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Luteal phase deficiency (LPD): a mysterious diagnostic entity with a complex history

Luteal phase deficiency (LPD): a mysterious diagnostic entity with a complex history

9 min read

Over 70 years ago, the concept of luteal phase deficiency or luteal phase defect (LPD) popped up in the scientific literature. The idea behind LPD is that there may be issues with hormone production or endometrial development in a subset of people and in a subset of cycles, and that these issues may be a culprit for infertility.

But, for decades, there has been controversy over what the symptoms are for LPD, how it’s diagnosed, whether it's actually related to infertility, and if and how it should be treated. In this post, we’ll give you the DL about this mysterious diagnostic entity — a fantastic example of how fertility science is always changing and being updated as new data comes in.

The bottom line up front: The lack of medical consensus on how to diagnose LPD and mixed associations between LPD and fertility make LPD and its implications really hard to study. Issues with luteal phase function may be related to fertility, but how to identify and treat those issues evades researchers and clinicians to this day.

Key takeaways

  • The luteal phase is an important part of the menstrual cycle during which implantation can occur and a pregnancy can be established. Abnormalities in the luteal phase could affect implantation and pregnancy.
  • Luteal phase deficiency (LPD) is a condition in which luteal phase activity is deemed "insufficient."
  • While there are several methods that have been proposed to diagnose LPD, there are currently no clear and clinically relevant standard tests to accurately define LPD and distinguish fertile from infertile people with ovaries.
  • There isn’t any evidence that progesterone treatment during the luteal phase improves pregnancy rates in people with suspected LPD in unstimulated cycles — but there also isn’t any evidence to suggest that it has negative effects.
  • More research is needed to better understand the basic workings of the luteal phase before we can figure out how to best diagnose LPD. Once LPD is well-defined, prospective studies can test links between LPD and infertility.

First: Why does the luteal phase matter?

Each phase of the menstrual cycle (the follicular phase, ovulation, and the luteal phase) is associated with its own unique physiological and hormonal changes to make conception possible. A small part of the brain called the pituitary releases follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which then signal for the release of estradiol and progesterone from ovarian follicles or the corpus luteum (more on that below!).

The luteal phase, which begins at or immediately after ovulation and ends at the start of menstruation, involves the following changes:

  • The follicle that was once home to the egg released during ovulation (which you can use LH surges to detect!) turns into a structure called the corpus luteum.
  • The corpus luteum starts pumping out progesterone and estradiol (a type of estrogen), which change the composition and thickness of the endometrium (aka uterine lining), making it as implantation-friendly as possible.
  • For this endometrial development, there needs to be high enough levels of progesterone and estradiol, and cells that can actually respond to the effects of these hormones.

If there is no endometrium, if the endometrium is way too thin, or if the actual composition of the endometrium isn’t developing as expected (studied through a process called histological dating), it could make implantation less likely.

What is luteal phase deficiency/defect (LPD)?

Like we mentioned at the top of this article, LPD first showed up in the research 70 years ago. In those 70 years, LPD has fluctuated between being a diagnosis with promise to explain infertility in some people, considered "clinically irrelevant" (ouch) by the American Society for Reproductive Medicine (ASRM) in 2015, and now something that could potentially be relevant but needs to be studied further.

Since LPD is an evolving concept, there are gaps in what we do and don't know about it. What we do know: The term LPD was created to acknowledge that issues with endometrial development during the luteal phase could be a cause of infertility or recurrent pregnancy loss. Despite the medical community's uncertainty on LPD, the logic is certainly sound — if someone is ovulating regularly and all other infertility testing is normal but they're still not getting pregnant or they're experiencing multiple pregnancy losses, it’s totally reasonable to think that one potential explanation is something during the luteal phase not functioning the way it should.

How is LPD diagnosed?

There isn't just one way physicians in reproductive endocrinology and infertility have found to accurately and relevantly diagnose LPD, but several ways have been suggested. Here are the most common methods, as outlined by a recent ASRM review:

1. Shorter luteal phases: Arguably the cheapest, least invasive, and easiest way some people suggest to diagnose LPD is based on luteal phase length or overall cycle length (all it takes is self-reporting!). The thinking here is that luteal phases in which there isn't sufficient endometrial development should be shorter than phases with sufficient endometrial development; therefore, shorter luteal phases or shorter overall cycles may be indicative of LPD.

There are, however, some limitations of this method of diagnosis:

  • There isn’t widespread agreement among LPD researchers about what cut-off should be used for “short.” Some people define an abnormal luteal phase length as being eight days or less, while others define 11 days or less as being short (in their latest committee opinion, ASRM goes with 10 days or less).
  • There’s a lot of variability from cycle to cycle in terms of how long luteal phases are. According to one recent study, while 40% of all cycles may have luteal phases of 11 days or less, only 3% of people have back-to-back cycles with consistently short luteal phases. This means someone could meet the criteria for LPD based on data from one cycle, but that they wouldn’t meet the LPD criteria during their next cycle.

2. Low progesterone levels: Because the endometrium develops in part due to the actions of progesterone, low serum progesterone levels could theoretically explain abnormalities in the luteal phase. Some people have proposed measuring progesterone daily across the luteal phase through blood tests and using the total amount of progesterone produced as a way to diagnose LPD, but this hasn’t been clinically evaluated — and most people who use progesterone to diagnose LPD rely on only one measurement.

This diagnostic method has some issues too:

  • Though we have cut-offs for mid-luteal progesterone levels that are indicative of ovulation (>3 ng/mL in serum), we don’t have any analogous validated cut-offs for where progesterone levels have to be to support a pregnancy. Because this makes it hard to know how much progesterone is “enough” for luteal phase function, a single luteal progesterone measure doesn’t mean all that much.
  • There is also considerable variability in corpus luteum function and progesterone production from cycle to cycle. While one cycle may have low luteal phase progesterone, the next might not, making it tricky to rely on a single measure from a single cycle to diagnose LPD.
  • Levels of progesterone fluctuate rapidly in the bloodstream (they can fluctuate by 8x within 90 minutes!), further complicating the ability of one progesterone measurement in isolation to tell us all that much.

3. "Abnormal" endometrial tissue: One of the core assumptions of LPD as a diagnosis is that there may be differences in the endometrium that decrease chances of implantation, or decrease the chances of an endometrium staying in place after implantation has occurred and a pregnancy has been established. Some researchers have suggested doing an endometrial biopsy in people with suspected LPD, which involves taking some endometrial tissue during the luteal phase and seeing whether it seems "normal" by comparing it to endometrial tissue from people without suspected LPD.

This method also has some limitations:

  • Biopsy-based measures aren’t as objective as things like hormone levels or number of days in a luteal phase. Scientists will examine endometrial tissue and, using their expertise, decide whether or not it looks like what we’d expect "normal" endometrial tissue to look like at that point in the cycle. But there’s not a general consensus among scientists on what is "abnormal" (also referred to as "out of phase") — and we don’t have a way of deciding who is "right" when these disagreements arise.
  • Perhaps unsurprisingly, there is also considerable variability in endometrial tissue from cycle to cycle. Studies that have assessed endometrial tissue in up to three back-to-back cycles found virtually no relationship between levels of endometrial development across cycles. This means that atypical endometrial development detected in one cycle doesn’t suggest consistent endometrial abnormalities in all cycles.

Some scientists have also suggested combining some of these diagnostic criteria, like progesterone measurements along with luteal phase lengths, but we’re waiting on clinical studies to support that diagnostic approach.

What’s clear is that the way LPD is diagnosed can differ significantly across studies and across physicians, making it really hard to systematically study. But many scientists love a good research challenge, so that hasn’t stopped them from trying to understand LPD as a clinical entity and its potential associations with infertility.

Are there treatments for LPD?

To date, there isn’t any strong evidence to support treatments for LPD. Progesterone supplementation would seem like a good place to start when searching for treatments, as some (albeit not particularly strong) evidence suggests progesterone supplementation is beneficial in in vitro fertilization (IVF) cycles:

  • There are no randomized controlled trials of progesterone supplementation improving pregnancy rates in natural, unstimulated cycles as a treatment for LPD, so we can’t say that it works or doesn’t work.
  • While recurrent pregnancy loss and LPD are considered to be separate clinical entities, some people think they might be related. Though we wouldn’t necessarily expect treatment options for one condition to work for another, there's some evidence that progesterone supplementation in non-IVF cycles may prevent pregnancy loss in people with recurrent miscarriage.
  • There is data to suggest supplemental progesterone can improve pregnancy outcomes in assisted reproductive technology (ART) treatment, but again, this doesn’t necessarily mean supplemental progesterone would be helpful in unstimulated cycles.
  • There also isn't strong evidence that levels of progesterone correlate with markers of endometrial development, meaning it’s unclear whether adding progesterone in the body would positively impact the endometrium.

All of the above said, because there's no reason to believe adding progesterone would negatively impact endometrial development and function, progesterone is sometimes prescribed by doctors in cases of suspected LPD.

Here's what Modern Fertility medical advisor Dr. Temeka Zore, MD, FACOG and reproductive endocrinologist at Spring Fertility has to say on the potential benefits of supplemental progesterone in unstimulated cycles: “While there certainly may be patients who could benefit from additional progesterone support in the luteal phase, we don't yet have good diagnostic and clinically relevant tests to determine who those individuals may be.”

There's also been some discussion among doctors about progesterone measurements and supplemental progesterone after a pregnancy has been detected. A developing pregnancy will produce human chorionic gonadotropin (hCG) to support the corpus luteum — and it will help with subsequent progesterone secretion until the luteal-placental shift (when the placenta takes over the vital role of producing what's necessary for fetal development, usually between 7-9 weeks in). When hCG levels are low because of an abnormal or ectopic pregnancy, progesterone levels are low too. In cases like these, supplemental progesterone would not be effective in treating the larger issue.

It’s tricky to draw conclusions about links between LPD and infertility. Since there are such big differences in how LPD is defined across studies, it’s hard to compare data from these studies —- it’s a bit like comparing apples to oranges.

“I think most of the fertility doctors in this field will agree with the importance of progesterone in preparing the endometrium for implantation and supporting an early pregnancy,” says Dr. Zore. “Where there is discrepancy is whether we have enough solid data that points to LPD as a cause of infertility.”

However, we can still look at the published research and try to make some sense of it all. More often than not, studies do not find a link between LPD (however they choose to define it) and infertility. When comparing fertile to infertile people with ovaries, there aren’t consistent differences in luteal phase length or endometrial development assessed via biopsy (shown here, here, and here).

It’s also the case that proposed markers of LPD, like short luteal phases, are very common among people who ovulate regularly (shown here, here, and here). There is also no evidence suggesting that a diagnosis of LPD is associated with lower ovarian reserve (aka a lower egg count).

Putting it all together, it’s unclear whether we can expect any differences in fertility in people with and without LPD.

What factors and conditions could affect LPD?

Just like there are many factors that affect hormone production, there are many that affect luteal function. Any conditions that affect the brain’s ability to kickstart hormone production, and any conditions that affect ovulatory function, will in turn affect the luteal phase.

ASRM provides a whole list of physiological states and conditions associated with LPD, including:

The bottom line? LPD is still a mystery

Here’s where we currently stand: We don’t yet know what the best way to measure and diagnose LPD is, and we don’t know whether it’s associated with infertility.

As scientists continue to study the luteal phase, we’ll gain more clarity about what "normal" and "abnormal" look like when it comes to luteal function, which will help us more clearly define diagnostic criteria for LPD. Once that’s figured out, we’ll be better able to study its potential associations with infertility and potential treatments. In the meantime, Dr. Zore recommends that individuals concerned about potential LPD should speak to their doctors about their individual history and work with them to make a treatment plan.

This article was medically reviewed by Dr. Temeka Zore, MD, FACOG, a fellowship-trained reproductive endocrinologist and infertility specialist and board-certified OB-GYN at Spring Fertility in San Francisco.

Did you like this article?

Talia Shirazi, PhD

Talia is a clinical product scientist at Modern Fertility. She's passionate about reproductive health + behavioral neuroendocrinology. Talia received her PhD in biological anthropology at Penn State.

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