Luteinized Unruptured Follicle (LUF): An explanation for ‘unexplained infertility’

Many of us have heard of anovulation, or the lack of ovulation in a given cycle, but how many of us know the many causes? In an Instagram reel from June 2024, fertility awareness instructor Christina Valenzuela explained a lesser-known cause of anovulation: Luteinized Unruptured Follicles (LUFs), sometimes called luteinized unruptured follicle syndrome. What is a luteinized unruptured follicle? How does it affect women’s fertility? And what are the signs and symptoms? 

Normal ovulation goes like this

Before we dive into the details of this specific form of anovulation, let’s review what’s supposed to happen. Every menstrual cycle is directed by a complex interplay between hormones. The four main reproductive hormones are follicle stimulating hormone (FSH), estrogen, luteinizing hormone (LH), and progesterone. 

At the beginning of the cycle, FSH stimulates the growth of an egg inside a follicle. As the egg matures, estrogen rapidly rises, triggering an LH surge. The LH surge causes ovulation, the release of the egg into the Fallopian tubes. The empty follicle is then luteinized, meaning it is changed into the corpus luteum. The corpus luteum produces progesterone and some estrogen for the remainder of the cycle. 

If conception occurs, the corpus luteum produces progesterone and estrogen throughout the first trimester until the placenta takes over hormone production. If conception doesn’t occur, the corpus luteum shrivels up at the end of the cycle. The decrease in estrogen tells FSH to rise, which it begins to do about four days before menstruation starts [1]. Then the whole cycle restarts. 

What is a luteinized unruptured follicle?

What goes wrong when a LUF occurs? As the name implies, a LUF means a follicle is luteinized or acted on by LH, but doesn’t rupture or release the mature egg [2]. LUFs have been found in couples struggling with infertility and in those who usually have healthy, ovulatory cycles [3]. Among fertility awareness professionals, LUF is considered a more hidden form of infertility because it hormonally presents as an otherwise healthy cycle. 

Unlike other forms of anovulation—where a corpus luteum never forms and the lack of ovulation can be detected by low or absent progesterone—in a LUF cycle, progesterone is still produced due to the luteinization of the follicle. Thus, the woman “looks” hormonally healthy but does not ovulate. 

What are the symptoms?

As a fertility awareness instructor for the FEMM method, I have been taught to look for subtle signs of potential LUFs in charts. These might include a slightly shorter luteal phase, a luteal phase that suggests hormonal imbalance, or a cervical mucus pattern during the ovulatory phase that shows a less-than-ideal estrogen rise. Despite these biomarker observations that could potentially signify a LUF, one cannot diagnose a LUF from charting alone. 

Again, LUFs often present as healthy cycles. Some women may experience mid-cycle pain or discomfort around the time ovulation should occur, but many have nothing unusual to report. Those charting basal body temperature will experience a normal increase in basal body temperature and progesterone blood draws will read as an otherwise healthy rise in progesterone levels [2]. 

What causes LUFs?

The exact cause of LUFs is unknown [3]. Some have hypothesized that chronic stress could play a factor in LUF [4]. This could be why most women will experience at least some LUFs whether they struggle with infertility or not. Many researchers agree that the syndrome of LUFs, where one experiences LUFs regularly, could be caused in part by some or all of the following factors: hormonal imbalances, pelvic inflammation, or hormonal disorders like PCOS, endometriosis, and hyperprolactinemia. Several small studies also suggest a connection between regular use of certain NSAIDs and LUFs in women with inflammatory conditions like rheumatoid arthritis [5][6]. 

How do you get diagnosed with LUFs?

Currently, ultrasound is the only accurate and noninvasive method of diagnosing LUFs [3]. Because a LUF cycle externally presents as an ovulatory cycle, it cannot be confirmed through cycle charts or blood draws [4]. The process of detecting a LUF involves daily transvaginal ultrasounds to monitor the follicle’s characteristics and growth, and to examine endometrial thickness.

Healthcare professionals trained in restorative reproductive medicine will utilize a series of ultrasounds to determine if a woman is ovulating or not. In the case of a LUF, the woman will experience the growth and luteinization of the follicle and increased thickness in her uterine lining without the release of an egg. If ovulation is not observed, your provider may suggest doing a progesterone blood draw to test for progesterone rise. If progesterone rises despite the lack of ovulation, that would help confirm a LUF. It is important to note that having a LUF occur once or multiple times does not necessarily mean you never ovulate. 

How often do LUFs occur?

The prevalence of LUFs is unknown and estimates vary among professionals. According to a 2006 study in the Journal of Human Reproduction, LUFs happen 10% of the time in normal, fertile women, but women struggling with infertility experience them at a higher rate [3]. Their study noted that women who undergo ART procedures appear to have an increased incidence of LUFs. One old 1980 study reported that half of their patients who had regular cycles but were infertile experienced LUFs regularly [7]. 

What is the treatment for LUFs?

LUFs were first identified in scientific literature in 1975, but they have not been well-studied and consequently few research studies exist to compare the effectiveness of treatment options. Women who experience LUFs regularly will generally be recommended to first try medications to make the body ovulate. These include ovulation induction medications like Clomiphene (Clomid) or Letrozole (Femara), gonadotropins, or human chorionic gonadotropin (HCG). These medications may be tried sequentially (as in, if one type of medication fails to trigger ovulation, try another) or simultaneously. 

This 2015 study points out the muddy waters around medication treatment of LUF, noting that while “Preovulatory injection of human chorionic gonadotropin (HCG) prevents or treats LUF syndrome…[LUF] has also occurred after the induction of ovulation with clomiphene/HMG [human menopausal gonadotropin] and HCG” such as women undergo as part of in vitro fertilization (IVF) [8]. That’s right. Medications intended to trigger ovulation could help with or cause LUF. 

If medications are ineffective, many healthcare clinicians refer women for IVF, which comes with risks for both mom and baby. 

The bottom line on luteinized unruptured follicles

Luteinized unruptured follicles represent a common, yet ill-understood, form of anovulation. More research is needed to understand why LUFs occur and how much their occurrence directly contributes to cases of long-term infertility. Perhaps most women will experience LUFs at some point during their fertile years, but the concern is when they occur regularly. 

The only method to definitively diagnose LUFs currently is through transvaginal ultrasounds, where the patient and provider can observe the growth and luteinization of a follicle without ovulation. As more people become aware of LUFs, we hope that researchers will continue to study why they occur and how they can be treated, so women who experience frequent LUFs can go on to experience healthy ovulatory cycles and, if desired, conceive. 

References:

[1] Miro F, Aspinall LJ. The onset of the initial rise in follicle-stimulating hormone during the human menstrual cycle. Hum Reprod. 2005 Jan;20(1):96-100. doi: 10.1093/humrep/deh551. Epub 2004 Oct 7. PMID: 15471927.

[2] Audebert A. LUF-syndrome: données actuelles [LUF-syndrome: recent findings]. J Gynecol Obstet Biol Reprod (Paris). 1990;19(2):135-43. French. PMID: 2182699.

[3] H. Qublan, Z. Amarin, M. Nawasreh, F. Diab, S. Malkawi, N. Al-Ahmad, M. Balawneh, Luteinized unruptured follicle syndrome: incidence and recurrence rate in infertile women with unexplained infertility undergoing intrauterine insemination, Human Reproduction, Volume 21, Issue 8, 1 August 2006, Pages 2110–2113, https://doi.org/10.1093/humrep/del113

[4] LeMaire GS. The luteinized unruptured follicle syndrome: anovulation in disguise. J Obstet Gynecol Neonatal Nurs. 1987 Mar-Apr;16(2):116-20. doi: 10.1111/j.1552-6909.1987.tb01446.x. PMID: 2952775.

[5] Tomioka RB, Ferreira GRV, Aikawa NE, Maciel GAR, Serafini PC, Sallum AM, Campos LMA, Goldestein-Schainberg C, Bonfá E, Silva CA. Non-steroidal anti-inflammatory drug induces luteinized unruptured follicle syndrome in young female juvenile idiopathic arthritis patients. Clin Rheumatol. 2018 Oct;37(10):2869-2873. doi: 10.1007/s10067-018-4208-x. Epub 2018 Jul 12. PMID: 30003441.

[6] Micu MC, Micu R, Ostensen M. Luteinized unruptured follicle syndrome increased by inactive disease and selective cyclooxygenase 2 inhibitors in women with inflammatory arthropathies. Arthritis Care Res (Hoboken). 2011 Sep;63(9):1334-8. doi: 10.1002/acr.20510. PMID: 21618455.

[7] Koninckx PR, De Moor P, Brosens IA. Diagnosis of the luteinized unruptured follicle syndrome by steroid hormone assays on peritoneal fluid. Br J Obstet Gynaecol. 1980 Nov;87(11):929-34. doi: 10.1111/j.1471-0528.1980.tb04454.x. PMID: 7437365.
[8] Azmoodeh A, Pejman Manesh M, Akbari Asbagh F, Ghaseminejad A, Hamzehgardeshi Z. Effects of Letrozole-HMG and Clomiphene-HMG on Incidence of Luteinized Unruptured Follicle Syndrome in Infertile Women Undergoing Induction Ovulation and Intrauterine Insemination: A Randomised Trial. Glob J Health Sci. 2015 Sep 1;8(4):244-52. doi: 10.5539/gjhs.v8n4p244. PMID: 26573024; PMCID: PMC4873591.