Tests of Pituitary Function: Gonadotropins in Women

From Lewis Blevins MD –  LH and FSH are produced by the pituitary gland under the regulation of pulsatile secretion of GnRH from the hypothalamus. LH stimulates the thecal cells around a developing egg in the ovary to produce testosterone. Testosterone is then shuttled into the follicular cells surrounding the egg which, in response to FSH, converts it to and then secretes estradiol, the primary estrogen in women. Estradiol is “measured” by and thus regulated by the hypothalamus and pituitary gland. FSH stimulates the follicular cells to Sertoli cells to do a number of important things including the recruitment of eggs and the production of a number of different proteins including follistatin, activin, and inhibin. Inhibin acts on the pituitary to inhibit FSH secretion. In general, estradiol inhibits FSH. However, in the first half of the cycle, estradiol stimulates LH secretion and leads to a mid-cycle LH surge that causes ovulation. After ovulation, the follicular cells that were nursing the egg turn into the corpus luteum and make progesterone. When a pregnancy occurs, the placenta makes hCG that maintains the corpus luteum and progesterone secretion. If pregnancy does not occur the corpus luteum dies and forms a scar. Estradiol builds then primes the uterine lining to set it up for pregnancy. Progesterone makes further important changes to prepare for implantation of a fertilized egg. When the corpus luteum dies the withdrawal of progesterone causes the uterine lining to break down and a period to start. 

The life of a corpus luteum is about 14 days. That time frame is fairly consistent from one woman to the next. So, if a pregnancy does not take place, menses will usually occur 14 days after ovulation. This is the case unless there is a luteal phase defect. The most common cause of a luteal phase defect is hyperprolactinemia. Progesterone elevates the woman’s basal body temperature by about 0.5 F. Thus, charts of basal body temperature, employing a special thermometer, can be used to determine ovulation so that intercourse can be timed in those desiring pregnancy. Estrogens also cause changes in cervical secretions and mucus that can be used to assess the adequacy of FSH ad estradiol production. The vaginal cells also become granular when exposed to estrogens and evaluating them under the microscope can provide a quick biological assessment of estradiol effect. There are test kits to detect the mid-cycle surge in LH.

The developing ovary has about 4 million potential eggs. Most of these are lost by the time a girl starts puberty at which time there are about 400,000 eggs in her ovaries. Some of these eggs die off without ever being brought to the brink of ovulation. Every month there are 2-4 eggs nursed to the brink of ovulation but only one will ovulate. The rest will resolve in a process known as atresia. Assuming a fertility span from 13 to 51 years this means, without pregnancy, the average woman will ovulate about 456 times in her life. Thus, only about 0.01 percent of the eggs in the fetal ovaries will ever be fully prepped for fertilization. It seems like a huge waste of genetic material yet this process guarantees that only the best eggs will ever be potentially fertilized. It is clear that the longer eggs sit in the ovaries the greater the likelihood of chromosomal defects acquired during the process of meiosis. Thus, the risk of Down syndrome and other chromosomal disorders is much greater in older mothers than in younger ones.

Estrogen circulates as a free molecule but most of it is bound to proteins, sex-hormone binding globulin (SHBG) and albumin. Obesity and some liver diseases can lower SHBG and thus total estrogen levels.

Fertility is a complicated topic. Suffice it to say that normal regular menses and an appropriate rise in basal body temperature 14 days before menses indicate normal function of the hypothalamic-pituitary-ovarian-uterine axis. Studies should be done to check for uterine abnormalities, anti-sperm antibodies, and other factors in women who appear otherwise normal in regards to hormone function and responses.

I do not routinely measure gonadotropin or estrogen levels in women who have regular and otherwise normal menses. If, however, one chooses to measure these then they are best done 5-7 days after the onset of menses. Conversely, LH, FSH, Estradiol, and Progesterone can be done 21-24 days after onset of menses if one wishes to confirm that ovulation did indeed occur as progesterone levels should be appropriate for the luteal phase of the cycle.

The progesterone withdrawal test is occasionally used in women who have no menses but who do have symptoms and signs suggesting they do have estrogen production. In this situation, progestins are prescribed for 10 days to attempt to convert the uterine lining. Then, the drug is withheld. A woman who makes sufficient estrogens, such as those with polycystic ovary syndrome or some women with a luteal phase defect, will have onset of menses 5 to 7 days after the progestin has been discontinued.

Women with ovarian failure will have low or undetectable estrogen levels along with elevations in LH and FSH. These women are said to have “primary hypogonadism.” Causes include Turner syndrome, ovarian resection, infections (mumps), chemotherapy, etc.

The average age of “natural” ovarian failure or menopause is 51 years. A number of illnesses and other disease processes, including those mentioned, and even a history of hysterectomy with the ovaries left in place, can lead to early menopause. Menopause is considered “normal” if it occurs after age 40. Earlier menopause due to ovarian failure should prompt evaluation of certain rare genetic disorders.

Most women of menopausal age have elevations in LH and FSH. Levels are usually greater than 50 mIU/mL. In a menopausal woman, measurement of the LH and FSH levels, which should be elevated, can serve as an indicator or inference of pituitary function. Of course, those with gonadotropin-secreting adenomas may have menopausal levels of LH and FSH. The clue that some of these women may a gonadotropin-secreting adenoma is that the tumor will have caused have other pituitary hormone deficiencies and yet the gonadotropins are elevated, a situation that is distinctly unusual in menopausal-aged women with hypopituitarism.

Another thing to keep in mind is that, in menopause, the pituitary is called upon to secrete large amounts of LH and FSH. It is simply trying to stimulate the ovaries not really understanding that they have failed due to age. The cells that produce LH and FSH increase in size and number. This can lead to pituitary enlargement and a situation we call pituitary hyperplasia. Sometimes, this process can cause headaches and, rarely, it can lead to visual field abnormalities. The LH and FSH levels are usually profoundly elevated. Normal levels are up to 20 mIU/mL. I’ve seen levels, on average, in pituitary hyperplasia of about 100-125 mIU/mL with the highest levels I can recall at about 185 mIU/mL!

Some reproductive age women with gonadotropin-producing pituitary adenomas will have elevations in LH and/or FSH with low estrogen levels because the gonadotropins do not work and the tumor compromises normal LH and FSH production by the remaining normal pituitary gland. Rarely, a woman will have elevations in estradiol when the gonadotropins do work in the setting of a gonadotropin-producing pituitary adenoma.

Women taking estrogens in high doses, such as oral contraceptives, will usually have suppressed LH and FSH levels. That’s how the estrogens and progestins in contraceptives work! The suppression can last 3-6 months after discontinuing birth control pills. A lack of menses for more than 6 months after discontinuation should prompt an evaluation for hyperprolactinemia. Of course, high dose estrogens can cause growth of prolactinomas.

Most patients with hypothalamic or pituitary dysfunction will have low or low-normal LH and FSH levels in the setting of low or low-normal estradiol levels. They usually are not ovulating and have no menses or menses that occur only a few times per year that are characterized as “spotting.” These women are said to have “central hypogonadism.” Causes include a myriad of pituitary and hypothalamic disorders, Kallman’s syndrome, septo-optic dysplasia, etc.

Hyperprolactinemia disrupts the cyclical and periodic secretion of GnRH from the hypothalamus and can shut down LH and FSH production causing a variety of disorders including simple infertility in the setting of “normal” menses, irregular menses due to a luteal phase defect, and complete cessation of menses with low estrogen levels. LH and FSH levels may be inappropriately normal or low in the setting of a low or low-normal estradiol.

Foto: Face by Andrew Morrell

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