The ovarian follicle is the functional unit of the ovary. At its centre lies an oocyte, wrapped in layers of granulosa cells and, in larger follicles, an outer shell of theca cells and blood vessels. Follicles do two jobs at once: they nurture the egg and they make hormones, chiefly oestradiol, that coordinate the reproductive cycle. Almost all of them, however, never ovulate. Understanding why most follicles die while a few reach ovulation is one of the central problems of reproductive biology.
The ovarian reserve: a finite stock
Follicles form before birth in humans, when clusters of germ cells break apart and each oocyte becomes enclosed by somatic cells, forming a primordial follicle. This process is accompanied by heavy losses of oocytes. The resulting stock of resting, non-growing follicles is called the ovarian reserve.
A widely cited model built from histological counts estimated that the non-growing follicle population peaks at around 300,000 per ovary, on average, at 18 to 22 weeks after conception, and then declines throughout life. By age 30 only about 12% of that peak remains in most women, and about 3% by age 40. Menopause is predicted when fewer than roughly 1,000 follicles are left, at an average age of about 50. The model also highlights large differences between individuals: the predicted age at menopause spans more than two decades across women. Age alone explains most, but not all, of this variation.
Why the reserve does not empty all at once is itself a research question. Studies in mice show that signalling molecules inside the oocyte, including the transcription factor FOXO3 and the enzyme PTEN, keep primordial follicles dormant. When these brakes are removed experimentally, follicles activate en masse and the ovary fails prematurely.
From primordial follicle to antral follicle
Follicles that leave the resting pool pass through recognisable stages: primary, secondary (or preantral) and antral, the last defined by a fluid-filled cavity. Early growth, up to the secondary stage, does not require the pituitary gonadotrophins. The process is slow. Detailed morphometric work on human ovaries suggests that several months are needed for a newly growing follicle to reach the preantral stage, and about 70 more days for it to reach a diameter of 2 millimetres.
From then on, follicle-stimulating hormone (FSH) becomes essential. It drives granulosa cell multiplication and differentiation, and it switches on the aromatase enzyme that converts androgens, made by the neighbouring theca cells, into oestradiol. This division of labour between theca and granulosa cells explains how the follicle becomes the main source of oestrogen during the first half of the cycle. Local factors also matter, including members of the TGF-β family made by the oocyte itself, a topic developed on the oocyte page.
Selection and ovulation
In each human cycle, a cohort of small antral follicles becomes sensitive to the rise in FSH that begins late in the previous luteal phase. Usually only one is selected to continue. The selected follicle grows quickly and, from the middle of the follicular phase, produces large amounts of oestradiol; the others regress through a form of programmed degeneration called atresia.
The mid-cycle surge of LH then transforms the dominant follicle within hours:
- LH induces EGF-like growth factors (amphiregulin, epiregulin and betacellulin) in the granulosa cells, which relay the signal to the cumulus cells around the egg;
- the cumulus cells secrete a hyaluronan-rich matrix and expand;
- the oocyte resumes meiosis;
- the follicle wall gives way to release the egg, and the remaining cells begin to luteinise, switching from oestradiol to progesterone production as the corpus luteum forms.
Mouse studies in which key relay molecules were deleted from granulosa cells showed that blocking this pathway prevents cumulus expansion, meiotic resumption, ovulation and luteinisation together.
Measuring the reserve: AMH and antral follicle count
The resting follicle pool cannot be counted in a living woman, so clinicians rely on indirect markers. Anti-Müllerian hormone (AMH), named for its role in the regression of the Müllerian ducts during male development, is produced by granulosa cells of growing follicles from the primary to the small antral stage. Blood levels therefore reflect the number of growing follicles. AMH rises from birth to a plateau in the mid-twenties, then declines and becomes undetectable at menopause. It correlates with the antral follicle count measured by ultrasound, and both vary widely between individuals.
These markers are useful for one purpose in particular: predicting how many eggs the ovaries are likely to yield under hormonal stimulation. The 2026 NICE guideline on fertility problems recommends using AMH or the antral follicle count to predict ovarian response in assisted conception, but advises against using AMH to predict the chance of natural conception, and against using FSH measurements to predict response. Reviews also point out that AMH assays are not standardised, so values from different laboratories cannot always be compared.
When follicle development goes wrong
Polycystic ovary syndrome (PCOS) is the most common disorder of follicle development. The World Health Organization estimates that it affects 10–13% of women of reproductive age, that up to 70% of them are undiagnosed, and that it is the most common cause of anovulation worldwide. Its cause is unknown. Despite the name, ovarian cysts are not required for the diagnosis. AMH levels tend to be high in PCOS. At the other extreme, premature ovarian failure has been linked in some women to mutations in genes needed for early follicle formation, such as NOBOX and FIGLA.
Established knowledge includes the finite, declining nature of the reserve, the gonadotrophin dependence of later follicle growth and the LH-triggered cascade of ovulation. Open questions include what controls the rate at which resting follicles are activated, why some women lose their reserve much earlier than others, and how well AMH can forecast the timing of menopause for an individual.
Sources
- Wallace WHB, Kelsey TW, PLoS ONE, 2010 — Human ovarian reserve from conception to the menopause
- Richards JS, Pangas SA, Journal of Clinical Investigation, 2010 — The ovary: basic biology and clinical implications (doi:10.1172/JCI41350)
- Gougeon A, Annales d’Endocrinologie, 2010 — Human ovarian follicular development: from activation of resting follicles to preovulatory maturation (doi:10.1016/j.ando.2010.02.021)
- Moolhuijsen LME, Visser JA, Journal of Clinical Endocrinology & Metabolism, 2020 — Anti-Müllerian hormone and ovarian reserve: update on assessing ovarian function (doi:10.1210/clinem/dgaa513)
- NICE guideline NG257, Fertility problems: assessment and treatment, 2026 — Investigation of fertility problems
- WHO, “Polycystic ovary syndrome” fact sheet
References from the journal archive
These articles were published in Reproduction, the Journal of Reproduction and Fertility or Reviews of Reproduction and are still cited at their old addresses on this domain. Each link leads to the publisher’s version through its DOI.
- ANTI-OVULATORY AND OTHER BIOLOGICAL PROPERTIES OF MEGESTROL ACETATE 17αACETOXY-6 METHYL PREGNA 4:6-DIENE-3:20-DIONE (B.D.H. 1298)
- DEVELOPMENT AND RADIO-RESPONSE OF THE PRENATAL BOVINE OVARY
- SOME CHEMICAL, IMMUNOCHEMICAL AND ELECTROPHORETIC PROPERTIES OF BOVINE FOLLICULAR FLUID
- OVARIAN STIMULATION TEST USING HUMAN MENOPAUSAL GONADOTROPHIN (HMG)
- CELL KINETIC STUDIES OF FOLLICULAR ATRESIA IN THE MOUSE OVARY
- FOLLICULAR FLUID
- OVULATION BLOCK BY INDOMETHACIN, AN INHIBITOR OF PROSTAGLANDIN SYNTHESIS: A STUDY OF ITS SITE OF ACTION IN RATS
- THE RÔLE OF FSH AND LH IN THE INITIATION OF OVULATION IN RATS AND HAMSTERS: A STUDY USING RABBIT ANTISERA TO OVINE FSH AND LH
- UPTAKE OF TRITIATED THYMIDINE BY PRIMORDIAL GERMINAL CELLS IN THE OVARIES OF THE ADULT SLENDER LORIS
- MATING, OVULATION AND CORPUS LUTEUM FUNCTION IN THE VOLE, MICROTUS AGRESTIS
- Evidence in vivo for the two-cell hypothesis of oestrogen synthesis by the sheep Graafian follicle
- Oestrous behaviour, follicular growth and ovulation during pregnancy in the hare ( Lepus europaeus )
- Ovarian function in the ewe after active immunization against testosterone
- Seasonal variations in the cyclic luteal ovarian activity in the Tadmit ewe in Algeria
- Concentrations of progesterone in the backfat of pigs during the oestrous cycle and after ovariectomy
- Induction of ovulation with chronic intermittent (pulsatile) administration of Gn-RH in women with hypothalamic amenorrhoea
- Prediction of bovine ovulation by a rapid radioimmunoassay for plasma LH
- A species difference between hamster and rat in the effect of oestrogens on growth of large preantral follicles
- Changes in FSH and the pulsatile secretion of LH during the delay in oestrus induced by treatment of ewes with bovine follicular fluid
- Concentration of gonadotrophins in the plasma of sheep given gonadal steroid antisera to raise ovulation rate
- Effects of corticosterone and dietary changes in the hen on ovarian function, plasma LH and steroids and the response to exogenous LH-RH
- Ram-induced growth of ovarian follicles and gonadotrophin inhibition in anoestrous ewes
- Rate and course of atresia during follicular development in the adult cyclic rat
- Melatonin directly stimulates the secretion of progesterone by human and bovine granulosa cells in vitro
- Postnatal ovarian follicle development in hypogonadal ( hpg ) and normal mice and associated changes in the hypothalamic—pituitary ovarian axis
- Effect of human chorionic gonadotrophin and indomethacin on ovulation, steroidogenesis and prostaglandin synthesis in preovulatory follicles of PMSG-primed immature rats
- Reproductive characteristics of lambs actively immunized early in life with inhibin-enriched preparations from follicular fluid of cows
- Importance of non-olfactory ram stimuli in mediating ram-induced ovulation in the ewe
- Ovarian steroid hormone involvement in endogenous opioid modulation of LH secretion in mature ewes during the breeding and non-breeding seasons
- Immunization against recombinant bovine inhibin α subunit causes increased ovulation rates in gilts
- Luteal-phase defect induced by deprivation of FSH at a specific period of the follicular phase prevents pregnancy in the bonnet monkey ( Macaca radiata )
- Pattern of follicular growth and resumption of ovarian activity in post-partum beef suckler cows
- Resumption of follicular activity in the early post-partum period of dairy cows
- Effect of progesterone on ovarian follicles, emergence of follicular waves and circulating follicle-stimulating hormone in heifers
- Association of immunolocalization of matrix metalloproteinase 1 with ovulation in hCG-treated rabbit ovary
- Ovarian follicular dynamics in Suffolk ewes at different periods of the year
- Response of porcine granulosa cells isolated from primary and secondary follicles to FSH, 8-bromo-cAMP and epidermal growth factor in vitro
- Synergistic effects of steroids with FSH on folliculogenesis, steroidogenesis and FSH- and hCG-receptors in hypophysectomized mice
- Follicular development from ovarian xenografts in SCID mice
- Stimulation of in vitro ovulation and contraction of brook trout ( Salvelinus fontinalis ) follicles by adrenaline through α-adrenoreceptors
- Ultrasonographic study of ovarian follicular dynamics in ewes during the oestrous cycle
- Ageing, infecundity and reproductive senescence in free-ranging female rhesus monkeys
- Ovulation rate and the concentrations of gonadotrophic and metabolic hormones in ewes fed lupin grain
- Angiogenesis in the ovary
- Apoptosis and ovarian function
- Nutrition, insulin and polycystic ovary syndrome
- Ovulatory cycles and anovulatory periods in the addax ( Addax nasomaculatus )
- The ovarian follicular wave pattern and induction of ovulation in the mated and non-mated one-humped camel ( Camelus dromedarius )
- Immunolocalization of CD18-positive cells in the bovine ovary
- Ovarian follicular dominance: the role of intraovarian growth factors and novel proteins
- Steroidogenic acute regulatory (StAR) protein (p25) and prohibitin (p28) from cultured rat ovarian granulosa cells
- Populations of granulosa cells in small follicles of the sheep ovary
- Effect of exogenous LH pulses on the fate of the first dominant follicle in postpartum beef cows nursing calves
- Effects of ageing and exogenous melatonin on pituitary responsiveness to GnRH in rats
- Reproductive hormone profiles in mares during the autumn transition as determined by collection of jugular blood at 6 h intervals throughout ovulatory and anovulatory cycles
- Roles of KIT and KIT LIGAND in ovarian function
- Cellular basis for paracrine regulation of ovarian follicle development
- Effect of LH on circulating oestradiol and follicular fluid factor concentrations during follicle deviation in cattle
- Effects of genistein on the periovulatory expression of messenger ribonucleic acid for matrix metalloproteinases and tissue inhibitors of metalloproteinases in the rat ovary
- Enhancement of aromatase activity by D-aspartic acid in the ovary of the lizard Podarcis s. sicula
- Genes controlling ovulation rate in sheep
- Immunolocalization of progesterone receptors in the canine ovary and their relation to sex steroid hormone concentrations
- Potential local regulatory functions of inhibins, activins and follistatin in the ovary
- Role of ascorbic acid in promoting follicle integrity and survival in intact mouse ovarian follicles in vitro
- Ultrasound and endocrine evaluation of the ovarian cycle and early pregnancy in the Sumatran rhinoceros, Dicerorhinus sumatrensis
- Effect of bone morphogenetic protein 2 (BMP2) on oestradiol and inhibin A production by sheep granulosa cells, and localization of BMP receptors in the ovary by immunohistochemistry
- Expression of the long (OB-RB) and short (OB-RA) forms of the leptin receptor throughout the oestrous cycle in the mature rat ovary
- Folliculogenesis and ovarian expression of mRNA encoding aromatase in anoestrous sheep after 5 days of glucose or glucosamine infusion or supplementary lupin feeding
- Regulation of ovarian function: the role of anti-Mullerian hormone
- The earliest stages of folliculogenesis in vitro
- Local changes in blood flow within the preovulatory follicle wall and early corpus luteum in cows
- Ovarian gonadotrophin surge-attenuating factor (GnSAF): where are we after 20 years of research?
- Variation in ovarian morphology in four species of New World moles with a peniform clitoris
- Bone morphogenetic protein (BMP) ligands and receptors in bovine ovarian follicle cells: actions of BMP-4, -6 and -7 on granulosa cells and differential modulation of Smad-1 phosphorylation by follistatin
- Effect of deslorelin implants on follicular development, parturition and post-partum oestrus in the tammar wallaby ( Macropus eugenii )
- Localization and temporal regulation of tissue inhibitors of metalloproteinases 3 and 4 in bovine preovulatory follicles
- Methods for quantifying follicular numbers within the mouse ovary
- Staging of ovine embryos and expression of the T-box genes Brachyury and Eomesodermin around gastrulation
- Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function in ruminants
- Effect of steroids and nitric oxide on pituitary hormone release in ovariectomized, peripubertal rats
- Follicular cysts occur after a normal estradiol-induced GnRH/LH surge if the corpus hemorrhagicum is removed
- Production of matrix metalloproteinases by cultured bovine theca and granulosa cells
- Short-term nutritional supplementation of ewes in low body condition affects follicle development due to an increase in glucose and metabolic hormones
- Anti-Müllerian hormone: a new marker for ovarian function
- Effect of intrafollicular indomethacin injection on gonadotropin surge-induced expression of select extracellular matrix degrading enzymes and their inhibitors in bovine preovulatory follicles
- Interactions between progesterone and tumor necrosis factor-α in the regulation of primordial follicle assembly
- Localization and temporal regulation of tissue inhibitor of metalloproteinases-4 in mouse ovary
- Quantification of healthy follicles in the neonatal and adult mouse ovary: evidence for maintenance of primordial follicle supply
- Relationships of changes in B-mode echotexture and colour-Doppler signals in the wall of the preovulatory follicle to changes in systemic oestradiol concentrations and the effects of human chorionic gonadotrophin in mares
- TGF-β superfamily members and ovarian follicle development
- The effects of IGF-I on bovine follicle development and IGFBP-2 expression are dose and stage dependent
- Changes in the expression of gallinacins, antimicrobial peptides, in ovarian follicles during follicular growth and in response to lipopolysaccharide in laying hens ( Gallus domesticus )
- Effect of negative energy balance on the insulin-like growth factor system in pre-recruitment ovarian follicles of post partum dairy cows
- Engaging in paced mating, but neither exploratory, anti-anxiety, nor social behavior, increases 5α-reduced progestin concentrations in midbrain, hippocampus, striatum, and cortex
- Mathematical modelling of oxygen transport-limited follicle growth
- Ovarian follicular cells have innate immune capabilities that modulate their endocrine function
- Regulation of adiponectin and its receptors in rat ovary by human chorionic gonadotrophin treatment and potential involvement of adiponectin in granulosa cell steroidogenesis
- Relationship between metabolic hormones and ovulation of dominant follicle during the first follicular wave post-partum in high-producing dairy cows
- Association of FSH receptor and CYP19A1 gene variations with sterility and ovarian hyperstimulation syndrome
- Developmental regulation of histone H3 methylation at lysine 4 in the porcine ovary
- Dietary unsaturated fatty acids influence preovulatory follicle characteristics in dairy cows
- Glial-derived neurotrophic factor promotes ovarian primordial follicle development and cell–cell interactions during folliculogenesis
- In vivo gene expression in granulosa cells during pig terminal follicular development
- Low reproductive success in Per1 and Per2 mutant mouse females due to accelerated ageing?
- Transcription factor p53 can regulate proliferation, apoptosis and secretory activity of luteinizing porcine ovarian granulosa cell cultured with and without ghrelin and FSH
- Two pathways for prostaglandin F2α synthesis by the primate periovulatory follicle
- Angiogenesis and vascular function in the ovary
- Changes in the glucose-6-phosphate dehydrogenase activity in granulosa cells during follicular atresia in ewes
- Effects of active immunization against growth differentiation factor 9 and/or bone morphogenetic protein 15 on ovarian function in cattle
- Expression of ovarian tumour suppressor OPCML in the female CD-1 mouse reproductive tract
- Gene expression profiling of bovine preovulatory follicles: gonadotropin surge and prostanoid-dependent up-regulation of genes potentially linked to the ovulatory process
- IGF1-induced AKT phosphorylation and cell proliferation are suppressed with the increase in PTEN during luteinization in human granulosa cells
- Multiple mechanisms of germ cell loss in the perinatal mouse ovary
- Ovarian aging in squirrel monkeys ( Saimiri sciureus )
- Spatiotemporal analysis of the protein expression of angiogenic factors and their related receptors during folliculogenesis in rats with and without hormonal treatment
- The hedgehog-patched signaling pathway and function in the mammalian ovary: a novel role for hedgehog proteins in stimulating proliferation and steroidogenesis of theca cells
- Anti-Müllerian hormone and polycystic ovary syndrome: a mountain too high?
- Effects of reproductive stage, GH, and 11-ketotestosterone on expression of growth differentiation factor-9 in the ovary of the eel, Anguilla australis
- Epidermal growth factor receptor kinase activity is required for gap junction closure and for part of the decrease in ovarian follicle cGMP in response to LH
- IGF1 induces up-regulation of steroidogenic and apoptotic regulatory genes via activation of phosphatidylinositol-dependent kinase/AKT in bovine granulosa cells
- Involvement of the SLIT/ROBO pathway in follicle development in the fetal ovary
- Metformin decreases IGF1-induced cell proliferation and protein synthesis through AMP-activated protein kinase in cultured bovine granulosa cells
- Premature ovarian failure
- Telomerase in the ovary
- The effect of monosaccharide sugars and pyruvate on the differentiation and metabolism of sheep granulosa cells in vitro
- The use of a ‘first-wave’ model to study the effect of nutrition on ovarian follicular dynamics and ovulation rate in the sheep
- Theca: the forgotten cell of the ovarian follicle
- Tracking the rejection and survival of mouse ovarian iso- and allografts in vivo with bioluminescent imaging
- A macrophage and theca cell-enriched stromal cell population influences growth and survival of immature murine follicles in vitro
- Autophagy is a cell survival program for female germ cells in the murine ovary
- Effects of omega-3 and -6 polyunsaturated fatty acids on ovine follicular cell steroidogenesis, embryo development and molecular markers of fatty acid metabolism
- Endocrine-disrupting chemicals in ovarian function: effects on steroidogenesis, metabolism and nuclear receptor signaling
- Expression and effect of resistin on bovine and rat granulosa cell steroidogenesis and proliferation
- Gene expression in mouse ovarian follicle development in vivo versus an ex vivo alginate culture system
- Granulosal and thecal expression of bone morphogenetic protein- and activin-binding protein mRNA transcripts during bovine follicle development and factors modulating their expression in vitro
- Signalling pathways involved in the cooperative effects of ovine and murine GDF9+BMP15-stimulated thymidine uptake by rat granulosa cells
- The developing ovary of the South American plains vizcacha, Lagostomus maximus (Mammalia, Rodentia): massive proliferation with no sign of apoptosis-mediated germ cell attrition
- Differentially expressed plasma microRNAs in premature ovarian failure patients and the potential regulatory function of mir-23a in granulosa cell apoptosis
- FGF10 inhibits dominant follicle growth and estradiol secretion in vivo in cattle
- Follicular assembly: mechanisms of action
- Identification of miRNAs associated with the follicular–luteal transition in the ruminant ovary
- Involvement of the oestrogenic receptors in superior mesenteric ganglion on the ovarian steroidogenesis in rat
- Mammalian foetal ovarian development: consequences for health and disease
- Ovarian VEGF165b expression regulates follicular development, corpus luteum function and fertility
- The expression, regulation and function of secreted protein, acidic, cysteine-rich in the follicle–luteal transition
- EP3 receptor isoforms are differentially expressed in subpopulations of primate granulosa cells and couple to unique G-proteins
- Ovarian signalling pathways regulated by leptin during the ovulatory process
- SMAD7 antagonizes key TGFβ superfamily signaling in mouse granulosa cells in vitro
- N -glycan profiling of bovine follicular fluid at key dominant follicle developmental stages
- PUMA regulates germ cell loss and primordial follicle endowment in mice
- Quantification of healthy and atretic germ cells and follicles in the developing and post-natal ovary of the South American plains vizcacha, Lagostomus maximus : evidence of continuous rise of the germinal reserve
- Role of leptin receptors in granulosa cells during ovulation
- Serum levels of insulin-like factor 3, anti-Müllerian hormone, inhibin B, and testosterone during pubertal transition in healthy boys: a longitudinal pilot study
- microRNA 376a regulates follicle assembly by targeting Pcna in fetal and neonatal mouse ovaries
- Molecular aspects of bovine cystic ovarian disease pathogenesis
- Neonatal exposure to xenoestrogens impairs the ovarian response to gonadotropin treatment in lambs
- Ovarian cancer: involvement of the matrix metalloproteinases
- Regulation of the ovarian oxidative status by leptin during the ovulatory process in rats
- The impact of passive immunisation against BMPRIB and BMP4 on follicle development and ovulation in mice
- Molecular determinants of a competent bovine corpus luteum: first- vs final-wave dominant follicles
- Reproductive age-associated fibrosis in the stroma of the mammalian ovary
- A single dose of allopregnanolone affects rat ovarian morphology and steroidogenesis
- Anti-Müllerian Hormone (AMH) and fertility management in agricultural species
- DHEA protects mitochondria against dual modes of apoptosis and necroptosis in human granulosa HO23 cells
- Detection and activity of 11 beta hydroxylase (CYP11B1) in the bovine ovary
- Ovarian fragment sizes affect viability and morphology of preantral follicles during storage at 4°C
- Syndecan 1 represses cell growth and FSH responsiveness in human granulosa cells
- The impact of laparoscopic ovarian drilling on AMH and ovarian reserve: a meta-analysis