Reproduction I: Gonadal Function

Question 1

Follicular phase of menstrual cycle

Answer 1

Ovarian follicles are recruited and developed, and this phase ends with the ovulation of a single mature ovum

Question 2

Luteal phase of the menstrual cycle

Answer 2

Progesterone produced by the corpus luteum (the remnants of the ovulated follicle) differentiates the uterine endometrium to prepare it for implantation of the (hopefully) fertilized ovum.

Question 3

Management of ovarian follicles

Answer 3

About 1-2 million ovarian follicles are present at birth, and this number decreases over the lifetime as follicles continuously undergo atresia (degeneration).

About 300,000 follicles remain by the time puberty begins, and when the supply of follicles is exhausted (roughly around age 50), menopause ensues.

Only about 400-500 follicles are ovulated in the average functional lifespan of the ovaries.

Question 4

Menstrual cycle diagram

Answer 4

Question 5

By definition, the follicular phase of each menstrual cycle begins . . .

Answer 5

By definition, the follicular phase of each menstrual cycle begins on the first full day of menstrual bleeding

This is set as day 1.

Question 6

Selection of the “dominant follicle”

Answer 6

As FSH and LH levels rise in the early follicular phase, the largest developing follicle emerges as the dominant follicle, producing larger amounts of estradiol, which feeds back to slightly suppress gonadotropin secretion toward the mid-follicular phase.

The dominant follicle also secretes inhibin B, which further suppresses FSH. The lack of FSH then causes atresia of all the non-dominant follicles that were activated.

However, the dominant follicle continues to grow and mature, partly because it increases expression of the FSH receptor, which allows it to continue developing and avoid atresia even in the face of lower FSH levels.

Question 7

Effects of estradiol on the endometrium

Answer 7

In the uterus, estradiol causes the endometrium to proliferate. As estradiol levels rise through the follicular phase, the endometrium proliferates and thickens in anticipation of implantation

Question 8

Ovulation

Answer 8

• Occurs about 36 hours after the beginning of the LH surge.
• The follicle ruptures through the outer capsule of the ovary and the ovum is released into the pelvic cavity, where it is taken up into the fallopian tubes
• Fertilization occurs in the distal 1/3 of the fallopian tube
• If the ovum is not fertilized within 24 hours after ovulation, it degenerates

Question 9

“Fertile period”

Answer 9

Sperm can live in the receiving reproductive organs (vagina, uterus, fallopian tubes) for 3-5 days

Thus, the 5 days preceding ovulation is the “fertile period” in which intercourse is most likely to lead to conception.

Question 10

Progesterone in the luteal phase

Answer 10

Progesterone is required for implantation and for maintenance of a pregnancy because it causes the now-thickened endometrium to mature and differentiate, inducing the in-growth of spiral arteries to provide circulation to an implanted embryo

This comes from the corpus luteum during the luteal phase, until the corpus decays. At this point, withdrawal of progesterone will initiate the beginning of menses, unless implantation of a fertilized ovum leads to hCG production which may rescue the endometrium from shedding and initiate pregnancy.

Question 11

The length of a menstrual cycle is counted from. . .

Answer 11

. . . the first day of bleeding of one period to the first day of bleeding of the next period

Question 12

“Normal” menstrual cycle lengths

Answer 12

• 24-35 days, but cycle length varies both among and within individuals
• Because the finite life span of the corpus luteum is relatively fixed, the luteal phase is quite consistent at about 14 days in most normal cycles.
• Variation in cycle length is mostly due to the variable duration of the follicular phase

Question 13

Moliminal symptoms

Answer 13

Symptoms of weight gain, mood changes, and acne preceding menses due to progesterone from the corpus luteum, as well as uterine cramping, which is caused by progesterone withdrawal.

Their presence indicates an ovulatory cycle with corpus luteum formation.

Question 14

The inclusion of progestin in combined hormonal contraception is important to avoid. . .

Answer 14

. . . prolonged exposure of the endometrium to estrogen alone.

Without the maturing effect of progestin and the periodic shedding induced by progestin withdrawal, continuous exposure to unopposed estrogen increases the risk of endometrial hyperplasia and carcinoma

Question 15

Progrestin-only contraception

Answer 15

• Can be given for those who have contraindications to estrogen
• As effective as combined OCPs and are taken continuously without a placebo week
• Can also be given as a depot injection every three months or as a subcutaneous implant
• Risks: There is a significant incidence of breakthrough bleeding, and prolonged treatment with progestin-only contraception may result in complications of estrogen deficiency such as low bone density (due to gonadotropin suppression)

Question 16

Levonorgestrel

Answer 16

• Given after intercourse to prevent unwanted pregnancy
• The most common form is the progestin levonorgestrel
• Works by feeding back to suppress LH at the pituitary level, preventing the LH surge that is required for ovulation
• Only effective if taken within 3 days of intercourse
• Prevents about 50% of pregnancies that might otherwise occur, IT IS NOT A GAURANTEE

Question 17

Emergency contraception

Answer 17

• Levonorgestrel
• Mifepristone

Question 18

Mifepristone

Answer 18

• Progesterone receptor antagonist
• When used after pregnancy is established, mifepristone can induce abortion by blocking the action of progesterone required to maintain the pregnancy
• When used prior to pregnancy establishment, mifepristone can also preventing ovulation and conception
• This tends to be the more controvertial form of contraception

Question 19

Intrauterine devices

Answer 19

• Small devices made of either copper or progestin-eluting plastic that are placed inside the uterus to provide long-term contraception.
• Create an inflammatory response in the uterus that suppresses the endometrium, thereby preventing fertilization and implantation
• IUDs are >99% effective in preventing pregnancy.
• Normal structure and function of the endometrium returns about a month after an IUD is removed

Question 20

Menopause can essentially be thought of as a form of . . .

Answer 20

. . . primary hypogonadism

Question 21

Onset of menopause

Answer 21

• Occurs between ages 40 and 58, average ~51
• Menses often become irregular in the months or years leading up
• Falling estradiol levels lead to symptoms of estrogen deficiency: Hot flashes, vaginal atrophy causing discomfort, dryness, or pain with intercourse; bone loss leading to osteroporosis, increased risk of cardiovascular disease.

Question 22

Treating menopause

Answer 22

• HRT with estradiol +/- progestin (depending on if the individual still has a uterus)
  
  • Effective for treating hot flashes and vaginal atrophy, and for reducing bone loss and decreasing fracture risk
  • However, HRT does not decrease cardiovascular risk, and it appears to increase the risk of stroke and thromboembolism.
  • HRT may be used cautiously for up to several years to treat menopausal symptoms, but long-term HRT is generally not recommended

Question 23

Oligomenorrhea

Answer 23

• Menses less frequent than normal
• Cycles longer than 35 days, or fewer than 9 cycles per year

Question 24

Amenorrhea

Answer 24

• Primary amenorrhea: Not beginning menstruation
• Secondary amenorrhea: Loss of periods after previously having them

Question 25

Most common cause of secondary amenorrhea

Answer 25

Pregnancy, of course

Question 26

Anatomic causes of amenorrhea

Answer 26

* Abnormalities of the uterus and its outflow tract may prevent menstrual flow * Malformations of any part of the fetal müllerian system (including the **uterus, cervix, or upper vagina**), **vaginal webs or septae**, or an **imperforate hymen** * If the obstruction is distal, patients may present with **cyclic abdominal/pelvic body** due to **distention of the uterus and fallopian tubes by retained menstrual blood** * Most anatomic causes are **congenital and cause primary amenorrhea** * **Asherman's syndrome** is secondary amenorrhea due to endometrial scarring and adhesions

Question 27

Anovulation

Answer 27

* **If ovulation does not occur** in a given cycle, **no corpus luteum forms**, and therefore there is **no progesterone withdrawal** and no coordinated shedding of the endometrium * Chronic anovulation is a common cause of amenorrhea. Anovulation can cause **either primary or secondary amenorrhea.** * Anovulation may be secondary to **hypogonadism, hyperandrosteronism** (and thus inhibition of central LH/FSH secretion), **or polycystic ovarian syndrome**

Question 28

Diagnosing PCOS

Answer 28

Question 29

Polcystic ovarian syndrome

Answer 29

* Affects **6-8%** of those born w/ female biological sex * Clinically a syndrome of **hyperandrogenism, oligo- or anovulation, and multiple ovarian cysts** * Insulin resistance also a component, and inviduals are at **higher risk for the metabolic syndrome** including obesity, hypertension, and dyslipidemia. * **Often have high estrogen,** almost never have low estradiol

Question 30

Clinical syndorme of hyperandrogenism

Answer 30

* Hirsutism (excess body hair) * Acne

Question 31

Workup for anovulation

Answer 31

* **Pregnancy must always be excluded** * Evaluation of **LH, FSH, estradiol** * Evaluation of common causes of disruption to this pathway: **prolactin, TSH** * If clinical signs of hyperandrogenism, **testosterone** * **Pelvic ultrasound** may diagose or exclude PCOS * **If primary, workup for congenital anatomic cause** (unnecessary for secondary unless indicated by something like Crohn's) * **Progestin withdrawal test**

Question 32

Progestin withdrawal test

Answer 32

* Useful to distinguish causes of decreased uterine bleeding * **Administer medroxyprogesterone for 5-10 days, then withdraw and see if menses ensues** * This test is basically an **assay for functional estradiol pathways** * **If estradiol levels are normal or high** (e.g., PCOS), the proliferating endometrium is stabilized and differentiated by the progestin and **withdrawal will enduce menses** * **If estradiol levels are low or estradiol is nonfunctional**, there is nothing to shed when the progestin is withdrawn, so **no bleeding is observed** * **Also tests the patency** of the genital tract

Question 33

Treatment of amenorrhea and oligomenorrhea

Answer 33

* Treatment of underlying cause * For **primary hypogonadism or irremediable secondary hypogonadism** (like Kallmann syndrome), treatment consists of **HRT with cyclic variation**, Oral contraceptive works for this purpose in those who have secondary amenorrhea * Treatment for PCOS is more involved and warrants its own discussion

Question 34

Treating PCOS

Answer 34

* Goals of treatment are to **decrease hyperandrogenism** and to **prevent the long-term risk of endometrial hyperplasia** from estrogen exposure, as well as **preventing development of the metabolic syndrome** * **Combined hormonal contraception** works to decrease hyperandrogenism by 1) **suppressing LH,** 2) **increasing levels of SHBG,** 3) **inhibition of GnRH-stimulated LH secretion**, and 4) **induction of cyclie menses preventing hyperplasia** (1 and 2 are estradiol effects, 3 and 4 are progestin effects) * **Exercise and weight loss** critical due to insulin resistance aspect * **Metformin** * **Spironolactone** used as anti-androgen * **Clomiphene or letrozole** can induce ovulation if individual plans on becoming pregnant

Question 35

Sex hormone binding globulin (SHBG)

Answer 35

* Stable binding partner and transport protein for sex hormones within the plasma * Elevation in this protein can decrease the effective activity of sex hormones

Question 36

Spironolactone as an anti-androgen

Answer 36

In addition to working as a mineralocorticoid receptor antagonist, spironolactone can work as a androgen receptor antagoist It is usually used in conjunction with OCPs for the treatment of hyperandrogenic symptoms, particularly hirsutism

Question 37

Inducing fertility in individuals with PCOS

Answer 37

* Fertility in those with PCOS is reduced largely because **low FSH levels are insufficient to recruit and develop follicles for ovulation** * **Clomiphene** (a selective estrogen receptor antagonist) or **letrozole** (an aromatase inhibitor) can induce ovulation in those with PCOS by decreasing the negative feedback of estradiol on FSH, **raising FSH level** * A potential side effect is an **increased risk of multiple gestation** if multiple follicles are ovulated and fertilized.

Question 38

Abnormal (or disordered) uterine bleeding

Answer 38

* Menstrual bleeding that is excessive in frequency (7 days), or volume * May be caused by **pregnancy, endometrial hyperplasia, coagulation disorders, or uterine neoplasms** * Always remember to address the possibility that the blood is not originating from the uterus -- bleeding can occur at any point in the genital tract, including the external genitalia, vagina, cervix, uterus, and fallopian tubes

Question 39

Endometrial hyperplasia

Answer 39

* Occurs when the endometrium is exposed to **excessive estradiol without adequate progesterone** * Conditions include **PCOS**, use of **estrogen-only hormone replacement**, or **estrogenomas** * Endometrium proliferates excessively and may become structurally unstable, causing unpredictable endometrial sloughing (“**overflow bleeding**") * Chronic endometrial hyperplasia may give rise to an endometrial carcinoma.

Question 40

Uterine neoplasms

Answer 40

* **Benign neoplasms:** * **Endometrial polyps** * **Leiomyomas (aka fibroid)**: Leiomyomas are benign smooth muscle tumors. Very common. Symptoms: excessive or irregular bleeding, pain with menses or with intercourse (dyspareunia), pregnancy loss, or infertility. * **Endometrial carcinoma:** Risk factors include postmenopausal menorrhagia, endometrial hyperplasia, obesity, nulliparity, late menopause, PCOS, family history, and a history of pelvic irradiation

Question 41

Diagnosing patterns of abnormal uterine bleeding

Answer 41

* **Pregnancy should always be excluded** * **Hormonal testing** (especially for estrogen excess and testosterone excess) * **Visualization** of anatomic lesions by ultrasound, CT, MRI * Intraluminal lesions may require **hysterosalpingogram** * Endometrial neoplasia is diagnosed by **endometrial biopsy**

Question 42

Hysterosalpingogram

Answer 42

Injection of radio-opaque dye into the uterine cavity for visualization by fluoroscopy

Question 43

Treatment of abnormal uterine bleeding

Answer 43

* **Combined hormonal contraception** is the main treatment for hormonally mediated forms of abnormal uterine bleeding * Estradiol component prevents shedding * Progestin component differentiates the endometrium into a more stable form * Higher doses may be needed initially to control severe acute bleeding * **Anatomic causes** (leiomyoma, carcinoma) **require surgical resection**

Question 44

Functional definition of interfility

Answer 44

An inability to conceive a pregnancy despite unprotected intercourse during the fertile period of the menstrual cycle for **more than 12 months** This is based on data that roughly 90% of couples will conceive within 12 months under these conditions

Question 45

Male Factor Infertility

Answer 45

* Male infertility accounts for ~50% of cases, at least in part * Many of these individuals (30-40%) have **idiopathic infertility** for which no specific cause can be determined * The remaining cases are caused by **primary testicular insufficiency** (as in Kleinfelter's/47,XXY or testicular irradiation), **secondary hypogonadism,** or **obstruction of the epididymus or vas deferens**, or other rare causes. * Evaluation includes **HPG axis assessment and semen analysis to assess number, mobility, and morphology**

Question 46

Female Factor Infertility

Answer 46

* Caused by almost any disorder resulting in **abnormal menstrual cycling** * **Most common is chronic anovulation** * Anatomic factors (**pelvic adhesions, endometriosis, and uterine or tubal abnormalities**) that prevent the normal migration of ova and/or implantation in the uterus * **Antiphospholipid syndrome** is associated with FF infertility * Other factors include older **age, tobacco or alcohol use, obesity, excessive exercise, and psychological stress**

Question 47

Evaluating female factor infertility

Answer 47

Evaluation is essentially the **same as for amenorrhea**, often with the **addition of a hysterosalpingogram** to assess uterine and tubal anatomy and patency.

Question 48

Standard of care in adolescents who identify as transgender

Answer 48

The physical changes of puberty often cause great distress to transgender individuals, and many of these changes are permanent and not reversible with medical treatment, or even surgery Therefore, the standard is to **suppress their innate puberty at an early stage**, then at a **later stage to initiate gender-affirming hormone therapy.**

Question 49

Pubertal suppression

Answer 49

* **Indicated only following diagnosis of gender incongruence** by a mental health professional * **Long-acting analogs of GnRH** (like **leuprolide**) are given to suppress FSH/LH secretion * Pubertal suppression should **begin when the patient first exhibit signs of puberty** (**Tanner stage 2 or 3**), or following **detection of LSH/FSH/estradiol/testosterone elevation on bloodwork** * These early physical changes are often associated with emotional distress, which is an element of gender dysphoria

Question 50

Gender-affirming hormone therapy

Answer 50

* Gender-affirming hormone therapy for transgender adolescents treated with pubertal suppression usually **begins around age 16** * . **Suppression of innate puberty with a GnRH analog is _continued_** while the patient receives gender-affirming hormone therapy * **In transgender adults** presenting **after puberty is complete**, a **GnRH analog** can be used to **suppress endogenous sex hormone production** and **gender-affirming hormone therapy can be initiated immediately.**

Question 51

Feminizing therapy

Answer 51

* **Estrogens** (most commonly **17β-estradiol**) are given to achieve normal female serum levels of estradiol. * This also suppresses endogenous FSH/LH * Testosterone levels usually do not drop into the normal female range * It should be known that certain preparations increase the risk of thrombosis * **Anti-androgens** (**spironolactone**) suppress testosterone production and/or block its effects * **GnRH agonists** (inhibit gonadotropin secretion, can be used in place of spironolactone) * **Gonadectomy** (eliminates endogenous hormone production, so anti-androgens and GnRH agonists are no longer needed)

Question 52

Masculinizing therapy

Answer 52

* **Testosterone** * Since testosterone disrupts endogenous HPG axis in these individuals, an anti-androgen or GnRH agonist is not necessary * **Testosterone increases erythropoiesis**, so **hematocrit** should be monitored, along with **weight and blood pressure** * Estradiol levels remain within the normal range in medically treated transgender men and do not rise. * As long as individuals assigned female at birth have breasts and a cervix, they should undergo routine screening for malignancy with mammograms and pap smears, respectively. * **Gonadectomy**

Question 53

Does gender-affirming hormone therapy result in infertility?

Answer 53

NO! Not always! So, all patients with gonads and who engage in sexual intercourse should be **counseled about fertility and the need for contraception before starting gender-affirming hormone therapy or undergoing surgery.**

Question 54

Feminizing or masculinizing surgery

Answer 54

* Aka sex reassignment surgery [SRS], gender-affirming surgery * Alters a transgender person’s appearance beyond that which is possible with hormones alone * **Feminizing procedures** in transgender women include **breast augmentation, facial feminization surgery**, and **laser hair removal**, as well as **orchiectomy, penectomy, and vaginoplasty.** * **Masculinizing procedures** include **mastectomy** and construction of a penis through **phalloplasty or metoidioplasty**, although reconstructive genital surgery is complex in transgender men

Question 55

Reproductive health for transgender women

Answer 55

* **Estrogen reduces spermatogenesis** by directly suppressing gonadotropins, and also **decreases sperm count and sperm motility** by decreasing testosterone levels. * These changes may or may not be reversible if estrogen is stopped. **Orchiectomy results in permanent infertility.** * **Fertility preservation** can be accomplished in adult individuals assigned male sex at birth by **sperm cryopreservation, testicular sperm extraction, or testicular tissue preservation** * However, transgender adolescents who have not undergone typical male puberty do not have sperm to preserve * Cryopreservation is expensive

Question 56

Reproductive health for transgender men

Answer 56

* Testosterone usually leads to **anovulation and amenorrhea,** which may or may not be reversible if testosterone is stopped * **Testosterone is a teratogen** and is contraindicated during pregnancy. * **Oocyte cryopreservation** can be offered to peri- or postmenarchal individuals using hormone-induced ovulation and ultrasound-guided oocyte retrieval * If eggs are immediately fertilized with sperm from a partner or donor, **embryo banking** is another possibility * **These procedures are _costly_**

Question 57

Alternative methods for starting a family for transgender individuals

Answer 57

**Adoption, assisted reproductive treatment** with donor sperm/egg, **cryopreserved sperm/egg**, and **surrogacy** are additional parenthood options for transgender individuals.

Question 58

What are the "cysts" in polycystic ovarian syndrome?

Answer 58

Arrested follicles which have halted maturation due to insufficient FSH. Found on ultrasound.

Question 59

PCOS summary

Answer 59

Question 60

PCOs treatment summary

Answer 60