Do ovaries produce estrogen before menarche?

Do ovaries produce estrogen before menarche?

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It is traditionally taught that estrogen is produced by the granulosa cells of the follicle. But before menarche, where does the estrogen come from? Is it from the thin layer of granulosa cells lining the primordial follicles? The adrenal zona reticularis produces androgens physiologically. Are they converted to estrogen? If yes, by whom? If not by the ovary, would the levels of estrogens be same in prepubertal boys and girls?

More importantly, are there estrogens in a girl before menarche? If yes wouldn't they cause endometrial changes?


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.

Order of changes in ovary.

1 - Menstruation
2 - Developing follicle
3 - Mature follicle
4 - Ovulation
5 - Corpus luteum
6 - Deterioration of corpus luteum

Contrary to male spermatogenesis, which can last indefinitely, folliculogenesis ends when the remaining follicles in the ovaries are incapable of responding to the hormonal cues that previously recruited some follicles to mature. This depletion in follicle supply signals the beginning of menopause.

Role in Reproductive Biology and Reproductive Dysfunction in Women

Lubna Pal , Hugh S. Taylor , in Vitamin D (Fourth Edition) , 2018


Menarche , that is, the onset of spontaneous menstruation, and each successive menstrual cycle is the end result of successful team play by a number of endocrine glands (hypothalamus–pituitary–ovary) and end organs (pituitary–ovarian follicle–endometrium). Not only does menarche herald the period of reproductive competence, but appropriate timing of the event holds both short- and long-term health implications. The average age at menarche for the Caucasian populations is approximately 11 years although subtle racial differences are recognized, and additionally timing of the event relates to other characteristics of a population, including nutritional status and environmental factors [32] . Whether too early (<9 years), or too late (>16 years), abnormal onset menarche has been associated with an increased risk for chronic health disorders, including CVD and related mortality, type II diabetes, and breast cancer (described with early age at menarche) [32] , as well as skeletal fragility (linked with late-onset menarche) [33] . Limited data have suggested that vitamin D deficiency may be a risk for early onset menarche. In a prospective cohort study of premenarchal girls (n = 242), girls with evidence of vitamin D deficiency (25(OH)D <50 nmol/L) were twice as likely to reach menarche during the observation period of 30 months compared with girls who were vitamin D sufficient [34] .

Hysterectomy and Migraine: What can you expect?

Hysterectomy is the surgical removal of a women’s uterus or womb. A hysterectomy can be “partial” or “total.” A “partial” or subtotal procedure involves removal of the upper part of the uterus—the fundus. The mouth of the uterus or cervix is not removed. This term has also been used to indicate one or more ovaries remain in the body. In a “total” or complete hysterectomy, the uterus and cervix are both removed. When the phrase is properly used, the ovaries again remain intact. The reasons vary for hysterectomies and so does the procedure. A hysterectomy frequently involves removal of both fallopian tubes and ovaries. Technically, this is not a hysterectomy, but a hysterectomy with bilateral salpingo-oopherectomy (BSO). A radical hysterectomy for cancer also involves lymph node and channel removal. Be clear on exactly the “type of hysterectomy” planned. For this reason, a detailed conversation about hysterectomy is necessary with your providers.

The Uterus and Ovary Hormones

The uterus does not produce the female sex hormones, estrogen, and progesterone. The ovaries produce estrogen and progesterone. In women after menarche and before menopause, the estrogen and progesterone levels change throughout the menstrual cycle. This happens as long as the ovaries are present, whether the uterus is present or not. For most women with migraine, the drop in estrogen just before menses is a big trigger for menstrual migraine. While the uterus does not produce estrogen or progesterone, it is influenced by them. Estrogen causes the lining of the uterus to build up every month in preparation for possible pregnancy. Progesterone stabilizes the lining of the uterus. When the egg does not implant, both estrogen and progesterone levels drop to low levels at the end of the menstrual cycle. With an intact uterus bleeding occurs. Removal of the uterus will result in no more menses.

Migraine and Hormone Swings

Menstrual migraine is due to sensitivity of the brain pain centers to normal change in hormone levels, especially estrogen. This menstrual headache is often the worst of the month. The effects of progesterone and its role in migraine are less certain. Researchers continue to work to increase our understanding of both estrogen and progesterone changes in migraine.

If only a hysterectomy has taken place with one or both ovaries left intact, then the ups and downs in estrogen and progesterone will continue. In this setting, one can expect little change in migraine pattern.

When a woman undergoes a hysterectomy with BSO, then the ups and downs in estrogen and progesterone no longer occur. This woman should improve if she had menstrual migraine before hysterectomy with BSO. This would at least seem logical especially for those with a hormonal trigger. BEWARE, however, a dramatic drop in estrogen and progesterone occurs with a hysterectomy with BSO. This drop can wreck havoc on a woman’s migraines.

Studies have looked at the effect of menopause on migraine. How women enter menopause with migraine seems to matter. Migraine women that are “thrown” into menopause with a hysterectomy with BSO frequently are worse. Women who “gently” go into menopause as their ovaries begin producing less and less estrogen and progesterone typically fare better. Statistics show that two of three women will experience improvement in their migraine if they go into menopause naturally. Only one of three women with migraine will experience an improvement in migraine with surgical menopause, meaning that their ovaries are removed.

Talking to your Surgeon about Hysterectomy

Many important medical indications exist for a hysterectomy. These include prolonged and heavy bleeding, cancer of the uterus or ovaries, severe endometriosis, or large fibroids. Therefore, it may not always be possible to avoid a hysterectomy. In this case, there are some steps a woman with migraine can take prior to the hysterectomy to help prevent a major worsening of her migraines. Here are some recommendations:

  • Discuss with your doctor if your ovaries are to be left in. In most cases, this is desirable to avoid the sudden drop in estrogen and progesterone. Leaving the ovaries in can also prevent hot flashes, night sweats, insomnia, vaginal dryness, and the increased risk of osteoporosis that are typical of menopause.
  • If the ovaries have to come out, see if an estradiol patch (such as Vivelle) can be worn immediately after the surgery to prevent the massive drop in estrogen. This concept is known as “add-back estrogen .” Non-oral forms of estrogen such as the patch can be better at creating steady levels of estrogen (important for migraine prevention) as opposed to oral estrogen therapies.
  • If estrogen after surgery is contraindicated, then start an oral preventive well before the surgery to help prevent post-hysterectomy migraines. If you are already on an oral preventive, consider upping the dose. A good choice may be a beta-blocker or an anti-epileptic, Gabapentin, or an SNRI (serotonin norepinephrine reuptake inhibitor) such as Venlafaxine (Effexor) or Duloxetine (Cymbalta). These medications have been shown to decrease vasomotor symptoms, such as hot flashes, as well as possibly prevent migraine.

Migraine and Hysterectomy Summary

A hysterectomy becomes a necessary surgery for many women with migraine. However, it should NEVER be done for the sole purpose of lessening migraine. Take the choice of leaving the ovaries in unless there is cancer or a high risk of ovarian cancer. Preparing ahead of time with migraine management before a hysterectomy can help lessen the negative impact on migraine.

Susan Hutchinson, MD, Director-Orange County Migraine &Headache Center, Irvine, CA.

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Fluctuations of Estrogen during Menopausal Stages


Although premenopause and perimenopause are used interchangeably, premenopause can be considered the first stage that begins with menarche and ends with the initiation of perimenopause.

It is during this time that a woman is in prime reproductive years as natural fluctuations of estrogen guide each menstrual cycle. Certain diseases and lifestyle factors may throw off hormonal balance and cause irregularities.


Perimenopause usually occurs two to eight years before the onset of menopause. It begins with irregular menstrual cycles and ends a year after the last menstrual cycle. Nevertheless, it is possible for women to experience symptoms as early as their mid-30s.

Although there is a continuous, natural decline in ovarian estrogen production, high levels of estrogen can evolve as the body compensates for the drop in progesterone production as well.


On average, the North American woman will reach natural menopause around age 51. However, as aforementioned, the beginning of the menopausal transition can occur earlier, causing a woman to reach menopause at a younger age.

Menopause is defined as a point in time when a woman has gone 12 consecutive months without a menstrual period. At this time, estrogen levels have been decreasing and fluctuating until menstruation stops.


After menopause, a woman is considered postmenopausal. For decades prior, the ovaries have produced the majority of the body's estradiol. During postmenopause, blood estrogen levels drop dramatically, and much of women's estrogen is derived from converting androgens to estrogen in body fat.

This lack of circulating estrogen triggers a new range of health risks aside from already burdening symptoms. These health risks from postmenopausal estrogen levels include osteoporosis and cardiovascular disease.

Female Reproductive System

The female reproductive system provides several functions. The ovaries produce the egg cells, called the ova or oocytes. The oocytes are then transported to the fallopian tube where fertilization by a sperm may occur. The fertilized egg then moves to the uterus, where the uterine lining has thickened in response to the normal hormones of the reproductive cycle. Once in the uterus, the fertilized egg can implant into thickened uterine lining and continue to develop. If implantation does not take place, the uterine lining is shed as menstrual flow. In addition, the female reproductive system produces female sex hormones that maintain the reproductive cycle.

During menopause, the female reproductive system gradually stops making the female hormones necessary for the reproductive cycle to work. At this point, menstrual cycles can become irregular and eventually stop. One year after menstrual cycles stop, the woman is considered to be menopausal.

What parts make-up the female anatomy?

The female reproductive anatomy includes both external and internal structures.

The function of the external female reproductive structures (the genital) is twofold: To enable sperm to enter the body and to protect the internal genital organs from infectious organisms.

The main external structures of the female reproductive system include:

  • Labia majora: The labia majora (“large lips”) enclose and protect the other external reproductive organs. During puberty, hair growth occurs on the skin of the labia majora, which also contain sweat and oil-secreting glands.
  • Labia minora: The labia minora (“small lips”) can have a variety of sizes and shapes. They lie just inside the labia majora, and surround the openings to the vagina (the canal that joins the lower part of the uterus to the outside of the body) and urethra (the tube that carries urine from the bladder to the outside of the body). This skin is very delicate and can become easily irritated and swollen.
  • Bartholin’s glands: These glands are located next to the vaginal opening on each side and produce a fluid (mucus) secretion.
  • Clitoris: The two labia minora meet at the clitoris, a small, sensitive protrusion that is comparable to the penis in males. The clitoris is covered by a fold of skin, called the prepuce, which is similar to the foreskin at the end of the penis. Like the penis, the clitoris is very sensitive to stimulation and can become erect.

The internal reproductive organs include:

  • Vagina: The vagina is a canal that joins the cervix (the lower part of uterus) to the outside of the body. It also is known as the birth canal.
  • Uterus (womb): The uterus is a hollow, pear-shaped organ that is the home to a developing fetus. The uterus is divided into two parts: the cervix, which is the lower part that opens into the vagina, and the main body of the uterus, called the corpus. The corpus can easily expand to hold a developing baby. A canal through the cervix allows sperm to enter and menstrual blood to exit.
  • Ovaries: The ovaries are small, oval-shaped glands that are located on either side of the uterus. The ovaries produce eggs and hormones.
  • Fallopian tubes: These are narrow tubes that are attached to the upper part of the uterus and serve as pathways for the ova (egg cells) to travel from the ovaries to the uterus. Fertilization of an egg by a sperm normally occurs in the fallopian tubes. The fertilized egg then moves to the uterus, where it implants to the uterine lining.

What happens during the menstrual cycle?

Females of reproductive age (beginning anywhere from 11 to 16 years of age) experience cycles of hormonal activity that repeat at about one-month intervals. Menstru means "monthly” – leading to the term menstrual cycle. With every cycle, a woman’s body prepares for a potential pregnancy, whether or not that is the woman’s intention. The term menstruation refers to the periodic shedding of the uterine lining. Many women call the days that they notice vaginal bleeding their “period,” “menstrual” or cycle.

The average menstrual cycle takes about 28 days and occurs in phases. These phases include:

  • The follicular phase (development of the egg)
  • The ovulatory phase (release of the egg)
  • The luteal phase (hormone levels decrease if the egg does not implant)

There are four major hormones (chemicals that stimulate or regulate the activity of cells or organs) involved in the menstrual cycle. These hormones include:

  • Follicle-stimulating hormone
  • Luteinizing hormone
  • Estrogen
  • Progesterone

Follicular phase

This phase starts on the first day of your period. During the follicular phase of the menstrual cycle, the following events occur:

  • Two hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH) are released from the brain and travel in the blood to the ovaries.
  • The hormones stimulate the growth of about 15 to 20 eggs in the ovaries, each in its own "shell," called a follicle.
  • These hormones (FSH and LH) also trigger an increase in the production of the female hormone estrogen.
  • As estrogen levels rise, like a switch, it turns off the production of follicle-stimulating hormone. This careful balance of hormones allows the body to limit the number of follicles that will prepare eggs to be released.
  • As the follicular phase progresses, one follicle in one ovary becomes dominant and continues to mature. This dominant follicle suppresses all of the other follicles in the group. As a result, they stop growing and die. The dominant follicle continues to produce estrogen.

Ovulatory phase

The ovulatory phase (ovulation) usually starts about 14 days after the follicular phase started, but this can vary. The ovulatory phase falls between the follicular phase and luteal phase. Most women will have a menstrual period 10 to 16 days after ovulation. During this phase, the following events occur:

  • The rise in estrogen from the dominant follicle triggers a surge in the amount of luteinizing hormone that is produced by the brain.
  • This causes the dominant follicle to release its egg from the ovary.
  • As the egg is released (a process called ovulation) it is captured by finger-like projections on the end of the fallopian tubes (fimbriae). The fimbriae sweep the egg into the tube.
  • For one to five days prior to ovulation, many women will notice an increase in egg white cervical mucus. This mucus is the vaginal discharge that helps to capture and nourish sperm on its way to meet the egg for fertilization.

Luteal phase

The luteal phase begins right after ovulation and involves the following processes:

  • Once it releases its egg, the empty ovarian follicle develops into a new structure called the corpus luteum.
  • The corpus luteum secretes the hormones estrogen and progesterone. Progesterone prepares the uterus for a fertilized egg to implant.
  • If intercourse has taken place and a man's sperm has fertilized the egg (a process called conception), the fertilized egg (embryo) will travel through the fallopian tube to implant in the uterus. The woman is now considered pregnant.
  • If the egg is not fertilized, it passes through the uterus. Not needed to support a pregnancy, the lining of the uterus breaks down and sheds, and the next menstrual period begins.

How many eggs does a woman have?

During fetal life, there are about 6 million to 7 million eggs. From this time, no new eggs are produced. At birth, there are approximately 1 million eggs and by the time of puberty, only about 300,000 remain. Of these, only 300 to 400 will be ovulated during a woman's reproductive lifetime. Fertility can drop as a woman ages due to decreasing number and quality of the remaining eggs.

Last reviewed by a Cleveland Clinic medical professional on 01/19/2019.


  • The American College of Obstetricians and Gynecologists. Your Changing Body: Puberty in Girls (Especially for Teens). Accessed 2/5/2019.
  • healthdirect. Female reproductive system. Accessed 2/5/2019.
  • US Department of Health and Human Services, Office on Women's Health. Menopause. Accessed 2/5/2019.
  • Planned Parenthood. Reproductive and Sexual Anatomy. Accessed 2/5/2019.
  • Centers for Disease Control and Prevention. Women's Reproductive Health. Accessed 2/5/2019.
  • Merck Manual. Menstrual Cycle. Accessed 2/5/2019.

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Ob/Gyn & Women's Health Institute

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Diseases & conditions

Most ovarian problems are caused by cysts. Ovarian cysts, growths on the ovaries, are common and most women will get them at least once, according to the Mayo Clinic. Most women don't even know when they have one because typically they are not painful or anything to worry about.

Polycystic ovary syndrome (PCOS) is an ailment defined by multiple cysts growing on the outer edge of the ovaries due to a lack of hormones that allow an egg to be released from the follicle. This disorder can lead to infertility and other serious complications such as heart disease, diabetes or stroke.

Sometimes a cyst will become cancerous. One in 75 women will develop ovarian cancer, according to the American Cancer Society. There are current tests that can help detect a woman's likelihood of developing ovarian cancer. In some cases, women choose to remove their ovaries as a precautionary measure.

"If you have your ovaries removed due to certain hereditary cancer screening results such as BRCA, then we also remove your fallopian tubes because you can also get cancer from your fallopian tubes," said Dr. Sarah Yamaguchi, an OB/GYN at Good Samaritan Hospital in Los Angeles, California. "However, even with that done, you can still get primary peritoneal cancer which is very similar to ovarian cancer."

Blood estrogen levels and breast cancer after menopause

Studies have shown postmenopausal women with higher blood levels of the estrogen estradiol have an increased risk of breast cancer [19,59-61].

A pooled analysis of data from 9 studies found the risk of breast cancer was twice as high among women with higher levels of estradiol compared to women with lower levels [19].

Health care providers don’t use blood estrogen levels to assess breast cancer risk. However, this measure may be useful in the future [63-65].

Certain factors may increase breast cancer risk by affecting estrogen levels.

Body weight is an important example. Estrogen is produced in fat tissue. In general, higher weight means more fat tissue and higher estrogen levels. This likely explains, at least in part, the increased breast cancer risk in women who are heavy after menopause.

Concluding Remarks and Future Perspectives

It is evident that, although for some phenotypes discussed in this review (such as age at menarche and menopause) GWAS have been true success stories, for others (PCOS, POI, ovarian reserve and response) the best is yet to come. The studies conducted so far have shown that some findings will support what is previously known or suspected (such as the involvement of DNA repair mechanisms in ovarian aging, or the importance of neuroendocrine mechanisms in PCOS susceptibility), while others will prompt new investigations. As analytical methods for finding causative genes or biological context improve, so will our knowledge on the genetics governing ovarian physiology. However, functional studies for validating the GWAS findings and for understanding how associated variants modify biological mechanisms largely remain an untouched territory in the context of ovarian biology.

While many gaps in our knowledge remain (see Outstanding Questions), we hope that new and innovative approaches to study design, valuable lessons from other phenotypes, and close collaboration between clinicians and scientists will pave the way for new discoveries and, more importantly, for novel means to harness GWAS findings on ovarian function for the benefit of the patients.

Outstanding Questions

How exactly are reproductive aging, ovarian reserve and ovarian disorders related at a genetic level? Can well-designed GWAS in phenotypes where this approach has not been used successfully, together with analytical methods for assessing genetic correlations, provide a sufficient answer?

How do the identified genetic associations exert their biological effects on these traits and conditions? Gene expression, methylation, and protein level datasets for follicular cell subpopulations, ovarian stromal cells, or even oocytes may complement our knowledge on how genetic variation modifies gene expression in ovarian tissue.

How can the findings from GWAS be successfully translated to individualizing healthcare in prevention, early diagnosis, and treatment?


Large population-based biobanks can be harnessed for genetic studies in ovary-related phenotypes to take research efforts to the next level.

New analytical methods that use GWAS summary statistics can be used to identify the most likely causal genes, pathways, underlying mechanisms, genetic correlations, and causal relationships between phenotypes.

There is significant genetic overlap between traits and disorders reflecting ovarian function, such as age at natural menopause, polycystic ovary syndrome, and premature ovarian insufficiency.

Results from large-scale genetic association studies can provide information for more personalized patient management.