 Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the ''CASP3'' gene. ''CASP3'' orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are als ...

(CASP3), which in turn interacts with

caspases Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cystei ...

6, 7, 8, 9, and 10 to induce apoptosis in granulosa cells. In addition, two intracellular inhibitor proteins, cellular

FLICE Caspase-8 is a caspase protein, encoded by the ''CASP8'' gene. It most likely acts upon caspase-3. ''CASP8'' orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present ...

-like inhibitory

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

short form ( cFLIPS) and long form (cFLIPL), which are strongly expressed in granulosa cells, may act as anti-apoptotic factors. Anti-Mullerian hormone (AMH) has been studied to be a key regulator in the ovaries in humans that inhibits follicular atresia. It has been proven that AMH reduces the growth of follicles and its upregulation proposes a potential pathophysiological pathway in PCOS. Using indirect comparators to derive this hypothesis, exploring different patient populations such as individuals who have polycystic ovary syndrome (PCOS) help support the hypothesis that AMH may be a key regulator in inhibiting follicular atresia. It has been proposed that enhanced levels of

Nitrogen oxide Nitrogen oxide may refer to a binary compound of oxygen and nitrogen, or a mixture of such compounds: Charge-neutral *Nitric oxide (NO), nitrogen(II) oxide, or nitrogen monoxide * Nitrogen dioxide (), nitrogen(IV) oxide * Nitrogen trioxide (), or ...

in rats can prevent atresia of the ovarian follicle, while depressed levels have the opposite effect.

Morphology

From studying dairy cows, two forms of follicular atresia have been identified: antral and basal.

Antral

Antral follicular atresia is characterized by the

of granulosa cells within the antral layers of the granulosa membrane and sometimes within the antrum itself. During this process, the presence of pyknotic nuclei in the antral layers of the membrane can be observed.

Apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

ensures that the follicle gets eliminated without triggering an inflammatory response. Antral follicular atresia causes no damage to basal granulosa cells. This type of follicular atresia is often considered the classic and most commonly observed form. In most species, it occurs throughout follicular development and is universally seen in large follicles (>5mm diameter).

Basal

Basal follicular atresia is characterized by the destruction of granulosa cells in the basal layer of the granulosa membrane.

Macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

s have often been observed, penetrating the basal lamina during this type of follicular atresia. These

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

s phagocytose the basal granulosa cells. An increased deposition of collagen in the theca layer of the follicle can also be observed. Basal follicular atresia causes no damage to antral granulosa cells.This form of follicular atresia has only been observed in small follicles of dairy cows (< 5mm diameter), and has not been reported in any other species.

Related diseases

Undergoing follicular atresia is necessary in order for mammals to maintain a healthy reproductive system. Mammalian ovaries ovulate about 1% of the follicles and the remaining follicles may go through atresia as it cycles through the growth phases. However, disorders in the regulation of follicle breakdown and generation can lead to various pathologies:

Premature ovarian failure

Premature ovarian failure (POF) (also called

premature ovarian insufficiency Primary ovarian insufficiency (POI) (also called premature ovarian insufficiency, premature menopause, and premature ovarian failure) is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of foll ...

) is the loss of ovarian function before the age of 40 due to follicular dysfunction such as accelerated follicular atresia. POF may present itself with characteristics and symptoms such as loss of menstruation for at least 4 months and also increased serum follicle-stimulating hormone (FSH) concentration (greater than or equal to 40 IU/L). There may be many causes of POF, ranging from genetic disorders to surgery, radiation therapy, and exposure to environmental toxicants. Accelerated follicular atresia due to chromosomal and genomic defects accounts for up to one-half of all POF cases. For example,

Fragile X syndrome Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features ma ...

Turner syndrome Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low h ...

, and various autosomal diseases such as

galactosemia Galactosemia (British galactosaemia, from Greek γαλακτόζη + αίμα, meaning galactose + blood, accumulation of galactose in blood) is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galacto ...

have been linked to follicular deficiencies. Smoking has also been found to increase follicular atresia and lead to premature ovarian failure. Some of the short term effects of POF are hot flashes, irregular heart beat/heart

palpitations Palpitations are perceived abnormalities of the heartbeat characterized by awareness of cardiac muscle contractions in the chest, which is further characterized by the hard, fast and/or irregular beatings of the heart. Symptoms include a rap ...

, night sweats, urogenital symptoms, and headaches; some of the more long-term consequences of POF are

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

, infertility, cardiovascular diseases, and possible premature death.

Ovarian follicular cysts

When an ovarian follicle fails to undergo atresia and release an egg, it can grow to form a cyst. This may be due to an overproduction of FSH or an inadequate supply of LH. Most follicular cysts are harmless and resolve on their own within several months. However, rarely a cyst will grow to be very large (greater than 7 cm), cause abdominal pain, or rupture, in which case pain relievers or emergency surgery may be required. If the cyst lasts for longer than a few months, a physician may recommend surgical removal or testing to determine if it is cancerous. Ultrasound is a common method of visualizing a cyst to determine treatment.

Ovarian Cancer

Ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...

is highly prevalent amongst humans who have ovaries and leads to many deaths in the United States. Since FSH inhibits follicular atresia, the overproduction of FSH can lead to excessive follicle formation and increased risk of ovarian cancer. The inability to regulate granulosa cell apoptosis and undergo follicular atresia, due to overexpression of certain genes, has been linked to the development of some hormone-related cancers (such as granulosa cell tumors) and chemo-resistance in mouse models. According to the gonadotropin theory, follicular depletion associated with incessant follicular atresia has also been hypothesized as a potential etiology for ovarian cancer, due to an increase in serum gonadotropins. This leads to an inflammatory environment which promotes cellular turnover and tumor development. Ovarian cancer is characterized by some generalized symptoms such as bloating or swelling in the abdomen,

pelvic pain Pelvic pain is pain in the area of the pelvis. Acute pain is more common than chronic pain. If the pain lasts for more than six months, it is deemed to be chronic pelvic pain. It can affect both the male and female pelvis. Common causes in include ...

, gastrointestinal symptoms (i.e. loss of appetite, nausea, constipation, and unexpected weight loss). Many people who are diagnosed with ovarian cancer also report feeling very full fast and many of them having a feeling on unexpected continuous bloating in their abdomen.

Polycystic Ovary Syndrome (PCOS)

Polycystic Ovary Syndrome, or PCOS affects 6-12% of humans with ovaries of reproductive age in the United States, and is one of the common causes of female infertility. The mechanism of PCOS is unknown, but is multifactorial. It has been observed that certain genes related to steroid and androgenic hormone production may contribute to development of the disease in individuals, environmental factors such as insulin resistance and obesity, and passing down of genetics from first degree relatives. Diagnosis of PCOS is based on meeting two of the three clinical criteria based on the Rotterdam Criteria: chronic anovulation (the ovum is not released from the ovary during menstrual cycle), hyperandrogenism (increased levels of androgen hormones, such as testosterone), and large number of ovarian cysts. Symptoms and characteristics of PCOS include irregular periods or missed periods, excess body hair or thinning hair, weight gain, acne. PCOS is correlated with other metabolic comorbidities. One of large concern is obesity and insulin resistance. This is of high interest when assessing treatment and management of PCOS. Other risk factors include traditional cardiovascular disease risk factors such as dyslipidemia and hypertension. Non-pharmacological management and treatment of PCOS include dietary intervention. While there is no one optimal diet or superior diet, as this disease is highly individualized, diets that impact weight loss and insulin resistance have been shown to improve reproductive function. Examples of these diets include the DASH diet (Dietary Approach to Stop Hypertension) and the ketogenic diet. However it is important to consult a medical professional before starting on such diet is safe. Pharmacological management may be recommended for those who have comorbid conditions, such as obesity, type 2 diabetes, etc. Guidelines suggest possible oral contraceptives in combination with metformin (anti-diabetic medication), and/or anti-androgen agents. As PCOS is a highly individualized condition, each individual's management and goals will look different.

References

{{DEFAULTSORT:Follicular Atresia Reproduction in mammals