Reproductive Endocrinology

GYN Development

From fetal life to 4 years of age many changes happen. The fetus is subjected to high intrauterine follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the mother, which peaks at 20 weeks gestation and then decreases until birth.

FSH and LH increase again from birth until 6 months of age, then gradually decrease until age 4.

As a result of the increased FSH and LH during fetal life, all oocytes are formed and partially matured by 20 weeks’ gestation.

The increase of FSH and LH until 6 months of age and gradual decrease until age 4 is responsible for Tanner stage 1 characteristics (described in detail below).

Gynecologic development refers to the reproductive changes that are driven by levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

The general order of events of normal female puberty proceed in the following order:

• Thelarche (the appearance of breast tissue)

• Adrenarche (adrenal androgen production)

• Pubarche (the appearance of pubic hair)

• Growth spurt

• Menarche (the onset of menses)

The mean age of menarche in the United States is 13 years (range 11-17 years). It occurs earlier in African Americans than Caucasians.

Females typically begin puberty one year before males at a mean age of 10.5 years as opposed to a mean age of 11.5 years for males.

The appearance of female secondary sexual characteristics are caused by estrogen.

From 4-8 years of age, there are low FSH, LH, and estrogen levels caused by GnRH suppression. This age range is also characterized by Tanner stage 1 characteristics.

Any sexual development that occurs during this age range is considered precocious, which is covered in more detail in the Precocious Puberty topic.

From 8-11 years of age, LH, FSH, and estrogen levels begin to increase.

This time period is marked by initial pubertal changes, which includes early breast development and pubic and axillary hair growth.

From 11-17 years of age, levels of LH, FSH, and estrogen rise to baseline mature levels of hormones.

Active puberty occurs during this time (age 11-17), and includes a growth spurt; progression through the Tanner stages is noted.

From 17-50 years of age, LH and FSH follow the menstrual cycle and there is a gradual increase in FSH and LH with ovarian insensitivity. This period is characterized by menstrual cycles and mature sexual characteristics (Tanner stage 5).

After age 50, LH and FSH levels increase with onset of ovarian failure progressing from perimenopause to menopause.

Perimenopause describes menstrual cycles becoming inconsistent, resulting in oligomenorrhea. More detail is provided in the Menopause topic.

Tanner Staging

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The Tanner staging system describes physical development based on external primary and secondary sexual characteristics.

Tanner stage 1 is prepubertal, characterized by breast development of only a papilla (nipple) and no pubic hair development.

During Tanner stage 2 there is breast budding with areolar enlargement and slight growth of fine labial hair.

During Tanner stage 3 there is further breast and areolar enlargement and further growth of pubic hair.

During Tanner stage 4 there is further breast enlargement with the areola and papilla forming a second growth above the level of the breast. The pubic hair becomes more coarse and spreads over much of the pubic region.

Tanner stage 5 is characterized by mature breast, where the areola recedes to the level of breast while the papilla remains extended. Pubic hair in this stage is coarse and extends from pubic region to medial thighs.

Primary Amenorrhea

Primary amenorrhea is defined as the

• absence of menses by age 15 in a patient with secondary sexual characteristics, or

• absence of both menses and secondary sexual characteristics by age 13.

The causes of primary amenorrhea can be grouped into the following categories:

• Hypothalamic and pituitary disease

  • Constitutional delay of puberty (cause of 14% of primary amenorrhea)

  • Functional hypothalamic amenorrhea

  • Isolated GnRH deficiency

  • Hyperprolactinemia

• Gonadal dysgenesis/Primary ovarian insufficiency (POI)

  • Turner syndrome (cause of 43% of primary amenorrhea)

  • 46, XY gonadal dysgenesis

  • POI

• Polycystic ovary syndrome (cause of 7% of primary amenorrhea)

• Outflow tract disorders

  • Müllerian agenesis (cause of 15% of primary amenorrhea)

  • Transverse vaginal septum (cause of 3% of primary amenorrhea)

  • Imperforate hymen

• Receptor abnormalities and enzyme deficiencies

  • Complete androgen insensitivity syndrome

  • 5-alpha-reductase deficiency

  • 17-alpha-hydroxylase deficiency

Note: The incidence is less than 5% if not stated.

Patients with normal secondary sexual characteristics but no menses by age 15 (or within 3 years of thelarche) have normal estrogen, indicating normal hypothalamic-pituitary-ovarian function, but a problem elsewhere.

Anatomic abnormalities include Mullerian agenesis (such as a blind-ending vagina), an imperforate hymen, or transverse vaginal septum.

In complete androgen insensitivity patients are genetically male and have testes, but lack testosterone receptors. Testosterone is converted to estrogen, leading to breast development. These patients lack pubic hair and have no uterus.

In the diagnosis of primary amenorrhea, if pregnancy has been ruled out then look for secondary sexual characteristics.

If female secondary sexual characteristics are present, perform

• a physical exam and ultrasound to look for anatomical abnormalities

• and a genetic analysis for XY genotype (androgen insensitivity).

If a uterus is present but secondary sexual characteristics are not present, check FSH and prolactin.

If a uterus is present and FSH is high, suspect:

• gonadal agenesis

• gonadal dysgenesis, or

• ovarian failure

• aromatase deficiency (tall stature, history of ambiguous external genitalia)

If FSH is low, suspect chronic anovulation including:

• Functional hypogonadotropic hypogonadism (stress, exercise)

• Kallman's syndrome

• PCOS (more commonly a cause of secondary amenorrhea, but it has been described as a cause of primary amenorrhea)

If a uterus is present and prolactin is high, rule out reversible causes (such as medications), then order a pituitary MRI to rule out prolactinoma.

Treatment of primary amenorrhea should induce menarche, or treat factors preventing menarche:

• Constitutional growth delay requires no treatment.

• Anatomic abnormalities may require surgical intervention.

• Hypogonadism/ovarian failure can be treated with hormone replacement with low-dose estrogen.

Secondary Amenorrhea

Secondary amenorrhea is defined as 6 months without menses in a woman who has passed menarche.

Note: While some sources only require 3 months without menses to diagnose amenorrhea, the American College of Obstetricians and Gynecologists uses the definition above.

In the diagnosis of secondary amenorrhea, if pregnancy has been ruled out, check:

• Thyroid function (TSH)

• Prolactin

Note: Some sources suggest testing for ovarian function (FSH) at this time, while others advocate checking FSH only if another cause cannot be found, or if the patient's history suggests ovarian failure. We will discuss both algorithms.

If thyroid function and prolactin are normal, perform a progestin challenge.

If a progestin challenge is positive (bleeding upon withdrawal of progestin), this indicates that there is adequate estrogen (so the endometrium grows), but no ovulation and thus no corpus luteum to secrete progesterone. In other words, it means there is anovulation despite adequate estrogen.

If hirsutism is present in a patient with secondary amenorrhea and a positive progestin challenge (i.e. adequate estrogen but anovulation), suspect:

• Polycystic ovarian syndrome

• Ovarian or adrenal tumor

• Cushing syndrome

If the progestin challenge test is negative, this indicates that the cause is:

• Inadequate estrogen (hypothalamic failure, hypogonadism, stress, etc) OR

• Anatomic outflow tract obstruction

If a progestin challenge is negative, administer an estrogen-progesterone challenge.

If the estrogen-progesterone challenge is negative, suspect Asherman syndrome (intrauterine adhesions, usually resulting from excessively vigorous instrumentation of the uterus) or an anatomic outflow tract obstruction.

Remember that, while Asherman syndrome is described as a complication of dilation and curettage procedures (D&Cs), Asherman syndrome is rare even in patients who have undergone multiple D&Cs.

If the progesterone challenge is negative but the estrogen-progesterone challenge is positive, this indicates inadequate estrogen. If not already performed, check an FSH level.

If FSH levels are high, suspect ovarian failure and perform a karyotype (47XXX or 45XO karyotype may lead to normal menarche with accelerated ovarian failure by age 20).

If FSH levels are low, suspect hypothalamic-pituitary dysfunction.

Investigate lifestyle causes (eating disorder, exercise) and, if none are apparent, order apituitary MRI (Kallmann syndrome vs. pituitary adenoma vs pituitary necrosis).

If FSH levels are normal, check:

• Testosterone (ovarian tumor vs polycystic ovaries)

• DHEAS (adrenal tumor vs polycystic ovaries)

• 17-OH progesterone (congenital adrenal hyperplasia)

Hypothalamic-pituitary dysfunction should be treated with GnRH or gonadotropin replacement in patients who are attempting to conceive.

Estrogen replacement prevents osteoporosis, and should be combined with progesterone to prevent endometrial hyperplasia.

Possible acquired causes (eating disorders, excessive exercise, etc) should be investigated, and treated if present.

Premature ovarian failure should be treated with estrogen and progesterone replacement.

Prolactinomas should be treated with surgical removal or with dopamine agonists.

Behavior modification should be considered for patients that have amenorrhea due to eating disorders, excessive exercise, or obesity.

Asherman syndrome can be treated with estrogen and lysis of adhesions.

Thyroid dysfunction and Cushing causing amenorrhea should be treated according to the specific pathology. For more information on the treatment of thyroid dysfunction and Cushing's syndrome, see the following topics:

• Hashimoto's thyroiditis

• Hyperthyroidism

• Cushing's syndrome

• ACTH-Dependent Cushing's Syndrome

• ACTH-Independent Cushing's Syndrome

Female Infertility

A diagnostic evaluation for infertility should be initiated in female patients under age 35 who fail to conceive after 12 months of regular unprotected intercourse.

Infertility evaluation may be initiated sooner in patients at increased risk for infertility, including:

• age > 35 years (evaluate after 6 months of infertility)

• history of oligomenorrhea or amenorrhea

• known or suspected uterine, tubal, or peritoneal disease (including advanced endometriosis)

• decreased fertility in the male partner

Bear in mind that this means that an evaluation for infertility is indicated in up to 15% of patients, since 85% of patients are expected to conceive within the first year (see Family Planning Overview for more information).

When possible, the male and female partners should be evaluated at the same time.

Ovulatory dysfunction is responsible for approximately 40% of female infertility, making it the most common cause of infertility.

The most common cause of ovulatory dysfunction is polycystic ovarian syndrome.

Ovarian reserve (future reproductive potential as a function of the number and quality of remaining oocytes) is most commonly evaluated with

• serum FSH and estradiol, drawn on cycle day 3 (the third day after onset of menses)

• antral follicle count by transvaginal ultrasound

• serum AMH level

**Note: In the past, the clomiphene citrate challenge test was used to evaluate ovarian reserve. This test has been supplanted in clinical practice by the serum tests named above.

Ultrasound (especially 3-D ultrasound and saline infusion sonography) and MRI may be used to exclude uterine anatomic abnormalities, including leiomyomas and unicornuate/bicornuate/etc uterus.

Hysterosalpingography (HSG) is used to define the shape of the uterine cavity and to ensure patency of the fallopian tubes.

In addition to the usual medical history (past medical history, surgical history, medications, allergies), the history of a patient with suspected infertility should include:

• Duration of infertility

• Previous infertility treatments

• Menstrual history (menarche/cycle length/duration of menses)

• Pregnancy history

• Coital history

• Previous methods of contraception

• Past medical history (with attention to endocrine diseases, pelvic diseases, and pelvic surgeries)

• Previous abnormal Pap smears

Physical examination should aim to rule out major causes of infertility (PCOS, thyroid disease, prolactinoma) and should include:

• Body mass index

• Thyroid exam

• Breast exam

• Signs of androgen excess (hirsutism, virilization, acne)

• Pelvic exam

PCOS

Polycystic Ovarian Syndrome (PCOS), also known as Stein-Leventhal syndrome, is a hypothalamic-pituitary disease that results in enlarged, polycystic ovaries and chronic anovulation, which leads to elevated estrogen and androgen production and atypical follicle development.

The pathogenesis is poorly understood. It is thought that high amplitude GnRH pulses, cause increased pituitary LH leading to ovarian (theca interna) androgen synthesis and increased androgen aromatization to estrogens in adipose tissue.

In patients with PCOS, the ovaries are hypersensitive to insulin. Insulin stimulates the ovarian theca cells to secrete androgens, while inhibiting hepatic sex-hormone binding globulin. The result is increased free androgens.

The classic presentation of polycystic ovarian syndrome is an overweight young woman presenting with:

• Oligomenorrhea

• Hirsutism

• Virilism

• Infertility

• Acne

• Insulin resistance (seen in 50-70% of women with PCOS)

Decreased FSH leads to follicular degeneration with fluid-filled cyst formation (hence polycystic). Bilateral ovarian enlargement may be found on bimanual examination.

Menstrual dysfunction due to PCOS manifests as amenorrhea, oligomenorrhea, and breakthrough bleeding, which are all the result of anovulation.

Diagnosis of polycystic ovarian syndrome requires at least two of the following (Rotterdam criteria):

• Anovulation

• Excess androgens

• Polycystic ovaries (12 or more cysts per ovary)

Laboratory findings associated with PCOS include:

• Classically LH:FSH ratio > 3, but often just LH > FSH

• Increased DHEA

• Increased androstenedione

• Positive progestin challenge

It is important to note that 17-OH progesterone is normal, and can be used to differentiate from atypical congenital adrenal hyperplasia, which presents with similar clinical symptoms in young adult females.

Ultrasound findings associated with PCOS include enlarged ovaries with 12 or more follicles per ovary.

Complications of PCOS include:

• Increased risk of endometrial cancer, due to increased estrogen

• Infertility due to anovulation

• Increased risk of diabetes mellitus type II

• Hypertension and ischemic heart diseasebecause of the high prevalence of obesity and insulin resistance

• Ovarian torsion because of enlarged ovaries

Note: Some studies have also shown an increased risk of breast cancer.

Oral contraceptives and continuous progestins such as the levonorgestrel (mirena) IUD and etonogestrel (nexplanon) implant can be used to decrease endometrial proliferation and, thus, decrease the risk of endometrial cancer. ALL patients with PCOS who are not currently trying to conceive should be treated with oral contraceptives or continuous progestins.

Exercise and weight loss are recommended for patients with PCOS to address insulin resistance and associated obesity.

Progestin alone for 7 days each month can induce bleeding and prevent endometrial hyperplasia.

Spironolactone has antiandrogen effects, which can be used to treat hirsutism if oral contraceptives alone do not resolve the symptoms. Note: spironolactone must be stopped during pregnancy due to the risk of antiandrogenic effects in a male fetus.

Clomiphene is an antiestrogen, which will induce follicle growth and maturation (and thus ovulation) by preventing negative feedback of estrogen on FSH. Letrozole (Femara) is also used.

Metformin can help facilitate weight loss, improve cholesterol, reduce blood pressure, and reduce cardiovascular risk in patients with insulin resistance. Some women have shown to start ovulating with the use of metformin alone.

Statins can be considered if lipids and testosterone levels need to be lowered.

Antibiotics can be used to treat acne associated with PCOS.